PHARMACOKINETICS

Pharmacokinetics means the movement of the drug into, through and out of the body (figure
1). It studies “what the body does to a drug”. It can be classified in two phases:
§ Invasion:
o The active substance is freed from the dosage form (liberation);
o Absorption from the administration site;
o Distribution into the human body;
§ Elimination:
o Metabolism (biotransformation);
o Excretion of drugs.

Figure 1 – The relationship between the pharmacokinetic phases and concentration at the
site of action

THE ABSORPTION OF DRUGS

The absorption of a certain drug depends on:

§ the drug’s physicochemical properties;
§ the formulation;
§ the route of administration:
o oral;
o sublingual;
o rectal;
o parenteral: intravenous (IV), intramuscular (IM), subcutaneous (SC),
intraarterial, intraarticular, intradermic;
o topical;
o inhalational.
If a drug is not administered IV, it must cross some semipermeable cell membranes
(biologic barriers) before it reaches the systemic circulation. This membranes contain a
bimolecular lipid matrix, responsible for their permeability characteristics.
The drugs may cross this membranes by (figure 1):
§ passive diffusion:
o the drug diffuses through the cell membrane from a region of high concentration
to one of low concentration;
 o does not require energy;
o transport against a concentration gradient cannot occur;
o diffusion rate depends on:
§ the gradient between the two spaces;
§ the molecule’s lipid solubility: lipid-soluble drugs diffuse more rapidly;
§ size: smaller molecules pass more rapidly;
§ ionization: the unionized form penetrates easily;
§ the area of absorption: the small intestine has a large area of absorption;
§ facilitated passive diffusion:
o the drug diffuses through the cell membrane by combining with some carrier
molecules from this cell membrane;
o does not require energy;
o transport against a concentration gradient cannot occur;
o the availability of carriers limits the process;
§ active transport:
o needs carrier molecules;
o does require energy;
o transport against a concentration gradient can occur;
o specific, only for drugs structurally similar to endogenous substances;
§ pinocytosis:
o the cell membrane invaginates, encloses fluid or particles, forming a vesicle that
moves to the interior of the cell;
o does require energy.

Figure 1 – Passage of drug molecules through the cell membrane

ORAL ADMINISTRATION
§ most widely used in therapy;
§ the drugs are administered orally, as tablets (tab.), capsules (caps.), gel, syrup or solution
(sol.);
§ the factors influencing the absorption of an orally administered drug are the:
o pH of the gastrointestinal (GI) secretions;
 o surface area per luminal volume;
o blood perfusion;
o type of epithelium;
o duration of contact;
o presence of food (e.g. fatty food slows gastric emptying, food reduces absorption
of drugs) or other drugs (antacids slow the gastric emptying, Metoclopramide
hastens the gastric emptying);
o pharmaceutic form of administered drug.
§ the absorption site:
o the oral mucosa has a thin epithelium and rich vascularity, but contact is usually
too brief for substantial absorption;
o the stomach has a large epithelial surface, but a thick mucous layer and a short
transit time, decreasing the gastric absorption;
o most absorption occurs in the small intestine, because it has the largest surface
area in the GI tract and the membranes are more permeable than those in the
stomach;
§ after the absorption (figure 2), an orally administered drug will reach, via the port vein,
the liver, where it will be variable affected by the first hepatic passage effect (more
important for Xiline, Propranolol, Nitroglycerine, Morphine). This effect may so greatly
limit the bioavailability of orally administered drugs, that alternative routes of
administration must be employed to reach the therapeutic effective blood levels;
§ some of the drugs are excreted through the bile into the duodenum, being absorbed again
in the small intestine. This is the entero-hepatic cycle;
§ some drugs will not be absorbed and their effect will be local, limited to the digestive
tract.

Figure 2 – The circulation of an orally administered substance and some drugs that are
affected in this process

§ Advantages:
o self-administration is possible;
 o in case of overdose, the excess of drug can be removed by inducing vomit or via
gastric wash-out;
o most economical;
o no risk of infection.
§ Disadvantages:
o not useful in emergencies (the therapeutic effect appears later), comatose
patients, newborn, young infants and patients presenting vomit, convulsions and
agitation;
o some drugs cannot be administered orally because they:
§ are inactivated by the acidity in the stomach (Penicillin G) or by
digestive enzymes (Heparin, Insulin);
§ can be more or less metabolized during the first hepatic passage (Xiline);
§ may have unpleasant taste;
§ may be strong irritants to the gastric mucous membrane
(Phenylbutazone, Indometacin);
o unreliable or inconsistent absorption due to food or other drug effects.
Bioavailability refers to the speed and quantity of a drug that enters the systemic circulation
and accessing the site of action. It is determined by the properties of the dosage form.
§ Bioequivalence means that two or more drugs, when administered to the same patient
in the same dosage regimen, result in equivalent concentrations of drug in plasma and
tissues;
§ Therapeutic equivalence means that two or more drugs, when administered to the same
patient in the same dosage regimen, have the same therapeutic and adverse effects.
§ causes of low bioavailability:
o the first hepatic passage effect;
o insufficient time for absorption in the GI tract;
o formation of a complex (e.g. between Tetracycline and Calcium);
o hydrolysis by gastric acid, digestive enzymes and metabolism by luminal
microflora;
o some molecules (highly ionized and polar) does not dissolve readily or cannot
penetrate the epithelial membrane;
o old age, genetic phenotype, stress, achlorhydria, malabsorption syndromes,
previous GI surgery;
§ Bioavailability (Bd) is usually assessed by determining the:
o maximum (peak) plasma drug concentration (cmax);
o peak time (when maximum plasma drug concentration occurs) (Tmax);
o area under the plasma concentration–time curve (AUC) – the most reliable
measure of a drug's bioavailability (see fig. 1).

coral
Bd% = ---------- x 100
cIV

or

AUC oral
Bd% = ------------- x 100
AUC IV

Abbreviations: Bd – bioavailability; C - blood or plasma concentration; AUC - area under the plasma
concentration–time curve
 Figure 2 - Plasma concentration-time relationship of a drug administered by a route of
administration which requires absorption (AUC – area under the curve, Tmax – peak time,
T1/2 – half life, cmax – maximum plasma drug concentration, c1/2 – half of the maximum
concentration)

§ drug products may be considered bioequivalent in extent and rate of absorption if their
plasma concentration curves are essentially superimposable.

The Half-life (T1/2) means the time required to reduce by one half the plasmatic concentration of
the drug. This can be calculated according to the plasma concentration-time relationship (figure
2) or to the formula:

ln 2 x Vd 0,693 x Vd
T1/2 = ---------------- = ------------------
Cl Cl

Abbreviations: T1/2 – half-life, Vd - volume of distribution; Cl - clearance of a drug

SUBLINGUAL ADMINISTRATION
§ the drug is placed in the space between the gum and the jugal mucous membrane or
sublingual;
§ the drug is absorbed fast (1-2 minutes), through the sublingual mucous membrane (rich
vascularization) and reaches the superior cava vein, via the lingual and intern maxillary
veins (the first hepatic passage effect is avoided);
§ the drugs must be non-irritants for the oral mucous membrane, have an acceptable taste
and must dissolve and be absorbed rapidly;
§ Advantages:
o this route of administration can be used in emergencies (Nitroglycerine,
Nifedipine).

RECTAL ADMINISTRATION
 § the drugs are administered intrarectally as suppositories (sup.), enema, cream or gel,
aiming to obtain a local or a systemic therapeutic effect;
§ the drug is absorbed through the rectal-colic mucous membrane; a part of it follows the
superior rectal vein reaching the port system, then the liver, where it undergoes the first
hepatic passage and the other part follows the inferior and middle rectal veins, reaching
the inferior cava vein, then the systemic circulation (figure);
§ the therapeutic effect appears slowly, for about 30-40 minutes after administration;

Figure – The circulation of drugs after rectal administration

§ Advantages:
o this route of administration can be used in infants and patients with severe vomit;
o it allows the administration of drugs with unpleasant taste or smell and strong
irritants of gastric mucosa;
§ Disadvantages:
o part of the drug suffers the effect of the first hepatic passage;
o the normal bacterial population of the colon could inactivate certain drugs;
o unpredictable pharmacological response;
o rectal mucosal irritation possible.

PARENTERAL ADMINISTRATION
§ Intravenous administration: the drug reaches directly the systemic circulation after
injecting it in the vein (injection, drip);
§ Intramuscular administration: drugs can be administered in the muscular area, located
in the superior-extern quadrant of the gluteal region, on the anterior area of thigh or in
the deltoidian area;
§ Subcutaneous administration: drugs can be administered in the subcutaneous conjuctive
tissue on the external area of the thigh, posterior area of the arm or the periombilical
area;
§ Intraarterial administration is rarely used in therapy, only in:
o patients having diabetic or atherosclerotic arteriopathy (vasodilators);
o patients with tumors (cytostatics);
o radiology (radio-opaque substances);
 § Advantages:
o the drugs are rapidly absorbed (useful in emergencies); the therapeutic effect
occurs:
§ almost immediate after IV administration;
§ in 15-20 minutes after IM administration;
§ in 30-40 minutes after SC administration (low absorption);
o exact control over the administered dose:
§ IV route: large quantities of liquids;
§ IM route: 1-25 ml;
§ SC route: 1-3 ml;
o suitable for drugs not absorbed via oral route, too iritant or inactivated in the
stomach or intestine;
o drugs can be administered to non-compliant patients;
o it’s possible to deliver continuous medication (drip).
§ Disadvantages:
o patients are not typically able to self-administer;
o risk of HIV, hepatitis and other infectious diseases;
o need for strict asepsis and qualified medical staff; if not done properly,
potentially fatal air or fat emboluses, abcesses can occur;
o increased risk of anaphylactic reactions;
o the parenterally administered drugs must be: sterile, apyrogenic, clear, neutral
(pH 7.4) and isotonic;
o belonephobia (the fear of needles and injection), especially among children;
o more risk of addiction when it comes to injecting drugs of abuse.

TOPICAL ADMINISTRATION
§ it consists in the direct application of the drug on the skin or mucous area (as ointments,
lotions), aiming to obtain a local or systemic therapeutic effect;
§ the drug crosses the skin by passive diffusion;
§ the cutaneous permeability varies based on: the anatomic location, skin’s level of
hydration, cutaneous integrity, modality of application for dermatologic preparations
and the excipients;
§ the application of the drug on mucous membranes usually aims to obtain a local
therapeutic effect (e.g. anti-glaucoma, nasal decongestive action, oral antiseptic etc.); if
the drugs are too concentrated or the mucous membrane has an increased permeability
(because of local inflammation), systemic adverse effects may occur (e.g. increased
blood pressure (HBP) after abuse of nose drops containing ephedrine);
§ drug systems with controlled release are used in therapy for different situations (e.g.
Nitroglycerine for ischemic cardiopathy, Scopolamine to prevent motion sickness); they
release the active substances during hours or days;
o Advantages:
§ easy to use;
§ ensure stable blood concentrations for drugs, over a long period of time;
§ minimal risk of adverse effects;
o Disadvantages:
§ frequent contact allergic reactions;
§ the drug cannot be applied on damaged skin, because of the increased
absorption.
INHALATIONAL ADMINISTRATION
§ the drugs (anesthetics, bronchodilators) are administered via inhalation, in order to
obtain a systemic or local effect;
§ Advantages:
o cortisones, administered via inhalation, don’t induce systemic cortisone effects
and they are not depressing the corticosuprenalian gland;
§ Disadvantages:
o difficulty of self-administration in children or elderly patients;
o local adverse effects may occur (e.g. irritation of the bronchial mucous
membrane, buccal candidosis).

THE DISTRIBUTION INTO THE HUMAN BODY

After a drug enters into the systemic circulation, it will be distributed into the body’s tissues.
The distribution of a certain drug depends on:
§ the blood perfusion (for poorly perfused tissues, distribution is very slow);
§ the tissue mass;
§ the tissue binding;
§ the regional pH;
§ the permeability of the cell membranes.

The APPARENT VOLUME OF DISTRIBUTION (Vd) is the theoretical volume of fluid

into which the total drug administered would have to be diluted to produce the concentration in
plasma. The Vd is the ratio between the amount of drug in body (administered dose) and the
concentration of the drug, measured in blood or plasma.

D (mg)
Vd =
C (mg/l)

Abbreviations: Vd - volume of distribution; C - blood or plasma concentration; D - the administered drug dose.

Different drugs have different Vd. Drugs that remain in the circulation have a low Vd. Some
drugs distribute mainly into the fat tissue, others remain in the extracellular fluid and others are
bound to specific tissues.
§ acidic drugs (Aspirin, Warfarin), that are highly protein-bound (albumin) have a small
Vd;
§ basic drugs (Amphetamine), that are extensively taken up by tissues, have a large Vd.
The physical volumes (l/kg body weight) for some body compartments:
§ water:
o total body water: 0.5-0.7 l/kg;
o extracellular water: 0.2 l/kg;
o blood: 0.08 l/kg;
o plasma 0.04 l/kg;
§ fat: 0.2-0.35 l/kg;
§ bone: 0.07 l/kg.
The factors influencing the volume of distribution are:
§ the degree of drug-plasma protein binding;
§ partition coefficient of the drug in fat;
§ the patient’s age, gender, body composition, other diseases.
BINDING OF DRUGS TO PLASMA PROTEINS
In the bloostream, drugs are transported as:
§ Unbound drug, available for passive diffusion into the extravascular space, determing
the drug concentration at the active site (efficacy);
§ Reversibly bound to plasma proteins: albumin, a1-acid glycoprotein, lipoproteins
(figure 3).

a. b.
Figure 3 – a. The unbound drug reaches the effector cell, producing the desired effect;
b. The drug is highly bound to plasma proteins, the final effect is low

Drugs can also bind and be accumulated in:

§ body fat (poor vascularization); storage in fat initially shortens the drug’s effect, but
then prolongs it;
§ cells, because they bind to proteins, phospholipids and nucleic acids.
Usually, binding is reversible and obeys the law of mass action:

k1
Free drug + protein Drug-protein complex
k2

Abbreviations: k1 - the association rate constant; k2 - the dissociation rate constant.

At equilibrium:

k2
KD =
k1

Abbreviations: KD - the equilibrium dissociation constant.

The equilibrium dissociation constant (KD) is a measure for the drug’s affinity to proteins:
§ low KD means high affinity;
§ high KD means low affinity.

DISTRIBUTION INTO THE CENTRAL NERVOUS SYSTEM (CNS)

“The blood-brain barrier (BBB) is a collection of cells that press together to block many
substances from entering the brain, while allowing others to pass.” “The BBB is like a gateway
to the brain. It is almost always locked, keeping out many diseases. Unfortunately, it also keeps
out medications as well." The distribution of drugs to the brain tissue is restricted because of
the BBB, especially for water-soluble drugs. Inflammatory diseases, like meningitis increase
the BBB permeability.

PLACENTAL DISTRIBUTION
The placenta allows diffusion because it is thin, has a big surface and rich vascularization. The
diffusion (mostly simple diffusion) depends on the period of pregnancy. Lipid-soluble drugs
pass more easily from the maternal blood into the fetal circulation, compared to drugs with low
lipid-solubility. The fetus is exposed to all drugs taken by the mother. The placental distribution
is a concern because certain drugs may induce congenital abnormalities. The most dangerous
period of time is between 15-60 day of pregnancy, when organogenesis occur, and some drugs
may produce teratogenic effects.
 PHARMACOKINETICS cont.

DRUG BIOTRANSFORMATION (METABOLISM)

Most biotransformation occur at some point between absorption and elimination. The main
organ for drug metabolization is the liver. Other tissues that have considerable activity are: the
intestinal wall, the lungs, the skin and the kidneys. The goal is to make the drug easier to excrete.
The consequences of drug metabolisation are the transformation of active drugs into:
§ inactive metabolites (majority of cases) (e.g. Phenobarbital into
Hydroxyphenobarbital);
§ active metabolites (e.g. Codeine into Morphine);
§ more active than the parent compound.
An inactive drug that has an active metabolite is a prodrug (e.g. Levodopa into Dopamine).
There are four main patterns of drug metabolism:
§ oxidation - most oxidation steps occur in the endoplasmic reticulum;
§ reduction;
§ hydrolysis;
§ conjugation.
The drug metabolism rates are different from one patient to another, influenced by:
§ genetic factors;
§ other diseases (e.g. chronic liver diseases, heart failure);
§ drug interactions.
Metabolism occurs in two phases (figure 4):
§ phase I (oxidation, reduction, hydrolysis) reactions usually convert the parent drug to a
more polar metabolite, by introducing or unmasking a functional group (-OH, -NH2, -
SH);
§ phase II (conjugation) reactions, when an endogenous substrate, such as glucuronic acid
(glucuronidation), sulfuric acid (sulfoconjugation), acetic acid (acetylation) or amino
acid combines with the newly established functional group to form a highly polar
conjugate.

Figure 4 – The two phases of liver drug metabolism

THE CYTOCHROME P 450 (CYP 450) is the most important enzyme system of phase I
metabolism, a microsomal superfamily of isoenzymes that catalyze the oxidation of drugs. This
enzymes can be induced or inhibited by many substances or drugs, leading to drug interactions,
that may affect the metabolism and Cl of various drugs. If one drug inhibits the CYP-mediated
metabolism of another drug, the second one may accumulate within the body possible inducing
toxicity. Some examples of:
 § enzyme inhibitors (increasing the drug’s effect): Amiodarone, Cimetidine,
Ciprofloxacin, Cloramphenicol, Erithromycin, Fluconazole, grapefruit juice, Isoniazid,
Ketoconazole, Metronidazole, Omeprazol, Sodium valproate,
Trimethoprim/Sulfamethoxazole.
§ enzyme inducers (decreasing the drug’s effect): alcohol, Carbamazepine, Griseofulvin,
Phenobarbital, Phenytoin, Rifampicin, smoking.
In elderly people, the liver’s capacity for metabolism through the CYP 450 enzyme system is
reduced by aproximatively 30%, because of the reduced liver volume and decreased hepatic
blood flow, resulting difficulties in drug metabolization. The same situation occurs in neonates,
because the liver microsomal enzyme system is only partially developed.

THE EXCRETION OF DRUGS

The routes of excretion are:

§ the renal excretion;
§ the biliary excretion;
§ the contribution of intestine, saliva (not really a method of excretion, because the drug
will be swallowed and reabsorbed - salivary recycling), sweat, breast milk and lungs to
excretion is small.

THE RENAL EXCRETION

The principal organs of excretion are the kidneys. They excrete water-soluble substances. The
functional unit of the kidney is the nephron in which there are three major processes to consider
(figure 5):
§ glomerular filtration - accounts for most drug excretion; about 20% of the plasma
reaching the glomerulus is filtered through the glomerular endothelium; only unbound
drugs to proteins are contained in the glomerular filtrate;
§ tubular reabsortion – almost all water and electrolytes are reabsorbed from the renal
tubules back into the blood circulation; when urine is acidic weak, acid drugs tend to be
reabsorbed and when urine is more alkaline, weak bases are more extensively
reabsorbed; useful in intoxications: e.g. in Phenobarbital (weak acid) overdose we can
increase drug excretion by administering sodium bicarbonate injection (more alkaline
urine);
§ tubular secretion – an active, energy dependent process and there may be competitive
inhibition of the secretion of one compound by another (e.g. Penicillin excretion in
competition with Probenecid).
 Figure 5 – The major processes of renal excretion

The clearance of a drug (Cl) is a pharmacokinetic parameter, measuring the excretion of drugs.
The drug’s rate of elimination, by all routes, normalized to the concentration of drug in some
biological fluid, can be calculated whith the formula:

Velocity of drug elimination

Cl =
C

Abbreviations: Cl – clearance of a drug; C – concentration of drug.

The Cl could be:

§ the plasmatic clearance (Clpl) of a drug is the volume of plasma that is completely
freed of drug per time unit. It is important because we can calculate the maintaining
dose of a drug.

Clpl = Vd x ke

Abbreviations: Clpl – plasmatic clearance; Vd – volume of distribution; ke – the elimination rate constant.

§ the organ clearance indicates the efficacy of one organ to eliminate the drug out of
plasma, depending on the intrinsic Cl and the blood flow of this organ. The renal drug
Cl is correlated with exogenous creatinine Cl or serum creatinine concentration. Factors
that may affect the renal Cl are:
o renal diseases;
o rate of filtration;
o drug secretion rates;
o changes in plasma protein concentration;
o renal blood flow.
§ the total systemic clearance, counting the elimination by all participating organs such
as kidney, liver, lungs, muscle or blood:

Cl systemic = Clrenal + Clhepatic + Clother organs

THE BILIARY EXCRETION
Some drugs and their metabolites are excreted by the liver into the bile. In the enterohepatic
cycle, a drug secreted in the bile is reabsorbed into the circulation from the small intestine
(figure 4). There can be also competition between compounds.

Figure 4 - The enterohepatic circulation

The factors that may affect the hepatic Cl are:

§ liver diseases;
§ extent of plasma protein-bound drug;
§ hepatic blood flow.

THE PULMONARY EXCRETION

Gaseous and volatile substances are excreted through the lung. Most of the volatile anesthetics
are extensively eliminated in expired air.

CHANGES IN THE INTRINSIC CLEARANCE of a drug could occur due to:

§ organ diseases (renal failure, hepatic failure, chronic hepatitis);
§ reduced organ blood flow (heart failure, renal arthery stenosis);
§ social factors (tobacco smoke or chronic ethanol use induce some hepatic microsomal
drug metabolizing enzyme isoforms);
§ dietary considerations (e.g. grapefruit juice contains chemicals that are potent inhibitors
of some enzymes localized in the intestinal wall mucosa; calcium can chelate
tetracyclines or fluoroquinones);
§ age (e.g. neonates have reduced hepatic metabolism and renal excretion due to relative
organ immaturity; elderly patients exhibit differences in absorption, hepatic
metabolism, renal Cl and Vd;
§ genetic factors, affecting some enzymes involved in the metabolism of drugs.

Table 1 - Pharmacokinetic parameters of some drugs for a 70 kg patient

Drug Oral bioavailability (%) Total clearance (ml/min) Vol. of distribution (l)
Acetaminophen 63 350 67
 Valproic acid 100 8,4 9,1
Amikacin - 77 15
Amoxicillin 93 370 29
Ampicillin 25-70 270 20
Aspirin 68 650 11
Carbamazepin > 70 89 98
Cephalexin 90 300 18
Cephalotin - 470 18
Chloramphenicol 75-90 250 64
Chlordiazepoxide 100 26 21
Cimetidin 62 840 150
Clonidine 74 210 150
Diazepam 100 27 77
Digitoxin > 90 3,2 36
Digoxin 60-70 130 640
Disoyramide 83 90 55
Erythromycin 18-45 420 50
Ethambutol 77 600 110
Furosemid 40-60 140 7,7
Gentamycin - 90 18
Hydralazine 20-60 420 110
Imipramine 47 1400 1050
Indometacin 98 110 65
Lidocaine 35 640 77
Meperidine 52 1200 290
Methotrexate 65 105 28
Morphine 20-30 1100 220
Nortriptyline 51 500 1300
Phenobarbital > 80 6,5 62
Prazosin 57 210 42
Procainamide 83 350-840 130
Propranolol 36 840 270
Quinidine 70 330 190
Sulphamethoxazol 100 22 15
Tetracycline 77 130 91
Theophylline 96 48 35
Tobramycin - 77 18
Tolbutamide 93 21 11
Trimethoprim 100 150 130
Tubocurarine - 160 21
Verapamil 19 830 280
 PHARMACODYNAMICS

Pharmacodynamics studies “what a drug does to the body”. It involves:

§ receptor binding;
§ postreceptor effects;
§ drug interactions.
The pharmacologic response is determined by the binding of a drug to its target. The
concentration of a drug at the receptor site influences the drug’s effect.

DRUG RECEPTORS
§ are protein macromolecules or just a specific structure within a macromolecule,
interacting with the drugs, froming a complex that triggers the biologic effect;
§ are located on the cell membrane or within the cytoplasm;
§ some drugs are using as receptors the sites on the macromolecules that are specific to
and physiological acted upon by endogenous molecules, such as chemical mediators,
hormones;
§ recognize the chemical signal of certain molecules (agonists) due to the presence, in the
center area, of a binding site (a chemical, electric an spatial complement);
§ present accessible ionic groups, while most of the drugs contain weak acid or weak basic
groups, forming reversible chemical bindings, determing the receptor activation
(conformational changes, leading to the transmission of a signal from the membrane
toward the inner side of the cell);
§ types of receptors:
o receptors formed from a protein, including a membrane channel (see fig. 4).
Examples:
§ cholinergic receptors, nicotinic subtype: the acetylcholine (Ach) acts on
the cholinergic receptors, opening the sodium membrane channel and
triggering an equal inward current;
§ the gamma-aminobutyric acid (GABA) receptors have a chloride
channel which opens as a response to the aminoacids action, triggering
a negative chloride current, leading to hyperpolarization and inhibition.

