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Lesson 01

Inflammation and
Allergy

I nflammation is a complex dynamic response of tissues to damaging (noxious)

stimuli. It is a basic component of many disease processes. An inflammatory
stimulus may be physical (e.g. heat, ionizing radiation and ultraviolet rays),
biological (e.g. bacteria, viruses, fungi and other parasites), or chemical (e.g.
toxins, acids and bases and proteins, polysaccharides, and other organic compounds). When
an individual faces any one of these tissue-damaging stimuli, its immune system calls an
array of powerful defensive responses that constitute acute inflammatory reaction.

Acute inflammation comprises interrelated vascular and cellular changes in affected tissues,
which are aimed at removing or neutralizing the offending stimulus, and repairing injured
tissues. Acute inflammation is necessary for the survival of the affected individual. Although
it serves to protect the individual, the inflammatory process may at times be brought
inappropriately against otherwise harmless substances, such as pollen or against certain body
tissues. The response under such circumstance may then produce damage, which may
constitute a disease process (e.g. anaphylaxis, autoimmune hemolytic anemia and lupus
erythematous). Such cases require drug therapy.

Before taking up drug used for therapy of inflammation and allergy, let us first review the
features of acute inflammatory reaction and immune response. A good knowledge of these
processes is essential to understanding the action of anti-inflammatory and
immunosuppressant drugs.
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Signs of Inflammation. Local acute inflammation has five cardinal signs

Signs of Acute Inflammation

Pain –due to stimulation of pain local receptors

Altered function –usually reduced activity
Redness –due to transient hyperemia
Increased temperature –due to increased blood flow
Swelling –due to increased vascular permeability

[Remember P A R I S ]

These signs result from the vascular and cellular changes occurring in the affected tissue.
How these signs are generated during inflammation will be discussed shortly.

COMPONENTS OF ACUTE INFLAMMATION

Acute inflammation is the earliest response to tissue damage.

The acute inflammatory reaction has two main components:

(a) Innate non-immunological, and
(b) Acquired immunological

Components of Inflammatory Reaction

An innate non-immunological response

Vascular events
Cellular events

The acquired specific immune response

These components are discussed in sequence. In following the discussion, it will be helpful to
keep in mind a picture of a staphylococcal skin infection in a puppy, or perhaps an acute
inflammation you had say a splinter or infected ingrown nail.

The Vascular Events

The vascular events are summarized below.

Summary of Vascular Events

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Initial vasoconstriction to limit the spread of injury.

Reflex dilatation of small arterioles (vasodilation)
This vasodilation results in increased blood flow.
Then the blood flow along these vessels slows down leading to stasis of the blood.
The pooling of blood in the area of inflammation results in increased
permeability of the post-capillary venules.
Increased vascular permeability results in exudation.

Vasodilation and increased blood flow

Following an initial vasoconstriction, small blood vessels adjacent to the area of tissue
damage become dilated with increased blood flow, then the flow through these vessels slows
down and become static.

Activation of endothelial cells leading to increased permeability

Partially due to anoxia and lack of nutrient supply, the vascular endothelial cells swell and
retract so that they no longer form a complete intact internal lining.

The vessels become leaky, permitting the passage of water, salts and small molecular-sized
proteins to leak out is the small soluble molecular sized proteins from plasma into the
damaged area (exudation).

One of the main proteins to leak out is the small soluble molecule fibrinogen, which is
eventually transformed into insoluble fibrin.

Migration of leukocytes (strictly, a cellular event)

Circulating neutrophils initially adhere to the swollen endothelial cells (margination), and
then actively migrate through the basement membrane vascular epithelium (emigration),
passing into the area of tissue damage. Later, small numbers of blood monocytes (or
macrophages) and lymphocytes migrate in a similar way.

This migration process, called chemotaxis, is caused by the attraction of leukocytes to

chemical substances (chemotoxins) produced in the site of tissue damage.

The objectives of these initial reactions to an inflammatory stimulus are three fold, and are
summarized below.
Functions of Acute Inflammation

The transient material, called the acute inflammatory

To dilute the offending noxious stimuli exudate, which accumulates in the affected area,
(weakens the enemies) carries proteins fluids and cells from the local blood
vessels into the damaged area to bring about local
defenses.
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To eliminate damaging agents If an infective agent (e.g. bacteria) is present in the

(gets rid of the enemies) damaged area. It can be destroyed and eliminated by
the components of the exudate.

Removal of inflammatory tissue debris The damaged tissue can be broken down and partly
(cleans up the battlefield) liquefied, and the debris removed from the site of
damage.

The Cellular Events

As noted above the vascular and cellular events overlap. In fact, the division of the
inflammatory process into vascular and cellular events in mainly for ease of discussion.
These events however constitute a continuum of inflammatory events of the cells involved in
the inflammation some (e.g. vascular endothelial cells, mast platelets, and tissue
macrophages) are normally present in tissues while others (e.g. platelets, and leukocytes) gain
access into the tissue from the blood.

Of course, you already know that leukocytes are classified into:

(a) Polymorphonuclear cells (neutrophils, basophils and eosinophils), and
(b) Mononuclear cells (monocytes and lymphocytes).

The main cellular events in acute inflammation, all of which are caused by chemical
mediators, overlap with the vascular events as we have seen above. Let us now look into
some features of these cells relevant to inflammation.

Vascular endothelial cells

During inflammation the endothelial cells of the small arterioles are “activated” to
secrete:
a. Nitric oxide (NO) and prostacyclin, both of which induce vascular relaxation and
inhibit
platelet aggregation
b. Endothelin, plasminogen activator, platelet-activating factor (PAF), thromboxane A2,
angiotensin II, and several cytokines, all of which cause vasoconstriction
c. These cells also express or manufacture several intercellular adhesion molecules
(ICAM), and a variety of receptors including those for histamine, acetylcholine, and
interleukin-1.

Endothelial cell function also involved in angiogenesis (formation of new blood vessels),
which occurs in wound repair, chronic inflammation and cancer. Neutrophils and other
migrating blood cells adhere to the vascular endothelium only when the endothelial cells are
“activated”.

Polymorphonuclear cells (PMNs)

The PMNs are characterized by having nuclei with varying shapes (banded, lobed or
segmented). All of them are found in circulating blood, but may migrate to sites of
inflammation.
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The neutrophils are the first of the leukocytes to enter the area of inflammation – the “first
line” of defense. Normally inactive, neutrophils have to be activated to enhance their capacity
for phagocytosis, bacterial killing, and generation of some inflammatory mediators. They
have to develop the ability to more actively in a directional fashion (chemotaxis) from the
vessels towards the area of tissue damage.

The eosinophils have capacities similar to those of the neutrophils and in addition, release a
number of potent granule constituents that can damage multicellular parasites such as worms
and mites. These constituents include eosinophil cationic protein, a peroxidase, the eosinophil
major basic protein, and a neurotoxin.

The basophils are very similar in many aspects to mast cells (see below.)

Mast cells

The mast cell morphologically similar to basophil, but are predominantly found in tissues
rather than in the circulating blood. Mast cell’s membrane contains surface receptors for both
immunoglobulin E (IgE) and for complement components C3a and C5a (see under Activated
Complement Components).

Mast cells can be activated to secrete histamine (and other mediators) through stimulation of
these receptors and by direct physical damage.

Other substances released by mast cells include:

(a) Heparin or (heparan)
(b) Eosinophil chemotactic factor of anaphylaxis
(c) Neutrophil chemotactic factor
(d) ẞ-glucoronidase
(e) Neutral proteases
(f) Superoxide dismutase
(g) Peroxidases
(h) Leukotrienes,
(i) Prostaglandins
(j) Nerve growth factor, and
(k) Some interleukins.

Monocytes/Macrophages

The monocytes enter the area of inflammation at a later stage, several hours after the
polymorphs. Like neutrophils, they also adhere to endothelium, and migrate into the tissue in
response to specific chemotaxic substances (chemokines). In the tissue, monocytes are
transformed into macrophages (literally “big eaters”, the neutrophils used to be called
macrophages, the “little eaters”). The macrophages bind with bacterial lipopolysaccharides
(LPS) by means of cell surface receptors, and subsequently generate and release cytokines
that act on vascular endothelial cells to further increase vascular permeability, attract other
leukocytes, and cause fever. In areas of inflammation macrophages engulf debris, dead cells
and microorganisms.

Platelets
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Involved primarily in blood coagulation, platelets also play a role in inflammation. Also
called thrombocytes, they generate thromboxane A₂ (TXA₂) and platelet-activating factor
radicals, and pro-inflammatory cationic proteins. Platelet-derived growth factor
contributes to the repair processes following tissue damage.

Neurons

Some neurons (type C and Aծ fibers) in inflamed areas release inflammatory neuropeptides
when appropriately stimulated. Type C and Aծ fibers transmit pain impulses to the central
nervous system. During injury and inflammation, they generate chemical mediators such as
kinins, serotonin (5-hydroxytryptamine, 5-II), which act on receptors and stimulate the
release of neuropeptides (e.g. neurokinin A and substance P). These substances mediate
pain sensation.

Natural killers

Natural killer (NK) cells are specialized lymphocytes that are active in non-immunological
reactions. They kill target cells, such as virus-infected cells and cancer cells that lack the
major histocompatibility complex (MHC) molecules. MHC molecules normally present in
normal cells inhibit NK cells by acting on the inhibitory receptors on the NK cells
themselves.

How inflammatory mediators bring about the cellular, as well as the vascular events will be
taken up a bit later, but let us, for the moment, talk about inflammatory exudates, after which
will discuss the specific immunological response to inflammation.

The Acute Inflammatory Exudate

The inflammatory exudate is composed of fluids, electrolytes, proteins, cellular elements and
some inflammatory mediators. All of these components are derived from the blood as a result
of vascular and cellular changes of the innate non-immunological response that occur in the
blood vessels in the surviving tissue around the area of damage.

The inflammatory exudate is controlled by the production and diffusion of chemical

messengers (or mediators) derived both from damaged tissues, and from acute inflammatory
exudate itself.
Components of Exudate Type of Exudate

Fluid containing salts and high concentration of Predominant in serous exudate

proteins including immunoglobulins
Fibrin, a high molecular weight filamentous insoluble
protein. Predominant in fibrinous exudate
Many neutrophils from the white blood cell
population
A few macrophages, which are phagocytic cells Predominant in purulent exudates
derived from blood monocytes, and
A few lymphocytes
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The fluid in the acute inflammatory exudates carries nutrients, mediators and
immunoglobulins.

Fluids and salts may dilute or buffer any locally produced toxins
Glucose and oxygen can diffuse into the area of inflammation to support the macrophages.

The fluid also allows diffusion of mediators of inflammation particularly plasma-derived

precursors (see below) within the damaged tissue.

The fluid is constantly circulating to the local lymph nodes and assists in later development
of a specific immune response.

Immunoglobulins in the exudates may act as opsonins

THE SPECIFIC IMMUNOLOGICAL RESPONSE

The host’s immunological defense mechanism is more specific and therefore more efficient
than the innate response against invading pathogens. The major cells involved here are the
lymphocytes, which are of three main groups.

Main groups of lymphocytes

B cells Responsible for body production- the humoral immune response

T cells Responsible cell-mediated immune reactions

Natural killer Specialized non-T and non-B lymphoid cells that are active in
cells non-immune innate response (see above)

The Induction Phase of Immunological Response

This phase involves the production of B cells and T cells from uncommitted lymphocytes.
The antigenic molecules are presented to the lymphocytes by the antigen-presenting cells or
APCs. The APCs engulf and process the antigen, and present it to uncommitted CD4+ T
helper lymphocytes (also called T helper precursor) in association with histocompatibility
complex (MHC) molecules

These CD4 cells develop interleukins-2 (II-2), a cytokine which act on the same cells
(CD4+) causing their proliferation, producing clones of activated T cells (called Th0 cells)
Th0 cells give rise to two subsets of T helper cells Th1 and Th2 cells.

The action of specific interleukins determines whether Th1 cells or Th2 cells develop II-12
(produced by APC’s) stimulates development down the Th1 pathway, II-4 (produced by
some Th0) determines development down the Th2 pathway.
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The Th1 pathway controls cell-mediated responses

Some Th1 secrete macrophage-activating cytokines and other cytokines. Some secrete
interferon-gamma (IFN-y), which activates CD8+T cells to become cytotoxic cells (Tc) that
kill virally infected host cells. II-4 derived from Th2 cells inhibits Th1 function.

The Th2 pathway controls antibody (humoral)-mediated responses: IFN-у derived from Th1
cells inhibits Th2 function.

The effect phase of the immunological response

This phase involves how the cells, which are produced in the induction phase, act to eliminate
antigens. This action may be antibody-mediated or cell-mediated.

Antibody-mediated response

Antibodies or immunoglobulins have two functions;

 To recognize and interact with specific antigens
 To activate one or more, the host’s defense system

When antigens bind with the Fb fractions of the antibodies, antigen-antibody complexes are
formed. The complement proteins bind with the exposed (Fc) portions of the antibody, which
results in the activation of the complement sequence producing, among other things, C3a (an
anaphylotoxin), C3b (a chemotactic factor), and C3b (an opsonin)

Details of complement activation are discussed later

Phagocytic cells (neutrophils and macrophages) also have receptors to the Fe portion of the
antibody. The antibody, by acting as an opsonin, greatly facilitates phagocytosis. Antibody
can form a link between a parasite (e.g. worm) and eosinophils, which are then able to
damage or kill the parasite. IgE antibody can attach to mast cells and basophils to stimulate
these cells to release histamine and other inflammatory mediators (see under “Histamine”
below). Histamine is implicated in certain allergic reaction.

Cell-mediated immune response

In virally infected cells, the virus-derived peptides, in association with MHC, are presented to
the cell surface. CD8+ T cells recognize this MHC-peptide complex and destroy the virus
infected cells. The cytokine-producing T cells also activate macrophages also produce and
release many other cytokines, toxic oxygen and neutral proteases (to kill extracellular
microorganisms), complement components, eicosanoids, fibroblast stimulating factor,
pyrogens (fever-inducing substances), and factor that activate coagulation cascades. The
production of memory cells during first exposure to antigen greatly accelerates and makes
more effective the immunological response to subsequent exposure.
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Now, we are ready to tackle the role of chemical mediators of inflammation.

CHEMICAL MEDIATORS OF INFLAMMATION

Acute inflammation starts when there is damage to tissue. The tissue reacts through vascular
and cellular changes. These changes are mediated by substances, which are collectively
called autocoids. Autocoids (from Greek autos=self and akos=medicinal agent or remedy)
are substances present in the body and act near the sites of their synthesis. They are
sometimes called local hormones, and are presented below.
I. Mediators derived from plasma
Specific Mediators
Origin
Bradykinin and Kallidin
Kinin system
Activated Hageman Factor (XII)
Clotting system
Plasmin
Thrombolic System
C3a, C3b, and C5a, C5b
Complement pathway
II. Mediators derived from cells

Synthesized and released only when needed (i.e., not stored)

Synthesized stored Prostaglandins
in cells Leukotrienes
histamine Platelet-activating factor
Cytokines
Nitric oxide

HISTAMINE

Histamine is derived from the amino acid histidine. It is distributed throughout the animal
and plant kingdom, present in venom, bacteria and plants. The blood of the goat and rabbit is
relatively histamine, while blood of horse, dog, cat and rat is relatively low in histamine.
Histamine is always present in damaged tissues, decomposing tissue extract, and putrefying
(decaying) ingesta rich in proteins.

Histamine is stored mainly by mast cells, which are abundant in the gastrointestinal mucosa,
bronchial mucosa, and skin. It is also stored in basophils circulating in the blood. It is
implicated in allergic reactions. Non-mast-cell histamine is secreted by histaminocytes in the
stomach and by histaminergic neurons in the brain.

In allergy, histamine is released as a result of interaction of the antigen and the antibody IgE
on the surface of mast cells (or basophils). The presence of an antigen stimulates the
production of IgE, which then binds to the surface of receptors on mast cells. [Note that C3a
and C5a can also induce receptor-mediated histamine secretion; see under “Mast Cells” on
page 5.] The antigen that binds to the IgE that is attached to the mast cells.

The antigen-antibody complex activates phospholipase C in the mast cell membrane, which
catalyzes the breakdown of membrane phospholipids (specifically phosphatidyl inositol)
resulting in the release of diacyglycerol (DAG) and inositol-1, 4, 5-triphosphate (ITP). DAG
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and ITP by some mechanism cause the release of calcium ions (Ca²⁺) from the intracellular
stores (such as the endoplasmic reticulum), or allow calcium entry into the cytosol.

The elevated free cytosolic Ca²⁺ induces the fushion of the mast cell secretory granules with
the cell membrane resulting in the release of the histamine and other proinflammatory
substances associated with it.

Other than that mediated by the antigen-antibody complex, histamine may also be released
following administration of many compounds including drugs such as amides, amidine,
quaternary ammonium compounds, pyridinium compounds, piperidines, alkaloids, and
antibiotic bases. These drug-stimulated histamine release are not allergic in the nature since
there is no involvement of an antibody.

Some physiological roles of histamine

 Histamine secreted by histaminocytes in the stomach regulates gastric acid secretion

(excessive secretion causes hyperacidity and ulceration)
 Histamine secreted by histaminergic neurons in the brain act as neurotransmitter in
the CNC (involved in motion sickness)
 Histamine secreted by mast cells acts as mediator of early inflammatory reactions

The Triple Response to Histamine

Intradermally injected histamine produces the so-called triple response of Lewis (first
described by Sir Thomas Lewis). Not all signs of inflammation, however, can be produced by
histamine so administered. Histamine therefore is not the only mediator of inflammation. At
best it is involved only in the initial stage of the inflammatory process

Triple response to histamine

Red spot A few millimeters around the site of injection is due to
immediate direct vasodilator effect of histamine.
Flare A bright red irregular outline from the original red spot due to
reflex dilatation of the adjacent small vessels.
Wheal A localized edema due to leakage of plasma fluid through the
abnormality permeable walls of the small blood vessels.

Histamine does not cause pain

Aside from vascular reactions described above, histamine also causes pruritus (itch) but not
pain. Because of the vascular reactions associated with it, histamine is thought to have a role
in the development of inflammation. Histamine’s effects, however, occur early, is short-lived
and incomplete, and therefore, it may be not be essential for the development of the most
characteristic changes which produce the lasting tissue alteration during inflammation.

Types of histamine (H) receptors

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Three distinct histamine receptors have been recognized, more may be described in the
future.

Selective
Receptor Function Agonist
Antagonist
Mediates most inflammatory
H1 and are antagonized by the Histamine Mepyramine
classical anti-histamines
Has a role in gastric acid
H2 Histamine
secretion; an action blocked Cimetidine
Dimaprit
by specific H2 antagonists
Histamine
H3 Description is still
(R)-methyl Thloperamide
incomplete
histamine

The vasodilation and increased vascular permeability in response to histamine is mediated by

both H1 and H2 receptors on mast cells and basophils, histamine prevents further histamine
release by these cells, a negative feedback process.

Three Ways to Counteract the Inflammatory Effect of Histamine

There are three types of drugs that may be used to prevent or reverse the action of histamine
in clinical cases. These are summarized in the table below.

Mode of action Drugs to use

1. Prevent release of histamine by inhibiting the Epinephrine
responses of sensitized cells basophils to Theophylline
specific antigen. Cromolyn sodium
(or cromoglycate Na)

2. Physiologically antagonize histamine effects. Epinephrine

Theophylline
Aminophylline

3. Block H1 receptors of histamine Various classical anti-

histamine agents (see
below)

Dosages

Epinephrine
Dog/Cat: 0.5 to 1.5 ml of 1:10,000 solution IV, repeat in 30 min (for
anaphylaxis)
Horse/Ruminant: 1.0 ml of 1:1,000 solution per 45 kg b.w, IM, IV, SC.

Theophylline
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Dog: 6 to 11 mg/kg tid-qid, PO, IM, IV

Cat: 4mg/kg tid PO: 0.1 mg/kg tid. IM, IV
Horse: 1mg/kg qid, PO
CAUTION: monitor for drug toxicity

Aminophylline:
Dog: 10mg/kg tid, PO, IM, IV
Cat: 5mg/kg bid-tid PO or 4 mg/kg bid PO, IM
CAUTION: monitor for drug toxicity

Cromolyn sodium
Horse: 80 mg nebulized once daily, or
200 to 300 mg nebulized per horse

NOTES:
Cromolyn sodium (Cromoglycate sodium) and its analog Nedicromyl

 Cromolyn sodium

Cromolyn sodium is poorly absorbed from the gut, and is usually given inhalation as
nebulized solution or powder. Only 10% of inhale drug is absorb 50% of absorbed portion is
excreted I bile ad 50% in urine. Nedicromyl is better absorbed than cromolyn sodium.

Their mechanism of action is uncertain. Although cromolyn sodium is believe to stabilize

mast cells and thus prevent histamine release, this does not constitute its major mechanism of
action.

More significant clinical action are:

 Depression of release of certain neuropeptides
 Antagonism of tachynin receptors, and
 Inhibition of platelet activating factor (PAF) interaction with platelets and
eosinophils.

 Theophylline and Aminophylline (Theophylline ethylene diamine)

These xanthine derivatives are bronchodilators used in the management of attack of

bronchospasm. They have positive chronotropic and inotropic effects, and mild diuretic
effects.

Mode of Action
 They inhibit phosphodiesterase (PDE) enzyme that catalysis the breakdown of cyclic
AMP. This action results in an increase (accumulation) of cyclic AMP, which
attenuates the action of inflammation.
 Also, they cause relaxation on smooth muscle, which could be also be related to their
effect on cyclic guanine monophosphate (cyclic PDE)

Unwanted effects include:

 Anorexia
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 Nausea and vomiting

 Nervousness and tremor are seen with concentrations higher than the clinically
effective levels
 Sometimes-fatal cardiac arrhythmias may occur.

Drugs that inhibit microsomal cytochrome P450 enzymes which may increase the serum
level and the likelihood of adverse effects:
 Erythromycin
 Ciprofloxacin
 Ca2+¿ ¿ channel blockers
 Allopurinol
 Fluconazole and
 Cimetidine,

Inducers of cytochrome P450 that decrease the therapeutic effect of drugs:

 Phenobarbital and
 Phenytoin

Because of the very narrow margin of safety, extreme precaution should be taken in
administering theophylline and aminophylline.

 Epinephrine (Adrenaline)

By acting on specific adrenergic receptors, epinephrine causes peripheral vasoconstriction,

bronchodilation and cardiac stimulation; effects that counter histamine effects.

THE CLASSICAL (H1) ANTIHISTAMINES

The classical or H1 antihistamines are not as widely used in animals as in people because of
two reasons: (a) antihistamines have varying effectiveness in animals, and (b) glucocorticoids
(see Lesson 2) are available and more effective. However, in some cases, antihistamines may
be used in treating dogs and cats with chronic pruritus of undetermined causes, or those with
short-term pruritus nut do not tolerate glucocorticoids. The antihistamines tend to be effective
when used for treatment of type I anaphylaxis, including urticarial and atrophy.

Antihistamines may have varying degrees of anticholinergic, sedative (CNS depression) and
sometimes local anesthetic effects. When histamines are used for purely peripheral action, all
CNS effects such as dizziness are unwanted. Excessive dose may cause convulsion especially
in young animals. The peripheral ant muscarinic effects, such as dryness of the mouth, are
always unwanted.

Dosage of Some (H1) Antihistamines

Brompheniramine Dog & Cat 0.2-2 mg/kg p.o. BID

Cetirizine Dog 0.5-21 mg/kg BID

[Cetirizine lacks sedative
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action]

Dog 2-12 mg p.o. BID or TID

Chlorpheniramine
Cat 0.2-4 mg/kg p.o. BID

Clemastine Dog 0.5-1.5 mg BID

0.3-2 mg/kg p.o., BID

Cyproheptadine Dog & Cat
with anti-serotonin effect

[Cyproheptadine also blocks 5-HT receptors]

Large & Small
1-1.5 mg/kg p.o., IM, SC
Dimenhydrinate animals
8 mg/kg p.o., TID
Dog
prominent anti-motion sickness

Large animals 0.5 mg/kg p.o., IV q12h

Small animals 1-2 mg/kg p.o., IV q12h
anti-motion sickness, causes marked;
Diphenhydramine
sedation with anti-cholinergic effect
cream or gel available for topical
application

Doxylamine Dog & Cat 1-2 mg/kg BID

Hydroxyzine Dog & Cat 2-4 mg/kg BID or TID
Hystapyrrodine Cream for topical application
Loratidine
[Loratidine lacks Dog 10 mg p.o. SID
sedative action]
Meclizine Specific for motion sickness

12-25 mg/animal IM, Sid or BID

Promethaine Dog & Cat 0.2-1 mg/kg p.o. long acting marked
sedation prominent anti-motion sickness

[Promethazine has weak alpha – adrenoreceptor blocking action.]

Large & Small
Pyrilamine 1-2 mg/kg IM, IV, SC;
animals
cause prominent sedation
Terfenadine
[Terfenadine has no
sedative action; can
Dog & Cat 0.2-2 mg/kg oral BID
cause potentially
fatal cardiac
arrhythmia]
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Fexofemadine – a nontoxic metabolite of Terfenadine now available for use]

0.5-2 mg/kg p.o. BID

Trimepraine Dog & Cat
sedation; anticholinergic effect

1-2 mg/kg p.o. IV

Large animals 1.5 mg/kg p.o. q8h sedation with usual
Tripelennamine
Small animals doses
ataxia & convulsion when overdose

THE EICOSANOIDS
(Prostaglandins, Prostacyclin, Thromboxane’s and Leukotrienes)

Arachidonic acid (20 carbons), the most abundant precursor of eicosanoids (eicosa – 20, may
be derived by elongation of dietary linoleic acid (18 carbons), and is usually esterified to
second carbon (C2) of cell membrane phospholipids. Arachidonic acid is liberated from this
site during cell damage by the action of activated phospholipase A2. Alternatively,
phospholipase C is first activated, followed by an increase in cytosolicC a2, which in turn,
stimulates phospholipase A2 that eventually release arachidonic acid.

PROSTANOIDS, THROMBOXANES AND LEUKOTRIENES

The prostaglandins (PG) are also called prostanoids because they share the chemical features
of a hypothetical substance 20-carbon prostanoic acid with a five-member cyclopentane ring
and two hydrocarbon side-chains.

Prostaglandins are not stored in tissues, but are rapidly formed and released when tissue is
damaged. Thus, the synthesis of prostaglandins is intimately related to their release and
action. Phospholipase A2 is involved in the regulation of biosynthesis of prostaglandins by
causing the release of the precursor arachidonic acid. Two major enzyme systems – cyclo-
oxygenage and lipoxygenase – use arachidonic acid as substance

The cyclooxygenase reaction

Arachidonic acid is converted by cyclo-oxygenase (COX; also called endoperoxide

synthase) to cyclic endoperoxides (PGG₂ and PGH₂). These endoperoxides have short half-
life of 30 to 45 seconds.

COX cyclic endoperoxidase

Arachidonic Acid PGG₂ PGH₂

There are two identified cyclooxygenase isoenzymes:

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1. Cyclooxygenase -1 (COX-1)
A constitutive enzyme, which sub serve a number of physiologic role.
Inhibition of COX-1 is believed to underlie the most significant “side effects”
of non-steroidal anti-inflammatory drugs (NSAIs: aspirin-like drugs)

2. Cyclo-oxygenase-2 (COX-2)
COX-2, on the other hand, is induced during inflammation, and inhibition of
COX-2 accounts for the therapeutic action of NSAIDs.

From the endoperoxides, the synthetic process may follow three different paths.

PGF2a , PGE₂, PGD₂

Thromboxane A₂ (TXA₂) TXB₂

PGH₂
Prostacyclin (PGI₂) 6 keto - PGFl a

The Lipooxygenase reaction

Arachidonic acid is also converted by lipooxygenase to three hydroperoxy-

cicosatetraenoic acid (HPETE) namely:

1. 15-HPETE

2. 12-HPETE (in platelets and leukocytes), and

3. 5-HPETE (in leukocytes only)

Unlike the other two, this serves as a substrate for the enzyme leukotriene
synthase, and is further transformed into various leukotrienes (LTs):
a. First to LTA₄,
b. Then to LTB₄
c. And LTC₄.
d. From LTC₄ are formed LTD₄, LTE₄ and LTF₄.

HPETE’s are unstable and may be converted to their corresponding hydroxyl fatty acid,
known for short HETE.

LTC₄ and LTD₄ are the slow-acting substance of anaphylaxis (SRS-A). They are 1000 times
as potent as histamine in increasing vascular permeability.

The role of prostaglandins in inflammation

Prostaglandins are pathologically important in inflammation but not as essential. They have
an array of metabolic effects. Even in the same organ-system, a PG can oppose the action of
another PG. As mediators of inflammation, PGs cause edema but less than the produced by
histamine and bradykinin. Leukocytes produce PGs a function enhanced during phagocytosis.
PGE is chemotactic for leukocytes. PGs are release during fever and may produce fever
 P a g e | 17

themselves. They do not cause pain but sensitize pain receptors to mechanical and chemical
stimulation so that pain seems to be magnified.

Action of Prostaoids

Prostanoids act on specific prostanoid receptors – IP, TP, EP (EP1, EP2, EP3), FP,
and DP

Prostanoi Receptors Effects

d

Causes vasodilation, inhibition of platelet aggregation, relaxation of gut

PGD₂ DP
and uterine muscles, modify pituitary hormone release

PGF₂ F Causes myometrial contraction leutolysis bronchoconstriction

Cause vasodilation, inhibition of platelet aggregation, renin release and

PGI₂ IP
natriuresis

TXA₂ TP Cause vasoconstriction, platelets aggregation and bronchoconstriction

Cause bronchoconstriction, contraction of gut muscles stimulation of

EP1
intestinal fluid secretion

Causes stimulation of intestinal fluid secretion, relaxation of gut

EP2
muscles
PGE

Causes contraction of intestinal muscles, inhibition of gastric acid

secretion, increase in gastric mucus secretion, inhibition of lipolysis,
EP3
inhibition of neurotransmitter release, and contraction of pregnant
uterus

Action of leukotrienes

LTB₄ acts on specific LTB₄-receptors and is a powerful chemotactic agent for bit neutrophils
and macrophages. It also increase the formation of membrane adhesion molecules and
production of toxic oxygen products and release of granules enzyme. LTD₄ and LTC₄ appear
to have specific receptors too. They cause increased respiratory mucus secretion, reduced
blood pressure, coronary vessel constriction, wheals and flare, and increased nasal vascular
 P a g e | 18

permeability. Leukotrienes have been implicated in bronchial hyperactivity in human

asthmatic and cardiovascular changes of acute anaphylaxis. Inhibitors of 5- lipooxygenase
such as zileutin, are being developed for chemical use.

Metabolism of prostanoids and leukotrienes

Prostanoids. PGE and PGF are rapidly metabolized (bio transformed) in the lungs by
prostaglandin dehydrogenase. The depression of capacity of the lungs to metabolized PGs
may result in increased levels of PE₂ and PGF₂ₐ.

The factors that inhibit prostaglandins dehydrogenase include:

 Nitrate
 Irradiation (X-ray ionizing radiation, and ultraviolet light), and
 Bacterial endotoxins.

Leukotrienes LTB₄ is converted to 20-hydroxy LTB₄ by special membrane-bound P450

enzyme, which occur in neutrophils. It is then further oxidized to 20-carboxy LTB₄, LTC₄
and LTD₄ are metabolized to LTE₄ and excreted in the urine.

Clinical uses of prostaglandins

Prostaglandins are generally more useful clinically:

1. Synthetic analogues of prostaglandins have found use in certain clinical condition

Analogues of PGs are being used investigational:

(a) In the treatment of peptic ulcer, bronchial asthma, and
hypertension
(b) As abortifacients, and
(c) To prevent formation of platelet clumps.

2. For treatment of certain fertility problems

3. Induce parturition at term by intra-amniotic infusion of PGF₂ₐ or by vaginal

suppository of PGF₂ₐ

4. For estrus synchronization in mares, cows, awes and sows with the use of analogues:
fuprostenol, cloprostenol, dinoprost, tromethamine, prostalene and tiaprost

5. For cardiovascular therapy to ensure the patency of ductus arteriosus in some instance
of congenital heart disease before corrective surgery (use PGI₂), in peripheral vascular
disease of the legs (use PGE₁), in cardiopulmonary by-pass operation. Prostacyclin
(PGI₂), a platelet de-aggregator, is used to prevent blood clotting during the operation

6. gastrointestinal therapy to promote the healing of gastric and duodenal ulcers (use
PGEs) by to mechanisms – inhibition of gastric acid secretion and cytoprotection of
gastric lining and to correct paralytic ileus (use PGF₂ₐ), and (f) as bronchodilators
(use aerosol form of PGE₁ or PGE₂)
 P a g e | 19

A summary of the physiological and pharmacological effects of eicosanoids

(For information only, do not memorize)

Effects Eicosanoids
Vasodilation PGEs, PGAs and prostacycline (PGI)
Hypotensive effect PGI 5X more potent than PGE
Vasoconstriction TXA₂
Hypertension then prolonged hypotension LTC₄ and LTD₁
Plasma Exudation Leukotrienes (more potent than histamine)
Increase Renal Blood Flow, Diuresis, PGE₂ and PGI₂
Natriuresis, Kalliuresis
Inhibition of Chloride Reabsorption PGE₂
Renin Secretion PGE₂, PGD₂, and PGI₂
Bronchodilation PGE₁ PGF₂, PGI₂ (slight)
Bronchoconstriction PGF₂ₐ, TXA₁, LTC₄, and LTD₄
Inhibition of Gastric Acid Secretion PGE, PGF and PGI₂, PGI prevents diarrhea
produced by other PGs
Increase gut motility PGE, PGF and LTs; abdominal cramps, vomiting
and diarrhea: side effects of PG therapy
Relaxation of Uterus PGE (on non-gravid); PGI₂
Contraction of uterus PGE (on gravid); PGF (all the times)
Leutolysis PGF₂ₐ (in sheep, cattle, horses and pigs)
Platelet aggregation TXA₂
Platelet disaggregation PGI₂,PGE₁ (less potent)
Stimulate erythropoiesis PGI₂, PGA₂, PGE₁ and PGE₂
Chemotaxis LTB₄
Stimulate histamine release PGD₂, 5-HPETE, 5-HETE
Inhibit histamine release PGE₂ and PGI₂

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)

The NSAID’s are a heterogeneous group of compound which are often chemically unrelated.
The prototype of these agents is aspirin, hence they are also called aspirin –like drugs.

Common properties of NSAIDs

 All are weak acid with pKa of 4.3 or less.

 Protein binding is 95 to 99%.
 All tend to accumulate in stomach, small intestine and kidney where they may cause
Pathological lesions.
 All inhibit enzymes (specifically COX-1 and COX-2) which form prostaglandins
And therefore slowly reduce tissue prostaglandins.
 All reduce pain in inflamed tissue through reduction of tissue prostaglandin levels.
 All reduce fever by inhibiting prostaglandins synthesis
 P a g e | 20

Clinical Uses of NSAID’s

NSAID’s are used as:

1. Analgesic
2. Antipyretic and
3. Anti-inflammatory

Central analgesia probably has limited contribution to overall efficacy of NSAIDs but
peripheral analgesia is more important. Careful selection of individual NSAIDs may be
necessary to reduce the likelihood of adverse gastrointestinal, renal or hepatic effects.

In veterinary medicine, NSAIDs are used for treatment of:

1. Acute inflammation of musculoskeletal system
2. Non immune inflammation of the musculoskeletal system and anaphylactic reactions
cattle
3. Equine colic, but may unsure correct diagnosis
4. Acute respiratory disease in calve and pigs.

Because of its ability to prevent platelet aggregation (through inhibition thromboxane

formation aspirin), aspirin is used to reduce thromboembolus (intravascular clot) formation
associated with heartworm disease in dog and with hypertrophic cardiomyopathy in cats.

Flunixin and Phenybutazone are used systemically in the management of non-ulcerative

keratitis (inflammation of cornea) in the horse. Dogs undergo intraocular surgery may be
given aspirin before surgery to minimize the postoperative increase in protein content of
aqueous humor.

Other uses of NSAIDs include:

 Induction of analgesia before, during and after surgery

 NSAID’s may also be given in cases of immunological diseases such as systemic

lupus and rheumatoid arthritis

 NSAIDs are shown to stimulate T-suppressor cells in their -action against T-helper
cells and autoantibody-producing B cell

 NSAIDs are used as an adjunct in the non-special treatment of pics affected with
porcine respiratory and reproductive syndrome (PRRS), a viral infection

 They also employed as adjunct to treatment infection of gastrointestinal tract to

suppress the inflammatory components of the disease

Some Specific NSAID’s

 P a g e | 21

 Usually administered orally and converted to salicylic acid

within a few minutes
 Concentration of salicylic acid persist log after conversion from
aspirin
 Following oral administration of aspirin to cats at different dose
showed plasma half-life to be exceedingly long and dose-
Aspirin
dependent.
 Elimination is most rapid in herbivores, slowest in carnivores
and intermediate in omnivores
 Overdosing with aspirin-like drug should be avoided in cats
because this species cannot metabolized and eliminate aspirin
as readily as other species.

 Similar to aspirin, but less commonly used

 Do not use in animals less than 30 days old.
Sodium salicylate
 Like aspirin, it cannot relieve visceral or sharp excruciating
pain

Methylsalicylic acid
Used externally as a counter-irritant.
(Oil of Wintergreen)

 Recommended in horses for treatment of inflammatory

Naproxen conditions involving pain and lameness, such as “tying up”
syndrome

 A simple derivative of phenylpropoinic acid

 Metabolized in the liver and may cause gastrointestinal
Ibuprofen
irritation and bleeding but less frequently than with aspirin.
Shares the pharmacological effects of aspirin

 Inhibits both the cyclooxygenase and some lipoxygenase.

Ketoprofen  Approved for use in horses (US), dogs and cats (Canada,
Europe)

 Usually not included with NSAIDs for it is devoid of anti-

Paracetamol inflammatory effects but retains antipyretic and analgesic
(Acetaminophen) effects
 More appropriately called non-opiate analgesic
 P a g e | 22

 Used to treat acute or chronic osteoarthritic disease in the

Meclofenamic acid horse and chronic musculoskeletal disease in the dog, slow
onset action

Mefenamic acid
Tolfenamic acid

 Effective for the most colic cases excluding severe bowel

Flunixin meglumine distension or displacement.
 Useful in treatment of endotoxin shock

 Not to be given in dogs of fetal effect

Indomethacin
 In horsed it causes CNS disorder

 Frequently beneficial in the treatment of soft-tissue or non-

articular rheumatism including capsulitis, laminitis and
bursitis.
 Most widely used in horses
Phenylbutazone  Toxic effects include agranulocytosis, leukopenia, and tissue
sloughing when injected extravascular.
 Phenybutaone-induce agranulocytosis found in man has not
been seen in animals. [Agranulocytosis characterized by
severe neutropenia]

 Widely used to treat equine colic and other condition of GI

spasm or hypermobility in both large and small animals. It
has been banned for human use due to associated
agranulocytosis.
 Its value in the treatment of spasmodic condition in small
Dipyrone
and large animas has been questioned (probably due to
potential to produce agranulocytosis)
 Toxic effects include agranulocytosis and leukopenia
 It is advisable to monitor the hematologic condition of the
animal before and during us.

 Inhibits chondrocyte and synoviacyte synthesis of PGE₂

Etodoplac  Effective and safe for control of lameness associates with
hip dysplasia
 P a g e | 23

 It is a metabolite phenylbutazone has similar properties as

Oxyphenbutazone
pneylbutazone

 Rapidly absorbed in the stomach and reaches 80% of its

peak plasma concentration in 1 hour
Piroxicam
 The long half-life (45 h) of his compound permits once a
day or longer dosing interval

 A new NSAIDs similar to Ibuprofen, specifically used to

treat arthritis in dog.
 Used in dogs for treatment of osteoarthritis
 Potency equals indomethacin and surpasses aspirin or
Caprofen
phenylbutazone.
 Hepatotoxicity ia an unexpected adverse effect in geriatric
dog.
 Not as safe as in cats as in dogs.

Dosages of some NSAID’s

Dog 25 mg/kg q8h, oral

Cat 10 mg/kg q48h, oral
Aspirin Horse 30 mg/ kg q12h, oral
Cattle 100 mg/kg q12h, oral
Pig 10mg/kg q6h, oral
Dog 10 mg/kg q12h, IV
Sodium salicylic
Horse 35 mg/kg q6h
5 mg/kg, IV, 10 mg/kg oral as top dressing on feed
following IV dose continued q12h up to 14 consecutive
Horse
Naproxen days
5 mg/kg, oral maintain with a 2-2.3 mg/kg oral once a
Dog
day
Meclofenamic Dog 1.1 mg/kg/day, oral for 5-7 days
acid Horse 2.2 mg/kg/day oral for 5-7 days
Mefenamic acid Dog 10-40 mg/kg/day in divided doses
Tolfenamic acid Dog 4mg/kg in divided doses, IV or SC
Dog 1.0 mg/kg/day for 3 days
Flunixin
Horse 1.1 mg/kg/day, IM or IV for 5 days
meglumine
Cattle 2.2 mg/kg, IM or IV
22mg/animal/day IV not to exceed 800 mg/animal/day;
Dog
44 mg/kg in 3 divided doses oral, not to exceed 800
mg/day regardless of body weight.
Phenylbutazone
1-2 g/454 kg daily in 3 divided doses IV for maximum
Horse of 5 days, 2-4 g/454 kg oral, not to exceed
4g/animal/day.
 P a g e | 24

Dog/Cat 125 mg/4.5 kg IV, IM or SC may be repeated 1-2 times

daily 8 hours; 28 mg/kg oral
Dipyrone
5-10 g/animal IV, IM or SC, may be repeated 1 to 2
Horse
times daily at hours interval
Piroxicam Dog 300 micrograms/kg every other day
Caprofen Dog 2mg/kg bid

PLATELET-ACTIVITING FACTOR (PAF)

The platelet-activating factor (PAF) is a polar lipid released from leukocytes and causes
platelets to aggregate. The term, however, is quite misleading since PAF has action on variety
of different target cells. Like the eicosanoids, it is not stored but synthesized in response to
stimulation. It is generated and released from most inflammatory cells when these are
stimulated. Its inflammatory effects, which incidentally are also inhibited by NSAIDs, are
mediated through action on specific receptors.

Role of platelet-activating factor in inflammatory

 Vasodilation (causing erythema)

 Increased in vascular permeability (wheal formation). PAF is 100x more potent
vasodilator than bradykinin and histamine
 Platelet aggregation, which is accompanied by release of thromboxane A₂ (TXA2)
 In induced lysosomes to generate superoxide, and serves as chemotaxin for
neutrophils, which in turn release leukotrienes (specifically LTB₄). LTB₄ is believe
to mediate the effect of PAF.
 It also causes aggregation of monocytes and degranulation of eosinophils.
 It activates phospholipase A₂ with generation of eicosanoids.
 It causes contraction of smooth muscles of the gut, uterus and lungs.

CYTOKINES

Cytokines are polypeptide production released by connective tissue and activated

lymphocytes and monocytes. There are more than 50 cytokines identified. They all act on
specific high-affinity receptors, which are up-regulated (i.e., increased in number) in the cell
when it is stimulated.

The Cytokine Superfamily includes:

 Interleukins
 Chemokines
 Colony – Stimulating Factors
 Nerve – Growth Factor
 Interferon
 Transforming Growth Factor (TGF)
 Tumor Necrosis Factor Families

Role of Cytokines:
1. Induction of cell adhesion molecules on endothelium
 P a g e | 25

2. Induction of PGI2 synthesis

3. Induction of PAF synthesis induction of fever, anorexia
4. Stimulation off acute-phase protein synthesis in the liver

Nitric Oxide

Nitric oxide is a small molecule that is locally synthesized by endothelium and macrophage
through the activity of the enzyme, nitric oxide synthesis. It is powerful cause of vasodilation
and increase vascular permeability. As an important re-active oxygen intermediary, it can
also mediate cell and bacterial killing.

Vasoactive Peptides (Kinin System – Bradykinin and Kallidin)

Bradykinin is a nonpeptide (arg-pro-pro-gly-phe-ser-pro-phe-arg) while Kallidin has an

additional lysine and amino terminal.

Activation of kinins

Kinins are activated by protease enzyme kallikrein. Kallikreins are produced by activation of
the inactive precursor kallikrein, which is present in plasma. The clotting factor XII
(Hageman factor), initially activated on exposure to collagen, cleave pre-kallikreins into
active kallikreins. The kallikreins then cleave the substrate kininogen to form active kinins.
The types of kininogens are high-molecular weight kininogen (HMW-K) which is activated
to bradykinin, and lower molecular weight kininogen which activated to kallidin.

Physiological Roles of Kinins

Both bradykinin and kallidin have very short half-life (about 15 seconds) in the plasma. They
are readily metabolized by kininase II, which is identical to angiotensin converting enzyme
(ACE), and by the slower- acting kininase.

What do kinins do in such an evanescent existence?

 They mediate nociception (perception of damaging stimuli)
 Take part in the regulation of blood pressure
 Aid in maintenance of fluid and electrolyte imbalance, and
 Mediate inflammation

Role of kinins in inflammation:

 Bradykinin is one of the most potent endogenous vasodilators known. Its vasodilator
action is partly due to the generation of PGI2 and the release of nitric oxide.
 It increases vascular permeability 15 time more than does histamine.
 It is also a very powerful pain producing agents an effect that is potentiated by
prostaglandins
 It induces leucocyte migration (chemotaxis)
Kinin receptors

Bradykinin acts on at least three types of receptors:

1. B1
2. B2, and
3. B3
 P a g e | 26

Stimulation of these receptors, specifically B2, activates phospholipase C, and causes an

increase in cytosolic calcium. It also activated phospholipase A2 resulting in the synthesis of
various eicosanoids.

