Antianginal Drugs

Antianginal drugs are agents that can stop and prevent pain in ischemic heart disease /
cardiac angina by improving the balance of oxygen supply and demand. Angina pectoris,
the principal syndrome of ischemic heart disease, is pain that result from an unbalance
between myocardial oxygen demand and supply delivered by the coronary vessels.
Increasing of myocardial oxygen requirements can be produced by increasing in the
force of contraction, increasing of the heart rate and/or by increasing of left ventricular
wall tension. In parallel, occlusive coronary artery lesions due to atherosclerosis or
reversible narrowing due to coronary spasm or thrombi, are the most common factors
which are reducing supply of oxygen to myocardium.
Classic angina (angina of effort or exercise) is due to coronary atherosclerotic occlusion;
vasospastic or variant angina (Prinzmetal) is due to a reversible decrease in coronary
blood flow; unstable angina (crescendo) presents as an acute coronary syndrome with
platelet aggregation.

Drug strategies in classic and vasospastic angina involve:

- Increasing of oxygen delivery by reducing vasospasm (nitrates and calcium channel
blocking drugs).
- Reducing oxygen requirement by reducing of pulmonary vascular resistance, CO, or
both (nitrates, calcium channel blocking drugs, and beta blockers).

The major categories of antianginal drugs are the nitrates, the calcium channel blocking
drugs, beta blockers and other compounds.

NITRATES

Nitrates are the primary therapy for acute episodes of cardiac angina.
The mechanism of action of nitrates involves activation of the nitric oxide (NO)
pathway. NO has been identified as the endogenously released endothelium-derived
relaxing factor. The formation of NO in endothelial cells can be triggered by ACh,
bradykinin, histamine, and serotonin.
Nitrates are converted to S-nitrosothiols which are releasing NO which activates
guanylyl cyclase within the smooth muscle cell to form cGMP, which effects a
relaxation of vascular smooth muscle.
Nitrates form NO, causing marked dilation of large veins which lead to decreasing of
preload and cardiac work and decrease cardiac oxygen requirement. Nitrates also
improve collateral blood flow, decrease coronary vasospasm, and inhibit platelet
aggregation. At high doses, nitrates cause arteriolar dilation and decrease cardiac
afterload and cardiac oxygen requirement.
Nitrates decrease infarct size and post-MI mortality.
Nitrates are considered as crisis therapy and/or as prophylactic treatment of cardiac
angina.
Tolerance to the effect of nitrates is occurring when chronic therapy is considered
(mainly for long acting preparations). Considering that, the current recommendation is
to provide a nitrate-free interval of 8 to 12 hours daily to prevent tolerance.
As side effects, the most important are hypotension and headaches (occurs at therapy
initiation or in case of dose increase and decrease significantly after 1 – 2 weeks of
therapy due to physiological tolerance).
Other side effects flushing, reflex tachycardia and fluid retention (possibly
counterproductive), tachyphylaxia-require "rest periods" of more than 12 hours.
Another possible side effect is methemoglobinemia (more likely with nitrites, e.g., amyl
nitrite).

Nitroglycerin

Nitroglycerin is available in oral, sublingual, transdermal, and IV forms.

Isosorbide Mono-or dinitrate; oral, some extended-release.

CALCIUM CHANNEL BLOCKING DRUGS

Calcium channel blocking drugs are acting by blocking of L and T type of membranal
voltage activated calcium channels.

Dihydropyridines (e.g., Nifedipine as slow release forms, amlodipine) are largely

vascular selective.
Are used as prophylactic therapy in all types of cardiac angina and also as anti-HTN
medication, treatment of migraine headaches and Raynaud’s disease.
In prophylactic therapy of cardiac angina are administered orally.
As side effects hypotension and reflex cardiac tachycardia, peripherical edemas,
headache, constipation can be mentioned.
Caution with use of rapid-onset forms in emergency treatment of angina or HTN.
Verapamil and Diltiazem improve oxygen delivery by dilating coronary arteries and
coronary resistance vessels and reduce oxygen demand by reduction of heart rate and
afterload.
They produce vasodilation but also block Ca2+ channels in the heart and reduce cardiac
output.
They are less indicated as antianginal medication.
Severe bradycardia, AV block and aggravation of congestive heart failure (due to
inotropic negative effect) are possible side effects that can be added to those associated
to dihydropyridines treatment.
BETA BLOCKERS

Have no direct actions on vascular smooth muscle in angina. They act directly on the
heart reducing HR, force of contraction, and CO and reduce oxygen requirement.
Effective prophylactically in angina of effort (not vasospastic) and offset reflex
tachycardia caused by nitrates. Beta blockers are used also to treat hypertension and as
antiarrhythmic medication.
They are acting as beta receptors antagonists and competitive inhibition of the effect of
circulating and locally released catecholamines.
Most beta blockers have been used (for other characteristics see sections on autonomic
drugs and antihypertensive drugs).
Non-selective beta blockers (propranolol), selective beta1 blockers (atenolol,
metoprolol) and beta blockers with intrinsic sympathomimetic activity (pindolol,
acebutolol) are used as antianginal treatment.
Also, other compounds which associate an alpha and beta blocker effect (carvedilol)
have been shown equivalent to isosorbide.
Such drugs are administered in therapy of cardiac angina in most of the cases orally, as
once or twice daily preparation.
They are well tolerated by the patients in most of the cases.
As side effects, depression of myocardial contractility, bradycardia, bronchoconstriction,
peripherical vasoconstriction, sexual dysfunction, depression, sleep disturbances and
nightmares, decreasing of glucose tolerance in diabetics are possible in case of therapy
with non-selective beta blockers. In case of administration of selective beta 1 blockers or
compounds with intrinsic activity the side effects produced via beta1 receptors are less
important.

OTHER COMPOUNDS

Nicorandil, a vasodilator which reduce cardiac preload and afterload and decrease
cardiac effort. Is acting by activation of potassium channels.

Trimetazidine, is improving cardiac metabolism and block ATP depletion in cardiac

cells.

Ranolazine, decrease cardiac contractility by influencing of sodium influx.

Ivabradine, decrease cardiac frequency by direct inhibition of “funny” ion channels at

sinusal node.
Antianginal Drugs LP

Angina pectoris is the principal syndrome of ischemic heart disease, angina pain
occurring when oxygen delivery to the heart is inadequate for myocardial requirement.

Drug strategies in classic and vasospastic angina involve:

↑ oxygen delivery by ↓ vasospasm (nitrates and CCAs).
↓ oxygen requirement by ↓ PVR, CO, or both (nitrates, CCAs, and beta blockers).

NITRATES

The mechanism of action of nitrates involves activation of the nitric oxide (NO)
pathway. The formation of NO in endothelial cells can be triggered by ACh, bradykinin,
histamine, and serotonin.
NO activates guanylyl cyclase to form cGMP, which effects a relaxation of vascular
smooth muscle.
Nitrates form NO, causing marked dilation of large veins →↓ preload →↓ cardiac work
→↓ cardiac oxygen requirement. Nitrates also improve collateral blood flow, decrease
coronary vasospasm, and inhibit platelet aggregation. At high doses, nitrates cause
arteriolar dilation →↓ afterload →↓ cardiac oxygen requirement.
Nitrates decrease infarct size and post-MI mortality.

Nitroglycerin

Nitroglycerin is available in oral, sublingual, transdermal, and IV forms.

Treatment for angina crisis:

Rp. Nitroglycerin tablets 0.5 mg

I pack
Ds. Orally, one tablet in the beginning of the crisis

CALCIUM CHANNEL ANTAGONISTS (CCAs)

Drugs

Dihydropyridines (e.g., Nifedipine)

Are largely vascular selective. Caution with use of rapid-onset forms in emergency
treatment of angina or HTN.
Verapamil and Diltiazem
Also block Ca2+ channels in the heart →↓ CO.
BETA BLOCKERS

Have no direct actions on vascular smooth muscle in angina. They act directly on the
heart →↓ HR, force of contraction, and CO →↓ oxygen requirement.
Effective prophylactically in angina of effort (not vasospastic) and offset reflex
tachycardia caused by nitrates.
Most beta blockers have been used (for other characteristics see sections on autonomic
drugs and antihypertensive drugs).
Carvedilol: an alpha and beta blocker that has been shown equivalent to isosorbide.

Chronic treatment of angina

Rp. Carvedilol tablets 25 mg

XXX tablets
Ds. Orally, 1 tablet/day, in the mornimg
Antiarrhythmic Drugs LP
CLASS I: Na CHANNEL BLOCKERS

Class 1A

block fast Na channels (↓ INa)- Preferentially in the open or activated state-"state-dependent" blockade.
↑ action potential duration (APD) and effective refractory period (ERP) block K channels (↓ IK,
delayed rectifier current); may also ↓ ICa,
Quinidine

In addition to the above, causes M-block, which can ↑ HR and AV conduction.

May also cause vasodilation via alpha block with possible reflex tachycardia.
Orally effective, wide clinical use in many arrhythmias; in atrial fibrillation, need initial digitalization
to slow AV conduction.

Procainamide
Less M block than quinidine and no alpha block, but more cardiodepressant.
Orally effective, often substituting for quinidine. Prolongs APD.

Adverse effects: systemic lupus erythematosus (SLE)-like syndrome (30% incidence) more likely with
slow acetylators, hematotoxicity (thrombocytopenia, agranulocytosis), CNS effects (dizziness,
hallucinations), CV effects (torsades).

Class 1 B

↓ Vmax (in tachyarrhythmias): block fast Na channels (↓ INa,).

Less state-dependent, block inactivated channels-preference for tissues partly depolarized (slow
conduction in hypoxic and ischemic tissues).
↓ APD-due to block of the slow Na+ "window" currents.

Lidocaine

IV use in arrhythmias post-MI, during open heart surgery, or due to digitalis; drug of choice (DOC) for
arrhythmias following attempted cardioversion.
Clearance depends markedly on liver blood flow, and rapid first-pass effects preclude oral use.
Adverse effects: CNS toxicity culminating in seizures in severe OD. Least cardiotoxic of conventional
antiarrhythmics.
Treatment for a patient with severe ventricular arrhythmia after MI
Rp. Lidocaine, ampoules 50 mg
VI ampoules
Ds. Inj. i.v., 100 mg (2 ampoules) in bolus and then i.v. intravenous infusion with 200 mg lidocaine in
200 ml saline solution

Phenytoin

An antiseizure drug, used occasionally in digitalis OD to reverse AV block.

Orally active drug.
Treatment of ventricular extrasystole produced by Digoxin overdose

Rp. Phenytoin, tablets 200 mg

I pack
Ds. Orally, 1 tablet/day

Class 1 C

↓↓ Vmax,-block fast Na channels especially His-Purkinje tissue.

No effect on APD.
No ANS effects.

Propafenone, Flecainide and Encainide

Limited use because of pro-arrhythmogenic effects leading to ↑ sudden death post-MI and when used
prophylactically in VT.

CLASS II: BETA BLOCKERS

↓ SA and AV nodal activity.

↓ Slope of phase 4 (diastolic currents) of AP in pacemakers.
Prevent betal adrenoceptor activation, which would normally ↑ cAMP.
Propranolol (nonselective) and the cardioselective drugs: atenolol, metoprolol, esmolol.
Antiarrhythmic uses: prophylaxis post-MI and in supraventricular tachyarrhythmias (SVTs);
esmolol (IV) is used in acute SVTs.

Treatment for a patient with supraventricular extrasystoles

Rp. Metprolol, tablets 50 mg

I pack
Ds. Orally, 1 tablet every 12 hours.

CLASS III: K+ CHANNEL BLOCKERS

↑ APD and ERP, especially in Purkinje and ventricular tissues.
↓IK (delayed rectifier current) slowing phase 3 (repolarization) of AP.

Bretylium

IV use (backup) in life-threatening ventricular arrhythmias.

Releases amines and is pro-arrhythmogenic (torsades).

Amiodarone

Activity mimics all antiarrhythmic drug classes (I, II, III, and IV); blocks Na, Ca, and K channels.
↑ APD and ERP in all cardiac tissues.
Half-life 30 to 60 days.
Effective in a wide range of atrial and ventricular arrhythmias.
Adverse effects: pulmonary fibrosis, corneal deposits, blue pigmentation ("smurf" skin), photoxicity,
thyroid dysfunction, ↑ LDL-C, torsades, hepatic necrosis.
Sotalol

Two enantiomers, both of which ↑ APD and ERP (↓ IK delayed rectifier current), and one acts as a
beta1 blocker to ↓ HR and AV nodal conduction.
Approved for prophylaxis in life-threatening ventricular arrhythmias.
Adverse effects: lassitude, impotence, depression, torsades, AV block.

CLASS IV: Ca2+ CHANNEL BLOCKERS

↓ SA and AV nodal activity.

↓ Slope of phase 4 (diastolic currents) of AP in pacemakers.

Verapamil

Prototype Ca2+ channel blocker.