§ Time scale: miliseconds.

Fig. 4 - Structure of a receptor including a membrane channel

o membranar receptors with enzymatic activity which bind the agonist at the
extracellular end and at the intracellular end, it has an enzymatic (tyrosinkinase)
activity, which leads to the phosphorylation of other enzymes and intracellular
effects(see fig. 5). Examples:
§ insulin receptors;
§ erythropoetin receptors.

§ Time scale: minutes to hours;

Fig. 5 - Structure of a receptor with enzymatic activity

o receptors shaped as serpentines, formed from a receptor protein for the agonist
and a coupling protein, having a controlling activity, plus the effector system
formed by an enzyme or an ionic channel. The receptor protein crosses the cell
membrane seven times (three loops in the inside area and three loops on the
outside). At the extracellular end there is the “–NH2” terminal group, while the
“–COOH” group is located at the intracellular end. The coupling with
controlling proteins is completed at the level of loop three, the intracellular one,
and of terminal region six. The controlling proteins are called proteins G
(binding the guanine nucleoside). The formation of the agonist complex,
protein-receptor, triggers the positive or negative activation of certain effective
enzymes (adenylcyclase, phospholipase) which activates the second messenger
system (cAMP, cGMP, DAG, IP3) or modify of certain calcium or potassium
membrane channels, corresponding to certain neurotransmitters, like
noradrenaline, dopamine, Ach, serotonine (see fig. 6). Examples:
§ a and b adrenergic receptors;
§ cholinergic receptors, muscarinic subtype;
§ dopamine receptors;
§ angiotensin receptors;
§ opioid receptors.

§ Time scale: seconds to minutes.

 Fig. 6 - Structure of a G protein coupled receptor with the effector system formed by an enzyme

o intracellular receptors; the agonists (corticosteroid hormones, thyroid

hormones, vitamin D) cross the membrane and enter the cell, binding at the DNA
level and inducing conformational changes at this site, leading to the
transcription of specific genes (see fig. 7). Examples:
§ steroid receptors.

§ Time scale: hours.

Fig. 7 - Structure of an intracellular receptor

§ The drug-receptor interaction respects the mass action law, and is completed through
different ionic binds, Van der Waals and covalent binds, hydrogen bridges.

K1
Drug (D) + Receptor (R) DR biologic effect
K2

The drugs have:

§ efficiency or intrinsic activity - the drug’s capacity of modifying the receptor’s structure
and activating the associated effecting systems; it depends on the number of receptors
on which the drug binds and the duration of binding;
§ potency - the quantity of required drug to produce 50% of the maximum effect.
The receptors have:
§ a binding site - the electrical, chemical and spatial complement of the drug molecule;
§ selectivity - the degree to which a drug acts on a given site relative to other sites; it
relates largely to physicochemical binding of the drug to cellular receptors;
§ affinity - the ability of the drug to bind to the receptor.
Parameters characterizing the pharmacodynamic activity of a drug:
§ type of action:
o stimulant (exciting) pharmacodynamic action (e.g. Adrenaline on the heart);
o inhibitory (depressing) pharmacodynamic action (e.g. barbiturics on the CNS);
§ potency of action, expressed by dose: high potency means low dose and vice versa (e.g.
Morphine has an analgesic potency ten times higher than Mialgin);
§ latency - the period of time between the administration of the drug and the occurrence
of the pharmacodynamic effect (e.g. Heparin acts immediately, while Trombostop after
a longer latency period, of 48 hours);
§ selectivity - the drug’s capacity of influencing a limited area in the body (e.g. cardio-
selective b1 blockers);
§ efficiency is the drug’s capacity, expressing the maximum possible effect.
Drugs that bind to receptors and act upon them, producing specific effects, are called agonists
(see fig. 8). There are two types of agonists:
§ total or full agonists have maximal efficiency, producing maximal effect;
§ partial agonists have submaximal efficiency, producing a submaximal effect, compared
to the total agonists (e.g. Morphine is a total agonist and Nalorphine is a partial agonist).
Drugs that are bonded to the receptors without activating them are called antagonists. They
obstruct the binding of agonists to the receptors, preventing receptor activation. Receptor
antagonists can be classified as:
§ reversible antagonists, readily dissociate from their receptor;
§ pseudo-irreversible antagonists slowly dissociate from their receptor;
§ irreversible antagonists, form a stable, permanent or nearly permanent chemical bond
with their receptor.
Antagonism can be:
§ competitive - when binding of the antagonist to the receptor prevents binding of the
agonist to the receptor;
§ noncompetitive - when agonist and antagonist can be bound simultaneously, but
antagonist binding reduces or prevents the action of the agonist.

Fig. 8 – Mechanism of action regarding agonist and antagonist activity

OTHER MECHANISMS OF ACTION OF DRUGS WITHOUT INVOLVING
RECEPTORS
§ chemical and physico-chemical mechanism, whith acid or basic reactions: e.g. the
gastric antiacid drugs;
§ through the osmotic mechanism: e.g. osmotic laxatives, osmotic diuretics (Manitol);
§ biochemical mechanism, meaning the enzymatic inhibition by inactivating the active
center of the enzyme: e.g. NSAIDs inhibit cyclooxygenase (COX);
§ releasing or blocking the release of active endogenous substances: e.g. Morphine
stimulates the release of endorphins with analgesic effect, Disodic cromoglycate blocks
the release of Histamine, mechanism useful in the treatment of bronchial asthma;
§ blocking the ionic channels and obstructing the ionic transmembrane transport: e.g.
calcium channel blockers (Nifedipine, Verapamil), sodium channel blockers
(Quinidine), potassium channel blockers (Amiodarone).

FACTORS INFLUENCING THE ACTION OF DRUGS

The pharmacodynamic action of a drug depends on:
§ patient-related factors:
o age:
§ newborn and infants have incomplete enzymatic equipment, increased
permeability of the BBB, decreased renal excretion;
§ in elderly people there is a decreased liver function, glomerular filtration,
muscular mass and hypoalbuminemia.
o nutritional status;
o alcohol use;
o diseases, like genetic disorders, malnutrition, diabetes mellitus, thyrotoxicosis
and Parkinson’s disease may decrease receptor sensitivity or alter the level of
binding proteins.
§ drug-related factors:
o chemical structure;
o dose; types of dose:
§ the maximal dose per one administration or in 24 hours is the largest
quantity of drug that can be administered once, respectively in 24 hours,
without toxic effects;
§ the therapeutic dose (the most frequently used) is smaller than the
maximal dose and it ensures a satisfactory therapeutic effect;
§ the loading dose (the attack dose) is the largest dose administered at the
initiation of a treatment in order to reach an efficient concentration of the
drug in a short time (e.g. for some antibiotics, digitalis);
§ the maintaining dose is the dose required in order to maintain an efficient
concentration of the drug;
§ the children dose, calculated based on the body weight, age or body
surface;
§ environmental factors.
The safety or risk evaluation for a certain drug is done using the therapeutic index (TI) (see fig.
9):

LD50 the medium lethal dose

TI= =
ED50 the medium efficient dose
If the TI is lower than 10, the drug is active, requires attention and supervised administration.
It must be than 1 for drug to be usable. If the value is higher than 10, the drug needs no special
precautions. Example: Digitalis has a therapeutic index of 2; Penicillin more than 100.

Fig. 9 – Graphical representation of the therapeutic index

 DRUG INTERACTIONS

Drug interaction takes place if one drug affects the pharmacological response of a
second drug given at the same time. In medical practice it is customary to prescribe or
administer two or more drugs and interactions may occur. Drug interactions may be due to
pharmacokinetic or pharmacodynamic effects.
The pharmacokinetic interactions can occur during absorption, distribution, metabolism and/or
elimination. Examples of pharmacokinetic interactions are: Tetracycline and Iron, Tetracycline
and Calcium, Furosemide and Magnesium hydroxide.
The pharmacodynamic interactions are:
§ Synergism - two drugs, acting in the same direction, are administered together:
o Addition synergism - the total effect is the sum of effects of each drug
considered separately (e.g. Aspirin associated with Paracetamol);
o Enhancing synergism - the total effect is greater than the sum of effects of each
drug considered separately; it can be:
§ direct - the drugs act in the same direction, but through different
mechanisms of action (e.g. Penicillin associated with Kanamycine );
§ indirect - one drug suppresses an antagonist action of another drug (e.g.
sympatholytics associated with Insulin, causing hypoglycemia);
§ Antagonism, occurs during the administration of drugs having opposing actions and the
effect of one of the drugs will be diminished or abolished by the second drug; it can be:
o chemical - the drug presents neutralizing action (e.g. Aspirin and Sodium
bicarbonate);
o physiologic - the two drugs act upon different receptors, but their effects are
canceled (e.g. sympathomimetics and parasympathomimetics);
o pharmacologic - the antagonist stops the agonist from acting upon the receptors.
In conclusion, the consequences of drug interactions can be:
§ increased drug effects;
§ decreased drug effects;
§ desired consequences; e.g.:
o Hydralazine in association with Propranolol: the b adrenergic receptor blockade
prevents the reflex tachycardia, the undesirable effect of Hydralazine;
o opioid-induced respiratory depression may be counteracted by administration of
the opioid receptor antagonist Naloxone;
§ adverse effects (toxic reactions).

ADVERSE EFFECTS OF DRUGS

The adverse effects are undesired reactions caused by the administration of certain drugs. The
determinig factors are:
§ drug-related:
o physical and chemical characteristics;
o dose;
o route of administration;
o pharmacokinetic characteristics.
§ patient-related:
o age;
o gender;
o genetic characteristics;
o physiologic specifics;
 o pathologic specifics.

TOXIC ADVERSE EVENTS

§ toxic reactions:
o are dose related;
o occur because of direct action of drugs upon tissues;
o hepatotoxicity: Paracetamol, Isoniazid, Halotane, Rifampicin, Amphotericin B;
o renal toxicity: Furosemide, Phenacetin, aminoglycosides;
o medular toxicity: cytostatics, Chloramphenicol.
§ teratogenic reactions:
o occur because of the administration of certain drugs to pregnant women,
especially during the first three months;
o e.g.: anticancer drugs, aminoglycosides, oral anticoagulants, androgen and
estrogen hormones, Phenitoine;
§ mutagenic reactions:
o they produce changes in the genotype and after generations phenotype
modifications;
o e.g.: anticancer drugs, Metronidazole, antiepileptics, neuroleptics;
§ carcinogenic reactions:
o e.g.: Aminophenazone, Cimetidin.

IDIOSYNCRATIC ADVERSE EVENTS

§ are not dose related;
§ occur because of the genetic predisposition of the patient;
§ after drug administration the result is a abnormal response of the body;
§ e.g.: some patients have a decrease in the level of glucose-6-phosphatdehidrogenase and
there is a high risk of severe hemolysis after administration of Nitrofurantoine,
Furazolidone, Doxorubicine, Nalidixic acid or Phenacetin.

IMMUNOALERGIC ADVERSE EVENTS

§ are not dose related;
§ type I (anaphylactoid) reactions:
o an immediate reaction;
o triggered by the coupling of the antigen (the drug) to the antibody
(immunoglobulines E) from the surface of mastocytes and basophilic cells,
causing the release of histamine, kinine, leucotrienes and prostaglandin;
o the most severe response is the anaphylactic shock;
§ type II (cytotoxic) reactions:
o the reaction between the antibody (immunoglobulines G and M) and the cells
that had become antigenic because of fixing the drug, results in cell distruction
(blood cell lysis);
o e.g.: hemolytic anemia (penicillins, Rifampicin), granulocytopenia
(Aminophenazone), thrombocytopenia (Quinidine, sulfamides, thiazidic
diuretics);
§ type III (immune complexes) reactions:
o the complexes between the antigen (drug) and antibody (immunoglobulines G
and M) will be fixed on small vessels or basal membranes, causing inflammatory
reactions: serum sickness (sulfamides, penicillins, antiepileptics, antitiroidians),
Quincke edema, rash (Aspirin, penicillins), vascularitis, polymorphic erythema,
Stevens-Johnson erythema ;
 § type IV (cell mediated) reactions:
o delayed reactions;
o the sensitized T cells will release lymphokines producing inflammation and
edema;
o e.g.: contact dermatitis after local administration of Neomycin or Kanamycin.

TOLERANCE-TYPE ADVERSE EVENTS

§ tachiphylaxis (acute tolerance):
o a form of drug tolerance, with decrease of effect intensity, occurring suddenly
after repeated administrations;
o because of the chemical mediators depletion or the prolonged receptor blockage;
o e.g.: sympathomimetics.
§ mitridatism:
o the capcacity of the organism to tolerate doses that would otherwise induce
nocive effects after the first administration;
o e.g.: Atropine, Arsenic, Nicotine.
§ dependence (tolerance induced by the repeated administration of drugs):
o psychological dependence - the psychological need to use a toxic in order to
obtain an affective effect;
o physical dependence - the necessity to continue the administration of a toxic in
order to prevent some symptoms (the abstinence syndrome): anxiety, apathy,
insomnia, anorexia, nausea, vomit, diarrhea, sweating, lacrimation, diffuse pain,
cardiovascular and respiratory symptoms, blood pressure oscillations;
o tolerance - the progressive diminuation of the effect after repeated
administration, respectively the necessity to increase the dose in order to obtain
the desired effect;
o psychotoxicity (e.g. Morphine, Heroine, Opium, Cocaine, LSD).
 ADRENERGIC DRUGS

The sympathetic nervous system allows the body to function under stress („fight or
flight”).

THE ADRENERGIC RECEPTORS

§ they are a class of G protein-coupled receptors, targets for catecholamines;

§ a1-adrenergic receptor activation results in:
o vasoconstriction;
o decreased bronchial secretion;
o decreased digestive motility;
o contraction of the splenic capsule;
o uterine smooth muscle contraction;
o mydriasis;
o increased glycogenolysis and gluconeogenesis;
o decreased insulin secretion.
§ a2-adrenergic receptor activation results in:
o decreased release of the transmitters Ach and norepinephrine (presynaptic
inhibitory effect);
o increased platelet aggregation.
§ β1 – adrenergic receptor activation results in:
o positive inotropic, chronotropic and dromotropic effect on heart;
o CNS stimulation;
o increase renin secretion;
o lipolysis with increasing free-fatty acid concentration in blood.
§ β2 – adrenergic receptor activation results in:
o peripheral vasodilation;
o bronchodilation;
o uterine smooth muscle relaxation;
o GI smooth muscle relaxation;
o increased glycogenolysis and gluconeogenesis;
o increased insulin secretion.
Some of the effects of the sympathetic nervous system stimulation are:
§ stimulate sweat glands;
§ constrict peripheral vessels;
§ increase blood flow to skeletal muscles;
§ reduce blood flow to abdomen;
§ increase chronotropic and inotropic effects;
§ bronchodilation;
§ decrease digestive activity;
§ relax smooth muscle in wall of bladder;
§ release glucose stores from liver.

SYMPATHOMIMETIC DRUGS
(ADRENERGIC AGONISTS)

Classification
§ Direct acting
 o Non-selective:
§ a1 a2 β1 β2: ADRENALINE (Epinephrine)
§ a1 a2 β1: NORADRENALINE (Norepinephrine)
§ β1 β2 : ISOPRENALINE
o Selective:
§ a1 : PHENYLEPHRINE
METHOXAMINE
OXYMETAZOLINE
XYLOMETAZOLINE
§ a2 : CLONIDINE
GUANABENZ
GUANFACINE
METHYLDOPA
§ β1 : DOPAMINE
DOBUTAMINE
§ β2 : SALBUTAMOL
SALMETEROL
TERBUTALINE
FORMOTEROL
FENOTEROL
METAPROTERENOL
CLENBUTEROL
§ Mixed acting
o a1 a2 β1 β2, releasing agent: EPHEDRINE
§ Indirect acting
o releasing agents: AMPHETAMINE
TYRAMINE
o uptake inhibitor: COCAINE
o MAO/COMT inhibitors: PARGYLINE
ENTACAPONE
DOPA – dopamine, NE – norepinephrine, NET – norepinephrine transporter, MAO –
monoaminooxidase, COMT – catechol-O-methyltransferase

v ADRENALINE (EPINEPHRINE)

Mechanism of action
§ Adrenaline is an endogenous sympathomimetic catecholamine, a hormone secreted by
the medullosuprarenalian gland;
§ it is a broad-spectrum sympathomimetic (acting on a1, a2, b1 and b2 receptors).
Pharmacodynamic actions
§ vascular effects:
o on veins: strong constriction, increasing peripheral resistance in the skin,
mucosa, kidney, spleen;
o on arteries: precapillary constriction and decreased cutaneous blood flow;
dilation and increased blood flow in the skeletal muscle, in the cerebral and
coronary area.
§ cardiac effects:
o heart rate increases - tachycardia (increased velocity of A-V conduction =
positive dromotropism);
o shortens the refractory period of the atrium and ventricle;
o contractility increases, therefore the cardiac work will be increased, especially
for the left ventricle ® cardiac output increases ® oxygen consumption
increases;
 o moderate increase of the systolic blood pressure, as a consequence of the heart
stimulation and of the diminished peripheric resistence, via vasodilation in the
skeletal muscle;
o automaticity increases (predisposes to arrhythmias).
§ blood pressure effects: mild increase of the blood pressure values due to an increase in
the systolic pressure and a decrease in the diastolic one.
§ smooth muscle effects:
o bronchial muscle: relaxation ® bronchodilation;
o on intestine: relaxation of intestinal smooth muscle, contraction of sphincters;
o on urinary bladder: relaxation of bladder muscles, contraction of sphincters;
o on uterine muscle: during the last month of pregnancy reduces uterine tone and
contractions ® delay premature labor;
o on splenic capsule: contraction.
§ CNS effects: excitation, anxiety.
§ metabolic effects:
o hyperglycemia: stimulation of glycogenosis (b2), decrease of glucose up-take by
cells; decrease insulin secretion (a);
o peripheral lipolysis, with an increase in the amount of free fatty acids;
o increase basal metabolism and oxygen consumption.
Indications
§ anaphylactic shock, due to:
o stimulation of the heart;
o increased blood pressure;
o release of laryngeal edema;
o induction of bronchodilation.
§ bronchial asthma crisis: SC in emergency because it produces bronchodilation and
decongestion of the mucosa;
§ cardiac arrest (associated with electric shocks and cardiac massage): intracardiac
administration, in small doses or 0.5 ml sol. 1‰;
§ local hemostatic in epistaxis, esophageal varicose veins, ulcer;
§ decongestant of the conjunctival mucosa (conjunctivitis) or nasal mucosa (rhinitis);
§ in association with Lidocaine, for the vasoconstrictor effect, which prolongs the
duration of the local anesthesia.
Contraindications
§ HBP;
§ ischemic cardiopathy, arrhythmias (tachycardia).
Adverse effects
§ anorexia, tremor, dizziness, headache, palpitations;
§ HBP, stroke, arrhythmias (ventricular fibrillation);
§ in patients having ischemic heart disease it may trigger acute myocardial infarction
(MI);
§ pains in the forehead area.

v NORADRENALINE (NOREPINEPHRINE)

Mechanism of action
§ Norepinephrine is equipotent to Epinephrine in its reactions on b1-receptors, and
slightly less potent on a-receptors;
§ it has very little effect on b2-receptors.
Pharmacodynamic actions, similar to the one of epinephrine, especially on:
 § vessels: over arterioles and small veins it induces vasoconstriction resulting in a total
peripheral resistance increase, along with increased systolic and diastolic blood
pressure; this produces a compensatory vagal reflex that slows the heart rate; cardiac
output may actually decrease, although coronary blood flow is increased.
Indications
§ serious acute hypotensive states ® vascular collapse, with systolic blood pressure less
than 50 mmHg.
Adverse effects
§ anorexia, palpitations, headaches;
§ HBP.

v DOPAMINE

Mechanism of action
§ Dopamine is a direct cathecolamine, acting on adrenergic and dopaminergic receptors
(D1, D2, D3).
Pharmacodynamic actions
§ cardiac effects:
o positive inotropism: Dopamine increases myocardial contractility through
activation of b1 adrenergic receptors resulting in increased cardiac output;
o increase systolic blood pressure, with little effect on diastolic pressure
§ kidney effects: low doses enhance glomerular filtration rates, renal blood flow (renal
vasodilation) ® increase plasma Cl.
Indications
§ cardiogenic, traumatic, hypovolemic shock – especially in patients with oligouria (low
diuresis);
§ acute pulmonary edema;
§ chronic refractory congestive heart failure.
Adverse effects
§ tachyardia, arrhythmias;
§ anginal pain.

v DOBUTAMINE

Mechanism of action
§ Dobutamine is a direct b1-receptors agonist;
§ it does not act on dopaminergic receptors.
Pharmacodynamic actions
§ cardiac effects:
o strong positive inotropic effect;
o medium chronotropic effect = causes limited increase in heart rate;
o increase cardiac output;
o increase coronary blood flow.
Indications
§ congestive heart failure (after acute MI);
§ chronic congestive heart failure.
Adverse effects
§ arrhythmias (ventricular ectopy);
§ increased ventricular rate in patient with atrial fibrillation;
§ anginal pain.
 v EPHEDRINE

Mechanism of action
§ Ephedrine is a mixt sympathomimetic, acting:
o indirectly, by releasing norepinephrine in the sympathetic ends;
o directly, by acting on a and b receptors.
Pharmacodynamic actions:
§ similar to the one of epinephrine and norepinephrine, but it lasts longer because it is not
destroyed by monoamine oxydase (MAO);
§ HBP (both systolic and diastolic) by cardiac stimulation and vasoconstriction.
Indications:
§ hypotension;
§ rhinitis (as a nasal decongestant);
§ bronchial asthma (less recommended because it produces tachyphylaxis).
Preparations:
Ephedrine - Ephedrine tab. 50 mg, vials 10 mg/ml, 50 mg/ml

SYMPATHOLYTIC DRUGS

ALPHA-BLOCKERS

Classification
§ Synthetic:
§ Non-selective agents (a1 and a2):
PHENTOLAMINE
PHENOXYBENZAMINE
TOLAZOLINE
§ Selective agents (a1):
DOXAZOSIN
PRAZOSIN
TERAZOSIN
§ Natural: ergot alkaloids:
ERGOTAMINE
DIHYDROERGOTAMINE antimigraine action
METHYSERGIDE
ERGOTOXINE antiischemia action
DIHYDROERGOTOXINE
NICERGOLINE
ERGOMETRINE uterine contraction stimulants
METHYLERGOMETRINE

SYNTHETIC ALFA BLOCKERS

Mechanism of action
§ a1-adrenergic receptor blockade inhibits vasoconstriction caused by endogenous
catecholamines, thus reducing peripheral resistance and venous pressure, decreasing
blood pressure;
§ a2-adrenergic antagonists increase norepinephrine release from nerve endings;
§ they also lower plasma LDL cholesterol, VLDL and triglyceride levels and increase
HDL cholesterol levels;
 § Phentolamine also blocks 5-HT (serotonin) receptors and causes mast cell histamine
release.