Mechanism by which Drugs may counteract the Action of Bradykinin

Kinin receptor blockers include:

 des - ARG9 [LEU8] bradykinin- blocks B1
 des- ARG10 [LEU2] kallidin -block B1
 By blocking the
 des-ARG [4-hydroxy-PRO3-D-PHE7]
bradykinin receptors
Bradykinin blocks B1 and B2. These has been used to
relieve cold symptoms in humans

 By inhibiting Aprotinin has been used in treatment of acute pancreatitis

kallikreins and carcinoid syndrome

ACTIVATED COMPLEMENT COMPONENTS

Complement is a collective term referring to heat labile factor in the extra cellular fluids. If
antibodies, which are directed against the surface of the cells, and are able to fix complement,
a cytotoxic reaction may occur.

The complement system has at least:

 11 serum proteins (C1q, C1r,C1s,C2 to C9), and
 3inhibitors (C1,C2 and C3 inhibitor)

Complement Activation
Complement can be activated either by:
1. The Classical Complement Activation Pathway or
2. The Alternative Complement Activation Pathway

The Classical Complement Activation Pathway

 C1q subunit binds with antibody, and is activated.

Activation of C1  Activated C1q activates C1r which in return, activates C1s
 Activated C1s has esterolytic and proteolytic properties

Activation of C4
 C1s activates C4 by cleaving a fragment and forms, C1,4,
which causes immune-coagulation and virus neutralization
 Activated C4 has several functions; binds to cell membrane
 P a g e | 27

adjacent to the antibody (which is bound to the epitope of

the antigen and C1q)
 Activated C4 also interact with C1s which leads to a more
efficient cleavage of C2

 C2 is activated by cleavage by the action of C1s and C4

 Activated C2 remains associated with C4 (C4, 2)
Activation of C2
 C42 increases vascular permeability
 C4, 2 is called C3 convertase

 C4, 2 splits C3 into two fragments: C3a and C3b

 C3b attaches the membrane in its immediate vicinity and
also binds with C4, 2 to form C4, 2, 3 also called C5
convertase
Activation of C3
 C4, 2, 5 cause immune adherence, enhance phagocytosis
and viral neutralization
 C3a has important biological properties and can cause
anaphylaxis, chemotaxis and histamine release

 C5 is split by C5 convertase (C4, 2, 3) into C5a and C5b

Activation of C5, C6
 C5b combines with C6 and C7 to form complex on the cell
and C7
membrane (C5, 6, 7 can also cause chemotaxis)

 C5, 6, 7 focuses the activities of C8 and C9 onto the target

Activation of C8, and cell membrane
C9  C8 and C9 so directed produce “holes” on the membrane
which result in cell lysis

The Alternative Complement Activation Pathway

It may be triggered by any of the following:

 Liposaccaride (LPS)
 Endotoxin from the cell walls of gram-
negative bacteria
This another way of activating C3
 Cell walls of some bacteria
 Cell wall of yeast (Zymosan)
 Aggregate IgA
 Factors present in cobra venom.

C3b exist in trace amounts in It combines with a serum factor called factor b,
normal serum forming a complex C3bB
 P a g e | 28

C3bB is further activated by serum

factor D which cleaves factor B C3bBb act as a C3 convertase and release C3a, C3b
while it is attached to C3b to from remaining C3
generate the enzyme complex
B3bBb

C3bBb combines again with factor  This amplification is delicately balanced by

B, and the cycle is repeated the fact that C3bBb complex dissociates
yielding more C3 convertase, rapidly
thereby amplifying the amount of
C3 convertase and the amount of  This dissociation is regulated by a serum
C3 that becomes activated protein called properdin, which acts to
stabilize the C3bBb complex

Once activated by either the classical or alternative pathway:

 C3 interacts with other serum components to activate late-acting complement that

cause extensive cellular damage

 When platelets or mast cells are the target or the complement reaction, mediators of
inflammation may be released and activated

 Activated complement component can also participate in inflammation by virtue of

their chemotactic properties and their ability to enhance phagocytosis.

COMPONENTS OF BLOOD-CLOTTING FACTOR MECHANISM

Blood clotting is initiated by activation of Hageman factor (Factor XII). Factor XII
interacts with the kinin-kallikrein system resulting in the generation of vasoactive kinins.
Factors XII by itself increase vascular permeability. In disseminated intravascular
coagulation (DIC) as that occurring in toxemia, the involvement of the inflammatory process
in such abnormality of blood coagulation may be a critical outcome or the disease.

The best “anti-inflammatory” agent in such clinical setting is heparin (an anticoagulant)

Blood clotting is discussed in a separate lesson.

THROMBOLYTIC SYSTEM

Plasminogen activator derived from endothelium by the action of bradykinin generates

plasmin, a thrombolytic enzyme. Plasmin activities the complement system, as well as Factor
XII (Hageman Factor) of coagulation, lyses fibrin to form fibrin degeneration products which
increase vascular permeability.
 P a g e | 29

Lesson 02
 P a g e | 30

Glucocorticoids
and
Immunosuppressan
t Agents

G lucocorticoids are steroidal agent produced and released by the adrenal cortex.

The pharmacological actions of glucocorticoids may be considered under three

main headings:
1. General effects on metabolism, water and electrolyte balance and organ system
2. Negative feedback effects on the anterior pituitary and hypothalamus
3. Anti-inflammatory and immunosuppressive effects.

Cells of the adrenal cortex secrete endogenous glucocorticoids. The term corticosteroid
applies to any steroidal hormone secreted by the adrenal cortex but is often used
synonymously with glucocorticoids. Adrenal steroids are divided into three main groups
based on their physiological activity.

Major Class of Adrenal Steroids:

1. Glucocorticoids
Cortisol and corticosterone, predominantly affect carbohydrate metabolism

2. Mineralocorticoids
Aldosterone, predominantly affect electrolyte and water metabolism

3. Adrenal sex hormone

Mainly androgens, have limited importance

Only glucocorticoids (including their synthetic analogues) are discussed here

 P a g e | 31

STRUCTURE – ACTIVITY RELATIONSHIP

Cortisol (Hydrocortisone) and Corticosterone

Two most important naturally occurring glucocorticoids:

1. Cortisol
Predominates in human beings, pigs, and dogs
2. Corticosterone
Predominates in rabbit, mouse, and rat

The ruminant secretes sizable amount of both. Both of these glucocorticoids have some
degree of mineralocorticoids activity. The structure of cortisol is shown below. These are
four rings in the steroid structure and are designated here as rings A, B, C, and D.
substitutions in each ring affect its glucocorticoids activity.

Effects of structural modification of cortisol structure.

a. Ring A
 The double bond at c4 and keto group at C3 are essential for activity.
 Reduction of the double bond and the keto group result in loss of activity
 A double bond at C1 enhances the glucocorticoid activity and decreases
mineralocorticoid activity
b. Ring B
 An α – fluorination at C9 increase both the glucocorticoid and
mineralocorticoid activity
 An a- methylation at c6 enhances the glucocorticoid effect
c. Ring C
 The b-hydroxyl group at C11 is essential for activity.
 Changing the position of this hydroxyl group from b to a, or changing it to
keto group, eliminates the biological activity of the corticosteroid.
 Cortisone, a glucocorticoid commonly use in clinical therapy, differs from
cortisol only in having a keto- rather than B-hydroxyl group at C11.
 Cortisone is inactive, but can be transformed to cortisol in the liver. It is not
useful when administered topically or injected in joints.
d. Ring D
 All useful have a-hydroxyl group at C17.
 The OH group at C21 must be free for biological activity.
 Pharmaceutical preparation glucocorticoids maybe esterified at C21 to alter
their solubility and duration for action but must be de – esterified in the body
to be able to exert their biological action. For example, sodium succinate
esters are more soluble than acetate esters; the onset of action of succinate
ester is sooner and the duration of action shorter than acetate esters
 α - or β – methylation at C16 markedly decreases mineralocorticoid effect
 In addition, b- methylation may induce parturition when administered during
the last trimester of pregnancy.
 α – hydroxylation at C16 also markedly decrease mineralocorticoids effect.

Pharmaceutical Formulations of Glucocorticoids

 P a g e | 32

The glucocorticoid base refers to the non-esterified steroid component and determines its
glucocorticoid, an anti-inflammatory potency, and extents its duration of action.

COMPARISON OF GLUCOCORTICOIDS

Anti-inflammatory Mineralocorticoid Duration of

Drugs
potency potency action

SHORT ACTING
Hydrocortisone 1 ++ <12
Cortisone 0.8 ++ <12

INTERMEDIATE
ACTING 3.5 + 12 – 36
Prednisone 4 + 12 – 36
Prednisolone 5 0 12 – 36
Methylprednisolone 5 0 12 – 36
Triamcinolone

LONG ACTING
Paramethasone 10 0 >48
Betamethasone 25 0 >48
Dexamethasone 30 0 >48

Esterification of glucocorticoids is influenced the duration of action and mode of

administration, for example:

Glucocorticoids Ester Pharmacological properties

 Phosphates Rapid onset of action; for IV and IM routes

 Hemmisuccinate Rapid onset of action; for IV and IM routes

 Acetate, diacetate, Slow absorption; available as depot; action last days

tebutate duration

 Acetonide Poorly water soluble; used as depot

 Pivalate
 P a g e | 33

Very long duration of action (weeks to months)

By feedback mechanism glucocorticoids may be suppress the hypothalamus-pituitary-

adrenal axis

The ability of glucocorticoid formulation to suppress the hypothalamus-pituitary-adrenal axis

(HPAA) is determined by:

 The dose
 Potency of the base, and
 Duration of the action of the formulation.

The period of anti-inflammatory effectiveness of most glucocorticoids parallel the HPAA-

suppressive time, HPAA suppression leading to a secondary hypoadrenocorticism is one of
the major adverse effects of the glucocorticoids therapy.

Therapeutic success with fewer side effects is possible with alternate-day therapy.

This stems for the fact that some preparation have slightly longer anti-inflammatory or
immunosuppressive action than their action to suppress the HPA axis.

Control of Glucocorticoid Secretion

Stress

Hypothalamus

Corticotropin releasing hormone (CRH)

Inhibit
PITUITARY GLAND

Corticotropin

ADRENAL CORTEX Inhibit

Cortisol

The Hypothalamus-Pituitary-Adrenal Axis (HPAA)

The cells of the adrenal cortex secrete endogenous glucocorticoids (cortisol and
corticosterone). The secretion is regulated by hypothalamus-pituitary-adrenal axis (HPAA).
 P a g e | 34

See illustration above. Respond to the influence of the circadian rhythm (biological clock)
and the changing stress condition of the animal, the hypothalamus secretes corticotropin –
releasing hormone (CRH), which is brought to the anterior pituitary through the
hypothalamus-pituitary portal system. In the anterior pituitary, CRH stimulate the secretion
of the hormone corticotropin (ACTH). ACTH gets to the adrenal medulla by way of the
blood circulation and stimulate the secretion of glucocorticoids by the cells of the adrenal
cortex.

The secretion of corticotropin by the anterior pituitary is episodic rather than continuous. In
the normal animal, the blood glucocorticoid concentration varies with the circadian rhythm.
The pattern of changing, however differs between species.

For example:
 The dog which are generally active during daytime (diurnal), have high blood
glucocorticoid concentration during the day, and low at night
 Cats, which are active at night (nocturnal), show the reverse pattern.

Circulating glucocorticoids (endogenous or exogenous) exert a negative feedback to the

pituitary and hypothalamus. A high concentration of (endogenous or exogenous)
glucocorticoid circulating in the blood inhibits the release or CRH from the hypothalamus,
and ACTH from the anterior pituitary.

The inhibition become irreversible especially with prolonged use and repeated administration
of glucocorticoids. When this happens, the adrenal cortex may not be able to produce
endogenous cortisol resulting in hypoadrenocorticism (Addison’s disease). Some ways to
minimize this adverse effect of glucocorticoids in clinical practice will be discuss later in this
lesson.
Physiological Role of Glucocorticoids

Knowledge of the physiological role of glucocorticoids is essential in the rational and safe
use of these agents in clinical situations. These roles are outlined below.

Physiological Effect of Glucocorticoids

 Regulate the volume and composition of body fluids mainly through their
mineralocorticoids action

 Increase the rate of gluconeogenesis

 Reduce protein synthesis

 Promote redistribution of body fat in the hypercorticoid state, allow lipolysis to

occur in response to lipolytic agents (ACTH, glucagon, catecholamines, TSH).
Although glucocorticoids are not the main stimulator of lipolysis the process will
not occur in its absence.

 Make the animal able to resist the effects of noxious stimuli (such s during
inflammation) and of various form of physical and emotional stress.
 P a g e | 35

Glucocorticoids control inflammation by:

 Maintaining circulation and normal vascular permeability

 Stabilizing lysosomal membrane

 Inhibiting production of prostaglandins

 Blocking free radical formation through inhibition of phosphate A

Pharmacological Effects of Glucocorticoids

The pharmacological effects of glucocorticoids are produced by rather than high doses. When
a clinician administers a glucocorticoid to a patient, effect other than those originally desired
may also occur. These side effect may be harmful to the patient and at times mat result in a
condition far worse than the original problem that had required treatment with
glucocorticoids.

 Effects on energy metabolism

Glucocorticoid have anti insulin (hyperglycemic action) action, which may lead to
increase glucose production from amino acid by way of gluconeogenesis, and to
reduce the rate of incorporation of amino acid into proteins. Blood levels of both
insulin and glucagon may rise in response to glucocorticoid administration. Quite
expectedly diabetes mellitus may occur in animal with diminished insulin secretor
capacity (those animals are termed pre-diabetics). In such a case muscle wasting
(secondary to rate of protein synthesis) is not uncommon. Lipolysis may be increase
in some areas of the body causing in abnormal distribution of fats.

 Effects on water and electrolyte balance

Glucocorticoids in large amounts (hyperadrenocorticism or Cushing’s disease)
inevitably lead to polyuria (excretion of excessive volume or urine), and polydipsia
(excessive thirst) no glucocorticoid is absolutely devoid of mineralocorticoid activity
(sodium- retaining and potassium- losing action). In addition to the effect of
increasing extracellular fluid volume, glucocorticoids increase the glomerular
filtration rate, and are required in physiological amounts for the maximal dilution of
urine. Overdose may be leads to hypernatremia (retention of high sodium
concentration in blood) and to hypokalemia (low potassium concentration in blood).

 Effects on cardiovascular functions

These effects are in addition to the indirect effect on electrolyte and water balance.
Glucocorticoids directly increase the force and frequency of heartbeat. They block the
increased vascular permeability induced during acute inflammation, which then
reduce the transport of plasma protein into areas of damage, and thus maintains the
microcirculation. The presence of glucocorticoids is necessary for maximal sensitivity
 P a g e | 36

of blood vessels to catecholamine action. Therefore, they contribute the maintenance

of vascular tone.

In cardiovascular shock, the formation of vasoactive products of lipid peroxidation

(arachidonic acid cascade) such as vasoconstrictor thromboxane A2, may be
decreased by glucocorticoids by inhibiting phospholipase A2, but probably only in the
early stage of membrane disruption.

 Effects of CNS
The effects or glucocorticoid on the CNS are rarely describe in domestic animals, but
may have marked effect on the psyche resulting in a form of mental and physical
dependence. In human beings, glucocorticoids may induce a feeling of euphoria.

 Effects on endocrine system

In addition to being diabetogenic (anti- insulin), glucocorticoids also have marked
effect on hypothalamic and pituitary function. Corticotropin (ACTH), thyrotropin
(TSH), and growth hormone (GH) synthesis and secretion may also be suppressed by
glucocorticoids.

 Anti-inflammatory and immunosuppressant effects

Glucocorticoids are used to advantage to suppress the immune system. They cause
lymphocytopenia and eosinopenia an effect secondary to cell redistribution and/or
lysis, and lead to increase de-margination of neutrophils. Glucocorticoids do not seem
to decrease antibody production but have their most important effect on the
suppression of leukocyte accumulation at inflammatory sites. Viral interferon
synthesis may be inhibited as well as the phagocytic capacity of monocytes and other
macrophages.

The anti-inflammatory of effects are usually what the clinician’s desire when using
glucocorticoids.

At pharmacological doses, glucocorticoids:

1. Inhibit both the early and late manifestation of inflammation.
2. In addition to contributing to the maintenance of the microcirculation and cell-
membrane integrity, glucocorticoids interfere with the progressive digestion and
disruption of connective tissue and cells, possibly through stabilizing lysosomal
membranes.
3. They decrease the formation of induce histamine, and histamine produce by cells
during injury whose action is not inhibited by antihistamine.
4. Glucocorticoids also antagonize toxin and kinins and reduce the resultant
inflammation.

Most of these effects however, are nonspecific, that is, they occur regardless of the
nature of the initial insult. When used to suppress tissue graft rejection,
glucocorticoids suppress the initiation and generation of an immune response more
efficiently.
 P a g e | 37

Therapy with glucocorticoids (and other steroids for that matter) is not without
danger. One should always remember that serious adverse side effects may occur side
by side with the desire effects.

Mechanism of Action of Glucocorticoids

Glucocorticoids enter cells and bind with specific cytoplasmic receptors, which are found in
vitually all tissues. This interaction causes the receptor to undergo conformation change with
exposes a DNA-binding domain. The steroid-receptor complexes move into the nucleus and
bind to steroid-response elements in the DNA. The effects is either to repress (prevent
transcription of) or to induce (initiate expression) particular gens.

Repression result from inhibition of the action of various transcription factors such as AP-1
and NF-Kb. These transcription factors normally usually switch on the genes for COX-2,
various cytokines, and the inducible from of nitric oxide synthase. Induction involves the
formation of specific mRNAs. Which direct the synthesis of specific proteins.

Much is now known about the anti-inflammatory and immunosuppressive actions of the
glucocorticoids, but their metabolic action are less well understood.

Glucocorticoids Preparation Commonly Used In Veterinary Medicine

Route Properties Example

Those with very rapid onset and short  Hydrocortisone sodium succinate
duration are used in emergency  Hydrocortisone sodium phosphate
situation such as hemorrhagic-shock and  Prednisolone sodium succinate
anaphylaxis. These are fast-acting
(within1 min) with short plasma half-
Parenteral life (1-2 h), but are rather expensive
Preparation

Those with rapid onset and intermediate  Dexamethasone phosphate

duration are used in emergency  Dexamethasone in propylene
situation. These are effective within 5- glycol
45 min with medium plasma half-life (3-
4 hrs)

Those with slow onset and long duration  Triamcinolone acetonide

are for skin and joints.  Methylprednisolone acetate
 P a g e | 38

Those with short duration are used for  Prednisolone - mimics diurnal
acute and chronic condition and for cortisol production in most
alternate –day therapy animals; causes sodium retention
Oral (not significant in dogs and cats)
Preparation
 Prednisone- converted to
prednisolone in the liver

 Methylprednisolone

Those with slow onset and intermediate  Triamcinolone acetonde

duration are used for acute disease  Dexamethasone in propylene
processes used for once-a-day therapy. glycol

Some Complications of Glucocorticoids Used In Therapy

 Iatrogenic hyperadrenocorticism ( Cushing’s syndrome )
 Adrenal insufficiency on withdrawal due to pituitary or hypothalamic suppression
 Unmasking or exacerbation of diabetes mellitus
 Hypertension
 Behavioral changes
 Reduced threshold for seizures (contraintradicated in epilepsy and other convulsive
disorders)
 Pancreatitis
 Liver function disorder
 Gastrointestinal ulceration
 Diarrhea
 Growth retardation
 Excessive catabolism
 Osteoporosis
 Myopathy and muscle weakness
 Calcinosis cutis
 Poor wound healing
 Alopecia and thinning of skin
 Aggravates infections disease
 Suppression of immune response

Modes of Glucocorticoids use in Therapy

After having learned of the various real adverse effects of glucocorticoids, it seems it would
be better for the patient, and for the veterinarian, not to use glucocorticoids at all. Not so!
 P a g e | 39

When used properly and with diligent monitoring of patient under therapy, glucocorticoids
can be a valuable therapy of important clinical conditions.

When planning to use glucocorticoids, we must seriously consider the following

principles:
1. Diagnose first! If diagnose is delayed ill after glucocorticoids therapy has been
started, the effects of the steroid may mask the sign of the disease, and accurate
diagnose may not be attained.
2. Define the specific objectives of using glucocorticoids.
3. Use appropriate dose, frequency and duration of medication (see number 5.)
4. Remember that corticosteroids are not curative. They do not remove the cause of
the disease.
5. Doses of glucocorticoids are arrived all by tiral and error, and must be reevaluated
constantly
6. Use intermittent therapy (as opposed to continuous therapy) whenever and wherever
possible
7. Avoid using glucocorticoids is infection disease. Cushing’s syndrome, diabetes
mellitus, late stages of pregnancy, and animals predisposed to epileptic like seizures
8. Steroid with greater mineralocorticoid activity are contraindicated in heart and
renal disease
Question to answer before starting Glucocorticoid Therapy

The safety glucocorticoids use may be improved if specific answer to these question can be
made before starting therapy.
1. How serious is the underlying disorder?
2. How long will therapy be required?
3. Is the patient predisposed to any of the complication of steroid therapy?
4. What is the anticipated glucocorticoids dose?
5. Which glucocorticoids preparation should be used?
6. Have other modes of therapy been utilized to minimize thee steroid dosage, and to
minimize the side effects?
7. Is alternate day regimen indicated?

Mode of Usage of Glucocorticoids

There is no right dose of a glucocorticoid in a given clinical situation. Guidelines based on

clinical experience and published reports are presented as a means for comparison of classes
of usage and to provide a starting point of therapy.

 Physiological replacement therapy

This is used in the treatment of:
1. hypoadrenocorticism (Addison’s disease)
2. In iatrogenic HPA axis suppression, and
3. Adrenalectromized patients.

Only short acting preparation should be used and administered orally.

For dogs – give once a day every morning: for cats – give once a day every evening.
 P a g e | 40

Supplemental dose given in moderate stress- increase the dose 2-5x; in severe stress-
increase dose 5-20x

Dosage
Hydrocortisone or cortisone 0.2-1 mg/kg
Prednisone or prednisone 0.1-0.2 mg/kg

 Intensive short-term and shock and shock therapy

The significance of glucocorticoids in all forms of shock is still controversial, but
some evidence suggest that early treatment (probably <4 hours after induction of
shock in dogs) may lead to increase rate of survival, particularly in hemorrhagic and
septic shock. The mature of the formation particularly the ester may effects the speed
of cellular entry of glucocorticoids during shock. The potential detrimental effects of
massive doses of glucocorticoids should always be considered.

 Anti-inflammatory and Anti – allergic Therapy

This is commonly employed in:
a. Symptomatic therapy of pruritic dermatoses
b. Allergic pulmonary disease, and
c. Allergic gastroenteritis

Dosage:
Prednisolone:
For induction 1.1 mg/kg divided oral, bid until desired effect is
attained
For maintenance 0.55 - 2.2 mg/kg oral every 2 days

Methylprednisolone:
1.1 mg/kg IM, SC every o1-3 weeks

Prednisolone, dexamethasone, triamcinolone, and betamethasone may also be used.

Always tailor the dose to individual patient and effect.

 Immunosuppressive therapy (“immunosuppressive Agents “)

This use is designed for:
a. Immune mediated thrombocytopenia
b. Autoimmune hemolytic anemia
c. Systemic lupus erythematosus, and some forms of neoplasm.

The following principles of immunosuppressive therapy with glucocorticoids must be

followed:
 USE corticosteroids whose side effects and efficacy are well documented
 USE highest dose for a period until sign abate then decrease gradually, giving
time for HPAA to recover
 REDUCE the dose until 1.1 mg /kg prednisolone on alternate days few long
term effects need to decrease further.
 P a g e | 41

 DO NOT discontinue therapy until 2 to 3 months in remission: otherwise more

likely to recur.
 ADD other immunosuppressive drug if response has been limited; if there is
no response, probably nothing will work.
 REDUCE the dose glucocorticoids if there are steroid side effects; and
increase the dose of the other immunosuppressive drugs

Dosage
Prednisolone (for induction ) 2.2-6.6 mg/kg divided bid until effects
Dexamethasone (for maintenance) 2-2.2 mg/kg every 2 days
Prednisolone (for maintenance) 0.33-1.1 mg/kg

 Chronic palliative therapy

This is employed in the condition such as chronic arthritis, hip dysplasia, etc. dosing
may be intermittent or on alternate-day basis. Do not withdraw erratically, this may
lead to pseudorheumatism. Nonsteroidal analgesics (NSAIDs) may be used to
supplement glucocorticoids particularly on “off” day (see below)

 Alternate-day therapy (ADT)

Has an advantage of causing less suppression of HPAA, and fewer side effects.

The following are guidelines for ADT:

 If dose is high and duration of therapy is prolonged ( greater than 2 weeks),
double the dose on “on” days and taper the dose on “off” days by 25% per
cycle (usually 1 day to 2 weeks)
 If therapy is short (less than 2 weeks), steroid may not be given on “off” days
 If clinical signs of disease occur on “off” days, supplement with replacement
dose on those days, or add Nonsteroidal therapy.
 If relief is not maintained by ADT, giving a single dose in the morning is the
next best thing

 Common Pitfalls of Alternate Day Therapy

 Using ADT ass primary therapy
 Using long-acting preparation
 Changing too quickly from daily medication to ADT at high steroid doses
 Failure to use supplement

An example of ADT regimen. For a 20 kg dog being treated for autoimmune

hemolytic anemia
 P a g e | 42

Week 1 - 40 mg prednisolone divided bid

Week 2 - 30 mg prednisolone divided bid
Week 3 - 20 mg prednisolone divided bid

“ON” day “OFF” day

Week 4 - 40 mg morning 15 mg morning
Week 5 - 40 mg morning 10 mg morning
Week 6 - 40 mg morning 5 mg morning
Week 7 - 40 mg morning 0
Week 8 - 30 mg morning 0
Week 9 - 20 mg morning 0
Week 10- 10 mg morning 0
Week 11- 5 mg morning 0
Week 12 - off treatment

Miscellaneous or special usage

 Topical therapy – dermatological
 Intralesional or sublesional administration (particularly in horse ) has systemic effect,
can cause steroid arthropathy
 Ophthalmic disorders: retinitis, choroiditis, optic, neuritis, orbital cellulitis
 Neurologic disease

Weaning from steroids

Proper weaning from long-term glucocorticoids therapy should be tedious and drawn
out. Animals do not complain of minor aches and pains or of changes in mood.

However, the following signs might suggest that further prolongation of the weaning
process is necessary;
 Dullness
 Mental depression
 Increase fatigability
 Incoordination
 Unthriftiness and weight loss
 Diarrhea
 Behavioural changes

Adrenal Cortex Antagonists

Hyper function of the adrenal cortex is rare, although cushing’s disease has been reported in
the dog and horse.

Adrenal blocking agents, which would have some clinical indication under this condition are:

1. o,p’DDD
A relative of DDT, is 1,2- dichloro-2,2 (p – chlorophenyl) ethane. This
compound has been found to suppress adrenal cortical activity in the dog, but
it is less successful in other species. Rats and monkeys are unaffected.
 P a g e | 43

Prolonged therapy with o,p’DDD in goats caused atrophy of the cortex and
transitory cytopathologic effects of adrenal cortical cells of calves

2. Amphenome B
Is (3, 3- bis p-aminophenyl butane). It inhibits 17 - ketosteroid production in
human and dog

3. Metyrapone
Effectively blocks cortisol production but not corticosterone production inn
young pigs

IMMUNOSUPPRESSANT AGENTS

Most immune suppressant drug act in the induction phase of the specific immunological
response (see Lesson 1) resulting in the reduction of lymphocytes proliferation. There are
also some effects on the effector phase.

These agents may be classified based on the mechanism of action:

Mechanism Example
 Inhibitors of interleukins-2 (1L2)  Cyclosporin
 Tacrolimus
 Rampamycin (a.k.a sirolimus)
 Inhibitor of cytokine gene expression  Glucocorticoids
 Cytotoxic agents  Cylosphosphamide
 Chlorambucil
 inhibitors of purine and pyrimidine  Azathioprine
synthesis  Mycophenolate mofecil
 Blockers of T-cell molecule involved in  Immunoglobulins (monoclonal and
signaling polyclonal antibodies)

Clinical Uses

The immunosuppressant agents are used commonly in therapy of autoimmune disease, and
prevent and treat transplant rejection. Its use, however may entail some adverse effects, most
common of which are (a) decrease response to infection, and (b) facilitation of the emergence
of malignant cells.

Specific Drugs

 Cylosporin A
It is one of the 9 cylosporin A through, each is a cyclic peptide. Cylosporin is very
lipophilic and hydrophobic and must be solubilized before administration

It specifically inhibits T cells early in their immune response to antigenic and

regulatory stimuli without affecting suppressor T cells. Cylosporin binds with its
cytoplasmic receptor protein cyclophilin. The resulting cylosporin – cylosphilin
 P a g e | 44

complex then binds with calcineurin (a phosphatase). This binding inhibits the
calcium-stimulated phosphatase activity leading to failure to dephosphorylate
regulatory proteins. Dephosporylation of these proteins is essential to their
translocation into the nucleus where they serve as subunits of transcription factors.
Translocated regulatory proteins set to motion the transcription of gene for 1L-2.
Synthesis of 1L-2 is therefore inhibited in the presence of cyclosporin.

Cyclosporine is given orally or intravenous. Absorption from the gut is generally poor
but more absorbable preparation have been developed.

Unwanted effects of cylosporin is include:

 Nephrotoxicity
 Hepatotoxicity, and
 Hypertension

Less severe side effects are:

 Anorexia
 Hirsutism (in human) tremor
 Paraesthesia, gum hypertrophy, and
 Gastrointestinal disturbance.

There seem to be no depression of bone marrow with cylosporin

 Tacrolimus (a.k.a FK506)

It is macrolide antibiotic with a very similar mechanism of action to cylosporin. The
main difference is that its cytoplasmic receptor is not cyclophilin but protein called
FK binding protein (FKBP). Tacrolimus is active at lower concentration than
cylosporin.

 Rapamycin (sirelinus)
Rapamycin, another macrolides, also binds with FKBP. However, the rampamycin-
FKBP complex does not bind with calcinuerin nor does it effects IL-2 transcription. It
interferes with signal transduction pathway blocking the cell cycle of activated T cells
in G1 phase by inhibiting a novel kinase called mTOR

 Glucocorticoids
Immunosuppression by glucocorticoids involves both their effects on immune
response and their anti-inflammatory actions (discussed earlier). Like cyclosporine,
glucocorticoids restrain the clonal proliferation of T cell through decreasing
transcription of the gene for IL-2 and many other cytokine genes including of those
TNFa, INFy, IL-1 and many other interleukins in both the induction and effector phase
of immune response

 Cyclophosphamide
It is an alkylating agent with particular action on lymphocytes. As a
immunosuppressant it effects the clonal proliferative phase of the immune response
and reduce both antibody-mediated and cell-mediated immune reactions.

 Chlorambucil
It is another alkylating cytotoxic agent similar to cyclophosphamide
 P a g e | 45

 Azathioprine
It is used particularly for tissue rejection in transplant surgery. It is metabolized to
mercaptopurine, a purine analogue that inhibits DNA synthesis. Both cell-mediated
and antibody-mediated immune reactions, and are depressed by this drug since it
inhibits clonal proliferation in the induction phase of the immune response by a
cytotoxic reaction on dividing cells.

 Mycophenolate mofetil
A semi-synthetic derivative of a fungal antibiotic, it is converted to mycophenolic
acid, which restrains the proliferation of both B and tT lymphocytes and reduces the
production of cytotoxic. T cells by inhibiting inosine monophosphate dehydrogenase.
This pathway is essential for de novo purine synthesis B and T lymphocytes are
particularly dependent on this enzyme.
 P a g e | 46

Lesson 03

Drugs Acting on
the Respiratory
System

T he functional efficiency of the respiratory system depends upon its ability to

deliver oxygen to the tissues and to remove carbon dioxide from them. Most
disease of the respiratory system involve inflammation and changes in airway
caliber and in the degree of respiratory tract secretion.

Most of the clinical signs of disease of the respiratory system can be attributed to anorexia or
hypoxia.

Anoxia
Specifically refers to the complete failure of the tissues to get adequate supply of
oxygen

Hypoxia
 P a g e | 47

Refers to the reduce supply of oxygen, and is the more appropriate term for the usual
condition accompanying respiratory disorder.

Types of Hypoxia

 Anoxic hypoxia
Refers to defective oxygenation of blood in the pulmonary circuit and is
usually caused by a primary disease of the respiratory tract

 Anemic hypoxia
Due to deficiency of haemoglobin per unit volume of blood but the blood
oxygen tension is normal

 Stagnant hypoxia
Caused by a reduction of the rate of blood flow to and from the capillaries

 Histotoxic hypoxia
Result from the failure of the tissue oxidation system in the presence of fully
oxygenated blood.

The body compensates for hypoxia

When anorexia develops rather slowly, the body compensates for the effect oxygen
lack on tissues. The depth and rate of respiratory movement increase (hyperpnoea).
This increase is mediated by the chemoreceptors in the carotid and aortic bodies. The
spleen contracts to express reserve blood into the circulation. Thus, momentarily
increasing the number of circulating red blood cell (RBC) to carry oxygen to tissue
later, the bone marrow produces more RBC (erythropoiesis), as a response to increase
oxygen demand. More red blood cells are produce by, which may eventually result in
polycythemia (increase number of RBC). The heart rate and stroke volume also
increase to maximize the delivery of oxygen to tissues.

If these compensatory mechanism fail to maintain adequate supply of oxygen to

tissue, sign of dysfunction appear in various organs including the brain, heart,
kidneys, liver and gastrointestinal tract. These sign are associated with the retention of
excessive carbon dioxide in the body, a condition term hyper apnea. Failure to rid the
body of this excessive carbon dioxide leads respiratory acidosis.

Principal manifestation of respiratory insufficiency

Initially the body tries to rid itself of excessive carbon dioxide by means of
abnormally increasing the depth and in rate of respiration ( hyperpnea). Dyspnea
occurred when breathing becomes difficult and labored. Later, when the condition is
not corrected, cyanosis (bluish discoloration of skin and mucous membrane) sets in.
in some cases, epistaxis (nose-bleeding) may occur.
 P a g e | 48

Principles of treatment of the respiratory system

 Antimicrobial therapy
Bacterial infections involving the respiratory system are treated with
appropriate antimicrobial drugs. Since they are not specific respiratory drugs,
antimicrobial agents are taken up later lessons

 Surgery
Obstruction of upper respiratory tract may require tracheotomy in some cases

 Oxygen therapy
Admission of oxygen is not often adopted in the treatment of large animals,
but may be used more frequently in small animals. Oxygen therapy, however,
is useful only in cases of anoxia and when the respiratory tract is not
completely obstructed

 Artificial respiration
This may be instituted by intermittent – positive pressure ventilation (IPPV)
during open – thoracic surgery or paralysis with a muscle relaxant drugs or
poisons

 Administration of central respiratory stimulants

Such as pierotoxin, metrazole, nikethamide, caffeine, amphetamine, and
yohembine may be needed in certain instances such as during an overdose of
certain anesthetic. Extreme precautions are needed when instituting
medication with these drugs as they may cause severe adverse reactions

 Anti – inflammatory drugs, bronchodilators, expectorant, antitussives, and

mucolytics may be useful in some cases

 Supportive therapy
Artificial feeding, correction of acid – base abnormalities, fluid therapy, etc.,

Drugs affecting the respiratory system

Included in this lesson are agents used in the symptomatic treatment of respiratory disease.
Remember that treatment of respiratory disease will seldom be successful unless the principal
cause of the disease is removed.

Alteration in the quantity and quality of respiratory secretions accompanies many respiratory
disorders. In general, an increase in the volume of secretion is a beneficial protective
response in many respiratory disorders as it dilutes and facilitates removal of offending
agents from the respiratory tract. Gross overproduction of respiratory secretions, however,
may lead to obstruction of the airways to the point that asphyxia (a condition of hypoxia
combined with hypercapnia) may occur. Respiratory secretions may at times be abnormally
reduced. Drugs may be used to increase or decrease the volume of respiratory secretion.
 P a g e | 49

A. Drugs to increase respiratory secretion

This group includes the expectorants. Expectorants are drugs that increase the volume
and fluidity of secretions in the respiratory tract. Production of more fluid secretion
encourages the movement of respiratory debris towards the mouth, at the same time
soothes irritated mucous membranes. Expectorants may act directly or indirectly on the
respiratory mucosa.

Expectorants
Type Mode of Action Examples

 Act directly on the cells of  Eucalyptus

the respiratory lining and  Pine oil
stimulate them to increase  Camphor
Directly – acting their secretory activity  Lemon oil
expectorants  Potassium iodide
 They may be administered
orally or by inhalation in the
form of aerosol

 When administered orally,  Ammonium carbonate

cause irritation of the nerve  Ammonium chloride
endings in the stomach and  Potassium iodide
thereby provoke a mild  Potassium citrate
vomiting reflex. One of the  Guaifenesin
Indirectly – acting components of this reflex is
expectorants an increase in the volume of
respiratory secretion. Severe
vomiting with the
administration of these
drugs may be a sign of over
dosage

 Liquefy hardened  Acetylcysteine

respiratory debris for easier (carbocysteine)
Mucolytics
expectoration (more details
below)

Expectorants are not too dramatic in their effect and there have been questions as to
whether they are of value at all. They are probably of some use when there is actual
drying of the mucous membrane and in the removal of inflammatory debris. The soothing
action of expectorants on irritated mucous membranes exerts some degree of antitussives
(cough – suppressing) action (see below).
 P a g e | 50

B. Drugs to inhibit or reduce respiratory secretion

These include the ɑ - adrenergic stimulants, classical (H1) antihistamines, and

anticholinergic agents:

INHIBITORS OF RESPIRATORY SECRETION

Categories Mode of Action Examples

 Constrict blood vessels in mucous  Phenylephrine

membranes of the upper respiratory  Phenylpropanolamine
tract thereby decreasing their  Oxymethazoline
leakiness (a decongestant action)  Propylhexedrine
ɑ - Adrenergic  Tuaminoheptane
stimulants  That can be administered orally but
the most effective route of
administration is by direct
instillation by way of the external
nares

 Block the effects of histamine  For examples see under

which is released in certain allergic ANTI – INFLAMMATORY
disorders and which provokes DRUGS
Antihistamines increased respiratory secretion

 They proved not too effective in

domestic animals

 Have potential use in preventing  Atropine sulfate

excessive respiratory secretions due
to cholinergic stimulation such as
during organophosphate poisoning.
Anticholinergics
 May lead to production of
excessively sticky secretion in the
respiratory tract

The inhibitors of respiratory secretion are used in the management of acute and chronic
rhinitis. The ɑ - adrenergic stimulants are almost always the best choice.

C. Mucolytics and Proteolytic enzymes

These are used to degrade and liquefy inflammatory debris. Because of this, mucolytics
are often included with expectorants (see above). Inflammatory materials such as mucus
 P a g e | 51

plugs and necrotic debris accumulate in many respiratory disorders and can potentially
lead to obstruction of the respiratory tract. Certain drugs have been used in an attempt to
liquefy the debris so it may be expelled readily by coughing.

Notable examples of mucolytics are Acetylcysteine (syn. Carbocysteine) and

Bromhexine

Examples Mode of Action

 Breaks the disulfide bonds in mucus resulting in its

liquefaction

 Also has been used as antidote for acetaminophen

(Paracetamol) poisoning

 In the latter case, Acetylcysteine serves as a precursor

Acetylcysteine of glutathione, a naturally occurring substance which
neutralizes reactive metabolites of Paracetamol

 For the mucolytic effect, Acetylcysteine is best

administered by direct instillation into the respiratory
tract. It may cause a reactive bronchoconstriction and
must therefore be given in combination with a
bronchodilator (see below)

 Increase the volume and fluidity of respiratory

secretion by a different mechanism

 It brings about an increase concentration of

immunoglobulin and of administered oxytetracycline
Bromhexine in bronchial secretion. This is due presumably to
increasing membrane permeability

 Has also been used with some success in the

treatment of infectious tracheobronchitis (kennel
cough) in conjunction with antibiotic therapy

Examples of clinically useful proteolytic enzymes are pancreatic dornase, trypsin,

streptokinase, and streptodornase. They are usually administered by inhalation
(nebulization) to degrade inflammatory materials in cases of severe respiratory disorders

D. Antitussives

Antitussives are drugs used to suppress cough. Cough is a protective reflex initiated by
the presence of foreign materials in or by irritation of the respiratory tract. The reflex
which involves the cough center in the brain is characterized by rapid contraction of the
diaphragm and the intercostal muscles, and by a forceful expulsion of air from the
respiratory tract.
 P a g e | 52

Antitussives
Categories Mode of Action Mode of action and remarks
Centrally – acting antitussives
 Non – selectively depress the cough center
 Codeine in the medulla oblongata which may also
 Diheydrocodeine lead to depression of other parts of the CNS
 Dihydrocodenone (narcosis)
 Morphine  Codeine and Hydrocodeine seem to have
 Narcotic
(analgesic and antitussive) fairly high degree of selectivity for the
antitussives
cough center while opiates are highly
efficacious for they are addicting and are
subject to dangerous drug control
 Opiates are relatively toxic in cats

 Similar to narcotic antitussives with rather

 Dextromethorphan selective action on cough center but are
 Noscapine deemed not to be habit – forming.
 Butorphanol  Dextromethorphan, a derivative of opiate
 The Phenothiazine narcotic, has retained the ability to depress
tranquilizers the cough center but is not addicting. It has
little or no analgesic activity. It still
produces some degree of sedation
 Non – narcotic  Noscapine is as potent as dextromethorphan
antitussives  Butorphanol is 100x more potent than
codeine and does not have narcotic effects.
 The Phenothiazine tranquilizers such as
trimeprazine combined with a corticosteroid
have some degree of antitussive action in
addition to their bronchodilator and sedative
action. Drugs such as these may have
particular value in cats

 Act directly on the respiratory mucous

 Menthol membranes to produce soothing or local
Locally – acting
 Tincture of benzoin anesthetic effect.
antitussives
 Benzonatate  They may be administered orally or by
inhalation

Three ways by which coughing can be suppressed:

1. By reducing the viscosity in the airways with mucolytics
2. By soothing irritated respiratory mucus membrane with local antitussives, and
3. By depression of the cough center in the brain with central antitussives.
Antitussives may be centrally acting or locally acting.

Antitussives should be used only in cases of non – productive cough to prevent trauma to
the respiratory tract and allow the patient to rest. They may be contraindicated in cases of
productive cough. The combination of an expectorant and an antitussive may seem
irrational but does not seem to cause untoward effect in human as well as in animals.
 P a g e | 53

E. Bronchodilators

Bronchodilators cause relaxation of the bronchial smooth muscles and increase the
functional capacity of the respiratory tree. Their effect is not too pronounced in the
normal respiratory system but they have dramatic ability to counteract pathological
bronchoconstriction. A wide variety of endogenous substances mediate
bronchoconstriction. These include acetylcholine, histamine, serotonin, bradykinin,
and prostaglandins. The major components responsible for bronchodilation are the β₂
- adrenergic receptors.

Bronchodilators
Drugs Remarks

 Counteract bronchoconstriction caused by

histamine released during allergic reaction
Antihistamines
 These are not too effective because a variety of
(for examples see
other inflammatory mediators are also released
Lesson 1)
against which antihistamines have no neutralizing
effect

 Can counteract acetylcholine – induced

bronchoconstriction but acetylcholine probably has
Anticholinergics
little role in the pathogenesis of bronchoconstrictor
(atropine and atropine –
disorder
like compounds
 Atropine is a specific antidote to organo –
phosphate – induced bronchoconstriction

 It is not a bronchodilator and is of no value in the

treatment of acute bronchospasm
Cromolyn sodium  By preventing the release of histamine from mast
cells, it is useful as a prophylactic agent to prevent
attacks in chronic bronchoconstrictor disorders

 Have dual action to cause bronchodilation and

Corticosteroids reduction of inflammatory swelling of the
(for examples, see respiratory tract
Lesson 2)  They may be administered IV in acute attacks and
orally in chronic bronchoconstrictor disorders

Methylxanthines
(Theophylline,  Potent bronchodilators which act in the manner
Aminophylline, and similar but not identical to the sympathomimetics
Caffeine)  They can be used when refractoriness (or tolerance)
develops with prolonged use of sympathomimetics
(see below)
 P a g e | 54

 Intravenous administration may be used in acute

attacks; orally for chronic disorders (may be drugs of
choice for these conditions)

 Highly potent and efficacious drugs for the

management of acute and chronic
bronchoconstriction
 The mechanism of action involves direct simulation
of β₂ - adrenergic receptors in the bronchial smooth
muscles resulting in bronchodilation
 A major problem is the development of tolerance to
sympathomimetics
Sympathomimetics  This tolerance is caused by a progressive reduction
in the number of adrenergic receptors with chronic
use of sympathomimetics
 Once tolerance develops to one, all the other
sympathomimetics are ineffective
 Normal reactivity to sympathomimetics can be
restored by switching to another group of drugs such
as xanthines for a period of time.