Cardioselective, but also blocks vascular Ca2+ channels -> hypotension.

Indications – paroxistic supraventricular tachicardia (PSVT). Prophylaxis in reentrant nodal and atrial
tachycardias-not Wolff-Parkinson-White syndrome
(WPW). Avoid in VT, as may progress to VF. In digitalis toxicity, can ↓ delayed after-depolarization.
Adverse effects: GI distress, dizziness, flushing, hypotension, AV block, CHF-avoid use con-
comitantly with beta blockers.

Rp. Verapamil, tablets 80 mg

I pack
Ds. Orally, 1 tablet every 8 hours
Antiarrhythmic Drugs
Cardiac arrhythmia consists in any disorder of rate, rhythm, origin or conduction of impulses within
heart and can be occur on any other heart disease or without a pre-existent heart disease.
The antiarrhythmic drugs are effective in correction and prevention of cardiac arrhythmias, they can
correct or suppress abnormal electrical cardiac impulses by changing the action potential of cardiac
cells.
The antiarrhythmic medication can act by influencing (blocking or enhancing) of cell membrane
transport of Na+, K+ or Ca2+
The antiarrhythmics are classified based on their mechanism of action, based on their effects on Na+,
K+ or Ca2+ ion fluxes and they are divided into four classes: I, II, III and IV and further class I is
divided in Ia, Ib and Ic.

CLASS I: Na CHANNEL BLOCKERS

Class 1A

The antiarrhythmics in this class block fast Na channels (↓ INa)- Preferentially in the open or activated
state-"state-dependent" blockade.
↑ action potential duration (APD) and effective refractory period (ERP) block K channels (↓ IK,
delayed rectifier current); may also ↓ ICa,
The compounds in this category are decreasing conduction and enhance refractory period.
They are effective in therapy of atrial and ventricular arrhythmias.

Quinidine
In addition to the above, quinidine has anticholinergic effect, which can ↑ HR and AV conduction.
May also cause vasodilation via alpha block with possible reflex tachycardia.
Orally effective, wide clinical use in many arrhythmias; in atrial fibrillation, need initial digitalization,
or administration of verapamil or beta blockers to slow AV conduction.
Adverse effects: nausea and vomiting, cinchonism (GI, tinnitus, ocular dysfunction, CNS excitation),
hypotension, prolongation of QRS and increases QT interval associated with syncope (torsades).
Drug interactions: hyperkalemia enhances effects and vice versa; displaces digoxin from tissue binding
sites, enhancing toxicity; may oppose effects of AChE inhibitors in myasthenia.

Procainamide
Less anticholinergic effect than quinidine and no alpha block, but more cardio-depressant.
Orally effective, often substituting for quinidine. Prolongs APD.
Adverse effects: systemic lupus erythematosus (SLE)-like syndrome (30% incidence) more likely with
slow acetylators, haemato-toxicity (thrombocytopenia, agranulocytosis), CNS effects (dizziness,
hallucinations), CV effects (torsades).

Class 1 B

↓ Vmax (in tachyarrhythmias): block fast Na channels (↓ INa,).

Less state-dependent, block inactivated channels-preference for tissues partly depolarized (slow
conduction in hypoxic and ischemic tissues).
↓ APD-due to block of the slow Na+ "window" currents.
Lidocaine
IV use in arrhythmias post-MI, during open heart surgery, or due to digitalis; drug of choice (DOC) for
arrhythmias following attempted cardioversion.
Clearance depends markedly on liver blood flow, and rapid first-pass effects preclude oral use.
Adverse effects: CNS toxicity culminating in seizures in severe OD. Least cardiotoxic of conventional
antiarrhythmics.

Phenytoin
An antiseizure drug, used occasionally in digitalis intoxication to reverse AV block.
Orally active drug.

Class 1 C

↓↓ Vmax,-block fast Na channels especially His-Purkinje tissue.

No effect on APD.
No ANS effects.

Propafenone, Flecainide and Encainide

Are ecting at atrial and ventricular level. Limited use because of pro-arrhythmogenic effects leading to
↑ sudden death post-MI and when used prophylactically in ventricular tachyarrhythmias (VT).

CLASS II: BETA BLOCKERS

↓ SA and AV nodal activity.

↓ Slope of phase 4 (diastolic currents) of AP in pacemakers.
Prevent beta1 adrenoceptor activation, which would normally ↑ cAMP.
Propranolol (nonselective) and the cardioselective (beta1 selective) drugs: atenolol, metoprolol,
esmolol.
Antiarrhythmic uses: prophylaxis post-MI and in supraventricular tachyarrhythmias (SVTs);
esmolol (IV) is used in acute SVTs.

CLASS III: K+ CHANNEL BLOCKERS

↑ APD and ERP, especially in Purkinje and ventricular tissues.

Mainly ↓↓IK (delayed rectifier current) slowing phase 3 (repolarization) of AP. They decrease
conduction and enhance refractory period.
The drugs in this category are acting at atrial and ventricular level but are considered for therapy of
severe cardiac arrhythmias due to their significant arrhythmogenic risks.

Bretylium
IV use (backup) in life-threatening ventricular arrhythmias.
Releases amines and is pro-arrhythmogenic (torsades).

Amiodarone
Activity mimics all antiarrhythmic drug classes (I, II, III, and IV); blocks Na, Ca, and K channels.
↑ APD and ERP in all cardiac tissues.
Half-life 30 to 60 days.
Effective in a wide range of atrial and ventricular arrhythmias.
Adverse effects: pulmonary fibrosis, corneal deposits, blue pigmentation ("smurf" skin), photo-toxicity,
thyroid dysfunction, ↑ LDL-C, torsades, hepatic necrosis.

Sotalol
Two enantiomers, both of which ↑ APD and ERP (↓ IK delayed rectifier current), and one acts as a
beta1 blocker to ↓ HR and AV nodal conduction.
Approved for prophylaxis in life-threatening ventricular arrhythmias.
Adverse effects: lassitude, impotence, depression, torsades, AV block.

CLASS IV: Ca2+ CHANNEL BLOCKERS

↓ SA and AV nodal activity.

↓ Slope of phase 4 (diastolic currents) of AP in pacemakers.

Verapamil
Prototype Ca2+ channel blocker.
Cardioselective, but also blocks vascular Ca2+ channels -> hypotension.
Indications – paroxistic supraventricular tachicardia (PSVT). Prophylaxis in reentrant nodal and atrial
tachycardias-not Wolff-Parkinson-White syndrome
(WPW). Avoid in VT, as may progress to VF. In digitalis toxicity, can ↓ delayed after-depolarization.
Adverse effects: GI distress, dizziness, flushing, hypotension, AV block, CHF-avoid use con-
comitantly with beta blockers.

OTHER ANTHYARRHYTMICS

Acetylcholine
Decrease supraventricular heart activity in all aspects (decrease conductibility, excitability, contractility
and heart frequency). The compound is acting on muscarinic receptors M2 mainly and, by that, is
opening K+ channels with cell membrane hyperpolarization. Vagal stimulation, via acetylcoline, can
stop supraventricular paroxistic arrhythmias.
Adenozine is effective in supraventricular paroxistical tachyarrhythmias. Is acting on specific adenosinic
receptors and is oppening potasium channels with membranar hyperpolarization. Is administered IV, in
bolus, and has short effect.
Digitalics are effective in management of supraventricular arrhytmias when they are decrease
ventricular frequency. Digitalics are arrhytmogenic drugs but in some particular conditions they can
stop arrithmias by inducing of an inballance inbetween conductibility (decreased) and activity potential
duration (ADP) and effective refractory period (ERP) (decreased).
 Aminoglycosides

Aminoglycosides chemically these substances consist of two or more ozone-type

sugars which are amines (aminoglycosides).
There are 4 families:
• streptomycin family (streptomycin) extracted from Streptomyces griseus,
• neomycin family (neomycin, paromomycin, spectinomycin, ribostamycin
and lividomycin) extracted from Streptomyces fradiae,
• kanamycin family (kanamycin, amikacin, gentreptacine and tobramycin)
extracted from Streptomyces kanamyceticus
• gentamicin family (gentamicin, sisomycin and netilmycin), secreted by the
actinomycete species Micromonospora.

Other authors classify aminoglycosides into 3 generations:

• generation I, which includes streptomycin, kanamycin, spectinomycin,
paromomycin and neomycin,
• generation II, which includes gentamicin, tobramycin and sisomycin, and
• generation III, which includes amikacin, dibekacin, netilmycin and
isepamicine.
The antimicrobial spectrum of aminoglycosides is narrow including especially
Gram-negative bacilli (E. coli, Klebsiella, Salmonella, Shigella, Yersinia, Proteus,
Haemophilus), tuberculosis bacillus (Koch bacillus), but also Gram-positive and
negative cocci. For example, streptomycin is very active in M. tuberculosis, Brucella and
Yersinia, being indicated in the treatment of TB, plague, tularemia, brucellosis or
enterococcal infections.
As a mechanism of action, aminoglycosides irreversibly inhibit bacterial protein
synthesis by binding to the aminoacyl site of the 30S ribosomal subunit, which results
in altered RNA transcription resulting in the synthesis of toxic proteins and cell death.
Toxic proteins may persist in microbes longer than the antibiotic so that the toxicity of this
antibiotic is maintained even after their disappearance from microbes, a phenomenon
known as post-therapeutic effect, present especially in the tubercle bacillus. They have an
absolute bactericidal action that settles quickly and is dose dependent. After diffusion
through membrane channels, aminoglycosides are actively transported transmembrane
through an oxygen-dependent process. This active transport is inhibited if the intracellular
pH is low or under anaerobic conditions, the aminoglycosides being ineffective on
anaerobic bacteria. At the same time, the transport of intracellular aminoglycosides is
favored by antibiotics that inhibit the formation of the cell wall, such as penicillins,
cephalosporins and vancomycin. This explains the synergistic relationships between these
antibiotics and aminoglycosides.
1
 Resistance is cross-linked between aminoglycosides in the same family, but is not
usually cross-linked between families. And it is produced by the synthesis by
microorganisms of enzymes that inactivate aminoglycosides by adenylation, acetylation or
phosphorylation; reduction of the intracellular penetration capacity of the antibiotic by
genetic modifications of the proteins involved in its transport; alteration of the receptor
protein on the 30S ribosomal subunit; activation of efflux mechanisms.
From a pharmacokinetic point of view, aminoglycosides have several
peculiarities. Due to the polar molecule, aminoglycosides are not absorbed from the
digestive tract, but are not destroyed locally. Therefore, they should never be given orally
if you are treating a systemic infection. In this situation aminoglycosides are administered
only as an intramuscular or intravenous injection. If administered orally, they are effective
in the treatment of digestive infections, achieving high concentrations in the digestive tract
and are virtually free of systemic toxicity because they are not absorbed.
Aminoglycosides diffuse well in some tissues such as the kidneys, inner ear or
placenta and very little in bronchial secretions, bone, aqueous humor or CSF.
Aminoglycosides are eliminated by the kidneys in a proportion of 94%, the rest
is eliminated through feces, saliva and other body fluids. Urinary concentrations exceed
the plasma level 25-100 times per hour after parenteral administration. Because it is
relatively difficult to eliminate from the body, it is administered every 12 hours.
Aminoglycosides are ototoxic and nephrotoxic. Toxicity occurs especially in the
case of therapies lasting more than 5 days, after high doses, in elderly, in patients with pre-
existing renal or otic impairment.
Ototoxicity (60-65%) refers to toxicity to the acoustic-vestibular apparatus.
Toxicity to the acoustic branch is manifested at first by ringing in the ears, changes
in sound perception, deafness.
Vestibular manifestations begin with headache, nausea, vomiting, dizziness, gait
disorders, balance, movements in general.
Renal impairment requires regular monitoring of blood urea and creatinine. It is
usually reversible.
At high doses aminoglycosides can cause neuromuscular block with a risk of
respiratory paralysis (apnea). Other possible side effects are minor allergic reactions,
endophlebitis.
Aminoglycosides are indicated in infections with germs sensitive to those
antibiotics.
Aminoglycosides are contraindicated in patients with hearing impairment,
severe renal impairment, myasthenia gravis, hydroelectrolytic disorders or
pregnancy. The use of aminoglycosides in the newborn and young child should be done
with caution as it is difficult to establish cochlear involvement.

2
 Antibiotics that inhibit protein synthesis

This group comprises a series of antibiotics that bind reversibly to bacterial

ribosomes (either the 30S subunit or the 50S subunit and thus inhibit protein synthesis
generally having a bacteriostatic effect), as well as a series of antibiotics that inhibit protein
synthesis by inhibiting RNA- DNA polymerase dependent.