Indications
§ essential HBP;
§ HBP episodes in pheochromocytoma (Phenoxybenzamine, Phentolamine);
§ benign prostate hypertrophy (reduced bladder and prostate resistance because of a1-
adrenergic receptor blockade);
§ coronary artery disease;
§ hyperlipemia.
Adverse effects
§ postural hypotension; significant orthostatic hypotension following first-dose after
Prazosin or Terazosin administration;
§ dizziness, headache, fatigue;
§ palpitations;
§ hydrosaline retention (needs use of a diuretic);
§ nausea.
Therapeutic notes
§ Phenoxybenzamine and Phentolamine are administered IV in pheochromocytoma, prior
to surgery; because of the reflex tachycardia, they are very rare used in the treatment of
HBP;
§ Tolazoline is less potent than Phentolamine or Phenoxybenzamine;

ERGOT ALKALOIDS
v ERGOTAMINE

Mechanism of action
§ Ergotamine is a glomerular a-blocker only after high doses;
§ it is an a-adrenergic drug after low doses (therapeutic doses).
Pharmacodynamic actions
§ antimigraine action;
§ weak increase in uterine tone.
Therapeutic uses
§ migraine;
§ vascular-cause headaches.

v ERGOTOXINE

Pharmacodynamic actions
§ vasodilator by eliminating the spastic component:
o increases cerebral blood flow;
o increases retina blood flow;
o increases muscular blood flow;
§ bradycardia, especially when sympathetic tone is increased in vascular wall.
Indications
§ chonic treatment in: cerebral atherosclerosis, ischemic cerebral attacks, retinal
circulation disorders, vestibular disorders;
§ Raynaud syndrome;
§ obliterating arteriopathies (low efficiency).
 v ERGOMETRINE

Pharmacodynamic actions
§ stimulates the tone, frequency and amplitude of uterine contractions;
§ hemostatic uterine action via closing the venous sinuses in the myometrium.
Indications
§ prophylaxis and treatment of post-partum and post-abortum bleedings;
§ lochie retention.
 CHOLINERGIC DRUGS

PARASYMPATHOMIMETIC DRUGS

Mechanism of action
Ach is the neurotransmitter for the sympathetic and parasympathetic automatic ganglia, the
preganglionic fibres ending in the adrenal medulla and the postganglionic fibers of
parasympathetic. It is a quaternary ammonium ester that is rapidly hydrolised by
acetylcholinesterase and plasma cholinesterase. Ach released from the presynaptic membrane:
§ binds to the cholinergic receptors resulting in activation of the cholinergic receptors;
§ binds to acetylcholinesterase and inactivates Ach.

THE RECEPTORS

§ the muscarinic receptors are stimulated by muscarine, an alkaloid existing in certain

poisonous mushrooms.
o there are several classes of muscarinic receptors: Ml (on gastric parietal cells),
M2 (on cardiac cells and smooth muscle), M3 (on exocrine glands and smooth
muscle), M4, M5;
o location:
§ on autonomic effector organs: heart, brain, exocrine glands, smooth
muscles;
§ on ganglia of peripheral nervous system.
§ the nicotinic receptors are stimulated by nicotine.
o location: CNS, autonomic ganglia, adrenal medulla, neuromuscular junction.

Some of the effects of the parasympathetic nervous system stimulation are:

§ pupillary constriction;
§ increased secretion by digestive glands;
§ increased smooth muscle activity along the GI tract;
§ bronchoconstriction;
§ reduced heart rate and negative inotropic effects.
Classification
§ Direct acting (stimulating the nicotinic or muscarinic receptors)
o Choline esters:
ACETYLCHOLINE (all Ach receptors)
CARBACHOL (all muscarinic and some nicotinic receptors)
METHACOLINE (all muscarinic receptors)
BETHANECHOL (M3 receptors)
o Natural alkaloids:
PILOCARPINE
ARECOLINE
MUSCARINE
NICOTINE
§ Indirect acting
o Reversible cholinesterase inhibitors
NEOSTIGMINE
PHYSOSTIGMINE
PYRIDOSTIGMINE
EDROPHONIUM
 DONEPEZIL
o Irreversible cholinesterase inhibitors (organophosphate compounds)
ECHOTHIOPHATE
ISOFLUROPHATE
MALATHION

DIRECT CHOLINERGIC AGONISTS

Mechanism of action
§ they act directly upon the cholinergic receptors, stimulate them and produce
characteristic effects.

v ACETYLCHOLINE

Parmacodynamic actions
The muscarinic effects appear after small doses.
§ cardiac effects:
o decrease of the cardiac output and the heart rate:
§ decrease the contraction force of the atriums (negative inotropism);
§ decrease of the firing rate at sinoatrial node.
o decrease in blood pressure.
§ respiratory effects:
o bronchoconstriction;
o stimulation of bronchiolar secretion.
§ digestive effects:
o stimulation of the GI smooth muscles;
o stimulation of the gastric secretion (gastric acid hypersecretion);
o stimulation of the intestinal secretion and motility;
 o stimulation of the gall bladder.
§ urinary system effects:
o stimulation of the urinary bladder;
o increased tone of detrusor urine muscle.
§ eye effects:
o miosis (constriction of pupille sphincter muscle);
o stimulation of cilliary muscle contraction (for near vision);
o decrease of the intraocular pressure (after local administration).
§ CNS effects – stimulation.
§ exocrine glands – hypersecretion.
The nicotinic effects appear only after large doses.

v CARBACHOL

Mechanism of action
§ it has both nicotinic and muscarinic action;
§ it is biotransformed by esterases at a much slower rate when compared to Ach;
§ it has a strong action on GI system, urinary bladder, eye.

Indications
§ glaucoma, applied localy (the clinical use is limited due to its high potency and long
duration of action);
§ stimulation of postoperative atonic urinary bladder;
§ stimulation of atonic intestinal smooth muscle.
Adverse effects
§ gastric acid hypersecretion.
Preparations
Carbachol - Miostat opthalmic sol.

v METACHOLINE

Mechanism of action
§ acts on the cardiovascular system.
Indications
§ Raynaud syndrome;
§ paroxystic tachycardia

v BETHANECOL

Mechanism of action
§ it has a strong muscarinic action and no or little nicotinic action;
§ acts on smooth muscle of bladder and GI tract (duration of action – aproximately one
hour).
Indications
§ stimulation of atonic bladder;
§ stimulation of atonic intestinal smooth muscle.
Adverse effects
§ salivation, abdominal pain, diarrhea;
§ sweating;
§ low blood pressure.
 v PILOCARPINE

Chemistry
§ it is an alkaloid from leaves of Pilocarpine jaborandi.

Pharmacodynamic actions. Mechanism of action.

§ it has muscarinic action;
§ rapid miosis (contraction of the cilliary muscle);
§ lowering of the intraocular pressure as a result of increased drainage of aqueous humor,
due to the extreme efficiency in opening the trabecular meshwork surrounding
Schlemm's canal; the vision is fixed at a certain distance and focussing becomes
impossible;
§ stimulates secretions (sweat, saliva, tears).
Indications
§ glaucoma (the effect lasts 4-6 hours);
§ iritis, irido-capsulitis;
§ lithiasis of the salivar glands;
§ the intoxication with Atropine (administrated IV).
Adverse effects
§ sweating;
§ salivation;
§ pain in the eyebrow region (at the beginning of the treatment);
§ may appear tolerance at ocular effects.
Preparations
Pilocarpine - Dropil ophtalmic sol. 2%

INDIRECT CHOLINERGIC AGONISTS

Mechanism of action
Anticolinesterases form a complex with acetylcholinesterase and inhibit it's hydrolyzing
activity of Ach. Therefore, Ach accumulates in the synaptic gap and the Ach's effects are
prolonged and very strong.

v NEOSTIGMINE

Chemistry
§ it is a quaternary amonium compound.
Pharmacodynamic actions
§ muscarinic effects – stimulates the motility of the digestive tract and of the urinary
bladder;
§ nicotinic effects – stimulates the contractility of the skeletal muscles (at small doses).

Pharmacokinetics
§ Absorption: it is not well absorbed orally;
§ Distribution: it does not penetrate the biological membranes and does not enter the CNS;
§ Biotransformation and elimination: it is destroyed by plasma esterases and is excreted
in the urine.
Indications
§ myasthenia gravis;
 § intestinal or bladder atony;
§ antidote for tubocurarine and other competitive neuromuscular blocking agents;
§ glaucoma.
Adverse effects
§ nausea, vomit, salivation, abdominal pain, diarrhea;
§ sweating.
Contraindications
§ pregnancy;
§ bronchial asthma;
§ Parkinson’s disease.
Preparations
Neostigmine – Miostin vials

v PHYSOSTIGMINE

Pharmacodynamic actions
§ muscarinic effects – miosis and decreased intraocular pressure (the effects last for 24 -
48 h);
§ nicotinic effects – contraction of scheletal muscles.
Indications
§ glaucoma;
§ treatment of overdoses of drugs with antichiolinergic actions (Atropine, phenothiazines,
tryciclic antidepressants).
Adverse effects
§ local irritation after a long lasting administration.

v PYRIDOSTIGMINE

Pharmacodynamic actions
§ the action is similar with Physostigmine, but more intensive and prolonged.
Indications
§ postoperative intestinal atony;
§ myastenia gravis.

v EDROPHONIUM

Mechanism of action
§ acts mainly on scheletal muscle (short duration of action).
Indications
§ diagnosis of myastenia gravis;
§ antidote for tubocurarine.

v ECOTHIOPHAT

Mechanism of action
§ irreversible anticolinesterases are able to form a covalent bind with a serine “–OH” at
the active site of acetylcholinesterase; the enzyme is permanently inactivated and the
 restoration of acetylcholinesterase activity requires the synthesis of new enzyme
molecules; following covalent modification of acetylcholinesterase, the phosphorylated
enzyme slowly releases one of its isopropyl groups; the loss of an alkyl group is called
aging and makes it impossible for chemical reactivators such as pralidoxime to break
the bond between the remaining drug and the enzyme.
Indications
§ glaucoma (topically), resulting an intensive lowering in intraocular pressure which lasts
for 1 – 2 weeks.
Adverse effects
§ specific cataract after long treatment with high doses.

CHOLINERGIC ANTAGONISTS

Classification
§ natural
ATROPINE
SCOPOLAMINE
§ synthetic
PIRENZEPINE HOMATROPINE
PROPANTELINE TRIHEXYPHENIDYL
TROPICAMIDE BUTILSCOPOLAMINE
Mechanism of action
§ they block the muscarinic synapses of the parasympathetic nerves; the effects of
parasympathetic inervation are thus interrupted.

v ATROPINE

Chemistry
§ Atropine is a belladona alkaloid.
Mechanism of action
§ it has a high affinity for muscarinic receptors where it binds competitively, preventing
Ach from binding to that site.
Pharmacodynamic actions
§ cardiac effects:
o small doses – bradycardia and low blood pressure;
o usual doses – tachycardia.
§ digestive effects:
o xerostomia;
o inhibition of the gastric acid secretion;
o antispasmodic on the gall bladder.
§ urinary system effects:
o reduces the hypermotility state of the urinary bladder.
§ respiratory effects:
o decreased bronchiolar secretion;
o bronchodilation, inhibit the bronchospasm.
§ eye effects:
o mydriasis;
 o unresponsiveness to light;
o cyclopegia (inability to focus for near vision);
o high intraocular pressure;
o diminished tears secretion.
§ CNS effects:
o at high doses it stimulates the CNS (confusion, hallucination, delirium, collapse
of the circulatory and respiratory systems, death);
o favorable effect in Parkinson’s disease.
Pharmacokinetics
§ Absorption: it is rapidly absorbed after oral or parenteral administration;
§ Distribution: well diffused in tissues and organs;
§ Biotransformation and elimination: partially metabolized by the liver, eliminated
primarily in the urine.
Indications
§ preanesthetic agent, because it reduces the secretion in the upper and lower respiratory
tract;
§ antidote in the intoxication with anticolinesterases (Pilocarpine and organophosphate
compounds);
§ MI (it treats sinus node bradycardia or a high grade AV block);
§ in ophtalmology: because of the mydriatic and cyclopegic effect which permits the
measurement of the refractive errors without interference by the accomodative capacity
of the eye.
Adverse effects
§ xerostomia (dry mouth);
§ blurred vision;
§ "sandy eyes";
§ urinary retention;
§ restlessness, confusion, hallucination, delirium, convulsions, coma.
Preparations
Atropine - Atropine sulfate vials

v SCOPOLAMINE

Chemistry
§ Scopolamine is a belladona alkaloid.
Pharmacodynamic actions
§ the effects are similar to those of Atropine but with a short duration of action and two
times higher than the effects of Atropine;
§ acts mainly on exocrine glands and eye;
§ produces sedation but at higher doses can instead produce excitement.
Indications
§ preanesthetic agent (in association with Morphine);
§ motion sickness;
§ Parkinson’s disease.

v PIRENZEPINE

Mechanism of action
§ diminishes the excitosecretory vagal influences and decreases the basal gastric
secretion, thus having antispastic and antisecretory effects;
 § blocks the Ml muscarinic receptors;
§ it has the same efficiency with Cimetidine in the treatment of the gastric ulcer.
Indications
§ active gastric and duodenal ulcer;
§ reflux esophagitis;
§ Zollinger-Ellison syndrome.

v PROPANTELINE

Indications
§ gastric ulcer;
§ hyperacid gastritis
 PULMONARY PHARMACOLOGY

ANTICOUGHING AGENTS

There are two types of cough: productive cough, which leads to removal of sputum from the
lungs and dry cough, with no removal of sputum. Mainly, the physician must treat the
underlying cause. A productive cough should not be suppressed until the cause has been
identified, because sputum needs to be cleared.
Classification
§ antitussives;
§ expectorants.

ANTITUSSIVES

They are symptomatic drugs which diminish or stop the dry coughing reflex by depressing the
coughing center or by depressing the function of sensitive receptors located in the respiratory
mucosa.

v OPIUM and MORPHINE

Mechanism of action
§ they have an anticoughing action, by depressing the bulbar coughing center;
§ they block moderate or intense pain;
§ they reduce the psihoaffective implications of coughing.
Indications
§ bronchopulmonary cancer (anticoughing effect and major analgesic effect);
§ aortic aneurysm;
§ pulmonary infarct;
§ costal fractures;
§ pneumothorax;
§ hemoptysis.
Adverse effects
§ high addictive risk;
§ possible bronchial spasm;
§ they thicken the bronchial secretions;
§ depression of the respiratory center to respiratory arrest, at high doses.
Therapeutic notes
§ less used because of the adverse effects.

v CODEINE (METHILMORPHINE)

Mechanism of action
§ it has an anticoughing action, by depressing the bulbar coughing center;
§ Codeine has a mild analgesic action, significantly weaker than Morphine;
§ weak sedative action.
Pharmacokinetics
 § Biotransformation: Codeine is considered a prodrug, since it is metabolised to the
primary active compounds morphine and codeine-6-glucuronide; the conversion occurs
in the liver and is catalysed by the CYP 450 enzyme.
Indications
§ dry cough;
§ diarrhea;
§ irritable bowel syndrome;
§ mild to severe pain, in association with analgesics.
Contraindications
§ administration at children under 3 years, because of the risk of inducing convulsions;
§ in patients with severe respiratory failure.
Adverse effects
§ sleepiness;
§ constipation;
§ depression of the repiratory center.
Therapeutic notes
§ the effect appears slowly, in aproximatively two hours and remains for six hours;
§ it has no addictive risk (unlike Morphine).
Preparations
Codeine plus Phenobarbital – Codenal tab.
Codeine – Codeine phosphate tab.

v NOSCAPINE

Mechanism of action
§ Noscapine has an anticoughing action similar to Codeine, but it does not depress the
respiratory center, has no analgesic effect and has no addictive risk.
Preparations
Noscapine – Noscapine syrup

v GLAUCINE

Pharmacodynamic effects
§ compared to Codeine, Glaucine has a weak anticoughing effect, which lasts for a short
while; it needs frequent administration and has low therapeutically compliance.

v CLOFEDANOL

Pharmacodynamic effects
§ compared to Codeine, Clofedanol has a weak anticoughing effect, which lasts for a short
while, leading to low compliance;
§ it has also a local anestetic effect and a weak antihistaminic H1 action.
Presentations
Clofedanol - Calmotusin oral sol.

v DEXTROMETHORPHAN

Pharmacodynamic effects
§ it is an antitussive that has no analgesic or sedative effects, does not depress respiration
in usual doses and is nonaddictive.
Preparations
Dextromethorphan – Humex, Tussin syrup, tab.

v OXELADINE

Pharmacodynamic effects
§ Oxeladine acts like Codeine, by depressing the respiratory center and is preferred for
children.
Preparations
Oxeladine – Paxeladine caps., syrup

EXPECTORANTS

Expectorants are drugs which ease the elimination of bronchial secretions, by increasing their
quantity and/or fluidifying them.
Classification
§ Secretolytic expectorants (mucolytics);
§ Secretostimulant expectorants.

SECRETOLYTIC EXPECTORANTS (MUCOLYTICS)

Mechanism of action
Mucolytics lower the viscosity of the mucus, by breaking down the chemical structure of the
mucus’ molecules and ease the elimination of bronchial secretions.
Indications
§ acute bronchitis;
§ chronic bronchitis in acute episode;
§ bronchiectasy;
§ mucoviscidosis.

v BROMHEXIN

Mechanism of action
§ it is a mucolytic with mild action which lowers the viscosity of the sputum, by altering
the mucine structure.
Presentation
Bromhexin – Bromhexin tab., oral sol.

v AMBROXOL

Pharmacodynamic effects
§ Ambroxol is a mucolytic with intense action and a longer half-life (t1/2) than Brofimen
(better therapeutic compliance).
Indications
§ acute and chronic bronchitis;
§ COPD.
Presentation
Ambroxol – Tussefar syrup
 v ACETYLCYSTEINE

Mechanism of action
§ mucolytic with intense action because of the group “thiol”, a reducing group with action
in destroying the disulphide bonds (S-S) of the mucus and forming of new bonds
between mucus and the fragments of the mucoproteine (from sputum).
Indications
§ acute or chronic bronchitis;
§ bronchiectasy;
§ pneumonia;
§ mucoviscidosis;
§ lung tuberculosis;
§ intoxication with Paracetamol, as the antidote (IV drip).
Contraindications
§ bronchial asthma, because it can produce bronchospasm.
Preparations
Acetylcysteine - ACC, Brunac, Fluimucil, Siran syrup, caps., tab., vials

v CARBOCISTEINE

Mechanism of action
§ mucolytic which helps the recover of the bronchial epithelium; improves the function
of bronchial cilia and antagonize the local kinins involved in bronchial inflammatory
processes.
Preparations
Carbocisteine – Humex syrup
SECRETOSTIMULANT EXPECTORANTS
Mechanism of action
§ increase the secretory activity of the tracheobronchial glands by increasing the water
content in the mucus of the bronchial mucosa;
§ amplify the movements of bronchial mucosa cilia;
§ increase the peristaltic of bronchial mucosa and improve the elimination.
Their therapeutic action is definitely lower than of the mucolytics.

v GUAIAFENESIN

Indications
§ acute or chronic bronchitis;
§ gout, because of the uricosuric action.
Adverse effects
§ nausea, vomiting;
§ sedation, after high doses;
§ kidney stones of uric acid (rarely).
Preparations
Guaiafenesin – Coldrex Broncho, Robitussin Expectorans syrup, oral sol.
 ANTIASTHMATICS

Classification
§ Bronchodilators
§ Anti-inflammators

BRONCHODILATORS

Classification
§ Beta 2 adrenergic agonists;
§ Cholinergic antagonists;
§ Musculotropes.

BETA 2 ADRENERGIC AGONISTS (b2 SYMPATHOMIMETICS)

Classification
§ with short action
TERBUTALINE CLENBUTEROLE
SALBUTAMOLE REPROTEROL
FENOTEROLE METAPROTERENOL
§ with long action
SALMETEROL
FORMOTEROL
Mechanism of action
§ the stimulation of the b2-adrenergic receptors at bronchial level (smooth muscle) causes
the activation of adenilatcyclase, increasing the cAMP, activating proteinkinase and
inhibiting the myosin phosphorilation, lowering the intracellular calcium level, with the
final result the relaxation of bronchial muscles;
§ may increase mucociliary transport;
§ the mechanism for long duration of Salmeterol and Formoterol is the high liposolubility,
creating a depot effect.
Indications
§ the first choice drugs for bronchial asthma patients in all stages.
Adverse effects
§ tolerance after repetead administrations.

Therapeutic notes
§ the bronchodilators with short action are considered symptomatic medication having an
intense bronchodilator action which appears in 15 minutes, reaches a peak in 60-90
minutes and declines in 3-4 hours; they have no anti-inflammatory action;
§ the bronchodilators with short action are administered in the prophylaxis or treatment
of bronchial asthma chrises;
§ the bronchodilators with long action have an intense bronchodilator action that lasts for
aproximatively 12 hours, plus an anti–inflammatory action;
§ the bronchodilators with long action are administered in persistent bronchiolar asthma
(easy, moderate and severe stage);
§ they can be administered orally, via inhalation or parenteral.
Preparations
Terbutaline – Aironyl syrup
Salbutamole – Ventolin aerosole
Fenoterole – Berotec aerosole
Salmeterol – Serevent aerosole
Formoterol – Oxis inhalatory powder

CHOLINERGIC ANTAGONISTS

Mechanism of action
§ they block the bronchial muscarinic receptors, the vagal constriction of the smooth
muscles and the bronchiolar secretion.
Adverse effects
§ dry mouth, pharyngeal irritation;
§ tachycardia;
§ urinary retention;
§ agitation;
§ loss of ocular accommodation;
§ increase of intraocular pressure at glaucoma patients.
Therapeutic notes
§ they are prescribed as an alternative to b2-adrenergic bronchodilators in patients with
coronary diseases;
§ they are weaker bronchodilators compared to b2-adrenergic drugs and that’s why they
are considered as an alternative medication;
§ the effect appears in 30 minutes and lasts for about 8 -12 hours;
§ Ipratropium is especially effective in the management of asthma in the elderly and a
treatment of choice for b-blocker-induced bronchospasm.
Preparations
Atropine – Atropine vials
Ipratropium bromide – Ipravent aerosole

MUSCULOTROPES

Chemistry
§ Theophylline is a xantic base related with caffeine:
o Theophylline: 1,3-dimethylxanthine;
o Caffeine: 1,3,7-trimethylxanthine.
Mechanism of action and pharmacodynamic actions
§ they inhibit the phosphodiesterase, increasing the intracellular cAMP with relaxation of
bronchial muscles and cardiac stimulation;
§ are weaker bronchodilators than b2-adrenergics;
§ weak anti-inflammatory action;
§ CNS effects:
o increased alertness, insomnia;
o tremor;
o convulsions, after very high doses.
§ cardiovascular effects:
o direct positive chronotropic;
o direct enhanced myocardial contractility;
o reduced blood viscosity (unknown mechanism).
§ GI tract effects:
o stimulates secretion.
 § renal effects:
o weak diuretics, because of increased glomerular filtration and reduced
tubular sodium reabsorption.
Pharmacokinetics
§ Biotransformation and elimination: metabolic products include demethylated xanthines
which are excreted in the urine.
Indications
§ bronchial asthma crisis;
§ spastic chronic bronchitis;
§ interchrises treatment of bronchial asthma, not satisfactory controlled by inhalator
corticotherapy.
Adverse effects
§ nausea, vomiting;
§ irritability, insomnia;
§ palpitations, precordial pain.
Therapeutic notes
§ they are used as an alternative medication for bronchial asthma;
§ pay attention to dose because overdosing is easy to obtain;
§ after IV administration, the effect appears in 5 minutes.
Preparations
Theophylline – Teotard caps.
Aminophylline – Miofilin tab., caps., vials

ANTI-INFLAMMATORS

CORTICOTHERAPY
Inhalatory corticotherapy
Mechanism of action
§ they have a strong anti-inflammatory action in all phases of inflammation, evidentiated
at:
o cellular level: binds on specific cytoplasmic receptors, creating a complex which
enters in the nucleus where it interacts with DNA causing activation of
Lipocortine which activates A2 phospholipase and lowers the leucotrienes and
prostaglandins;
o histological level: reduce/abolish the histological lesions on the bronchial
mucosa - diminish the swell of mucosa, mucus hypersecretion, subepithelial
fibrosis.
Indications
§ persistent bronchial asthma, despite correct antiasthma treatment;
§ COPD;
§ mucoviscidosis.
Adverse effects
§ oropharingian candidosis (prevented by using spacers, mouth washes with bicarbonated
water or spitting after each inhalation);
§ irritative cough after inhalation, because of the solvent (oleic acid);
§ dysphonia due to miopathy of vocal chords musculature;
§ a lower resistance to infections;
§ low bone density.
Therapeutic notes
§ the most efficient anti-inflammatory medication;
 § the first choice medication in persistent bronchial asthma light, moderate and severe
stage;
§ makes possible in the case of severe bronchial asthma treated with systemic
corticotherapy (oral, IV) a significant decrease of doses, which means lowering the side
effects;
§ the clinical effect appears in a few weeks of treatment: reduced number of asthma
attacks during the day and the night and significantly improves the performance at
effort.
Preparations
Beclometasone – Becotide aerosole
Fluticasone - Flixotide aerosole
Flunisolide – Aerobid aerosole
Budesonide – Pulmicort inhalatory powder

Systemic corticotherapy
§ it is administrated only in severe cases of bronchial asthma, as short as possible:
o oral administration - Prednisone tab. 5 mg; after improvement oral doses are
gradually reduced in a few days to total suppressing of the therapeutic scheme,
being replaced by inhalatory corticotherapy;
o IV administration - Hemisuccinate hydrocortisone vials (1-4 vials once) or
Metilprednisolone 1 mg/kg every 6 hours.