 Has very potent, prompt, but transient

bronchodilator action.
 Stimulates both beta and alpha adrenergic receptor
and is useful for acute conditions where it can be
given parenterally.
 Epinephrine  Not ideal for use in chronic disorders because of
fleeting effect
 Parathion for inhalation is available.
 Not effective when given orally.
 Can have serious cardiac complications
 P a g e | 55

 A pure β₂ - adrenergic stimulator

 Action is comparable to epinephrine and most
 Isoproterenol effective if given parenterally or by inhalation
 Not effective when given orally
 Like epinephrine, it has potent cardiovascular effect

 Has slower onset but more prolonged effect (4 -6

hours).
 Ephedrine  Better used for chronic than for acute disorders
 Less potent but is effective when given orally but
can cause marked CNS stimulation

 Such as albuterol, metaproterenol, terbutaline, and

clenbuterol, are also sympathomimetic drugs but
 Selective
they are specific β₂ - adrenergic stimulants without
bronchodilators
affecting β₁ - receptors in the heart
 Have prolonged effects after oral administration
 P a g e | 56

Given below are doses of some respiratory drugs.

DRUGS DOSAGES
EXPECTORANTS
Guaifenesin Horse 0.1 to 0.2 g/50 kg b.w. oral qid
ANTITUSSIVES
Dog 0.55 mg/kg oral
Butorphanol
0.055 mg/kg SC
Codeine Dog 0.1 to 0.3 mg/kg oral tid
Dextromethorphan Dog/Cat 1 – 2 mg/kg oral bid
MUCOLYTICS
50 ml/hr (of 10% aqueous solution) for
Dog
30 – 60 min bid by nebulization

Acetylcysteine Cat 140 mg/kg IV repeat q6h at 70 mg/kg for

7 treatments
Horse/Ruminants 2 – 5 ml/50 kg (of 10% solution) bid or
tid as aerosol
Bromhexine Dog/Cat 1 mg/kg oral q12h

BRONCHODILATORS
Dog 10 mg/kg oral q6 – 8h
Cat 6 mg/kg oral q12h
Aminophylline
Horse 5 – 10 mg/kg oral TID
Calf: 0.5 – 1 g/kg oral QID
Dog 2 mg/kg oral q8h
Ephedrine Cat 1 mg/kg oral q8h
Horse 0.7 mg/kg oral BID
0.5 – 1.5 ml (of 1:10,000 sol’n) IV
Dog/Cat
repeat 30 min for
anaphylaxis
Epinephrine 4 – 8 mg/450 kg IM, SC, (IV only for
Horse
emergencies such as
anaphylaxis)
Sheep 1 – 3 ml of 1:10,000 sol’n IM, SC
Dog 6 – 11 mg/kg oral, IM, IV, tid – qid
Cat 4 mg/kg oral tid
Theophylline 0.1 mg/kg IM, IV tid
Horse 1 mg/kg oral qid
Ruminants 28 mg/kg oral once a day
Albuterol Dog 0.02 - - 0.04 mg/kg oral OD – TID
Clenbuterol Horse 0.8 – 3.2 µg/kg oral BID
0.8 µg/kg IM or slow IV BID
Terbutaline Dog 2.5 mg/kg oral, SC, tid
Cat 1.25 mg/cat oral bid or
0.625 mg/ cat oral, SC, bid
 P a g e | 57

Horse 0.02 – 0.06 mg/kg IV bid

Lesson 04

Cardiovascular
Drugs

A
 P a g e | 58

Short review of the essential points of cardiac electrophysiology will help us understand the
actions of drugs affecting cardiovascular functions.

The role of Potassium (K⁺)

The resting membrane potential (RMP) of myocardial cells is controlled mainly by the
difference between the intracellular and extracellular concentrations of potassium ions (K ⁺).
the usual intracellular and extracellular concentrations of potassium are: [K ⁺]ᵢ = 150 mM and
[K⁺]ₒ = 4 mM, respectively. Because of the steep potassium concentration gradient across the
cell membrane, some K⁺ slowly flow outward through the K⁺ leak channels and leaving the
inside more negative in relation to the outside. As the positively charged potassium ions go
out, the membrane becomes polarized with negative and positive side.

The role of Sodium (Na⁺)

The myocardial cell membrane may undergo a partial depolarization either by decreasing the
outflow of K⁺ (reducing the negativity of the cytoplasmic side of the membrane) or by letting
a little Na⁺ to flow inward through the K⁺ leak channel (making the membrane inside more
positive or less negative). Either way, the membrane becomes partially depolarized until
reaching a certain level called threshold potential which then causes the opening of the
sodium channels and becomes activated.

These channels are said to be voltage – dependent for they are activated only when there is an
initial change (toward positive) in the membrane potential. When the sodium channels are
opened or activated, more sodium ions rush in. this movement is easy because both the
concentration and electrical gradients of sodium are directed inward. That means Na ⁺ flows
from outside where it is more concentrated to the inside where it is less concentrated and
since it is positively charged, it is attracted to the negative inside. The rushing in of sodium
ions passes over the threshold potential and consequently produces an action potential
(impulse). In the process, K⁺ is repelled by the increasing positivity or reduced negativity of
the intracellular space. K⁺ then is forced to flow out.

The role of the sodium pump

The presence of sodium inside the cell activates the sodium pump or Na ⁺ - K ⁺ - ATPase.
This membrane – bound enzymes pumps out 3 sodium ions in exchange for 2 potassium ions.
The activation of the sodium pump tries to restore resting membrane polarity. Once the
resting membrane potential is restored, the condition is again made conducive to the outward
K⁺ flow as before, and another round of depolarization occurs.

The varying RMP values among different cardiac cell types

The impulse – conducting system of the heart consists of the sino – atrial (SA) node,
atrioventricular (AV) node, purkinje fibers, and myocardial cells. These specialized cells
have resting membrane potentials in increasing order; lowest (least negative inside) in the SA
node and highest (most negative inside) in the myocardial cells. The one with the least RMP,
 P a g e | 59

the SA node, is the most excitable and therefore sets the pace of activation of the heart, thus
serving normally as the pacemaker of the heart. The RMP in any of these calls can be altered
by pathological disturbances such as hypoxia (due to myocardial infarction) and electrolyte
imbalances (e.g. hypokalemia or hyperkalemia).

Types of myocardial fibers

The myocardial muscle fibers may be grouped into fast – response fibers and slow –
response fibers. This classification, however, is not permanent in the sense that a fast –
response fiber may become a slow – response fiber, or the other way around, depending upon
the pathological conditions of the fibers. For example, a fast – response fiber may become a
slow – response fiber if it subjected to hypoxia. It may then revert to a fast fiber when
hypoxia is corrected.

Fiber Type Properties

 Have RMP of – 90 mV
Fast – response fibers  When depolarized, produce rapid upstroke (phase 0) of action
potential
 Impulse conduction along these fibers is rapid (0.3 – 3 m/sec)

Slow – response  Have RMP of - 60 mV

fibers  When depolarized, produce slower upstroke of action potential
 The impulse conduction is much slower (0.1 – 1 m/sec)

Once a myocardial cell is activated (stimulated) by an appropriate stimulus, the rate of rise
(slope) of phase 0 of the action potential, and the velocity of conduction of this action
potential (impulse) is directly proportional the value of the initial RMP. In other words, the
more negative the RMP, the greater is the rise of phase 0 and the faster is the rate of impulse
conduction. The RMP of a fast – response fiber may be reduced under ischemic condition
(due to hypoxia or blood supply); conduction of impulse along these fibers is slowed down
and constitutes a “heart block”.

The myocardial action potential

An action potential is defined as the sequence of voltage changes occurring as a result of

changes in ionic conductances (i.e. the ease of flow of ions) across the cell membrane.

The myocardial action potential has five phases:

 Phase 0 (depolarization)
Have 2 components:
 The fast component
Mediated by the movement of Na⁺ through the “fast channels”
(in myocardium and purkinje fibers) that is voltage –
dependent. These fast channels are fully activated between -70
and -50 mV. As the depolarization progresses, these channels
are inactivated. The time course for inactivation is about 0.5
 P a g e | 60

millisecond. The reactivation of that voltage – dependent Na⁺

channels occurs in phase 3

 The slow component

Mediated by the inward movement of Ca⁺ through the “slow
channels” (especially in the SA node and AV nodal cells)

 Phase 1 (limited repolarization)

Presumed to be caused by Cl⁻ influx and partially to K⁺ efflux

 Phase 2 (plateau)
Due to the algebraic sum of the inward Ca²⁺ and the outward K⁺ current,
calcium channel are also voltage – dependent and is activated at -40 mV. The
time course for inactivation is 50 milliseconds. When calcium current ceases,
potassium outflow continues to cause phase 3

 Phase 3 (rapid repolarization)

Is due to the time – dependent outward current of K⁺ and during this phase,
the Na⁺ channels are reactivated

 Phase 4 (diastole)
Characterized by a restored intracellular K ⁺ concentration caused by Na ⁺ - K ⁺
- ATPase pump. The RMP remains constant in the myocardial cells and
purkinje fibers. However, spontaneous depolarization to threshold potential
occurs in the sinus and AV nodal cells due to progressive decrease in K⁺
permeability (or to slow inward movement of Na⁺ and Ca ⁺⁺). In these tissues,
the RMP becomes progressively less negative. The threshold potential is
eventually reached and an action potential is produced. The frequency of
discharge of action potential is determined by: (a) the distance between the
maximal diastolic potential (phase 4) and the threshold potential and, (b) the
slope of the diastolic depolarization (phase 4), that is the greater the slope, the
earlier the threshold potential is reached and thus more frequent firing.

The refractory period

Refractoriness is defined as the inability of an excitable tissue to respond to elicit action

potential. This can be absolute, relative, or effective.

 Absolute refractory period

At 0 to -60 mV, premature stimuli will not elicit action potential
 Relative refractory period
At -60 to -90 mV, progressive reactivation of the Na⁺ channels occurs.
Premature stimuli will elicit action potentials with slow response
characteristics
 Effective refractory period
Refers to a minimal interval between two propagating impulses
 P a g e | 61

With the foregoing short review, we are now ready to discuss specific drugs acting on the
heart. If you feel these are not enough, you may consult any reference on cardiovascular
physiology or your old notes in physiology for a more detailed discussion.

Digitalis Glycosides

The digitalis glycosides, also known as cardiac glycosides, are important drugs used for the
treatment of congestive heart failure. They have the ability to increase the force of
myocardial contraction and to increase cardiac output in failing heart.

Botanical sources of digitalis glycosides

All digitalis glycosides are derived from plants of similar species which are collectively
called “fox gloves” by the shape of their flowers. Shown below are active principles and their
plant species of origin.
PLANT SOURCES ACTIVE GLYCOSIDES
Digitalis purpuria Digitoxin, gitoxin, and gitalin
Digitalis lanata Digitoxin, digoxin, and gitoxin
Strophantus kombe Strophantin
Strophantus gratis Ouabain

The skin glands of some species of toad contain cardioactive poisons similar to cardiac
glycosides but they are of toxicological importance only.

Cardiovascular action of Digitalis Glycosides

The cardiovascular response to digitalis glycosides results from a complex of direct and
indirect actions on the heart.

The direct action of digitalis glycosides produces a positive inotropic effect (i.e. increased
force of heart contraction).

This effect includes:

 Increased force of myocardial contraction
 Increased rate of development of myocardial tension, and
 Decreased time of peak tension followed by faster relaxation

This positive effect of digitalis doesn’t seem too dependent upon adrenergic
stimulation; it is believed to be a consequence of inhibition of the sodium pump.

Digitalis binds with the sodium pump (Na⁺/K⁺-ATPase) at the binding site of K⁺ thus
preventing the active transfer of K⁺ back to the inside cell. Consequently Na⁺ is not moved
from the inside to the outside, at least not yet. How can this change lead to a positive
inotropic effect? Three explanation have been offered:

The following repolarization the sodium pump (Na⁺/K⁺-ATPase) returns Na⁺ to the outside
and K⁺ to the inside of the cell. A secondary sodium-calcium exchange mechanism is also
present in the cell membrane and removes intracellular sodium. When the sodium pump is
inhibited by digitalis, the calcium-sodium exchange becomes the predominant mechanism for
 P a g e | 62

extruding sodium from the intracellular calcium increases causing stronger myocardial
contractions in the failing heart.

In a resting (unexcited) cell, the intracellular calcium is normally exchanged for extracellular
sodium (that is sodium in; calcium out). Since intracellular sodium is increased when the
sodium pump is inhibited, there is lesser tendency for more sodium to flow in and for calcium
to flow out. Calcium then accumulates inside.
Most of the accumulated calcium is stored in the sarcoplasmic reticulum. Consequently,
greater amount of calcium is released from the sarcoplasmic stores during each about of
action potential, resulting in stronger force of myocardial contraction.

By a mechanism not clearly defined, increased inward calcium current occurs at phase 2 of
myocardial action potential.

The indirect action of digitalis glycosides is made through the parasympathetic autonomic
nervous system. This action effect the electrical activity of the purkinje, atrial and ventricular
fibers, which in turn influence the excitability and automaticity of the cardiac tissues.

Excitability is defined as the magnitude of an electric impulse required in producing an action

potential. More excitable cells require less electric impulse.

Digitalis glycosides have the following effects on the myocardium that influence
excitability:
 Decreased action potential duration (ADP)
 Decreased duration of phase 2
 Increased slope of phase 4
 Increased refractory period of atrial and ventricular myocardium
 Less negative resting membrane potential (RMP); decreased amplitude of the action
potential; decreased rate of conduction.

At toxic levels of digitalis glycosides, the RMP becomes markedly reduced (becomes much
less negative than usual) causing a further decrease in amplitude of action potential.
Remember that relationship between RMP and the rate of rise of action potential is that as
RMP decreases the rate of rise of action potential is also reduced (see above). This then leads
to reduced conduction velocity. Since under this condition the difference between RMP and
threshold potential is narrow, the myocardial fibers then become more excitable and take on
the properly of slow-response fiber.
Automaticity is the term to describe the behavior by which cardiac tissues spontaneously
generate action potential. The extracellular concentration of potassium ions influences the
action of cardiac glycosides on automaticity.

At low extracellular potassium concentration. [K], digitalis glycosides enhance automaticity.

At normal or high [K]˳ digitalis glycosides cause the appearance of after-depolarization, or
depolarization appearing immediately following repolarization. This may lead to abnormal
activity of the heart.

After-depolarization initially appears as subthreshold depolarization early during phase 4. As

toxicity progresses, after-depolarization progressively increase in amplitude and reaches the
threshold causing an additional action potential.
 P a g e | 63

This action potential then leads to an extra heartbeat called an “ectopic beat” (beat outside of
the normal cardiac rhythm).

Effect of Digitalis on the Electrical Activity of the Sino-atrial and Atrio-ventricular

Nodes

Most of the clinically important effect of a digitalis glycoside on the rate of formation of
impulses by the SA and AV nodes are due to its indirect action through the vagal
(parasympathetic) influences on the heart.

The pacemaker activity (spontaneous depolarization) of the SA node is slowed by

parasympathetic stimulation following digitalis administration. Knowing that the
parasympathetic nervous system has an inhibitory effect on the heart, we can expect that
there will be an increase in the refractory period and a decrease in the conduction velocity in
cardiac cells under digitalis effects.

The indirect vagal (parasympathetic) action specifically on the atria and ventricles is
believed to mediate the early effects of digitalis on conduction and refractoriness. This action
of digitalis on the atria and the ventricles also leads to a decrease in contractility (a negative
inotropic effect). This is indirect contrast to the desired effect of digitalis on failing heart.
Yes, this in true but the direct effect on the sodium pump is far greater that the indirect effect.

The direct positive inotropic effect, therefore, overshadows the indirect negative inotropic
effects on atria and the ventricles. It is clear then that the observed positive inotropic effect of
digitalis in a failing heart is the net effect of its direct and indirect actions.

The mechanism of the indirect vagal action of digitalis include:

 Direct stimulation of the centers in the brain

 Sensitization of the carotid sinus baroreceptors to changes in blood pressure, and

 Enhancement at the myocardial level of the response to acetylcholine.

Systemic effects of digitalis

Aside from its effect on the heart, digitalis glycosides also affect other organs. Their effect on
other organs are considered side effects, which may or may not be of benefit to the patient.
 P a g e | 64

 A minimal increase or even a slightly decrease in cardiac output.

On normal heart  Increased total peripheral resistance due to centrally stimulated
sympathetic vasomotor tone, and to direct vasoconstriction effect

 There is a definite increase in contractile vigour.

 The capacity is increased at any level of end-diastolic pressure
resulting in complete systemic emptying of the cardiac content.
 A reduction of heart size results from one efficient cardiac
On failing heart
emptying during systole
 The resulting hemodynamic adjustment eventually causes the
reduction of the compensatory sympathetic tone, and therefore
decrease systemic blood pressure

 Digitalis tends to cause diuresis when edema is present.

On the kidney  This diuresis id primarily due to the improvement of the failing
heart and not to a direct action on the kidney

 Gut disturbances characterized by anorexia, salivation, diarrhea,

and vomiting may be observed during therapy with digitalis
glycosides.
On gastrointestinal
 Vomiting may be due to direct irrritaion of the gut and to effect on
tract
the chemoreceptor trigger zone.
 Gut disturbances are commonly used as indicator of adequate
blood levels o digitalis in patients

On CNS  Minor CNS depression may be observe with digitalis.

Pharmacokinetics of digitalis glycosides

Administration and absorption

Digitalis glycosides are usually administered orally, and in fact oral administration is
preferred to injections. Ouabain, however, is given by injection only. For acute heart
failure ouabain is given by IV; acts in 3-10 minutes attaining peak action in 0.5-2
hours. IM injection causes irritation at injection sites. Oral administration especially
of digoxin and digitoxin is common in the usual clinical setting.

Digitoxin is more readily absorbed from the gut than digoxin. The rate of absorption
may be influenced by the specific pharmaceutical preparation of the drug. Example,
as digoxin tablets have onset of action of 15-30 min, peak in 6-8 hours. An alcoholic
solution or elixir of digoxin has a similar onset of action as tablet but peaks in 1-2
hours Elixir generally has poor shelf.
Distribution
 P a g e | 65

In the dog, digitoxin is bound to plasma protein to about 5 times greater than digoxin.
There is a greater likelihood of drugs interaction with digitoxin than with digoxin.
Digitalis glycosides cross-placental barrier but do not usually cause ill effects on the
fetus.

Elimination
Elimination of digitoxin and digoxin in dog is quite different from its elimination in
human beings. In human, digoxin is eliminated by direct renal excretion while
digitoxin is by hepatic metabolism. In dogs, both digoxin and digitoxin are eliminated
by both direct real excretion and hepatic metabolism. Digoxin and digitoxin have
similar half-lives in the dog, but have different half-lives in humans.

Clinical Uses

Congested heart failure (CHF)

Treatment with digitalis is an important part of therapy of CHF, also called dilated
cardiomyopathy (DCM). Therapeutic measures other than the use of digitalis
include reduction of dietary sodium intake, diuretic therapy, rest, etc.

For cardiac arrhythmias

Digitalis glycosides are drugs of choice for supra ventricular arrhythmias including
atrial tachycardia, atrial flutter and atrial fibrillation. While digitalis make atrial
myocardium more excitable, it at the same time effectively block or greatly reduces
the number of impulses being conducted through the A-V node, causing less number
of impulses reaching the ventricles than are produced in atria. Over- excitation of the
ventricles is thus prevented.
Digitalis is beneficial in the treatment of ventricular arrhythmias that are associated
with congestive heart failure (poor circulation, anorexia, and ventricular ectopic
beats), in which digitalis improves coronary artery perfusion and oxygenation.
Otherwise digitalis should not be used to treat ventricular arrhythmias.

Pre-surgery use
Digitalis may be used prophylactically in older animals to be operated on to pre-empt
possible heart failure under general anesthesia. This practice is controversial and is
not generally recommended.

Toxicity
Digitalis glycosides are one of the most dangerous drug groups in clinical practice,
having a relatively narrow safety margin. The dose for digitalization is about 40% of
the lethal dose. Cardiac arrhythmias are the most severe toxic effect especially
ventricular fibrillation. Hypokalemia is a common side-effect of digitalis. Important in
the pathogenesis of digitalis-induced cardiac arrhythmias is the depletion K⁺ from
cardiac cells. K⁺ depletion is exacerbated by factors that deplete body K⁺ such as
diuretics. Corticosteroids and prolonged diarrhea. Other factors increasing sensitivity
to digitalis are acidosis, hypoxia, hypothyroidism and catecholamines. Stopping
medication usually reverse usually reverses toxicity. Oral or parenteral K⁺ and an
appropriate antiarrhythmic agent may be needed in some cases.
Dosage
There is no fixed dose for the administration of cardiac glycosides (Digitalis). The
treatment of patients for congestive heart failure should be individualized and the
 P a g e | 66

recommended doses should be regarded as guide only. The dose may be decreased or
increased depending upon the clinical response of the patient. In view of the more
recent pharmacological studies the older techniques of rapid digitalization (loading)
now appear unwarranted. The therapeutic serum levels of digoxin may be attained in
the dog given the maintenance dose only as early as 8 hours after the second dose.
Hospitalization and rapid digitalization becomes unnecessary. To hasten digitalization
in more severe cases, however, a loading dose may be given. Digitalization is usually
accomplished in 7 to 14 days.

Dosage of digitalis glycosides for dogs

MAINTAINANCE
ROUTE DRUG LOADING DOSE (mg/kg) DOSE
(mg/kg)
0.11-0.22; ⅟4 of total dose given
Oral Digoxin 0.022 daily
q12h
0.44; ⅟4 of the total dose given
Oral Digitoxin 0.11 daily
q12h
0.022-o.o44 given in 3 divided
IV Digoxin Oral digoxin 0.011 q12h
doses over 24h
0.022-0.033 in divided doses
IV Ouabain Oral digoxin 0.01 q12h
over 24 h

The dose of digitalis glycosides may be based on body surface area (BSA) expressed in units
of m, rather than on body weight. To convert kg to BSA, use the formula: BSA (m) – kg
(0.112). The doses of digoxin for dogs based on BSA are (a) for loading dose: 0.66 mg/m and
for maintenance: 0.22 mg/m.

Doses for other species

 Cat:
 digitalization not recommended
 DIGITOXIN- not recommended
 DIGOXIN- oral 0.01 mg/kg

 Horse
 for supraventricular tachycardia: DIGITOXIN- oral 0.033-0.066 mg/kg;
DIGOXIN- oral 0.66 mg/kg IM, IV 0.022 mg/kg; OUABAIN- IM, IV 0.0132-
0.022 mg/kg
 Cattle
 For supraventricular tachycardia: DIGITOXIN- IM 0.031 mg/kg; DIGOXIN-
IM, IV 0.0132-0.022 mg/kg

ACE Inhibitors

One of the complications of congestive heart failure is hypertension, which may be treated
with hypotensive agents.

An angiotensin-converting enzyme (ACE) inhibitor

 P a g e | 67

 May be indicated for hypertension

 A carboxypeptidase enzyme that cleaves the C-terminal of angiotensin I which is then
converted to the more potent angiotensin II. Angiotensin stimulate vasoconstriction
leading to increase in blood pressure.

1. Captopril
The first ACE inhibitor to be developed but enalapril is the most commonly
used in animals. Other ACE inhibitor now available include lisinopril,
ramipril, perindopril and trandolapril (Note: captopril and lisinopril unlike
the others are not prodrugs and are therefore directly acting.)

2. Enalapril
A prodrug that is converted to the active enalapril, which competes with
Angiotensin I for ACE. Enalapril reduces the workload of the heart as a result
of both arterial dilation and reduced fluid retention. Enalapril is well absorbed
in the gut but has a slow onset of action (4-6h) with duration of 12-14h that
allows 2 times daily dosing. The dose must be reduced accordingly in case of
congestive heart failure and renal failure. Enalapril is indicated for treatment
of heart failure in dogs, and hypertension in dogs but not in cats. It is
contraindicated in dogs with known ACE inhibitor hypersensitivity.

Adverse reactions to enalapril include:

 GI distress (anorexia, vomiting, and diarrhea)
 Lethargy
 Hypotension
 Anemia
 Angioedema, and
 Vasculitis.

It is not to enalapril is given with potassium-sparing diuretics, metformin, and

high
doses of potassium penicillin

Dose of Enalapril

Dog: 0.5 mg/kg oral q12-24h

Cat: 0.25 mg/kg to 0.5 mg/kg oral q12-24h

Antiarrhythmic Drugs

Arrhythmia is any deviation from the normal heart rate and rhythm. Not all arrhythmias are
pathologic. Some may be present but may not require treatment. Many are fatal. Arrhythmias
occur more frequently than you think, especially in small animals (dog and cats). If an
arrhythmia is of a type that need to be treated, then knowledge of important prerequisites to
effective therapy is in order. These include: accurate diagnosis (more of this will be learned
in Medicine courses), and good knowledge of antiarrhythmic drugs (our concern in
Pharmacology).
 P a g e | 68

General classification Of Arrhythmias

 Paroxysmal atrial tachycardia

Supraventricular (atrial, AV nodal)  Atrial flutter
 Atrial fibrillation
 Premature ventricular contraction
Ventricular  Ventricular tachycardia
 Ventricular fibrillation

Requirement for a “Normal” Cardiac Rhythm

 The impulse must be sinus origin. That is, the sino-atrial node must be the pacemaker.
 The frequency of sinus impulse must be within an optimal range. For example, 80-
120 beats/minute in dogs.
 The rate of contraction must occur at regular interval. However, dogs normally show
group of regularly spaced impulses separated from similar group by longer interval.
This separation occurs regularly in association with breathing. This is termed as
“regularly irregular: rate.
 Every sinus impulse must be transmitted through the AV node
 There must be a normal intraventricular transmission.
 Any deviation from this normality constitutes an arrhythmia.

Diagnosis of Arrhythmia

 Cardiac arrhythmia should be suspected in cases of:

 Metabolic diseases such as diabetes mellitus and hyperthyroidism
 Heatstroke
 Physical trauma
 Infections
 Collapse, seizures, coma and sudden death

Screening for arrhythmia may be done by auscultation (listening to body sounds with
stethoscope).
Listen for abnormal heart sounds and correlate their occurrence with respiration. Each
heartbeat should cause a femoral pulse. Look for any pulse deficit (heartbeat without
corresponding femoral pulse). A jugular pulse, when present, is abnormal.
Electrocardiography (ECG) is the most specific way to diagnose cardiac arrhythmias.

Remember however that”:

a. Form of arrhythmia with similar ECG profile may have different causes
b. Pharmacological actions of anti-arrhythmic drugs vary
c. Anti-arrhythmic drug may cause arrhythmia themselves, and
d. The effects of theses drug depend in part upon the underlying state of cardiac cells.

Causes of Arrhythmia

 Abnormal impulse generation or altered automaticity

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The term automaticity is used to describe the behavior by which cardiac fibers
spontaneously generate action potential. It is a feature common to all cardiac
conduction tissue (including the myocardium), and is believed to be related to
the slow inward movement of calcium ions. Abnormal impulse generation
maybe one of four types.

ENHANCED NORMAL AUTOMATICITY

This is characterized by enhanced responsiveness to catecholamines, which

then increase Ca⁺⁺ conductance during diastole (sinus and atrial tachycardia).

 Abnormal Automaticity

The myocardial cells may acquire the property of automaticity as a result of

decreased resting membrane potential (RMP) [Hypoxia results in decreased
Na-K-ATPase activity and to reduced RMP] Oxygen therapy must be
considered in the treatment of arrhythmias.

 Triggered Activity

After-depolarization reaching threshold potential which result in repetitive

firing of the cell (probably due to large increase in intracellular Ca⁺⁺).

 Sick-sinus syndrome

The vagal activity increase K⁺ conductance (outward current) which

repolarizes the cell

ABNORMAL IMPULSE CONDUCTION

Conduction
Refers to the progression movement of an action potential from on area of
myocardium to another. A unidirectional block is required for the re-entry mechanism
to occur.

Slow impulse

Unidirectional block

Re-entering impulse

Cardiac stretch and local tissues hypoxia may reduce the speed of impulse conduction
through segments of myocardium, resting in the re-excitation of recently depolarized, but no
 P a g e | 70

longer refractory, tissue. This phenomenon, known as re-entry, is responsible for coupled
beats (called bigeminy) and AV nodal and ventricular tachycardia.

Classes of Anti-arrhythmic Drugs

Class I
Membrane Stabilization drugs Divided into three Subclasses

Members of this class reduce inward Na⁺ current

and bring about the following:  Quinidine
 Decreased conduction velocity (decreased  Procainamide
maximum rate of depolarization and action  Disopyramide
potential amplitude)
Subclass IA  Increased threshold potential
 No effect on RMP
 Decreased slope of phase 4
 Little effect on abnormal automaticity
 Increased effective refractory period, and
prolongs duration of action

 Lidocaine
Members of this class increase the outward K⁺  Phenytoin
current and bring about the following:  Tocainide
 Increased conduction velocity  Mexiletin
 Increased threshold potential  Aprindin
 Hyperpolarization of cells having reduced RMP’s
Subclass IB such as due to hypoxia and anemia
 Decreased slope of phase 4
 A major effect on abnormal automaticity
 A minimal decrease in effective refractory period
and a minimal shortening of action potential
duration

 Encanide
Membrane of this class have action and effects as  Lorcainide
those in subclasses IA and IB but with very little  Flecainide
Subclass IC
effect on refractoriness and on action potential  Propafenone
duration

Class II
The antiarrhythmic effect of this group results from  Propranolol
a selection ꞵ-adrenergic blocking action (can also  Timolol
increase the outward K⁺ current and decrease the  Alprenolol
inward Na⁺ current). Member of this class produce  Pindolol
the following effects:  Metotrolol
 Decrease conduction velocity at very high doses
 Competitive blockade of enhanced automaticity
resulting from adrenergic stimulation.
 Increased the effective refractory period and the
 P a g e | 71

action potential duration of the AV node


Class III
Their major effect is to lengthen action potential  Bretylium
Inhibitors of
duration and refractory period primarily in the  Amiodarome
Norepinephrine
Purkinje fibers and ventricular myocardium  Sotalol
release
 Verapamil
Drug belonging to this class:  Nifedipine
 Block Ca⁺⁺ entry into myocardium cells  Diltiazen
 Have no effect on inward Na⁺ current
 Restore normal intracellular Ca⁺⁺ [Diltiazem, having
concentration. little antiarrhythmic
 Have greater utility in supraventricular affect, is also used
Class IV as antifungal agent
Calcium entry arrhythmias where slow calcium current has
in humans]
blocker greater influence on action potential of the AV
node than that on the ventricle
 Affectively suppresses ventricular rate in atrial
flutter and fibrillation (see similar effect of
digitalis).
 Have supplement or replaced digitalis and
propranolol for these arrhythmias


Individual Antiarrhythmic Drugs of Proven Useful in Veterinary Medicine

1. QUINDINE SULFATE
A dextro-stereoisomer o quinine, an antimalarial drug

Direct action
 Decreases maximal rate of phase 0
 Decreases slope of phase 4
 Decrease spontaneous depolarization of Purkinje fibers, but spares the
automaticity of the SA node (controls automaticity)
 Prolongs the effective refractory period of atrial and ventricular myocardium
without affecting the normal pacemaker cells (controls atrial fibrillation)

Indirect action
 Atropine-like vagolytic action
 Contributes to the effectiveness of treating atrial tachyarrhythmias
 May increase ventricular rate (especially when given IV)

Pharmacokinetics
 P a g e | 72

Usually given orally, quinidine is absorbed rapidly (in 60 to 90 min). It is

biotransformed in the liver and excreted in urine. Half-life varies with species:
dog-6h, pony -4h, cat- 19h

Clinical use
For atrial fibrillation in dogs and horses: also for ventricular premature beats.

Adverse effects
 Cardiac depression- AV block, windened QRS complex
 Decreased cardiac output, hypotention
 Extra-cardiac effect- gastrointestinal upset, CNS depression, anaphylactic-like
reaction has been reported in the horse

2. PROCAINAMIDE
Action
 Has direct actions similar to quinidine but the indirect effects are not
pronounced
 More effective in controlling ventricular arrhythmias

Pharmacokinetics
 Absorbed rapidly from GI tract
 Liver metabolites may be cardioactive; excreted rapidly in urine

Clinical Use
For ventricular ectopic beats or ventricular tachyarrhythmias.

Adverse Effects
Similar to those of quinidine, but with less GI effects.

3. LIDOCAINE (without epinephrine)

Action
 Improves conduction and shortens action potential duration in Purkinje fibers
and myocardium
 Not effective in controlling supraventricular arrhythmias

Pharmacokinetics
 Absorbed well when given orally, but cause severe GI disturbance
 Given as bolus IV injection 2% solution for immediate effect (lasts for 10-20
min.), then by slow drip for more sustained effect
 Biotransformed in the liver

4. PHENYTOIN (Diphenyldantoin)
Action
Similar to lidocaine; also used as inti-septic.

Pharmacokinetics
 Absorbed slowly from GI tract
 Rapid biotransformation in dogs

Clinical use
 P a g e | 73

 Especially good for digitalis-induced ventricular arrhythmias (drug of choice)

 More intelligent use of digitalis has supplanted this use of phenytoin

Adverse effects
Sedation; when given IV, sinus bradycardia, ventricular fibrillation and arrest.

5. PROPRANOLOL
Action
Antiarrhythmic action due to adrenergic blocking effect (decreased
spontaneous firing in SA node)

Pharmacokinetics
Well absorbed orally, extensive first-pass effect (hepatic metabolism)

Clinical uses
 for severe atrial fibrillation unresponsive to digitalis
 sinus tachycardia associated with anesthesia
 ventricular arrhythmias
 hypertrophic cardiomyopathy

Adverse effects
Bradycardia, hypotension, bronchoconstriction; Dangerous to use in heart
congested heart failure.

DOSAGE

Dog 6-20 mg/kg p.o. q8h

QUINIDINE
Cat Not Recommended

6 mg/kg p.o. q4h; 6 mg/kg IV bolus followed

by
PROCAINAMIDE Dog
10-40 mcg/kg/min continuous IV infusion;
8-10 mg/kg IM

Dog 4 mg/kg IV bolus, followed by 50 mcg/kg/min

LIDOCAINE continuous IV infusion

Cat 0.25-0.5 mg/kg IV given over 5 min

4-8 mg/kg p.o. divided 3-4x daily; 4 mg/kg

PHENYTOIN Dog
slow IV

Dog 0.5-1.0 mg/kg p.o. q6h; 0.05-0.15 mg/kg IV to

PROPANOLOL effect
Cat 2.5-5 mg/kg p.o. for <6 kg b.w. q8-12h
 P a g e | 74

Lesson 05

Diuretic Agents

D iuretics are drugs that increase urine output, with enhanced excretion of
electrolytes and water. They are used to remove edema fluids of various causes.

A functional kidney is required for diuretics to be effective.

A Short Review of Renal Physiology

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The formation of urine involves three main physiological processes namely

glomerular filtration, tubular reabsorption, and tubular secretion.

Glomerular filtration

In a normal nephron there is a net force of about 25 mmHg that tends to push fluid out
of the glomerular capillaries into the glomerular capsule. About 99 percent of the
glomerular filtrate is normally reabsorbed across the renal tubular epithelium. It is
therefore a rather inefficient attempt to produce a diuretic effect by influencing the
glomerular filtration rate (GFR). Certain drugs, however, produce diuresis by virtue of
their action on glomerular filtration. Examples of such drugs are the xanthine
derivatives (theophylline and caffeine) and the cardiac glycosides (digoxin, digitoxin),
which produce diuresis by their influence on renal blood flow.

Tubular reabsorption

Tubular reabsorption of sodium is the most important process influencing the final
volume and concentration of urine. The proximal convoluted tubules are responsible
for 66 percent of the sodium glomerular filtrate reabsorbed by the kidney.

Sodium ion diffuses across the luminal membrane of the proximal convoluted tubular
epithelium. It is subsequently transported actively across the basolateral membrane by
the sodium pump into the interstitial fluid, from which it diffuses into the capillaries.
Chloride ion and water follow Na + to maintain ionic and osmotic equilibrium. Aside
from diffusion with chloride (quantitatively the most important), sodium reabsorption
is also facilitated by co-transport with uncharged substances or acidic anions, and by
counter-transport with hydrogen ions. Reabsorption of bicarbonate, glucose, amino
acids, and other organic solutes also occurs in the proximal convoluted tubules.

The cells of the descending loop of Henle are relatively impermeable to sodium,
chloride, and potassium. Water is reabsorbed in the thin portion of the descending
limb of the loop of Henle due to the osmotic forces generated in the hypertonic
medulla interstitium. The ion transports in the ascending loop of Henle are critical
for proper function of the countercurrent mechanism in the renal medulla. The
ascending loop tubule is not permeable to water, and the fluid in the lumen becomes
progressively diluted. The counter-transport between sodium and hydrogen ions does
not appear to occur in the loop of Henle, and little if any bicarbonate is processed.

In the distal convoluted tubules, reabsorption of Na+ also occurs but little or no
water is reabsorbed. The rate of sodium reabsorption at this site is less than in the
ascending limb. Na+ is reabsorbed in exchange for K + at the collecting duct. This
exchange transport is driven by aldosterone, a mineralocorticoid secreted by the
adrenal cortex. Here, there is a direct relationship between Na + reabsorption and the
secretion of H- and K+. Calcium is actively reabsorbed at this site under the influence
of the parathyroid hormone (PTH).

The wall of the collecting duct becomes permeable to water in the presence of
antidiuretic hormone (ADH or vasopressin, secreted by the posterior pituitary). When
 P a g e | 76

this happens, water is reabsorbed due to the hyperosmolarity of the medullary

interstitium.

Tubular secretion

Tubular secretion is an active process, which occurs mostly in the proximal tubule.
There exist separate secretory mechanisms for organic acids and organic bases.
Inhibition of these mechanisms may affect drug excretion, but is not important in the
action of diuretics.

Atrial Natriuretic Hormone

Atrial natriuretic hormone (ANH), first described in 1984, is involved in the control
of ECF. It is synthesized from a prohormone and stored as a peptide in granules of in
atrial myocardial cells. Concentration increases above baseline when ECF expands,
blood pressure increases, or dietary salt intake increases. Renal blood flow and
glomerular filtration are subsequently increased. Sodium excretion also increases,
presumably by a direct tubular action of ANH. Peripheral vasodilation can result in
decreased blood pressure. Effects occur rapidly but are not sustained, suggesting that
ANH is a mechanism that can store equilibrium rapidly.

Clinical Uses of Diuretics

Diuretics are used to remove edema fluids caused by various disorders. Three
strategies exist for movement of inappropriate fluid accumulation (edema).

Three approaches to the treatment of edema:

 Correction of underlying disease (often not possible)
 Restriction of dietary or other sodium intake
 Administration of diuretics

Of these, the administration of diuretics remains the cornerstone for treatment of

edema or volume overload.

Therapeutic indications for diuretics include:

 Maintenance of urine flow
 Mobilization and reduction of inappropriate ECF stores such as that
manifested as edema
 Correction of specific ion imbalances
 Reduction in the rate if intraocular fluid formation causing glaucoma
 Reduction of blood pressure, and
 Reduction of pulmonary blood pressure

Classification of Diuretics
 P a g e | 77

Diuretics are classified by their mechanisms of action and include loop diuretics, carbonic
anhydrase inhibitors, thiazides, osmotic diuretics, and potassium-sparing diuretics. Rational
selection of diuretics is based on the appreciation of their mechanisms of action. All diuretics,
except the osmotic diuretics and carbonic anhydrase inhibitors, target sodium or chloride
reabsorption by tubular cells, effectively preventing the normal ion gradient by renal tubular
cells. Diuretics that increase net urinary excretion of sodium chloride or sodium bicarbonate
are referred to as natriuretic.

 OSMOTIC DIURETICS

 Mannitol
Mannitol is the most useful osmotic diuretic. Following intravenous injection,
mannitol is filtered at the glomerulus. Since it is not reabsorbed by the renal
tubules, it remains in the renal tubular fluid and osmotically attracts large
volumes of water, which is flushed through the kidney.

The most common indication for mannitol is to relieve cerebral edema to

reduce the pressure and volume of the cerebrospinal fluid. It is not used in
most other edematous states because of its weak tendency to rid the body of
edema fluid. Other clinical uses of mannitol include prophylaxis of acute renal
ischemia and acute changes in renal tubular permeability excretion of certain
poisons, may be due to noxious substances. Mannitol may be administered to
evaluate acute oliguria and to encourage urine output in conditions of low
glomerular filtration rate and reduced urine flow. It is contraindicated in
cardiovascular shock as it can worsen cardiovascular hypovolemia.

Mannitol is relatively safe. However, it can cause cardiovascular overload if

not excreted, and it also induces minor histopathological changes such as
vacuolization of kidney cells.

 DIURETICS THAT INCREASE GLOMERULAR FILTRATION RATE

This group include the xanthine derivatives such as Caffeine, Theophylline,

Theobromine and Aminophylline, and the cardiac glycosides Digoxin, Digitoxin,
and Ouabain. This group of diuretics increases GFR through their action on renal
circulation. They may inhibit sodium reabsorption but cause relatively mild diuresis
and potency may vary with the drug and with the animal species.

Xanthine derivatives have other actions not directly related to diuresis. CNS
stimulation, cardiac stimulation, and bronchodilation.

Digitalis glycosides exert their diuretic effect by improving the blood circulation in
patients with failing heart. They do not cause diuresis in patients without congestive
heart failure.

 CARBONIC ANHYDRASE INHIBITORS

 P a g e | 78

Examples of carbonic anhydrase inhibitors include Acetazolamide,

Dicholorphenamide, Methazolamide, and Ethoxolamide. They inhibit carbonic
anhydrase in renal tubular cells which results in a decreased production of H+ for
Na+/H+ exchange. Thus, Na+ remains in the tubular urine and attracts water
osmotically causing diuresis. Carbonic anhydrase inhibitors cause large loss of
sodium bicarbonate and water. The characteristic large outpouring of bicarbonate ions
results in alkaline urine and ultimately, in systemic acidosis. Systemic acidosis
reduces the response of the patient to the action of carbonic anhydrase inhibitors.

Carbonic anhydrase inhibitors reduce the rate of production of aqueous humor in the
eye and are useful in treating glaucoma. They also have some anti – epileptic action
but are not used for this purpose. The major clinical use of carbonic anhydrase
inhibitors is to relieve increased intra – ocular pressure in glaucoma. For certain
edematous state, they are used as an adjunct to a more powerful diuretic.

Acetazolamide has also been used to remove udder edema in dairy cows. When
injected, it causes minor pain at injection site.

 THIZIDES

Examples
Chlorthiazide Hydrochlorthiazide
Hydroflumethiazide Bendroflumethiazide
Benzithiazide Trichlomethaizide
Methychlorthiazide Metholazone
Quinethazone Chlorthalidone
Polythiazide Cyclothiazide

Thiazides are believed to inhibit Na+ and Cl- reabsorption in the early
distal tubule of the nephron. The mechanism of this inhibition is not
fully known but his action may be related to inhibition of ATPase
activity. They produce pronounced diuresis which the carbonic
anhydrase inhibitors is independent of the acid – base status. Thiazides
have a tendency to develop hypokalemia due to large loss of
potassium. Hyperglycemia (presumably due to inhibition of insulin
secretion), hypomagnesemia, and hypercalcemia are also observed
with thiazides.

 LOOP DIURETICS

Examples:
Furosemide Ethaycrynic acid
Bumetanide Muzolimine

Loop diuretics inhibit Na+ and Cl- reabsorption throughout the nephron but especially
in the ascending loop of Henle. They produce extremely potent and sustained diuresis.
The diuretic effect is seen within 30 min. after oral administration and peaks in 1 – 2
h; within 10 – 15 min. after IM or IV, peaks in 30 – 45 min. the effect may last for 6 –
8 h. About 30% - 40 % of Na+ filtered is lost in urine. Large Cl- loss may lead to
 P a g e | 79

hypochloremic alkalosis but diuretic effect is not diminished. Potassium loss is a

major side effect.

Loop diuretics are used to treat most edematous conditions but may have adverse
effects in the form of volume and electrolyte disturbances and ototoxicity (deafness).
Because of the latter, these drugs should not be used with known atotoxic agents such
as the aminoglycoside antibacterial.

 POTASSIUM – SPARING DIURETICS

 Spironolactone

Competitively inhibits aldosterone in the collecting duct region. Na+/K+

exchange in this region is impaired and sodium remains in the tubular urine. It
is not too useful as a sole diuretic but useful in combination with potassium –
depleting diuretics such as thiazides and loop diuretics. The onset of action
is 2 -3 days. There is a rapid development of tolerance (reduced effect).

 Triamterene

Acts on the collecting duct but its action is not associated with aldosterone. It
is a weak diuretic when used alone but when combined with a thiazide, the
effect is more effective than that caused by either drug.

