Autacoids

Definition: Chemical substances produced locally

to help the remedy of local injures. (Autos
means self, akos, means Remedy ,so the
meaning is self remedy)

Examples: histamine, serotonin, endogenous

peptides, prostaglandins, Bradykinine,
eicosanoids, angiotensine II, leukotrienes ,etc.
Details of Histamine as a prototypes
of autacoids:
Chemical properties of histamine:
• Chemically, histamine is 2-(4-
imidazolyl)ethylamine and has the formula
C5H9N3. Histamine is synthesized by the
decarboxylation of the amino acid histidine, a
reaction catalyzed by the enzyme L-histidine
decarboxylase . It is a hydrophilic vasoactive
amine (thus the name).
Sites of histamine release:
• Mast cell site:
• Pulmonary tissue (Mucosa of bronchial tree),
skin, GIT
• Non mast cell site: CNS, Epidermis of skin, GIT,
cells of rapidly growing tissues, basophils, etc.
•  
•  
 Sites of histamine storage:

• Mast cell in most tissues

• Basophils in blood
• Epidermis of skin
• Cells in gastric mucosa and
• Neurons in CNS
 Histamine release mechanisms:
• 1. Following tissue injure
• 2. Antigen antibody
reaction(anaphylaxis)
• 3. Drug induced exocytosis: Drugs
increase calcium influx and occur
exocytosis of histamine.
Histamine release mechanisms:

1. Following tissue injure:

a) Tissue injure
b) Rupture of mast cell membrane
c) histamine release
d) vasodilation and inflammatory
responses
2. Antigen antibody reaction(anaphylaxis):
• a) Antigen exposure of mast cell
• b) Formation of antibody(IgE)
• c) IgE fixed on mast cell membrane
• d) Sensitization of mast cell
• e) Further exposure of antigen (allergen)
• f) Antigen antibody reaction
• g) Rupture of mast cell membrane, and
histamine release and anaphylaxis
 Pharmacological actions : 
• Pharmacological actions
• 1. CVS :- Histamine dilates small blood vessels resulting in
hypotension accompanied by reflex (Spontaneous )
tachychardia.
• 2.CNS:- Cerebral blood vessels dilate producing severe
throbbing (Burning)headache.
• Skin: itching and pain
Triple response Red spot at the site (flush) – due to local
capillary dilation. Flare – redness surrounding the flush due to
arteriolar dilatation. Wheal – local oedema due to the escape
of fluid from the capillaries.
• Bronchus: Bronchoconstriction
• GIT: muscle contraction, abdominal cramp(spasm)
Pathophysiological Actions of Histamine

• Cellular mediator of immediate hypersensitivity

reaction and acute inflammatory response
• Anaphylaxis
• Seasonal allergies
• Duodenal ulcers
• Systemic mastocytosis (facial flushing, itching, a
rapid heartbeat, abdominal cramps due to
maximization of mast cell in various organs)
• Gastrinoma (Zollinger-Ellison Syndrome)
 Histamine Receptors: Types, Distribution and
Function
• H1 – Smooth muscle, endothelium, CNS.
Bronchoconstriction, vasodilation, separation of
endothelial cells, pain and itching, allergic rhinitis, motion
sickness.
• H2 – gastric parietal cell, vascular s.m. cell, basophils.
Regulate gastric acid secretion, vasodilation, inhibition of
IgE-dependent degranulation.
• H3 - CNS cells, and some in peripheral NS. Presynaptic,
feedback inhibition of histamine synthesis and release.
They also control release of DA, GABA, ACh, 5-HT & NE
• H4 - Highly expressed in bone morrow and white blood
cells. Mediate mast cell chemotaxis.
 Triple Response of Willis
Subdermal histamine injection causes:
1. Red spot (few mm) in seconds: direct
vasodilation effect , H1 receptor
mediated
2. Flare (1cm beyond site): axonal reflexes,
indirect vasodilation, and itching, H1
receptor mediated
3. Wheal (1-2 min) same area as original
spot, edema due to increased capillary
permeability, H1 receptor mediated
 Histamine shock
• 1.Large dose of histamine administration
• 2. Dilate small blood vessel and increase
capillar y permeablity
• 3.More blood is traped in the periphery and
plasma escapes from the circulation
• 4. Diminish effective blood volume
• 5.Reduce venous return
• 6. decrease cardiac output and decrease bp
and occur shock
 Clinical Uses of H1 Antihistamines
• Allergic rhinitis (common cold)
• Allergic conjunctivitis (pink eye)
• Allergic dermatological conditions
• Urticaria (hives),(irritating types)
• Angioedema (swelling of the skin)
• Puritus (dermatitis, insect bites)
• Anaphylactic reactions (severe allergies)
• Nausea and vomiting (first generation H1-
antihistamines)
Classification of H1 receptor
antagonists:
• H1 receptor antagonists are classified as first
generation and second generation ,