Tetracyclines

Tetracyclines have a structure consisiting in a four-rings nucleus having different

radicals.
• Chlortetracycline, oxytetracycline, tetracycline belong to the first generation.
• Demeclocycline, methacycline, doxycycline, minocycline and
rolitetracycline belong to the 2nd generation.
Tetracyclines act bacteriostatically, inhibiting bacterial protein synthesis by
reversibly binding to the 30S ribosomal subunit of bacteria. After being actively
transported, by an energy-dependent process in the bacterial cell, it inhibits the synthesis
of bacterial proteins by blocking the amino-acyl-tRNA binding of the ribosome.
Initially, their spectrum of antibacterial activity was wide, being active on
aerobic and anaerobic Gram-positive and Gram-negative bacteria, as well as on
spirochetes and so-called transition germs (chlamydia, mycoplasma, rickettsia).
Tetracycline resistance is cross-linked.
Because tetracyclines have good intracellular penetration, they are preferred in
infections with intracellular bacteria (Chlamydia, Mycoplasma, Rickettsia). They are also
effective in brucellosis (Brucella), recurrent fever (Borelia recurrentis), cholera (Vibrio
cholerae), tularemia (Francisella tularensis), Lyme disease, malaria (if P. falciparum is
resistant to chloroquine). They are advantageous in atypical pneumonias caused by
Chlamydia, Coxiella, Francisella, Mycoplasma, Legionella, Pasteurella.
Bacterial resistance to tetracyclines sets in slowly and is plasmid-type. The most
important mechanism of resistance is to increase the activity of a pump that actively
transports tetracycline outside the bacterial cell. Other mechanisms of resistance are
decreased access to ribosomes due to decreased active intrabacterial transport or chemical
inactivation.

3
 The pharmacokinetic profile differs depending on the active substance.
Thus, the classic tetracyclines (tetracycline, oxytetracycline) are absorbed in a
proportion of 70% in the stomach, duodenum and in the first part of the small
intestine. Their absorption is low in case of gastric hypoacidity, in the presence of food
(especially dairy products), as well as drugs containing bivalent and trivalent cations
(calcium, magnesium, aluminum, iron). With these substances, tetracyclines form non-
absorbable chelates. Some of the amount of tetracycline administered orally remains in the
intestinal lumen and alters the saprophytic bacterial flora, which can frequently cause
intestinal dysmicrobisms.
Doxycycline and minocycline, second generation tetracyclines, have a higher
bioavailability of approximately 95% after oral administration. As such, compared to
classical tetracyclines, they do not disturb the intestinal flora so much, but they are not
useful in infectious diarrhea, as is sometimes the case with tetracycline.
Depending on T1/2, 2 groups are distinguished:
• short-acting tetracyclines such as tetracycline (T1/2 up to 9 hours) and
• long-acting tetracyclines including doxycycline and minocycline (T1/2 up to
17 hours). h).
Plasma protein binding is 20-65% for tetracycline, while for doxycycline it is 80-
90%.
Tetracyclines accumulate in bones and teeth and achieve high concentrations in milk
due to their calcium chelating properties. They achieve concentrations in the bile 10 times
higher than the serum ones. Some of the active substance in the bile is reabsorbed in the
intestine (entero-hepatic circuit), which helps maintain elevated plasma levels for a longer
period of time.
Classic tetracyclines are eliminated 50% by the kidneys and 40% by the feces. In
contrast, doxycycline is not eliminated either by the liver or by the kidneys, but is slowly
eliminated by backscatter in the colon as inactive chelates, without significantly
influencing the intestinal bacterial flora. It does not accumulate significantly in liver and
kidney failure. Tetracyclines are partially excreted by glomerular filtration (50%
tetracycline and 10% minocycline).
As possible side effects, the staining of the teeth in yellow-brown and the inhibition
of growth in length due to the accumulation in the teeth and bones, due to their remarkable
affinity for the calcium ion. Tetracyclines should not be used in children under 7 years of
age or in pregnant women, especially in the last trimester of pregnancy.
Oral tetracyclines are irritating to the digestive tract and can cause epigastric pain,
nausea, and vomiting. Tetracyclines (except doxycycline and minocycline) can produce
intestinal dysmicrobisms by destroying saprophytic intestinal flora. They can cause
diarrhea through intestinal irritation. Tetracyclines can also be nephro and hepatotoxic
especially if administered in high doses. Caution is thus required in liver and kidney
patients. Exhausted tetracycline preparations should not be used, as they may cause severe
kidney disease, known as Fanconi's syndrome (proximal tubulopathy). Other side effects
4
that may occur after tetracyclines are neurotoxic side effects manifested by vestibular
syndrome or moderate intracranial hypertension syndrome. Tetracyclines can also cause
hemolytic anemia, thrombocytopenia, neutropenia or eosinophilia.
In addition, second-generation tetracyclines may cause photosensitization reactions
(the patient should avoid sun exposure during treatment), or rash.
Tetracyclines are contraindicated in pregnancy, lactation, children under 7 years of
age, in conditions of sun exposure, in people allergic to tetracyclines and are to be avoided
in conditions of renal failure due to cumulative effects.

Macrolides

The macrolide family has as main representative erythromycin. All antibiotics

belonging to this class are based on a large cyclic structure that can contain between 14-16
carbon atoms, so these antibiotics are called macrolides. Depending on the number of
atoms in the lactone nucleus, macrolides can be composed of 14 atoms obtained either
naturally (eg erythromycin, oleandomycin) or by semisynthesis (roxithromycin,
dirithromycin, flurithromycin, clarithromycin), compounds with 15 atoms (azithromycin)
also known as azalides or compounds with 16 atoms obtained naturally (josamycin,
kitamycin, spiramycin, midecamycin) or by semisynthesis (rokitamycin, myocamycin).
Some macrolides have antibacterial properties, others antifungal (polyene
macrolides). Erythromycin and other compounds with 14 carbon atoms also have a
stimulating effect on intestinal motility as well as an anti-inflammatory effect.
The antibacterial spectrum of macrolides is narrow, somewhat similar to that
of penicillin, comprising mainly Gram-positive and negative cocci (streptococcus,
staphylococcus, pneumococcus, N.meningitidis, N. gonorrhoea), aerobic Gram-positive
bacilli (B.anthrteris, C.diph , Listeria), Gram-negative aerobic bacilli (Bordetella,
Helicobacter pylori, Campylobacter, Legionella), spirochete (Leptospira, Borellia,
Treponema). In addition, macrolides are also active on penicillin-resistant microbes
(Chlamydii, Mycoplasme). Macrolides are of choice in toxoplasma gondi infections
(spiramycin, clarithromycin, azithromycin), in those with Mycobacteria
(clarithromycin, azithromycin) or in Cryptosporidium infections.
Erythromycin, like other macrolides, has bacteriostatic or bactericidal
properties, depending on the concentration of the antibiotic and the microbial species. It
is also active against intracellular germs, achieving high concentrations in macrophages
and polynuclear leukocytes.

5
 Pharmacokinetics. Its action is optimal at an alkaline pH, when the non-ionized
form predominates. Erythromycin has a relatively low bioavailability after oral
administration. Digestive absorption is reduced by the presence of food. Erythromycin
stearate, propionate and estolate are stable preparations against stomach hydrochloric acid.
T1/2 of erythromycin is 2 hours. It is 74% bound to plasma proteins. It has a good tissue
diffusion, especially at the level of the respiratory tract, at the skin level and at the
urogenital level. It penetrates slightly into the CNS, CSF or aqueous humor. It is
metabolized by the liver and then excreted in bile and faeces in high concentrations.
Subsequently, a small part is excreted in the urine.
Pharmacodynamics. It acts by reversibly binding to the 50S ribosomal subunit
and by preventing the synthesis of bacterial proteins. The fixation process is
competitive for erythromycin, clindamycin and chloramphenicol, which may lead to
antagonistic interactions.
Erythromycin proprionil is administered orally, erythromycin lactobionate and
erythromycin gluceptate can be administered intravenously.
Erythromycin is the antibiotic of first choice in pneumonia with Mycoplasma
pneumoniae, in the treatment of legionnaires' disease (legionellosis), pneumonia with
Chlamydia trachomatis in infants, severe forms of enterocolitis with Campylobacter jejuni,
diphtheria, whooping cough, erythrasma. It is indicated as an alternative to penicillin in
patients allergic to penicillin, who have streptococcal, pneumococcal, mild staphylococcal
infections, anthrax, actinomycosis, recent syphilis, Listeria monocytogenes infections.
The mechanism by which erythromycin resistance is established is multiple and can
be explained by alteration of the binding site, the existence of an active efflux mechanism,
or by an enzymatic modification of macrolides mediated by esterases or
phosphotransferases.
Adverse reactions: Digestive irritants (nausea, vomiting, diarrhea and abdominal
pain that may be explained by binding of the antibiotic to the motilin receptor in the
gastrointestinal smooth muscle). If given as an injection, it can cause local reactions, with
intramuscular injection being very painful, while the intravenous route can cause
thrombosis. Intravenous administration of high doses of erythromycin may temporarily
affect hearing. The most severe side effect that erythromycin can cause is cholestatic
hepatitis. Erythromycin can sometimes cause allergic events with fever, rash, eosinophilia
or even anaphylactic shock.
Erythromycin may have clinically significant drug interactions by inhibiting
cytochrome P450 and slowing the metabolism of some associated drugs. Combination with
terfenadine, astemizole (anti-H1 antihistamines) and cisapride can sometimes cause severe
arrhythmias, especially torsade de pointes.
Other macrolide antibiotics generally have erythromycin-like properties.
Roxithromycin and clarithromycin have a higher bioavailability of erythromycin
after oral administration and a longer half-life. In addition, they have a high penetrability
in macrophages and leukocytes. A specific indication for clarithromycin is therapy to
6
eradicate Helicobacter pylori infections in patients with gastric or duodenal ulcers. The
regimens used usually vary, with one or more antibacterial chemotherapeutics being
associated with gastric antisecretors.
Josamycin is similar to erythromycin, having a higher bioavailability after oral
administration.
Azithromycin is more active than chlamydia than erythromycin, against
H.influenzae, Legionella, Neisseria, Bordetella and Salmonella. It has a good
bioavailability after oral administration but is reduced by concomitantly administered
foods or antacids. It is excreted entirely in the bile and only in a small proportion in the
urine. It does not affect the function of the cytochrome P450 enzyme system.
Spiramycin is a macrolide of choice in Toxoplasma gondi or Cryptosporidium
infections.
Dirithromycin has a rapid absorption after oral administration that is not influenced
by the presence of food in the stomach.

Other antibiotics that act by inhibiting protein synthesis

Glycylcyclines

Glycycyclines (eg tigecycline) are antibiotics with bacteriostatic or bactericidal

effect (depending on dose and species).
It works by inhibiting the synthesis of bacterial proteins in the 30S ribosomal
subunit, preventing the binding of tRNA to the specific site at the ribosomal level.
Acts mainly on aerobic Gram-positive cocci (streptococci, methicillin-resistant and
methicillin-sensitive staphylococci, including vancomycin-intermediate staphylococci
(VISA) and glycopeptide-intermediates (GISA), enterococci, including penicillin-resistant
vancomycin-resistant strains) and penicillin-resistant), anaerobic Gram-positive cocci
(peptostreptococci), aerobic Gram-positive bacilli, anaerobic Gram-positive bacilli (Cl.
Difficile, Cl. perfringens), mycobacteria and chlamydia. Germs such as Providentia and
Proteus are resistant to tigecycline.
Pharmacokinetically, tigecycline has a long T1/2 (over 40 hours), binding in
proportion of over 70% to plasma proteins, good tissue diffusion, predominantly biliary
elimination.

7
 As side effects tigecycline can cause digestive disorders, photosensitization, hepatic
cytolysis or even acute pancreatitis. It is contraindicated in pregnancy, in children under 8
years, in case of sun exposure or in the case of those allergic to tetracyclines.
Tigecycline is indicated for the treatment of intra-abdominal infections of
unspecified etiology, including nosocomial infections, severe soft tissue infections or adult
community-acquired pneumonia. Tigecycline is active in Cl.difficile infections and is the
only therapeutic alternative in Acinetobacter infections in combination with colistin.
Tigecycline is administered in venous infusion slowly.

Phenicol antibiotics

Chloramphenicol and thiamphenicol are the main representatives.