 Amiloride

Directly inhibits the reabsorption of sodium and promote the conservation of

potassium. Its action is not associated with aldosterone. It is rarely used alone
but is used in combination with thiazides or loop diuretics

DOSAGES

Dog/Cat 10 mg/kg oral QID (for metabolic acidosis

Dog 2 – 5 mg/kg oral TID (for glaucoma)
Acetazolamide Cat 50 mg/kg IV once; 7 mg/kg oral TID
Horse 2.2 mg/kg oral BID – TID
Cattle 6 – 8 mg/kg oral in food or water
Dose is not yet established but 1 mg/kg has
Amiloride
been used successfully in sheep
Dog/Cat 20 – 40 mg/kg oral BID
Chlorthiazide Dog 2 – 4 mg/kg oral BID – TID
Cat: 1 mg/kg oral BID – TID
Ethacrynic Acid Dog/Cat 0.2 – 0.4 mg/kg IM, IV q4 – 12 h
Ethoxolamide Dog: 2 – 15 mg/kg/24h oral; in divided doses
Hydroflumethazin Dog 1 mg/kg oral q12 h
e
Hydrochlorthiazid Dog/Cat 2 – 4 mg/kg oral BID
e Horse 0.5 mg/kg oral BID
Mathazolamide Dog 1 – 2 mg/kg/24 h oral
 P a g e | 80

Spironolactone Dog/Cat 1 – 2 mg/kg oral BID

Triamterene Dog 1- 2 mg/kg oral BID

Dog 2 – 4 mg/kg oral, IM, IV BID – TID

(for diuresis heart failure)
Cat 1 – 4 mg/kg oral IM, IV, SC BID – TID
(for diuresis – heart failure)
Dog/Cat 1 – 2 mg/kg oral, SC, OD – BID
(for ascites from liver
failure);
1 – 2 mg/kg IM, IV, BID – TID
(for diuresis –
Furosemide hypercalcemia);
5 – 20 mg/kg IV PRN
(to initiate diuresis in acute renal
failure)
2 – 4 mg/kg oral IM, IV q4 – 12 h
(for pulmonary edema);
1 – 2 mg/kg oral BID (for hypertension)

Horse 1 – 3 mg/kg IM, IV BID

Ruminants 2.2 – 4.4 mg/kg IV BID
Dog/Cat 1 – 2 g/kg IV q6h; OR
1 – 2 mg/kg of a 5 – 10% solution given
by IV infusion at 4 ml/min, 15 minutes or
to effect; alternatively,
Mannitol
250 – 500 mg/kg is administered IV as a
(20% Sol)
test dose.
This is to be repeated if diuresis occurs
Horse 0.25 – 2 g/kg slow IV
Ruminants 1 – 2 g/kg IV
 P a g e | 81

Lesson 06

Drugs Affecting
Blood Coagulation

T here are two general classes of drugs affecting blood clotting – hemostatic and
anti – hemostatic. Hemostatics are drugs used to prevent or attenuate bleeding
which can be given topically or systematically. Anti – hemostatics are used to
limit the formation of thrombi and are categorized into:
 Anti – coagulants drugs that prevent blood coagulation
 Fibrinolytics (thrombolytics) are drugs that increase the activity of plasmin
(fibrinolysin), the endogenous compound that is responsible for dissolving clots; and
 Anti – thrombotics (anti – platelet agents) are drugs that control platelet activity
Hemostasis is the spontaneous arrest of bleeding from damaged blood vessels. I’m sure you
have experienced bleeding from a minor cut from the skin. Granting that you are not a
hemophiliac (bleeder), you would notice that bleeding from a minor skin cut eventually stops
even though you did not do anything about it. Save for a mild inflammation, you’d be alright.
At first, the damaged blood vessels go into spasm (severe constriction) in an attempt to close
the cut ends blood vessels and thus reduce further blood loss. Then the platelets (also called
thrombocytes) stick to the exposed collagen of the blood vessels to form a plug. This platelet
plug is not very stable so that it needs to be reinforced with fibrin, forming blood clot.
Fibrin formation occurs in three stages:

1. Activation of factor X
 P a g e | 82

a. Damage to blood vessels exposes the negatively charged collagen. If this may
sound familiar, it’s because I’ve mentioned this in a previous lesson. You
recall that Factor XII or Hageman Factor is activated to XIIa upon exposure of
the exposed collagen and other surface factors. (Note: “a” means activated). It
is also activated by the action of Kallikrein (ka) in the presence of high
molecular weight kininogen (HMW – K) or Fitzgerald Factor.

b. XIIa, in the presence of HMW – K, activates more prekallikrein (or Fletcher

Factor) to kallikrien. At the same time, XIIa activates more inactive Factor
XII, and also Factor XI (or Plasma Thromboplastin Antecedent, PTA) to Xia.

c. Xia in the presence of Ca2+ proteolytically activates Factor IX (Christmas

Factor or Plasma Thromboplastin Component, PTC) to IXa.

d. IXa, in the presence of Factor VIII (Antihemophilic Globulin), Ca2+, and

phospholipid micelles (PL), activates factor X (Stuart Prower Factor) to Xa.

2. Formation of Thrombin
Factor Xa with factor V (Proaccelerin), Ca2+ and phospholipid, activates Factor II
(Prothrombin) to IIa (Thrombin).

3. Formation of Thrombin

a. IIa removes two pairs of small peptides from factor I (Fibrinogen)

followed by aggregation of soluble Fibrin (Factor I’)

b. IIa also activates Factor XIII (Fibrin Stabilizing Factor) to XIIIa

c. XIIIa then promotes cross – linking of the fibrin monomers into insoluble
fibrin clot (Factor I’’)

What has just been described is the intrinsic system of blood coagulation which has
all the necessary factors contained within the circulation. Another system, the
extrinsic system, operates when blood is exposed to tissue factors outside of the
circulation during tissue damage.

The extrinsic system is faster in forming blood clot than the intrinsic system. During
tissue injury, when blood escapes from the blood vessels faster blood clotting occurs.
The formation of Xa takes several minutes in the intrinsic system while it takes much
less time in the extrinsic system.

Both systems must be intact for hemostasis to occur.

a. (Proconvertin) is activated to VIIa by Xia and ka, which are all from the
intrinsic system
b. VIIa, in the presence of Factor III (Tissue Thromboplastin) and Ca2+,
activates X to Xa
c. The next steps are identical to that of the intrinsic system
 P a g e | 83

Blood can coagulate inside the blood vessels

In our normal day – to – day, blood vessels are subjected to some forms of stress such
as from increased blood flow and pressure, pressure from sitting too long on a hard
surface, ischemia due to transient lack of blood flow, etc. these factors may cause
some slight damage to vascular endothelium (but without escape of blood), which
triggers the intrinsic system leading to coagulation. The resultant intravascular
clotting, an attempt to repair the damage, is very well regulated.

Thrombus or intravascular clot will form if intravascular clotting is not regulated

Thrombus (pl. thrombi) when formed can block blood flow to tissues. Small pieces
of the thrombus may chip off (now called embolus; pl. emboli), be carried away in
circulation to block tiny vessels in vital organs. This is really life – threatening. The
body has intrinsic mechanisms to regulate blood clotting and prevent thrombus
formation.

These mechanisms are:

1. Inhibition of fibrin formation and
2. Lysis of formed fibrin.

Inhibition of fibrin formation may be accomplished in two ways:

a. One way to inhibit fibrin formation is mediated by the plasma proteins: α – 1
antitrypsin, α – 2 macroglobulin, α – 2 antiplasmin, and antithrombin. These
proteins rapidly inactivate coagulation proteins (factors) as they are released
from injured vessels.

Disseminated intravascular coagulation (DIC) occurs when activated

coagulation factors overwhelmed these fibrin – inhibitory proteins. DIC may
occur during massive tissue injury, cardiovascular shock, and bacterial sepsis.

b. Another way of fibrin is through the action of thrombin. We have seen

thrombin (Factor IIa) as favoring the formation of blood clot by converting
fibrinogen to fibrin. When circulating thrombin binds with a protein receptor
called thrombomodulin which is present in vascular endothelial cells,
thrombin is modified such that it is now able to activate the substance called
protein C. Protein C, together with Protein S and phospholipid complex,
inactivates Factor VIIIa (antehemophilic globulin) and factor Va
(proaccelerin). This leads to failure of fibrin formation
Fibrin, once formed, may be removed (fibrinolysis)

Fibrinolysis is mediated by plasmin. Injured cells release inactive plasminogen which

is then converted to plasmin. Here’s how: kallikrein which had been activated from
prekallikrein by Factor XIIa, converts plasminogen to plasmin either directly or
through the activation of plasminogen activator protein which in turn converts
plasminogen to plasmin. Plasmin, once formed, can itself activate more plasminogen.
Exogenous streptokinase also converts plasminogen to plasmin.
 P a g e | 84

Normally, plasmin remodels the thrombus by proteolytic digestion of formed fibrin. α

2-Antiplasmin inactivates plasminogen. Under normal conditions, there is a good
balance between anti – coagulation and pro – coagulation in the body.

Fibrinolytic agents are used clinically:

 Streptokinase and streptodornase

Synthesized by streptococcal organisms.

 Urikinase
Prepared from culture of human renal cells

These three enzymes are used in the treatment of wounds that do not respond to:
a. Antibacterial therapy
b. Burns
c. Ulcers,
d. Chronic eczemas
e. Ear hematomas,
f. Otitis externa,
g. Osteomyelitis,
h. Chronic sinusitis
i. And other chronic lesions.

They are available as powders for local or systemic administration

Tissue plasminogen activator (tPA)

Activates plasminogen bound to fibrin. Its use should be limited to limited to
case of thrombosis (rather than prevention).

Cost and lack of refined doses and selectivity have limited the use of
thrombolytic drugs for treatment of thromboembolism in dogs and cats (and
other animals).

SYSTEMIC HEMOSTATICS (PROCOAGULANTS)

Normal blood
Fresh serum is indicated for emergency treatment in cases of acute –
hemorrhagic syndrome due to deficiency of clotting factors and in
thrombocytopenia.

Vitamin K
Vitamin K is required (as a cofactor) for the ϓ-carboxylation of glutamic acid
residues in Factors II, VII, IX and X. without this carboxylation, these
coagulation factors are not functional. The absorption of vitamin K may be
inhibited by intestinal disorders but can be enhanced by fat. Its utilization in
 P a g e | 85

the synthesis of the clotting factors is impaired in liver disease. The coumarin
anti – coagulants including bishydroxy – coumarin and warfarin interfere
with the role of vitamin K in the synthesis of active clotting factors II, VII, IX,
and X.

Vitamin K is used as an antidote to coumarin group of anticoagulants and to

prevent hemorrhage secondary to liver failure. It is used in poultry for vitamin
K deficiency associated with sulfonamide and other antimicrobial therapy
which are known to cause abnormality in blood coagulation. Vitamin K is not
effective in countering heparin – induced anticoagulation.

Forms of Vitamin K
1) Vitamin K1 (Phyloquinone or phylotonadione)
If plant origin; the only natural vitamin K available for
therapeutics use; can be given orally or parenterally. It
is more effective than other analogues. Anaphylactic
reactions have been observed with intravenous
administration, perhaps due to the carrier substance
such as polysorbate 80, a known histamine releaser.

2) Vitamin K2 (Menaquinone)
A natural metabolite of gut microorganisms.

3) Vitamin K3 (Menadione)
The synthetic form and must be metabolized to active
form. It is usually absorbed too slow to be used
effectively in acute conditions, but it can be used for
chronic therapy once the acute crisis has been resolved.

Protamine sulfate
A low molecular weight protein found in certain fish. It forms stable salt with
acidic heparin, and is used only to antagonize heparin-induced hemorrhages.
When used otherwise, protamine has anticoagulant properties interfering with
the reaction of thrombin and fibrinogen.

Desmopressin
A synthetic analogue of vasopressin used to treat central diabetes insipidus,
also transiently elevates serum concentration of von-Willebrand factor (VWF).
[Also called Factor VIII-related antigen, VWF circulates as a complex with
Factor VIII, and mediates platelet adhesion to subendothelial surfaces – the
first step in clot formation]. Desmopressin causes the release of preformed
VWF from endothelial cells and macrophages. However, repetitive
administration results in depletion of storage pools and loss of procoagulant
effect. The peak response to desmopressin is 1-2 hours after treatment.

LOCAL HEMOSTATICS

Local or tropical hemostatic drugs may be classified as:

1. Clotting factors
 P a g e | 86

2. Artificial matrices
3. Astringents, and
4. Local vasoconstrictors

Lyophilized concentrates of one or more clotting factors

Usually provide an artificial factor or structural matrix that facilitate clotting.
An intact hemostatic mechanism is necessary for their efficacy. These are
absorbable products and are indicated for capillary oozing from small
superficial vessels.

Examples are:
o Thromboplastin
o Thrombin, and
o Fibrinogen.

Examples of artificial matrices include:

o Absorbable gelatin sponge and
o Oxidized cellulose.

Astringents
Act locally by precipitating proteins. These agents do not penetrate tissues and
thus are restricted to surface cells. They can be damaging to surrounding
tissues.

Examples are:
o Ferric sulfate
o Silver nitrate and
o Combinations that include tannic acid.

Epinephrine and norepinephrine

Hemostatic drugs by virtue of their vasoconstrictive effects. They are included
in topical medications to decrease blood flow to the tissues.

Thromboplastin USP
Used as a local hemostatic in surgery; available as spray or direct application
in sponge.

Thrombin USP: One NIH unit equals thrombin required to clot 1 mL of

standard fibrinogen solution in 15 minutes. It is used for control of bleeding
from parenchymatous tissues, cancellous bones, dental sockets, laryngeal and
nasal surgery. Available as powder or solution.

Fibrin foam
Applied directly to hemorrhagic area

Absorbable gelatin sponge USP

 P a g e | 87

Absorbs blood several times its weight and is applied on bleeding area
following closure of surgical wound. It liquefies in 3 to 5 days and is absorbed
in 4 to 6 weeks. It is used for capillary of venous bleeding.

Oxidized Cellulose USP

Is used as temporary packing of bleeding points

ANTI - COAGULANTS

Anticoagulants interfere directly or indirectly with the clotting cascade. Several in

vitro anti - coagulants are used for blood collection intended for transfusion therapy
and laboratory examination and should be considered as drugs. All, except heparin,
act by effectively removing Ca2+ from the cascade system.

Systemic Anti - coagulants

 Heparin sodium
Is a heterogenous mixture of polysulfated glycosaminoglycans
(anionic). Glycosaminoglycans are a family of structurally diverse and
distinct polyanionic complex carbohydrates. Heparin was named
because of its initial discovery in the liver. It is stored in masts cells
along with other glycosaminoglycans. Heparin is also stored in
basophils and vascular endothelium.

The mechanism of action of heparin as an anti - coagulant is indirect. It

facilitates the serine proteinase inhibitor Antithrombin III (ATIII)
by binding to aminolysyl residues of heparin cofactor II (HCII).
These Anti - coagulants normally form stable complexes and
subsequently inhibit clotting factors. This combination antagonizes
thrombin (most important) and the activated forms of Factors IX, X,
XI, XII. Heparin serves as the template for antithrombin – thrombin
antagonism.

Clinically, heparin is administered parenterally and used to prevent and

treat venous thrombosis and pulmonary embolism. It is also used as an
anti - coagulant in blood transfusion.

 Vitamin K antagonists
Are of toxicological importance in veterinary medicine. Some are used
as systemic anti - coagulants in human patients. Warfarin and
bishydroxycoumarin are absorbed in the gut and are 90% protein –
bound. They can be stored in the liver and inhibit the hepatic
utilization of vitamin k. Other preparations include: 4 –
hydroxycoumarin, Phenprocoumon, Acenocoumarol, Dicoumarol,
Indan – 1, 3 – dione, and Anisindione.

Anti - coagulants for blood samples for laboratory examination

Sodium oxalate
As 20% solution: use 0.01mL for each mL of
blood to be collected (2 mg/mL)
 P a g e | 88

Sodium citrate As 25%: use 0.01 mL/mL of blood (2.5 mg/mL)

Edetate disodium
(Disodium *EDTA)
Use 1 mg/mL of blood
*Ethylendiamine
tetra – acetic aid

Heparin sodium Use 75 units/10 mL of whole blood

Anti - coagulants for Blood Transfusion

Sodium citrate solution

Sodium citrate 2.5 g

Sodium chloride 0.9 g
Use 10 mL/90 mL of blood
Distilled water q.s. 100.0
mL

Acid Citrate Dextrose (ACD) Solution

Sodium citrate 25.0 g

Citric acid 8.0 g
Dextrose 24.5 g Use 15 mL/100 mL of blood
Distilled water q.s. 1000.0
mL

Note that the toxicity of citrated blood varies with the rate of injection
and the total dose

FIBRINOLYTICS
Fibrinolytic agents increase the activity of plasmin (fibrinolysin), the endogenous
compound that is responsible for dissolving clots.

 Streptokinase, Urokinase, and Streptodornase

Streptokinase and streptodornase

Synthesized by streptococcal organisms.

Urikinase
Prepared from culture of human renal cells

These three enzymes are used in the treatment of wounds that do not respond
to:
a. Antibacterial therapy
b. Burns
c. Ulcers,
d. Chronic eczemas
e. Ear hematomas,
 P a g e | 89

f. Otitis externa,
g. Osteomyelitis,
h. Chronic sinusitis
i. And other chronic lesions.

Streptokinase may be useful for the treatment of feline thromboembolic

disease. They are available as powders for local or systemic administration.

 Tissue Plasminogen Activator (tPA)

 Tissue plasminogen activator activates plasminogen bound to fibrin. Its use
should be limited to cases of thrombosis (rather than prevention).

ANTITHROMBOTHICS

These are drugs that control platelet activity. Aspirin and related compounds cause
irreversible and thus long – lasting negative effect on platelet activity which is
clinically manifested as prolonged bleeding time. The antiplatelet effect of aspirin can
be separated from its other actions by administration of a low dose.

Despite reports of inconsistent antiplatelet effect, aspirin remains the α component of

therapy directed toward prevention and treatment of arterial thrombosis.

DOSAGES

For treatment of coumarin poisoning:

10 – 30 mg IV or IM (multiple sites,
Dog
repeat daily for 2 days)
Vitamin K1 1 -2 mg/Kg IV repeat after 6 hours, then
Cat 1 -2 mg/Kg IM daily for 2 days, then
1- 2 mg/Kg p.o. daily for 3 -5 days

Large animals 0.25 – 2.5 mg/Kg IM

Menadione Included in some pharmaceutical preparation

Use 1 to 2% solution for infusion.

Protamine Do not use greater than 50 mg over a 10 – minute period
Use 1 to 1.5 mg to antagonize each mL of heparin
 P a g e | 90

1 µ/Kg IV (diluted in 50 ml saline and

infused over 15 to 30 min)
Desmopressin Dog
Repeat as needed (von Willebrand’s
disease)

Generally used at 10 mg/1000 ml IV drip as needed

40 to 80 units/Kg may be given SC 3

times daily or
Heparin Dog
10 to 20 units/Kg IV, then 5 units/Kg IV
3times daily

Cat 200 units/Kg 3 times daily may be used

As an antithrombotic

0.5 mg/kg q12h in normal dogs

Aspirin Dog
10 mg/kg in heartworm infested

Cat 25 mg/kg twice weekly

Lesson 07
 P a g e | 91

Drugs acting on
the Digestive
System

T he treatment of the gastrointestinal diseases presents a number of special

challenges that arise from the following characteristics of the digestive system.
The digestive system is the usual route of drug administration. Drugs affect the
function of the gastrointestinal tract (GIT), which, in turn, affects the rate of drug
absorption

The GIT responds to drug action even without the drug entering the circulation. The entero –
hepatic re – cycling of absorbed drugs can be exploited in the design of therapeutic regimen.
Drugs may be acted upon by gut microbial flora resulting in activation or activation of certain
drugs. Some drugs (prodrugs) may require microbial action to attain full therapeutic activity.

Oral administration makes drug – to – drug and drug – to – food interactions possible and can
influence the absorption and effectiveness of various therapeutic agents. The gut is also one
of the richest endocrine organs of the body. So, any dysfunction of the GIT somehow
influences the effectiveness of orally administered drug.

Principles of Therapy of Gastrointestinal Disorders

The pathophysiology of symptoms of individual patients should be well understood so

that therapy will be more selective and therefore more effective. Sometimes, therapy
may be empirically directed at symptoms during diagnostic evaluation of patients, or
when diagnostic analysis failed to yield a full understanding of the cause of the
symptoms. This empirical treatment is done to alleviate the discomfort of the patient
and should not be considered as specific treatment, or as the sole treatment.

Some symptoms may be eliminated by withdrawal of the offending agents and may
not require further pharmacological treatment. Treatment is oftentimes not necessary.
At times, gastrointestinal therapeutics may require interruption of normal
 P a g e | 92

physiological processes. Therapy is often aimed at reducing the functional stimulus to

inflamed or diseased organs. When treating chronic diseases, diagnose first, and
always consider the negative effects of the drugs to be used.

Categories of Drugs used in GI Therapeutics

Emetics Drugs to induce vomiting

Anti-emetics Drugs to prevent vomiting

Antacids Drugs to neutralize excessive gastric acidity

Adsorbent Chemically inert substances that adsorb, dissolved, or suspended

substances such as gases, toxins, or bacteria

Astringents Substances that produce protein – precipitating action limited to the

surface of cells. The permeability of the cell membrane is reduced
but the cells remain viable

Cytoprotectants Substances that form thin layer over skin or mucous membrane in
order to prevent contact with possible irritants

Carminitives Substances used as flavorings in some drug and food preparations.

Their main effect is expulsion of gas and reduction of foam formation

Cathartics Substances that hastens the rate of passage of material through the
GIT and promote defecation

EMETICS

Emetics are indicated whenever there is a need to evacuate the stomach of its contents
such as:
 During poisoning with non – corrosive materials to reduce further absorption of the
poison. Induction of emesis should not be attempted when corrosive agents had been
ingested. In this case, an adsorbent and a cathartic may be tried
 Emptying the stomach prior to induction of anesthesia. Emesis prior to induction of
anesthesia does not always ensure complete emptying of the stomach. Fasting the
patient for at least 12 hours is best whenever possible.

Emetics may be centrally acting or locally acting

 P a g e | 93

Stimulate the Chemo – receptor Trigger Zone (CTZ) in the area

CENTRALLY
posterior of the medulla oblongata. The CTZ then stimulates the
ACTING EMETICS
vomiting center

 The most important example of this group

 Used to be classed as a narcotic but is no longer.
 Very reliable emetic for dogs
 Causes CNS excitation in cats (be cautious when used in cats)
Apomorphine
DOSAGE:
Dog: 0.04 mg/kg IM or SC
Causes vomiting, 1 min., long enough to completely
empty the stomach

 A sedative analgesic with an emetic side effect

(occasional in dogs: always in cats)
Xylazine
DOSAGE:
Dog/Cat: 1.0 mg/Kg IV
Always produces emesis in cats but only occasionally in dogs

 Has been used as an emetic but vomiting was not consistent.

 May cause toxic effects and even death.
Ipecac syrup
 An old drug but may still be part of some pharmaceutical
preparations being used today

 Causes vomiting, defecation, and broncho – constriction when

used in high doses.
 Beware of these effects whenever a prostaglandin is being used
Prostaglandin F2ɑ
for any purpose.
 Not used as a regular antiemetic
 Quite dangerous

More useful for emergency cases far away from the

LOCALLY ACTING
hospital or clinic:
EMETICS
May be administered by pet owners at home

DOSAGE:
3% Hydrogen peroxide Dog/Cat: 5 mL oral
May induce vomiting in 5 – 10 minutes

DOSAGE:
Dog/Cat: 1 tsp.
Sodium chloride
Placed at the back of the tongue
May cause vomiting
 P a g e | 94

Copper sulfate
Zinc sulfate
Freshly ground mustard seed

ANTI – EMETICS

Vomiting is a common complaint in small animal practice and can usually be

controlled with anti - emetics. Common indications for anti - emetics are motion
sickness and vomiting associated with metabolic diseases. They should not be used
longer than 3 days as they may mask the underlying disorder.

Examples of anti - emetics include:

 Some Anti – histamines
 Some Phenothiazine Tranquilizers
 And Prokinetic drugs

The prokinetic drugs include metoclopramide, cisapride, and domperidone

 Depress the CTZ through central anti – dopaminergic

effects
 Sensitizes the smooth muscles of the proximal GIT to
the action of acetylcholine and improves coordination of
esophageal, gastric, and duodenal contractions. It
therefore accelerates gastric emptying and speed of
Metoclopramide small intestinal transit of ingesta
 It is used to treat intractable emesis such as that
associated with anti – cancer therapy, canine parvovirus
infection, recovery from gastric dilatation and chronic
gastritis
 Not a dopamine antagonist but may enhance the release
of myenteric acetylcholine
 P a g e | 95

 Unlike metoclopramide, enhancement of gut motility

includes the large colon
 Indicated for treatment of dysmotility disorders
including chronic constipation and megacolons in cats,
delayed gastric emptying in dogs, and idiopathic post –
operative ileus in horses
Cisapride
 Contraindications: hypersensitivity, gut obstruction,
hemorrhage and perforation, pre – existing
cardiovascular disease
 Toxic effects include fatal arrhythmias – reason for
revocation of approval of use in human medicine (which
affects availability of the drug to veterinary medicine)

 Like metoclopramide, it is a dopamine antagonist but

does not penetrate well into the CNS
Domperidone
 With less anti – emetic effect than metoclopramide
 Not much used in animals

DOSAGE:

Anti - histamines

Dimenhydrinate Dog/Cat 12.5 – 25 mg/kg oral q8h

Diphenhydramine Dog/Cat 2 -4 mg/kg oral q8h

Dog 25 mg/dog, oral Give 1 hour before travelling

Meclizine
Cat 12.5 mg/cat, oral
Phenothiazine Tranquilizers
Chlorpromazine Dog/Cat 0.5 mg/kg oral, IM
Acepromazine Dog/Cat 1 mg/kg, oral, IM
Promethazine Dog/Cat 2 mg/kg oral, 1 h before trip
Trifluperazine Dog/Cat 0.03 mg/kg q12h IM
Triflupromazine Dog/Cat 0.2 mg/kg oral, IM q8h
Prokinetics
 P a g e | 96

Metoclopramide
0.1 – 0.3 mg/kg, oral, IM
Dog
0.01– 0.02 mg/kg IV drip for severe emesis

Horse 0.6 mg/kg q4h oral

0.25 mg/kg tid – qid SC, IV

Ruminants 0.3 mg/kg q4 – 6h SC

Cisapride
Dog
0.25 – 0.5 mg/kg q8h for delayed gastric emptying

Cat 1 mg/kg q8h or 1.5 mg/kg q12h

(for chronic constipation or megacolon)

Horse 0.4 mg/kg

ANTACIDS

Antacids are indicated for hyperchlorhydia and peptic ulcers and for grain
engorgement toxemia in large animals. They may act systematically or locally by
neutralizing acid. Drugs that specifically inhibit gastric acid secretion may also be
considered antacids.

 The only example is sodium bicarbonate

 May produce systemic alkalosis
 Has a disadvantage of adding burden to the kidneys
 Has rapid action
 Examples are: Magnesium oxide, magnesium hydroxide (milk of
magnesia), magnesium silicate, calcium carbonate, calcium hydroxide,
and aluminum hydroxide
Systemic  Local antacids are not absorbed and therefore do not cause systemic
antacids alkalosis. Excessive use however, may cause catharsis (increased
peristalsis)
 Aluminum salts may lead to phosphate depletion. Phosphate deficiency
is characterized by muscle weakness and bone demineralization
 By raising the pH of the GIT, antacids depress the absorption of drugs
which are weak acids. They also decrease the secretion of pepsin
 Antacids should not be used concurrently with inhibitors of gastric acid
secretion
 P a g e | 97

 Block H2 histamine receptors which abound in the gastric mucosa and

mediate acid secretion
 Examples: cimetidine, ranitidine, and famotidine
Inhibitors
 Effects not related to H2 blockade
of gastric
1. Cimetidine and ranitidine inhibit cytochrome P – 450 enzymes
acid
2. Ranitidine inhibits glucuronidation of Paracetamol also inhibits
secretion
the renal clearance of basic drugs that are secreted by the renal
tubules
3. Cimetidine has an anti – androgen effect

Dosage
Cimetidine Dog/Cat 5 mg/kg oral q6 – 8h
Ranitidine Dog/Cat 2 mg/kg oral q8 – 12h
Dog 5 mg/kg oral, IM, SC once daily
Famotidine
Horse 0.23 mg/kg IV q8h as adjunct to ulcer treatment

ADSORBENTS

These drugs, which are not absorbed from the gastrointestinal tract and either line the
mucosa or adsorb toxic compounds, are often incorporated into anti – diarrheal
mixture, or are used alone.
 Usually available in combination with pectin (a protectant)
 Generally safe but long term use may cause gastric carcinoma
Kaolin  The use in neonatal diarrhea is questionable because there has
(hydrated been indication that it is unable to adsorb bacterial endotoxin
aluminum silicate) causing diarrhea in young animals
 It inhibits the absorption of certain drugs such as tetracycline
 Do not administer kaolin together with other drugs

Local antacids  May be considered as adsorbent because they adsorb gastric acid

 It is a residue of destructive distillation of various organic

materials and treated in such a way as to increase the surface
area of the particles
 Burned toast or wood charcoal, contrary to popular belief, is
Activated charcoal useless as an adsorbent
 Activated charcoal is one of the components of the “universal
antidote” to poisoning. The other components are magnesium
oxide (an antacid) and tannic acid (an astringent)
 The universal antidote is generally inferior to activated charcoal

CYTOPROTECTANTS
 P a g e | 98

These drugs form a coating of the gastrointestinal mucosa that prevents irritation or
erosion caused by potentially harmful substances.

Pectin  Purified carbohydrate from citrus or apple rinds

 Examples: colloidal bismuth subcitrate, tripotassium dicitratobismutate,

Bismuth bismuth subsalicylate
chelates  Coat ulcer base, adsorb pepsin, enhance local prostaglandin synthesis, and
stimulate bicarbonate secretion

 A complex of aluminum hydroxide and sulfated sucrose which in the

Sucralfat presence of acid, releases aluminum, acquires strong negative charge and
e binds to positively charged proteins; forms complex gels with mucus and
thus prevents degradation of mucus by pepsin

ASTRINGENTS

Astringents cause coagulation of mucosal surface proteins thus protecting mucosa

from irritating substances.

Examples include botanical substances such as:

 Tannic acid
 Krameria
 Gambir
 Nutgall
 Catechu
 Querium, and
 Geranium.

The beneficial effects of astringents are:

 Protection of tissues from irritating substances
 Reduction of intestinal secretion
 Reduction of absorption of toxic materials
 Reduction of inflammation (in case of bismuth subsalicylate)

CARMINITIVES

Include mostly spices which prevent gastrointestinal gas formation or promote gas
expulsion from the gut.

Examples are:
 Simethicon
 Poloxalene
 Turpentine
 Camphor
 Peppermint, and
 Capsicum
 P a g e | 99

CATHARTICS

Cathartics promote defecation by increasing fecal volume or consistency.

Their clinical uses include:

 Treatment of constipation
 Removal of toxic material from GIT
 To soften stool for mechanical reason as in rectal, vaginal, or uterine prolapse
and during post – surgical care when straining may be detrimental
 Sometimes to remove gut edema fluid

The term “cathartic” is used synonymously with the term “laxative”. Strictly, a
laxative is only a mild cathartic.

According to the intensity of effect, cathartics are classified:

 As laxative (mild)
 Purgative (mild to severe), or
 Drastic (very severe)

And according to the mechanism of action, a cathartic may be a:

 Stimulant
 Bulk, or
 Lubricant cathartic

Stimulant cathartics

These are thought to stimulate mucosal lining of the GIT and thereby initiate a
myenteric reflex that would enhance intestinal transport

They are known to provoke fluid accumulation in the lumen by activating

cyclic AMP – dependent secretory mechanism (similar to the action of cholera
toxin) and inhibit absorption of water

These are 4 types of stimulant cathartic:

 Emodin
 Resinous
 Irritant oils
 Miscellaneous
 P a g e | 100

Types of Stimulant
Examples Properties
Cathartic
 Available in combination with other
substances such as carbamylcholine
(Carbachol)
Emodin irritant
 Of vegetable origin, derived from anthacene
cathartic
but its main ingredient is emodin which is
present in a glycoside form
Emodin acts on the
 The onset of action is slow (4 – 8 hours
large intestine
even up to 24 hours)
presumably by Cascara sagrada
 Recommended for use in cattle, horses, pigs,
irritating the mucosa
dogs, and cats
Cassia Rhamnus,
 Other sources of emodin
Aloe, and Senua
 A synthetic analogue of emodin
 A slow – acting cathartic (onset is 10 – 12
hours)
 Some absorption may occur and discolor
urine reddish violet (alkaline) or yellowish
brown (acidic)
 With prolonged use, the myenteric plexus
actually degenerates resulting in loss of
Danthron intestinal motility
 Danthron is commonly recommended for
horses

DOSAGE of Danthron

Horse 14 – 40 grams

Sheep 2.5 – 5 GRAMS

Cat 100 – 250 milligrams. Do not repeat

Cattle 0 – 45 grams
 P a g e | 101

Dog 300 – 400 milligrams

Type Examples Properties

Jalap Rarely used nowadays
RESINOUS IRRITANT Colocynth Podophylum Act on small intestine causing
CATHARTICS (has been used to remove severe drastic effect
warts)
Castor oil is from Ricinus
communis (castor bean). A
IRRITANT OIL
triglyceride of ricinoleic acid. It
(IRRITANT
is non irritating by itself and
CATHARTIC)
therefore can be used
externally in the eye. Ricinoleic
When ingested they are Castor oil
acid when released in the GIT
acted upon by intestinal Croton oil
irritates both the small and
lipases to form sodium and Linseed oil
large intestine, resulting in
potassium salts of the Olive oil
increased peristalsis with a
release of fatty acids
rapid onset of action.
These salts then irritate the
Sometimes it causes a little
gut mucosa.
colic. It is used primarily in
dogs, cats, calves and foals.

Dosage
Foal/Calf/Pig 30-180 mL oral
CASTOR OIL
Dog/Cat 4-30mL oral
LINSEED OIL Horse 0.5-1.0 L oral

Type Examples Properties

Miscellaneous Has prolonged action due to enterohepatic
Phenolphthalein
Irritant Cathartics circulation
 P a g e | 102

Stimulates colonic smooth muscles and

myenteric plexus
Effective for simple constipation but
Bisacodyl repeated use may cause damage to the
myenteric plexus
Its action is prolonged by enterohepatic
circulation

Pig 1-2 grams

PHENOLPHTHALEIN Dogs 0.03-0.2 grams
Cat 15-65 milligrams
Weighing <5kg 5mg daily
Dog weighing 5-15 kg 10 mg daily;
BISACODYL Dog/Cat
Dog weighing >20 kg 15-20 mg
daily

Bulk Cathartics
Bulk cathartics have action milder than that of the stimulant cathartics. They
increase the fluidity of intestinal content to facilitate defecation. They also
increase the bulk of intestinal content, which then distend the bowel wall and
bring about reflex peristalsis. There are two types of bulk cathartics: Saline
cathartics and gel bulk cathartics.
Ionic compounds with one or more non-absorbable or
slowly absorbable ions
Magnesium These ions make the intestinal fluid hyperosmotic so
sulfate that fluid is drawn into the gut resulting in catharsis.
SALINE
(Epsom’s salt) 500 grams of these salts retain 12 to 15 liters of water
BULK
in the gut within 1-4 hours.
CATHARTIC
Sodium sulfate With Epsom’s salt the patient may get appreciable
S
(Glauber’s absorption of magnesium that may result in CNS
salt) depression and neuromuscular blockage.
In case of poisoning with Epsom’s salt, give patient
activated charcoal and a stimulant cathartic.

DOSAGES
MAGNESIUM SULFATE Cow 0.24-0.48 kilogram
as purgative Sheep 60-120 grams
Cow 60-120 grams
MAGNESIUM SULFATE Sheep 7.5-15 grams
as laxative Horse 30-60 grams
Pig 15-30 grams
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GEL (OR SIMPLE) BULK Methylcellulose Indications

CATHARTICS
 Hydrophilic colloids or  Constipation resulting from diets
indigestible fibers Psyllium consisting of concentrated food
 Attract water and swell Compounds with low fiber content
causing an increase in the  Diarrhea. Since gel cathartics trap
bulk of intestinal content Bran large amount of water, they are
and subsequently increase useful in symptomatic treatment of
the rate intestinal transit Agar diarrhea. Under this condition they
 They are mild and are decrease the speed of intestinal
commonly used in human transit by decreasing the fecal fluid
to increase dietary bulk content.
 To facilitate the expulsion of
ingested sharp objects from small
intestine, but surgical treatment
may be the best for cases like this

Lubricant Cathartics
These cathartics lubricate intestinal wall or intestinal content. Two types of
lubricant cathartics: emollients and fecal softeners.

 Lubricates intestinal mucosa and interferes with

water absorption
 Especially useful when straining is to be avoided
as in rectal prolapse
Mineral oil  Prolonged used of mineral oil may interfere with
absorption of nutrients like the fat-soluble
vitamins, calcium and phosphate.
 It may cause paradoxic constipation.
EMOLLIENT
LUBRICANT  Examples:
CATHARTIC Docosate sodium and Docosate calcium
S  These are surfactants, wetting agents or
Fecal detergents.
softeners  They reduce the surface tension of intestinal
contents allowing the fecal matter to be easily
penetrated by water
 They have slow onset of action (1-2 days)
 They can induce hypovolemic shock in horses!
 Do not use docosate salts with mineral oil!

DOSAGES
Large animals 0.5-2 liters
MINERAL OIL
Small animals 2-50 milliliters
Cattle/Horse 5-10 grams/animal
DOCOSATE SALTS Dog 15-120 mg/animal
Cat 15-30 mg/animal
 P a g e | 104

MOTILITY MODIFIER

There are two groups of gut motility modifiers:

(1) Prokinetics and
(2) Inhibitors of motility

Prokinetics coordinate gastrointestinal movement.

Examples are:
Metoclopramide and
Cisapride (See under antiemetics)

Inhibitors of motility
These are antispasmodic.
There are two subgroups of motility inhibitors:
1) Anticholinergics and
2) Opiates

Anticholinergics include:
 Atropine
 Tincture of belladonna
 Propantheline
 Isopropramide
 Methscopolamine

Opiates inhibit the propulsive gut movement but enhance anal sphincter tone
and segmental gut movement. These effects increase the transit time of
ingesta. They also reduce intestinal fluid secretion.

Examples are
 Diphenoxylate
 Loperamide and
 Codeine
 P a g e | 105

Dosage of Opiates
DIPHENOXYLATE Dog/Cat 0.1mg/kg q8h
LOPERAMIDE Dog 0.08 mg/kg q8h
CODIENE Dog/Cat 0.25-0.5 mg/kg q6h

INHIBITORS OF INTESTINAL FLUID SECRETION

These agents used in the treatment of secretory diarrhea, fall under four
categories:

1. ANTICHOLINERGICS (see above)

2. PHENOTHIAZINE TRANQUILIZERS
Examples:
Chlorpromazine and
Trifluperazine

The mechanism of action may involve the inhibition of calmodulin, a

calcium-binding protein required in intestinal ion and fluid secretion

3. OPIATES (see above)

4. NSAID’s
Examples:
Bismuth subsalicylate and
Flunixine meglumine

NOTES:

Successful treatment of gastrointestinal diseases may require more than the

use of drugs described in this lesson. Many clinical cases may necessitate the
administration of antimicrobial and anti-parasitic drugs, fluid replacement in
case of diarrhea, anti-inflammatory agents in cases of inflammatory processes
involving the gut, etc. Also be aware of the conditions which may benefit
more when no drugs are used.
 P a g e | 106

Lesson 08

Fluid Therapy

A Animals do suffer from varying degrees of body fluid loss (dehydration) and
electrolyte, acid-base and nutritional imbalances under various clinical
conditions. Dehydration and electrolyte imbalance can be corrected with fluid
therapy. The treatment of nutritional imbalance of an anorexic patient is not
generally required if the duration of therapy is less than five days.

The Body Fluid

The total body water is about 60% of body weight in adult; about 80% in the young.
The extracellular fluid (ECF) comprises 30% of the body weight: 5% is plasma; 25%
interstitial fluid. The intracellular fluid (ICF) is also 30% of body weight.
 P a g e | 107

Physiological Divisions of Extracellular Fluid (ECF) Compartment

Represent 8% of the body weight

Fast-equilibrating compartment
Equilibrates (fills up) within 60 mins
Slow-equilibrating compartment Larger than fast-equilibrating compartment
Equilibrates in 15 hours

Electrolyte Composition of the Body Fluid in mEq/L

ELECTROLYTES ICF ECF

Cations
Na+ 13 142
K+ 155 5
Ca2+ 2 5
Mg2+ 35 2
Anions
Cl 2 106
HCO3- 10 30

PO42- 113 2
Organic acids 0 5
Rate of IV Fluid Administration

Generally the rate of intravenous fluid infusion should not exceed 100 mL/kg/hr for
dogs and cats, but may be faster in large animals. The basis for this limit is that faster
infusion rate that recommended may unduly overload the physiologically “fast-
equilibrating” ECF compartment. When this happens, the patient shows signs of
“overhydration” while still suffering from the effects of fluid deficit. Too fast a rate
administration may result in one or more of the ff. signs: tachycardia, increased urine
formation, pulmonary edema, dyspnea and coughing. Must be reduced or
appropriately adjusted in cases of cardiac and renal failures, shock and during
anesthesia.

Factors Affecting Distribution of Body Fluids

 Ionic composition of the fluid

Type of electrolytes

 Osmolality
Number of particles in solution

 Tonicity
Compatibility between ECF and ICF

Regulation of Body Fluid and Electrolytes

 P a g e | 108

The maintenance of the body fluids depends upon the appropriate regulation of input
and output via the gut, skin, kidneys and lungs, which is influenced by
neuroendocrine mechanisms. These mechanisms involve vasopressin (antidiuretic
hormone, ADH), renin-angiotensin, mineralocorticoid (aldosterone), and vasomotor
mechanisms. If the fluid output exceeds input, dehydration results.

TYPES OF DEHYDRATION

1. Hypertonic Dehydration Results from the Joss of pure water or loss hypotonic fluid
2. Hypotonic Dehydration Results from the loss of hypertonic fluid
3. Isotonic Dehydration Results from the loss of isotonic fluid

Acid-Base Balance

The normal plasma pH is around 7.4. Blood pH is continually re-adjusted

based on the production of volatile acids such as CO 2/H2CO2 and fixed acids
such as lactic acid during metabolism.

The mechanisms for adjustment include:

 Blood bluffers – by hemoglobin and Bicarbonate
 Respiration – by removal or retention of CO2
 Renal mechanisms – is long-acting; for fine adjustment

Assessment of Acid-Based Abnormality

Qualitative assessment of acid-base balance may be obtained from clinical

history and clinical signs (e.g. vomiting, diarrhea, respiratory dis-orders, etc.)
For example, Chronic vomiting and increased respiratory (hyperventilation)
can lead to dehydration and loss of acid (alkalosis), and greatly reduced
respiratory rate to acidosis.

 If less than 5; indicates acidemia

 If more than 8; alkalemia
Urine pH  An iatrogenic alteration of serum potassium causes an inverse
relationship between plasma pH and urine (i.e.. hyperkalemia
causes pH reduction, hypokalemia causes pH increase).
 P a g e | 109

 It is defined as the difference between commonly measured

cations and anions, that is ([Na+ ] + [K+]) minus ([Cl+] + [HCO3-]
 The normal anion gap 12-16 mEq/L (for dogs and cats)
 The anion gap increases during normochloremic metabolic
Anion
acidosis owing to increased acid production or decreased acid
gap
elimination
 Remember that accurate and quantitative information regarding
therapy can only be obtained through appropriate lab. Test. There
is no substitute to specific lab tests.

Assessment of Fluid Deficit

The Degree of Dehydration can be assessed from clinical history, by physical
infection, and by simple lab tests.

The clinical History should include:

 The time period over which fluid loss occurs
 Presence of anorexia, vomiting, diarrhea, polyuria, blood loss and
extensive burns.
 Extensive and excessive insensitive fluid loss as panting and fever, and
3rd space losses must be estimated. Third space loss refers to losses due
to effusion or sequestration of fluids.

Physical examination is a common way to estimate fluid loss by following this

general guide (most useful in dogs and cats)

5% dehydration Subtle clinical changes

With definite delay in return of skin to normal
6-8% dehydration position, eyes sunken in orbits, dry mucous
membrane

12-15% dehydration Signs of hypovolemic shock, and impending death.

Simple laboratory tests such as PCV, total plasma proteins, and urine
specific gravity (normal = 1.048) may also be useful.

Amount of Fluid to Be Administered

The volume of fluid required by a dehydrated patient is the sum of the:

 Volume to replace the deficit,
 Maintenance volume, and
 Volume to replace contemporary loss

The replacement volume (= deficit) in liters is equal the body weight multiplied by
the estimated percent dehydration. For estimate of % dehydration; see above the
maintenance volume is approximately 40-60 ml/kg/day. The replacement of
contemporary losses from vomiting, diarrhea, polyuria, large wounds, panting fever,
 P a g e | 110

or blood loss estimated on case-to-case basis. The sum of these volumes is the
estimated total volume to be infused within a 24-h period. The subsequent fluid doses
are usually the sum of the maintenance and contemporary loss only.

Types of Fluid for Infusion

One of several types may be used in most therapeutic needs. Attempt must be made as
much as possible to replace with fluid similar to what has been lost.

0.9% Na Cl solution, is isotonic solution with 308 mOsm/L and pH 5.7

Normal saline
Na 154 mEq/L
solution (NSS)
Cl 154 mEq/L

5% Dextrose in Hypotonic with 252 mOsm/L, pH 5 and 171

water (D5W) Calories/L: Dextrose 50 g/L

Isotonic with 272 mOsm/L, pH 6.7 and 9

Calories/L
Lactated Na 130 mEq/L
Ringer’s K 4 mEq/L
solution (LRS) Ca 3 mEq/L
Cl 109 mEq/L
Lactate 28 mEq/L

LRS with 50 g/L dextrose added is hypertonic

D5W in LRS
With 525 mOsm/L, pH 5.1 and 179 calories/L

10% Dextrose Hypertonic with 505 mOsm/L, pH 5 and 342

in water Calories/L Dextrose 100 g/L

Many others special fluids are also available.