INHIBITORS OF MASTOCITAR DEGRANULATION

v DISODIC CROMOGLICATE

Mechanism of action
§ inhibits the release of histamine from mastocites and the release of excessive amounts
of leukotrienes from leucocytes and mastocites, preventing the onset of bronchial
asthma chrises;
§ inhibits the actions of platelet aggregation factor;
§ it has no bronchodilating activity.
Pharmacokinetics
§ Absorption: poorly absorbed (approximatively 10%).
Indications
§ prophylaxis of allergic bronchial asthma;
§ prophylaxis of aspirin-induced bronchoconstriction;
§ prophylaxis of allergic rhinitis and conjunctivitis;
§ prophylaxis of bronchial asthma to cold and irritative substances (e.g. toluene
diisocyanate, wood dusts).
Adverse effects
§ sometimes throat irritation, cough, dry mouth, wheezing;
§ occasionally local nasal irritation at the beginning of the treatment.
Preparations
Disodic cromoglicate – Intal aerosole, nasal sol.

v NEDOCROMILE

Chemistry
§ it is a high potent derivative of disodic cromoglicate.
Preparations
Nedocromile – Tilade aerosole

v KETOTIFENE

Mechanism of action
§ inhibits the release of histamine from mastocites and excessive production of
leukotrienes;
§ inhibits bronchoconstriction, eosinophiles accumulation, and aerial ways hiperreactivity
induced by PAF;
§ determines prolonged blocking of the H1-histaminergic receptors from bronchia and
vessels.
Indications
§ prophylaxis of bronchial asthma, rhinitis, keratoconjunctivitis (allergic).
Therapeutic notes
§ it has no effect on the installed crises!
Preparations
Ketotifene – Zaditen tab., caps., oral sol.

ANTILEUKOTRIENES - a new class of drugs, since 1998.

v MONTELUKAST SODICUM

Mechanism of action
§ acts as selective antagonist of leukotrienic receptor.
Indications
§ bronchial asthma in adults and children older than 2 years;
§ bronchial asthma induced by Aspirin;
§ prophylaxis of effort induced bronchoconstriction.
Contraindications
§ hypersensitivity to any of the components.
Adverse effects
§ abdominal pain;
§ headaches;
§ allergic reactions.
Therapeutic notes
§ the treatment with Montelukast sodicum brings an extra clinical advantage in patients
with inhalatory corticotherapy;
§ the dose of corticosteroids may be reduced progressively, under medical observation;
§ at some patients inhalator corticotherapy may be discontinued;
§ do not use in bronchial asthma crisis!
Preparations
Montelukast sodicum – Singulair tab.

LIPOOXYGENASE INHIBITORS

Mechanism of action
§ they inhibit the lipooxygenase, an important enzyme involved in the leucotrienes
synthesis.
Interactions
 § it is metabolized by CYP 450 and can decrease the Cl (increase the concentration) of
Theophylline, Warfarin, Propranolol.
Indications
§ long term prophylaxis of bronchial asthma crysis.
Preparations
Zileuton – Zyflo tab.
 ANTIHYPERTENSIVE DRUGS

Antihypertensives are drugs that decrease the blood pressure through different
pharmacodynamic mechanisms. The high blood pressure (HBP) is an increase in systolic
blood pressure value that exceeds 140 mmHg and/or the diastolic one over 90 mmHg. In time
it can lead to severe complications, like stroke, heart failure, acute pulmonary edema or renal
failure. That is why an early diagnosis and a correct treatment of HBP are very important. The
target is to obtain a value of 140/90 mmHg, and in patients with diabetes and/or ischemic
heart disease even less, 130/80 mmHg.
The classification of high blood pressure, according to the blood pressure values:
● HBP stage I (mild): 140 – 159 / 90 - 99 mmHg
● HBP stage II (moderate): 160 – 179 / 100 – 109 mmHg
● HBP stage III (severe): more than 180 / 110 mmHg
The lifelong treatment in HBP is administered to decrease the blood pressure, to
maintain it as close as possible to the normal values and to prevent the complications. The
drug treatment should always be associated with some nonpharmacological measures: the
reduced salt and animal fat intake, smoking cessation, reducing overweight and the sedentary
behaviour.
The blood pressure is in direct relation with the cardiac output and the peripheral
vascular resistance. The physiological adjustment of blood pressure is made by:
● The vegetative nervous system: the sympathetic nervous system increases the blood
pressure by increasing the cardiac output and the peripheral vascular resistance. The
parasympathetic nervous system decreases the blood pressure by inducing
bradycardia, vasodilation and decreasing the cardiac output.
● The renin-angiotensin-aldosteron system (RAAS): renin, produced by the
juxtaglomerular cells in the kidney acts on angiotensinogen, resulting angiotensin I
(vasodilator), converted to angiotensin II, a strong vasoconstrictor and stimulator of
aldosteron secretion.
● The renal regulation of blood pressure: the renal artery perfusion pressure directly
regulates sodium excretion and influences the RAAS.
Classification
1. Diuretics
2. Renin-angiotensin-aldosteron system inhibitors
3. Sympatholytics
4. Calcium channel blockers
5. Direct vasodilators

DIURETICS

Diuretics are drugs that stimulate the renal elimination process of sodium and water,
decrease the plasmatic volume and the cardiac output, reducing the blood pressure values.
Classification. Diuretics are divided in 4 classes:
● Thiazides and related agents
▪ Benzothiadiazines
HYDROCHLOROTHIAZIDE
▪ Thaizid-like
CHLORTHALIDONE
INDAPAMIDE
● Loop diuretics
FUROSEMIDE ETHACRYNIC ACID
 BUMETANIDE PIRETANIDE
● Potassium sparing diuretics (antialdosteronics)
SPIRONOLACTONE AMILORIDE
EPLERENONE TRIAMTERENE
● Osmotic diuretics
MANNITOL
GLYCEROL
SORBITOL
Mechanism of action
The diuretics used in the treatment of HBP have different sites and mechanisms of
action (see the figure below)

THIAZID DIURETICS
The thaizid and loop diuretics are the most commonly prescribed diuretics in the
treatment of HBP.
Pharmacokinetics
● They are well absorbed after oral administration.
● They are renally eliminated and can produce active concentrations in the renal tubule,
acting on the luminal pole of the tubule cell.
● The duration of action for Hydrochlorothiazide is 12 hours and for Chlorthalidone 48-
72 hours.
Pharmacodynamics
● Thiazides have a mild diuretic action compared to loop diuretics.
● Lead to an increased water and electrolite (K+, Na+, Cl-) elimination, considered to be
hypokalemiant diuretics.
● Their antihypertensive action is mild to moderate, acting by decreasing the volemia,
cardiac output and taking sodium and water out of the vascular smooth muscle cells,
lowering the degree of vascular wall edema and vascular peripheral resistance.
Mechanism of action
● The thiazides act especially at the dilution segment of the contort distal tubule,
inhibiting the reabsorption and increase the elimination of water and electrolytes
(sodium, potassium, chloride, bicarbonate).
● In contrast to loop diuretics the calcium reabsorption is promoted.
 ● Administered in a high dose, they can inhibit the carbonic anhydrase.
Indications
● Mild or moderate HBP
● Heart failure
● Mild cardiac, hepatic or allergic edema
Adverse effects
● Hypokalemia (rare compared to Furosemid); can increase the risk of digitalis
intoxication.
● Hypomagnesemia, probably through the functional coupling between the elimination
of potassium and magnesium.
● Hypercalcemia (contrarily to loop diuretics).
● Hypochloremia, hypochloremic alcalosis.
● Reduced tolerance to glucose (hyperglycemia tendency) in predisposed patients.
● Metabolic: hyperuricemia, hyperglycemia and hypercholesterolemia; more intense
after Hydrochlorothiazide, less after Indapamide.

LOOP DIURETICS
♦ Furosemide

Pharmacokinetics
● After IV administration, the diuretic effect appears rapidly, in the first 5 minutes.
● After oral administration it is well absorbed in the gastrointestinal tract.
● It binds to plasma proteins 99%.
● The T1/2 is aproximatively one hour.
● It is renally eliminated and can be found in active concentration in the renal tubule
lumen.
Pharmacodynamics
● The diuretic action is intense and rapid, lasts for 6-7 hours and consists of a large
elimination of water and electrolytes (K+, Na+, Cl-, Mg2+), useful in hypertensive
crisis.
● Loop diuretics increase the renal plasma flow (because they increase prostaglandine
level and renin) and are useful in renal failure.
Mechanism of action
● The loop diuretics act on the ascending Henle loop, inhibiting the co-transport system
for sodium, potassium, chloride, with the elimination of great amounts of water and
this electrolytes.
Indications
● HBP crisis, because they decrease rapidly the plasma volume, the cardiac output,
decreasing the blood pressure.
● Acute pulmonary edema.
● Renal failure.
● Sever heart failure, because of reducing edema and pulmonary overload.
● Edema in liver cirrhosis or nephrotic syndrome.
Adverse effects
● Hypokalemia.
● Metabolic: hyperuricemia, hyperglycemia.
● Dehydration, especially in elderly.
● Temporary deafness.
Contraindications
● Hypovolemia or dehydration.
 ● Severe hypokalemia.
● Severe hyponatremia.
Drug interactions
● NSAIDs and glucocorticoids decrease the antihypertensive effect of Furosemide.
● The association with other antihypertensive drugs increases the risk of hypotension.

POTASSIUM SPARING DIURETICS (HYPERKALEMIANTS,

ANTIALDOSTERONICS)

♦ Spironolactone, Eplerenone

Pharmacokinetics
● They are well absorbed from the digestive tract, metabolised in the liver, renally and
digestive eliminated.
● The T1/2 for Spironolactone is 14 hours, for Eplerenone 3-5 hours.
● The latency is 24 hours, the effect lasts for 48 hours.
Mechanism of action
● Because of the similar structure to aldosterone, they will bind to the receptors in the
convoluted distal and collector tubule, decreasing the reabsorption of sodium, with
natriuretic effect, but retain potassium and hydrogen.
● They have a weak diuretic action.
Indications
● Heart failure.
● Primary or secondary hyperaldosteronism.
● Hypokalemia (arrhythmia, ileus, miastenia gravis)
● Edema, in association with loop diuretics (Furosemide).
Adverse effects
● Hyperkalemia.
● Endocrine disturbances: sexual impotence, gynecomastia in male patients, hirsutism
and amenorrhea in female patients. This effects are mild after the administration of
Eplerenone.
Contraindications
● Hyperkalemia.
● Acute renal failure, severe liver failure.
● Caution in chronic renal failure.
Drug interactions
● The association with other potassium sparing diuretics or potassium salts increase the
risk of hyperkalemia.
● The association with converting enzyme inhibitors needs potassium level monitoring.
● NSAIDs reduce the effect of Spironolactone.

OSMOTIC DIURETICS

♦ Mannitol, Glycerol, Sorbitol

Pharmacokinetics
● After IV administration, Mannitol is rapidly renally excreted, before it could have
been metabolised. Mannitol remains in the extracellular space. 80% of the IV
administered dose is renally eliminated in 3 hours.
Mechanism of action
 ● Administered IV, they increase the plasma osmolarity and actively mobilize the water
from tissues into the vessels, increasing the circulant volume. After glomerular
filtration, osmotic diuretics remain in the urin, were they retain the osmotic equivalent
of water, increasing the elimination.
Indications
● Prevention of anuria in the early phases of acute renal failure.
● Acute intoxications.
● Cerebral edema.
● Acute congestive glaucoma.
● Not to be used in the treatment of HBP.
Adverse effects
● Administered in high doses, they produce a circulatory overload, with an increase in
blood pressure and acute pulmonary edema.
Contraindications
● Edema in heart failure or acute pulmonary edema.
● Dehydration
● Intracranial bleeding
● Persistent oligo- or anuria after testing (5 minutes after the administration of 0,2 g/kg
Mannitol, diuresis should be at least 40-50 ml/hour)

RENIN-ANGIOTENSIN-ALDOSTERON SYSTEM (RAAS) INHIBITORS

Classification
● Angiotensin converting enzyme (ACE) inhibitors
BENAZEPRIL MOEXIPRIL
CAPTOPRIL PERINDOPRIL
CILAZAPRIL QUINAPRIL
ENALAPRIL RAMIPRIL
FOSINOPRIL SPIRAPRIL
LISINOPRIL TRANDOLAPRIL
● Angiotensin II receptor antagonists (sartans, AT1 receptor blockers)
LOSARTAN TELMISARTAN
VALSARTAN OLMESARTAN
EPROSARTAN CANDESARTAN
IRBESARTAN
● Direct renin inhibitors
ALISKIREN
Mechanism of action
RAAS inhibitors act at different levels of the RAAS (see the figure below).
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS (ACE INHIBITORS)

ACE inhibitors are widely used in the therapy of HBP and heart failure, because the
RAAS is involved in their pathogenesis. They have several advantages: decrease the degree of
left ventricular hypertrophy, increase the life expectancy, do not develop tolerance, reflex
tachycardia or influence the metabolism.
Mechanism of action. Pharmacodynamics
● They inhibit the ACE, reducing the angiotensin II, substance with strong
vasoconstricting effect, causing vasodilation and reduction in peripheral resistance,
without modifying the cardiac output or heart rate.
● This drugs inhibit the myocardial fibrosis induced by angiotensin II, preventing and
reducing the ventricular hypertrophy, increasing the lifespan of this patients.
● They inhibit the remodelling after acute myocardial infarction (AMI).
● ACE inhibitors increase bradykinin levels (vasodilating effect) and prostaglandin
synthesis.
● Stimulate the prostaglandin E2 synthesis, with vasodilating and diuretic effect.
● Inhibit the aldosteron secretion, reducing renal sodium and water reabsorption.
● Increase sodium excretion through intrarenal mechanisms.
● Act through reducing the central sympathetic tone, modulation of baroreflexes,
decreasing the antidiuretic hormone production.
● Lower the biosynthesis and presynaptic release of Norepinephrine, plus increase its
reuptake in the periphery.
● Provides renoprotection in renal diseases, including diabetic nephropathy, through
proteinuria reduction.
Indications
● HBP, especially in left ventricular hypertrophy or after AMI.
● Chronic heart failure.
● Diabetic nephropathy.
Adverse effects
● Hypotension, especially in case of previous diuretic treatment, renal artery stenosis,
heart failure, hypovolemia (fever, vomiting) or low sodium diet. That is why the
 treatment will be initiated with small doses and the diuretic administration will be
stopped for a short period, if needed.
● Renal failure, especially in case of bilateral renal artery stenosis, in single kidney
stenosis or in ischemic nephropathy, because normally the glomerular perfusion
pressure is determined by the afferent arteriolar vasodilation and the efferent arteriolar
vasoconstriction. The glomerular perfusion pressure may drop, with concomitant signs
of acute renal failure.
● Dry cough and bronchial spasm in 5-20% of the cases, because of bradikinin
accumulation.
● Angioneurotic edema.
● Allergic reactions, itching, exanthem.
● Loss of taste or metallic taste (rare, specific for Captopril).
Contraindications
● Angioedema.
● Pregnancy and lactation period.
● Bi- or unilateral renal artery stenosis.
● Advanced renal failure.
● Aortic stenosis, mitral stenosis, hypertrophic myopathy.
● Autoimmune diseases (colagenosis) and immunosuppressant therapy.
● Hypersensitivity reactions to the treatment.
Drug interactions
● Should not be associated with other ACE inhibitors.
● The risk of hypotension increases in case of association with other antihypertensive
drugs.
● There is a risk of leukopenia, in association with Allopurinol, glucocorticoids,
immunodepressants and anticancer drugs.
● NSAIDs inhibit prostaglandin synthesis, with sodium and water retention, which
reduces the antihypertensive effect of ACE inhibitors.
● The association with potassium, potassium sparing diuretics or Heparin, increases the
risk of hyperkalemia.
● ACE inhibitors increase the effects of Lithium salts.
● In case of patients treated with oral antidiabetic drugs or Insulin, a higher frequency of
hypoglycemia or glycemia fluctuations was detected.
● Alcohol consumption increase the risk of hypotension. Smoking lowers the effect of
ACE inhibitors.

ANGIOTENSIN II RECEPTOR ANTAGONISTS (SARTANS)

This class was introduced in 1995 in the therapy of HBP and heart failure.
Pharmacokinetics
● After oral administration they are rapidly absorbed and have a different
bioavailability.
● Food lowers the Valsartan absorption by 40%.
● Losartan and Candesartan are considered to be prodrugs.
Mechanism of action and pharmacodynamics
● There are evidences that angiotensin II is produced by alternative routes, not involving
the converting enzyme (the most important, but not single way). Just inhibiting this
enzyme will not stop the secondary routes of producing angiotensin II. That is why a
new class of drugs, blocking of the angiotensin II receptors, was developed.
 ● They cause selective inhibition upon the angiotensin-II receptor type AT1 (without any
effect on AT2 receptors), resulting in vasodilation.
● The hypotensive effect is a result of the reduction in peripheral resistance, without
modifying the cardiac output and heart beat.
● The nephroprotecting effect is done by decreasing the proteinuria, slowing down the
disease progression.
● Uricosuric effect.
Indications
● HBP.
● Heart failure (only Candesartan, Losartan and Valsartan).
● Diabetic nephropathy with or without renal failure.
Adverse effects
● Hyperkalemia.
● Dry cough, less common compared to ACE inhibitors.
● Orthostatic hypotension, especially in associated treatment with diuretics and
dehydration.
● Dizziness, headache.
● Fetal toxicity.
● After the prolonged administration of Olmesartan, a reversible enteropathy can rarely
occur.
Contraindications
● Pregnancy, breastfeeding.
● Liver failure or colestasis.
● Bilateral renal artery stenosis;

DIRECT RENIN INHIBITORS

♦ Aliskiren

Pharmacokinetics
● After oral administration, it has a low bioavailability and a T1/2 of 40 hours.
Mechanism of action
● Aliskiren is a direct renin inhibitor, inhibiting the angiotensin I and II synthesis,
producing vasodilation, decreasing the aldosteron secretion and blood pressure.
Indications
● HBP.
Adverse effects
● Diarrhea is the most frequent side effect.
Drug interactions
● The association of Aliskiren with Cyclosporin, Quinidine and Verapamil is forbidden.
● The association with other inhibitors of the RAAS is to be avoided.

SYMPATHOLYTICS

This class includes the drugs that act as sympathetic inhibitors, central or peripheral,
and adrenergic receptor (alpha and beta) antagonists (see also the “Adrenergic drugs”
chapter).

Classification
● Beta-blockers
 ▪ Nonselective agents
PROPRANOLOL OXPRENOLOL
SOTALOL PINDOLOL
TIMOLOL CARTEOLOL
▪ Selective agents
ESMOLOL BETAXOLOL
ATENOLOL NEBIVOLOL
METOPROLOL ACEBUTOLOL
BISOPROLOL CELIPROLOL
▪ Alfa and beta blockers
LABETOLOL
CARVEDILOL
● Alfa-blockers
Non-selective agents (á1 and á2):
▪
PHENTOLAMINE
PHENOXYBENZAMINE
TOLAZOLINE
▪ Selective agents (α1):
PRAZOSIN
DOXAZOSIN
TERAZOSIN
● Sympathetic inhibitors with central action
METHYLDOPA GUANFACINE
CLONIDINE MOXONIDINE
GUANABENZ
● Sympathetic inhibitors with peripheral action
GUANETIDINE
GUANADREL
RESERPINE
● Sympathetic inhibitors with mixed action
URAPIDIL

BETA BLOCKERS

Beta-blockers are the cardiovascular drugs with the most indications. They
competitively block the beta adrenergic receptors, preventing their stimulation by
norepinephrine released from the vesicle storage or by circulant cathecolamines (epinehrine
and norepinephrine). This drugs are administered in younger patients with hyperreninemia.
Their cardioprotective effect after AMI and the beneficial effect in the treatment of heart
failure, consolidated their position as first line drugs in HBP therapy.
Despite having the same mechanism of action, beta blockers are classified accroding
to the specific side effects, resulting from their cardioselectivity, the intrinsic
sympathomimetic activity or their liposolubility.
● Cardioselectivity is related to the blocking intensity of the beta 1 cardiac receptors, in
comparison to the beta 2 bronchial and vascular receptors.
● Intrinsic sympathomimetic activity (ISA) is the capacity of some beta blockers to
interact with beta receptors, producing a measurable agonist effect.
● Liposolubility differentiates them. Atenolol and Nadolol have a low liposolubility and
do not cross the blood-brain-barrier, have reduced adverse effects, are slowly
 metabolized and have a prolonged pharmacodynamic activity. Propranolol,
Metoprolol and others have a high liposolubility.
Classification
● Non-selective agents (block the β1 and β2 receptors)
▪ Without ISA
PROPRANOLOL (liposoluble)
SOTALOL (hydrosoluble, potassium channel blocker)
TIMOLOL
▪ With ISA
OXPRENOLOL (liposoluble)
PINDOLOL
CARTEOLOL
● Selective agents (block the β1 receptors)
▪ Without ISA
ESMOLOL
ATENOLOL (hydrosoluble)
METOPROLOL
BISOPROLOL
BETAXOLOL (liposoluble)
NEBIVOLOL (liposoluble)
▪ With ISA
ACEBUTOLOL
CELIPROLOL
● Beta blockers with alpha blocking action
LABETOLOL
CARVEDILOL (liposoluble, with α1 blocking action)
Mechanism of action
● They block the β-adrenoceptors, decreasing the heart rate, contractility (decreased
myocardial oxygen demand), systolic blood pressure, the renin, angiotensin II and
aldosteron production.
● Carvedilol is a nonselective beta blocker with α1 blocking action, useful in the
treatment of HBP and heart failure.
● Labetolol reduces the blood pressure because of the nonselective beta blocking effect,
selective alpha blocking action and ISA, with peripheral vasodilation and a low
decrease in the cardiac output, administered in mild/medium HBP and hypertensive
emergencies.
● They decrease the nocturnal melatonin release, causing sometimes sleep disturbances.
● The mechanism of the favourable and paradoxal effect in patients with heart failure is
unknown.
Pharmacodynamic action
● Upon the heart they have a negative inotropic, chronotropic, dromotropic and
bathmotropic effect. The actions of beta blockers are:
▪ Antiarrhythmic, because they decrease the automatism, slow down the
conduction, increase the refractory period duration in the sinus and
atrioventricular node (the heart frequency is not influenced in resting
condition, but only in effort or sympathetic stimulation).
▪ Antianginal and coronarodilating effect, because they block the
stimulating sympathetic actions upon the heart, producing bradycardia,
lower contraction force, with a decreased cardiac output and oxygen
 consumption. Bradycardia and the prolonged diastolic period eases the
blood redistribution to the subendocardic ischemic areas.
▪ Antihypertensive, because they decrease the cardiac output through:
o Blocking the β1 cardiac receptors (inhibiting the
heartstimulating beta adrenergic influences), with bradycardia
and reduced inotropism.
o Blocking the central adrenergic β formation, reducing the
peripheral sympathetic tonus.
o Decreasing the renin secretion (because of blocking the β
receptors in the juxtaglomerular zone) and plasmatic renin
activity.
o Blocking of the presynaptic receptors and the release of
norepinephrine in the synaptic cleft.
● They decrease intraocular pressure by lowering aqueous umor secretion. Only Timolol
and Betaxolol have this antiglaucoma effect (administered as eye drops).
● The antianxiety effect, with reduced tremor and vegetative symptoms of emotions, is
observed in case of liposoluble beta blockers (Propranolol), which can reach the brain.
They are useful in anxiety. For example Propranolol is found in the drug Distonocalm,
together with other antianxiety substances.
Indications
● HBP
● Arrhythmias (Esmolol, Sotalol): supraventricular tachyarrhythmias,
sympathoaderenergic arrhythmias (hyperthyroidism), atrial flutter and fibrillation,
ventricular arrhythmias (after AMI, coronary disease).
● Angina, post AMI (Atenolol, Metoprolol, Propranolol).
● Heart failure (Bisoprolol, Carvedilol, Metoprolol, Nebivolol), starting with small
doses, increasing slowly (not to decompensate the patient with the negative inotropic
effect )
● Glaucoma (Betaxolol, Timolol) as eye drops.
● Anxiety (Propranolol).
● Migraine prophylaxis (Timolol, Propranolol).
Adverse effects
● Contraction of the bronchiolar smooth muscles (bronchospasm, dyspnea) worsening
bronchial asthma (nonselective beta blockers).
● Decreased myocardial contractility (negative inotropic effect).
● Decreased heart rate (bradycardia).
● Atrioventricular conduction disturbances (heart block).
● Peripheral ischemia, with cold extremities, up to Raynaud syndrome.
● Decreased glucose tolerance and masking the hypoglycemia symptoms in diabetic
patients.
● Rebound phenomena at sudden cease of treatment.
● Sexual dysfunction.
● Fatigue, insomnia, dizziness, strange dreams.
Contraindications
Absolute
● Heart block.
● Severe bradycardia.
● Severe bronchial asthma.
● Severe depression.
● Severe peripheral vasospastic diseases (necrosis, gangrene).
Relative
● COPD.
● Raynaud syndrome.
● HBP in pregnancy.
● Vasospastic angina.
● Diabetes mellitus.