Chloramphenicol has an antibacterial spectrum, similar to tetracyclines and
includes Gram-positive, Gram-negative germs, mycoplasmas, rickettsiae. It is very
active against anaerobic germs, including B. fragilis.
Chloramphenicol acts bacteriostatically by inhibiting microbial protein
synthesis due to binding of bacterial ribosomes to the 50S subunit. Compared to H.
influenzae, N. meningitidis and Bacteroides, chloramphenicol may have a bactericidal
effect.
Resistance to chloramphenicol is mainly due to the production of acetyltransferase
that inactivates the antibiotic (plasmid-mediated).
Pharmacokinetically, it is rapidly absorbed after oral administration. It first passes
into the lymph and concentrates a lot in the lymph vessels and lymph nodes and only then
reaches the blood. This is of great importance in typhoid fever (the disease caused by
Salmonella typhi, which multiplies precisely in the lymph nodes, the place where
chloramphenicol is well concentrated). The tissue distribution is very good due to the fat
solubility of its molecule. It passes easily into the central nervous system and cerebrospinal
fluid (CSF). It is inactivated by hepatic glucuronidation. 90% of the urine is excreted in
inactive form and only a small percentage in active form. Chloramphenicol is inactive in
urinary tract infections even if it is caused by microbes on which it is active on the
antibiogram. Thiamphenicol is not converted to the liver and is excreted in the urine in
active form.
Chloramphenicol is administered mainly orally or by intramuscular injection 6-8
hours apart. There are also topical preparations for skin and mucous membranes that
contain 1% chloramphenicol.
It is indicated in severe infections, in which the sensitivity of the causative agent
and / or its location do not allow other therapeutic options. Thus, it is possible in typhoid
8
fever and other salmonellosis, in purulent meningitis with Haemophyllus influenzae, in
brain abscesses or in bacterial encephalitis, especially with Gram-negative anaerobic
bacteria. They are also indicated in lung infections.
Clinical use is currently very limited due to its high toxicity and the fact that many
resistant bacteria have been selected.
Among the most serious adverse reactions are hematological, medullary aplasia,
with leukopenia and agranulocytosis, with frequently irreversible evolution. It is very likely
of an idiosyncratic nature, the phenomena being independent of the dose and being able to
develop even after a time after the end of the treatment. There are also benign, toxic, dose-
dependent hematopoietic accidents, manifested by anemia, leukopenia and
thrombocytopenia. Chloramphenicol may cause severe haemolytic anemia in patients with
glucose-6-phosphate dehydrogenase deficiency.
Another very serious, often fatal, side effect is "gray syndrome", which occurs
in newborns, most often after 4 days of treatment, when high doses of chloramphenicol are
given. It is manifested by anorexia, vomiting, diarrhea, dehydration, cyanosis, lethargy.
Other side effects reported are those in the digestive tract manifested by nausea, vomiting,
diarrhea. Toxic neuro-psychic complications may also occur with optic neuritis,
ophthalmoplegia, confusion or depression. Fennel can also cause coagulation disorders by
interfering with the action of vitamin K. In the treatment of typhoid fever, brucellosis or
syphilis with high doses of chloramphenicol, Herzheimer's reactions may occur.
Chloramphenicol is contraindicated in people allergic to chloramphenicol, in those
with pre-existing haematological disorders, in infants and especially in premature infants,
in case of renal insufficiency or in pregnant women.
Thiamphenicol achieves higher concentrations in the bile and urine. It is
administered parenterally, i.m.

Lincosamide antibiotics

Lincomycin and clindamycin, although structurally different from erythromycin,

have similar activity to it, acting bacteriostatically by inhibiting bacterial protein
synthesis after binding to the 50S ribosomal subunit at a common site with
erythromycin. They can also have a bactericidal effect at high doses and only against
certain germs. As such, lincosamides, erythromycin, and chloramphenicol may compete
for the same binding site, so the combination of these antibiotics is not recommended. In
addition, lincosamide resistance is cross-linked to erythromycin resistance.
The activity spectrum of lincosamides includes aerobic Gram-positive cocci such as
staphylococci or streptococci, aerobic Gram-positive bacilli (B.antracis, C.diphteriae),
aerobic Gram-negative bacilli (Campilobacter), anaerobic bacteria (Cl. Perfringens,
Actinomyces, Prevotella) or other germs such as Mycoplasma hominis, Ch. Trachomatis.
9
Clindamycin is of choice in infections with Toxoplasma gondi, Plasmodium or
Pneumocystis sp.
Resistance to lincosamides can be explained by insufficient access of the antibiotic
to the site of action, or by alteration of the site of action. In the case of coagulase-negative
staphylococci, they have been found to secrete a nucleotidyltransferase that enzymatically
inactivates lincosamides.
The pharmacokinetics of these antibiotics differ depending on the compound.
Clindamycin has good absorption after oral administration which is not influenced by the
presence of food in the stomach. T1/2 is 3 hours for clindamycin, while for lincomycin it
is 5 hours. Once bound to plasma proteins, they have good tissue diffusion, including in
bone but limited in CSF. They are metabolized by the liver and eliminated in the bile and
urine. However, dose adjustment is required in case of hepatic and renal impairment.
Lincomycin is highly toxic, so its use is currently limited.
Clindamycin is indicated orally or by injection especially in the treatment of severe
infections with anaerobic germs except for meningeal localization. It is indicated in most
infections with Gram-positive and Gram-negative germs, especially in those with
Bacteroides fragilis. Although active on most Gram-positive bacteria, clindamycin should
be considered a reserve antibiotic because it promotes superinfection with Clostridium
difficile strains, developing severe pseudo-membranous colitis.
Clindamycin can cause side effects in the gastrointestinal tract, allergic reactions,
toxic hepatitis, or haematological disorders. Cases of cardiac arrest and hypotension have
been reported following bolus administration of this antibiotic. Clindamycin potentiates
the action of neuromuscular blockers when co-administered with them.

Synergistines antibiotics

Pristinamycin, dalfopristin and quinupristin are antibiotics in this class. It binds

to the 50S ribosomal subunit, thus preventing protein synthesis.
The spectrum of action of these antibiotics is the same as that of macrolides but they
have a higher activity on Gram-positive cocci such as pneumococci (even those resistant
to macrolides), staphylococci (even on some methicillin-resistant strains), enterococci
(only the combination dalfopristine / quinupristin). Synergists also act on gram-negative
cocci, anaerobic bacteria, mycoplasmas, chlamydia, legionella or coxielle.
The main side effects of synergists are gastrointestinal disorders and
hypersensitivity reactions.

10
 Ketolides
Telithromycin, cetromycin and solithromycin are antibiotics derived from 14-
atom semisynthetic macrolides.
Mechanism of action: blocks the synthesis of bacterial proteins by binding to the
50S ribosomal subunit. Their spectrum of action is similar to that of macrolides to which
Streptococcus peumoniae is added and some macrolide-resistant staphylococcal strains as
well as macrolide-resistant pyogenic streptococcal strains.
Pharmacokinetically, they have a very good oral bioavailability. They have a half-
life of 10 hours, which makes it possible to administer them in a single daily dose. It binds
in a proportion of 50-70% to plasma proteins. They enter the alveolar macrophages where
they achieve concentrations clearly higher than the serum ones. They are metabolized by
the liver and eliminated by the bile.
Indications: respiratory tract infections or ENT infections, especially sinusitis.
Side effects: digestive disorders such as nausea and vomiting, toxic hepatitis,
prolongation of the QT interval, exacerbation of myasthenia gravis. Ketolides may interact
with digitalis, benzodiazepines, statins or aminophylline (increasing serum levels of these
drugs).

Oxazolidinones
Linezolid, posizolid, toresolid and radezolid are the main representatives. Inhibits
bacterial protein synthesis by blocking the formation of the initial complex that associates
tRNA, mRNA and the 50S ribosomal subunit. They are bacteriostatic.
Oxazolidone-sensitive germs are Gram-positive cocci (streptococci, methicillin-
resistant and methicillin-sensitive staphylococci, enterococci, pneumococci), aerobic
Gram-positive bacilli (Bacillus spp., Corynebacterium spp., Listeria monocytogenes) and
mycobacteria. They are indicated in systemic infections with vancomycin-resistant
enterococci or methicillin-resistant or vancomycin-resistant staphylococci, in severe
nosocomial pneumonias with methicillin-resistant staphylococci or pneumococci resistant
to other antibiotics, in severe soft tissue infections, in mycobacterial infections.
Pharmacokinetics. Linezolid has an oral bioavailability of 100% and a half-life of
4-5 hours. It is 31% bound to plasma proteins. It has a good tissue diffusion, especially in
the alveolar macrophages of the lungs, in the bone, adipose tissue, in the muscles or in the
CSF. It is metabolized by oxidation. Does not interfere with the cytochrome P450 system.
85% of the kidneys are excreted, of which only 30-40% in unmetabolized form.
The drug can be administered either orally or intravenously, 12 hours apart.
Side effects of linezolid are digestive disorders, hepatic cytolysis, peripheral
neuropathy, optic neuritis, headache, insomnia or even acute psychosis. Prolonged
treatment can lead to myelosuppression with thrombocytopenia, probably through immune
mechanism, anemia and less often neutropenia.
11
 Fusidic acid

Fusidic acid has a steroidal structure. Inhibits protein synthesis in transfer RNA. At
usual doses it is bacteriostatic, but at high concentrations it becomes bactericidal. Its
spectrum of action includes aerobic Gram-positive cocci (such as Streptococcus pyogen,
methicillin-sensitive and methicillin-resistant staphylococcus, linezolid-resistant
staphylococcus) and anaerobes, Gram-negative cocci, Gram-positive bacilli
(corynebacteria, listers, N , Actynomices, clostridia), mycobacteria or chlamydia.
Pharmacokinetically, the drug has a digestive absorption of 95% after oral
administration, is more than 90% bound to plasma proteins and has a T1/2 of 5-6 hours. It
diffuses well in bones, joints, heart, kidneys, skin, bronchial secretions, aqueous humor
and is eliminated exclusively by the bile.
It is indicated in localized or generalized staphylococcal infections, in infections
with anaerobic Gram-positive germs, in the prophylaxis of bone or soft tissue infections in
trauma, or in gonococcal infections resistant to other antibiotics.
Side effects: digestive, allergic, hepatic disorders, immune thrombocytopenia or
rhabdomyolysis if statins are combined.
Fusidic acid can be administered orally or by intravenous infusion at a very slow
rate. Cyclosporine-like immunosuppressive properties have also been described with the
drug.

Macrocyclic Antibiotics

The only representative, fidaxomycin, has a nonpeptide macrolide structure.

Inhibits RNA polymerase, thus inhibiting protein synthesis.
Its spectrum of action is extremely narrow, acting only on Clostridium difficile.
The antibiotic is very little absorbed from the digestive tract, has a half-life of 11
hours, is eliminated digestively after it has been previously hydrolyzed.
Digestive disorders (nausea, vomiting, abdominal pain) and haematological
disorders (anemia) are among the most common side effects.

12
 Rifamycins

Rifampicin is the first representative of the class.

Rifampicin is active on mycobacteria, including Mycobacterium tuberculosis on
Gram-positive and Gram-negative shells, including methicillin-resistant staphylococci,
Gram-positive bacilli including Clostridium difficile and some Gram-negative bacilli such
as H. Influenzae, Bacteroides or Legionella. In addition, it acts on some enterobacteriaceae,
chlamydia, and even some poxviruses.
It has bactericidal action especially against rapidly dividing germs (including
extracellular germs as well as germs contained in phagocytes or present in abscesses or
lung cavities). The antibiotic acts by inhibiting protein synthesis due to inhibition of DNA-
dependent RNA polymerase. Human RNA polymerase does not bind rifampicin, so it is
not affected. In the case of poxviruses, the antibiotic blocks a late stage of assembly,
probably by interfering with the formation of the envelope of viral particles.
Resistance develops rapidly in one step. The resistance is due to a gene mutation
that alters RNA polymerase and prevents antibiotic binding at this level.
Pharmacokinetics. Rifampicin is administered orally, benefiting from very good
digestive absorption. It is widely distributed in tissues, achieving higher than plasma levels
in the liver, lungs, bones, CSF, serosa, bile and urine. It enters the tuberculous casein and
staphylococcal abscesses. The time of ½ is 2-5 hours. It is metabolized in the liver by 80-
90% and excreted in the urine by 30%. Rifampicin has tuberculosis as its main indication.
Rifampicin can also be used in endocarditis, osteomyelitis or septic arthritis with
Staphylococcus aureus, sepsis with Gram-negative germs resistant to other antibiotics,
Legionella pneumonia, meningitis with penicillin-resistant pneumococci or leprosy.
The main adverse reaction of rifampicin is toxic liver damage, with a risk of
reversible hepatitis, in 1% of patients. May produce asymptomatic cytolysis or cholestatic
jaundice. It can cause immunoallergic accidents, being characteristic the appearance after
a few months of treatment of a syndrome that simulates the flu (flu-syndrome). Interstitial
nephritis, thrombocytopenia, hemolytic anemia may also occur, probably also through an
immunoallergic mechanism. Can turn urine, tears, even contact lenses red. It may have a
moderate immunosuppressive effect, especially of cell-mediated immunity. It has an
inductive effect on hepatic microsomal enzymes, which favors the metabolism of
associated drugs, with a decrease in their plasma levels (glucocorticoids, estrogens,
antidiabetic sulfamides, oral anticoagulants, digoxin, ketoconazole, chloramphenicol,
cyclosporine). For the same reason it is contraindicated in patients with porphyria.
Increases urinary excretion of methadone, causing withdrawal symptoms in patients
addicted to this drug. Rifampicin is given orally, im, or iv.
Rifabutin and rifamixin are other compounds in the rifamycin class.

13
 Antibiotics with peptide structure
Antibiotics with peptide structure act on the cell wall or cytoplasmic membrane
and have bactericidal effect.