Routes of Administration

The intravenous route is usually employed for replacing sudden and extensive losses.
In small-sized animals, the intraperitoneal route may be used for quick absorption. For
less critical cases, or for maintenance, fluids may be administered subcutaneously
(SC). Subcutaneous compartment, however, has limited volume, and absorption is
greatly limited especially when peripheral vasoconstriction is present. Avoid this
route with D5W because equilibration of ECF with a pool of electrolyte-free
solution may aggravate electrolyte imbalance. Since the fluid does not contain any
electrolyte, intracellular and intravascular electrolytes may be drawn into the
subcutaneously infused D5W. The oral route is ideal for hypertonic, high caloric
density fluids.
 P a g e | 111

Rate of Administration

 The usual is 100 ml/kg/h (see above).

 Rapid administration is not necessary in chronic diseases
 Administer the calculated deficit and the maintenance requirement within 24 hr
 Monitor cardiovascular and renal-function while fluid is being administered
 Whenever possible, replace fluid deficit prior the anesthesia and surgery
 A basal fluid administration of 5-10 ml/kg/h is recommended during surgery

Monitoring Fluid Therapy

 Measure body weight regularly during therapy.

 Determine urine output.
 Measure central venous pressure
 Look for signs of overhydration:
 Nasal discharge
 Chemosis
 Restlessness
 Cough and dyspnea
 Polyuria
 Exophthalmos
 Diarrhea
 Vomiting

Acid-Base Imbalance

Without laboratory tests, therapy may result in a variety of acid-base, osmolality, and
electrolyte disorders.

Metabolic acidosis is the most frequently diagnosed acid-base abnormality in

animals, and may require enrichment of the infusion fluid with sodium bicarbonate.

The bicarbonate deficit is estimated as the difference between 25 mEq/L and the
actual measured plasma bicarbonate to be administered is equal to the product of the
body weight and the bicarbonate deficit (b.w x bicarbonate deficit). If metabolic
acidosis is obvious of imminent as in cardiopulmonary arrest, a safe approach is to
administer 1 mEq/k IV. Therapeutic attempts to correct acid-base abnormality other
than metabolism acidosis should be directed toward the primary cause.
 P a g e | 112

Lesson 09

Introduction to
Chemotherapy

C hemotherapy refers to the use of drugs or chemicals to treat or prevent diseases

caused by infectious organisms like viruses, bacteria, fungi, and protozoa. It also
includes parasitic worms, arachnids, and insects. In popular usage, we associate
the term chemotherapy with drug treatment of cancer. This is not farfetched if we
realize that neoplastic cells has become foreign to the body and are therefore considered as
another “organisms”. Chemotherapy is based on the principle of selective toxicity which is
the property of substances of being more harmful to certain living organisms but not to
others. For example, insecticides are selectively toxic to insects, antibacterials to bacterial
organisms, anthelmintics to worms, etc. Drugs used for chemotherapy are generally called
chemotherapeutic agents or anti – infective agents and are classified according to the type
against which they act.
Classes of Chemotherapeutic Agents
 Antibacterial – vs. bacteria
 Antiviral – vs. viruses
 Antiprotozoan – vs. protozoans
 Antifungal (antimycotic) – vs. fungi
 Anthelmintics – vs. parasitic worms
 Antineoplastic (anticancer) – vs. neoplastic cells
An antimicrobial is a natural or synthetic drug that acts against one or more types of
microorganisms. The term antibiotic refers strictly to a substance produced by various
 P a g e | 113

species of microorganisms (bacteria, fungi, yeast, etc.) which inhibits the growth of another
microorganisms. Most antibacterial and a few other anti – parasitic drugs are antibiotic by
definition. Today, the term “antibiotics” include not only those that are naturally produced
but also those that are partly or fully synthesized in pharmaceutical laboratories.

The Chemotherapeutic Triad

To institute an effective antimicrobial therapy, a veterinarian requires knowledge of

the chemotherapeutic triad that consists of the host (patient), the pathogen (disease –
causing organism) and the drug (chemotherapeutic agent), and of how they interact
with each other (see below).

DRUG

1 4
2 3

6
PATHOGEN HOST

1. THE DRUG ACTS ON PATHOGEN

Eradication, inhibition of growth, selective pressure

2. THE PATHOGEN ACTS ON DRUG

Inactivation of the drug, drug resistance

3. THE DRUG ACTS ON HOST

Toxicity, allergy, biological alteration, immunosuppression

4. THE HOST ACTS ON DRUG

Excretion and biotransformation

5. THE PATHOGEN ACTS ON HOST

Causes the diseases

6. THE HOST ACTS ON PATHOGEN

Immune mechanisms eliminates the pathogen and resolves the diseases
Some Useful Definitions
Minimum inhibitory concentration The lowest dilution of drug that prevents visible
(MIC) growth in broth or agar after 18 – 24 hours of
incubation
 P a g e | 114

The lowest concentration or dilution of drugs

Minimum bacteriocidal that sterilizes the medium or results in a 99.9%
concentration (MBC) decline in bacterial count

Inhibition of growth after the antibiotic level

falls off below the MIC. This may not be
Post – antibiotic effect (PAE)
observed with all antibiotics

The drug is capable of killing bacterial

Bacteriocidal organisms at clinically achievable concentrations

The drug, at clinically achievable concentrations,

inhibits bacterial growth but does not kill the
Bacteriostatic organisms; when the drug is removed, bacterial
growth may resume

General considerations in Chemotherapy

Every clinician should realize that:

 Chemotherapeutic drugs are subjected to the same disposition process as any

other xenobiotics (foreign substances)

 Chemotherapeutic drugs may exert adverse effects on the host

 The host’s response to the chemotherapeutic drug may in large measure

determine the success or failure of the therapy

 The immune competence, reticulo - endothelial reaction and leukocyte

response as well as the function of the organ systems are important facets of the
success of therapy

Antibacterial Agents

When an antimicrobial drug is used to treat bacterial infections in animal patients,

several possible outcomes of therapy may be expected; only one of which is
beneficial. These are:
 No effect
 Super – infection – new infection arising from the use of broad – spectrum
antibacterials
 Induction of bacterial resistance to drug
 P a g e | 115

 Toxic effects
 Adverse reaction with other drugs or with nutrients
 Allergy
 Drug residues in animal tissues
 Bacteriocidal or bacteriostatic effect

The bacteriocidal or bacteriostatic effect is what clinicians is after in using

antibacterial agents but it cannot be achieved at all times without inducing
concurrently one or more of the non – beneficial effects. Several factors must
therefore be considered in order to reduce the chances of getting the non – beneficial
effects of the drug. These factors are included in the principles of antimicrobial
therapy.

General Principles of Antibacterial Therapy

1. The infection should be specifically diagnosed

a. Successful therapy usually requires specific diagnosis but a reasonable
preliminary diagnosis is often all that is possible initially

b. Treatment should be aimed at a specific pathogen whenever possible.

However, mixed infections do occur and pose problems in therapy

c. Conclusive microbiological diagnosis oftentimes is difficult. The treatment

may be based on past clinical experience, that is a clinician may diagnose an
infection by “educated guess”

d. Examination of direct smear with Gram stain is also helpful to establish at

least general type of pathogens involved in infections

2. The appropriate drug must be selected

a. The antibiotic to use for a particular bacterial infection must be one to which
the infecting organism is sensitive

b. Antibiotic sensitivity test provides a sound foundation from which to proceed

with the selection of appropriate antibacterial drugs

c. Sensitivity test takes time and may not be too important in emergency cases. It
is not always advantageous to wait for the result of bacterial culture and of
sensitivity test before starting an antibacterial therapy

d. In selecting appropriate antibacterial drugs, it is best to consider the following:

i. Probable microorganisms involved in infection

ii. Result of sensitivity test (if any)
iii. Pathogenicity of the organisms involved
iv. Presence and nature of pathological lesions
v. Acuteness of infection
vi. Pharmacokinetics (physiological disposition) of the drugs
 P a g e | 116

vii. Potential drug toxicity

viii. Organic dysfunction in the host
ix. Drug interactions
x. Cost of treatment (especially in treating food animals)

3. The appropriate dose must be given

a. The dose and frequency of administration must achieve adequate therapeutic
levels at the site of infection for a sufficient period of time without causing
serious side effects

b. For example, gentamicin is effective against Gram – negative bacterial

infection of the lungs but is poorly absorbed in the gut

c. If gentamicin is given in feed or drinking water for the treatment of respiratory

infection, cure cannot be expected because the drug will not be able to attain
sufficient antibacterial concentration in the lungs. Gentamicin must be given
by injection for this purpose

4. The dose schedule must be followed for 3 to 5 days or longer to ensure elimination of
pathogens and to prevent relapse. If the patient shows improvement before the end of
the set course of therapy, continue the course of medication

5. The drug must be available at the site of infection in a concentration above the
minimum inhibitory concentration (MIC) of the drug for the bacterial species
involved. The MIC of an antibacterial for one species may not be the same for another
species

6. Supportive therapy and ancillary treatments, nutritional support and nursing care must
be instituted: fluid therapy, warmth rest, and proper nutrition

BACTERIAL RESISTANCE TO ANTIBIOTICS

Acquired resistance of organisms to chemotherapeutic drugs is a major problem in

antimicrobial therapy and results in changing patterns of sensitivity for many
microorganisms. It is the main reason for antibiotic sensitivity testing as a
requirement in the treatment of infections. Microorganisms have evolved an array of
ingenious alterations that allow them to survive in the presence of antibiotics, some of
which will be discussed for individual drugs or groups of drugs. The development of
resistance to antibiotics involves a stable genetic change heritable from generation to
generation.

Ways of acquiring resistance:

 Mutation
 P a g e | 117

In any large population of antibiotic – susceptible bacteria, there is likely a

small minority group, which is relatively resistant to the drug. There is no
evidence that these mutants are actually caused by a previous exposure to a
particular drug. Such mutations happen by chance and the resulting alteration
is usually specific for a single drug or class of drugs. Resistance then becomes
a problem in clinical setting due to selection. When the use of a particular drug
is widespread, the sensitive strains are suppressed and the resistant ones
multiply unimpaired, in time the resistant strains predominate.

 Transduction
This occurs when a bacteriophage (a virus) carries genetic materials for
antibiotic resistance in a newly infected bacterial cell. The DNA can be
incorporated in the new bacterium and antibiotic resistance passed on to its
progeny. Transduction is particularly important in the transfer of antibacterial
resistance among strains of Staphylococcus aureus where bacteriophages can
carry plasmids (extrachromosomal DNA) that code for multiple antibiotic
resistances.

 Transformation
This involves the incorporation into bacteria of DNA that is contained in the
environment. The importance of this method is unknown.

 Conjugation
This refers to the passage of resistance genes from cell to cell by direct contact
through sex pilus or bridge. This can occur not only within species but also
between species of bacteria (i.e. from non – pathogenic to pathogenic
bacteria). The DNA transferre is contained in plasmids and consists of two
parts: the first part codes for resistance and is termed R – factor. The second
codes for the transfer apparatus and is termed resistance transfer factor
(RTF). The R – factor often codes for resistance to multiple antibiotics. The
efficiency of this process is low but selective pressure applied through the use
of antibiotics has led to the slow development of plasmids for multiple drug
resistance especially among enteric organisms. The multiple – drug resistant
Enterobacteriaceae are a serious problem creating a constant demand for new
antibiotics.

CLASSIFICATION OF ANTIBACTERIAL AGENTS

Classification According to Effect on Bacteria

 Kill bacteria at the minimum inhibitory concentration (MIC)

 Penicillins and cephalosporins by virtue of their action requires
active multiplication of bacteria to be effective
 When its concentration is below MIC, a bacteriocidal agent may not
Bacteriocidal kill bacteria but only inhibits bacterial growth
 Bacteriocidal agents are more prone to causing superinfections
because they may kill off normal bacterial flora which normally
inhibits pathogens
 P a g e | 118

 Inhibit bacterial growth and replication

 The normal defense mechanism of the patient must participate in
eliminating infectious bacteria
 Bacteriostatic agents may antagonize the action of some
Bacteriostatic bacteriostatic agents
 Some bacteriostatic drugs may become bacteriocidal when very high
doses are given or when high concentrations are attained in certain
body compartments such as the urinary tract but toxic effects on the
patient may appear

Bacteriolytic  Cause dissolution of bacterial cells

Classification According to Spectrum of Antibacterial Action

 Natural penicillins (Penicillin G. Penicillin V)

Against Gram –  Semi – synthetic penicillins (Oxacillin, Nafcillin, etc.)
positive  Macrolides (Erythromycin, Tylosin, Spiramycin, ets.)
Cocci and bacilli  Lincosamides (Lincomycin, Clindamycin)
 Vancomycin and Bacitracin

 Aminoglycosides (Streptomycin, Gentamicin, Neomycin,

Against aerobic Gram –
etc)
negative bacilli
 Polymyxins (Polymixin B, Colistin)

 Broad – spectrum penicillins (Ampicillins, Amoxicillin,

Broad – spectrum Carbenicillin, Piperacillin, etc.)
(vs. Gram – positive  Cephalosporins (Cephalosporins and many other)
and Gram – negative  Trimethoprim – sulfonamide combinations (TMP – S)
bacilli)  Tetracyclines (Chlortetracycline, Oxytetracycline,
Doxycycline, etc.)

Classification According to Mechanisms of Action

 Examples: Penicillins, Cephalosporins, Bacitracin,

and Vancomycin
 Usually bactericidal requires active bacterial
multiplication to be effective because new cell wall is
Inhibitors of cell wall produced during rapid bacterial cell multiplication
synthesis  Indicated for conditions when the host’s defense
mechanisms are depressed
 Have a greater tendency to induce superinfections
 Simultaneous use of bacteriostatic agents may
antagonize the effect of this group
 P a g e | 119

 Examples: Polymyxins
 Generally bacteriocidal
Disruptors of cell
 Their action is not dependent on the rate of active
membrane
bacterial growth or multiplication and therefore, may
be combined with bacteriostatic agents

 Examples: Aminoglycosides, Tetracyclines,

Macrolides, Lincosamides, Chloramphenicol,
Tiamulin, and Virginiamycin
Inhibitors of protein
 May be either bacteriocidal (aminoglycosides) or
synthesis
bacteriostatic (all the others)
 Their action is not dependent on the rate of bacterial
multiplication

 Examples: Quinolones, Flouroquinolones,

Novobiocin, Metronidazole, Nitrofurans and
Inhibitors of Nucleic Acid
Rifamycins
functions
 Inhibits the metabolism and functions of either RNA
or DNA are usually bacteriocidal
 Examples: Sulfonamides, Trimethoprim
 They are generally bacteriostatic but fixed
Inhibitors of Folate combinations of trimethoprim and sulfonamides are
Cofactor Synthesis bacteriocidal
 Flouroquinones (Norfloxacin, Ciprofloxacin,
Enrofloxacin, Danofloxacin)
While this classification has many important exceptions, it does aid the clinicians to
remember the antibacterial spectrum of each drug

Antibiotic targets

Cell
membrane Folate
cofactor
Cell wall

Nucleic
acid Protein
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Amoxicillin Bacitracin
Ampicillin
Penicillin

Ceftiofur

Cell wall

Colistin
Salinomycin

Bacterial cell
membrane

Furazolidone
Nitrofurazone Norfloxacin
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Dimeindazole

Trimethoprim
Sulfonamide

Sulfonamides

Folate cofactors

Tylosin Chloramphenicol
Erythromycin Florfenicol
Tilmicosin Lincomycin
Spiramycin Spectinomycin
Kitasamycin Tiamulin
Josamycin Valnemulin
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Lesson 10

Penicillins

T he penicillins belong to the beta – lactam groups of antibiotics together with the
cephalosporins (see Lesson !!). The Penicillins are derivatives of 6 –
aminopenicillanic acid. Developed in the 1930s, benzyl penicillin (penicillin G)
became available for veterinary use in the late 1940s. Penicillin is produced by
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Penicillium molds and was the first antibiotic available for clinical use. Today, the penicillin
group of antibiotics represents a large group of compounds. Only the primary ones used in
veterinary medicine are covered in this lesson.

Chemistry

The penicillin nucleus is made of a thiazolidine ring connected to a β – lactam ring

to which a side chain is attached. An intact β – lactam ring is essential for
antibacterial action. The side – chain alters the antimicrobial activity and the
pharmacokinetics of the molecule. The penicillins are weak organic acids and some
are not acid – stable (i.e. they are hydrolyzed by gastric acid). Most are relatively
unstable in solution and are therefore formulated as powders which have a relatively
short half – life once reconstituted.

Dosing of Penicillin (PCN)

In the early days of penicillin use, when it was relatively impure, it was measured by
bioassay. A unit of penicillin was that amount which gave a standard zone of
inhibition on a standard culture medium. Penicillin G (benzyl penicillin) is still
formulated and dosed based on units of activity.

1 mg sodium penicillin G = 1667 units

1 mg potassium penicillin G = 1595 units (1 unit = 1.6 µg)
1 mg procaine penicillin G = 1000 units (1 unit = 1 µg)

The dosage and antibacterial potency of the semi – synthetic penicillins are
expressed in terms of weight rather than in units (see below).

Mechanism of Action
The penicillins inhibit the third stage of bacterial cell wall synthesis. The 3 stages of
bacterial cell wall synthesis are:

 Formation of precursors (building blocks): inhibited by the antibiotic

VANCOMYCIN
 Formation of peptidoglycan chain: inhibited by the antibiotic BACITRACIN
 Cross – linking of chains: inhibited by PENICILLINS and
CEPHALOSPHORINS

The penicillins cause death and Lysis of bacterial cells, the mechanism of which
involves the role of penicillin – binding proteins (PBPs) and bacterial autolytic
enzymes. Classically, they will only kill growing and metabolically active bacterial
cells. They have reduced killing effects on “dormant” bacteria or bacteria whose
multiplication is inhibited by another antibacterial agent.

Pharmacokinetics
The rate of absorption of penicillins depends on the pharmaceutical formulation used.
They are weak acids with pKa of about 2.76 and tend to distribute into the
extracellular fluid, pleural fluid, pericardial fluid, and bile. Low concentrations are
attained in the prostate, brain, intraocular fluid, and phagocytic cells. Penicillin G
when given orally is degraded by gastric acid but phenoxymethyl penicillin (penicillin
 P a g e | 124

V) is relatively acid – resistant. Ampicillin and amoxicillin are also acid – resistant
and are fairly rapidly absorbed. Oral amoxicillin has greater bioavailability than
ampicillin.

The duration of action of penicillin salts following IM injection are as follows:

Sodium or Potassium penicillin G = 4–6h
Aqueous procaine penicillin G = 24 h
Procaine penicillin G in oil = 48 h
Benzathine penicillin G = several days

Distribution
The penicillins poorly penetrate certain body parts such as the eye, prostate, and
cerebrospinal fluid. However, inflammation enhances the penetrability of the
meninges and may be useful in the treatment of brain infections.

Excretion of penicillins is by renal mechanisms especially by tubular secretion.

Sufficient concentration of penicillin in urine is needed to affect urinary tract infection
caused by Gram – negative bacteria. Accumulation in the body is therefore expected
in case of renal disease. Competitor (weak acid) substances such as probenecid inhibit
tubular secretion of penicillins.
Antibacterial Spectrum and Clinical Use

The penicillins can be divided in 3 groups based on their antibacterial spectrum:

(1) Natural penicillins
(2) Penicillinase – resistant penicillins
(3) Broad – spectrum penicillins

 They have narrow spectrum of activity

NATURAL PENICILLINS
 Affect mainly Gram – positive bacteria but also affect
certain Gram – negative bacteria and most obligate
 Penicillin G
anaerobes
(benzyl penicillin)
 Used in the treatment of Gram – negative infections of
the urinary tract. Penicillin G attains higher than the
 Penicillin V
plasma concentration in urine. For this reason, it may
(phenoxymethyl penicillin)
be useful in the treatment of urinary tract infection
with susceptible bacteria

PENICILLINASE –
 Their use is generally restricted to infections caused
REISTANT PENICILLINS
by Penicillinase – producing bacteria (e.g.
Staphylococcus)
Examples:
 Less active against other Gram – positive bacteria than
Cloxacillin, Oxacillin,
Penicillin G
Dicloxacillin, Flucloxacillin,
 Not active against Gram – negative bacteria
Methicillin, Quinacillin
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 The spectrum of activity of drugs belonging to this

group is similar to that of Penicillin G group but with
BROAD – SPECTRUM
additional effect on many Gram – negative bacilli.
PENICILLINS
They are not quite as active as Penicillin G against
Gram – positive bacteria; also inactivated by
 Aminobenzylpenicillins
penicillinase
(e.g. Amoxicillin, Ampicillin,
 Aminopenicillins affect some Gram – negative
Becampicillin, Pivampicillin)
bacteria (Salmonella, Shigella, Proteus) but not good
for Klebsiella and Psedomonas
 Carboxypenicillins
 Carboxypenicillins are specifically active against
(Carbanicillin, Indanyl
Pseudomonas
cabenicillin, Ticarcillin)
 Ureidopenicillins have very broad spectrum activity:
 Ureidopenicillins
affective against (many Gram – negative and Gram –
(Piperacillin, Azlocillin,
positive bacteria including Psedomomas,
Mezlocillin)
Enterobacter, and Klebsiella
 Expensive

Penicillinase
An enzyme produced by certain bacteria which specifically destroys penicillin
antibiotics. It is a form of a β – lactamase enzyme. However, there is no
evidence that some bacteria have shown or developed resistance to the
penicillinase – resistant penicillins.

Clavulanic acid, Sulbactam, and Tazobactam

Substances that serve as false substrate for penicillinase. These substances
protect a penicillin antibiotic from destruction by penicillinase. These
substances have been combined with amoxicillin, ticarcilin, and other
penicillins. In general, as the Gram – negative spectrum increases, the potency
in the Gram – negative spectrum decreases for the penicillin group of
antibiotics.

Antibacterial Susceptibility Profile of Penicillin Antibiotics

 Benzyl Penicillin G

 Good
Aerobic all beta – hemolytic streptococci (S. agalactiae, S. canis, S.
zooepidemiicus, S. dysagalactiae, S. suis, S. uberis): Bacillus
anthracis, most corynebacteria (C. pseudotuberculosis, C. renale):
Erysepelothrix rhusopathiae, Listeria monocytogenes, anaerobic
Clostrdium sp., Fusobacterium sp. And some Bacteroides sp.

 Variable
Staphylococcus aureus, S. intermedius

 Moderate
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Actinobacillus sp., Borrelia sp., Brucella sp., Haemophilus sp.,

Leptospira sp., Moraxella sp., Pasteurella sp., Proteus sp., T.
equigenitals, Treponema sp.,

 Resistance
Enterobacteriaceae (except a few Proteus sp.), Bacteroides fragilis,
Bordetella sp., most Campylobacter sp., Nocardia

 Penicillinase resistant – penicillins

 Reserved strictly for treatment of penicillinase producing staphylococcal

organisms

 Aminobenzyl penicillins

 Good
As for benzyl penicillin but also good vs. Borrelia sp., Leptospira sp.,
Moraxella sp.

 Variable
Actinobacillus sp., E. coli., P. mirabilis, and Salmonella and
widespread resistance by Enterobacteriaceae (though they are
technically susceptible)

 Moderate
As for benzyl penicillin and Campylobacter sp., R. equi, and
enterococci

 Resistance
Bacteroides fragilis, B. bronchiseptica, Citrobacter sp., Enterobacter
sp., Klebsiella sp., other Proteus sp., P. aeruginosa, Serratia sp.,
Yersinia enterocolitica

 Ureidopenicillins

 Noted for increased activity against Gram – negative bacteria compared to

cabenicillin or ampicillin especially vs. Klebsiella sp., and P. aeruginosa

 These are susceptible to beta lactamases so resistance among

Enterobacteriaceae is not frequent and most Enterobacter and Serratia are
resistant.

 Carboxypenicillins

 Good Gram – negative activity vs. P. aeruginosa and Proteus sp.

Adverse Reactions to Penicillins

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The direct toxicity of penicillins is generally low. Allergic reactions ranging from
delayed hypersensitivity skin reaction to acute anaphylaxis may occur. Species most
susceptible to allergic reactions are hamsters and guinea pigs.

CNS Toxicity occurs with intrathecally – administered penicillin G..

G. Nephrotoxicity has been reported with the use of methicillin in human but may
also occur in animals.

Superinfection is most likely to occur with broad – spectrum penicillins. Mild cases
results in diarrhea and overgrowth of toxin – producing bacteria can cause death.
Penicillins are contraindicated in herbivore such as guinea pigs, hamsters, rabbits, and
chinchillas for this reason.

Further notes on some Specific Penicillins

 Acid stable
 can be given orally
Cloxacillin  food interferes with absorption
 expensive
 use only as last resort

 Not acid – stable

Methicillin
 should be given parenterally

 Parenteral and oral

Ampicillin  susceptible to penicillinase
 with low toxicity

 Similar to ampicillin in spectrum, toxicity, and

susceptibility to penicillinase
Amoxicillin  greater degree of absorption after oral
administration but not really important in most
domestic animals

Hetacillin  Similar to ampicillin

Pivampicillin  converted to ampicillin in the system
Becampicillin  improved bioavailability
 P a g e | 128

 Effective against Proteus and Pseudomonas

 for parenteral use only
 Indanyl carbenicillin is the oral form
 Use with caution in cats
Carbenicillin  With very short half – life
 Causes rapid development of resistance
 Expensive
 Use only in treating gentamicin – resistant
Psedomonas

Usual Dosage of Penam Penicillins in Animals

Amoxicillin Dog/Cat: 20 – 30 mg/kg oral q8 – 12h

Poultry: 20 mg/kg in drinking water

Amoxicillin Trihydrate Horse: 10 mg/kg IM q12h

40 mg/kg in feed for 10 days
Ampicillin sodium
10 – 20 mg/kg IM, IV q6 – 8h
Ampicillin
Dog/Cat: 20 – 30 mg/kg oral q8h
Benzathine Penicillin
40,000 IU/kg q72h for highly sensitive infections only
Carbenicillin
Dog: 50 mg/kg IM, IV q6 – 8h
Carbenicillin Indanyl
Sodium Dog: 50 – 100 mg/kg oral q8h
Clavulanic acid
Amoxicillin Dog/Cat/Calf: 14 mg/kg oral q12h
Cloxacillin
40 mg/kg oral, IM q8h
Oxacillin
40 mg/kg oral, IM q8h
Flucloxacillin
Dog/cat: 15 mg/kg oral q6h
Methicillin
25 – 50 mg/kg IM, IV q6h
Penicillin G
Dog/Cat: 25K IU/kg oral q6h
Penicillin G sodium
15K – 20K IU/kg, IV q6 – 8h
Phenoxymethypenicillin
Dog/Cat: 8 mg/kg oral q8h
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Procaine penicillin
25K IU/kg IM q12 – 24h
Ticarcillin
50 – 75 mg/kg IM, IV q6 – 8h

Lesson 11

Cephalosporins

T he Cephalosporins constitute a large group of related antibiotics. The first

cephalosporins were isolated from a fungus Cephalosporium acremonium in 1948.
Since then many derivatives have been developed.

Chemistry

The cephalosporins, like the penicillins, contain a β – lactam ring but the adjacent ring
is a 6 – membered instead of 5 – membered. The active nucleus of most
cephalosporins is 7 – aminocephalosporanic acid. Substitutions at 3 different places in
its structure modify its pharmacokinetics and antibacterial activity.

Mechanism of Action
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Cephalosporins are bacteriocidal by inhibiting bacterial cell wall synthesis in a

manner similar to the penicillins.

Antibacterial Spectrum and Clinical Use

The cephalosporins are often classified by “generations”. The term generation, as it

was originally devised, separates cephalosporins based on the chronology of their
development and to some degree on their in vitro antibacterial potency and spectrum
of activity

Classification by generations also gives an idea when most cephalosporins were

developed:

Generation Properties

 Introduced in human medicine in 1960s and 1970s

 Broad spectrum, affecting most Gram – positive cocci
including:
 Penicillinase – producing staphylococci
First Generation  Some Gram – negative bacilli (Escherichia coli, Salmonella,
Proteus, Klebsiella, and Shigella)
 Some activity against anaerobes but inactive against
Streptococcus faecalis and Pseudomonas
 Relatively sensitive to β – lactamase (cephalosporinase)
produced by Gram – negative bacteria

 Introduced in the 1970s

 With increased Gram – negative spectrum
 They are more resistant to Gram – negative β – lactamase and
are effective against species that are resistant to the first
generation
 The spectrum also includes more strains of Klebsiella,
Second Generation
Proteus, Providencia, and Enterobacter. However, there is
some decreased activity against Gram – positive bacteria, most
noticeable with penicillinase – producing staphylococci
 A few members of this generation (e.g. cefoxitin) have
increased activity against anaerobes.
 They are inactive against Psedomonas

Third Generation
 Introduced in the early 1980s
 Primarily with Gram – negative spectrum
 They have greatly enhanced resistance t Gram – negative β –
lactamase
 Increased activity against Gram – negative bacteria including
strains resistant to the first and second generations
 They have some activity against isolates of Pseudomonas (but
activity varies among compounds)
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 They have decreased activity against Gram – positive cocci as

compared with the first and second generations

 With extended spectrum of activity compared with the third

Fourth Generation
generation
 Has increased stability from hydrolysis by ß – lactamases

Some second and third generation cephalosporins have peculiarities in their spectrum
which are different from others in the group. While these peculiarities can be
important in human medicine, they are of little significance in veterinary medicine
because very few second and third generation cephalosporins are used in animals.

Cephalosporins used to be considered “second – line” antibiotics but is now used as

first choice in many infections. It is better to use penicillins first and then, if
unsuccessful, use cephalosporins. However, cephalosporins may be the drugs of
choice against Klebsiella. Some bacteria produce specific cephalosporinase and others
produce less specific ß – lactamases which can inactivate both cephalosporins and
penicillins. In general, cephalosporins are resistant to penicillinase. Cephalosporins
vary in their susceptibility to ß – lactamases. They vary both between generations and
within generations. Generally, the order of susceptibility is: FIRST > SECOND >
THIRD > FOURTH.

Pharmacokinetics
Only the first and second generations are adequately absorbed when administered
orally. All the other cephalosporins must be administered parenterally. Some may be
given subcutaneously. They are all absorbed when given intramuscularly.

Cephalosporins are distributed similarly as the penicillins. They distribute well to the
extracellular fluid reaching therapeutic levels in most tissues and fluids including the
pericardial fluid, bile, and infected bones. In the absence of acute inflammation,
cephalosporins, with a few exceptions, do not reach useful levels in the CSF.
Cefuroxime, Moxalactam, Cefotaxime, and Ceftizoxime penetrate into the CSF in
sufficient concentrations to treat meningitis.

Most cephalosporins are excreted unchanged in the urine by glomerular filtration and
tubular secretion. A few are reabsorbed significantly such that renal clearance is less
than glomerular filtration rate corrected for protein binding. A few (such as
cephalothin, cephapirin, and Cefotaxime) are metabolized by the liver through de –
acetylation. Cefoperazone and Moxalactam are excreted primarily in the bile.

Adverse Reactions
In general, cephalosporins are safe drugs with low incidence of adverse reactions.
Hypersensitivity reactions are most common which can be an immediate reaction
(anaphylaxis, bronchospasm or urticaria), or a more delayed reaction such as skin
rash. Cephalosporins may have variable cross – reactivity with penicillin
hypersensitivity. However, if the reaction to penicillin was mild, there is a low risk of
anaphylactic reaction to cephalosporins. If the reaction to penicillin was severe, be
very cautious in administering this drug.
 P a g e | 132

Renal toxicity manifests as renal tubular necrosis. Cephalosporidine is the most

nephrotoxic of cephalosporins. This toxicity is also well documented with cephalothin
which is toxic at high doses or in patients with renal failure. Nephrotoxicity may be
enhanced with concurrent use of aminoglycoside antibacterials and the diuretic
furosemide. The nephrotoxicity of the other cephalosporins is not well established.
Other toxicities include gastrointestinal disturbances, local irritation and pain from IM
injection, thrombophlebitis from IV injection, drug fever, non – specific
lymphadenopathy, and very rarely, bone marrow depression.

Individual Drugs

 First Generation Cephalosporins

These are the most used in veterinary medicine and the least expensive among
the cephalosporins. Often used to treat bone infections (osteomyelitis) caused
by organisms resistant to other drugs. They are also used prophylactically in
surgery especially for prosthesis implants.

Examples:
ORAL PARENTERAL
Cefadroxil Cephaloridine Cephadrine
Cephalexin Cephapirin Cephalonium
Cephaglycin Cephalothin Cephalexin
Cephradin Cefazoline
Cephacetril

 Second Generation Cephalosporins

These are also used extensively in veterinary medicine primarily to treat
Klebsiella infections and some other resistant Gram – negative infections.

Examples:
ORAL PARENTERAL
Cefaclor Cefuroxime
Cefuroxime Ceforanide
Cefoxitin
Cefonicid
Cephoxazole
Cefamandole

 Third Generation Cephalosporins

These are rarely used in veterinary medicine and are very expensive.

Examples:
ORAL PARENTERAL
Ceftriaxone Cefotaxime
Ceftazidime Cefoperazone
Cefmenoxime Cefsulodine
Cefixime Moxalactam
Ceftiofur
Ceftizoxime
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Moxalactam technically an oxa – ß – lactam (replaces sulfur), is slightly more

active against Pseudomonas than the other third generation drugs except
Cefoperazone. It is the best of the third generation cephalosporins against
anaerobes, about equal with cefoxitin.

Cefoperazone is the most active against Pseudomonas but antipseudomonal

penicillins and aminoglycosides are still the drugs of choice. It is eliminated
primarily in the bile. Bleeding problems have been noted with the use of this
drug.

 Fourth Generation Cephalosporins

May be used in the treatment of infections due to Gram – negative bacilli -
resistant to the third generation cephalosporins.

Examples:
Cefepime

Useful Dosages

Dog/Cat 4 – 20 mg/kg TID oral

Cefaclor Calves 3.5 mg/kg q12h oral
Horse 20 – 40 mg/kg tid, oral
Dog/Cat 22 mg/kg q12h oral
Cefadroxil Calves 12 mg/kg q12h oral
Horse 22 mg/kg bid, oral
Dog/Cat 10 – 30 mg/kg q8h IM, IV
Cefamandole
Horse 10 – 3- mg/kg q4 – 8h IV, IM
Dog/Cat 5 – 15 mg/kg q6h IM, IV
Cefazoline Horse 15 – 20 mg/kg q8h IM, IV
Ruminants 22 mg/kg tid IM (withdrawal meat 30 days)
Cefonicid Horse 10 – 15 mg/kg once daily IM, IV
Dog/Cat 30 mg/kg q6 – 8h IM
Cefoperazone
Horse 30 – 50 mg/kg bid – tid IM, IV
Ceforanide Horse 5 – 10 mg/kg bid IM, IV
Dog/Cat 20 – 40 mg/kg q8h IM, IV, SC
Cefotaxime Goat 50 mg/kg q12h IM
Horse 25 – 50 mg/kg q8h IM, IV
6 – 20 mg/kg tid IM, IV, SC or
Dog/Cat
Cefoxitin 6 – 40 mg/kg tid – qid IM, IV, SC
Horse 30 – 40 mg/kg q6 – 8h IM, IV
Dog/Cat 25 mg/kg bid – tid IM, SC
Ceftazidime
Horse 25 – 50 mg/kg bid IM, IV
Cattle 1 mg/kg q24h IM
Ceftiofur
Horse 25 – 50 mg/kg once or twice daily IM

Ceftizoxime Horse 25 – 50 mg/kg bid – tid IM, IV

Ceftriaxone Horse 25 – 50 mg/kg bid IM, IV
 P a g e | 134

25 – 50 mg/kg tid IM, IV or

Cefuroxime Horse
250 – 500 mg/kg bid oral
Cattle 7 mg/kg IM daily
Sheep/Pig 10 mg/kg IM daily
Cephalexin 10 – 15 mg/kg bid oral or
Dog/Cat 10 – 15 mg/kg q12h (loading dose then
oral)
Horse 10 – 30 mg/kg q8 – 12h IM, IV
Dog/Cat 20 – 40 mg/kg q6 – 8h IV only; painful IM
Cephalothin
Horse 20 – 40 mg/kg tid – qid IM, IV
Dog/Cat 20 – 30 mg/kg tid IM, IV, SC
Cephapirin Horse 20 mg/kg q8h IM, IV
Cattle 300 mg in mastitis tube
Cephradine Dog/Cat 20 – 40 mg/kg tid oral, IM, IV
Calves 7 mg/kg q12h oral
Moxalactam Dog/Cat 50 mg/kg q6 – 8h IM, IV

Lesson 12
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Bacitracin,
Vancomycin, and
Polymyxins

B ACITRACIN

Bacitracin is a polypeptide antibiotic produced by a strain of Bacillus subtilis

isolated in 1943 from a contaminated compound fracture of a girl named Tracy.
Commercial preparations actually contain multiple components. Bacitracin A is the major
component.

Mechanism of Action

Bacitracin is a bacteriocidal that inhibits the second stage of bacterial cell wall
synthesis by inhibiting the phospholipid carriers that transfer mucopeptide building
blocks to the growing cell wall.

Antibacterial Spectrum and Clinical Use

Bacteria susceptible to bacitracin include gram – positive cocci and bacilli;

staphylococci including ß – lactamase producers and group A streptococci. It is
particularly useful against Clostridium perfringens infections in pigs and poultry and
also active against Actinomyces and Fusobacterium
 P a g e | 136

Bacitracin is not absorbed orally and may be used for gut sterilization before
gastrointestinal surgery. It is mainly used for topical application for superficial
infection of the skin and mucous membranes, and is often combined with polymyxin
B or neomycin for this purpose.

Although used to prevent and treat Clostridium perfringens enteritis in pigs and
poultry, it is more commonly employed for improvement of growth rate, feed
conversion efficiency, and egg production in poultry, and as a growth promotant in
cattle and pigs. However, the use of any antibiotic for this purpose in food animals is
strongly discouraged.

Resistance to bacitracin develops rarely in sensitive strains but most Gram – negative
organisms are inherently resistant.

Pharmacokinetics

Bacitracin is poorly absorbed orally through the skin, mucous membrane, or wound
but is absorbed considerably from IM sites. It is widely distributed if given
parenterally but is seldom if at all administered by parenteral routes because of
toxicity.

Adverse Reaction and Toxicity

Parenterally administered bacitracin causes nephrotoxicity. Toxicity may also occur

when large amount is absorbed from extensive burn wound. For this reason, it is not
used for systemic therapy. There may be rare hypersensitivity reaction following
topical use.

Some Useful Drugs

Calves/Lambs/Pigs: 5 – 50 g/ton of feed (up to 16 weeks of age)

Zinc
5 – 20 g/ton of feed (16 – 24 weeks of age)
Bacitracin
5 – 80 mg/ton of feed (by addition to milk replacer)

Layer Hens: 15 – 100 g/ton of feed

Zinc
Broiler Chickens/Turkeys: 5 – 50 g/ton of feed (up to 14 weeks of age)
Bacitracin
5 – 20 g/ton of feed (5 – 26 weeks of age)

VANCOMYCIN

Vancomycin is a high molecular weight glycopeptide and is a fermentation product of

Streptomyces orientalis that inhibits the transfer of the glycopeptide chain from the
phospholipid to the acceptor site during bacterial cell wall synthesis.

Antibacterial Spectrum and Clinical Use

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Vancomycin is bacteriocidal to most Gram – positive aerobic cocci and bacilli while
Gram – negative bacteria are resistant. Like bacitracin, resistance to Vancomycin is
rare but can occur.

Pharmacokinetics

Vancomycin may be administered IV as hydrochloride for treatment of

staphylococcal infection that responds to nothing else. It is not absorbed orally and
can be used to treat Clostridium perfringens enteritis in animals but bacitracin is a less
expensive alternative.

Adverse Reactions and Toxicity

Vancomycin is very toxic and highly irritating to tissues and can cause
thrombophlebitis, deafness, and nephrotoxicity. In humans, the adverse effects
include hypersensitive skin reaction, pain at intramuscular injection sites, histamine –
like reactions (when administered by rapid IV) and ototoxicity. There is not much
information on toxicity in domestic animals.

Some Useful Dosages

Vancomycin is not recommended for use in animals as it is reserved for use in

selected human infections that have been resistant to most antibiotics.

20 mg/kg IV at 12h intervals

Vancomycin
Diluted in at least 200 ml of 5% dextrose solution
General dose for
animals:
5 – 10 mg/kg oral BID

POLYMYXINS

The polymyxins are polypeptide antibiotics isolated from soil bacteria on 1947 to
1950. Although there are many polymyxins, only two are clinically useful:
Polymyxin B (from Bacillus polymyxa) and Polymyxin E also called Colistin (from
B. colistinus)

Chemistry

The polymyxins are simple, basic polypeptides with molecular weight of around
1,200 and act as cationic detergent and are readily water – soluble. 1 mg of polymyxin
 P a g e | 138

B is equivalent to 10,000 units, and 1 mg of Colistin is equivalent to 30,000 units

(Note: this unit equivalent is based on biological assay that applies only to
polymyxins. Penicillin units are different).

Mechanism of Action

The polymyxins bind to phospholipids in cell membrane and alter the osmotic
pressure, selective permeability, and regulatory properties of cell membrane. This
action results in a bacteriocidal effect. Disruptors of cell membrane such as the
polymyxins, unlike the penicillins, may be used in combination with bacteriostatic
drugs since their antibacterial action does not require rapid multiplication of bacteria.
Polymyxins, specifically Colistin, have additional anti – endotoxin and antipyretic
effects. As basic (cationic) drugs, they may combine with endotoxin which is anionic.

Drug Interactions

Highly reactive, the polymyxins bind to quaternary ammonium compounds (such as

some disinfectants), and to other antibacterial drugs such as tetracyclines,
chloramphenicol, sulfonamides, and carbenicillin.

Antibacterial Spectrum and Clinical Use

The spectrum of activity of the polymyxins is narrow. It is active primarily against

Gram – negative bacteria: Enterobacter, E. coli, Salmonella, Shigella, Pasteurella,
Bordetella, Pseudomonas, Brucella, and Klebsiella while Proteus is resistant. Useful
in Gram – negative infections of skin, eye, and ear; and also useful in Gram –
negative enteric infections of cattle and swine.

The polymyxins are synergistic against P. aeruginosa with tetracyclines,

chloramphenicol, sulfamethoxazole, and carbenicillin. Gram – positive bacteria are
resistant. Like bacitracin, the polymyxins are not used systematically because of
toxicity and because of the availability of better choices of antibacterials.

The major clinical application in veterinary medicine includes (a) oral treatment of E.
coli and Salmonella, and (b) treatment of Pseudomonas infections such as otitis
externa and superficial lip infection. Part of the therapeutic mechanism in Gram –
negative infection may relate to their ability to bind bacterial endotoxins.
Pharmacokinetics

Because of their cationic nature, polymyxins are not absorbed orally and poorly
absorbed from the gut and through the skin and mucous membrane. Absorption is
rapid following IM and SC administration (parenteral polymyxins may cause toxic
effects). The polymyxins distribute within the extracellular fluid only but do not get to
the CSF. Tissue binding is important and bound drug is not active. The polymyxins
bind to kidney, liver, lung, heart, and skeletal muscle and are excreted unchanged by
the kidneys over several days.

Polymyxin B as sulfate is for both oral and parenteral use. Colistin as sulfate is for
oral administration and as sulfomethate for parenteral.
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Adverse Reactions and Toxicity

Nephrotoxicity
In the form of reduced tubular perfusion may progress to decrease urine
output, and this is the most important adverse reactions to polymyxins. This
adverse effect occurs at therapeutic doses but is reversible if the drug is
discontinued

Neurotoxicity
Occurs in the form of a dose – dependent curare – like paralysis which is
additive with other drugs such as aminoglycosides and muscle relaxants that
act on the neuromuscular junction. This paralysis may result in respiratory
arrest. Some local allergic reactions may occur but rarely.

Some Useful Dosages

Cow with severe coliform mastitis: 2.5 mg/kg IM

Polymyxin B Other animals: 2.5 mg/kg IV q12h
5 mg/kg oral q12h

Colistin
3 mg/kg q12h IM
Sulfomethate

Colistin
Pigs with colibacillosis: 5 – 10 mg/kg oral
Sulfate

Lesson 13
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Sulfonamides and
Potentiated
Sulfonamides

S SULFONAMIDES

Sulfonamides (or sulfa drugs) were discovered in the early 1930s when
sulfanilamide was observed to be active portion of the azo dye, protonsil. Protonsil
had been shown to protect laboratory animals from bacterial infection. As many as 5,400
derivatives of sulfanilamide were subsequently synthesized and tested but only less than 30
were developed into therapeutically useful drugs. All sulfonamides are derivatives of
sulfanilamide.

While sulfonamides are antimicrobial agents, they are not antibiotics by the true
definition of the term since they are not derived from microorganisms. However, it is now
common to refer to synthetic antibacterial drugs as “antibiotics”.

Common Sulfonamides

For general purpose

(systemic)  Sulfacetamide
 Sulfamethizole
 Sulfisoxazole
 Sulfathiazole
 Sulfamethoxazole
 Sulfachlorpyridazine
 Sulfadimethoxine
 Sulfabromethazine
 Sulfamethoxypyridazine
 Sulfadiazine
 Sulfanilamide
 Sulfaethoxypyridazine
 Sulfadoxime
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 Sulfapyridine

 Phthalysulfathiazole
For gastrointestinal use  Succinylsulfathiazole
(not well absorbed from the  Sulfaguanidine
gut)  Sulfaquinoxaline
 Sulfazalizine

For urinary infection  Sulfisoxazole

 Silver sulfadiazine
(useful for treatment of burns and chronic
For topical use otitis)
 Sulfacetamide
 Mefenide

Chemistry

(Please refer to the chemical structure of sulfonamide; sorry not included here!)