• First generation: Meclizine,

cyclizine,Promethazine etc.
• Second generation: Ceterizine, loratadine,
fexofenadine etc.
 First Generation
Antihistamines,characters:
• Small, lipophilic molecules that could cross the BBB
• Not specific to the H1 receptor
• Groups:
– Ethylenediamines
– Ethanolamines
– Alkylamines
– Piperazines
– Tricyclics
• Common structural features of classical antihistamine
– 2 Aromatic rings
– Connected to a central Carbon, Nitrogen or CO
– Spacer between the central X and the amine
– Usually 2-3 carbons in length
– Linear, ring, branched, saturated or unsaturated
– Amine is substituted with small alkyl groups eg CH3
•
Example and features of Second
Generation Antihistamines
• CETIRIZINE (Zyrtec)
• LORATADINE (Claritin)
• Terfenadine
• Acrivastine
• Astemizole
• AZELASTIN (Intranasal Spray)
• E
Second Generation Antihistamines,characters

• Modifications of the First Generation Antihistamines

to eliminate side effects resulted in the first
Generation Antihistamines
• More selective for peripheral H1 receptors
• Less sedative cns effects
• Comparatively large molecule, hydrophilic and cant
cross BBB
• Examples:
– terfenadine
– loratadine
– cetirizine
– mizolastine
– Astemizole
Side effects: Weaken CVS activity
 Third generation antihistamine
• Levoceterizine
• Desloratadine
• Fexofenadine
• All are more effective and possess less side
effects than than first and second generations
antihistamines.
 Second generation H1-receptor
antagonists,comparative study
Acrivastine (Semprex-D) Astemizole (Hismantol)
•This drug has a long duration
of action
•It suppresses the formation
of edema and puritus
•It doesn’t cross the BBB
•It has been taken off the
market in most countries
because of adverse
interactions with erythromycin
•This drug relieves itchy and grapefruit juice
rashes and hives
•It is non-sedating because it
does not cross the BBB

http://en.wikipedia.org/wiki/Image:Acrivastine.svg http://en.wikipedia.org/wiki/Image:Astemizole.png
 Second generation H1-receptor antagonists
antagonists,comparative study

Loratadine (Claritin) Terfenadine (Seldane)

•It is the only drug of its class •It was formerly used to treat
available over the counter allergic conditions

•It has long lasting effects and does •In the 1990’s it was removed from
not cause drowsiness because it the market due to the increased
does not cross the BBB risk of cardiac arrythmias

http://en.wikipedia.org/wiki/Image:Loratadin.svg http://scienceblogs.com/moleculeoftheday/images/terfenadine.gif
 Second generation H1-receptor
antagonists,comparative study
Azelastine Levocabastine
Olopatadine
(Livostin)
(Astelin or Optivar) (Patanol)

•It is a mast cell stablilizer

•Available as a nasal spray
(Astelin) or eye drops for
•Both of these drugs are used as eye
pink eye (Optivar)
drops to treat allergic conjunctivitis

http://en.wikipedia.org/wiki/Image:Azelastine.png http://en.wikipedia.org/wiki/Image:Levocabastine.png
 Third generation H1-receptor
antagonists,comparative study
• These drugs are derived from second generation antihistamines
• They are either the active enantiomer or metabolite of the second
generation drug designed to have increased efficacy and fewer side
effects
Levocetirizine (Zyzal)
•This drug is the active enantiomer of cetirizine and is
believed to be more effective and have fewer adverse
side effects.
•Also it is not metabolized and is likely to be safer than
other drugs due to a lack of possible drug interactions
(Tillement).
•It does not cross the BBB and does not cause
significant drowsiness
•It has been shown to reduce asthma attacks by 70%
in children
http://en.wikipedia.org/wiki/Image:Levocetirizine.png
 Third generation H1-receptor
antagonists,comparative study
Deslortadine (Clarinex) Fexofenadine (Allegra)

•It was developed as an

•It is the active metabolite of
alternative to Terfenadine
Lortadine
•Fexofenadine was proven to be
•Even though it is thought to be
more effective and safe
more effective, there is no
concrete evidence to prove this
http://en.wikipedia.org/wiki/Image:Desloratadine.png http://en.wikipedia.org/wiki/Image:Fexofenadine_Structure.png