1. Antibiotics with glycopeptide structure: vancomycin, teicoplanin,

telavancin, bleomycin, ramoplanin and decaplanin.

These antibiotics have narrow antibacterial spectrum - aerobic and anaerobic Gram-
positive bacteria - Streptococcus pyogen, Streptococcus viridans, Streptococcus
pneumoniae, enterococci, methicillin-sensitive and methicillin-resistant Staphylococcus
aureus, aerobic Gram-positive bacilli, B. , C.diphteriae, Listeria monocytogenes, Gram-
positive anaerobic bacteria - Peptostreptococcus, Actinomyces, Clostridium difficile.
Glycopeptides have degenerative bactericidal similar with beta-lactam antibiotics -
inhibits the synthesis of the bacterial wall by blocking the activity of transglycosylases and
transpeptidases.
Indications: severe infections with staphylococci, pneumococci, streptococci or
enterococci, with germs resistant to other antibiotics, in digestive decontamination of
immunocompromised patients, in the prophylaxis of infectious endocarditis, in patients
with beta-lactam allergy.
Pharmacokinetics. Glycopeptides are not absorbed digestively. Have affinity for
plasma protein and a good difusion into urine, pericardium, pleural, synovial liquid, liver.
They penetrate the cerebrospinal fluid with difficulty. Can cross the placental barrier. In
the newborn, in the presence of inflammation, vancomycin achieves better levels in the
CSF compared to those achieved by the adult. It is eliminated by renal excretion - caution
in patients with renal impairment.
Vancomycin. It acts on aerobic Gram-positive bacteria. It can be administered
orally or intravenously (for systemic effects). In addition to the above indications common
to all glycopeptides, vancomycin can be administered orally in pseudo-membranous colitis
with Clostridium difficile. Vancomycin should be considered a reserve antibiotic, with
strict indications, due to the risk of developing resistance.
Side effects - local irritation, phlebitis at the injection site, oto- and nephrotoxicity,
transient neutropenia, hypersensitivity reactions, increased hepatic transaminases. Rapid
intravenous injection may cause a transient reaction, called "red man syndrome" due to the
release of histamine through a non-allergic mechanism. It is contraindicated in pregnant
women or in case of allergy to glycopeptides.
Teicoplanin has similar action to vancomycin but higher potency. It is
administrated only injectable. Teicoplanin is less oto- and nephrotoxic than vancomycin.
High doses can cause thrombocytopenia or eosinophilia. Compared to vancomycin,
teicoplanin produces anaphylactic shock more frequently.

14
2. Polypeptide antibiotics: polymyxin E, polymyxin B, bacitracin, gramicidin.

Polymyxins are active on Gram-negative bacilli with absolute bactericidal effect by

altering the cytoplasmic membrane. Spectrum - enterobacteriaceae, Pseudomonas,
Acinetobacter, Haemophilus or Pasteurella.
Pharmacokinetics. Polymyxins B and E are administered systemically in the
treatment of infections with multidrug-resistant Gram-negative bacilli.
They can be administered orally for the strictly local effect of the digestive tract in
digestive decontamination, in local intra-articular, intraconjunctival applications, in the
external auditory canal (otitis externa) or on the skin (skin infections).
Polymyxin B sulfate can be administered orally, topically in the form of solutions
or ointments or even injected intraarticularly. For local applications it is usually
conditioned in pharmaceutical forms in combination with bacitracin and / or neomycin,
being indicated for the treatment of various eye or skin infections. Oral administration is
useful in colibacillary dyspepsia in infants and children, and systemic use is reserved for
severe infections with sensitive Gram-negative bacilli - Enterobacteriaceae or
Pseudomonas aeruginosa.
Side effects - nephro and neurotoxicity; at high doses it can cause paralysis of the
striated muscles, with apnea.
Polymyxin E (colistin) acts similarly to polymyxin B, having the same indications
and generally the same toxic side effects. It is better tolerated than polymyxin B. It is
administered orally for local effects in the intestine but is most often applied topically on
the skin or mucous membranes.
Bacitracin and gramicidin are polypeptide antibiotics active on most Gram-positive
bacteria, Treponema pallidum, gonococcus, meningococcus and anaerobic cocci. They
have a degenerative bactericidal action, by preventing the formation of the bacterial wall.
They are not used systemically due to their high nephrotoxicity. Sr are used only in local
applications for ophthalmic or skin conditions, in combination with neomycin and / or
polymyxin.

3. Lipopeptide antibiotics. Daptomycin.

It is a lipopeptide antibiotic with bactericidal action by destroying cell membranes.
Spectrum: Gram-positive bacteria especially methicillin-resistant or methicillin-sensitive
staphylococci with localization, especially systemic, endocardial or osteoarticular, in
enterococcal infections or in infections of the skin and soft tissues. Daptomycin is an
alternative to glycopeptides for the treatment of bacterial endocarditis with beta-lactam-
resistant Gram-positive cocci.

15
 4. Phosphomycin
It is a phosphonic acid-derived antibiotic that inhibits bacterial wall synthesis by
inhibiting the synthesis of peptidoglycan precursors. It is active on Gram-positive cocci
(pneumococcus, staphylococcus, even methicillin-resistant), Gram-negative cocci
(Neisseria spp), Gram-negative bacilli (enterobacteriaceae, Serratia). Phosphomycin is
indicated in severe osteoarticular, meningeal infections with multidrug-resistant Gram-
negative bacilli, in low urinary tract infections.

Synthetic chemotherapeutics

This group includes synthetic antibacterial chemotherapeutics such as sulfamides,

trimethoprim, quinolones and nitrofurans.

1. Antibacterial sulfamides and trimethoprim

Sulfamides are synthetic chemotherapeutics, p-aminobenzenesulfonamide group.

The antibacterial properties of these compounds and the resistance of microbes are
cross-linked between these substances.
The antibacterial spectrum is wide, including bacteria such as H. influentzae,
Enterobacteriaceae, Shigella, E.Coli, chlamydia, mycoplasmas, actinomycetes, nocardia,
some protozoa such as toxoplasmas, Pneumocystis, plasmodias.
Are indicated in urinary tract infections with sensitive germs, trachoma, chlamydia
genital and lung infections, nocardiosis, toxoplasmosis, or Crohn's disease. They can be
useful in biliary and respiratory infections, sinusitis, bacillary dysentery, in infectious
diarrhea, in herpetiform dermatitis. It is combined with trimethoprim to increase
antibacterial efficacy.
The mechanism of action is bacteriostatic, by interfering with the bacterial folic
acid synthesis. The selectivity of action on bacteria derives from the fact that pathogenic
microorganisms synthesize their own folic acid, starting from paraaminobenzoic acid,
while the cells of the macroorganism do not synthesize their folic acid, but receive it
through food or medicine, so they will not be affected by sulfamides.
Pharmacokinetics. Most sulfamides are well absorbed by the digestive tract, are
highly bound to plasma albumin and are widely distributed in most tissues and serosa,
16
including the central nervous system, CSF, peritoneal fluid, pleural fluid. Are metabolised
by acetylation or hepatic glucuronidation; the acetylated products being inactive against
bacteria, but toxic and sometimes hardly soluble, being able to crystallize in urine.
Elimination is predominantly by glomerular filtration and is favored by alkalinization of
urine.
There are sulfamides that are hardly absorbed from the digestive tract and are used
to treat infectious diarrhea - phthalylsulfathiazole which is inactive and non-absorbable.
There are sulfamides for applications on the skin and mucousa, low allergenic, non-
irritating - sulfacetamide (there is an eye drop with sufacetamide, useful in conjunctivitis),
mafenide and silver sulfadiazine, recommended in the treatment of superinfected wounds
and burns.
Side effects: allergic reactions - fever, prurit, rash, Stevens-Johnson syndrome,
Lyell syndrome. Sulfamides develop cross-allergy: a patient allergic to one sulfamide may
be allergic to all sulfamides. The most allergenic route of administration is the cutaneous-
mucosal route. Sulfamides are highly concentrated in the urine - they are very active in
urinary tract infections; if the volume of urine excreted in 24 hours is small and the pH of
the urine is acidic, sulfamides may precipitate in the renal tubules and hematuria,
crystalluria, renal colic, or even renal failure may occur. Therefore, during treatment with
sulfamides it is recommended to ingest water and alkalinization of urine (diet to be rich in
vegetable). Also, sulfamides can cause digestive intolerance with lack of appetite, nausea,
vomiting. Other adverse reactions: haematological disorders (haemolytic anemia, immune
agranulocytosis or idiosyncratic adverse reactions in patients with glucose-6-phosphate
dehydrogenase deficiency, aplastic anemia), hepatitis, hypothyroidism, polyneuritis,
convulsions. In newborns, bilirubin levels may increase with nuclear jaundice.
Sulfamethoxazole is used to treat urinary tract infections in adults.
Trimethoprim has a sulfamide-like spectrum, but higher potency. It is active on
most Gram-negative bacilli. It acts bacteriostatically by inhibiting bacterial dihydrofolate
reductase, preventing the conversion of dihydrofolic acid to tetrahydrofolic acid, the active
metabolic form of folic acid. The affinity for the bacterial enzyme is almost 50,000 times
higher than for the similar enzyme in the cells of the human body, thus explaining the
selective toxicity only on microorganisms.
Pharmacokinetics. Trimethoprim is given orally because it has good intestinal
absorption. Urinary concentration is 100 times higher than plasma. For this reason, it is
chosen for the treatment and prevention of urinary tract infections, usually in combination
with sulfamides.
Trimethoprim is generally well tolerated. It can cause rashes or very rarely
megaloblastic anemia due to folic acid deficiency.
The sulfamethoxazole-trimethoprim combination, commonly called co-trimoxazole
is the most widely used. Spectrum of activity: enterobacteriaceae, actinomycetes,
Nocardia, Neisseria, Yersinia pestis, Vibrio cholerae. The sulfamide-trimethoprim
combination is an example of antibacterial synergism through drug potentiation. It has a
bactericidal effect and a broader antibacterial spectrum than each component. This is
17
explained by the sequential inhibition of two steps in the active folate formation chain. The
main indication of this association is acute or recurrent urinary tract infections with
sensitive germs - E. coli, Klebsiella, Enterobacter, Proteus mirabilis and P. morgani. It is
also of first choice in bacillary dysentery in children and in pneumonia with Pneumocystis
carinii. Trimethoprim-sulfamethoxazole combinations are contraindicated in patients with
allergy to one of the two components, in newborns and pregnant or lactating women, in
patients with hepatic or renal impairment, porphyria or glucose-6-phosphate
dehydrogenase deficiency.

2. Antibacterial quinolones

Nalidixic acid is excreted rapidly in the urine and thus has no systemic antibacterial
effects, being used to treat low urinary tract infections.
Fluoroquinolone - ciprofloxacin, norfloxacin, efloxacin, pefloxacin,
moxifloxacin, levofloxacin. They have a wide spectrum - enterobacteriaceae, E.Coli,
Proteus, Enterobacter, methicillin-sensitive staphylococci, neiseria, Campylobacter,
Legionella, Vibrio ch, on mycoplasmas, chlamydia, rickettsya but also on atypical
mycobacteria. Methicillin-resistant staphylococci, S. pneumoniae, enterococcus, nocardia,
listeria, or anaerobic germs are resistant.
They have bactericidal action by inhibiting bacterial DNA gyrase by preventing the
relaxation of supraspiral DNA, a process necessary for normal transcription and
replication. This disrupts the functionality of DNA and makes it impossible to segregate
chromosomes and plasmids normally, stopping cell division and killing sensitive germs.
Bacterial resistance is chromosomally mediated and is due to changes in bacterial DNA
gyrase that becomes insensitive to the action of quinolones.
Pharmacokinetics. The bioavailability of quinolones after oral administration is
very good, diffuses tissue well and achieves higher concentrations of serum in the
respiratory tract, kidneys, liver, bile, muscles, bone, skin. It is metabolized by the liver and
then excreted in the urine. Ciprofloxacin is eliminated bile in active form.
Norfloxacin is the least active on Gram-positive and Gram-negative germs, but is
actively eliminated in the urine, so it is indicated in urinary and prostate infections with
sensitive germs. It can also be useful in the treatment of digestive infections.
The other antibacterial fluoroquinolones (ciprofloxacin, ofloxacin, pefloxacin,
mefloxacin, sparfloxacin, moxifloxacin and levofloxacin), due to their broad spectrum of
activity and very good tissue penetrability, including bone, urine, cerebrospinal fluid are
indicated in other systemic infections with sensitive germs - gastrointestinal infections,
typhoid fever and acute bacillary dysentery, lung infections, osteomyelitis, skin infections,
pulmonary tuberculosis (levofloxacin and ciprofloxacin are considered minor
antituberculosis).
18
 Ciprofloxacin is the fluoroquinolone of choice for intravenous administration in
systemic infections with multiple organic determinations (sepsis, bronchopneumonia,
infections with Gram-negative bacteria in neutropenic patients, peritonitis) in association
with beta-lactam antibiotics or aminoglycosides.
Side effects: digestive disorders - nausea, abdominal discomfort, vomiting,
diarrhea, central nervous symptoms - convulsions, delirium, hallucinations, headache,
dizziness, insomnia, allergic reactions - photosensitization to pefloxacin and levofloxacin,
osteomuscular - rupture of tendonalgia, tendonalgia , hepatic - hepatic cytolysis,
hematological - leukopenia, thrombocytopenia, hemolysis. It should be avoided in children
because it can affect the growth of cartilage and cause arthropathy or tendonitis with a risk
of tendon rupture. If combined with other medicines that prolong the QT interval, they can
cause torsades de pointes. May potentiate the effect of theophylline and oral anticoagulants.
Gastric antacids and sucralfate decrease their intestinal absorption. In combination with
non-steroidal anti-inflammatory drugs, they can trigger neurotoxic phenomena.