The amino nitrogen (N4) must be in the para position on the benzene ring and must
be unsubstituted for antimicrobial activity. The amide nitrogen (N1) is the primary
site of substitution. Substitution alters the pharmacokinetics of sulfonamides.
Heterocyclic aromatic substitutions yield the most potent compounds.

Sulfonamides behave as weak acids in physiological solutions. They have a wide

range of pKa from 4.8 to 8.6. As a class, sulfonamides are relatively insoluble in
water with few exceptions (Sulfisoxazole, Sulfachlorpyridazine, etc.). The solubility
of one sulfonamide is independent of that of the other sulfonamides in solution (law
of independent solubility), which is important in reducing toxicity when
sulfonamides are used in combination. They are more soluble in aqueous solution at
neural pH than acidic pH 5.5.

Mechanism of Action

They prevent bacteria from utilizing para – aminobenzoic acid (PABA) in the
synthesis of tetrahydrofolic acid by competitively inhibiting the bacterial enzyme
responsible for the incorporation of PABA into dihyropteroic acid, the immediate
precursor of dihydrofolic acid. Dihydrofolic acid (DHF) is further reduced to
tetrahydrofolic acid (THF) in a reaction catalyzed by THF reductase. THF serves
as a cofactor in one – carbon metabolism involved in DNA and RNA synthesis.

Most bacteria cannot utilize exogenous sources of folic acid. This explains the
selective toxicity of sulfonamides for bacteria. However, blood, pus, and tissue
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breakdown products reduce the antibacterial action of sulfonamides because the

bacterial requirement for folic acid is reduced in media that contain purine and
thymidine.

Antimicrobial Spectrum and Clinical Use

The broad antimicrobial spectrum of sulfonamides includes:

 Gram – positive aerobic and anaerobic bacteria,
 Gram – negative bacteria,
 Nocardia,
 Toxaplasma gondii (a protozoan),
 Coccidia, and
 Chlamydia

Originally (in 1940s) sulfonamides were active against Gram – positive and Gram –
negative bacteria but now many of these organisms are resistant. The correlation
between the in vitro sensitivity for sulfonamides is less than that seen with other
agents. Often, a higher concentration is needed in vivo that is predicted in vitro.
Widespread resistance has greatly limited the effectiveness of sulfonamides in treating
bacterial diseases in animals. Potentiated sulfonamides (trimethoprim – sulfonamide
combinations) have largely replaced sulfonamides as therapeutic agents used in
companion animals.

Primary clinical uses of sulfonamides include:

 Treatment of toxoplasmosis, chlamydiosis, and nocardioses (combined with
ampicillin and minocycline) sulfasalazine is commonly used in the treatment
of chronic colitis

Resistance to sulfonamides may be in the form of:

a. Enzyme adaptation
b. Chromosomal mutation and selection
c. Plasmid – mediated (R – Factor)

Organisms resistant to sulfonamides may have any of the following traits:

a. Increased capacity to synthesis of PABA
b. Decreased uptake of sulfonamides
c. Decreased affinity of dihydropteroate synthase for sulfonamides
d. Increase synthesis of dihydropteroate synthase

Resistance to one sulfonamide means cross resistance to all sulfonamides.

Pharmacokinetics

Absorption
Sulfonamides are rapidly absorbed with good bioavailability following oral
administration. There is good bioavailability even in ruminants. However, the
rate of absorption in the ruminants is slower than in monogastrics. Exceptions
are the gastrointestinal sulfonamides which are designed to remain in the GIT
(gut active). They are also absorbed following IM and SC administration.
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Intravenous formulations, however, are very irritating and can cause tissue
damage because of alkaline pH. The drug should not be administered through
this route. Extravascular injection may result in tissue sloughing. Absorption
is variable following topical, intra – uterine, and intramammary (very
irritating) administration.

Distribution
Sulfonamides are distributed widely in the body tissues and fluids including
synovial, peritoneal, ocular, and pleural fluids. The distribution varies with
individual sulfonamides and is dependent upon the lipid solubility, pKa and
protein binding of each sulfonamide. The degree of protein binding varies
from <10% to >90%. There is both drug – and species – dependent variation
in percent protein binding.

Penetration into the CSF is variable depending on the specific sulfonamide.

Concentrations of 10 to 80% of the serum level have been reported.
Sulfadiazine consistently attains the highest concentration in the CSF.
Diffusion into the milk is highly variable. Concentration in the milk following
parenteral administration is primarily dependent on the pKa of the
sulfonamide and also on lipid solubility and protein binding. In general,
sulfonamides with high pKa (>7) reach higher concentration in milk by ion –
trapping.

Biotransformation
Sulfonamides are extensively metabolized in animals with differences between
animal species and individual drugs. Acetylation is highest in human, then in
decreasing order, ruminant, horse, and cat. Dogs are unable to acetylate
sulfonamides and are therefore susceptible to sulfonamide toxicity.

Other metabolic biotransformations include:

a. Deacetylation
b. Oxidation (primarily hydroxylation)
c. Sulfate and glucoronide conjugation
d. Cleavage of the heterocyclic ring

The metabolites of sulfonamides are much less active than the parent drug.
Many of the acetylated metabolites are less soluble than the parent
sulfonamides and contribute to renal damage caused by these compounds.
Exceptions are the acetylated metabolites of the sulfapyridines. Sulfadiazine,
sulfamethazine, and sulfamerazine which have similar solubility to the parent
compounds sulfamethoxazole and sulfathiazole are the commonly used
sulfonamides with less soluble acetylated metabolites.

Excretion
The kidney is the primary route of elimination for sulfonamides and their
metabolites. The unbound sulfonamides in the blood are filtered by the
glomerulus. Sulfonamides in the renal tubules undergo tubular reabsorption.
 P a g e | 144

The extent of tubular reabsorption largely determines the rate at which a

sulfonamide is excreted in the urine. Sulfonamides that are extensively
reabsorbed have longer duration of effect. The extent of reabsorption is
dependent on the lipid solubility and pKa of the sulfonamide and the pH of the
tubular urine.

A few metabolites undergo active renal secretion:

a. Sulfathiazole (in horse, swine, and cattle)
b. Sulfamethazine
c. Sulfadimethoxine
d. Sulfamethoxazole

The rate of renal excretion largely determines the duration of action of

sulfonamides. Excreted parent sulfonamides and metabolites may reach high
enough concentration in the urine to afford bacteriocidal effect in the urinary
tract. Small amounts are eliminated in the feces, bile, milk, sweat, and tears.

Pharmaceutical Considerations
Sulfonamides often come as sodium salts to increase solubility. Monosodium salts are
caustic and to be administered by IV only. Disodium salts may be given IM, IP, etc.
sulfonamides are incompatible with calcium – containing solutions.

There is always a potential for crystalluria (renal deposits) with sulfonamides due to
insolubility. Using “triple sulfa” which is a combination of three sulfonamides of
varying solubility partially solves this problem. According to the law of independent
solubility, the presence of one sulfonamide in solution does not affect the solubility of
the other sulfonamides present in the same solution. Thus, in the triple sulfa, the dose
of the individual sulfonamides is proportionately reduced and the combination is less
likely to cause crystalluria.

Adverse Reactions
The major concern in sulfonamide therapy is the potential damage to the kidneys and
urinary tract. Sulfonamides and their metabolites, because of their limited water
solubility, tend to form crystalline aggregates in the urine as their concentration
increases.

The crystalline aggregates which lead to irritation and obstruction of urine flow are
deposited in the:
 renal tubules
 renal pelvis
 ureters, and
 urinary bladder
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This is more of a problem with older less soluble sulfonamides (e.g. sulfamethazine,
sulfamerazine, and sulfanilamide). Decreased urine output and low urine pH enhance
crystallization. Sulfonamides and their acetylated metabolites are less soluble at acid pH
(pH 5.5 and below).

To prevent or minimize renal toxicity:

a. Ensure adequate water intake
b. Keep urine on the alkaline side (caution when administered concurrently with
urine acidifiers like ascorbic acid)
c. Use triple – sulfa
d. Use more soluble sulfa (Sulfisoxazole, Sulfachlorpyridazine)
e. Combine sulfonamide with trimethoprim (see below)

Other adverse effects of sulfonamides include:

a. Gastrointestinal disturbances in the form of loss appetite
b. Vomiting
c. Rumen atony, and
d. Diarrhea

These effects are caused by direct irritation and by suppression of microbial activity in the
ruminant (very common).

Sulfonamides can also cause:

a. Drug – induced fever (common)
b. Hypersensitivity reaction (photosensitivity, skin and vascular reactions)
c. Hematologic toxicity (agranulocytosis, hemolytic anemia, thrombocytopenia)
d. Keratoconjunctivitis sicca and lens opacity (occurs after long term therapy)

Caused Keratoconjunctivitis in old dogs:

 Sulfadiazine
 Sulfasalazine

Peripheral neuritis and central and peripheral myelin degeneration may also be observed
in some cases as well as decreased egg production in poultry. Rapid IV injection may
lead to ataxia and collapse. Sulfaquinoxaline used to treat coccidiosis has caused death in
puppies. Hemorrhagic diathesis due to antagonistic effect on vitamin K production is
quite common in poultry.

Drug Interactions
Local anesthetics such as procaine, butacaine, and benzocaine contain a PABA
nucleus which when released by hydrolysis may decrease the effectiveness of
sulfonamides. The combined treatment with sulfonamide and procaine penicillin can
lead to such antagonism.

Individual Drug of Interest

Sulfonamides come in a wide variety of formulations.

Oral dosage forms include:

a. Tablets
b. Boluses
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c. Sustained release boluses

d. Water – soluble powders
e. Solutions, and
f. Feed premixes

Solutions for IV administration have very alkaline pH and are very irritating if
administered IM or SC. There are a few preparations buffered to neutral pH. Triple
sulfas were designed to reduce the renal toxicity of sulfonamide therapy. While the
solubility of each sulfonamide is independent of that of the others, the antimicrobial
effects of the three sulfonamides in combination are additive. Most triple sulfas for
veterinary use contain sulfamethazine, sulfathiazole, and one several other sulfas
including sulfanilamide, sulfamerazine, and sulfapyridine.

Some Useful Dosages

Drug Species Initial Maintenance Route and

Dose Dose Frequency
(mg/kg) (mg.kg)

Horse 66 66 Oral q8h

Sulfathiazole Cattle, Sheep 66 66 Oral q4h
Pig

Sulfamethazine Cattle 220 110 Oral q24h IV

Sulfadiazine All 50 50 Oral q12h

Sulfadimethoxine All 55 27.5 Oral q24h

Cattle 55 55 Oral q24h

Sulfaethoxypyridazine
Pig 110 55 Oral q24h

Sulfapyridine Cattle 132 66 Oral q12h

Succinylsulfathiazole All 160 80 Oral q12h

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POTENTIATED SULFONAMIDES

Potentiated sulfonamides refer to the various combinations of a sulfonamide and an

inhibitor of tetrahydrofolate (THF) reductase. Trimethoprim, the most commonly
used THF reductase inhibitor, is used in combination with selected sulfonamides in
veterinary medicine. Because of its very weak antibacterial activity, trimethoprim is
not used by itself in veterinary medicine and only rarely in human medicine.

The most useful potentiated sulfonamides are:

a. Trimethoprim – sulfadiazine
b. Trimethoprim – sulfamethoxazole, and
c. Trimethoprim – Sulfachlorpyridazine

There may be combinations of trimethoprim with other sulfonamides but these are the
most rational since these sulfonamides have pharmacokinetics similar to
trimethoprim. To ensure synergism, the sulfonamide and trimethoprim in combination
must be absorbed, distributed, and excreted together. Very short – acting
sulfonamides are excreted early leaving trimethoprim. On the other hand, long –
acting sulfonamides stay long after trimethoprim has been excreted.

Chemistry

Trimethoprim is a synthetically produced diaminopyridine compound and is a

weak base with a pKa of 7.2 and good lipid solubility.

Other diaminopyridine compounds which have found use in veterinary

medicine include:
 Pyrimethamine (an antiprotozoal agents)
 Diaveridine (anticoccidial), and
 Ormethoprim (antibacterial)

Mechanism of Action
Potentiators of sulfonamides were developed to selectively inhibit bacterial
dihydrofolate reductase. Trimethoprim, a structural analogue of the pteridine
portion of dihydrofolic acid reductase, is a competitive inhibitor of
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dihydrofolate reductase. The affinity of bacterial dihydrofolate reductase for

trimethoprim is much greater than that of eukaryotic cells. This creates a
selective toxicity for bacteria and a wide margin of safety for host animals.

Spectrum of Activity and Clinical Use

The combination of trimethoprim and sulfonamide (TMP – S) has a broad
spectrum of activity. Most sensitive are E. coli, Streptococcus, Salmonella,
Pasteurella, Shigella, Actinomyces, Nocardia, and some protozoan parasites.
Not sensitive are Leptospira and Pseudomonas. The combination is very good
for urinary tract infection.
Pyrimethamine, Diaveridine, and Ormethoprim may also potentiate
sulfonamides but they do not have much antibacterial effect. They are more
commonly combined with Sulfaquinoxaline for their synergistic effect against
coccidia and some other protozoan parasites.

Antibacterial preparations are in a fixed combination of 1part trimethoprim to

5 parts sulfonamide. However, the optimum antibacterial ratio in vivo is 1:20
which can be attained by a 1:5 ratio of trimethoprim and a sulfonamide.
Combinations intended for antiprotozoal therapy may not require this fixed
ratio.

The dosage is aimed at maintaining the concentration of the sulfonamide.

Resistance
All mechanisms of resistance to sulfonamides also apply to the sulfonamides
in combination with trimethoprim. The resistance to trimethoprim is both
chromosomal – and plasmid – mediated, and the mechanisms include:

 Production of dihydrofolate reductase with reduced affinity for

trimethoprim (the primary mechanism in clinical setting)
 Decreased permeability of bacterial cell to trimethoprim
 Overproduction of dihydrofolate reductase
 Mutation to thymine independence

Resistance develop[s rapidly to trimethoprim alone. However, an organism

may be resistant to the sulfonamide or to trimethoprim and still the
combination may still show synergism against the organism. Most commonly
an organism is resistant to the sulfonamide in the absence of trimethoprim.

Pharmacokinetics

Absorption
Trimethoprim is well absorbed orally. It is absorbed faster than sulfonamides
and therefore peaks sooner in the blood. It is degraded by rumen fluid and
therefore, is not orally bioavailable in adult ruminants. Absorption is usually
good following SC administration.

Distribution
Trimethoprim has a greater tissue distribution than sulfonamides. Its tissue
levels are greater than blood levels for most tissues (and body fluids). High
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concentrations are attained in tissues especially in the lungs, kidneys, CSF,

joint fluid, bone, prostate glands, and eyes. High tissue concentrations persist
for long period. High concentration of both trimethoprim and sulfonamide
occurs in the urine.

Biotransformation and Excretion

Metabolism of trimethoprim occurs in most species and is of major
importance in the ruminant. Oxidation and/or conjugation occur yielding less
active metabolites. [For the metabolism of sulfonamides, see previous lesson].
Ruminants excrete only 2 – 3% of unchanged trimethoprim in the urine.

Renal excretion is the primary route of elimination of trimethoprim and its

metabolite in the dog and human. The half – lives of trimethoprim and
sulfonamides in combination generally do not coincide in any animal species.
However, they are still generally effective clinically. The combination has
similar pharmacokinetic properties to sulfonamide alone. The best
combination, however, are those with short – acting sulfonamides such as
sulfadiazine, sulfamethoxazole, and Sulfachlorpyridazine.

Adverse Reactions and Toxicity

Trimethoprim has a wide margin of safety – 60,000 x more potent on bacterial
than on mammalian dihydrofolate reductase. A;; the problems which were
discussed for sulfonamides may occur with trimethoprim – sulfonamide
combination. Trimethoprim may cause clinical signs of folate deficiency in
animals that are borderline folate deficient such as those in poor nutrition or
on methotrexate (anticancer) therapy (rare).

Adverse reactions to the combination include:

 Superinfections
 Nausea and vomiting (generally tolerated)
 Blood dyscrasias (due to bone marrow depression)
 Hypersensitivity (quite common in Dobberman dogs)
 Anaphylaxis (in horses)
 Keratitis sicca with prolonged therapy (in dogs)
 Sterile abscess following SC injection

Drug Interactions
Trimethoprim – sulfa increases the risk of bone marrow suppression when
used with antimetabolites (6 – mercaptopurine and azathioprine) and
antifolates (methotrexate and Pyrimethamine).
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Some Useful Dosages

15 mg/kg oral q12h

Trimethoprim – sulfadiazine
15 – 50 mg/kg oral, IV, IM q24h

Trimethoprim – Sulfadoxime 16 – 24 mg/kg IV, IM q24h

55 mg/kg oral q24h initial:

Ormethoprim – Sulfadimethoxine
27.5 mg/kg oral q24h subsequent

Trimethoprim – Sulfachlorpyridazine 32 mg/kg oral in feed (poultry)

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Lesson 14

Aminoglycosides
and Spectinomycin

A MINOGLYCOSIDES

Aminoglycosides were developed as a result of the search for antibiotics to treat

Gram – negative infections. Streptomycin was isolated from Streptomyces
griseus in 1943. Since then, numerous other aminoglycoside antibiotics have been isolated
from various Streptomyces and Microspora species.

Compounds

Streptomycin Dihydrostreptomycin Neomycin

Kanamycin Gentamicin Paranomycin
Amikacin Tobramycin Sisomycin
Netilmicin

CHEMISTRY

The aminoglycosides consist of 2 – 3 aminosugars joined in glycoside linkage to a

hexose nucleus (aminocyclitol). Correctly referred to as aminoglycosidic
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aminocyclitols, these compounds are weak bases with pKa between 7.2 and 8.2
polycationic, polar, and very water soluble.

Mechanism of Action

The aminoglycosides bind with the free 30S ribosomal subunits so that it is made
unable to bind with mRNA and cause misreading of the genetic code. Because of the
misreading of the genetic code, there is failure of initiation of protein synthesis hence
no protein is produced. This leads to a bacteriocidal effect.

To understand better the mechanism of action of aminoglycosides and other bacterial

protein synthesis inhibitors, you must review the process of protein synthesis in
bacteria. Most protein synthesis inhibitors selectively inhibit the 70S bacterial
ribosomes. The 70S ribosome consists of two subunits: the 30S and the 50S ribosomal
subunits. Mammalian (eukaryotic) ribosomes are 80S and consist of two subunits:
40S and 60. Eukaryotic cells also contain mitochondria which have 70S ribosomes
similar to bacterial ribosomes. This may be important in explaining selective toxicity
and the “side – effects” of some of the antibiotics in the host cells.

Steps in Protein Synthesis

 Initiation
Occurs at a specific codon AUG which codes for f – met (formyl –
methionine)

 Elongation
Addition of more amino acids to the growing peptide chains

 Termination
Occurs on three specific codons; UAA, UGA, and UAG appearing. A specific
release factor binds and hydrolyzes the bond holding the peptide to the tRNA
in the P site. The mRNA dissociates from the 70S ribosome which then breaks
up into 30S and 50S subunits for recycling.

The entry of aminoglycosides into bacterial cells involves both passive diffusion
through aqueous pores and an active transport which requires ATP and is inhibited by
acid pH, lack of oxygen, hyperosmolarity, calcium and magnesium. Entry into the cell
is facilitated by the presence of drugs that interfere with the cell wall synthesis; hence,
the classic synergism between aminoglycosides and beta – lactam antibiotics.

The activity of the aminoglycosides is optimal in a slightly basic environment (pH 7 –

8).

Antibacterial Spectrum and Clinical Use

Aminoglycosides affect both Gram – positive (limited) and Gram – negative bacteria
(E. coli, Klebsiella, Enterobacter, Proteus, Pseudomonas, and Salmonella) but their
use should be restricted to severe Gram – negative infections. They are not effective
against anaerobic bacteria. Newer aminoglycosides are effective against resistant
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Gram – negative organisms like Pseudomonas and Proteus. Streptomycin (but not the
other aminoglycosides) is effective against tuberculosis

Aminoglycosides are synergistic with ß – lactam antibiotics. Gentamicin is commonly

synergistic with trimethoprim – sulfonamide combination against E. coli and
Klebsiella pneumonia.

Resistance

There may be rapid development of resistance especially with subtherapeutic

concentrations. The most important mechanism of resistance to aminoglycosides is
plasmid – mediated enzymatic destruction of the drugs. The enzymes are usually
localized in the bacterial periplasmic space near the site of drug transport through the
cell membrane. Many enzymes are capable of adenylating, acetylating, or
phosphorylating aminoglycosides exist. Cross – resistance among aminoglycosides is
not uncommon and depends on the specificity of the inactivating enzymes. Amikacin,
Apramycin, and netelmicin are very resistant to enzyme action.

Other mechanisms of resistance are failure of penetration and reduced affinity of

ribosomal binding site due to mutation of specific ribosomal proteins.

Pharmacokinetics

Absorption
Aminoglycosides are poorly absorbed from the gut (<1% of the oral dose)
because of their polar and polyionic nature. However, patients with impaired
renal function may get toxicity following repeated oral administration.
Significant absorption may occur, however, from inflamed gut, or from large
burns when applied topically. They may be rapidly absorbed systematically
from serosal surfaces of body cavities and from IM and SC injection sites.

The milk – to – plasma concentration ratio attained after parenteral

administration is 0.4 – 0.8 (or 1:2).

Distribution
Aminoglycosides are distributed only in the extracellular fluid. As obligate
polar molecules, they don’t cross the cellular barriers very well. They have
low plasma protein binding and reach therapeutic levels slowly in synovial,
peritoneal, and pleural fluids after repeated doses.

Aminoglycosides poorly penetrate into the CSF, eye, respiratory secretion, and
prostate. Concentrations in the bile reach one – third of the plasma level. They
tend to accumulate in kidney tissues by pinocytosis by the cells of the
proximal convoluted tubules. High concentrations is also attained in the
endolymph and perilymph of the inner ear (hence, predisposition to
ototoxicity).

These antibiotics are inactive in suppurative wounds because they bind to pus
(probably to DNA). Remember polymyxins?!!
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Excretion
Aminoglycosides are excreted mainly by glomerular filtration with some
tubular secretion and tubular reabsorption. High concentrations of unchanged
aminoglycosides are attained in the urine. Their elimination half – life is short
(about 1.5 – 3 hours) in domestic animals.

Tissue – bound aminoglycosides may still be detected in the kidneys 20 – 30

days after administration is discontinued. The elimination half – life of the
tissue – bound aminoglycosides is 30 – 700 hours in human, perhaps similar in
animals.

Adverse Reactions and Toxicity

Nephrotoxicity
All aminoglycosides are capable of causing renal damage.

Characterized by:
 Renal tubular cell necrosis
 Albuminuria
 Elevated blood urea nitrogen (BUN)
 Reduced urine output

A patient is predisposed to renal damage by previous:

 Renal disease
 Old age
 Dehydration, and
 Concurrent use of furosemide (a diuretic)

Acute tubular necrosis occurs more likely with prolonged therapy (6 – 7 days
or longer). Tubular casts and increased protein in the urine are characteristic
early signs of toxicity. Significant damage is already present when the BUN
and Creatinine are elevated. Gentamicin is the most nephrotoxic of the
aminoglycosides used systemically but all are nephrotoxic.

The therapeutic index for aminoglycosides is narrow, the nephrotoxic dose is

not much greater than the therapeutic dose. Dosage adjustment in patients with
renal impairment is very important. Concurrent therapy with nephrotoxic
drugs (e.g. amphotericin B, cephalothin) and loop diuretics as well as in the
presence of volume depletion, shock, and pre – existing renal disease can
enhance toxicity. Aminoglycosides – induced nephrotoxicity is thought to be
reversible but in veterinary medicine it is very difficult to keep a patient alive
long enough for its kidneys to repair themselves.

Ototoxicity
Damage to the auditory portion of the ear leads to deafness which is may be
permanent. Damage to the vestibular portion causes ataxia and incoordination
 P a g e | 155

especially in cats with prolonged exposure. Both vestibular and cochlear

(auditory) damage can occur with some preferential toxicity among
aminoglycosides. Those with predominantly cochlear (auditory) toxicity are
amikacin, kanamycin, and neomycin. Those with predominantly vestibular
toxicity are streptomycin and gentamicin. Tobramycin affect both portions
equally. Ethacrynic acid and other loop diuretics, and the ensuing volume
depletion may also enhance ototoxicity.

Neuromuscular Blockade
Curare – like paralysis is dose – related and may occur only with high doses.
Aminoglycosides inhibit pre – junctional release of acetylcholine while also
reducing post – synaptic sensitivity to acetylcholine. This may become
significant only when other neuromuscular inhibitors such as muscle relaxants
and anesthetics are concurrently administered. Neostigmine and calcium
antagonize the neuromuscular blockade produced by aminoglycosides and are
used in the treatment of this form of toxicity.

Hypersensitivity reactions are rare.

Drug Interactions

Aminoglycosides and penicillins in solution or suspension in the same container

inactivate each other except penicillin G and streptomycin. Penicillin – streptomycin
suspension must be used within 24 hours after reconstitution. Interaction also occurs
in the body fluids when both types of antibiotic are present in high concentrations. In
usual doses, however, gentamicin, for some reasons, shows antagonism with
chloramphenicol, tetracyclines, and erythromycin.

Aminoglycosides will potentiate the toxicity of nephrotoxic drugs and neuromuscular

blocking drugs:
 They bind to pus, calcium and magnesium
 Neutralized by acid
 32x more active in alkaline urine

Individual Drugs

 Veterinary formulations contain Dihydrostreptomycin in combination

with procaine penicillin for IM, SC, and intramammary
administration.
 These are the first aminoglycosides made available
Streptomycin and  Now many organisms are resistant especially Gram – negative and
Dihydrostreptomycin especially in food animals. Both are especially ototoxic in cats.
 Special uses:
a. For eliminating kidney carrier state of leptospirosis in swine,
and
b. Concurrently with minocycline to treat brucellosis.
 Streptomycin is also used in the treatment of tuberculosis
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Neomycin:  Used orally for GI infections or to suppress GI microflora in hepatic

A mixture of encephalopathy and pre e- operatively for large bowel surgery.
Neomycin A and  However, it can cause malabsorption syndrome or GI superinfection
Neomycin B  Commonly used topically in ointments, otic and ophthalmic
(Framycetin) preparations and urinary irrigation solution

 Most active and has broadest

 Has broadest spectrum
 Particularly useful against Enterobacteriaceae
 Widespread use has caused resistant strains of bacteria
 Gentamicin rather than “Gentamycin” is the correct spelling since it is
Gentamicin
not a product of Streptomyces. Often, the aminoglycoside of choice
for serious Gram – negative infections caused by susceptible
organisms.
 It is given IV, IM, SC, ophthalmic and otic preparations, and for intra
– uterine infusion in mares
 Nephrotoxicity is the greatest problem.

 Not as active as gentamicin

Kanamycin  Has no activity against Psedomonas
 Active against many species of mycobacteria and mycoplasma

 Resistant to most bacterial enzymes that inactivate other

aminoglycosides
 Used for gentamicin – resistant Gram – negative infections (e.g.
Amikacin Pseudomonas, Klebsiella, and E. coli)
 Administered IV, IM, and SC
 Available for intra – uterine infusion in mares.
 Relatively expensive

 Has antibacterial activity which is almost identical to neomycin

Paranomycin  Has activity against Entamoeba hemolytica and some helminths

 Resists most of the plasmid – mediated degradative enzymes

Apramycin  Used for treatment of enteritis caused by Gram – negative
bacteria in piglets and calves

 Has reduced toxicity and enhanced antibacterial activity

Tobramycin compared to kanamycin
 More active than gentamicin against Pseudomonas aeruginosa
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Sisomycin  Very similar to gentamicin but less likely to cause ototoxicity

 Cross – resistance with gentamycin occurs

 Similar to Sisomycin but active against gentamicin – resistant

Netilmicin strains
 “Micin” indicate that it is not a Streptomyces product

Some Useful Dosages

Adjust the dose rate and frequency as needed.

Gentamicin 1 – 2 mg/kg IM, SC q8h

Kanamycin 4 – 5 mg/kg IM, SC q8h

Streptomycin 7.5 – 12.5 mg/kg IM, SC q12h

Amikacin 5 – 7.5 mg/kg IM, SC q12h

Netilmicin 1 – 2 mg/kg IM, SC q8h

Neomycin 0.5 – 1 mg/kg/quarter intramammary q24h

SPECTINOMYCIN

Spectinomycin is produced by Streptomyces spectabilis. It is a non – aminoglycoside

aminocyclitol and therefore, structurally related to aminoglycosides. However, it does not
contain aminosugars attached in glycosidic linkages.

Chemistry

Spectinomycin is also an aminocyclitol (similar to the nucleus of aminoglycosides)

but does not have a sugar attached to it. It is a weak organic base with two pKa’s (6.4
and 8.7). it has low lipid solubility but is highly water soluble and relatively stable in
solution.

Mechanism of Action
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Like the aminoglycosides, Spectinomycin binds with the 30S ribosome and inhibit
CHON synthesis but does not cause misreading of the genetic code. Unlike
aminoglycosides, it is bacteriostatic.

Spectrum of Activity and Clinical Use

Spectinomycin has a narrow spectrum including primarily Gram – negative bacteria

but not as active as the aminoglycosides. It has some activity against mycoplasma but
none against anaerobes.

It is used in veterinary medicine in the treatment of mycoplasma infections (usually in

combination with a lincosamide), diseases caused by Enterobacteriaceae, and
respiratory diseases caused by Gram – negative bacteria.

Resistance

Resistance to Spectinomycin can develop rapidly as a result of mutation or R – factor

transfer. Some resistance is the result of adenylation of Spectinomycin by bacterial
enzymes.

Pharmacokinetics

Spectinomycin is poorly absorbed from the gut (<10% in dogs) but rapidly absorbed
when given IM or SC. It has a low volume of distribution limited to extracellular fluid
because of poor lipid solubility.

Tissue concentrations of Spectinomycin seldom exceed 25 – 50% of the serum

concentrations. There is little penetration into the brain, aqueous humour, and bone.

It is excreted rapidly unchanged in the urine by glomerulus filtration; 75% of doses

are cleared in 4 hours; the half – life is only 60 minutes in most cases.

Adverse Reactions and Toxicity

Spectinomycin is relatively non – toxic even at high doses. Neuromuscular blockade

is its most significant toxicity but rare. It can potentiate other neuromuscular blocking
agents. IM injection may cause pain.

Some Useful Dosages

Spectinomycin
20 – 40 g/kg oral q8h for enteric infection
Horse: 10 – 20 mg/kg IV daily

Cattle/Sheep: 10 – 30 mg/kg IM, IV daily

Calf/Lamb: 7.5 – 12.5 mg/kg oral BID

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Pig: 25 g/100 L drinking water

10 – 20 mg/kg IM, IV

Piglet: 50 mg BID for <4.5 kg b.w.

100 mg for >4.5 kg b.w

Dog/Cat: 100 – 300 mg IM, IV daily

Poultry: 55 g/100 L drinking water

10 – 20 mg/kg IM, SC daily

Lesson 15

Tetracyclines
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T he tetracyclines are effective against a large number of different organisms and

were one of the first to be known as “broad spectrum: antibiotics.
Chlortetracycline was the first in the group to be isolated in 1944 from the
fungus Streptomyces aureofasciens all tetracyclines are derived from either
aureofasciens or S. rimosus directly or semi – synthetically.

Chemistry

All tetracyclines are amphoteric (capable of acting both as acid and as base) and
crystalline salts can be formed either with strong acids or strong bases. The most
common salt is the hydrochloride, except for doxycycline which is available as
doxycycline hyaclate (doxycycline hemiethanolate hemihydrate). The tetracyclines
are most lipid soluble in the zwitter - -ion form, at their isoelectric point (pH 5.6 for
all tetracyclines except minocycline which is a full pH unit higher). Minocycline and
Doxycycline are most lipid soluble. All tetracyclines are not very stable in aqueous
solution and are heat labile.

Mechanism of Action

Tetracyclines are bacteriostatic by inhibiting protein synthesis. By reversibly binding

to 30S ribosomal subunit, they block the attachment of aminoacyl transfer RNA
(tRNA) to the messenger RNA (mRNA) receptor site (A site). Protein synthesis is
started but not completed.

The entry of tetracyclines in the Gram – positive bacterial cells requires two
processes:
 Passive diffusion through hydrophilic pores in the outer cell membrane
 Active transport through the inner cell membrane

They can be bacteriocidal at higher concentrations.

Spectrum of Activity and Clinical Use

 Gram – positive bacteria including Bacillus, Listeria, Erysipelothrix, some

Streptococci. Many strains of Staphylococcus are resistant.

 Gram – negative bacteria including Hemophilus, Brucella, Yersinia, Pasteurella,

and Francisella. Many strains of E. coli, Klebsiella, Enterobacter, H. influenza,
Proteus vulgaris, and Pseudomonas aeruginosa are resistant.

 Action on anaerobes may account for gastrointestinal upset

 Other organisms affected are Mycoplasma, Chlamydia, Anaplasma, Rickettsia,

Actinomyces, and Nocardia

Mechanism of Resistance
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Bacterial organisms may acquire resistance to tetracyclines by reducing uptake of

drug by plasmid – mediated or chromosomally mediated means. Generally, there is
cross – resistance among the tetracyclines. Minocyclines is often active strains of S.
aureus resistant to other tetracyclines.

Pharmacokinetics

Absorption

All tetracyclines are adequately absorbed after oral administration to treat

systemic infections. Doxycycline and Minocycline, which are more lipophilic,
are more completely absorbed (90 – 100%). Other tetracyclines are
incompletely absorbed. Effective levels are attained in 2 to 4 hours.

Tetracyclines form relatively insoluble chelates with di – and tri – valent

metals (Ca²⁺, Mg²⁺, Al²⁺, Fe³⁺). Administration of tetracyclines with dairy
products, antacids and iron preparations can greatly reduce their oral
absorption. If given orally to fasted animals, a high blood level may be
obtained. Food, including dairy products and minerals does not interfere with
absorption of doxycycline and minocycline. Tetracycline may be absorbed
after IM or SC injection but can be very painful and damaging to tissues. They
are also absorbed following intra – uterine or intramammary infusion.

Distribution

Tetracyclines have wide volume of distribution in the body but distribution

may vary depending on the lipid solubility and protein binding of the
individual drug. The volume of distribution is relatively greater than body
water due to tissue binding. The highly lipid soluble tetracyclines
(doxycycline and minocycline) concentrate in tissues to a greater extent than
the less soluble ones.

All tetracyclines reach high concentration in the kidney, bile, liver, lung, and
sites of active ossification. There is good penetration in synovial fluid, sinuses,
mucosa, and milk. They cross the placenta and enter fetal circulation and
amniotic fluid. The older tetracyclines penetrate the brain, CSF, eye, and
prostate but may accumulate when injected at high doses IV over a period of
time. The newer more lipid soluble tetracyclines distribute to these tissue well.
Tetracyclines are stored in reticuloendothelial cells of the liver, spleen and
bone marrow, in bone, and in the dentine and enamel of unerupted teeth.

Elimination

Tetracyclines are eliminated in the urine and feces. They undergo entero –
hepatic circulation. Most of the dose is excreted unchanged by the kidney via
glomerular filtration. There may be some degree of tubular reabsorption
depending on lipid solubility and urine pH (alkaline urine increases excretion).
Doxycycline and minocycline are exceptions because they are primarily
excreted in the feces by direct mucosal secretion, as inactive conjugate or
 P a g e | 162

chelate. Doxycycline and minocycline undergo some metabolism in human

but little has been noted in the dog.

Adverse Reactions and Toxicity

In general, tetracyclines are non – toxic. Dogs and cattle usually tolerate the drugs but
cats and horses have more problems. Tetracyclines cause gastrointestinal upset due
to alteration of normal GI flora which can result in superinfection with toxin
producing bacteria and fungi, and by direct irritation of the GI tract.

 Dogs may vomit or have diarrhea but giving the drug with food can lessen GIT
upset Avoid tetracycline in dogs in the last 3 weeks of pregnancy and the first
month of life

 High oral doses can suppress rumen fermentation in cattle

 In cats, oral doses can result in diarrhea, colic, vomiting, depression, fever, and
anorexia which severely limit their use in cats

 In the horse, therapeutic doses (IV) of tetracycline have been associated with
apathy, anorexia, severe diarrhea, and even death. Tetracyclines should be used
cautiously in the horse.
The degree of effect is dose – dependent. Tetracyclines cause:

 Staining of teeth
 Enamel hypoplasia
 Stunt bone growth in young animals

Hepatotoxicity has been reported in dogs (and people) especially in patients with
impaired renal function.

A clinical syndrome characterized by nausea, vomiting, polyuria, polydipsia,

proteinuria, acidosis, glycosuria, and aminoaciduria (Fanconi – like syndrome) has
been observed in patients given outdated and degraded tetracycline. Rapid IV
administered of oxytetracycline to cattle and horse can produce collapse.

The vehicle propylene glycol used in the formulation is probably the cause. Rapid IV
administration in cow can precipitate signs of milk fever (hypocalcemia).

Other adverse reactions include:

 Phototoxicity
 Hypersensitivity reactions
 Anaphylaxis (rare), and
 Increased catabolism
 Increased blood urea nitrogen (BUN)
 P a g e | 163

Individual Drugs

Chlortetracycline  Mostly used as feed additive in cattle, pigs, and poultry

(Aureomycin)  Has poor oral absorption which is approximately 35%

 Given orally, IV, and IM

 Used therapeutically in small animals
Tetracycline
 Also used for chemicals pleurodesis to obliterate the
pleural space in malignant effusions

 Given IV, IM, SC, as ophthalmic, ointment, oral,

intramammary, and as feed additive
 Primarily approved therapeutic tetracycline in food animal
Oxytetracycline and equine medicine
 Long – acting preparation of oxytetracycline is available
which can give therapeutic levels for 72 hours when
injected IM

 Given oral, and IV

 Can be given less frequently and at lower doses than older
tetracyclines
Minocycline
 Very expensive
 CNS side effects and vestibular toxicity which was seen in
50% of people were not found in dogs

 Given oral, and IV

Doxycycline  Can be given less frequently
 Can be used without dosage adjustment in renal failure

Some Useful Doses

 P a g e | 164

Dog/Cat: 7 mg/kg IM, IV q12h

Tetracycline
20 mg/kg oral q8h

Dog/Cat: 7 mg/kg IM, IV q12h

Cattle/Sheep/Pig: 5 – 10 mg/kg IM, IV q24h
Oxytetracycline
Calf/Foal/Lamb/Piglets: 10 – 20 mg/kg oral q8 – 12h
Horse: 5 mg/kg IV

Dog: 5 – 10 mg/kg oral q24h

Doxycycline
5 mg/kg q24h

Lesson 16

Chloramphenicol
and its Derivatives

C hloramphenicol is produced by Streptomyces venezuelae, a soil organism first

isolated in 1947 from a soil sample from Venezuela. Chloramphenicol use in
animals intended for food is now banned in the Philippines because
chloramphenicol is known to cause humans aplastic anemia.

Chemistry
 P a g e | 165

Chloramphenicol is a derivative of dichloroacetic acid and contains a nitrobenzene

moiety which makes it fairly unique among natural antibiotics. It is highly lipid
soluble, only slightly water soluble, and very stable. Thiamphenicol is a derivative
of chloramphenicol wherein one of the hydroxyl groups in the benzene ring is
replaced by a methylsulfonyl group. Florfenicol is a derivative of thiamphenicol
wherein one of the hydroxyl groups is replaced by a fluorine atom.

Mechanism of Action

Chloramphenicol and its derivatives which are primarily bacteriostatic, inhibit protein
synthesis by binding to 50S ribosomal subunit. This action prevents the binding of the
amino acid – containing end of tRNA to its ribosomal binding site. They can also
inhibit mitochondrial protein synthesis in mammalian cells. The mammalian
erythropoietic cells seem to be particularly sensitive to these drugs.

Antimicrobial Spectrum and Clinical Use

Chloramphenicol has a broad spectrum of activity similar to that of tetracyclines, with

a good Gram – negative spectrum including: Haemophilus, Salmonella, E. coli,
Enterobacter, Klebsiella, Proteus, and Pasteurella. Pseudomonas aeruginosa is
resistant. Anaerobic bacteria, rickettsia, chlamydia, and mycoplasma are also affected.

It is very useful for:

 Salmonella infections
 Brain abscesses
 Bacterial meningitis
 Intra – ocular infections

In humans, its use is restricted to typhoid fever, or other severe infections against
which no other antibacterial agents are effective. In general, chloramphenicol should
probably be used as a second choice antibacterial but may be a first choice for some
deep infections of the eye.

The rapid elimination of chloramphenicol in the horse and frequent dosing needed to
maintain therapeutic level throws some doubt on its usefulness in the horse.

Thiamphenicol and Florfenicol have very similar antibacterial spectrum as

chloramphenicol. In general, thiamphenicol is less potent than chloramphenicol about
half as active as chloramphenicol but with equal activity against Haemophilus,
Bacteroides fragilis, and streptococci. Florfenicol is more potent than thiamphenicol
and is active against some strains resistant to chloramphenicol. Chloramphenicol and
its derivatives have similar pharmacokinetics and may show cross – resistance.

Mechanism of Resistance
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Resistance to chloramphenicol has increased since the drug was first introduced.
Plasmid – mediated resistance is very important in Gram – negative bacteria. A
specific acetyltransferase acetylates chloramphenicol to an inactive compound. In
Staphylococcus aureus, an inducible form of chloramphenicol acetyltransferase has
been demonstrated.

Pharmacokinetics

Absorption
Absorption of chloramphenicol after oral administration in monogastric
animals is rapid with good bioavailability but absorption after IM or SC is
unpredictable. In adult ruminants, orally administered chloramphenicol is
inactivated by rumen microorganisms.

Distribution
Chloramphenicol has a very wide distribution in the body due to high lipid
solubility. It penetrates intracellular as well as extracellular fluid. Highest
concentrations are attained in the liver, bile, and kidney. Therapeutic
concentration is attained in the brain, CSF, eye, prostate, and milk.
Chloramphenicol crosses the placenta and may affect the fetus. It may
penetrate the eye following topical or subconjunctival administration.

Elimination
Hepatic metabolism is the principal process of elimination of
chloramphenicol. Chloramphenicol glucoronide is the main metabolite
excreted (90%); others are de – acylated or dehalogenated metabolites (2%),
and unchanged drug (8%). There are species variations in the rate of
glucuronidation and his corresponds with variations in elimination half – life.

For example:
 In the horse, the half – life is about 1 hour, and
 In cat, about 5 hours
 Neonates cannot conjugate chloramphenicol as rapidly as adults
and this results in elimination half – life considerably longer than
in adults

Adverse Reactions and Toxicity

Chloramphenicol may:
 Reduce appetite
 Cause vomiting
 Weight loss
 Dehydration
 CNS depression
 P a g e | 167

The effects are seen more frequently in cats than in dogs. Bone marrow suppression
(hypoplasia) occurs in most species given high levels of the drug, and is dose –
dependent and reversible.

It is characterized by:
 Anemia
 leukopenia, and
 thrombocytopenia
Humans are the only species that develop non - dose – dependent irreversible aplastic
anemia as a result of chloramphenicol therapy (or exposure to chloramphenicol
residues in food). Since there is no safe level set for humans, chloramphenicol is
banned for use in food animals in many countries including Philippines. There is a
claim that thiamphenicol and Florfenicol does not cause bone marrow aplasia in
humans.

Hypersensitivity reaction occurs rarely.

Chloramphenicol inhibits hepatic drug metabolism specifically oxidation and

glucuronidation. Consequently, it prolongs the effects of drugs that are
dependent on hepatic microsomal enzymes for their elimination (e.g.
phenobarbital, phenytoin, lidocaine). Like other broad spectrum antibacterials,
chloramphenicol may cause superinfection.

“Grey Syndrome” occurs in neonatal humans, and in young and adult cats.
This syndrome is characterized by cardiovascular collapse and cyanosis, and is
associated with deficient glucoronide conjugation in neonates and in cats.

Formulations

 Chloramphenicol is available in capsules and liquid suspension for oral

administration, and as ophthalmic ointment

 Chloramphenicol free base is exceedingly bitter so that formulations are in the

form of esters

 Chloramphenicol palmitate – tasteless; for oral use; inactive as is, but

hydrolyzed to active drug in the circulation.

Some Useful Dosages

Cat: 45 – 60 mg/kg oral, IV, IM q12h

Dog: 45 – 60 mg/kg oral, IV, IM q6 – 8h
Chloramphenicol
Horse: 50 mg/kg oral q6 – 8h
50 mg/kg IV q2 – 4h
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Lesson 17

Macrolides

T he macrolides are a group of antibacterials with a similar structure. All of which

have been isolated from Streptomyces spp. Bacteria. The term Macrolides refers
to the larger ring structure in these compounds.

Compounds

Erythromycin Tylosin Spiramycin

Oleondomycin Kitasamycin Josamycin
Rosaramicin Tilmicosin Roxithromycin

Chemistry

Macrolides contain a many – membered lactone ring to which are attached to one or
more deoxysugars. They are weak bases with pKa of 7.1 (Tylosin) or 7.8
(erythromycin). They are highly lipid soluble and their salts have good water
solubility.

Elimination of macrolides is primarily through demethylation in the liver. The

metabolites are excreted in urine and feces. A small amount of unchanged drug is
eliminated in the urine.
 P a g e | 169

Adverse Reactions and Toxicity

Gastrointestinal disturbances
Gastrointestinal are the most common reactions and are dose – related. These
are manifested as vomiting and occasional diarrhea in small animals or
diarrhea in the horse. These can also be a problem in guinea pigs, rabbits, and
hamsters.