ALPHA BLOCKERS

Classification
● Non-selective agents (á1 and á2):
PHENTOLAMINE
PHENOXYBENZAMINE
TOLAZOLINE
● Selective agents (á1):
PRAZOSIN
DOXAZOSIN
TERAZOSIN
Mechanism of action
● They cause inhibition of α1 adrenoceptor mediated vasoconstriction, thus reducing
peripheral resistance and venous pressure.
● They also lower plasma LDL cholesterol, VLDL and triglyceride levels and increase
HDL cholesterol levels.
Indications
● HBP episodes in pheochromocytoma (Phenoxybenzamine, Phentolamine IV).
● Rarely in HBP, because of the reflex tachycardia.
● Prostate hyperplasia (reduced bladder and prostate resistance).
● Coronary artery disease.
● Hyperlipemia.
Adverse effects
● Postural hypotension.
● Dizziness, headache, fatigue.
● Palpitations.
● Hydrosaline retention (a diuretic is needed).
● Nausea.

SYMPATHETIC INHIBITORS WITH CENTRAL ACTION

Mechanism of action
● They are α2-adrenoceptor agonists, causing activation of presynaptic α2-adrenoceptors
(inhibition of noradrenaline release and vasodilation which is dominating) and
postsynaptic α2-adrenoceptors (vasoconstriction).
● They reduce the activity of the vasomotor centre in the brain, causing reduced
sympathetic activity, vasodilation, reduced heart rate and cardiac output.
Indications
▪ HBP, when first-line antihypertensive drugs are ineffective or contraindicated. They
are second- or third-line drugs in the treatment of HBP, administered orally. Clonidine
can be given by IV infusion.
▪ Methyldopa is safe for HBP in pregnancy, asthmatic patients and those with heart or
renal failure (it does not modify renal blood flow).
Adverse effects
▪ Orthostatic hypotension.
▪ Dry mouth.
▪ Decreased psychomotor performances.
▪ Male sexual dysfunction.
▪ Galactorrhea.
▪ Raynaud syndrome.
▪ Diffuse parenchymal liver injury, fever, hemolytic anemia (Methyldopa).
▪ Withdrawal HBP crisis on stopping treatment (Clonidine).
Contraindications
● Depression.
● Liver disease.
● Alcohol consumption.
● Pheochromocytoma.

SYMPATHETIC INHIBITORS WITH PERIPHERAL ACTION

Mechanism of action
● Guanadrel inhibits the function of peripheral postganglionic adrenergic neurons. It is a
false neurotransmitter, inactive at adrenergic receptors.
● Reserpine acts by blocking uptake of biogenic amines into synaptic vesicles, leading
to depletion of these neurotransmitters and vasodilation.
Indications
● Mild-moderate HBP.
Adverse effects
● Sedation.
● Depression, parkinsonism (Reserpine).

SYMPATHETIC INHIBITORS WITH MIXED ACTION

♦ Urapidil
Mechanism of action
● Urapidil acts by blocking the postsynaptic á1 receptors, reducing the peripheral
vascular resistance and blood pressure.
● It stimulates the serotoninergic (5-HT1A) receptors centrally, inhibiting the reactive
increase of the sympathetic tone.
Indications
● HBP, in association with other antihypertensives (orally).
● HBP emergency (IV), if nitrates and Nifedipine are not effective.
Contraindications
● Pregnancy and lactation period.

CALCIUM CHANNEL BLOCKERS

Calcium channel blockers were introduced into therapeutics in 1960 as antianginal and
antiaarrhythmic drugs. Their antihypertensive action has been prooved because of their
capacity of reducing the vascular tone, producing vasodilation and a lower peripheral vascular
resistance.
The benefits of using the calcium channel blockers in the treatment of HBP are: they
decrease the blood pressure values because of reduced peripheral vascular resistance, control
the blood pressure for 24 hours, with a neutral effect upon the metabolic risk factors, a good
tolerance, a protective effect upon the “target” organs and an antiatherogenic action.
Classification
● Dihydropyridines
NIFEDIPINE NIMODIPINE
AMLODIPINE NISOLDIPINE
FELODIPINE NITRENDIPINE
LERCANIDIPINE
● Non-Dihydropyridines
o Benzothiazepines
DILTIAZEM
o Phenylalkylamines
VERAPAMIL
GALLOPAMIL
Mechanism of action
● The inhibition of L-type calcium channels in the smooth muscle produces a decrease
in the intracellular calcium concentration. Dihydropyridines act by blocking the
calcium channels in the vascular cells, non-dihydropyridines in the myocardial cells
and nodal tissue, each with significant effects upon their action site.
Pharmacodynamic action
● Vasodilation with a decrease in the peripheral vascular resistance and blood pressure
(especially for the dihydropyridines).
● Negativ inotropic effect (especially for Verapamil and Diltiazem), slowing down of
the heart rate and atrioventricular conduction, coronarodilation on coronary arteries
and collateral circulation (especially for the dihydropyridines).
● Other effects (dihydropyridines) are the prevention of a cerebral artery spasm after a
stroke and the increasing in renal blood flow (preferred in HBP with chronic renal
failure).
From the pharmacological point of view, calcium channel blockers have:
● An antianginal action, because they reduce the oxygen consumption and improve the
collateral circulation, by: decreasing the heart rate, the myocardial contractility, the
afterload and increasing the coronary blood flow (especially in the big coronaries).
● An antihypertensive action, because of arterial vasodilation (not venous) with an
increase of the big arteries compliance and decrease of peripheral vascular resistance.
The renal blood flow is improved with an increased diuresis. They produce an
inhibitory effect upon the heart, lowering the cardiac output.
● An antiarrhythmic effect (only Verapamil and Diltiazem), because they inhibit the
calcium influx in the myocardial cells with a slow action potential (sinoatrial and
atrioventricular node) and depress the myocardial contractility function. They decrease
the atrioventricular conduction velocity and the sinusal frequency. Nifedipine
increases the heart rate, but the other dihydropyridines have no significant influence
upon it.
● An antiatherogenic action, by inhibiting the atheroma plaque formation, the
accumulation of calcium and lipids in the arterial wall.
Indications
● Ischemic cardiopathy, especially in unstable angina. In effort induced angina, they are
associated with beta blockers.
● In mild HBP as monotherapy, especially dihydropyridines, but in severe HBP in
association with other antihypertensives.
 ● Verapamil and Diltiazem are administered in supraventricular tachyarrhythmias
(paroxysmal supraventricular tachycardia, atrial flutter or fibrillation).
● Raynaud syndrome (dihydropyridines).
● Cerebral vascular spasms after subarachnoidian bleeding (Nimodipine).
Adverse effects
● Bradycardia (Verapamil, Diltiazem).
● Heart block (Verapamil, Diltiazem).
● Hypotension, reflex tachycardia (Nifedipine).
● Peripheral edema, in 10% of the cases, because of vasodilation, which are not treated
with diuretics.
● Headache (up to 10% of the cases), dizziness, fatigue.
● Flushing.
● Constipation (Verapamil).
Contraindications
● Heart failure NYHA III and IV class.
● Heart block of II or III degree (Verapamil, Diltiazem).
● Sick sinus syndrome (Verapamil, Diltiazem).
● Aortic stenosis, obstructive hypertrophic cardiomyopathy (dihydropiridines).
● Systolic blood pressure under 90 mmHg, shock.
● Unstable angina, AMI, in the first 4 weeks.
● Pregnancy, lactation period.
Drug interactions
● The association between dihydropyridines and nitrates increase the hypotension and
reflex tachycardia risk.
● Verapamil/Diltiazem should not be associated with beta blockers.
● In case of Digoxin or Theophylline association, their plasmatic concentration is
increased.
● NSAIDs reduce the efficiency of calcium channel blockers in decreasing the blood
pressure.

DIRECT VASODILATORS

Direct vasodilators are antihypertensive drugs, which act directly upon the resistance
vessels, relaxing the arteriolar smooth muscle, with a significant decrease in the peripheral
vascular resistance and blood pressure.
Classification
● Oral vasodilators
HYDRALAZINE
MINOXIDIL
● Injectable vasodilators
DIAZOXID
SODIUM NITROPRUSSIDE
Mechanism of action
The peripheral vasodilation activates the baroreceptors in the reflexogenic areas,
leading to compensatory reflex phenomenon (tachycardia, increase of cardiac output) and
increase in renal artery pressure (with secondary hydrosaline retention). This limits the
hypotensive effect in monotherapy, with a compulsory association of diuretics and beta
blockers to direct vasodilators.

ORAL VASODILATORS
 ♦ HYDRALAZINE

Hydralazine is the oldest vasodilator and still in use.

Pharmacokinetics
● It suffers the first hepatic passage in a high degree.
Mechanism of action
● Hydralazine interferes with the action of inositol triphosphate in vascular smooth
muscle, reducing the peripheral resistance.
Pharmacodynamics
● It produces a stronger vasodilation in the coronarian, cerebral, splanchnic and renal
area, compared to the muscular and cutaneous region. Hydralazine produces a rather
low reducing of blood pressure in the long term treatment of HBP, because of the
compensatory mechanisms.
Indications
● Moderate and severe HBP, in triple therapy, orally, together with a diuretic and a beta
blocker.
● HBP emergencies, IV.
Contraindications
▪ Systemic lupus erythematosus;
▪ Tachycardia.
Adverse effects
● Common for the class: tachycardia, angina pectoris, sodium and fluid retention,
headache, facial erythema, nasal congestion.
● Specific for Hydralazine: polyneuritis (through pyridoxine deficiency), lupus
phenomenon, anemia, leucopenia.

♦ MINOXIDIL

Pharmacokinetics
● It has a more intense and prolonged action (24-72 hours), compared to Hydralazine.
Mechanism of action. Pharmacodynamics.
● Minoxidil activates vascular smooth muscle ATP-sensitive potassium channels,
resulting in hyperpolarization of the cell membrane, causing reduced calcium entry
through L-type channels and inhibition of smooth muscle contraction (vasodilation).
● It is the strongest vasodilator, but it needs the association with diuretics.
Indications
● Severe HBP (orally), resistant to other antihypertensive drugs. Because of its adverse
effects, it is the drug of last choice in the long-term treatment of HBP.
● Baldness (topical cream).
Adverse effects
● Common for the class (see Hydralazine).
● Specific for Minoxidil: reversible hirsutism (hypertrichosis) in 80% of the cases, in 3-
6 weeks after the beginning of the treatment.
Contraindications
● Pheochromocytoma.
● Porphyria.

INJECTABLE VASODILATORS
 They are administered IV in hypertensive emergencies (Hypertensive crisis,
hypertensive encephalopathy).
♦ DIAZOXID

Diazoxid is a structural derivative of Chlorothiazide.

Pharmacokinetics
● The hypotensive effect appears after 5-20 minutes and lasts for 4-24 hours.
Mechanism of action. Pharmacodynamics.
● It acts similar to Minoxidil, activating the potassium channels, causing vasodilation
(stronger arteriolar).
● Diazoxid has also a hyperglycemiant effect, through the inhibition of insulin secretion
(contraindicated in diabetes).
Indications
● In the past in HBP emergencies (IV) as second line drug.
● Symptomatic treatment of hypoglycemia in insular tumors.
Contraindications
● Diabetes mellitus.

♦ SODIUM NITROPRUSSIDE

Pharmacokinetics
● After IV infusion, the effect appears immediately, is brutal, and requires constant
monitoring.
Mechanism of action. Pharmacodynamics.
● It decomposes into “NO” inside smooth muscle cells, that activates guanylyl cyclase,
increasing intracellular cGMP levels and causing vasodilation (arterial and venous).
Indications
● HBP crises or controlled hypotension in surgery or heart failure, but in many countries
it has been withdrawn from the market.
Adverse effects
● Severe hypotension.
● Headache, dizziness.
Contraindications
● Severe hepatic impairment.
● Megaloblastic anemia.
● Nausea, abdominal pain.
● Palpitations.
 POSITIVE INOTROPIC DRUGS

Positive inotropic drugs are substances that increase the contraction force of the
myocardium, useful in the treatment of acute and chronic heart failure.
Heart failure means a systolic ventricular dysfunction because of a pressure/volume
overload or a direct negative effect upon the myocardial fibers. The consequence is a dilation
and compensatory hypertrophy of the ventricle, to maintain a systolic pressure. The final
effects will be a decreased cardiac output and venous stasis, with symptoms of fatigue,
dyspnea, signs of pulmonary (stasis crackles) and systemic (hepatomegaly, jugular vein
distension, edema) congestion.
Secondary, some neuroendocrine compensatory mechanisms of feedback will be
activated: the adrenergic and RAAS, with vasoconstriction, sodium and water retention and
heart stimulation.
The four main elements in heart failure: contraction deficiency, tachycardia, increased
pre- and afterload, are influenced by:
● Inotropic positive drugs, increase the contraction force.
● Diuretics, eliminate the sodium and water excess and reduce the preload.
● Vasodilators decrease the pre- and afterload, making it easier for the heart.
Classification
1. Digitalis (cardiac glycosides)
DIGOXIN
DIGITOXIN
STROPHANTIN
2. Phosphodiesterase inhibitors
THEOPHYLLINE MILRINONE
AMINOPHYLLINE ENOXIMONE
AMRINONE
3. Sympathomimetics (adrenergic and dopaminergic drugs)
ADRENALINE ISOPRENALINE
DOPAMINE PRENALTEROL
DOBUTAMINE PIRBUTEROL
Mechanism of action

Fig. – Positive inottropic drugs - mechanism of action

 CARDIAC GLYCOSIDES

They are used for over 200 years, as extracts of vegetal origin. Digoxin is extracted
from Digitalis lanata leaves, Digitoxin from Digitalis purpurea leaves and Strophantin from
Strophantus gratus seeds. There are also some semisynthetic derivatives, like Beta-methyl
digoxin.
Cardiac glycosides possess an aglycone steroid nucleus, responsible for the
pharmacological activity, an unsaturated lactone ring, responsible for the cardiotonic activity
and a sugar residue component, responsible for the pharmacokinetic behaviour (see figure).

Fig. - Structure of the cardiac glycosides

Pharmacokinetics
The pharmacokinetic features of any drug are influenced by its hydro- or
liposolubility. Digitoxin is very liposoluble, Digoxin has a medium liposolubility and
Strophantin is hydrosoluble. Digoxin is preferred because it has a good digestive absorption, a
short T1/2 and a lower overdosage risk (see table). Digitoxin is administered in patients with
heart failure and chronic renal failure, because it is mostly metabolised through the liver. It
needs special precautions in pregnant women, because it crosses the placenta. Strophantin has
limited usage, in emergencies.

Table - Pharmacokinetic parameters of the cardiac glycosides

Cardiac glycoside Absorption (%) Binding on T½ Elimination
(oral administration) plasma proteins (%) (hours)
DIGITOXIN >90 >90 168 90%
hepatic
metabolised
DIGOXIN 55-75 25 38-40 80% renal
STROPHANTIN 1-3 0.5 21 100% renal

Factors that may influence cardiac glycosides pharmacokinetics are:

● The age of the patient. Because of the decreased muscle mass in elderly, digitalis form
a stronger bond in the myocardium, with an increased risk of myocardial toxicity. As a
consequence, the dose will be reduced by half in patients over 65 years.
 ● Renal insufficiency. The effect will be of an increase in the Digoxin’s T1/2 and
digoxinemia. The Digoxin dose will be decreased according to the renal clearance or it
will be replaced by Digitoxin.
● Hepatic insufficiency. Because of the decreased Digitoxin metabolisation, the dose
will be reduced by half or replaced by Digoxin.
● Hypokalemia (a result of diuretic treatment) increases the myocardial binding of
digitalis, with a higher cardiac toxicity. It will be corrected by oral or IV potassium
chloride administration.
● Hypomagnesemia, frequently associated with hypokalemia, worsens the arrhythmias
in digitalis intoxication.
● Hyperthyroidism causes resistance to digitalis treatment, with the necessity of
increasing the digitalis dose.
● Hypothyroidism decreases the tolerance to digitalis, with the necessity of decreasing
the digitalis dose.
● Alcalosis is more arrhythmogenic in the presence of digitalis.
Pharmacodynamics
● The cardiac effects are:
o Positive inotropic action, with an increase in the contraction force and velocity
of the normal and insufficient myocardium, especially upon the left ventricle.
This will decrease the ventricular ejection duration and increase the ventricular
ejection volume, diastolic filling time and telediastolic volume. As a
consequence, the heart is emptied better and more efficient. The positive
inotropic effect is more significant upon the insuffficient heart, compared to
the normal myocardium. The efficacy of the positive inotropic action is
proportional to the administered dose and digitalis serum levels. The prolonged
administration of digitalis does not cause tolerance. The positiv inotropic
action is the main pharmacodynamic effect of digitalis. Because of the
increased contraction force and the duration of diastolic filling time, the
cardiac output and heart pumping efficacy are significantly increased.
o Negative chronotropic action, with a decrease in the heart rate, because of the
reduced sinus node discharge. It is a result of the direct vagal centre
stimulation (vagal hyertonia) and baroreceptors, in the carotid sinus and aortic
arch, activation. These are not stimulated in heart failure because the cardiac
output and the arterial pressure are lower, compared to normal. The
baroreceptors stimulation will result in a depressing effect, with vasodilation
and bradycardia.
o Negative dromotropic action, slowing down the atrio-ventricular conductance.
This is done because of an increased refractory period at the atrio-ventricular
node and the bundle of His, with an antiarrhythmic effect in rapid atrial
fibrillation rhythm, by blocking the atrial impulses.
o Negative batmotropic action is proarrhythmic. After therapeutic doses or upon
a normal myocardium, this effect is inessential, but in case of an excessive
dose, or on an unhealthy myocardium, digitalis might have a proarrhythmic
effect, by increasing the effective refractory period, increasing the atrio-
ventricular excitability. That is why, in patients under chronic digitalis
treatment, arrhythmias may occur.
The EKG effects of digitalis glycosides are: a decrease in the heart rate, prolonged PR
(may be a sign of toxicity), shortening of QT interval, ST segment depression with upward
concavity and decreased amplitude or T wave inversion.
 ● The extracardiac effects are:
o Upon kidneys: increased diuresis due to improved renal blood flow and
increased glomerular filtration.
o Upon vessels, through a direct effect on α-adrenoceptors: arteriolar
vasoconstriction, with increased peripheral resistance, and increased venous
tone, increasing the preload. This digitalis effects appear only after higher
doses than the usual used for the positive inotropic effect.
o Upon CNS: vagal tone activation after therapeutic doses.
Mechanism of action
● Cardiac glycosides act by inhibiting the membrane sodium/potassium-ATPase pump
(see figure above). This increases intracellular sodium concentration, thus reducing the
sodium gradient across the membrane and decreasing the amount of calcium pumped
out of the cell by the sodium/calcium exchanger during diastole. Consequently, the
intracellular calcium concentration rises, thus increasing the force of cardiac
contraction and maintaining normal blood pressure.
Indications
● Supraventricular arrhythmias: atrial fibrillation and atrial flutter with rapid ventricular
response.
● Congestive heart failure (not the first choice drug).
The treatment with cardiac glycosides is called digitalization which may be slow or
rapid with the objective of attaining a steady state of plasma concentration of drug in cardiac
patient. It depends on the degree of emergency, the presence of renal or hepatic failure, the
serum creatinine or creatinine clearance, the previous digitalization, the product’s
pharmacokinetic and the route of administration.
The treatment starts with a loading dose: the first dose is 1/3 of the loading dose and
the rest can be administered in:
▪ 24 hours - rapid digitalization
▪ 2-3 days - medium digitalization
▪ 6-7 days - slow digitalization
The signs of the loading dose efficiency are: a decrease heart rate, the reduction of
edema and hepatomegaly, the disappearance of jugular turgescence, the improvement of
dyspnea and an increased diuresis.
The treatment continues with a maintenance dose (0.25 mg/day; 0.125 mg/day in
elderly), the dose that is given to maintain the concentration of drug in blood.
Adverse effects
● Digitalis intoxication, can occur in 2-20% of the patients, because of the low
therapeutic index, of 2-3.
o Predisposing factors: high doses, old age, renal insufficiency, hypokalemia,
hypomagnesemia, active cardiac ischemia, myocarditis, cardiomyopathy and
cardiac amyloidosis;
o Diagnosis: bradycardia, A-V block, bigeminal extrasystoles, delirium,
nightmares, fatigue, disturbance of colour vision (xanthopsia), anorexia,
nausea, vomiting, abdominal pain;
o Treatment:
▪ Stop the administration of cardiac glycosides;
 ▪ Activated charcoal (adsorbs digitalis) or Cholestiramine;
▪ Furosemide;
▪ Correct hypokalemia and hypomagnesemia;
▪ Treat bradyarrhythmias (Atropine), supra-ventricular tachycardias
(β-blockers or Verapamil) and ventricular arrhythmias (Lidocaine,
Phenytoin, cardioversion);
▪ Digibind (specific Digoxin antibody Fab fragments).
Contraindications
● Bradycardia, heart block.
● Hypokalemia associated with the use of diuretics.
● Severe ventricular arrhythmias: ventricular tachycardia or extrasystoles.
● Heart failure due to diastolic dysfunction.
Drug interactions
● Increase Digoxin absorption: antacids, Kaolin/Pectin.
● Increase Digoxin toxicity: diuretics, Amphotericin B, corticosteroids.
● Increase Digoxin levels: Verapamil, Diltiazem, Quinidine, Amiodarone.
● Increase bradycardia: β-blockers, antiarrhythmics.
● Increase the risk of arrhythmias: sympathomimetics.

PHOSPHODIESTERASE INHIBITORS

Mechanism of action
● By inhibiting the phosphodiesterase they raise the concentration of cAMP, resulting in
positive inotropic effects and modest diuretic effects. Cardiac output is increased, and
pulmonary wedge pressure and total peripheral resistance are reduced, without much
change in heart rate or blood pressure.
Indications
● Acute heart failure, resistant to other drugs, administered IV.
Adverse effects
● Nausea, vomiting, abdominal pain;
● Arrhythmias;
● Liver dysfunction;
● Hypersensitivity.

BETA-ADRENOCEPTOR AGONISTS

Indications
● In the short-term use of acutely decompensated heart failure, administered IV.
 ANTIARRHYTHMIC DRUGS

Classification (Vaughan Williams)

▪ I. Sodium channel blockers
o I. A prolong repolarization :
QUINIDINE
PROCAINAMIDE
DISOPYRAMIDE
o I. B shorten repolarization:
LIDOCAINE MEXILETINE
TOCAINIDE PHENYTOIN
o I.C little effect on repolarization:
FLECAINIDE
PROPAFENONE
MORICIZINE
▪ II. Beta blockers
PROPRANOLOL METOPROLOL
ESMOLOL ATENOLOL
▪ III. Potassium channel blockers
AMIODARONE BRETYLIUM
SOTALOL (also β- IBUTILIDE
blocker) DOFETILIDE
▪ IV. Calcium channel blockers
VERAPAMIL
DILTIAZEM
▪ V. Antiarrhythmics that work by other or unknown mechanism
ADENOSINE
DIGOXIN

Mechanism of action
 CLASS I A ANTIARRHYTHMICS

Mechanism of action
▪ they block the voltagedependent sodium channels in their open or refractory state.
Their effects are to slow phase 0 (increasing the effective refractory period) and phase
4 (reducing automaticity), and to prolong action potential duration.
Indications
▪ ventricular arrhythmias;
▪ prevention of paroxysmal recurrent atrial fibrillation;
▪ Wolff-Parkinson-White syndrome (Procainamide).
Contraindications
▪ heart block;
▪ sinus node dysfunction;
▪ cardiogenic shock;
▪ severe uncompensated heart failure;
▪ systemic lupus erythematosus (Procainamide).
Adverse effects
▪ arrhythmias: A-V block, torsades de pointes;
▪ cinchonism: nausea, vomiting, diarrhea, tinnitus, headache, vertigo, auditory and
visual disturbances;
▪ hypersensitivity, thrombocytopenia, agranulocytosis;
▪ lupus-like syndrome (Procainamide): arthralgia, arthritis, pleuritis, pericarditis,
parenchymal pulmonary disease;
▪ hypotension (Disopyramide).