Nitrofurans

Nitrofurans are substances that alter proteins, nucleic acids and bacterial lipids.
a. Nitrofurans for urinary use. They are urinary antiseptics and have selective
antibacterial activity on the germs involved in the production of urinary tract infections,
without systemic antibacterial effect.
Nitrofurantoin is a 5-nitrofuran derivative, being active on most germs found in
the etiology of urinary tract infections, especially colibacilli, but also Klebsiella, Proteus,
Salmonella, enterococci or staphylococci. The risk of developing resistance during
treatment is low. The mechanism of antibacterial action is not specified.
Side effects - digestive, allergic, polyneuritis, megaloblastic anemia. Acute
hemolysis occurs in those with glucose-6-phosphate dehydrogenase deficiency.
Nitrofurantoin is contraindicated in patients with allergy to nitrofurans, with advanced
renal impairment, in patients with glucose-6-phosphate dehydrogenase deficiency, in the
last period of pregnancy and in the newborn.

b. Nitrofurans for digestive use - active substances on Salmonella, Shigella, E.

Colli, on Gram-positive cocci, amoeba or Trichomonas, indicated in non-invasive bacterial
or parasitic digestive infections. These medicines are not absorbed if taken orally. Their
side effects are limited to gastrointestinal disorders manifested by nausea and vomiting.
The compounds cannot be administered to newborns and premature infants due to the
immaturity of the digestive mucosa.
Furazolidone is a nitrofuran derivative that can be active as an antibacterial in
digestive tract infections and even in cholera therapy.

19
 Tuberculosis treatment

Tuberculosis is a major public health problem. The treatment of tuberculosis has

two objectives: individually - cure the disease and community - reduce the risk of infection
and / or disease in the community.
Mycobacterium tuberculosis populations in various types of lesions are extremely
varied. The histopathological structure of the lesions is complex and the multiplication
conditions different. In active tuberculous lesions there are simultaneously germs in full
exponential multiplication, germs with slow multiplication, germs with occasional
multiplication and dormant germs. Antituberculosis treatment must combine several
chemotherapeutics and is long-lasting, because tuberculosis is a chronic disease and the
bacterial population is not homogeneous in terms of cell divisions, which leads to the rapid
development of resistance.
There are two types of anti-tuberculosis chemotherapies - major or first choice
represented by: isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin; minor or
reserve represented by: ethionamide, clofazimin, protionamide, aminosalicylic acid,
cycloserine, capreomycin, kanamycin, amikacin, ansamycin, ofloxacin, ciprofloxacin,
moxifloxacin. Minor ones are indicated when patients develop side effects to major ones
or when bacilli are resistant to them.
Standard treatment uses highly bactericidal regimens that follow the WHO strategy.

Major antituberculosis drugs

Rifampicin - is a semi-synthetic antibiotic derived from rifamycin B.

Rifampicin is also active on germs other than the Koch bacillus. It has bactericidal
action on rapidly dividing germs, both extracellular and those contained in phagocytes,
abscesses or lung cavities. Prevents protein synthesis by binding to the β subunit of DNA-
dependent RNA polymerase. Human RNA polymerase does not bind rifampicin and is not
affected. It develops resistance quickly, in a single step, especially when administered
alone, which is why it must be combined with other anti-tuberculosis chemotherapeutics.
Pharmacokinetics. It is well absorbed after oral administration, good tissular
distribution - higher concentrations than plasma, in the lungs, liver, bile and urine.
Side effects. It is generally well tolerated; usual doses cause significant side effects
in less than 4% of patients. The most important adverse reaction is toxic damage to the
liver with a risk of reversible hepatitis, especially in those who are taking other substances
with liver toxicity at the same time (alcohol) or in patients with pre-existing liver disease.
20
 May produce immunoallergic side effects: interstitial nephritis, eosinophilia,
thrombocytopenia, haemolytic anemia and flu-like syndrome at high doses. May turn urine,
tears, contact lenses orange. It has an enzymatic inducing effect (CIP1A2, 2C9, 2C19,
23A4), which favors the metabolism of drugs administered concomitantly with their
decrease in plasma levels (digoxin, disopyramide, mexiletine, ketoconazole, propranolol,
verapamil, cyclosporine, bark reverse transcriptase inhibitors - HIV). Increases urinary
excretion of methadone and may cause withdrawal syndrome and is contraindicated in
patients with porphyria.

Isoniazid - HIN - isonicotinic acid hydrazide, has an intense mycobactericidal

action on both germs in rapid intracellular multiplication and those in the extracellular
environment.
Pharmacokinetics. It is well absorbed after oral administration and the distribution
is appropriate in most organs and serosa, respectively in the cerebrospinal fluid and caseous
material. Isoniazid is acetylated in the liver, under the action of N-acetyl-transferase type
2. The process of hepatic acetylation shows important genetic variations, depending on the
population type: "slow acetylators" -which have a relatively weak acetyl-transferase
activity, half-life in these there are a little over 3 hours and "fast acetylators" -with a more
intense activity of acetyl-transferase, which makes the half-life of about one hour. Isoniazid
is considered to be less effective when administered in rapid acetylators, and slow
acetylators present a risk of accumulation of the substance in conditions of hepatic
impairment.
Side effects. Toxic liver damage, peripheral neuritis, more common in slow
acetylators, alcoholics and diabetics. Isoniazid inhibits the metabolism of phenytoin,
carbamazepine and ethosuximide which causes neurological manifestations, inhibits the
metabolism of theophylline which causes tachycardia and arrhythmias, inhibits the
metabolism of vincristine which causes weakness. Combination with enzyme-inducing
drugs such as rifampicin may increase the risk of isoniazid hepatotoxicity by stimulating
the formation of toxic metabolites.

Ethambutol - inhibits arabinosyl-transferase III involved in the synthesis of

arabinoglycan, an essential component of the mycobacterial wall. The cell barrier is altered
and transmembrane permeability is increased for lipophilic drugs such as rifampicin,
ofloxacin.
Pharmacokinetics. Bioavailability after oral administration is good. It does not
pass through the meninges normally, but has medium absorption through the inflamed
meninges, which allows its use in tuberculous meningitis. It is eliminated by the kidneys,
as such, in a proportion of 80%. Ethambutol resistance is a consequence of a change in the
gene that synthesizes mycobacterial arabinosyl-transferase.
Side effects - retrobulbar optic neuritis, green and red dyschromatopsia vision
disorders, narrowing of the peripheral visual fields, central scotoma, reduction of renal
21
elimination of uric acid, pruritus, abdominal pain and allergic reactions. Pyrazinamide -
has a bactericidal effect on the tubercle bacillus, on the bacillary populations that multiply
slowly in macrophages. It quickly develops bacterial resistance, which is why it is used in
polychemotherapeutic schemes. After oral administration it is well absorbed and has a good
distribution in the tissues, achieving active concentrations in the cerebrospinal fluid in
patients with meningitis. It is inactivated by hepatic metabolism and eliminated by the
kidneys. It is hepatotoxic, can cause hyperuricemia with arthralgias and gout attacks,
allergic reactions manifested by fever, rash, photosensitization.

Streptomycin - aminoglycoside active against M. tuberculosis, atypical

mycobacteria (M. kansasii, M. avium) as well as against some Gram-negative, Gram-
positive and Gram-negative bacilli. It binds irreversibly to the 30s subunit of bacterial
ribosomes with bactericidal effect. It quickly develops resistance when used alone, which
is why it is always used in polychemotherapy regimens. Due to the polar molecule, it is not
absorbed from the gastrointestinal tract. It is administered intramuscularly. Achieves
therapeutic concentrations in the pleural fluid. It is eliminated by the kidneys in a
proportion of 70-80%. Toxic side effects - toxicity on the VIII nerve, with predominance
on the vestibular branch, high nephrotoxicity in case of renal failure, allergic phenomena
with rash.

Minor antituberculosis drugs

Minor antituberculosis drugs are used in case of resistance to major antituberculosis

drugs, which are of first choice, if patients do not respond favorably to treatment or in
situations where some major antituberculosis drugs are contraindicated for reasons of
toxicity to the patient.
Aminosalicylic acid - acts specifically bacteriostatic on the tuberculosis bacillus by
preventing the synthesis of folic acid, by competitively inhibiting dihydropteroate
synthetase 1. It can cause digestive, hepatic and renal side effects that limit its use.
Cycloserine - is active against the tuberculosis bacillus and against some atypical
mycobacteria as well as other microbes. It works by inhibiting the synthesis of the bacterial
wall.
Kanamycin and Amikacin - are aminoglycosides used in selected cases of
tuberculosis resistant to major chemotherapeutics. Amikacin is more commonly used
because it is also effective on atypical mycobacteria and multidrug-resistant strains.
Ethionamide - chemically related to isoniazid, is active on M. tuberculosis, both
intracellular and extracellular germs. May cause relatively common postural hypotension,
gynecomastia, and rash.

22
 Fluoroquinolones - Ciprofloxacin, Levofloxacin, Ofloxacin, Moxifloxacin are
very broad spectrum chemotherapeutic drugs that include mycobacteria M. tuberculosis,
M. avium, M. intracellulare, M. kansasii but also other actinomycetes (Noocardia,
Actinomyces). They have bactericidal effect and also act intracellularly on germs
phagocytosed in macrophages, at lower concentrations than serum ones.
Capreomycin - specifically inhibits the tuberculosis bacillus by inhibiting protein
synthesis. Bacterial resistance to capreomycin develops with monotherapy; combination
with aminoglycoside antibiotics due to vestibular and renal toxicity is prohibited.
Rifabutin and Rifapentin are derivatives of rifampicin and inhibit the DNA-
dependent β-RNA polymerase subunit. They are only parenterally active and are used in
the treatment of atypical mycobacteria and for the prophylaxis of disseminated infections
with M. avium. Side effects may include rash, gastric intolerance and neutropenia.
Rifabutin may turn the skin, urine, feces, saliva, and contact lenses orange.

23
Anticancer drugs

Cancer treatment involves multiple therapeutic modalities - surgery, radiation therapy,