Hypersensitivity reactions including anaphylaxis can occur but are rare.

There can be pain and swelling after IM injection, and thrombophlebitis after
IV.

Hepatotoxicity and cholestatic hepatitis

Hepatotoxicity and cholestatic hepatitis occurs occasionally in humans,
primarily with estolate esters. Erythromycin can cause increased blood levels
and toxicity of theophylline and oral anticoagulants probably by interfering
with their metabolism.

Individual Drugs

Erythromycin
This is a second – choice antibacterial for most applications. Therapeutic are
used mainly vs. Gram – positive bacteria including penicillinase – producing
staphylococci and streptococci. Some Gram – negative bacteria such as
Bacteroides, Haemophilus, and Actinobacillus. Bordetella is often sensitive.

Erythromycin is often used for:

 streptococcal and staphylococcal infections in penicillinase – allergic
patients

 prostatic infections caused by Gram – negative organisms (pH of

prostatic fluid, 6.3 is too low for maximal activity)

 mycoplasma infections

 campylobacter jejuni infections need to start early (in 4 days of

infection) to be effective

 foal pneumonia caused by susceptible strains of Rhodococcus equi (in

combination with rifampicin)

 acute mastitis

Tylosin
This is also a second choice antibacterial for most application. Less active
against bacteria except Brachyspira hyodysenteriae but is more active against
 P a g e | 170

Mycoplasma. Used primarily in food animal medicine (including poultry) as

feed additive.

Spiramycin
This is several times less active against bacteria than erythromycin. Not as
effective against Mycoplasma as Tylosin and Tiamulin (See next lesson).
Despite relatively poor activity in vitro, it has exceptional ability to
concentrate in tissues. Has same application as Tylosin but may be a drug of
choice against cryptosporidiosis.

Oleandomycin, Josamycin, Kitasamycin, and Rosaramicin

These all have activity similar to erythromycin, Tylosin, and Spiramycin.
Oleandomycin may be used to treat clinical toxoplasmosis in dogs but
clindamycin is better.

Tilmicosin
In cattle, this is used for the treatment of respiratory disease caused by
Pasteurella spp. Produces cardiovascular toxicity in species other than cattle.

Some Useful Dosages

Cattle: 8 – 15 mg/kg IM q12 – 24h

Erythromycin Cat: 15 mg/kg oral q8h
Foals: 25 mg/kg IM q8h

Cattle: 10 – 20 mg/kg IM q12 – 24h

Pig: 10 mg/kg IM q12 – 24h
Tylosin
7 – 10 mg/kg oral q8h
Cat: 10 mg/kg q12h
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Lesson 18

Pleuromutilins

T he useful plerumutilins in veterinary medicine are Tiamulin and valnemulin. These

are semisynthetic derivatives of the naturally occurring diterpene antibiotic
pleuromutilin. They have outstanding activity against anaerobic bacteria and
mycoplasma. Valnemulin is several folds more potent than Tiamulin. The
Pleuromutilins are used exclusively in animals and largely in swine.

Chemistry

The Pleuromutilins are:

 Lipophilic
 Weak organic base
 With a pKa of about 7.6

Antimicrobial Spectrum and Clinical Use

The antimicrobial spectrum of Tiamulin and valnemulin is similar to that of tylosin

but has greater activity. They are active against a few Gram - negative aerobic species
but are inactive against Enterobacteriaceae although sub - inhibitory concentrations
may reduce adhesive properties of enterotoxigenic E. coli.

Activity against anaerobic bacteria and mycoplasma is better than that of macrolide
antibiotics. They are used for swine dysentery (Brachyspira hyodysenteriae) and
chronic swine pneumonia and in strategic medication to prevent and treat common
infections of pigs. Their use as growth promoter in swine is no longer encouraged.
 P a g e | 172

Although they are not active against most enteric bacteria, they seem to prevent
colonization of E. coli in intestinal mucosa.

Resistance

As with macrolides, chromosomal mutation to resistance of Tiamulin emerges on in

vitro passage to bacteria in the presence of the drug. The rate of emergence is
significantly lower with tylosin. Mycoplasma, which have become resistant to tylosin,
have slightly increased resistance to Tiamulin but mycoplasma resistant to Tiamulin
are completely resistant to tylosin. The variation in bacterial resistance with other
macrolides and lincosamide antibiotics may include modest increases and resistance
to Spectinomycin and chloramphenicol.

Pharmacokinetics

Little information has been published on the pharmacokinetics of tiamulin and

valnemulin but it is generally similar to macrolides antibiotics. In ruminants, Tiamulin
is rapidly absorbed orally, half – life: 25 minutes aft 25 minutes aft IV. It penetrates
cell wall and is concentrated several fold in milk. Concentration in other tissues is
several times that in serum. The half – life in dogs after IM, is about 4.7 hour.

Drug Interactions

Drug interactions are likely to be similar to those described for lincosamides and other
macrolides. A definite synergism between the pleuromutilins with any of the
tetracyclines (particularly chlortetracycline) has been well established.

Combinations of a pleuromutilin at therapeutic concentrations with ionophore drugs

(e.g. Salinomycin, monensin) at recommended doses produce primary ionophore
myotoxocoty in chickens, calves, and pigs. On the other hand, the use of prophylactic
levels in feed has not been shown to produce such interaction problems. Fatal effect
has been encountered when therapeutic doses of a pleuromutilin are combined with
ionophores such as monensin, narasin, and Salinomycin.

There may be irritation at IM injection sites but no irritation with sesame oil – based
preparation. IV injection has caused neurotoxicity and death in calves. Pleuromutilins
should not be administered to horses and other herbivores with expanded large
intestines (guinea pigs, rabbits) because of danger of destruction of large bowel flora
and predisposition to colitis.

Some Useful Dosages

Tiamulin
Pig: 60 ppm (mg per liter) in water for 5 days or
10 – 15 mg/kg IM for 2 – 3 days for swine dysentery

200 ppm in the feed for 5 – 10 or

3 mg/kg in drinking water for swine pneumonia
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Valnemulin Pig: 3 – 5 mg/kg b.w. OR 75 ppm in feeds

Lesson 19
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Lincosamides

T he lincosamides are another group of antibiotics isolated from Streptomyses spp.

of bacteria.

Clindamycin and Lincomycin are compounds useful in veterinary medicine

Chemistry

The lincosamides are:

 Highly lipid soluble
 Weak organic bases
 pKa 7.6

Derivative of Lincomycin: Derivative of Clindamycin:

*7 – chloro *7 – deoxy

Mechanism of Action

The lincosamides are 50S bacteriostatic. They inhibit protein synthesis by binding
with 50S ribosomal subunits

Spectrum of Activity and Clinical Use

The spectrum of activity includes primarily Gram – positive cocci including some
penicillin – resistant staphylococci, anaerobes including Bacteriodes fragilis, some
Clostridium, some Nocardia, and Actinomyces, some Mycoplasma, and Brachyspira.
Enterococci and Gram – negative bacilli are resistant.

Resistance

Resistance to lincosamides occurs as enzyme – mediated methylation of ribosomal

RNA. Mutation may cause resistance in streptococci and staphylococci. There is
usually cross – resistance between clindamycin and Lincomycin, and between
lincosamides and macrolides.

Pharmacokinetics
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Absorption of lincosamides is rapid following IM or oral administration.

Clindamycin has better oral absorption than Lincomycin and food does not
significantly alter absorption than Lincomycin. They may also be given IV.

Lincosamides are widely distributed in the body. They can penetrate intracellular fluid
but not the CSF. High lipid solubility, ion – trapping can result in high concentration
of lincosamides in some tissues and body fluids. High concentrations are achieved in
skin, bones, and joints. Lincosamides may be the drug of choice for osteomyelitis.
High concentrations may also be achieved in milk (4 – 7 x plasma levels) and bile.
Generally, they are high protein bound.

Clindamycin undergoes hepatic metabolism to form inactive metabolites which are

excreted in urine and bile. Lincomycin may not be metabolized but evidence has been
conflicting.

Adverse Reactions and Toxicity

GI disturbances are the major adverse effect, vomiting especially in cats; diarrhea
resulting from pseudomembranous colitis caused by Clostridium difficile. For this
reason, lincosamides are contraindicated in the horse, rabbit, guinea pig, hamsters.
Dogs are relatively resistant to GI disturbances. Gastroenteritis occurs as fatal colitis
in horses and in cattle, oral lincomycin as low as 7 – 10 ppm in feed causes
inappetence, diarrhea, ketosis and reduced milk production. Hypersensitivity reaction
is rare.

Lincosamides can produce or potentiate neuromuscular blockade in high

concentration (can be reversed by drug withdrawal and calcium injection), additive
effect with anesthetic and skeletal muscle. Do not administer by rapid IV, may cause
cardiac depression.

Individual Drugs

Lincomycin
Is approve for use in dogs, cats, swine, and poultry, and is available as
injection, oral tablets, soluble powder, and feed premix. It is not a first line
drug in veterinary medicine but it is used to a limited extent. Lincomycin is
used to:

 Treat Gram – positive infections in animals allergic to penicillin

 Treat skin infections and staph. osteomyelitis in small animals
 Treat and prevent mycoplasma infections in food animals
 Control swine
 Treat anaerobic infections

It is available in combination with Spectinomycin as a water – soluble powder

for use in poultry.
 P a g e | 176

Clindamycin
Is not used very frequently in veterinary medicine but may be used for
treatment of toxoplasmosis in dogs and cats. It is used for Gram – positive
infections. Other antibiotics that are less expensive and have less effect are
usually preferable.

Some Useful Dosages

Cattle: 10 mg/kg IM q12h

Pig: 10 mg/kg IM q12h
7 mg/ kg oral in feed
Lincomycin
Dog: 20 mg/kg IM q24h
Cat: 12 mg/kg IM q12h
25 mg/kg oral q12h

Clindamycin Cat: 10 mg/kg IM or oralq12h

Lesson 20
 P a g e | 177

Nitrofurans and
Nitroimidazoles

N ITROFURANS

The Nitrofurans have broad antibacterial activity but their toxicity largely limits
their use to topical application to the treatment of intestinal infections, and to the
treatment of urinary tract infection.

Compounds

Nitrofurazone ` ` `Furazolidone Nitrofurantoin

Furaltadone Nifuratel ` ` Nifuroquin

Chemistry

The members of the Nitrofurans group are moderately lipophilic and vary in their
water solubility. Nitrofurazone and Nitrofurantoin are weak acids with pKa of 7.1.
Nitrofurazone is water – soluble and Nitrofurantoin is practically insoluble in water.

Mechanism of Action

The Nitrofurans, which are bacteriocidal, serves as substrates of bacterial reductase

enzymes. These drugs are degraded to various poorly characterized reduction
products which then cause breakage of bacterial DNA strands.

Antibacterial Spectrum and Clinical Use

The spectrum of activity includes:

 Gram – negative bacteria: Escherichia coli, Salmonella, Klebsiella, some
Proteus
 Gram – positive bacteria an Mycoplasma
 Some protozoa (coccidia, trypanosomes)
 With activity against Trichomonas vaginalis and Trichomonas fetus of cattle
 Furazolidone is effective against an aerobic bacteria

Resistance is slow to develop and only to a limited degree.

 P a g e | 178

Pharmacokinetics

Nitrofurantoin is well absorbed after oral administration but is rapidly excreted in the
urine. They may be some metabolism. The blood and tissue concentrations are too
low for treatment of systemic infections. The mean concentrations attained in the
urine are between 50 to 250 micrograms/ml, therefore, it is quite useful in the
treatment of urinary tract infection. Antibacterial activity is favored by acidic urine.

Nitrofurazone and Furazolidone on the other hand are poorly soluble an d are not
absorbed from the gut.

Adverse Reactions and Toxicity

Toxic reactions to Nitrofurans can be severe if drugs are administered parenterally or

if a large amount of drug is absorbed. Nausea, vomiting, and diarrhea can be common
after oral administration.

Other forms of nitrofuran toxicity include:

 Acute pneumonitis
 Interstitial pulmonary fibrosis
 Polyneuritis and central nervous effects
 Hemorrhagic diathesis with thrombocytopenia
 Anemia
 Leukocytopenia
 Prolonged bleeding time

Local toxicity and hypersensitivity reactions may occur.

Contraindicatioins:

Its carcinogenic properties prompted authorities to ban the use of nitrofurans in

humans and animals.

Individual Dugs

Nitrofurazone
Nitrofurazone has anti – protozoal activity and is primarily used topically to
treat wounds and infections of the eye, ear, skin, and reproductive tract. It is
used as a feed additive in chickens to control coccidiosis. Water – mix and
solution are available to treat intestinal infections, primarily in swine.

Nitrofurantoin
Nitrofurantoin can be use to treat lower urinary tract infections in small
animals but it can be quite toxic and this limits its use.

Furazolidone
Furazolidone is used a feed additive in poultry and swine to control intestinal
infections and coccidiosis. Oral solution is availab le for intestinal infections
in piglets.
 P a g e | 179

Some Useful Dosages

The general dose of nitrofurans to livestock is 10 – 12 mg/kg for 5 – 7 days

In pigs, 100 – 500 ppm in feeds

Dog: 4 mg/kg oral TID for 5 – 7 days

Nitrofurantoin
For urinary tract infections

NITROIMIDAZOLES

The Nitroimidazoles are used in veterinary medicine for their activity against
anaerobic bacteria. They are similar in spectrum of activity and mechanism of action to the
nitrofurans but are not active against aerobic bacteria

Compounds

Metronidazole (common) Dimetridazole Ronidazole

Tinidazole Ipronidazole

Chemistry

The Nitroimidazoles are heterocyclic compounds base on a five – membered nucleuss

similar to that of the nitrofurans.

Mechanism of Action

The Nitroimidazoles undergo a non – enzymatic reduction of the nitro group to

produce products that interfere with DNA functions and antibacterial effect.
Reduction occurs under anaerobic conditions. Unlike that of the nitrofurans, reduction
is not enzymatically controlled.

Antimicrobial Spectrum and Clinical Use

The Nitroimidazoles are bacteriocidal to most Gram – positive and Gram – negative
anaerobic bacteria. Some (such as metronidazole and Dimetridazole) are effective
against protozoan parasites: Trichomonas fetus, Giardia lamblia, and Histomonas
meleagridis

Dimetridazole is used against swine dysentery (caused by Brachyspira

hyodysenteriae).
.
Resistance
 P a g e | 180

Resistance is rare among usually susceptible bacteria, a characteristic shared with the
nitrofurans. Resistance involves reduced intracellular drug activation.

Pharmacokinetics

Metronidazole
 Well absorbed after oral administration in monogastric species
 Distributed widely in tissues (including CNS)
 Penetrates the brain and cerebrospinal fluid
 Extensively oxidized and conjugated in the liver and excreted in the urine

There is limited information about the pharmacokinetics of the other Nitroimidazoles

in animals.

Adverse Reactions and Toxicity

 Peripheral neuropathy and epileptiform seizures

 Nausea and vomiting
 Rumen dysfunction
 Neurotoxicity (seizures is increased/prolonged dosages)

Some Useful Dosages

Dog: 25 – 50 mg/kg BID oral

Metronidazole
Horse: 20 – 25 mg/kg BID oral
Cattle: 75 mg/kg 3x at 12h interval IV (for trichomoniasis)

Cattle: 60 – 100 mg/kg oral or IM for 5 days

Swine: 0.007 – 0.02% in feed or
Dimetridazole 0.006 – 0.0125% in water (vs. swine dysentery)
Turkey: 150 – 200 ppm in water (o prevent blackhead)
600 – 800 ppm in water (to treat blackhead)

Swine: 60 – 120 ppm in feed or

Ronidazole
0.006% in water (vs. swine dysentery)

Tinidazole Horse: 10 – 15 mg/kg

 P a g e | 181

Lesson 21

Quinolones,
Rifamycins, and
Novobiocin
 P a g e | 182

Q UINOLONES

The original quinolone drugs (nalidixic, oxolinic, and pipemedic acids)

introduced in 1960s, had bacterial activity restricted to Gram – negative
aerobes, and were administered orally for urinary tract infections in monogastric animals.
Their use was limited by the development of resistance and their toxicity.

One derivative, Flumequine, is used mainly for enteric infections of food animals.
Addition of flourine atom at position 6 and a piperazenyl or pyrrolidinyl group at position 7
(Flouroquinolones), dramatically increased both the spectrum of activity and potency. (refer
to chemical structures of quinolones).

Mechanism of Action

The quinolones inactivate DNA gyrase enzyme. DNA gyrase is essential in the
process of DNA replication. The active enzyme consists of two pairs of subunits
called subunits A and B. The quinolones inactivate DNA gyrase by inhibiting the
subunit A which is fewer in number than the subunit B.

First Generation Quinolones

 Nalidixic acid
 Oxolinic acid
 Pipemedic acid, and
 Cinoxacin

Pharmacokinetics
Nalidixic acid is almost completely absorbed after oral administration.
It is extensively and rapidly metabolized and is excreted as inactive
conjugate.

Spectrum of Activity and Clinical Use

Effective against most Gram – negative aerobes except Pseudomonas
aeruginosa. Inactive against Gram – positive and anaerobic bacteria.
Used in the treatment of urinary tract infection caused by Gram –
negative bacteria. It is too toxic to use in dogs and cats.

Adverse Reactions
 Serious CNS stimulation
 Seizures in dogs
 Hepatic necrosis
 Irritation at injection sites

Second Generation Quinolones

 Flouroquinolones
 Flumequin
 Norfloxacin
 P a g e | 183

 Ciprofloxacin
 Enoxacin
 Perfloxacin
 Ofloxacin

Third Generation Quinolones

 Enrofloxacin
 Danofloxacin , and
 Marbofloxacin

All these drugs belonging to the second and third generation quinolones have a
common 4 – quinolone nucleus and carboxylate constituent at carbon 3, a 6 – flouro
and a 7 – piperazino substituent. All have enhanced activity against DNA gyrase.

Pharmacokinetics

Rapid and adequate absorption after oral administration, distribute widely in body
fluids, penetrate in to CSF in meningitis. The extent of biotransformation varies with
specific drugs. Excretion is partially through the kidney.

Spectrum of Activity

It is very active against Enterobacteriaceae and many other Gram – negative rods
including Pseudomonas aeruginosa. It is lower but therapeutically useful activity
against Gram – positive aerobes and inactive against anaerobes. With the exception of
Flumequine, all have some activity against mycoplasma, rickettsia. Norfloxacin is
less potent than ciprofloxacin, Enrofloxacin, and Danofloxacin.

Adverse Reaction

Gastrointestinal symptoms:
 Nausea
 Vomiting
 Anorexia

This has limited available data on toxicity in animals and may be toxic for dogs and
cats.

Some Useful Dosages

Norfloxacin Dog/Cat: 22 mg/kg q12h oral

(dog not <8 months)

Dog/Cat: 2.5 mg/kg q12h oral or IM

(dog not <8 months)
Enrofloxacin Ruminants: 2.5 – 5 mg/kg q24h oral, IM, SC
Swine: 2.5 – 5 mg/kg q24h oral, IM
Poultry: 50 ppm in water, oral
0.05 mg/bird SID, IM
 P a g e | 184

Ciprofloxacin Dog/Cat: 5 – 8 mg/kg q12h oral

Flumequine Poultry: 12.5 mg/kg in drinking water

RIFAMYCINS

Compounds:
 Rifamycin SV
 Rifampin
 Rifamide

Mechanism of Action
 Rifamycins interfere with DNA – dependent RNA polymerase
 Prevents formation of mRNA
 Bacteriocidal

Pharmacokinetics

Rifamycins are readily but incompletely absorbed from the gut and diffuse
rapidly into tissues reaching concentrations exceeding those in serum. They
are biotransformed to several metabolites and excreted in bile and in urine.
They may be administered by IM or IV routes.

Spectrum of Activity and Clinical Use

They are active against Gram – positive bacteria, anaerobes, and some
mycobacteria. Rifampin is the most active drug known against Staphylococcus
aureus. Very active against Mycobacterium tuberculosis but most other
mycobacteria are resistant. Gram – negative bacteria are generally resistant but
Brucella and other fastidious organisms are susceptible. It is active against
Chlamydia and use in foals to control Corynebacterium equi – induced
pneumonia. This is often administered in combination with other antibiotics
such as penicillin and erythromycin due to the ready development of
resistance.

Adverse Reactions and Toxicity

There is no report of adverse effects in animals but may be teratogenic. They

should not be administered in animals with liver disease.

Some Useful Dosages

Rifampin
Horse: 5 mg/kg bid oral
Foal: 5 mg/kg SID oral
Dog: 5 mg/kg SID oral
 P a g e | 185

Sheep and Calves: 20 mg/kg SID oral

Cattle: 10 mg/kg IM or IV

NOVOBIOCIN

Mechanism of Action

 Inactivate the subunit B of DNA gyrase

 Bacteriostatic

Pharmacokinetics

 Well absorbed from the gut

 Mainly excreted in the bile
 Enterohepatic occurs

Spectrum of Activity and Clinical Use

It is very active again st Staphylococcus aureus. It is less active against

Streptococci and the more fastidious gram – negative bacteria (Haemophilus,
Brucella). Mycoplasmas are moderately susceptible usually bacteriostatic, and
used to treat bacterial mastitis in cows, but is no longer as commonly used
because of the availability of more effective antibiotics.

Adverse Reaction

 Inhibition of liver metabolism

 Eosinophilia
 Thrombocytopenia
 Leukopenia
 Skin rashes in cows with intramammary infusion of the drug
 P a g e | 186

Lesson 22

Miscellaneous
Antibiotics

V IRGINIAMYCIN

Virginiamycin is an antibiotic mixture as a fermentation product of

Streptomyces virginiae. It belongs to the depsipeptide group of antibiotics which
include Gramicidin S and Pristinamycin.

Mechanism of Action

Virginiamycin interferes with protein synthesis by distorting the ribosomal A

site to inhibit the binding f of aminoacyl tRNA and the peptidyl transferase
reaction.

Spectrum of Activity and Clinical Use

It is mainly active against Gram – positive aerobic and anaerobic bacteria.

Most Gram – negative bacteria are resistant but Leptospira sp., Treponemna,
Hyodysenteriae, and Haemophilus species are susceptible. Mycoplasmas are
often susceptible. It is used to promote growth in animals at 5 to 10 ppm.

Pharmacokinetics
 P a g e | 187

Not absorbed from the gut. Little else is known.

Adverse Reaction

Possible cross – resistance with macrolides and lincosamides

MONENSIN
A polyether ionophore antibiotic

Mechanism of Action
 Competes with sodium in the cell membrane
 Causes passive transport of potassium ions out of the cell for hydrogen ions
 Low intracellular pH kills the cell

Spectrum of Activity and Clinical Use

 Active against Gram – positive bacteria and against coccidian
 Used as anticoccidial in poultry
 Used to improve feed conversion efficiency in ruminants

Adverse Reaction
 Highly toxic to horses and to ruminants at doses 5 – 1 times those
recommended
 Fatal when administered together with tiamulin

LASALOSID, NARASIN, and SALINOMYCIN

 All these are carboxylic polyether ionophores
 Have anticoccidial activity
 Used to improve the efficiency of ruminal fermentation

Salinomycin is used as a growth promoter in swine but may be fatal when combined
with therapeutic concentrations of tiamulin.

FUSIDIC ACID
A lipophilic steroid antibiotic

Mechanism of Action
 Prevents protein synthesis by inhibiting the binding of aminoacyl tRNA to the
ribosomal A site

Spectrum of Activity and Clinical Use

 Bacteriocidal activity against Staphylococcus aureus and Mycobacterium
tuberculosis
 Has been used in the treatment of serious staphylococcal infection in humans
when other drugs have failed
CARBADOX and OLAQUINDOX
Quinoxaline NN dioxide derivatives

Mechanism of Action
 Inhibits bacterial DNA synthesis
 P a g e | 188

 Denatures pre – existing DNA (similar to that of nitrofurans)

 More effective under anaerobic conditions

Spectrum of Activity and Clinical Use

 Highly effective against Clostridia and Brachyspira hyodysenteriae
 Also effective against Chlamydia and Protozoa
 Used as growth promoter in pigs but is now banned for use in food animals
because of carcinogenic effect

Adverse Reaction
 Bacterial resistance
 Overdose retards growth
 Hypokalemia due to adrenal cortex dysfunction

ISONIAZID
A hydrazide of isonicotinic acid and is the most potent anti – tuberculosis drug used
in humans. The mechanism of action is unknown.

Spectrum of Activity and Clinical Use

 Effective against Mycobacterium tuberculosis, M. bovis, and Actinomyces
bovis
 Used at 11 to 22 mg/kg orally once daily to treat actinomycosis in cattle

Adverse Reaction
 Neurotoxic effects resulting from a relative deficiency of pyridoxine which is
inhibited by isoniazid
 Accidental ingestion of 66 mg/kg by a dog led rapidly to convulsion.

FOSFOMYCIN and FOSFONOMYCIN

These are phosphoric compounds

Mechanism of Action
Inhibit the first part of the cell wall synthesis in Gram – positive bacteria by
inhibiting the formation of phosphoenolpoyruvate.
(Review the process of cell wall synthesis)

Spectrum of Activity and Clinical Use

 Good activity against Gram – negative and some Gram – positive bacteria
 Has been used in Spain for respiratory, gastrointestinal, and urinary tract
infection of humans
 Not yet used in the Philippines
METHENAMIDE

 It decomposes u der acid condition to release formaldehyde.

 When absorbed, liberates formaldehyde in urine
 Used as non – specific urinary antiseptic

FLAVOMYCIN (BAMBERMYCIN)

 A bambermycin is used as growth promoter in swine

 P a g e | 189

 Has a curing effect on antibiotic resistant plasmid in Enterobacteriaceae decreasing

resistance transfer

Lesson 23
 P a g e | 190

Antifungal Agents

F 
ungal infections are classified according to the location of the infection:

Dermatophytic infections
(Dermatophytoses) are the most common fungal (mycotic) infection. They
involve the skin, hair, and nails. Most dermatophytes can be treated with
topical antifungal agents

 Mucocutaneous infections
Involve moist skin and mucous membrane (GIT, perianal, and vulvovaginal
areas), and can be treated with topical application of Amphotericin B,
miconazole, clotrimazole, nystatin, and with oral ketoconazole for chronic
infection

 Systemic infections
Occurs less frequently, and is usually chronic in nature. They are rather
difficult to diagnose. Treatment of systemic infections is with parenteral
antifungals

Classification of Antifungal Agents According to the Mode of Application:

1. Agents for Topical Application

These are indicated for superficial infections. Some antifungal preparations
may contain a keratolytic component. Some agents such as resorcinol and
salicylic acid, have both keratolytic and fungicidal activity. Topical
antifungal drugs come in different pharmaceutical forms
 For skin:
a. Solution
b. Lotion
c. Spray
d. Powder
e. cream, and
f. ointment
 For intravaginal use:
 P a g e | 191

a. irrigant solution
b. ointment
c. tablet, and
d. suppository

2. Agents for Systemic Application

These must be absorbed into the blood circulation and are used for treatment
of systemic mycoses but may also be used for Dermatophytoses when
distributed into the kin

TOPICAL ANTIFUNGAL AGENTS

 Undecyclenic Acid (USP)

Is fungistatic for superficial infections involving skin areas with little hair.
Available as powder or 10% alcoholic solution. Used in combination with zinc
and salicylanilide for improved efficacy

 Caprylic Acid and Propionic Acid

Are used to treat dermatophytoses. Propionic acid is also incorporated in
manufactured animal feeds to help control fungal growth (in animal feeds)

 Benzoic Acid
Is the main ingredients in Whitfield’s Ointment (formula: 6% benzoic acid,
3% salicylic acid). It has fungistatic as well as a keratolytic property

 Salicylic Acid
Is used in the treatment of chronic superficial skin infections. It has moderate
fungistatic activity but with good keratolytic action. Included in many topical
antifungal preparations, it requires the presence of water to produce keratolytic
effects. It may cause skin irritation

 Ciclopirox Olamine
Has a broad spectrum antifungal activity. It is effective against Candidia
(yeast), Epidermophyton, Microsporum, and Trichophyton but has limited
penetration of epidermis and is available in 1% solution

 Tolnaftate
Used against Epidermophyton, Microsporum, and Trichophyton infections. It
has no effect on bacteria and on Candidia spp. It may be administered with
griseofulvin for more immediate topical effect and is available as 1% cream,
solution, or powder

 Candidicin
A fungicidal polyene antibiotic and used primarily for moniliasis

 Haloprogin
A synthetic antifungal agent used against Microsporum, Trichophyton, and
Candidia and is available as 1% cream or solution

 Iodochlorhydroxyquin
 P a g e | 192

Has both antifungal and antibacterial activity and is used for localized
dermatophytoses complicated by bacterial infection. It is available as 3%
cream, ointment, or powder

 Natamycin
Also known as PIMARICIN. It is a fungicidal polyene antibiotic effective
against a wide range of filamentous and dimorphic fungi and yeasts. It is used
for local application against ringworm, in udder for yeast mastitis, and on the
eyes for mycotic keratitis and is available as 2.5% or 5% solution

 Cuprimyxin
A broad spectrum antifungal with antibacterial activity. After application, the
myxin component is released from the copper complex and is effective against
Microsporum, Trichophyton, and Candidia

 Nystatin
A polyene antibiotic which is the first antimycotic antibiotic to be discovered.
It binds to sterols in fungal cell membrane resulting in increased membrane
permeability and cell destruction. Its absorption time from the gut is
negligible. It is not available for parenteral administration due to its renal
toxicity. When used topically, it does not cross skin and mucous membrane.
This has fairly broad – spectrum of activity including yeast and various fungi,
and is used against Candidia, Microsporum, and Aspergillus and may cause
local burning and itching sensation in area of application and gastrointestinal
upset
Dose:
Dog 22,000 units/kg/day
Poultry 62.5 – 250 ppm in drinking water

 Clotrimazole
An imidazole which is used for topical treatment of Epidermophyton,
Microsporum, Trichophyton, and Candidia, and is available as 1% cream, or
solution

 Ketoconazole
Also an imidazole which is a broad spectrum antifungal and is used also for
dermal and systemic fungal infection. It I effective against Coccidiodes
immitis, Cryptococcus neoformans, Histoplasma capsulatum, Blastomyces
dermatitidis, Candidia spp., Aspergillus sp., and Sporothrix spp. It has an
antagonistic effect with amphothericin B. For Blastomycosis in dogs, use 30
mg/kg daily for 2 months

 Thiabendazole
A benzimidazole which has antifungal as well as anthelmintic activity and
may reduce aflatoxin formation in infected feed. It is effective against
Blastomyces, Fusarium, Candidia, Penicillum, and Trichophyton

 Iodine Preparations
Include Tincture of Iodine, Potassium Iodide, and Iodophores
 P a g e | 193

 Dyes
Under this are:
 Carbol – Fuchsin solution
Composition:
0.3% basic fuchsin
4.5% phenol
10.5% resorcinol
5.0% acetone
10% ethyl alcohol
Application:
Clean the affected area with soap and water, dry and
apply medication once or twice a day for one week

 Gentian Violet
Used for candidiasis and other fungal infections. May be
available alone or in combination with Benzathonium chloride
(a disinfectant)

SYSTEMIC ANTIFUNGAL AGENTS

 Griseofulvin
An oral fungistatic antibiotic against dermatophytes that inhibits fungal cell
mitosis by binding to microtubules disrupting the mitotic spindles.
Administered orally, it is variably absorbed from the gut. The rate of
absorption depends greatly on particle size and is enhanced by high fat meal.
Absorbed griseofulvin distributes to growing nails and skin, and binds to
keratin to make the cells resistant to fungal infection. The drug is
biotransformed in the liver an excreted in the urine. This is also effective
against Epidermophyton, Microsporum, Trichophyton, and Sporothrix. It must
be given for prolonged period usually for several weeks to months. Adverse
reactions to griseofulvin include occasional diarrhea and nausea, hepatic
toxicity (has been reported), and teratologic effects in cats.
Dose
Horse 10 mg/kg daily for 20 days; oral
Dog/Cat 7 – 20 mg/kg/day for 3 – 4 weeks; oral
Cattle 7.5 mg/kg for 7 days (in feed)

 Amphotericin B
Polyene antibiotic for systemic infections which binds to ergosterol, the
principal sterol of the fungal cell membrane and causes cell destruction. It is
active in both growing and resting cells. Additionally, it causes oxidative
 P a g e | 194

damage to fungal cell in vitro and enhances cell – mediated immunity in the
host. Not absorbed after oral administration, it is usually administered IV for
systemic effect. Little amphotericin B penetrates the CSF and excretion is
through the urine and bile

It has a broad spectrum of activity including:

 Coccidiodes immitis
 Cryptococcus neoformans
 Histoplasma capsulatum
 Blastomyces dermatitidis
 Candidia albicans, and
 Aspergillus spp.

It has no activity against protozoa and bacteria and been the most important
drug available for the treatment of systemic fungal infections but its place is
being challenged by ketoconazole.

Adverse reactions include:

 Fever
 Reversible renal toxicity leading to azotemia
 Hypochronic normocytic anemia, and
 Cardiac arrhythmias.

Concurrent use of flucytosine decreases the dose required to treat cryptococcal

infection
Dose

5 mg/kg IV 3 x a week;
On the first day, dilute the total dose in 20 ml of 5% dextrose and
Dog
5 ml is given. If no acute anaphylactic response develops give
the remainder over 45 second

For Cryptococcus neoformans

Cat Incremental doses beginning with 1 mg/day up to 50 mg on the
75th day

0.5 – 1.5 mg/kg every other day

Horse
IV diluted in 1 liter of 5% dextrose

 Flucytosine
A fluorinated pyrimidine derivative converted in sensitive fungi to 5 –
fluorouracil. Mammalian cells do not convert floucytosine to fluorouracil.
This is further biotransformed to 5 – flouro – deoxyuridylic acid, an inhibitor
of thymidylate synthesis, and thus DNA synthesis

It is well absorbed from the gut and with minimal binding to plasma protein, it
penetrates into tissues and the CSF. Largely excreted in the urine unchanged.
 P a g e | 195

Amphotericin B which can reduce renal function, may increase the toxicity of
flucytosine when they are used in combination

Flucytosine is active against:

 Most Cryptococcus neoformans
 80 – 90% of Candidia
 Most Torulopsis and
 Cladosporium.

Cryptococcus is the major indication for floucytosine.

The majority of yeast isolates from bovine mastitis are resistant. Major
application is for treatment of cryptococcal infection in cats

Adverse reactions include:

 Reversible anorexia
 Nausea
 Vomiting, and diarrhea
 Thrombocytopenia and leukopenia due to depression of bone marrow

Toxicity is more frequent in case of azotemia or when administered

concurrently with amphotericin B. Also combination with ketoconazole in cats
is especially toxic.

Dose

30 – 50 mg/kg tid – qid oral or

Dog
50 – 75 mg/kg tid oral

Cat 0.1 – 0.2 mg daily oral

 Ketoconazole
Inhibits the fungal enzyme sterol 14 – alpha demethylase and therefore
interferes with the biosynthesis of ergosterol and bind to phospholipids in the
fungal cell membrane. This results in cell leakage. It also interferes with
cytochrome C oxidase and with peroxidase resulting in increased in
intracellular peroxide and cell death

Ketoconazole is well – absorbed after oral administration. Simultaneous

administration of the drug with histamine receptor H2 antagonist (e.g.
cimetidine) or antacids, decreases its rate of absorption. Food does not affect
absorption.

It is biotransformed in the liver and excreted in the bile and urine

Ketoconazole is generally fungistatic against a wide range of filamentous

fungi including dermatophytes, yeast, and dimorphic fungi. About 75% of
yeasts from bovine mastitis were sensitive to ketoconazole
 P a g e | 196

Although relatively well – tolerated particularly when compared to

amphotericin B, adverse reactions may be observed such as:
 Inappetence,
 Pruritus
 Alopecia, and
 Reversible lightening of the hair in dogs.

Cats are more sensitive and may develop anorexia, depression, diarrhea, and
fever. Ketoconazole may be embryotoxic and teratogenic; not given to
pregnant animals

Dose

5 – 10 mg/kg oral for 4 – 5 weeks for ringworm;

Dog/Cat
10 mg/kg oral 3 x daily for systemic infection

Lesson 24

Drugs against
Antiprotozoan
Parasites
 P a g e | 197

T he parasitic protozoa differ to some extent from the pathogenic bacteria and fungi.
Many protozoan parasites require arthropod intermediated hosts for complete
development. They are generally closer in biochemical make – up to the
mammalian cells than are the pathogenic bacteria and fungi. This poses a problem
with regard to the selective toxicity of the antiprotozoan agents

Mechanisms of Action of Antiprotozoan Agents

The majority of the antiprotozoan drugs interfere with biosynthetic mechanism of the
cells especially nucleic acid synthesis. A few disrupt membrane function. Many affect
energy metabolism. Selective toxicity appears to be due to differences in
permeability. The mechanisms of selective toxicity are more or less well – defined.
Examples of sites of action having no equivalent in vertebrate cells are L – α –
glycerophosphate oxidase (in trypanosomes) and Dihydro – pteroate synthetase (in
sporozoa)
DRUGS INTERFERING WITH ENERGY METABOLISM

 Tryparsamide and Melarsoprol (ARSENICALS)

These drugs specifically inhibit pyruvate kinase of the trypanosomes by reacting
with the sulfhydryl (- SH) groups of the enzyme. They are used in the treatment
of African sleeping sickness (trypanosomiasis) in humans.

Melarsoprol (Mel B) is more commonly used than Tryparsamide that may cause
blindness, which is why it is very seldom used today. Melarsoprol may cause
encephalopathy, abdominal colic, and vomiting

 Pentostam (Sodium stibogluconate) (ANTIMONIALS)

Interacts with the sulfhydryl group of glycolytic enzymes specifically that of
phosphor – fructokinase and is used to treat cutaneous leishmaniasis

 Suramin
Its mechanism of action is obscure but L – alpha glycerol – phosphate oxidase
of the African trypanosomes which is concerned with the oxidation of NADH, is
sensitive to suramin. It is used to treat trypanosomiasis and has a marked
curative effect but is less useful for prophylaxis against Trypanosoma evansi, T.
brucei, T. equinum, and T. equiperdum. It is a synergistic potentiator of
phenanthridines and of aminoquinaldine derivatives (see below)

Dose

4 g/45 kg IV as a single dose

Horse
Or divide it into 3 parts and give over a period of 3 weeks

Dog 0.2 g IV repeat for 6 days

 Robenidine (also called ROBENZIDINE)

 P a g e | 198

Inhibits the respiratory chain phosphorylation and ATPase activity in rat liver
mitochondria. A similar action may occur in coccidian. The basis of selective
toxicity is unknown and is both coccidiostatic and coccidiocidal. It is used for
prevention and treatment of coccidiosis in poultry

 Buquinolate, Decoquinate, and Methylbenzoquate (4 –

HYDROXYQUINOLONES)
These drugs block the respiratory chain phosphorylation at a point near the
cytochrome B. the antitropozoite (anticoccidial) action has no apparent
explanation since the energy metabolism beyond glycolysis does not occur until
the schizont stage. They are used as broad – spectrum anticoccidials; arrest
sporozoite development but do not kill. Sporozoite development may
recommence when medication is withdrawn too early. Methylbenzoquate is
used for the prevention of coccidiosis in broiler chickens; administered
continuously from first day to slaughter
Dose
Methylbenzoquate 0.001 – 0.002% in feed
Buquinolate 0.00825% in feed
Decoquinate 0.003% in feed

 Menoctone and Ubiquinone 8 (NAPHTHOQUINONES)

These agents block electron transport down the respiratory chain by acting as
analogues of coenzyme Q and cause swelling of the mitochondria and are used
as anti – malarial drugs

 Primaquine (8 – AMINOQUINOLONES)
The action of primaquine is very similar to that of naphthoquinones and is
used as an anti – malarial drugs

 Diiodohydroxyquin and Iodochlorhydroxyquin (8 – HYDROXYQUINOLONES)

The mechanism of action is similar to naphthoquinones and to 8 –
Aminoquinolines and are used in the treatment of amoebiasis.

Iodochlorhydroxyquin is also used as an antifungal

Dose
Based on doses for humans
Diiodohydroxyquin 500 mg tid for 10 days
Iodochlorhydroxyquin 600 mg tid for 21 days

DRUGS INTERFERING WITH CELL MEMBRANE FUNCTION

 Amphotericin B
Disrupts cell membrane functions by binding to membrane sterols. The
membrane becomes leaky to cations. It is used for the treatment of cutaneous
leishmaniasis and also an antifungal agent

 Monensin, Lasalocid, Salinomycin, Narasin, and Maduromicin

(POLYETHER IONOPHORES)
 P a g e | 199

These ionophores specifically inhibit the transport of potassium ions and are
used for treatment of coccidiosis in poultry. They prevent the first sexual cycle
by inhibiting the development of first generation schizonts and cause
retardation of development of immunity to coccidiosis. They are suitable for
addition to broiler feed but should not be mixed with the feed for laying birds.
They should not be fed to horses and other equines and must not be used
together with other coccidiostat. Ionophores have been observed to cause
death of host animals when used with therapeutic levels of tiamulin and
valnemulin (pleuromutilins)

Dose
Monensin 0.01 – 0..121% in feed
Lasalocid 0.005 – 0.0075% in feed
Salinomycin 0.01% in feed
Narasin 0.007%
Maduromicin 0.0005 – 0.0006%

DRUGS INTERFERING WITH SYNTHESIS OF COFACTORS

 Amprolium
Is as structural analogue of thiamine or vitamin B1, a cofactor of a number of
decarboxylase enzymes, used as an anti – coccidial by inhibiting chiefly the
first generation schizonts; effective in the early stages of infection. It is used as
a preventive and therapeutic drug against Eimeria tenella and E. acervulina in
broilers and may be used as a preventive anticoccidial in layers. Adverse
reactions include bleeding disorders but addition of vitamin K in the diet
reduces mortality

 Sulfanilamide, Sulfaquinoxaline, Sulfadimethoxin, Sulfamonomethoxin, and

Ethopabate
(SULFONAMIDES and SUBSTITUTED PARA – AMINOBENZOIC ACID)
These drugs act as analogues of the growth factor p – aminobenzoic acid
(PABA) and therefore block the synthesis of tetrahydrofolate. They are widely
used for treatment of coccidiosis, malaria, and bacterial infections. Prolonged
use can cause hemorrhagic syndrome in birds.

Sulfamonomethoxine is used also for leukocytozoonosis in birds at 1 g/liter

of drinking water

Ethopabate is usually combined with Amprolium for prevention of

coccidiosis in poultry; given at 0.0004 to 0.004%

 Diaveridine, Ormethoprim, and Pyrimethamine (4 – DIAMINOPYRIMIDINES)

These drugs inhibit the synthesis of tetrahydrofolate reductase level resulting
in disruption of one - carbon transfer reactions important in protein and DNA
synthesis. They are synergistic with sulfonamides.
 P a g e | 200

Diaveridine and Pyrimethamine are used as coccidiostats in combination

with sulfadimidine or Sulfaquinoxaline

Pyrimethamine is used for treatment of toxoplasmosis; also used for

leukocytozoonosis and usually in combination with a sulfonamide

DRUGS INTERFERING WITH NUCLEIC ACID SYNTHESIS

 Homidium Bromide (Ethidium Br), Dimidium Br, Pyrithidium Br, and

Isometamidium
(PHENANTHRIDINES or AMINOPENANTHRIDIUMS)
The phenanthridines inhibit DNA polymerase and DNA – primed RNA
polymerase as a result of intercalation of the drugs with DNA which leads to a
local unwinding and lengthening of the DNA helix and thus interfere with its
function as a primer in the nucleic acid synthesis. They are sued for treatment
of trypanosomiasis (Trypanosoma congolense and T. vivax) but less active
against T. brucei; inactive against T. evansi

Dose

Homidium Br 1 mg/kg as single IM injection

curative and prophylactic for a month

Pyrithidium Br 2 mg/kg IM

 Quinine (see notes for Chloroquin and Quinacrine below)

 Chloroquin and Quinacrine (4 – AMINOQUINOLONES)

Act in the same way as the phenanthridines although Chloroquin is primarily
concerned with inhibition of hemoglobin degradation causing amino acid
starvation of the parasite. Both are used for treatment of malaria.

Chloroquin in addition has an anti – inflammatory property and is used for

rheumatoid arthritis and discoid lupus erythematosus

Quinacrine is used for giardiasis in dogs:

a) For large breeds - give 200 mg/dog tid on the first day and bid on the
subsequent 6 days
b) For small breeds – give 100 mg/dog bid for 6 days

 Nifurtimox (Lampit), Nitrofurazone, and Furazolidone (5 – NITROFURANS)

These nitrofurans inhibit DNA synthesis by breaking DNA strands.

 P a g e | 201

Nitrofurazone has anticoccidial and antibacterial activity and is used as a

preventive anticoccidial (0.0005%) in feed, and as a curative anticoccidial
(0.002%); may cause nervous signs when treatment is continued for more than
12 days

Furazolidone is used against E. tenella (0.11 or 0.0055% in feed) and usually

in combination with Nitrofurazone (0.0008 furazolidone and 0.0055%
Nitrofurazone)

Nifurtimox is for treatment of Chaga’s disease

 Radanil (2 – NITROIMIDAZOLES)
See notes under Metronidazole, Dimetridazole, and Ipronidazole below

 Metronidazole, Dimetridazole, and Ipronidazole (5 – NITROIMIDAZOLES)

Radanil and the 5 – Nitroimidazoles after appropriate drug metabolism may
interfere with nucleic acid synthesis by binding to DNA.