CLASS I B ANTIARRHYTHMICS

Mechanism of action
▪ they block the voltage-dependent sodium channels in their refractory state, decrease
action potential duration and increase the effective refractory period.
Indications
▪ treatment and prevention during and immediately after MI, though this practice is now
discouraged given the increased risk of asystole;
▪ ventricular tachycardia;
▪ epilepsy (Phenytoin).
Contraindications
▪ sinoatrial disorders;
▪ total A-V block;
▪ epilepsy or history of convulsions;
▪ porphyria.
Adverse effects
▪ hypotension;
▪ bradycardia;
▪ drowsiness, sedation, confusion, convulsions, paresthesia;
▪ dizziness, respiratory depression, severe hepatic failure (Lidocaine);
▪ nausea, vomiting, constipation, arrhythmias, bone marrow suppression, hepatitis
(Mexiletine);
▪ nausea, vomiting, peripheral neuropathy (Phenytoin).

CLASS I C ANTIARRHYTHMICS
Mechanism of action
▪ they are the most potent sodium channel blockers with little effect on repolarization.
Indications
▪ prevents paroxysmal atrial fibrillation;
▪ ventricular tachyarrhythmias.
Contraindications
▪ heart failure;
▪ history of MI.
Adverse effects
▪ anorexia, nausea, vomiting, constipation;
▪ dizziness;
▪ visual disturbances;
▪ arrhythmias.

CLASS II ANTIARRHYTHMICS
(BETA BLOCKERS)

Indications
▪ decrease MI mortality;
▪ prevent recurrence of tachyarrhythmias.

CLASS III ANTIARRHYTHMICS

(POTASSIUM CHANNEL BLOCKERS)

Mechanism of action
▪ they are potassium-channel blockers that prolong cardiac action potential duration and
the effective refractory period;
▪ Amiodarone also blocks sodium and calcium channels;
▪ Sotalol is a β-blocker with class III activity.
Pharmacokinetics
▪ For Sotalol: rapid and complete absorbed after oral administration, the t1/2 is 12 hours;
▪ For Amiodarone: the t1/2 is 20-100 days, which means slow onset of activity, slow
stabilization of blood levels and long Cl of the drug from blood if toxicity occurs.
Interactions
▪ Amiodarone increases the level of Digoxin and the effects of Warfarin or
Procainamide.
Indications
▪ supraventricular arrhythmias: atrial fibrillation and flutter;
▪ ventricular tachycardias.
Contraindications
▪ pheochromocytoma (Bretylium);
▪ A-V block, sinus bradycardia or thyroid dysfunction (Amiodarone);
▪ contraindications of β-blockers.
Adverse effects
▪ arrhythmias (torsades de pointes);
▪ hypotension, nausea and vomiting (Bretylium);
▪ thyroid dysfunction, liver damage, pulmonary disorders, photosensitivity and
neuropathy (Amiodarone);
 ▪ reduced ventricular function, bradycardia, bronchoconstriction, peripheral vascular
insufficiency, hypoglycemia and withdrawal symptoms (Sotalol).
Therapeutic notes
▪ Bretylium is administered IV while Amiodarone and Sotalol are administered orally or
IV.

CLASS IV ANTIARRHYTHMICS
(CALCIUM CHANNEL BLOCKERS)

Mechanism of action
▪ they are calcium antagonists that shorten phase 2 of the action potential, thus
decreasing action potential duration;
▪ they are particularly effective in nodal cells, where calcium spikes initiate conduction.
Indications
▪ prevent recurrence of paroxysmal supraventricular tachycardia;
▪ reduce ventricular rate in patients with atrial fibrillation or flutter.
Contraindications
▪ heart block;
▪ heart failure;
▪ WPW syndrome.

OTHER ANTIARRHYTHMICS

❖ ADENOSINE

Mechanism of action
▪ Adenosine causes myocyte hyperpolarization and delay in conduction.
Pharmacokinetics
▪ Biotransformation and elimination: it has an extremely rapid metabolism: the t1/2 is 10
seconds.
Indications
▪ supraventricular arrhythmias.
Contraindications
▪ heart block;
▪ sick sinus syndrome.
Adverse effects (lasting less than 30 seconds)
▪ facial flushing;
▪ chest pain;
▪ dyspnea.
Therapeutic notes
▪ it is administered IV.
 ANTIANGINAL DRUGS

ORGANIC NITRATES

Classification
▪ Short acting nitrates
GLYCERYL TRINITRATE (GTN) – NITROGLYCERINE (sublingual administration)
ISOSORBIDE DINITRATE (ISDN) (sublingual administration)
▪ Long acting nitrates
GLYCERYL TRINITRATE (GTN) – NITROGLYCERINE (local administration)
ISOSORBIDE DINITRATE (ISDN) (oral administration)
ISOSORBIDE MONONITRATE (ISMN) (oral administration)
PENTAERYTHRITYL TETRANITRATE (oral administration)
Mechanism of action
▪ most nitrates are prodrugs, denitrated to produce nitric oxide (“NO”), which activates
guanylyl cyclase, thereby increasing the concentrations of cyclic guanosine 3’,5’-
monophosphate (cGMP), dephosphorilation of the light chain of myosin which results
in smooth muscle relaxation and vasodilation;
▪ venodilation decreases preload and thus the oxygen demand of the heart, while
dilation of the coronary arteries increases blood flow and oxygen delivery to the
myocardium.
Pharmacokinetics
▪ Absorption: ISDN is completely absorbed after oral administration, but only 20%
enters into the systemic circulation as intact drug, the rest being converted to ISMN;
▪ Biotransformation: Hepatic first pass metabolism is high and oral bioavailability is
very low for GTN and ISDN. The t1/2 is 3 minutes for GTN, 10 minutes for ISDN and
280 minutes for ISMN.
Indications
▪ prophylaxis and treatment of angina;
▪ left ventricular failure.
Contraindications
▪ hypersensitivity to nitrates;
▪ hypotension;
▪ hypovolemia.
Adverse effects
▪ postural hypotension;
▪ tachycardia (reflex mediated);
▪ headache (dilation of menningeal arterial vessels), flushing and dizziness;
▪ drug rash (after pentaerythrityl tetranitrate).
Therapeutic notes
▪ the sublingual route of administration is rapid (onset of action 1-3 minutes) and
effective in acute attacks of angina;
▪ the oral (modified release) and transdermal routes of administration are used to
provide prolonged prophylaxis against angina attacks (3-10 hours);
▪ GTN can be given by IV infusion in emergencies, because of the rapid onset of action;
▪ to avoid nitrate tolerance, a drug-free period of approximately 8 hours is needed.

BETA BLOCKERS
(see antihypertensive drugs)
 CALCIUM CHANNEL BLOCKERS

Mechanism of action
▪ they block L-type calcium channels in the heart and in the vascular smooth muscle,
thereby reducing calcium entry into cardiac and vascular cells, reducing cardiac
contractility and causing vasodilation, which results in: reduced preload and afterload,
increased coronary blood flow, reduced cardiac contractility (reduced myocardial
oxygen consumption) and a decreased heart rate;
▪ dihydropyridines blocks L-type calcium channels in vascular cells;
▪ they do not affect cardiac contractility or conduction.
Indications
▪ prophylaxis and treatment of angina;
▪ HBP.
Contraindications
▪ heart block (Verapamil, Diltiazem);
▪ heart failure (Verapamil, Diltiazem);
▪ WPW syndrome;
▪ cardiogenic shock;
▪ advanced aortic stenosis (dihydropiridines).
Adverse effects
▪ hypotension;
▪ rash;
▪ bradycardia, heart block (Verapamil, Diltiazem);
▪ tachycardia (dihydropiridines)
▪ constipation (Verapamil, Diltiazem);
▪ peripheral edema (dihydropiridines);
▪ flushing, dizziness (dihydropiridines).
Therapeutic notes
▪ dihydropyridines are especially useful in angina associated with coronary vasospasm.

POTASSIUM CHANNEL ACTIVATORS

❖ NICORANDIL

Mechanism of action
▪ Nicorandil activates the potassium channels of the vascular smooth muscle and
potassium flows out of the cells, inhibiting the influx of calcium, and the contraction
(vasodilation).
Indications
▪ prophylaxis of angina.
Contraindications
▪ cardiogenic shock;
▪ left ventricular failure;
▪ hypotension.
Adverse effects
▪ headache;
▪ cutaneous vasodilation;
▪ nausea, vomiting.
 THE PHARMACOLOGY OF ANTITHROMBOTICS

Antithrombotic drugs are useful in thromboembolic diseases. They are indicated in the
prophylaxis and treatment of arterial and venous thrombosis, acute or chronic, depending on
the physiopathological mechanism of the thrombogenic process.
The thrombotic process occurs wherever one or more of the Virchow triad conditions
are present: endothelial lesion (predominant in the arterial system, with a white thrombus,
composed of platelet aggregates), blood stasis (predominant in the venous system, with a red
thrombus, composed of red blood cells and fibrin) and hypercoagulability, in some
hematological diseases.
Antithrombotic medication includes anticoagulants, fibrinolytics and antiplatelet
agents.

ANTICOAGULANTS

Anticoagulants are drugs which inhibit the blood coagulation, acting upon some
clotting factors.
The coagulation consists of multiple proteolytic reactions, in which an activated
zymogen transforms another zymogen in an active protease. The intrinsic pathway is
activated by the contact between blood and negative charged materials (glass, bacterial
lipopolysaccharides, endotoxins, endothelial structures, activated platelets). The faster,
extrinsic pathway is initiated by the interaction between the tissue factor and factor VII. In the
last coagulation phase, thrombin acts proteolytic, transforming fibrinogen into fibrin. The
fibrin net, containing red blood cells and platelets, form the thrombus. In the figure below, see
the coagulation cascade and the place where anticoagulant drugs act.
Classification according to the mechanism of action:
● Thrombin inhibitors
o Unfractionated heparin (UFH)
o Low molecular weight heparins (LMWHs)
▪ Certoparin ▪ Nadroparin
▪ Dalteparin ▪ Reviparin
▪ Enoxaparin ▪ Tinzaparin
o Heparinoids with saccharide structure
▪ Fondaparin
▪ Sulodexid
o Heparinoids, direct inhibitors of thrombin
▪ Hirudin ▪ Bivalirudin
▪ Lepirudin ▪ Dabigatran
o Direct inhibitors of Xa factor (the “xabans “)
▪ Apixaban
▪ Rivaroxaban
● Antivitamin K drugs (oral anticoagulants - OA)
▪ Acenocumarol
▪ Warfarin

UNFRACTIONATED HEPARIN (UFH)

Heparin is a heterogeneous preparation of sulfated mucopolysaccharide polymers,

extracted from porcine intestinal submucosa, purified as sodium or calcium salt, expressed in
international units (IU). 100 IU are equivalent to 1 mg of active substance. The molecular
weight is 5,000-30,000 Daltons (medium 15,000 Da).
Pharmacokinetics
● UFH can be administered only parenterally, because it is not absorbed through the GI
mucosa and is destroyed by the digestive enzymes after oral administration.
● It has a weak absorption after cutaneous administration.
● After UFH enters the circulation, heparin binds to plasma proteins, endothelial cells,
platelets and macrophages, resulting in a decreased bioavailability and an
unpredictable anticoagulant response after the administration of the same dose, to
different patients.
● It is metabolised through a rapid, saturable process, of intracellular depolimeryzation
and a slow, non-saturable one, at renal level.
● The latency is 20-60 minutes after subcutaneous administration and acts almost
immediate after IV.
● The T1/2 is dose-dependent, e.g.: one hour after the administration of 100 UI/kg IV, 2.5
hours after the administration of 400 UI/kg IV and 5 hours after the administration of
800 UI/kg.
● UFH does not cross the placenta, because of the high molecular weight and does not
enter the breast milk. It can be safely administered to pregnant women.
● It is renally eliminated.
Mechanism of action
● It has a complex, immediate and relatively short anticoagulant action, in vivo and in
vitro, because of acting directly upon some plasmatic coagulation factors (IIa, Xa,
XIIa, XIa and IXa). It needs the coupling to antithrombin III (the heparin cofactor), an
á2 plasmatic globulin. This coupling will result in conformational changes of
antithrombin III, accelerating the antithrombins’ III actions, with inhibition of
 thrombin and Xa factor (activated). In antithrombin III deficiency, the anticoagulant
effect of heparin will be lowered considerably.
● UFH has also an antiplatelet action, through the inhibition of the thrombocytes
adhesion and aggregation.
● Through lipoprotein lipase, an hydrolysing enzyme of triglycerides and very low
density lipoproteins, heparin has a lipolytic and plasma clarifying action.
● It also increases vascular permeability and inhibits the smooth muscle proliferation.
Indications
● High doses of UFH in: deep vein thrombosis (DVT), pulmonary embolism (PE), acute
coronary syndrome, prevention of coronary reocclusion after thrombolysis,
prophylaxis of thrombosis in hemofiltration, hemodialysis and extracorporeal
circulation.
● Low doses of UFH in: prophylaxis of postoperatory thrombosis or consumption
coagulopathy.
● In continuous IV administration, UFH will be administered as 5,000 IU initial IV
bolus for the immediate anticoagulant action, and then 800-1,500 IU/hour (medium
daily dose 32,000 IU) on automatic syringe. After thrombolysis the dose will be 1,000
IU/hour (24,000 IU/day).
● In SC administration, for a complete anticoagulant action, the initial dose is the same,
5,000 IU IV bolus for the immediate anticoagulant action, followed by a medium daily
dose of 35,000 IU/day, divided in two equal administrations, every 12 hours. The dose
is established according to indications and the results of the blood clotting test.
● The UFH therapy will be monitored by the activated partial thromboplastin time
(aPTT), with values that have to be maintained at:

aPTT = 1.5 – 2.5 x normal value (50-70 seconds)

If it exceeds 90 seconds, the bleeding risk is very high.

● The treatment should never be stopped abruptly, because of the hypercoagulability
risk, with thrombosis and embolism.
Adverse effects
● Bleeding. The risk increases proportionally with the dose and the prolongation of
clotting times. In low intensity bleeding, stopping the medication is enough, but if it is
severe, the antidote, Protamine sulphate should be administered. 1 ml of Protamine
sulphate antagonizes 1,000 IU of UFH.
● Thrombocytopenia, with or without thrombosis. The thrombocytopenia induced by
UFH is the most common drug induced thrombocytopenia. Frequent checking of the
platelet count is therefore necesasry
● Allergic reactions.
● Osteoporosis, only after higher doses than 15,000 IU/day, for over 6 months.
● Rarely, increased transaminases, a diffuse alopecia, tissue necrosis or
hyperaldosteronism, can be detected.
Contraindications
● Bleeding
● Renal or liver failure
● Thombocytopenia
● Diastolic HBP over 110 mmHg
● Endocarditis
● Diabetic retinopathy or any intraocular bleeding
● After a surgical intervention on the brain, bone marrow or eye
 ● Hemorrhagic stroke
● Surgery, severe trauma, birth, puncture, biopsy
● Gastrointestinal or urogenital bleeding
● Allergy
Drug interactions
● The association between UFH and antiplatelet agents (Aspirin), oral anticoagulants or
colloid solutions (Dextran) increases the bleeding risk.
● Nitroglycerine IV decreases the UFH effect.

LOW-MOLECULAR-WEIGHT HEPARINS (LMWHs)

♦ Certoparin, Dalteparin, Enoxaparin, Nadroparin, Reviparin, Tinzaparin

LMWH are obtained through the depolimerisation of UFH, with one third of its’
molecular weight. The dose is calculated according to the body weight, expressed in mg or
units antiXa.
Tha major advantage of LMWH over UFH is the predictibility of the anticoagulant
response. The treatment supervision with aPTT is no longer necessary (exceptions: in
children, pregnant women or renal failure) and adverse effects appear less frequent.
Pharmacokinetics
● The bioavailability after SC administration is good, over 90%.
● They have a longer T1/2 compared to UFH and constant, of 3-4 hours.
● LMWHs are renally eliminated.
Mechanism of action
● They inactivate mainly the Xa factor, with a low inhibitory effect upon thrombin (IIa).
In case of UFH, the inactivation ratio of Xa/IIa is 1/1, but for LMWH, it is 1/2 to 1/4.
Indications
● Prophylaxis of peri- and postoperatory thromboembolic accidents after general or
orthopedic surgical interventions.
● Treatment of DVT
● Pulmonary embolism
● Acute coronary syndrome
● In acute myocardial infarction (AMI), after fibrinolysis
● Long term treatment of thromflebitis, when oral anticoagulants are contraindicated
● They are administered SC, once or twice daily, according to the drug
● A LMWH can not be replaced with another LMWH, unless a clinical reexamination
and a dose adjustment are performed
● In case of overdose, Protamine sulphate is not as efficient compared to the overdose of
UFH
Adverse effects
● Bleeding
● Thrombocytopenia

HEPARINOIDS WITH SACCHARIDE STRUCTURE

♦ Fondaparin, Sulodexid

This heparinoids are synthetic analogues, sulphated saccharides, based on the structure
of the antithrombin binding region of Heparin. They do not modify the clotting times.
Pharmacokinetics
 ● They have a long T1/2.
Mechanism of action
● They bind to antithrombin III and have a selective, intense antiXa activity.
Indications
● Prophylaxis of DVT, especially after orthopedic intervensions on the lower limb
● Phlebothrombosis
● PE
● Acute coronary syndrome
● They are given as an once-daily SC injection
● In case of overdose, there is no antidote
Adverse effects
● Bleeding
● Thrombocytopenia
● Digestive intolerance
● Hypersensitivity reactions
Contraindications
● Bleeding
● Renal failure
● Acute bacterial endocarditis

HEPARINOIDS, DIRECT INHIBITORS OF THROMBIN

♦ Hirudin, Lepirudin, Bivalirudin, Dabigatran

Mechanism of action
● They directly and reversibly inactivate soluble or fibrin bound thrombin (without the
necessity of preliminary binding to ATIII). Usually, the clotting time measurement is
not required.
Indications
● Anticoagulant therapy in percutaneous coronay intervention (Bivalirudin)
● Anticoagulant therapy in heparin induced thrombocytopenia (Bivalirudin)
● Prophylaxis of DVT in patients undergoing hip and knee replacement
● Prophylaxis and treatment of venous thromboembolism
● Local treatment of hematomas (Hirudin)
Adverse effects
● Bleeding
● Thrombocytopenia
● Hypersensitivity reactions, up to anaphylactic shock (Lepirudin)
Contraindications
● Bleeding
● Clotting disorders
● Pregnancy and lactation period
● Renal failure with ClCreat. less than 30 ml/min
● Severe hepatic impairment

DIRECT INHIBITORS OF Xa FACTOR

♦ Apixaban, Rivaroxaban
Pharmacokinetics
● They are inactivated mainly in the liver, by the cytochrome CYP3A4.
● They are renally and biliary eliminated.
Mechanism of action
● They act directly and selective upon the Xa factor.
Indications
● Prophylaxis of venous thromboembolism after knee or hip arthoplasty
● DVT
● PE
● Atrial fibrillation
● Acute coronary syndrome with an increased level of biomarkers
● Usually are associated with an antiplatelet agent
● In case of overdose, there is no antidote
Adverse effects
● Bleeding
● Digestive intolerance
● Fever, fatigue
● Rare: thrombocytopenia, tachycardia
Contraindications
● Bleeding
● Liver failure
● GFR less than 15 ml/min
● Pregnancy and lactation period
Drug interactions
● They should not be associated with other anticoagulants

ORAL ANTICOAGULANTS (ANTIVITAMINS K)

♦ Acenocumarol, Warfarin

Antivitamins K are anticoagulants that are administered orally, usually in long-term

treatment.
Mechanism of action
● Prevent hepatic synthesis of coagulation factors II, VII, IX and X and endogenous
anticoagulants that depend on vitamin K to become active.
● Inhibit competitively the action of Vitamin K1 reductase (Vitamin K epoxide
reductase and Vitamin K chinone reductase), preventing the vitamin K epoxide cycle
and the sequential synthesis of coagulation precursors that lack Gamma-
carboxyglutaminic acid residues. Antivitamins K are not effective against complete
carboxilated coagulation factors.
● The in vivo anticoagulant action occurs after a 48-72 hour latency period, necessary
for the destruction of blood coagulation factors. The action is persistent for 7-10 days
after cessation of treatment.
Pharmacokinetics
● Fast intestinal absorption.
● 90% protein binding; a minor decrease, may lead to a significant increase in
anticoagulant action.
● They are metabolized in the liver with great individual variability. Metabolites are
eliminated through the kidney. They pass the placenta and slightly into the breast
milk.
Indications
● Prophylaxis and treatment of DVT
● AMI, thromboembolism prophylaxis in mitral rheumatism, atrial septal defect, cardiac
valvular prosthesis, dilatative cardiomyopathy, chronic atrial fibrillation and treatment
of primitive pulmonary hypertension.
● Treatment can be done alone (complete effect only after 5-7 days) or in combination
with Heparin. Heparin can be discontinued when INR is within therapeutic range for 2
consecutive days. It starts with an attack dose of 2 tablets/day, in a single dosing for 2-
3 days, then continue with a maintenance dose of 1 tablet daily based on the INR.

INR (International Nominalized Ratio) = 2 - 3

● The INR is initially controlled daily for 1 week, then 3 times a week for 2 weeks, then
monthly. The frequency of determinations should be increased whenever new drugs
are introduced that may influence the effectiveness of anticoagulation.
● The treatment should be never discontinued abruptly.
Adverse effects
● The risk of bleeding occurrence is proportional to the dose and prolongation of
bleeding time (Quick Time, INR). In the event of overdosing, the anticoagulant
administration should be stopped, and if the bleeding is severe, vitamin K and fresh or
concentrated plasma is to be administered.
● Hypersensitivity reactions.
● Cutaneous and subcutaneous necrosis due to a capillary hypercoagulability and
capillary thrombosis with subsequent bleeding in embolized tissues. These may occur
in the anterior thoracic region, thighs or buttocks after 3-5 days of treatment initiation.
High risk patients are those with hereditary protein deficiency C or S and
postmenopausal women with obesity.
● Reversible alopecia.
● Delay of callus formation.
 ● When given in the first trimester of pregnancy, oral anticoagulants can produce
teratogenic effects, with facial abnormalities, optic atrophy, digital abnormalities,
bone epiphysis calcifications and psychomotor retardation.
Contraindications
● Haemorrhage
● Uncontrolled HBP, diastolic blood pressure more than 110 mmHg
● Diabetic retinopathy
● Major trauma or surgery
● Pregnancy and lactation!
● Active ulcer
● Severe renal or hepatic impairment
Drug interactions
● Potentiatory interactions are the most dangerous due to the increased bleeding risk.
The mechanism relies on:
o An inhibition of the coumarin anticoagulants metabolism: Phenylbutazone,
Sulfinpyrazone, Metronidazole, Disulfiram, Biseptol, Cimetidin and
Amiodarone.
o Without influencing the plasma concentration, with potentiatory action: the
cephalosporins of the 2nd and 3rd generation, Clofibrate and Heparin.
o Through an antiplatelet effect act: Aspirin, NSAIDs, Ticlopidine and
betalactamins.
o In case of Erythromycin, anabolic steroids, Testosterone, Ketoconazole,
Fluconazole, Isoniazid, Piroxicam, Tamoxifene, Quinidine, Phenytoin,
Propafenone and Vitamin E, the potent mechanism is incompletely known.
o In patients with a poor vitamin K diet, sulfamides and broad-spectrum
antibiotics have a potentiatory effect by increasing the vitamin K deficiency.
● The inhibitory interactions cause anticoagulant efficacy to decrease and are achieved
through:
o Accelerating the anticoagulant metabolism: barbiturates, Rifampicin,
Carbamazepine, chronic alcoholism without hepatic failure.
o Prevention of intestinal absorption: Cholestyramine.
o Unknown mechanism. Nafcillin, Sucralfate.