chemotherapy. In principle, surgery and radiotherapy are loco-regional treatments, and
chemotherapy is systemic treatment. In particular, complex treatment that combines several
types of therapy is applied.
Anticancer chemotherapeutics are drugs that can selectively kill cancer cells. Most anticancer
drugs act by disrupting cell multiplication, especially influencing cells with a high rate of
multiplication - the selectivity of action is due to the fact that cancer cells have a very high
rate of multiplication. The effectiveness of anticancer drugs is higher when the size of the
tumor is small – is important to start anticancer therapy as early as possible. On the other
hand, reducing the size of the tumor through surgery or radiation therapy may increase the
effectiveness of antineoplastic drugs, which justifies the combined treatment of cancer.
However, anticancer chemotherapeutics not only affect the multiplication of cancer cells. but
also normal cells that have a high rate of multiplication: hematopoietic cells, digestive tract
cells, hair follicle, spermatogenesis, or embryo-fetal development if administered to pregnant
women producing hematological side effects - leukopenia, thrombocytopenia, digestive side
effects, alopecia, impaired spermatogenesis, dysmorphogenic reactions or congenital
malformations of the newborn if administered to the pregnant woman.
Hematopoietic marrow damage limits the use of anticancer drugs. It can be of 2 types:
- rapid impairment, up to 8-10 days after administration of cytostatics, recovered
quickly, in 17–21 days (cyclophosphamide, vinblastine).
- late damage, with a maximum after 27-32 days from administration and with late
recovery, in 42-50 days (carmustine, melphalan.)
These outbreaks of cytostatic bone marrow depression can be recovered by the body during
the treatment break, by switching hematopoietic cells from the resting state outside the
dividing cycle (G0 phase) to the proliferative (dividing) cycle. Approximately 15% of
hematopoietic cells are outside the division cycle (G0 phase) and they are very low or not at
all influenced by cytostatic drugs. In addition, the use of haematopoietic growth factors that
may correct hematopoietic changes induced by anticancer drugs is recommended.
The effect of anticancer chemotherapy also depends on the degree of synchronization of cell
multiplication, being all the more intense the higher the degree of synchronization.
Antigenically stimulated immunocompetent cells multiply synchronously, because their
multiplication is initiated by the antigenic stimulus - anticancer drugs have
immunosuppressive effect, especially in cell-type immunity and decrease the body's immune
defense capacity with favoring infections. However, the immunosuppressive effect is present
even at very low doses, which have very few other effects. This allows the use of some
anticancer drugs as immunosuppressants.
Phase-dependent anticancer drugs - act if the cells are in its S or M phase, by:
- Inhibition of nucleic acid formation - kills cancer cells in the S phase of the division
cycle, when DNA synthesis takes place.
 o metabolic analogues of purine or pyrimidine nitrogenous bases - form false
non-functional nucleic acids,
o it inhibits processes that underlie the synthesis of nucleic acids - inhibiting the
formation of active folic acid involved in the synthesis of nitrogenous bases.
- Alteration of tubulin, the proteic component of the division spindle microtubules.
Alteration of the dividing spindle blocks the cell cycle in the M (mitosis) phase. Their
effect is all the more intense the higher the percentage of cells in phase M and the
more synchronous the multiplication.
Phase-independent anticancer drugs - act on cells in the division cycle; are not active on cells
outside the division cycle, in the G0 phase, because these cells manage to repair the
biochemical damage induced by these drugs.
These anticancer drugs act on preformed DNA - they bind to the nucleic acid whose chemical
structure it changes, for example by alkylation by altering the DNA of all cells. Cells that have
a low rate of division are able to correct the disturbances induced by these drugs through
normal nucleic acid damage repair mechanisms so that they are very little affected. However,
if the cells divide rapidly, the biochemical damage induced by these drugs profoundly disrupts
the activity of those cells so that they are destroyed.
The biochemical lesions of nucleic acids produced by anticancer drugs explain the extremely
important side effects of these drugs - mutagenicity, carcinogenesis, dysmorphogenicity,
teratogenicity.
Resistance to anticancer drugs can develop by the appearance of genetic mutations that
make cancer cells less influenced by cytostatics, and is produced by pharmacodynamic or
pharmacokinetic mechanisms:
- pharmacodynamic mechanisms:
o cancer cells may appear that increase their ability to repair cytostatic-induced
lesions
o increases the concentration of intracellular substances to which the anticancer
drug is attached so that less DNA is attached
o increases the concentration of the metabolite with which the anticancer drug
competes
o increases the concentration of the anticancer drug inhibited enzyme so that
the dose of cytostatic administered becomes insufficient
o the enzyme is structurally modified and inhibited by the anticancer drug so
that the anticancer drug no longer attaches to it.
- pharmacokinetic mechanisms:
o cancer cells may appear that no longer allow the anticancer drug to enter the
cell,
o enzymes that bioactivate the cytostatic intracellularly disappear,
o a polyresistance - cross-resistance for cytostatics with different mechanisms of
action, by increasing the membrane concentration of P-glycoprotein encoded
 by the mdr gene (multidrug resistance) which expels cytostatics from the
cancer cell.
Cancer cell resistance to cytostatic drugs is important for some cases of treatment failure and
for relapses.
Pharmacokinetics. Most anticancer drugs are well absorbed - they can be taken orally. There
are cytostatics that are given by injection, sometimes strictly intravenously, or topical. Most
cytostatic drugs are metabolized in the body and result in inactive metabolic products.
However, there are cytostatics that are prodrugs - they become active only after bioactivation
and are administered only orally (cyclophosphamide).
Side effects.
- hematopoietic marrow damage with leukopenia and thrombocytopenia, less
frequently anemia. Hematological control is mandatory - blood counts before each
cytostatic treatment.
- decreased immunity - in patients undergoing cancer treatment the infections have a
severe evolution.
- damage to the digestive tract - stomatitis, gastritis, gastric or duodenal ulcer, diarrhea,
digestive bleeding.
- hair follicle damage - alopecia
- damage to the gonads - sterility
- mutagenic and carcinogenic effects
- dysmorphic or teratogenic side effects.
To these common side effects are added particular side effects, specific to each cytostatic
depending on its particularities.
The risk/benefit ratio for these drugs is only favorable in particular situations where the
benefit of these drugs is significant enough to outweigh the risks.
Contraindications - terminal cancer, pregnancy, especially in the first trimester, in sepsis and
in patients with coma, when the benefits fail to outweigh the risks.

1. Alkylating agents

Alkylating agents contain alkyl groups that react with the nucleic acids; they alkylate at the
level of nitrogenous bases, phosphate groups or at the level of proteins associated with
nucleic acids.
These drugs can be linked
- single-chain DNA - monoalkylation or intrachain alkylation,
- two nucleic acid chains thus forming interchain - bialkylation bridges.
The formation of interchain covalent bridges does not allow the 2 chains of DNA to separate
for the contained message to be copied as messenger RNA or for duplicating DNA for cell
division purposes. This explains the cytotoxicity of these substances.
Intra-chain alkylation - the nitrogen base is degraded and becomes dysfunctional, or it is
modified so that it no longer pairs properly, altering the genetic message. Monoalkylation
causes the death of cells on which the anticancer drug has acted, mutagenic or carcinogenic
effects.
Alkylating agents act on preformed DNA, regardless of its functional state, but the
consequences are visible only in the process of cell division, when the alkylated DNA cannot
be duplicated, in the case of intercatenary alkylation, or a wrong or incomplete message is
copied, in the case of intra-chain alkylation.
In cells that do not divide, the consequences of alkylation are not visible and the biochemical
damage are repaired by the physiological mechanisms of DNA error repair. This causes the
alkylating agents to act practically only on the cells in the division cycle.
Alkylating agents are broad-spectrum anticancer and are active in many types of cancer.
Resistance of cancer cells to alkylating agents can occur through several mechanisms and can
be cross-linked for all alkylating agents: increases the ability of cancer cells to repair
biochemical damage caused by alkylating agents, increases the intracellular concentration of
nucleophilic protein-containing proteins, so that they no longer become attached to nucleic
acids and no longer produce biochemical damage to them, the transport of the alkylating
agent inside the cell is prevented or the removal of the active metabolite of the drug from the
cell is accelerated.
These drugs act not only on cancer cells, but also on normal cells of the body that have a high
rate of multiplication - alkylating agents affect hematoforming bone marrow - leukopenia and
thrombocytopenia, digestive tract - mucous lesions (oral, intestinal), hair follicle - alopecia,
gonads - azoospermia in men and menstrual disorders in women, embryo-fetal development
if administered to pregnant women - dysmorphogenic and teratogenic effects. In addition,
they can have mutagenic and carcinogenic effects. There are also some irreversible side
effects caused by alkylating agents - pulmonary fibrosis, hepatic vein occlusion. Central
nervous system toxicity may occur, manifested by nausea and vomiting, as well as
psychopathological manifestations. The pharmacokinetics of these drugs differ from product
to product. The main chemical groups of alkylating agents include azotiperites,
ethylenamines, sulfonoxides, nitrosoureas and triazenes.
1.1. Azotiperite, nitrogen analogs of sulfiperite, are bifunctional agents that form chains of
DNA chains.
Chloromethine is very aggressive to tissues - it can only be given intravenously.
Cyclophosphamide is a prodrug. It can be given orally or intravenously. It is a broad-
spectrum anticancer chemotherapeutic used in a single administration or in various
polychemotherapeutic combinations in the treatment of many cancers. It produces side
effects characteristic of cytostatics being aggressive for the hematoforming marrow,
especially for myelogenesis, it causes in particular nausea and vomiting, alopecia and
hemorrhagic cystitis which requires the administration of large amounts of water during
treatment with this drug. Cyclophosphamide in small doses and in continuous treatment
is to be used as an immunosuppressant, a situation in which it is much better tolerated.
Other azotiperites are melphalan, used in the treatment of multiple myeloma, and
chlorambucil, used in the treatment of chronic lymphocytic leukemia.
1.2. Sulfonoxides - busulfan. It has toxicity for myelogenesis - useful in chronic granulocytic
leukemia.
1.3. Nitrozourea - carmustine (BCNU) and lomustine (CCNU), broad-spectrum alkylating
agents, effective in the treatment of brain tumors.
1.4. Triazenic compounds - dacarbazine, used in malignant melanoma, Hodgkin's lymphoma,
sarcomas.

2. Other anticancer drugs that affect preformed DNA

They are anticancer drugs that affect preformed DNA molecules by mechanisms other than
alkylation.
2.1. Procarbazine is metabolised in the body to generate DNA methylating compounds. It is
used in chemotherapeutic combinations, in the treatment of lymphomas.
2.2. Organic platinum compounds. They are broad-spectrum anticancer drugs, used in the
treatment of cancers of the head and neck, lung, esophagus, colon, bladder, ovary. Cisplatin
- toxic to the kidneys requiring the ingestion of large amounts of water. Carboplatin - less toxic
than cisplatin. Oxaliplatin - effective in colorectal cancer.
2.3. Antibiotics with anticancer effect by affecting preformed DNA (alters DNA chains):
dactinomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, bleomycin or mitomycin.
They have specific cardiac toxicity, especially in the case of anthracyclines (doxorubicin,
daunorubicin, epirubicin, idarubicin).
2.4. Topoisomerase inhibitors. Topoisomerases (topoisomerase I and topoisomerase II) are
nuclear enzymes that reduce the tensile stress of DNA so that DNA replication, repair, and
transcription are possible. Topoisomerase I inhibitors - topotecan and irinotecan. Topotecan
is an active drug as such, while irinotecan is a prodrug. Topotecan is used to treat ovarian
cancer and small cell lung cancer. Irinotecan is used to treat colorectal cancer. Side effects are
typical of anticancer drugs; irinotecan can cause severe diarrhea. Topoisomerase inhibitors II
- Podophyllotoxin derivatives, a spindle toxicant - etoposide and tenipozide. Etoposide is used
in combination with cisplatin in the treatment of small cell lung cancer, testicular cancer,
breast cancer, Hodgkin's and non-Hodgkin's lymphomas, acute myeloid leukemia, Kaposi's
sarcoma. Tenipozide is used in malignant lymphomas, brain cancers, bladder cancer. -
anthracycline antibiotics (doxorubicin, daunorubicin, epirubicin, idarubicin).

3. Antimetabolites

Antimetabolites are anticancer drugs with a chemical structure similar to nucleic acid
precursor metabolites, used by cells in nucleic acid synthesis instead of physiological
precursors, resulting in dysfunctional nucleic acid analogues. Some of these antimetabolites
are purine analogs, others are pyrimidine analogs. Also in this group are drugs structurally
analogous to folic acid, which interferes with the metabolism of folic acid, an important
substance in the synthesis of nitrogenous bases. These drugs inhibit the synthesis of nucleic
acids by acting in the phase S of the cell cycle - phase-dependent anticancer drugs. Their
effectiveness is higher the higher the percentage of cells in the S phase of the division cycle,
so the more intensely and synchronously the cells multiply.
3.1. Purine analogues - substances with a chemical structure similar to physiological purines.
Mercaptopurine is used in the maintenance treatment of acute lymphocytic leukemia in
children orally. It has hematopoietic and hepatic toxicity.
Azathioprine is a mercaptopurine derivative used as an immunosuppressant in the treatment
of autoimmune diseases, in the prophylaxis of graft rejection in organ transplantation, or in
the prophylaxis of the graft-versus-host reaction in patients with bone marrow
transplantation. It is administered orally and the low doses required for immunosuppressive
treatment are generally better tolerated. However, surveillance of hematopoiesis is required,
especially in terms of the number of leukocytes and platelets, and decreased immunity favors
infections.
Thioguanine is another purine antimetabolite commonly used in the treatment of acute
myeloid leukemia.
3.2. Pyrimidine analogues are substances with a chemical structure similar to physiological
pyrimidines.
Fluorouracil, the fluorinated derivative of uracil (5-fluorouracil), is commonly used in the
treatment of solid cancers.
Capecitabine is a precursor of fluorouracil. It undergoes the action of several enzymes, of
which thymidine phosphorylase, which generates fluorouracil, is found mainly in tumor cells.
Thymidine phosphorylase may be stimulated by docetaxel, an antineoplastic that appears to
have synergistic anticancer effects. It is used in the treatment of breast cancer, colorectal
cancer, gastric cancer.
Cytarabine or cytosinarabinozide. The drug is inserted into the forming DNA strand, inhibiting
the corresponding polymerase. It is mainly used for induction and maintenance treatment in
acute myeloid leukemia. It has high bone marrow toxicity - leukopenia, thrombocytopenia
and severe anemia.
Gemcitabine. It works similar to cytarabine. Gemcitabine is effective in treating solid tumors,
including lung and ovarian cancer.
3.2. Substances that interfere with folic acid metabolism.
Methotrexate, a folic acid analogue that inhibits folate reductase, an enzyme that converts
folic acid to tetrahydrofolic acid, the active form of folic acid. Unlike trimethoprim, which
inhibits bacterial dihydrofolate reductase with high specificity, methotrexate inhibits all
dihydrofolate reductases, both bacterial and human. As tetrahydrofolic acid is particularly
important in the synthesis of pyrimidine nucleotides, the formation (synthesis) of DNA is
prevented. It is used in the treatment of acute lymphoid leukemia in children and for the
treatment of choriocarcinoma. Methotrexate, in small doses, is also used as an
immunosuppressant in various autoimmune diseases, rheumatoid arthritis and psoriasis.
Medullary toxicity can be high. However, the toxicity of methotrexate is due to the deficiency
in tetrahydrofolic acid so that it can be treated by administering this substance, commonly
called calcium folinate or leucovorin.
Pemetrexed is another folic acid analogue. It is used to treat malignant pleural mesothelioma
and non-small lung cancer. It has virtually the same side effects as methotrexate, except for
rashes that can be prevented or treated by folic acid and vitamin B12.
Hydroxycarbamide, or hydroxyurea, inhibits deoxyribonuclease, thereby inhibiting DNA
synthesis. It is useful in chronic myeloid leukemia.
4. Toxicities of the division spindle