Radanil is used for treatment of Chaga’s disease

The 5 – Nitroimidazoles are for trichomoniasis, histomoniasis, and

amoebiasis. Before treatment of trichomoniasis in bulls with Ipronidazole
(IM), the bulls should receive a course of broad – spectrum antibacterial to
reduce preputial commensal bacteria which might inactivate the drug

Dose

50 mg/kg oral daily for 5 days or

Cattle 19 mg/kg IV daily for 5 days
For bovine trichomoniasis
Dimetridazole

Turkey 0.0125% in feeds for histomoniasis

Metronidazole For amoebiasis 250 mg/kg Tid for 5 – 10 days

 Pentamidine, Stilbamide, Phenamidine, and Diminazene Aceturate (Berenil,

Ganaseg)
(AROMATIC DIAMIDINES)
All of these agents bind with DNA and disrupts phosphoglyceride synthesis.

Diamidines and phenanthridines at low doses seem to exert a very specific

effect on kinetoplast DNA synthesis in trypanosomes. This may not be related
to the antitrypanosomal effect of the drug

Diminazene Aceturate is active against Trypanosoma congolense and T.

vivax; less effective against T. brucei and T. evansi but has no prophylactic
effect. It is well tolerated by ruminants and less well by horses. General
 P a g e | 202

adverse reaction to Diminazene may occur in dogs. It is used as a “sanative”

drug that is used when trypanosomes become resistant to other drugs. This is
also active against bovine trichomoniasis and babesiosis

Phenamidine is also used to treat babesiosis

Dose
Curative for trypanosomiasis 3.5 mg/kg SC or IM
Cattle 100 – 150 ml of 1% solution for trichomoniasis
Injected into the prepuce, retained for 15 minutes,
Diminazene
and massage the penis and prepuce thoroughly
Aceturate
Cattle and 2.0 mg/kg SC or IM for Babesia bigemina;
Dog 5mg/kg for B. bovis
Horse 5 mg/kg SC or IM
Horse 8.8 mg/kg for babesiosis
Phenamidine
Dog 15 mg/kg for babesiosis

DRUGS INTERFERING WITH PROTEIN SYNTHESIS

 Quinapyramine Chloride or Methylsulfate (Antrycide)

(AMINOQUINALDINS)

This drug seems to act by displacing Mg²+ and polyamines from the
cytoplasmic ribosomes of trypanosomes causing ribosomal aggregation and
inactivation. It is used for treating trypanosomiasis (T. congolense, T. vivax, T.
equiperdum, and T. equinum). Chloride salt – insoluble in water is used for
curative effect. Methylsulfate salt – soluble in water is used for prophylaxis
and is well – tolerated by ruminants; local and systemic reactions may occur in
horses and dogs

Dose

5 mg/kg as 10% aqueous solution

Divide dose into 2 – 3 parts and give every 6 hours
Antrycide Dogs/Horses
Suramine will increase the protective power of
Quinapyramine

 Tetracyclines, Oxytetracyclines, and Minocycline (TETRACYCLINES)

The dose for anaplasmosis is 6.6 – 11 mg/kg IM

 Clindamycin (LINCOSAMIDES)

Is used for toxoplasmosis

DRUGS INTERFERING WITH UNKNOWN MECHANISM

 P a g e | 203

 Clopidol (also called METRICHLORPINDOL)

(PYRIDINOLS)

Is a broad – spectrum anticoccidial used for prevention of coccidiosis in

broilers and replacement birds. It is administered in feed from day – old to
slaughter; at 0.0015% but should not be given to birds producing eggs for
human consumption

 (CARBANILIDES)
 Nicarbazine (anticoccidial)
Used for prophylaxis against E. tenella, E. necatrix, and E. acervulina.
It has a marked inhibitory effect on the second generation schizonts. It
is suitable for broilers; given for first 12 weeks of chicken life but
unsuitable for layers or breeding stock because of the effect on egg
color and hatchability. Adverse effects include interrupts egg – laying
period; reduces hatchability; mottled egg yolk

 Nitrophenide
Acts against E. tenella, E. necatrix. Give at 0.025% in feed. It inhibits
second generation schizonts

 Imidocarb dipropionate
Is used for treatment and prophylaxis of babesiosis and anaplasmosis

Dose
Imidocarb
Cattle 1.2 mg/kg SC or IM
For babesiosis Horse 2.4 mg/kg SC or IM
Dog 6 mg/kg SC or IM
For anaplasmosis Cattle 3 mg/kg
Amicarbalide
Cattle 5 mg/kg
For babesiosis
Horse 8 mg/kg

 Amicarbalide and Trithiadol

Effective against E. tenella, E. necatrix, E. acervulina, and E. maxima
at the rate of 0.06 – 0.09% in feed and may reduce hatchability so do
not use in breeders

 NITROBENZAMINES

 Dinitolmide (Zoalene)
An anticoccidial that inhibits the development of second – generation
schizonts but does not inhibit the development of immunity

 Nitromide
Also an anticoccidial which is a mixture of 30% N – acetyl – N’ – p –
nitrophenyl sulfanilamide, 25% 3,5 – dinitrobenzamide, and 5% 4 –
hydroxyl – 3 nitrophenylarsonic acid
 P a g e | 204

 Quinoronium Sulfate (QUINOLINE DERIVATIVES)

It inhibits DNA polymerase and is used for the treatment of babesiosis (B.
bigemina, B. bovis, B. divergence, B. canis)

Dose

Horse and Cattle 1 mg/kg twice with 24h interval

0.25 mg/kg
Dog
Inhibits cholinesterase in the hosts

 Halofuginone
A preventive anticoccidial; given at 0.0003% in feed

CHEMOTHERAPY OF SOME PROTOZOAN DISEASES

 COCCIDIOSIS
a. 2 important genera: Eimeria and Isospora
b. Coccidia may enter cells in liver (rabbit) and intestine (cattle, sheep, pigs,
goats, dogs, rabbits, and fowls)
c. A major problem in poultry industry
d. Infection is self – limiting
e. The parasites undergo 2 stages of multiplication:
1. Asexual (schizogony)
2. Sexual (sporogony)
f. The rapid multiplication during sporogony is the most pathogenic stage
g. Repeated infection may cause host immunity
h. Symptoms include:
1. Diarrhea or bloody feces
2. Heavily infected animals become emaciated and anorexic

Animals adopt a drooping posture and often huddle together for warmth
 P a g e | 205

LIFE CYCLE

Ingestion Release of 8 Sporozoites

Sporozoites
of sporozoites grow into
penetrate
oocysts into the schizonts,
host cells
host’s gut rupture and
release
merozoites

Male
Release 3rd Merozoites
microgametes
generation invade other cells
fertilize the female
schizonts or and develop into
to become
intracellular 2nd generation
infective zygotes
sexual schizonts
(oocysts) that are
gametocytes
discharged in the
host’s feces

 In Goat and Sheep

 Infection is chiefly confined to young (4 – 6 months old)
 Mixed infection is usual
 Treatment:
o Sulfaguanidine
2 g/day for 6 days

o Nitrofurazone
7 – 10 mg/kg daily for 7 days
May be given in feed at 0.0165% or 0.008% in drinking
water

o Amprolium
50 – 62.5 mg/kg in water or feed for sheep
100 mg/kg for 4 days or longer for goats

 In Cattle
 Infection occurs in all parts of the world
 Serious outbreak occurs in dairy herd
 P a g e | 206

 Commonly affected are 3 weeks to 6 months old

 Older cattle are carriers
 Treatment:
o Amprolium
Most effective drug at present
20 – 25 mg/kg in feed daily for 4 – 5 days

o Lincomycin HCl
1 g/calf in water for 21 days

o Sulfonamides
Not recommended

 In Pigs
 Treat with Nitrofurazone 0.44% in feed for 7 days

 In Dogs and Cats

 Infection is readily detected but the pathogenicity is questionable
 Should be differentiated from other enteritides
 Treatment: with combined sulfonamides (triple sulfa);
Sulfathiazole/Sulfathiazole/Sulfamethazole – 0.083 g/kg

 In Poultry
 The problem of coccidiosis is ubiquitous in poultry management
 It is difficult to avoid infection completely
 The clinical disease is dependent upon the number of oocyst ingested
by individual birds
 An outbreak of coccidiosis depends upon the factors that allow oocysts
to sporulate and remain viable
 There is no cross – immunity between species of coccidia
 Treatment:
o Anticoccidials are used usually in starter ration for broilers
o Protection is more important in fast – growing birds than the
egg – laying type where immunity and caging alter the
demands for anticoccidial drugs
o The emergence of resistant strains presents a major problem
 Methods to prevent the development of resistance:
o Switching around the 13 different classes of drugs
o “Shuttle Program” – a planned switch of drug in the middle of
growing period

 Curative treatment
Should be given immediately after diagnosis
o Sulfadimidine
0.2% in drinking water for 2 periods of 3 days
separated by 2 days without treatment
 P a g e | 207

o Sulfaquinoxaline
In feed at 5%

o Nitrofurazone with Furazolidone

0.0126% given over 7 day period; may be
repeated after a 5 – day interval

o Sulfonamides
Are active against schizont stage specifically the
second – generation schizonts

 Preventive medication
Prolonged continuous use of coccidiostatic compounds in feed
and water

DRUGS % in feed or water

Amprolium 0.0125
Buquinolate 0.0055
Clopidol 0.0125
Decoquinate 0.0030
Furazolidone 0.0055
Lasalocid 0.005 – 0.075
Monensin 0.0121
Methylbenzoquate 0.001 – 0.002
Nicarbazine 0.0125
Nitrofurazone 0.0055 – 0.01
Robenidine 0.0030 – 0.0060
Salinomycin 0.006 – 0.01
Sulfaquinoxaline 0.0125
Zoalene 0.0125

 TOXOPLASMOSIS
 Caused by Toxoplasma gondii
 Definitive hosts are domestic cat, jaguarondi, ocelot, mountain lion, and
leopard cat
 Intermediate hosts are almost all warm – blooded animals
 Of zoonotic importance
 Most infections are asymptomatic
 Complete eradication is by elimination of infected animals
 Treatment:
 P a g e | 208

The aim is to reduce shedding of oocysts

 Pyrimethamine
Found effective in monkeys and humans
Of little value against cyst forms
Synergistic with sulfonamides

 Clindamycin

 TRYPANOSOMIASIS
 Caused by blood parasites Trypanosoma spp. and with a few exceptions, these
organisms undergo cyclical changes in arthropod vectors
 Treatment:
 Suramin
Horse: 4 g/45 kg IV
Dog: 0.03 g/kg IV for 6 days

 Homidium Br
Cattle: used as 1 – 2.5% solution at 1 mg/kg IM
Protection lasts for about 5 weeks

 Pyrithidium Br
Cattle/Sheep/Goat: 0.5 mg/kg deep IM
Protection lasts for 6 – 10 months

 Diminazene Aceturate (Berenil, Ganaseg)

Has no prophylactic effect due to rapid excretion

 LEUKOCYTOZOONOSIS
 Treatment is usually not effective
 Prophylactic medication

 Pyrimethamine (1 ppm) and Sulfadimethoxine (10 ppm)

 Clopidol may also be used at 1.25 to 2.5 ppm

 BABESIOSIS
 Caused by Babesia spp
 Transmitted by arthropods
 Acute, often fatal infections characterized by fever and anemia
 Treatment:
 In addition to injection of babesiacide, supportive therapy is important
 Recovery is most likely when treatment is given early in the course of
infection in cattle
 Quinoronium sulfate is used in infections caused by all species but
does not eliminate infections
 Phenamidine isothionate
 Diminazene Aceturate
 P a g e | 209

 ANAPLASMOSIS
 Treatment:
 Tetracycline
11 mg/kg for 10 days

 Tetracycline TA
22 mg/kg, administer 4 doses, 3 days apart

 Imidocarb propionate
4 mg/kg, 2 weeks apart or daily for 3 days at 5 mg/kg

Lesson 25
 P a g e | 210

Anthelmintic
Drugs

P arasitic helminthes belong to Phylum Nematyhelminthes (roundworms) and

Phylum Platyhelminthes (flatworms) which includes the cestodes (tapeworms) and
the trematodes (flukes)

General Properties of Anthelminthic Drugs

 Older drugs have quite narrow spectrum of activity

 Newer drugs have broader spectrum of activity and they affect different species of
worms
 Most have relatively high level of selective toxicity for worms and therefore are safe
to the host but the exceptions are the organophosphate compounds
 Resistance to various chemical groups of anthelmintics is now recognized as a
problem

Qualities of Antiparasitic:
 Wide therapeutic index
Examples:
Toxic dose is at least 3x the therapeutic dose
 Effective after only 1 dose
 Easy to administer
 Inexpensive
 Does not leave residues
Important in food – producing animals

Mechanism of Action

 INTERFERE WITH ENERGY METABOLISM

 Inhibitors of Glucose transport
 Cyanide dyes
Examples:
Dithiazanine iodide

 Benzimidazoles
Examples:
Mebendazaole, Flubendazole
 P a g e | 211

 Disruptors of Glycogen metabolism

Examples:
Niridazole, a schistosomicidal nitrofurans that inhibits
phosphorylase phosphatase activity thereby accelerating the
depletion of glycogen reserve

 Inhibitors of Glycolysis
Examples:
Arsenicals such as Thiacetarsamide that binds to sulfhydryl (-
SH) group of glycolytic enzymes thereby altering the tertiary
structure of proteins and the active sites of enzymes in both
host and parasites

 Inhibitors of Mitochondrial reactions

Examples:
All benzimidazole except Mebendazole

 Uncouplers of Oxidative phosphorylation

Examples:
Salicylanilides and substituted phenols

 INTERFERE WITH NEUROMUSCULAR COORDINATION

 Cholinesterase Inhibitors (causing over – stimulation)
Examples:
Organophosphates, Coumaphos, Crufomate, Dichlorvos,
Haloxon

 Cholinergic Agonists (causing over – stimulation)

Examples:
Imidothiazoles: Levamisole, Fetramisole,
Pyrimidines: Morantel, Pyrantel

 Potentiators of Inhibitory Neurotransmitter (inhibition)

Examples:
Ivermectin (one of the avermectin antibiotics)

 Agents causing muscle hyperpolarization (inhibition)

Examples:
Piperazine
Phenothiazine

DRUGS AGAINST ROUNDWORMS

 BENZIMIDAZOLES
 Examples
Thiabendazole Albendazole Cambendazole
Fenbendazole Flubendazole Mebendazole
Oxfendazole Oxibendazole Netobimin
Febantel Thiophanate
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Thiophanate, Netobimin, and Febantel are probenzimidazoles. They

are biotransformed into benzimidazole in the body

 General Properties
 Low toxicity
 Some are teratogenic

 Mechanism of Action
 Inhibit energy metabolism
 All except Flubendazole and Mebendazole inhibit fumarate reductase
 Disrupt the function of cell microtubules. This is a slow process and
requires a prolonged contract between drugs and parasites
 They are more effective in ruminants and horses than in other species
 Divided doses are more effective than a single dose
 Oxfendazole (a sulfoxide) is the active metabolite of Fenbendazole and
Febantel
 Albendazole, Fenbendazole, Thiophanate, and Febantel are
biotransformed in the liver and re – secreted into the alimentary tract as
active metabolites

 Spectrum of Activity and Clinical Use

 Thiabendazole
 Well – absorbed and therefore may destroy larval forms in the
tissues
 May cause hypersensitivity reaction but this may be due to the
destruction of migrating larvae rather than due to the drug itself
 Has antifungal and antiyeast properties also

 Doses

Thiabendazole
66 mg/kg
Cattle 110 mg/kg for severe parasitism or
severe infection with Cooperia
Sheep and 44 mg/kg
Goat 66 mg/kg for severe parasitism
44 mg/kg
Horse
88 mg/kg for ascarids
Pigs 75 mg/kg
Laboratory 48 – 100 mg/kg
Animals

In Cattle
 Virtually 100% effective against all gastrointestinal
roundworms except Nematodirus, Ostertagia, and Trichuris
 P a g e | 213

 Higher doses may be needed for Cooperia

 Not effective against lungworms

In Horses
 Very effective against large and small strongyles and pinworms
(Oxyuris)
 The drug of choice against strongyles in foals
 Low activity against Parascaris and immature Oxyuris
 Combination with Piperazine or with trichlorfon (an
organophosphate) is effective against these parasites

In Pigs
 Effective against strongyles in piglets
 May be effective against Hyostrongylus rubidus, Strongyloides
ransomi, and Oesophagustomum dentatum

In Dogs and Cats

 Not usually a drug of choice for these species
 Has been used to control Strongyloides in dog colonies

 THE NEWER BENZIMIDAZOLES

Administered orally but higher doses are required to eliminate migrating
larvae

In Cattle
 Cambendazole, Fenbendazole, Albendazole, and Oxfendazole
Effective against adult and immature lungworm Dictyocaulus

 Parbendazole, Mebendaozole, and Thiophanate

Relatively ineffective against lungworm but all are effective
against all major gastrointestinal parasites

 Fenbendazole, Albendazole, Oxfendazole, and Thiophanate

Have most impressive effect on immature gastrointestinal
roundworms

 Fenbendazole
Effective against inhibited Ostertagia larvae

 Parbendazole
Causes death of Ostertagia larvae in abomasal modules
 Albendazole
Affects most species of roundworms, tapeworms, and liver
flukes

In Horses
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All are effective against adult forms of large strongyles, small

strongyles, pinworm (Oxyuris), small pinworm (Probstmayria), and
Trichostrongylus axel

 Cambendazole, Mebendazole, and Fenbendazole

Affects ascarids and also cambendazole may be used against
Habronema

 Mebendazole
Effective against lungworm at increased dose
Also affects equine tapeworm Anoplocephala

 Albendazole
Used against equine lungworm

In Pigs
All are effective against Hyostrongylus, Strongyloides ransomi,
Oesophagustomum dentatum, and Ascaris

In Dogs and Cats

 Mebendazole
Effective against hookworm, ascarids, whipworm, tapeworm
(Taenia): give at 22 mg/kg/day for 3 – 5 days

For whipworm: give 50 mg/kg/day for 3 days

 Fenbendazole
50 mg/kg/day for 2 – 3 days
Doses:
DRUG HORSE CATTLE SHEEP GOAT PIG DOG/CAT

Cambendazole 20 25 20 - 20 -
Fenbendazole 5 7.5 5 5 5 50
Mebendazole 8.8 - - - 1.25 22
Parbendazole - 30 15 – 30 - 25 – 30 -
Albendazole - 7.5 7.5 - 5 – 10 -
Oxfendazole 10 4.5 5 7.5 3 – 4.5 -
Oxybendazole 10 - - - 15 -
Flubendazole - - 10 - 5 -

 THE PROBENZIMIDAZOLES

 Febantel
Metabolized to true benzimidazoles similar to Oxfendazole and
Fenbendazole which are responsible for its pharmacological activity
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Teratogenic effect in sheep has been attributed to Oxfendazole metabolite

 Spectrum of Activity and Clinical Use

In Horses
o Large and small strongyles
o Adult ascarids and adult pinworms
o Effective against Gastrophilus bots (larvae) when
combined with trichlorfon

In Dogs and Cats

Usually in combination with praziquantrel (an anticestodal
agent) for hookworms, ascarids, and tapeworms

In Ruminants and Pigs

For GI worms and lungworms

 Thiophanate
 Metabolized to Lobendazole (not marketed)
 Effective against most nematodes of farm animals

 Netobimin
Metabolized to Albendazole sulfoxide by the gut microflora

 Doses

Febantel
Horse 6 mg/kg oral
Dogs and Cats 10 mg/kg for 3 days
Puppy and Kitten 15 mg/kg for 3 days
Ruminants 10 mg/kg
Pig 20 mg/kg
Thiophanate
Ruminants 50 mg/kg
Pig 5 – 12 mg/kg for 14 days
Netobimin
Ruminants 7.5 mg/kg
20 mg/kg for inhibited larvae flukes and tapeworms, oral
12.5 mg/kg by injection

 IMIDOTHIAZOLES

 Levamisole
Has nicotine – like action on the neuromuscular junction and minor ability
to inhibit fumarate reductase. Available for oral (drench, or feed additive)
and for parenteral (SC) administration which has better systemic effect

 Adverse Effects and Toxicity

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Reaction at injection site

Gut irritation
CNS stimulation
Salivation (nicotine – like reaction)

Horses are more sensitive to toxic effects than other species

 Spectrum of Activity and Clinical Use

A broad – spectrum anthelmintic

In Ruminants
Affects all major gastrointestinal roundworms (Haemonchus,
Ostertagia, Cooperia, Trichostrongylus, Bunostomum,
Oesophagostomum), lungworms (Dictyocualus), and eyeworm
(Thelazia)

In Horses
For ascarids, lungworms, and adult pinworms

In Pigs
Controls nodular worms (Oesophagostomum), ascarids,
Strongyloides ransomi, and Metastrongylus lungworm
In Dogs
Affects all stages of heartworm and also ascarids, and
hookworms, but not whipworms

In Chickens
Affects Ascaridia, Heterakis, Capillaria, and Oxyspirura
mansoni

 Tetramisole
 A racemic mixture of D – and L – isomers
 Anthelmintic activity is associated with L – form which is Levamisole
 Toxicity is associated equally with both forms
 Practically the same as Levamisole except for higher dose required and
greater likelihood of toxic reactions
 Doses
Levamisole
8 mg/kg oral or SC
Ruminants and Pigs 1o mg/kg as pour on
5 – 6 mg/kg SC for Thelazia
Horse 10 – 15 mg/kg oral or SC
Dogs and Cats 7.5 mg/kg SC
40 mg/kg in half the daily consumption of
Chicken
drinking water
Tetramisole
15 mg/kg oral or SC
Ruminants and Pigs
Not to exceed 4.5 g in cattle
Chicken 3.6 mg/kg/day for 3 days (for gapeworms)
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 ORGANOPHOSPHATES

Administered orally in various forms, well – absorbed from the gut, and
specifically larvicidal

 Examples
Dichlorvos
Trichlorfon (Metriphonate)

 Mechanism of Action
 Inhibition of cholinesterase resulting in paralysis of adult worms
 The mechanism of larvicidal action is unknown

 Toxicity
 Overdose leads to muscarinic and nicotinic signs
 Animals that are susceptible to toxic effects of organophosphates
include:
o Debilitated animals
o Dogs with hookworm
o Cattle with migrating warble fly larvae
o Animals concurrently medicated with succinyl – choline or
similar drugs
o Certain breeds of dogs
o Young animals
o Pregnant animals

 Treatment of toxicity:
Atropine sulfate and pralidoxime (2PAM)

 Spectrum of Activity and Clinical Use

Not as broad as that of the benzimidazoles but more commonly used in
pigs and horses

In Ruminants
Mainly for worms in the abomasum and upper small intestine and has
little effect on worms in the large intestine

In Horses
Good activity against ascarids, pinworms, and bots, less activity
against strongyles and are also used against stomach bots

In Pigs
Active against ascarids, Oesophagostomum and Trichuris
 P a g e | 218

In Dogs and Cats

Effective against ascarids and hookworms but safer drugs are available

 Doses
DICHLORVOS
Horses (feed formulation)
31 – 41 mg/kg
Foal (gel formulation)
20 mg/kg for bots
Pig 11.2 – 21 mg/kg
Dogs 27 – 30 mg/kg
Puppies/Cats 11 mg/kg

 TETRAHYDROPYRIMIDINES

 Examples
Pyrantel
Morantel

 Mechanism of Action
Nicotine – like depolarization of neuromuscular junction leading to
paralysis of the worms

 Pharmacokinetics
Poorly absorbed systematically and therefore, has less larvicidal
activity. The tartrate salt, however, is well absorbed in the pig and the
dog. The pamoate salt is less soluble in water and therefore, stays in
the gut

 Toxicity
Less toxic than OP’s and Levamisole

 Spectrum of Activity and Clinical Use

Has a broad spectrum of activity against gastrointestinal parasites of
ruminants, pigs, horses, dogs, and cats

In Horses
Effective against tapeworm Anoplocephala, against strongyles,
ascarids, and pinworms with variable effects
In Pigs
For ascarids and Oesophagostomum

In Ruminants
Against Haemonchus contortus (including Thiabendazole – resistant
strains), Ostertagia, Trichostrongylus, Nematodirus, and Cooperia

In Dogs
 P a g e | 219

For hookworms and ascarids but not too effective against whipworms

 Doses

Pyrantel tartrate
Horse 12.5 mg/kg
Pig 22 mg/kg maximum of 2 g/animal
Ruminants 25 mg/kg
Pyrantel pamoate
Horse 6.6 mg base/kg
Dog 5 mg base/kg for dogs over 2.2 kg, suspension
15 mg/kg for smaller dogs less than 2.2 kg
Morantel tartrate
Sheep 10 mg/kg
Cattle 8.8 mg/kg oral; 2% ointment for Thelazia eyeworm
Morantel fumarate
Sheep 12.5 mg/kg

MISCELLANEOUS ANTINEMATODAL DRUGS

 PHENOTHIAZINE
An older anthelmintic. The development of truly broad – spectrum anthelmintics
has reduced its clinical use

 Mechanism of Action
Not known and does not seem to be related to the amount of drug
absorbed by the worms

 Toxicity
 Safer in sheep than in other species
 Photosensitization, conjunctivitis, and corneal opacities in ruminants
 Hemolytic anemia and jaundice in horses
 Anemia in dogs and cats

 Spectrum of Activity and Clinical Use

Administered orally and are more easily absorbed by worms in gut
with fairly wide range of activity against gastrointestinal worms

In Ruminants
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100% effective against Haemonchus and Oesophagostomum and not

effective against larval stage

In Horses
100% effective against small strongyles and not effective against
ascarids. At present, used only for prevention rather than for
therapeutic purposes

 Doses

Phenothiazine
Sheep and Goat 25 – 30 g for weighing over 27 kg
12.5 g for 11 – 23 kg animals
Cattle 10 g/45 (maximum of 70 g)
Horse 3 g/45 kg for small strongyles
5 g/45 kg for large strongyles
(give ½ of the calculated dose daily for 2 days
Chicken 0.5 g/bird
Turkey 1 g/bird
Daily prophylactic dose
Sheep and Goat 0.25 – 0.5 g/animal
Cattle 0.5 g/45 kg
Horse Adult 2 – 5 g
Colt 1g

 PIPERAZINE
 Available as:
 Adipate (active Piperazine content = 37%)
 Chloride (= 48%)
 Citrate (= 35%)
 Dihydrochloride (-50 – 53%)
 Hexahydrate (= 44%)
 Phosphate (= 42%), and
 Sulfate (= 46%)

 Mechanism of Action
A non – depolarizing (curare – like) neuromuscular blockade resulting
in the paralysis of the worms

 Toxicity
With a wide margin of safety, large doses may produce emesis,
diarrhea, incoordination, and head pressing in dogs and cats

 Spectrum of Activity
Administered orally and therefore active only against adult worms in
the gut

In Horses
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For ascarids and small animal strongyles, less effective against

pinworms

In Dogs and Cats

For ascarids and hookworms

In Pigs
For ascarids and nodular worms

In Chickens
For ascarids

 Doses

Piperazine
Dog and Cat 45 – 64 mg/kg
Horse 110 mg/kg
Pig and Ruminants 110 mg/kg
32 mg/kg given in each of 2
Poultry successive feeding or in drinking
water for 2 days

 IVERMECTIN
 Mechanism of Action
Unique among anthelmintics in that it accentuates endogenous GABA
– induced inhibitory actions in worms to cause paralysis

 Pharmacokinetics
Orally and parenterally active, poor penetration of membrane barriers

 Adverse Reactions and Toxicity

 Clostridial infection at injection site in horses
 Some species and breed susceptibility – Collie dogs and Murray Grey
cattle are more susceptible to toxic effects of ivermectin
 Neurotoxic effects have been reported

 Spectrum of Activity and Clinical Use

 Broad – spectrum antinematodal affecting all species
 Larvicidal when given parenterally
 Also affects ectoparasites via systemic administration to he host
 No activity against trematodes and cestodes which are believed to
utilize GABA as neurotransmitter

In Ruminants
Effective against adult and fourth larval forms of Haemonchus,
Ostertagia, Cooperia, Trichostrongylus, Strongyloides, Bunostomum,
Nematodirus, Trichuris, Oesophagostomum, Dictyocaulus, and
Chabertia
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In Horses
For small strongyles, large strongyles, ascarids, pinworms, stomach
worms, intestinal worms, and lungworms. Also for Gastrophilus bots
and Onchocerca microfilariae
In Pigs
For immature and adult forms of Ascaris, Hyostrongylus,
Strongyloides, Trichuris, Oesophagostomum, Metastrongylus,
Stephanurus dentatus, and the intestinal stages of Trichenella

In Dogs
As a preventive for heartworm, effective against hookworms, ascarids,
and whipworms
 Doses

Ivermectin
Cattle 0.2 mg/kg SC
Sheep 0.2 mg/kg oral
Horse 0.2 mg/kg oral or IM
Dog 0.006 – 0.12 mg/kg oral

 n – BUTYLCHLORIDE
A liquid given orally in capsule for the control of ascarids and hookworms in dogs
and cats but has no effect on migrating larvae. Less effective against hookworms
than against ascarids and does not have satisfactory activity against parasites of
other domestic animals

 Toxicity
 Usually non – toxic when given therapeutically
 Safe unless the patient is debilitated or too young
 Fasting of animal for 12 – 24h prior to administration is required
 Give a laxative such as magnesium sulfate 30 minutes to 1 hour after
administration of n – butylchloride

 Doses
n – Butylchloride
Dog and Cats
Body weight < 2.25 kg 1 ml
2.25 – 4.5 kg 2 ml
4.9 – 9 kg 3 ml
9 – 18 kg 4 ml
>18 kg 5 ml
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ANTITREMATODAL DRUGS

 Albendazole
 Approved for use against mature liver flukes such as Fasciola hepatica in
cattle
 With 27 – day withdrawal period
 A teratogen

 Praziquantrel
 For lung flukes in dogs
 Also effective against liver flukes but too expensive to use in ruminants

 Clorsulon
 Most effective against mature and immature F. hepatica cattle
 Adverse effects is rare
 Mode of action is that it deprives flukes of metabolic energy source
 Preslaughter withdrawal period is 8 days and milk withdrawal period is 4 days

DRUGS USED PRIMARILY TO ERADICATE WHIPWORM

 PHTHALOFYNE
For oral and intravenous administration; toxic causes gut disturbances and
CNS depression

 GLYCOBIARSOL
For oral administration; poor systemic absorption, less toxic than phthalofyne

 BUTAMISOLE
Chemically related to Levamisole and used for treatment of whipworm and
hookworm in dogs

 Doses

Butamisole
Dog and Cat 24 mg/kg SC

 Toxicity
 Vomiting, ataxia, tremors, lateral recumbency, and convulsions
 Contraindicated in debilitated, or heartworm – positive dogs
 Do not use within 24h of bunamidine HCl (an anti – cestodal
treatment)

DRUGS USED MAINLY AGAINST HOOKWORMS

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 DISOPHENOL (DNP)
For dogs and cats, there is uncouple oxidative phosphorylation. Given orally or
SC
Affects only adult worms; repeat treatment in 2 – 3 weeks

 Toxicity
 Hyperthermia, tachycardia, dyspnea, convulsions, cataracts maybe
induced but usually disappears spontaneously
 Avoid hot environment and restrict exercise for a couple of days after
therapy
 Caution when used in sick and debilitated animals

 Dose
Disophenol
Dog 10 mg/kg SC

 THENIUM CLOSYLATE and BUTAMISOLE

 Effective against immature and adult canine hookworm
 Causes vomiting but no effect on the action of drugs as long as vomiting
occurs 2 hours after administration
 Has caused sudden death in Airdales and Collie dogs, so, don’t use this breed
 Administered orally; fasting or purgation not needed
 Effective against ascarids when administered concurrently with Piperazine

DRUGS USED IN THE MANAGEMENT OF CANINE HEARTWORM

In an existing case, use adulticide to kill adult worms, followed 6 weeks later by a
microfilaricide. Then give preventive daily during mosquito season and for 2 months
thereafter

 ADULTICIDES
Eliminate both immature and adult heartworms

 Sodium Thiacetarsamide
 An organic arsenical which is very irritating when injected
extravascularly
 Given IV for a couple of days to allow gradual kill of worms which
starts to die 5 – 7 days after treatment
 Release of decomposing dead worms into pulmonary circulation may
cause pulmonary thrombosis, cough, and fever
 Kidney and liver toxicity may be produced
 Keep dog confined and quiet 1 – 2 weeks after treatment
 Concurrent antibiotics and corticosteroids reduce deleterious effects of
dead worms
 In case of extravascular injection, dilute drug by infiltration of
injection site with normal saline solution and glucocorticoids
 Topical application of dimethylsulfoxide (DMSO) may also help
 P a g e | 225

 Melarsomine hydrochloride
 A new organoarsenical adulticide with efficacy superior to
Thiacetarsamide
 Administered by deep IM rather than IV injection, some muscle and a
few days of mild soreness may develop
 The filaricide efficacy of Melarsomine, unlike that of Thiacetarsamide,
can be graded by dose. It is possible to eliminate worms from heavily
infected dogs in stages, thereby distributing the impact of worm emboli
 Toxicity of Melarsomine differs from Thiacetarsamide by not causing
any hepatic necrosis
 Doses

Thiacetarsamide
Dog 2.2 mg/kg 2x a day for 2 days
Melarsomine

Two 2.5 mg/kg doses 24 hours apart and repeated in 4 months

Dog With this regimen all male and nearly all female worms are
eliminated by the first 2 doses

 MICROFILARICIDES
Given at 6 weeks after adulticides

 Dithiazanine iodide
 Given orally continuously until microfilariae disappear from the blood
 Give for 1 week then check for microfilariae. If still positive, give
another course of therapy. If still positive, give another course of
therapy at a higher dose

 Toxicity
Gut disturbances and potential nephrotoxicity

 Dose

Dithiazanine 6.6 – 11 mg/kg/day for 7 – 10 days

Other Microfilaricides but not approved for Use

Levamisole
Dose: 11 mg/kg/day up to 15 days

Fenthion
Pour on OP insecticide, applied topically on dorsal midline once a week; no
longer used because of toxic fatalities
 P a g e | 226

Ivermectin
Dose: 0.5 mg/kg in single oral dose

 PREVENTIVES

 Diethylcarbamazine (DEC)
 Also active against ascarids and hookworms in dogs and cats
 Maintenance of effective blood level during mosquito season
 Prevents development of larvae following mosquito bite
 Given daily during mosquito season and 2 months after season is over
 Puppies are started on therapy at weaning
 Remember, it is only a preventive
 Do not give to animals with existing heartworm infestation. Sudden
massive destruction of microfilariae may produce fatal anaphylactic
reaction. DEC “opsonizes” the microfilariae to the action of antibodies

 Ivermectin
Dose: 0.006 mg/kg once a moth prevents infestation

 Milbemycin oxime
Related to ivermectin and is used as a heartworm preventive at 0.25 –
0.5 mg/kg. It is effective against canine hookworms and other
roundworms

DRUGS USED TO CONTROL TAPEWORMS

An effective anticestodal drug must remove both the scolex and the body of the worm

 PRAZIQUANTREL
 Broad – spectrum
 Affects adult and juvenile forms of all species of tapeworms; certain lung and
pancreatic flukes
 Dose

Praziquantrel
Dogs 1 mg/kg for Taenia
2.5 mg/kg for Dipylidium
Cattle 10 – 50 mg/kg
Sheep 50 mg/kg
 NICLOSAMIDE
 A salicylanilide
 Uncoupler of oxidative phosphorylation
 Effective against Monieza, Taenia, and Dipylidium
 Not effective against Echinococcus granulosus
 Removes scolex and body of worms
 Relatively nontoxic with little systemic absorption
 Dose

Niclosamide
 P a g e | 227

Dog 100 – 157 mg/kg

Sheep 100 mg/kg
Cattle 50 mg/kg

 BUNAMIDINE
 Removes whole tapeworm
 Effective against all tapeworms of dogs and cats including Echinococcus
 Must not be given with cholinesterase inhibitors and can cause ventricular
fibrillation
 Toxic when given IV but oral route has been followed by fatalities
 Dose

Bunamidine
Dog 25 – 50 mg/kg after 3 – 4h fast

 BENZIMIDAZOLES

 Mebendazole
 Given 22 mg/kg/day for 3 days for Taenia of dogs and cats
 20 mg/kg at each of 2 treatments with 48h interval for adult
Echinococcus granulosus of dog
 20 mg/kg for Monieza of ruminants

 Fenbendazole
 50 mg/kg/day for 3 days for Taenia of dogs and cats
 15 mg/kg for Monieza of cattle and sheep

 Albendazole, Cambendazole, and Oxfendazole

 Against Monieza when given at regular doses

DRUGS AGAINST LIVERFLUKES

Development of liver flukes in the ruminant host

 Metacercariae are ingested
 Larvae migrate to liver via the peritoneal cavity (4 – 6 days)
 Migration in liver parenchyma (4 – 6 weeks)
 Larval migration in liver parenchyma is associated with acute signs of
liver fluke infestation
 At 7th week, migrate to bile duct
 At 8th week or later, adults lay eggs
 A good flukicide must affect both the young and adult flukes

 HALOGENATED HYDROCARBONS
 P a g e | 228

Not widely used anymore

 Examples
 Carbon tetrachloride
Used in sheep at 1 ml/animal
 Hexachloroethane
 Tetradichloroethane
 Hexachloroparaxylene

 SALICYLANILIDES

Uncouples oxidative phosphorylation in adult flukes

 Brotianide
3.5 mg/kg for 12 week old flukes
7.1 mg/kg for 6 week old flukes

 Clioxanide
15 mg/kg for adult flukes
40 mg/kg for immature flukes (6 weeks)
135 mg/kg for immature flukes (4 weeks)

 Closantel
2.5 mg/kg SC

 Oxyclzanide
15 – 20 mg/kg oral for adult flukes
45 mg/kg for immature flukes (acute fasciolosis)

 Rafoxanide
7.5 mg/kg for adult (100% effective), for immature (50% effective)
Available in combination with Thiabendazole
 SUBSTITUTED PHENOLS

Uncouples oxidative phosphorylation

 Bromsalans
100% effective against immature flukes
Dose:

Bromsalans 30 – 60 mg/kg

 Dibromsalans (5’ Bromo – 4 – bromosalicylanilide)

 Tribromsalans (3’, 5’ Bromo – 4 – Bromosalicylanilide)
 Hilomid (1:1 mixture of di – and Tribromsalans)
 Diaphene (1:3 mixture of di – and Tribromsalans)

 Hexachlorophene
25 mg/kg oral or SC
 P a g e | 229

 Bithionol
60 mg/kg oral

 Niclofolan
2.6 mg/kg (adult flukes)
6 mg/kg (6 weeks)
8 mg/kg (8 weeks) oral
0.6 – 1 mg/kg SC

 Nitroxynil
10 mg/kg SC only

 Clorsulon
3.7 mg/kg (adult flukes)
15 mg/kg (6 weeks)
30 mg/kg (8 weeks)

 AROMATIC AMIDES

 Examples
Diamphenithide affects the youngest stages of liver flukes
Effectivity diminishes as flukes mature

 BENZIMIDAZOLES

 Albendazole
7.5 mg/kg in sheep
15 mg mg/kg in cattle
 Triclabendazole
10 mg/kg has high activity against all stages of liver flukes
Unlike other benzimidazoles, Triclabendazole does not have effects on
roundworms and tapeworms
 P a g e | 230

Lesson 26

Pesticides

P
 P a g e | 231

esticides are chemical agents used against external parasites or ectoparasites (flies, lice, ticks,
fleas, mites, bots, and grubs).pesticides include insecticides and acaricides. Insecticides are
agents against parasitic insects while Acaricide are agents against parasitic arachnids.

Ectoparasites
Accurate identification of ectoparasites or correct diagnosis is based on clinical signs
prerequisite to selection of the most appropriate agent

 Arachnida
 Ticks
Affects mainly ruminants but may also affect horses, dogs, and poultry
 Mites
 Sarcoptidae includes:
o Mange mites (Chorioptes, Notoedres, Otodectes, Psorergetes,
Psoroptes, and Sarcoptes
o Demodicidae includes parasites causing demodectic mange
o Gamasidae includes the northern and red mites of poultry

 Insecta
 Diptera (flies)
 Anopleura (lice)
 Siphonaptera (fleas)
Methods of Application of Pesticides

 External Application
 Dipping
 Spraying
 Application by hand as dust, ointment, spray, foams, mist spray, aerosol, pour
on, spot – on
 By tags and strips
 By self – treatment devices

 Systemic Application
 As feed additive
 By injection
 By stomach tube
 By intranasal administration (for Oestrus ovis)

Pesticide Toxicity
 All pesticides are poisons and can be toxic to both warm – blooded and cold –
blooded animals
 Proper application of pesticides must be practiced to prevent injury to animals
 Acute signs of poisoning usually results from over dosage
 Horses show extreme sensitivity to various pesticide formulations
 Animals that are in stress, debilitated, very young, or very old must be treated with
pesticides with extreme caution if at all
 Cats are very sensitive to effects of pesticides because their grooming behavior and
deficient drug biotransforming capacity
 Animals should not be treated in confined and poorly ventilated area
 Do not apply pesticides in combination unless specified by the manufacturer
 P a g e | 232

 Precautions must be taken to prevent poisoning of the person administering pesticides

 Handlers must wear protective clothing including rubber gloves and mask especially
when handling spray, dust, and solutions of organophosphate and organochlorine
compounds
 Should contamination occur, wash off insecticide immediately. Medical assistance
may be called in more serious contamination when signs of poisoning are present
 Precautions must be practiced to prevent contamination of human food supply and
environment
 Waste solutions or empty containers should be carefully disposed of to avoid
contamination of streams, ponds, and pastures
 Do not re – use empty pesticide containers

CLASSIFICATION OF PESTICIDES

 According to Mode of Action

 Stomach Poisons
Must be eaten by parasites to be effective

 Contact Poisons
Enter the body of parasites through the skin

 Fumigants
Released into the atmosphere as a gas or a mist and enters the parasites
via respiratory system

 According to Chemical Structure

 Chlorinated hydrocarbons
 These are becoming less popular because of persistence in the
environment
 Lindane, bromocyclen, and methoxychlor are still used such as against
mange mites in pigs while DDT and Chlordane are no longer approved
for use
 Examples include:
Lindane
Bromocyclen
Methoxychlor
DDT
Chlordane

 Organophosphates
 Are both contact and Stomach poison
 Inhibits cholinesterase enzymes
 P a g e | 233

 OP’s are subjected to biotransformation in animal tissues resulting in

inactivation and the enzymes responsible for this inactivation are not
present in ectoparasites
 All OP’s are toxic to humans and animals by virtue of their
cholinesterase inhibitory activity
 Cholinesterase inhibition by OP’s in relatively less readily reversible,
if not totally irreversible
 Examples include:
Chlorvinphos Chlorpyriphos
Crotoxyphos Coumaphos
Cythioate Diazinon
Dichlorvos Dioxathion
Famfur Fenthoin
Malathion Phosmet
Tetrachlorvinphos Trichlorfon
 Carbamates
 Reversibly inhibit cholinesterase enzymes
 Examples include:
Carbaryl, and
Propoxur

 Pyrethrins and Pyrethroids

 Pyrethrins
o Are naturally occurring
o Extracted from chrysanthemum flower
o With rapid but brief action
o Relatively non – toxic to dogs and cats
o Often mixed with synergist 9see below) to enhance efficacy

 Pyrethroids
o Are synthetic compounds with greater potency than pyrethrin
o Examples include:
Cypermethrin Permethrin
Decamethrin Resmethrin
Allethrin Fenvalerate

 Rotenone
 A naturally occurring compound obtained from derris roots
 Largely superseded but still used in mixtures with other pesticides
 Used for car mite and demodectic mange in dogs

 Formamidines
 Offers an alternative for treatment of ticks and mange mites on
livestock where resistance to OP’s has developed
 Examples:
Amitraz which is an acaricidal compound that kills parasites by
inhibiting monoamine oxidase

 Synergist
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 Often included in formulations of topical preparations particularly

those containing pyrethrin
 They prolong the activity of a wide range of pesticide by inhibiting
microsomal enzymes of insects
 Examples:
Piperonyl butoxide
N – octyl – bicycloheptene
Dicarboxamide (MGK 264)
Sesamin
Sesamolin

 Insect growth regulators

 Used for flea control in premises (not on animals)
 Not directly insecticidal
 Prevents maturity of larvae into adult insects
 Often combined with other pesticides
 Examples:
Methoprene Diflubenzuron
Fenoxycarb Pyriproxyfen
Lufenuron

 Repellents
 Used in veterinary medicine but not yet well – established
 Examples:
Dimethyl phthalate
Deet (N – N – diethyl – m – toluamide)
D - Limonene
Linalool
Crude citrus oil extract

 Avermectins
 Examples:
Ivermectin
Abamectin
Doramectin

 Benzyl benzoate
 An acaricide used as an adjunct in the treatment of sarcoptic mange in
dogs
 Toxic to cats

 Sulfur
 For years, was the best external treatment for mange until the advent of
chlorinated hydrocarbons
 May be applied as ointments or oily suspension at a concentration of
1:8
 Still used for routine baths for dogs
 As powders diluted with talc, kaolin, etc., or as dispersible bath
powders combined with soaps and wetting detergents
 Examples:
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Sublimed sulfur
Precipitated sulfur
Monosulfiram

 Fipronyl
 Acts by a non – competitive inhibition of GABA, an essential
neurotransmitter of the CNS of invertebrates. By binding to a receptor
site inside the chloride channel, Fipronyl inhibits the intracellular flow
of chloride ions, thereby, inducing a rapid and sure death of the
ectoparasite due to hyper – excitation
 A contact insecticide
 Available as spray or spot – on preparation and may be applied on a
monthly basis