FIBRINOLYTICS

Fibrinolytics are drugs that produce fast lysis of the clot in the blood vessel obstructed
by thrombosis. Administration of this drugs is only performed under strict medical
supervision in intensive care units or the ambulance, in exceptional cases that endanger the
life of the patient (fulminant pulmonary embolism).
Classification according to the mechanism of action:
● Indirect activators of plasminogen
o Streptokinase
● Direct activators of plasminogen
o Urokinase
● Tissue plasminogen activators
o Alteplase
o Reteplase
o Tenecteplase

Mechanism of action
 ● Fibrinolytics activate directly or indirectly plasma plasminogen with plasmin
formation (fibrinolysin) that cleaves fibrin into soluble polypeptides, dissolving recent
clots.
Contraindications
Absolute
● Any bleeding
● Suspicion of aortic dissection
● Cancer or cranial trauma
● History of haemorrhagic stroke
● Major trauma or surgical interventions in the past 3 weeks
● Digestive bleeding in recent months
● Haemorrhagic predisposition, liver biopsy, lumbar puncture
Relative
● Treatment with oral anticoagulant
● Pregnancy or first week postpartum
● Long resuscitation with the possibility of rib fractures
● HBP over 180/110mmHg
● Internal bleeding in the last 2-4 weeks
● Acute kidney or liver failure
● Bacterial endocarditis
● Active peptic ulcer
● Allergy to Streptokinase (pruritus to anaphylactic shock). Therefore it is not given
under one year or for a duration longer than 5 days, when it becomes
ineffective. The antibody production is detected by determining the ASL titer,
Side effects
● Bleeding:
o Superficial, at the injection site (perform manual compression)
o Internal: gastrointestinal, urogenital, retroperitoneal, intracranial (the 1% most
feared incidence)
● Treatment of severe bleeding consists of:
o Stopping the fibrinolytic administration
o Administration of erythrocyte concentrates or fresh plasma.
o In lifethreatening situations, antifibrinolytics (Tranexamic acid) are
administered.

INDIRECT ACTIVATORS OF PLASMINOGEN

♦ Streptokinase

Sreptokinase is a protein produced by group B β-hemolytic streptococci.

Mechanism of action
● It increases the fibrinolytic activity of plasma, indirectly activates plasminogen,
intervening in the transformation of pro-activators into plasminogen activators.
Indications
● Acute pulmonary embolism
● High thrombophlebitis of lower limbs (femoral and iliac)
● Anterior AMI with ST elevation in at least two derivations. Associated administration
of Aspirin showed a prognosis improvement in this category of patients.
● Embolism and peripheral arterial thrombosis.
 ● Treatment is done as early as possible, for a short period of time (48 hours in
pulmonary embolism) and continues with anticoagulants.
● Streptokinase administration is mandatory under clinical and laboratory control (1-2
determinations / day). Thrombin time is to be maintained in a therapeutical range of:

Thrombin time = 2-3 x N

● IV infusion of Streptokinase will be preceded by the administration of Aspirin 150 mg

plus Hydrocortisone Hemisuccinate to counteract any allergic reactions.

TISSUE PLASMINOGEN ACTIVATORS

♦ Alteplase, Reteplase, Tenecteplase

This drugs are endogenous human glycoproteins, released from endothelial cells,
prepared by genetic recombination. Depending on the molecular weight and the way the
original chain is broken down, different preparations are obtained: Alteplase, Reteplase or
Tenecteplase. No preparation is superior to another in terms of therapeutic efficacy. All
representatives of this class are very active fibrinolytics, considered to be of second
generation. They have the advantage of not producing allergies as the previous category may
cause. Alteplase is currently considered to be the reference fibrinolytic.
Mechanism of action
● Predominantly activate fibrin-bound plasminogen, therefore having the advantage of
selective action at the thrombus level (do not produce major systemic fibrinolysis) and
are not antigenic.
Pharmacokinetics
● Reteplase shows a longer T1/2 (18 minutes) compared to Alteplase, and therefore
double bolus administration is allowed.
Indications
● Early treatment of AMI within the first 6 hours after onset
● Flebothrombosis
● Pulmonary thromboembolism
● Ischemic stroke
● The route of administration is IV
● Usually associated with Heparin or in combination with Streptokinase or Urokinase.
The cost of Alteplase therapy is over 20 times higher compared to Streptokinase
treatment.
Adverse effects
● Bleeding

DIRECT ACTIVATORS OF PLASMINOGEN

♦ Urokinase

Urokinase is an enzyme protein prepared from human kidney cell cultures, without
antigenicity and allergic reactions.
Mechanism of action
● Directly activates plasminogen and converts it into plasmin

Indications
 ● Pulmonary embolism
● Flebothrombosis
● Acute arterial thrombosis
● Recanalisation of arteriovenous shunts
● IV, in patients allergic to Streptokinase

ANTIPLATELET AGENTS

This drugs are useful in the prophylactic treatment of arterial thrombosis as they
prevent or reduce the formation of platelet thrombi in the arterial system, in the event of a
vascular wall injury.
They inhibit the various platelet functions, manifested by prolonged bleeding time,
preventing plaque adhesion and aggregation, and prolonging platelet life (shorter in
thromboembolic arterial disease).
Classification according to the mechanism of action:
● Antagonists of cyclooxygenase, with inhibition of thromboxane A2 synthase
▪ Acetylsalicylic acid
● Inhibitors of ADP-induced aggregation by inhibiting the platelet membrane receptor
activation pathway
o Thienopyridines
▪ Ticlopidin
▪ Clopidogrel
▪ Prasugrel
o Nonthienopyridines
▪ Ticagrelor
▪ Cangrelor (introduced in 2015)
● Platelet phosphodiesterase inhibitors
▪ Dipyridamole
▪ Cilostazol
● Specific platelet receptor blockers
▪ Abciximab
▪ Eptifibatide
▪ Tirofiban
● PAR-1 thrombin receptor antagonists
▪ Varopaxar (introduced in 2014)

CYCLOOXYGENASE ANTAGONISTS
 ♦ Acetylsalicylic acid

Acetylsalicylic acid (Aspirin) is the standard of antiplatelet agents.

Mechanism of action
● Acetylsalicylic acid is a long-acting antiplatelet agent that inhibits the synthesis of
thromboxane A2 by the irreversible platelet cyclooxygenase acetylation. The
consequence is the antiaggregation effect.
● Small doses inhibit cyclooxygenase 1, and high doses also cyclooxygenase 2 with
analgesic, antipyretic and anti-inflammatory effect.
● In addition, it lowers the platelet aggregation produced by collagen, adrenaline and
ADP.
Pharmacokinetics
● Bioavailability after oral administration is 50-75%.
● The maximum plasma concentration is obtained after 30-60 minutes.
● The anti-platelet effect lasts 7-10 days after stopping the administration.
Indications
● Primary prophylaxis of AMI
● Stent implantation
● Secondary prophylaxis of ischemic stroke
● Aspirin is administered at low doses of 75-325 mg to prevent bleeding complications,
orally, in one daily dosing after meal
Adverse effects
● Gastrointestinal bleeding
● Increases the incidence of peptic ulcer
● Resistance to Aspirin, which occurs in 5-40% of cases
● Allergy to Aspirin

INHIBITORS OF ADP-INDUCED AGGREGATION

♦ Ticlopidin, Clopidogrel, Prasugrel

♦ Ticagrelor, Cangrelor

Mechanism of action
● Inhibit ADP binding to platelet receptor P2Y12, inhibiting IIb / IIIa complex activation
(receptor binding, modulation of receptor conformation).
● Inhibits platelet activation and aggregation.
Pharmacokinetics
● Clopidogrel and Prasugrel are prodrugs (they become active only after hepatic
metabolism) with rapid absorption.
Indications
● Secondary prophylaxis of cardiovascular diseases
● Acute coronary syndrome
● Prevention of stent thrombosis
● Substitute for acetylsalicylic acid in allergic people
● Are usually given orally, in 1-2 doses, except for Cangrelor, which is administered IV
only, in infusion

Contraindications
 ● 10 mg Prasugrel/day is contraindicated in patients older than 75 years of age or less
than 65 kg in weight.
Adverse effects
● Bleeding
● Gastrointestinal disorders
● Leukopenia
● Dyspnea (Cangrelor)

PLATELET PHOSPHODIESTERASE INHIBITORS

♦ Dipyridamole, Cilostazol

Mechanism of action
● They inhibit the phosphodiesterase (which disrupts AMPc) with the increase in AMPc
level, which blocks platelet response to ADP and prevention of platelet activation.
● Dipyridamole blocks thromboxane synthetase and the thromboxane receptor,
preventing the formation of thromboxane A2, with inhibition of platelet aggregation.
Indications
● Dipyridamole is administered in the prophylaxis of AMI or stroke, alone or associated
with Aspirin (more effectively)
● Intermittent claudication (Cilostazol)

SPECIFIC PLATELET RECEPTOR BLOCKERS

♦ Abciximab, Eptifibatide, Tirofiban

Specific platelet receptor blockers are the most potent platelet antiaggregants at the
cost of increasing hemorrhagic risk.
Mechanism of action
● Have an antagonistic action against glycoprotein IIb /IIIa receptors, with inhibition of
fibrinogen binding by activated platelets, independently of the activating stimulus.
● Abciximab is a monoclonal antibody that irreversibly inhibits glycoprotein IIb/IIIa
receptor but can also act as anticoagulant by diminishing thrombin production.
● Tirofiban and Eptifibatide are competitive and reversible antagonists that act
specifically on the IIb / IIIa receptor subunit AIIb.
Pharmacokinetics
● T1/2 is 30-90 minutes
Indications
● Prophylaxis of ischemic complications after angioplasty and atherectomy
● Unstable angina
● Acute coronary syndrome (Eptifibatide, Tirofiban)
● Are given as an IV bolus or infusion
● Monitoring is needed: hemoglobin/hematocrit, serum creatinine, prothrombin time /
aPTT before treatment, then 6 hours after first administration, then daily and before
discharge
Contraindications
● Thrombocytopenia
● Allergy
Adverse effects
● Digestive bleeding or at injection site
 ● Severe acute thrombocytopenia, occurring within minutes or hours after
administration
● Headache, hypotension, chest pain, nausea, vomiting (Abciximab)
● Allergy (Abciximab)

PAR-1 THROMBIN RECEPTOR ANTAGONISTS

♦ Varopaxar

PAR-1 thrombin receptor antagonists are a recently introduced class of platelet

antiaggregants.
Pharmacokinetics
● It has a very good bioavailability of almost 100%.
● Peak plasma concentration is obtained within 1-2 hours.
● The platelet antiaggregant effect is 50% at 4 weeks after stopping the administration.
Contraindications
● Bleeding
Indications
● Secondary prophylaxis of cardiovascular trombotic events
 PHARMACOLOGY OF THE GASTROINTESTINAL DRUGS (I)

ANTIULCER DRUGS

Gastric or duodenal ulcer is a disease in which asymptomatic or symptomatic active

episodes (epigastric pain, dyspepsia) alternate with remission periods. It is the result of an
imbalance between aggressive (H+ ions, Helicobacter pylori infection, pepsin, bile acids,
nicotine, alcohol, Aspirin, NSAIDs, glucocorticoids, stress) and protective factors (bicarbonate,
mucus secretion, cell regeneration, local blood flow). Antiulcer drugs decrease/abolish the
aggression upon the mucous membrane and stimulate the protection factors.
The gastric acid secretion is controlled through a mechanism of vagal stimulation,
endocrine through gastrin (G cells in antrum), local release of histamine from enterochromaffin
cells. Stimulation of the parietal cells is the result of histamine, cholinergic, gastrin or
prostaglandin receptors activation (see figure). The first three types of receptors activate the
proton pump (H+/K+ ATP-ase), which pumps protons inside the stomach lumen in exchange
with K+. Antisecretory drugs decrease/abolish the H+ secretion by acting upon different cell
components responsible for the secretory mechanism. Prostaglandin receptors inhibit the proton
pump. The gastric acid secretion has a circadian rhythm, with an increased nocturnal secretion.
Besides the pharmacological treatment of ulcer, the patient has to stop smoking,
drinking alcohol and have a decreased intake of ulcerogenic drugs (NSAIDs, glucocorticoids).

Classification
Antiagressive drugs
§ Antacids
ALUMINIUM SALTS CALCIUM SALTS
MAGNESIUM SALTS SODIUM SALTS
§ Antisecretory drugs:
o Histamine receptor antagonists
CIMETIDINE NIZATIDINE
RANITIDINE ROXATIDINE
FAMOTIDINE
o Proton pump inhibitors
OMEPRAZOLE PANTOPRAZOLE
LANSOPRAZOLE RABEPRAZOLE
ESOMEPRAZOLE
o Anticholinergic drugs
PYRENZEPINE
o Prostaglandine agonists
MISOPROSTOL
Protective drugs
§ Coating agents: BISMUTH SALTS, SUCRALFATE
Antihelicobacter pylori drugs
§ Antibiotics: AMOXICLLIN, CLARITHROMYCIN, TETRACYCLINE
§ Chimiotherapics: METRONIDAZOLE, TINIDAZOLE, FURAZOLIDONE
§ Protective drugs: BISMUTH SALTS
§ Antisecretory drugs: OMEPRAZOLE, LANSOPRAZOLE, ESOMEPRAZOLE,
PANTOPRAZOLE, RABEPRAZOLE
 ANTACIDS

Mechanism of action
§ antacids are weak bases that neutralise the acid secreted by the parietal cells (the pH of
the gastric contents temporarily rises to 3-4); the onset of the neutralising action is 10-
15 minutes and lasts for 1-3 hours. In plus, they increase the mucus and bicarbonate
secretion;
§ Sodium bicarbonate reacts rapidly with hydrochloric acid resulting in carbon dioxide,
sodium chloride and water. Calcium carbonate reacts with hydrochloric acid, forming
calcium chloride. The neutralising power is greater compared to sodium bicarbonate.
Aluminium or magnesium hydroxide have a slow acid neutralising velocity;
§ liquids are more potent than tablets.
Indications
§ selfmedication (does not require prescription) in pyrosis due to gastritis, ulcer,
esophagitis;
§ prophylaxis in postsurgery stress ulcer.
Adverse effects
§ reactive hyperacidity;
§ intestinal motility problems;
§ calcium alkali syndrome.
Contraindications
§ renal diseases, because of accumulation risk.
Therapeutic notes
§ antacids are used for symptomatic relief;
§ the administration schedule: administration of one dose at one hour and three hours after
meals, meaning at least six administrations per day with decreased compliance to
therapy;
 § they may reduce the absorption of other drugs (Allopurinol, betablockers,
cephalosporins, digitalics, Iron, Indinavir, Isoniazid, Ketoconazole, tetracyclines,
Theophylline, L-thyroxine, vitamin B12). There has to be a pause of 2 hours between
administrations.

Pharmacodynamic properties of antacids

Antacid Duration Effects on Adverse effects Indication
of action intestinal motility
Sodium salts short - Alcalosis, hypernatremia no
Calcium salts long constipation Hypercalcemia, reactive no
hyperacidity
Magnesium long diarrhea Magnesium accumulation in yes
salts renal failure with risk of
neuromuscular paralysis
Aluminium long constipation Complexes with phosphates, yes
salts tetracyclines

v ALUMINIUM and MAGNESIUM SALTS

Adverse effects
§ aluminium compounds cause constipation;
§ magnesium compounds cause diarrhea;
§ toxicity can occur in patients with renal failure.

v SODIUM BICARBONATE

Sodium bicarbonate is sometimes taken as a popular home remedy for dyspepsia, but it
is not recommended because it is absorbed and if used in large amounts can cause systemic
alkalosis.

HISTAMINE RECEPTOR ANTAGONISTS

Pharmacokinetics
§ H2 antagonists are metabolised in the liver and eliminated renally unchanged (70%);
§ In liver or renal diseases, the dose has to be reduced;
§ They penetrate well in tissues and organs and have a high bioavailability (see table).
Mechanism of action
§ Because of their similar structure with histamine, they act by antagonising histamine at
H2 receptors, decreasing the acid secretion, especially the basal and nocturnal one;
§ They decrease the gastrin and vagal stimulated secretion;
§ The effect lasts for 3 hours during the day and 7 hours during the night.

H2 antagonist Bioavailability Daily dose Inhibition of Antiandrogenic

CYP450 effects
Cimetidine 60-80% 800 mg Yes Yes
Ranitidine 50-60% 300 mg (Yes) No
Famotidine 30-50% 40 mg No No
Nizatidine >90% 300 mg No No
Roxatidine 80-90% 150 mg No No
Indications (second line drugs)
§ duodenal ulcers (heal after 4–8 weeks);
§ gastric ulcers (heal more slowly and may require higher doses for a longer period of
time);
§ reflux esophagitis (GORD) requires high-doses in a long-term therapy;
§ Zollinger-Ellison syndrome, as the second choice (first choice is Omeprazole);
§ dyspepsia without any clear organic lesion.
Adverse effects
§ nausea, diarrhea, constipation;
§ allergies;
§ headache, dizziness, restlessness, confusion, depression in elderly;
§ cholestasis;
§ rare: tachycardia, bradycardia or hypotension (H2 receptors also in the heart and
vessels);
§ in intubated patients, they increase the risk of nosocomial pneumonia, because of the
increased pH, with airway bacterial population overgrowth.
Contraindications
§ pregnancy, lactation period;
§ children and teenagers (not sufficient studies);
§ liver or renal failure.
Therapeutic notes
§ in the ulcer treatment the patient will receive one dose, in the evening. Only in severe
cases we administer two doses daily;
§ many patients take H2 receptor antagonists indefinitely, or in repeated courses.

v CIMETIDINE

Pharmacokinetics
§ Absorption: well absorbed after oral administration, but can also be given IV;
§ Elimination: excreted unchanged by the kidney.
Interactions
§ inhibits drug-metabolising enzymes in the liver and may increase the effects and toxicity
of many drugs (e.g. Phenytoin, Theophylline, Phenobarbital, Propranolol, Warfarin).
Adverse effects
§ gynecomastia, azoospermia, decreased libido in men, amenorheea in women in long-
term use, because of the weak antiandrogen effects and increase of prolactine level;
§ confusion to psychosis may occur in older patients, patients with a history of psychiatric
disease and those who receive large doses for a longer period of time.
Therapeutic notes
§ reoccurrence of ulcer disease is common after therapy cessation.

§ RANITIDINE, FAMOTIDINE, NIZATIDINE

Pharmacodynamic actions
§ they have no CNS effects, no inhibition of drug metabolism and no antiandrogenic
effect.
 PROTON PUMP INHIBITORS

The proton pump inhibitors are more potent compared to antihistaminics H2 drugs. All
proton pump inhibitors are equally effective in the treatment of ulcer, including the antiHPy
action. Omeprazole was the first proton pump inhibitor introduced on the market. It can be
administered orally or IV.
Mechanism of action
§ the gastric hydrogen/potassium-ATPase enzyme („proton pump”) is irreversibly
inhibited by these drugs, and so acid production ceases (the gastric pH rises to 4-5);
§ acid secretion can only resume when new enzyme has been formed, and that’s why the
effect lasts for 24-72 hours.
Pharmacokinetics
§ because of their rapid metabolisation in gastric acid environment, their dosage form is
gastro-resistant capsules;
§ they are prodrugs, activated only in acid environment with a pH less than 4.2. As greater
the acidity, as stronger their effect will be;
§ they have a short half-life, of one hour.
Interactions
§ Omeprazole can inhibit some hepatic drug-metabolising enzymes.
Indications
§ duodenal ulcer (administered for 2-4 weeks);
§ gastric ulcer (administered for 4-8 weeks);
§ GORD (administered for at least 4-8 weeks);
§ Zollinger–Ellison syndrome;
§ HPy infection (administered for 7 days) in association with 2 antibiotics;
§ prophylaxis and treatment of iatrogenic gastropathy, induced by NSAIDS.
Adverse effects
§ nausea, vomiting, diarrhea, constipation;
§ headache, fatigue;
§ rare: visual and hearing disturbances, after IV administration;
Contraindications
§ pregnancy, lactating period;
§ children;
§ liver failure.
Therapeutic notes
§ they are the most effective acid suppressants: heal acid-related diseases in patients who
do not respond to other acid-modifying drugs;
§ have a high relapse rate in peptic ulcers unless Helicobacter pylori is eradicated.

ANTICHOLINERGIC DRUGS

§ PYRENZEPINE

Anticholinergic drugs are inferior in efficiency compared to the previous classes, but
they were considered to be the main antiulcer medication before the antihistaminic drugs were
introduced in therapy.
Pharmacokinetics
§ Pyrenzepine has a half-life of 10-12 hours.
Mechanism of action
§ act on muscarinic receptors, inhibiting the acid secretion.
Indication
§ gastritis, duodenitis
§ prophylactic treatment of iatrogenic ulcer (NSAIDS)
§ prophylactic treatment of stress ulcer (IV)
§ adjuvant treatment in upper digestive bleeding (IV)
Adverse effects
§ xerostomia;
§ urinating problems.
Contraindications
§ pregnancy;
§ glaucoma;
§ pyloric stenosis;
§ prostate hypertrophy.

PROSTAGLANDIN AGONISTS

v MISOPROSTOL

Mechanism of action
§ Misoprostol is an analogue of prostaglandin E1; the stimulation of Prostaglandin E1
receptors on gastric parietal cells decreases acid secretion;
§ it has a protecting effect on the mucosa of the stomach, by increasing mucosal blood
flow and mucus and duodenal bicarbonate secretion.
Indications
§ peptic ulcers;
§ prophylaxis and treatment of ulcer caused by nonsteroidal anti-inflammatory drugs
(NSAIDS);
§ induction of abortion.
Contraindications
§ in pregnant women, it may cause miscarriages.
Adverse effects
§ nausea, abdominal pain, diarrhea (5-15 % of the patients);
§ headache.

COATING AGENTS

Mechanism of action
§ they increase the protection of the mucosa, by forming a protective coating over the
ulcer crater, allowing healing to occur underneath;
§ they stimulate local prostaglandin release.

v BISMUTH SALTS

Mechanism of action
§ administered only orally, with minimum absorption and local effect;
§ protection of the mucosa;
§ has activity against Helicobacter pylori.
Indications
§ duodenal ulcer;
§ GORD;
 § diarrhea.
Adverse effects
§ metallic taste;
§ blackening of stool;
§ encephalopathy ( if administered in high doses, for more than two months at a time).

v SUCRALFATE

Chemistry
§ Sucralfate is a water insoluble complex of aluminum hydroxide and sucrose sulfate,
active only in acid environment.
Mechanism of action
§ it forms a protective layer on the ulcer;
§ it stimulates the secretion of mucus, prostaglandins and bicarbonate;
§ it has no acid-neutralising effect.
Indications
§ peptic ulcer;
§ GORD.
Adverse effects
§ constipation, because it contains aluminium;
§ aluminium toxicity in patients with renal failure.
Contraindications
§ pregnancy, lactation, children (not enough clinical studies);
§ renal failure, because of the accumulation risk.
Therapeutic notes
§ it heals peptic ulcers as effectively as histamine H2-blockers but is less convenient;
§ it should not be combined with antisecretory drugs.

TREATMENT REGIMENS AGAINST HELICOBACTER PYLORI INFECTION

Helicobacter pylori is a Gram-negative bacteria, that can inhabit various areas of the
stomach and duodenum, causing a chronic inflammation of the mucosa and in time leading to
duodenal and gastric ulcers and stomach cancer. Once Helicobacter pylori is detected in patients
with a peptic ulcer, the normal procedure is to eradicate it and allow the ulcer to heal. Because
of its’ very high resistance, we have to prescribe an association of proton pump inhibitors,
antibiotics and sometimes bismuth salts. If Helicobacter pylori infection is left untreated,
relapse rate is high. Some examples of the treatment regimens are:
Omeprazole + Amoxicillin + Clarithromycin 7 days
20mg twice daily 1g twice daily 500mg twice daily

Lansoprazole + Amoxicillin + Clarithromycin 7 days

30mg twice daily 1g twice daily 500mg twice daily

Omeprazole + Metronidazole + Clarithromycin 7 days

20mg twice daily 500mg twice daily 250mg twice daily

Bismuth subsalicilate + Metronidazole + Tetracycline 7 days

 525 mg four times daily 250 mg four times daily 500 mg four times daily

§ in case of resistance:
Omeprazole + Bismuth subcitrate + Tetracycline + Metronidazole 14 days
20mg twice daily 120mg twice daily 500 mg four times daily 500 mg four times daily
 ANTIEMETIC DRUGS

Nausea amd vomiting are protective reflexes, very important in adaptation. Nausea is
an unconditioned stimulus for learning and memory. Food that becomes associated with nausea
and vomiting will be avoided in future encounters. Vomiting is the forceful expulsion of gastric
and/or upper intestinal contents, the primary function of which is to remove ingested materials
or food that may be contaminated or potentially harmful. Possibly because of its importance,
the sensitivity of this reflex is very low, making it easily activated.

Classification
§ Dopamine receptor antagonists:
o Substituted benzamides:
METOCLOPRAMIDE
o Benzimidazol derivates:
DOMPERIDON
o Phenothiazines:
PROCHLORPERAZINE
THIETHYLPERAZINE
o Butirophenones:
DROPERIDOL
HALOPERIDOL
§ Antihistamines H1:
DIMENHYDRINAT MECLIZINE
HYDROXYZINE PROMETHAZINE
§ Anticholinergic drugs:
SCOPOLAMINE
§ 5-HT3 receptor antagonists:
GRANISETRON TROPISETRON
ONDANSETRON PALONOSETRON
§ Canabinoids:
NABILONE
DRONABINOL
CANNABIDIOL
§ Neurokinin 1 antagonists:
APREPITANT
FOSAPREPITANT
 DOPAMINE RECEPTOR ANTAGONISTS

§ METOCLOPRAMIDE

Mechanism of action
§ Metoclopramide binds to dopamine D2 receptors (receptor antagonist), in the
chemoreceptor trigger zone in the CNS and makes the gastrointestinal cells more
sensitive to acetylcholine;
§ it is also a mixed 5-HT3 receptor antagonist/5-HT4 receptor agonist;
§ leads to an increased gastrointestinal activity and rapid movement of food through the
upper digestive tract (direct acting) without stimulating gastric, pancreatic or biliary
secretions.
Indications
§ acute and chronic diabetic gastroparesis;
§ GORD;
§ postoperative nausea and vomiting;
§ intestinal transit of barium;
§ prevention of nausea and vomiting associated with cancer chemotherapy;
Adverse effects
§ headache;
§ extrapyramidal reactions (oculogyric crisis) in children or young women (treat with
Benzatropine);
§ increased prolactin concentrations, gynecomastia in prolonged use.
Therapeutic notes
v Metoclopramide is not effective in motion sickness.

v DOMPERIDONE

Domperidone is similar to Metoclopramide but is less likely to cause extrapyramidal

reactions.
 v PROCHLORPERAZINE

Mechanism of action and pharmacodynamic actions

§ anticholinergic effects;
§ sedative effects;
§ H1-blocking effects;
§ they block dopamine receptors in the chemoreceptor trigger zone.
Indications
§ control of severe nausea and vomiting including that associated with anesthesia;
§ intractable hiccoughs;
§ prevention of motion sickness;
§ vestibular disturbances in Meniere disease;
§ pregnancy sickness.
Adverse effects
§ sedation;
§ atropinic effects.

v DROPERIDOL

Droperidol was temporary withdrawn from the market in 2008 because of severe
cardiovascular side effects (arrhythmias, cardiac arrest).

ANTIHISTAMINES H1

Mechanism of action
§ they act on H1 receptors in the vomiting centre;
§ they also have weak anticholinergic and sedating effects.
Indications
§ motion sickness;
§ vestibular disease (often inappropriately in the elderly).
Adverse effects
§ sedation;
§ atropinic effects.

ANTICHOLINERGIC DRUGS

§ SCOPOLAMINE

Mechanism of action
§ they act on the vomiting centre especially;
§ also affect the gastrointestinal tract directly.
Indications
§ prevention of motion sickness.
Adverse effects
§ dry mouth;
§ confusion, fatigue, agitation.
Therapeutic notes
§ one patch should be applied to a hairless area of skin behind the ear five to six hours
before travel;
§ one patch can prevent travel sickness for up to 3 days.
 5-HT3 RECEPTOR ANTAGONISTS

Mechanism of action
§ they block serotonin receptors in the CNS and digestive tract.
Indications
§ severe nausea and vomiting after anticancer chemotherapy, radiotherapy or
postoperatively.
Adverse effects
§ constipation;
§ headache.
Therapeutic notes
§ they are reserved for cases where other drugs are ineffective.

CANABINOIDS

Mechanism of action
§ they act mainly on canabinoid receptor type 1 (CB1) which are distributed throughout
the central and peripheral nervous system, but also in many other sites throughout the
body, probably also on enterochromfinlike cells and the vagus.
Indications
§ control of delayed chemotherapy-induced nausea and vomiting.
Therapeutic notes
§ studies have proven their superiority compared to DOPA antagonists.

NEUROKININ 1 ANTAGONISTS

Mechanism of action
§ Aprepitant is a selective human substance P and neurokinin-1 (NK1) receptor antagonist
that inhibits chemotherapy-induced nausea and vomiting centrally in the chemoreceptor
trigger zone;
§ Aprepitant has also antidepressant and anxiolytic properties.
Indications
§ prophylaxis of acute and delayed phases of chemotherapy-induced nausea and
vomiting.
Adverse effects
§ loss of appetite;
§ headache
Therapeutic notes
§ they are administered together with a glucocorticoid and a 5-HT3 receptor antagonist.
 PHARMACOLOGY OF THE GASTROINTESTINAL DRUGS (II)

CHOLERETICS, CHOLAGOGUES AND OTHER BILIARY SECRETION

MODIFIERS

Choleretics are drugs which stimulate the production of bile by the liver. Cholagogues
and cholecystokinetics decrease biliary stasis by stimulating the flow of bile into the duodenum
(see figure). All choleretics are cholagogues. Magnesium sulphate is a pure, real cholagogue.
Other examples are: olive oil, sunflower oil or yolk.
Hydrocholeretics and colagogues are administered in biliary dyskinesia, contraindicated
in gallstones.

Classification
True choleretics:
§ PHENOBARBITAL
Hydrocholeretics:
§ OX BILE EXTRACT
§ DEHYDROCHOLIC ACID
§ CYNARA SCOLIMUS

TRUE CHOLERETICS

v PHENOBARBITAL

Mechanism of action
§ Phenobarbital, known for the anticonvulsant and sedative-hypnotic effects, induces also
hepatic enzyme metabolism (CYP450 system) in order to decrease serum bilirubin
levels.
Indications
§ neonatal hyperbilirubinemia;
§ cholestasis.
Contraindications
§ respiratory problems;
§ lactation period.
 HYDROCHOLERETICS

Mechanism of action
§ hydrocholeretics increase the volume of a diluted bile, but do not stimulate the secretion
of biliary constituents; excreted through the bile, they act by an osmotic mechanism;
§ through a choleretic and cholecystokinetic mechanism, they stimulate the antitoxic
function of the liver;
§ in plus, they have laxative, spasmolytic and antiinflammatory effects.
Indications
§ acute and chronic cholecystitis;
§ liver cirrhosis;
§ constipation.

OTHER MODIFIERS OF BILIARY SECRETION

Gall stones are present in 15-20% of the population, but only symptomatic forms should
be treated. Cholesterol is a frequent component of them. It is not soluble in water, poorly soluble
in bile. The precipitation of biliary salts in biliary cholesterol supersaturation results in the
gallstone formation. The risk factors for biliary lithiasis are known as the “6 F”: female, fat,
fair, forty, fertile and family.
By modifying the bile composition, the drugs which dissolve gallstones prevent the
precipitation and favour their dissolving. The pharmacological and/or surgical treatment
prevents complications such as acute cholecystitis or cholangitis, gall bladder perforation or
biliary pancreatitis.

v URSODEOXYCHOLIC ACID

Mechanism of action
§ acts by replacing endogenous biliary acids (hydrophobic), with ursodeoxycholic acid
(hydrophilic and nontoxic);
§ suppresses hepatic cholesterol secretion and inhibits intestinal absorption of cholesterol;
§ bile acids are used to gradually dissolve small cholesterol gallstones;
§ it has no influence on those containing calcium.
Indications
§ biliary lithiasis with cholesterol, radiotransparent gallstones (diameter less than 15 mm);
§ primary biliary cholangitis (formerly primary biliary cirrhosis); studies have
demonstrated a delayed necessity of liver transplant.
Adverse effects
§ diarrhea;
§ skin reactions.
Contraindications
§ cholecystitis;
§ obstruction of the biliary tract;
§ biliary contraction disorder;
§ pregnancy in the first trimester and lactating period.
Therapeutic notes
§ at least 6 months of treatment is required (up to 24 months);
§ the rate of success after 6 months is 60%, but recurrence is common;
§ bile acid treatment for gallstones is generally reserved for patients who are unfit for
surgery;
 § the treatment is very expensive.

v BILICHOL

Mechanism of action
§ decreases the endogenous production of cholesterol, prevents the formation of gall
stones, increases the biliary flow and has antispastic action;
§ inhibits the HMG-CoA reductase, desaturates the bile of cholesterol.
Indications
§ biliary duct diskinesia, cholecystitis, cholelythiasis; 1-2 caps., 3 times/day, before meal.

v ROWACHOL

§ almost the same as Bilichol, but indicated only in cholelythiasis.

 LAXATIVES AND PURGATIVES

Constipation is a rare and difficult evacuation of a hard and dry stool. This is a symptom
that appears often in elderly, sedentary patients or during pregnancy, but also could be
determined by an endocrine (hypothyroidism), digestive (diverticulitis, colorectal cancer,
hernia, hemorrhoids, anal fissures) or neurological (Parkinson’s disease, multiple sclerosis,
spinal lesion) disease. Drugs responsible for chronic constipation are: opioids, anticholinergics,
tricyclic antidepressants, neuroleptics, antihistaminics or spasmolytics.
Before initiating the treatment with laxatives, it is important to introduce a rich in fiber
diet, with 1.5-2 L of liquids daily and physical exercise.
This drugs are also administered to empty the intestinal content before colonoscopy or
surgical interventions, in painful anal lesions or to avoid vascular complications due to
increased intraabdominal pressure (aortic aneurism) or in food or drug intoxications, to rapidly
eliminate the ingested toxic substance.
The administration of laxatives results in a normal stool, regarding aspect and
consistency, obtained usually after 8-12 hours, sometimes days. If administered in high doses
they have a purgative effect. Purgatives eliminate the intestinal content, through a semisolid at
first then liquid stool, after a latency of 2-6 hours.
Laxatives are absorbed only 5-10% from the gastrointestinal tract, acting locally
through different mechanisms. It is forbidden to administer them in ileus, abdominal pain
without a detected cause, in acute intestinal diseases and with caution in pregnancy and lactation
period.
The misuse, chronic administration leads to dependence (reduced peristalsis) and
hydroelectrolytical imbalance like hypokalemia (decreases peristalsis), hyponatremia with
secondary hyperaldosteronism. Hypokalemia will be more severe if laxatives are associated
with loop diuretics or thiazides, glucocorticoids or Amphotericin B.
Classification
§ Bulk forming agents:
o fibers: plant based foods, METHYLCELLULOSE, PSYLLIUM SEEDS
§ Hyperosmotic agents: POLYETHYLENE GLYCOL (PEG, MACROGOL),
LACTULOSE, MAGNESIUM or SODIUM SALTS
§ Stool softeners: DOCUSATE, MINERAL OIL
§ Stimulant agents: SENNA, BISACODYL, CASTOR OIL
§ New laxatives: PRUCALOPRID, LINACLOTID, METHYLNALTREXONE

BULK FORMING AGENTS

v METHYLCELLULOSE, PSYLLIUM SEEDS

Mechanism of action
§ they resist enzymatic digestion, work locally by absorbing water, swelling and
increasing the bulk of the stool, stimulating the normal peristalsis and hence defecation;
§ the latency is long, of 12-36 hours.
Indications
§ constipation, as main therapy.
Adverse effects
§ crampy abdominal pain, flatulence, because of the fermentation process;
§ risk of ileus if not taken with sufficient liquids.
Contraindications
§ intestinal atony, obstruction;
 § immobility.
Therapeutic notes
§ it may take a few days for them to act fully;
§ these agents do not cause laxative dependence.

HYPEROSMOTIC AGENTS

v POLYETHYLENE GLYCOL (MACROGOL)

Mechanism of action
§ it is not absorbed and creates locally an osmotic pressure that will retain water in the
colon;
§ it has a laxative effect at low doses and a purgative effect at high doses.
Indications
§ Macrogol is frequently administered in chronic constipation, compared to other
laxatives, because the effect is predictible, directly related to the dose and if
administered together with electrolytes, the solely administration over a long period of
time is possible;
§ before colonoscopy or intesinal surgey.
Adverse effects
§ rare flatulence.

v LACTULOSE

Mechanism of action
§ Lactulose is a synthetic disaccharide (galactose plus fructose) which is not absorbed,
having a laxative effect through osmosis;
§ it is broken down by colonic bacteria to lactic, acetic and organic acids, which decreases
the local pH, reducing ammonia absorption, a beneficial effect in patients with liver
diseases (prevents encephalopathy).
Indications
§ constipation in elderly patients;
§ liver encephalopathy.
Adverse effects
§ abdominal pain, flatulence, diarrhea.

v SODIUM or MAGNESIUM SULPHATE

Mechanism of action
§ they decrease the viscosity of faeces by increasing their water content.
Indications
§ rare, before radiologic examinations or surgery, through enema (latency 30 minutes) or
oral (latency 2-5 hours);
§ Sodium sulphate (Glauber salt) was used in the past as a purgative in intoxications, after
the administration of activated charcoal; nowadays it is used rarely.
Adverse effects
§ abdominal pain, flatulence, diarrhea;
§ hydroelectrolytical imbalance;
§ in chronic administration of laxatives containing sodium, there is the risk of absorption
with consecutive retention of water, hypertension and edema;
 § in chronic administration of laxatives containing magnesium or in patients with
decreased renal function, there is a risk of hypermagnesemia with neuromuscular
problems, such as hyporeflexia, muscular weakness and paresis.
Contraindications
§ renal failure;
§ severe heart diseases.

STOOL SOFTENERS

v DOCUSATE, MINERAL OIL

Mechanism of action
§ they lubricate and soften the stool by adding water and fats to it.
Therapeutic notes
§ there is a risk of lipoid aspiration pneumonia.

IRRITANT PURGATIVE AGENTS

The irritant action increases the accumulation of water and electrolytes in the lumen of
the colon and enhances the colonic peristaltics by activation of local reflexes.

v SENNA

Pharmacokinetics
§ could be absorbed partially, with the risk of uterine contraction;
§ passes in the milk, producing diarrhea to the baby;
§ the latency is 8-10 hours.
Mechanism of action
§ antraquinone glycosides from senna leaves, aloe or rhizoma rhei, sold on the market in
form of laxative tee have prokinetic and secretory properties.
Indications
§ constipation, as second line drugs, administered for a short period of time.
Adverse effects
§ crampy abdominal pain after each dose;
§ electrolyte imbalance;
§ melanosis coli (pigmentation of colon mucosa): reversible, without increasing the
carcinoma risk;
§ laxative dependence;
§ dehydration;
§ they may cause atony of the bowel (if used chronically) creating a vicious cycle.
Contraindications
§ pregnancy, lactation period;
§ intestinal obstruction.

v BISACODYL

Pharmacokinetics
§ the latency is 6-8 hours after oral administration and shorter (30-60 minutes) after
intrarectal adinistration, as suppositories.
Mechanism of action
 § in small doses, it decreases the absorption of water from the inestine;
§ in large doses, it increases the absorption of water from the inestine.
Indications
§ constipation, after surgery, myocardial infarction, stroke;
§ hemorrhoids, anal fissures;
§ before diagnostic procedures of the digestive tract.
Adverse effects
§ abdominal pain after each dose;
§ electrolyte imbalance;
§ they may cause atony of the bowel (administer for maximum 10 days).

v CASTOR OIL

Mechanism of action
§ ricinoleic acid irritates the small intestinal mucosa, increasing peristalsis;
§ the latency is 1-3 hours.
Indications
§ emptying the intestine before surgery or diagnostic procedures, but nowadays there are
superior remedies.
Adverse effects
§ unpleasant taste, abdominal pain, diarrhea;
§ hydroelctrolytical imbalance.
Contraindications
§ intestinal obstruction;
§ purgative not used in intoxications, because it increases the absorption of toxins;
§ pregnancy, because it induces uterine contractions.

NEW LAXATIVES

v PRUCALOPRID
Mechanism of action
§ Prucaloprid is a 5HT4 antagonist with prokinetic effect.
Indications
§ women with chronic constipation wich did not respond or had intolerance after the
administration of conventional laxatives.
v LINACLOTID

Mechanism of action
§ Linaclotid is an agonist of guanilatcyclase C, which stimulates the intestinal secretion
of water and chloride.
Indications
§ irritable colon syndrome with constipation;
§ chronic constipation, in small doses.
Adverse effects
§ it is well tolerated.

v METHYLNALTREXONE

Mechanism of action
 § Methylanaltrexone is a peripheral (intestinal) opioid antagonist, without inhibiting the
central analgesia; this is an advantage over Naltrexone.
Indications
§ constipation caused by opioids, in the paleative treatment.
Adverse effects
§ possible intestinal perforation, risk which increases in association with anticancer
chemotherapics.
 ANTIDIARRHEAL DRUGS

Diarrhea means the elimination of three or more semisolid or liquid stools per day. It is
a symptom of a disease and that is why we should treat it only after the etiology is known.
Acute diarrhea is considered to be selflimiting (the traveller’s diarrhea in 4 days, food
toxinfection in 1-2 days). In more than 90% of the cases, diarrhea is determined by an infection:
Staphilococcus aureus (in icecream), E. coli, Clostridium perfringens, Norovirus, Rotavirus,
Vibrio cholerae, Salmonella (in eggs), Shigella, Campylobacter jejuni (in meat), amoebes.
The mycrobiological exam of the stool is made in severe cases, with dehydration, fever
over 39°, blood in stool, severe abdominal pain, duration of more than 48 hours without any
signs of improvement, extreme ages and immunodepressed patients.
Other causes incriminated in diarrhea, include: drugs (parasympathomimetics,
Misoprostol, loop diuretics, Theophylline, Lactulose or Acarbose), intoxications or ischemia.
A special form of diarrhea is induced by antibiotics, because of the change in normal bacterial
flora. This is usually selflimiting, after treatment stopping. Diarrhea caused by Clostridium
difficile, after the administration of Clindamycin, cephalosporins or Ampicillin can be
lifethreatening in case of pseudomembraneous cholitis.
Chronic diarrhea, with a duration of more than 4 weeks needs specific therapy. It is a
consequence of laxatives abuse, antacids with magnesium, carbohydrates, sweeteners, lactase
deficiency, intestinal resection, parasites, intestinal inflammatory diseases or neuroendocrine
tumors.
Especially in children, it is vitally important to replace fluid and electrolyte losses. Even
in severe cases of diarrhea, oral rehydration might be sufficient (see figure). Glucose will be
absorbed together with sodium through cotransport, which will attract water from the intestinal
lumen through an osmotic mechanism. This mechanism is not working if the composition of
the solution is not complied:

NaCl 3,5 g + KCl 1,5 g + NaHCO3 2,5 g + Glucose 20 g + water ad 1 L

Sweetened tee, lemonade or cola do not contain suffficient sodium and that is why they are
not useful.
Classification
• Symptomatic treatment
• Opioids: OPIUM, MORPHINE, LOPERAMIDE
• Antidiarrheal mycroorganisms: SACCHAROMYCES BOULARDII
• Mucoprotecting agents: DIOSMECTITE
• Anticholineric drugs: ATROPINE
• Etiological treatment
• CIPROFLOXACIN, in infections with: Campylobacter jejuni, Salmonella,
Shigella, Vibrio cholerae
• METRONIDAZOLE, in infections with: Clostridium difficilae
• AMPICILLIN, in infections with: Listeria monocytogenes
• VANCOMYCIN, in infections with: Stafilococus aureus

OPIOIDS

All opioids reduce peristalsis and increase sphincter tone by stimulating opioid
receptors in the bowel. Because, at the same time, elimination of toxins and infectious factors
is inhibited, indications are strict. They will not be administered in ulcerous colitis or
enterocolitis associated with the use of antibiotics.

v LOPERAMIDE

Pharmacokinetics
§ Loperamide is well absorbed after oral administration, but suffers from the first hepatic
passage and has a poor bioavailability;
§ does not pass through the BBB, has no analgesic effect and no risk of dependence.
Mechanism of action
§ the decrease in peristalsis allows absorption of fluids and consolidation of the stool.
Adverse effects
§ constipation.
Contraindications
§ ileus, constipation;
§ children;
§ diarrhea with fever or blood in stool;
§ ulcerous, pseudomembraneous colitis.

v OPIUM TINCTURE

Indications
§ patients with ileostomy, colonostomy;
§ acute, excessive diarrhea.
Adverse effects
§ high risk of dependence.
Contraindications
§ intestinal occlusion or subocclusion;
§ ulcerous colitis, because it could lead to toxic dilation of the colon.
 ANTIDIARRHEAL MYCROORGANISMS

v SACCHAROMYCES BOULARDII

Pharmacokinetics
§ Saccharomyces boulardii is a dried yeast, containing living mycroorganisms, forbidden
to be taken with hot or cold drinks.
Mechanism of action
§ it binds to pathogenic bacterias and slows down their growing;
§ it also has the capacity to decrease the enterotoxic effects of E. coli and Clostridium
difficilae.
Indications
§ acute diarrhea;
§ traveller’s diarrhea.
Adverse effects
§ allergy;
§ in mycrobiological stool testing, it can lead to fals positive results.
Contraindications
§ severe diarrhea;
§ immunodepressed patients;
§ children.

MUCOPROTECTING AGENTS

v DIOSMECTITE
Mechanism of action
§ Diosmectite is a natural aluminosilicate that increases viscosity and quantity of the
mucus layer and neutralises pathogens (viruses, bacterias, biliary salts, chemical
agents).
Indications
§ acute diarrhea;
§ irritable bowel.
Adverse effects
§ very well tolerated, also in case of children.
 DRUGS FOR INFLAMMATORY BOWEL DISEASES:
ULCERATIVE COLLITIS AND CROHN’S DISEASE

Therapeutic notes
§ the aim of treatment is to resolve the acute episodes and prolong remissions;
§ in addition to drug therapy, treatment involves correction of any nutritional deficiencies
and sometimes surgery for complications.

ANTI-INFLAMMATORY DRUGS

v CORTICOSTEROIDS

Mechanism of action
§ they act by inhibiting the synthesis of prostaglandins and leukotrienes.
Therapeutic notes
§ they are used:
o systemically in severe acute attacks (e.g. Prednisolone or Hydrocortisone);
o locally (enemas) for less severe acute attacks involving the large bowel, or as
maintenance therapy.

v AZATHIOPRINE, CICLOSPORIN

§ are occasionally used.

v INFLIXIMAB

Mechanism of action
§ it is a monoclonal antibody, that inhibits the actions of the inflammatory cytokine
tumour necrosis factor a.
Indications
§ refractory Crohn’s disease;
§ rheumatoid arthritis.

v AMINOSALICYLATES

Classification
§ SULFASALAZINE (a complex of a sulphonamide, sulfapyridine and 5-ASA);
§ MESALAZINE (5-ASA);
§ OLSALAZINE (two molecules of 5-ASA)
Mechanism of action
§ 5-Aminosalicylate (5-ASA) is the active drug that blocks the prostaglandins and
leukotrienes synthesis by inhibiting the enzymes COX and lipooxygenase.
Indications
§ ulcerative colitis;
§ Crohn’s disease;
§ rheumatoid arthritis.
Adverse effects
§ headache;
§ nausea, vomiting, diarrhea;
§ rashes;
 § blood disorders;
§ renal dysfunction;
§ infertility in males, because of decreased sperm count.
Therapeutic notes
§ they can be taken orally or rectally, as an enema.