Some anticancer drugs disrupt the formation of microtubules that make up the dividing
spindle by altering cell division function and blocking mitosis in metaphase - their anticancer
effect that manifests phase-dependent. microtubules exist in large quantities and in the brain
where they are involved in important cellular functions such as cell movement, phagocytosis
or axonal transport - the spindle toxicants produce neurological side effects, in addition to
the typical side effects of cytostatic drugs.
4.1. Alkaloids from vinca (Vinca rosea) are toxic to the spindle, by altering tubulin, the
component protein of the spindle; it binds to β-tubulin and prevents its polymerization with
α-tubulin and the formation of microtubules. It is administered intravenously in
polychemotherapeutic combinations, especially in the treatment of lymphatic cancers. The
main therapeutic limitation is bone marrow depression. They can also cause neurological side
effects. Vincristine is used to treat lymphomas and testicular cancer. Vinblastine is used to
treat leukemias and lymphomas. Vinorelbine is used to treat non-small cell lung cancer.
4.2. Taxanes are a group of drugs with a similar chemical structure that bind to β-tubulin, at
a site other than vinca alkaloids and, conversely than vinca alkaloids, stimulate tubulin
polymerization. Thus, aberrant microtubules are formed around other polymerization centers
than the physiological ones (centromeres). This profoundly disrupts cellular function so that,
in the end, mitosis is blocked in metaphase. They are used in the treatment of cancers of the
ovary, breast, lung, digestive tract, genitourinary tract, head and neck. In addition to the
common side effects of anticancer medicines, they can cause neurological phenomena.
Paclitaxel is a substance of natural origin (alkaloid from Taxus brevifolia). It is very slightly
soluble in water, which is why it is administered dissolved in a mixture of 50% ethanol and
50% polyethoxylated castor oil, which is extremely allergenic. There is also a pharmaceutical
form of paclitaxel bound to albumin nanoparticles called nab-paclitaxel which is water soluble
and has no risk of allergies.
Nab-paclitaxel penetrates cells better than paclitaxel because it uses some membrane
albumin transporters. But it seems to be the most neurotoxic taxane.
Docetaxel is a semi-synthetic compound with greater potency than paclitaxel. It is more
soluble in water than paclitaxel.
Cabazitaxel is also a semisynthetic product which, unlike other taxanes, is not a substrate of
P-glycoprotein. However, it is also an allergen.
Ixabepilone is a chemically different substance from taxanes, but which favors the
polymerization of tubulin having practically the same mechanism of action as taxanes. It is
possible for β-tubulin to attach to a site different from that to which taxanes attach and to
which alkaloids in vinca are attached. It is licensed for the treatment of breast cancer.
Estramustine is a substance whose chemical structure combines estradiol, an estrogenic
hormone, with normustine, an alkylating agent in the nitrogenous category. It is effective in
treating hormone-resistant prostate cancer.
4. Anticancer drugs with high specificity of action

It acts mainly on some biochemical and physiological elements specific to cancer cells. The
high specificity makes these drugs have a very limited spectrum of action, but their
effectiveness is generally high and the side effects are more limited than with other
anticancer drugs.
Asparaginase is an enzyme that hydrolyzes l-asparagine, an amino acid in the structure of
proteins. Unlike normal cells, however, some neoplastic cells are not able to synthesize l-
asparagine. Consequently, under the effect of asparaginase, they can no longer synthesize
some proteins that contain asparagine in their structure, have toxic phenomena and die. The
drug is effective in the treatment of acute lymphoblastic leukemia alone or in combination
with polychemotherapy. Side effects: liver disorders, allergic reactions up to anaphylactic
shock.
Retinoic acid is a normal constituent of the body involved in the growth and development of
myeloid cells through a specific receptor. Acute promyelocytic leukemia is characterized by a
genetic malformation that decreases the functionality of the retinoic acid receptor and
prevents the maturation of myeloid cells, with their accumulation in undifferentiated form.
The administration of retinoic acid favors the maturation of cells with spectacular remissions
of the disease, but unfortunately with frequent relapses. The drug is effective only in this
particular type of leukemia.
Arsenic trioxide is another useful drug in the treatment of acute promyelocytic leukemia. Its
mechanism of action is unknown, but it also induces the maturation of promyelocytes.
Streptozocin is a substance toxic to the cells of the Langerhans Islands in the pancreas, and is
used to produce experimental diabetes in laboratory animals. This selective toxicity has
allowed the use of this substance for the treatment of pancreatic islet cell cancer. May have
hepatic and renal toxicity.
Mitotane has selective toxicity to the adrenal cortex and is useful in the treatment of adrenal
cancer. As side effects may cause anorexia, nausea, drowsiness.
Tyrosine kinase inhibitors.
Imatinib specifically inhibits certain tyrosine kinases in cells of chronic myeloid leukemia
(Philadelphia chromosome cells) and is effective in treating chronic myeloid leukemia with
Philadelphia chromosome positive (Ph +). May have hematopoietic toxicity (neutropenia,
thrombocytopenia, anemia).
Dasatinib and nilotinib are very similar drugs to imatinib.
Gefitinib and erlotinib are drugs that inhibit the epidermal growth factor receptor (EGFR)
tyrosine kinase. They are used in the treatment of non-small lung cancers.
Sunitinib inhibits tyrosine kinase represented by one of the endothelial growth factor
receptor 2 (VEGFR2) and prevents the spread of tumors by neovascularization. It is effective
in treating kidney cancer.
Sorafenib inhibits tyrosine kinase represented by 3 VEGF receptors, VEGFR1, VEGFR2 and
VEGFR3, respectively. It is used in both the treatment of kidney cancer and the treatment of
hepatocellular cancer.
Monoclonal antibodies used as anticancer drugs are antibodies directed against proteins that
are expressed only on the surface of certain cancer cells.
Rituximab (mabthera) is a chimeric IgG1 monoclonal antibody directed against a glycoprotein
called CD20, a marker of B lymphocytes that is present on these lymphocytes from the stage
of B lymphocytes (B lymphoblast) to the stage of mature B lymphocytes. CD20 is present in
over 95% of B-cell non-Hodgkin's lymphoma cells. It is authorized for the treatment of non-
Hodkin's lymphoma. It can cause cytokine release, mass cell destruction, worsening
infections, and anaphylactic side effects.
Ibritumomab is an IgG1 antibody directed against the CD20 glycoprotein like rituximab. It is
authorized in the treatment of non-Hodgkin's lymphomas, including in patients with relapse
after rituximab or with rituximab-refractory lymphoma.
Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor,
VEGF. VEGF production is increased in cancers such as colorectal, lung, breast cancer.
Neutralization of the biological activity of VEGF determines the regression of tumor
vascularization, normalizes the remaining tumor vascularization and inhibits the formation of
a new tumor vascularization thus inhibiting tumor growth. The most common side effects are
high blood pressure, asthenia, diarrhea and abdominal pain. It is authorized alone or in
combination with other anticancer drugs for the treatment of metastatic cancers of the colon,
rectum, breast, lung, kidney.
Cetuximab is a chimeric monoclonal antibody directed against the human epidermal growth
factor receptor (EGFR). EGFR is overexpressed in some cancers such as head and neck, colon,
lung, breast, ovarian and kidney cancers. It is authorized in squamous cell carcinoma of the
head and neck and in metastatic colorectal cancer that expresses the epidermal growth factor
receptor (EGFR). The main side effects are skin reactions, hypomagnesemia and infusion-
related reactions.
Trastuzumab is a recombinant humanized IgG1 monoclonal antibody directed against human
epidermal growth factor 2 receptor (HER2). Primary breast cancers have 20-30%
overexpression of HER2. Patients whose tumors overexpress the HER2 receptor have a
shorter survival without signs of disease than those whose tumors do not overexpress HER2.
Trastuzumab inhibits the proliferation of human tumor cells that overexpress HER2 and is a
potent mediator of antibody-dependent cellular cytotoxicity (ADCC). It is licensed in the
treatment of metastatic breast cancer and HER2-positive early breast cancer after surgery,
chemotherapy and radiation therapy. The most common side effects are those related to the
infusion, such as fever and chills.
Thalidomide is an old substance initially used as a sedative, but later withdrawn from the
market because, when administered to pregnant women, it produced an epidemic of
congenital malformations in newborns (in the late 1950s and early 1960s more than 10,000
children were born malformations, in 46 countries, especially with the malformation called
facomelia characterized by the lack of arm and forearm, the hand being implanted directly by
the shoulder). However, modern clinical trials show that thalidomide is an effective drug in
the treatment of multiple myeloma. The mechanism of action is unknown, but it is likely to
act through an antiangiogenetic effect. As side effects (except for the very serious teratogenic
effect) it can cause drowsiness, sedation, constipation and neuropathy.
Lenalidomide is a thalidomide derivative with the same effects but less common and less
severe side effects.

Hormones used to treat cancer

Glucocorticoid hormones. In lymphatic cancers, leukemias and malignant lymphomas, the

lympholytic effect of cortisone may be present, although the decrease in the number of
circulating lymphocytes produced by cortisone in humans appears to be primarily due to their
redistribution, rather than their destruction. Cortisones decrease mitosis in lymphocytes. In
acute lymphoblastic leukemia in children and in lymphomas in both children and adults,
cortisone has a cytotoxic effect. They produce remissions faster than cytostatics. They are
also drugs of choice in multiple myeloma and chronic lymphocytic leukemia. In both lymphatic
and other cancers, the role of cortisone in the overall support of the body under the stress of
neoplastic disease is indisputably important. In some cases, the removal of tumor-associated
inflammation is of great pathogenic value. They often cause symptomatic relief of cancer. For
all these reasons, cortisone is frequently used in various polychemotherapeutic cancer
treatment regimens.
In addition to cortisone, the use of which is somewhat unspecified, there are some hormone-
sensitive cancers, especially prostate cancer, breast cancer and uterine cancer.
Specific hormonal treatment in such cancers can sometimes decisively influence the evolution
of those cancers. In prostate cancer, whose development is dependent on androgen
hormones, estrogen hormones are used, for example diethylstilbestrol or ethinylestradiol, or
drugs that block androgen receptors in the prostate, thus having an antiandrogenic action.
They can be: steroidal - cyproterone and megestrol, or non-steroidal - flutamide, bicalutamide
and nilutamide. Also for the purpose of decreasing androgenic influences, leuprorelin and
goserelin can be used, which reduce the secretion of androgens, being agonist analogues of
gonadorelin, the gonadotropin-releasing hormone.
Androgenic steroids, such as phenylpropionate testosterone, or antiestrogenic drugs, are
useful in breast cancer in women, whose development is dependent on estrogen hormones.
The most widely used antiestrogen is tamoxifen, a drug that blocks only estrogen receptors
in the breast. Fulvestrant is a pure antiestrogen which, unlike other receptor blockers, after
its attachment to estrogen receptors also causes the internalization of receptors and their
decrease in density. Aromatase inhibitors - anastrozole and letrozole inhibit the conversion
of androgens to estrogens and are preferred in postmenopausal women. Progestins, for
example medroxyprogesterone acetate, can sometimes be useful in the treatment of
advanced endometrial cancer.
Antihypertensive drugs

Antihypertensive medication, used in the treatment of hypertension (HTA), comprises drugs

that lower blood pressure, acting through different pharmacodynamics mechanisms.
High blood pressure is a commonly encountered chronic condition, which can cause cardiac,
cerebral and renal complications in evolution, being considered a major cardiovascular risk
factor. It consists in the persistent increase of the blood pressure values over 140mm Hg for
the systolic value and over 90 mm Hg for the diastolic one.
The aim of the HTA treatment is both to reduce the blood pressure values and to prevent its
complications. Antihypertensive treatment is chronic, practically lifelong, and aims to lower
and maintain blood pressure as close to normal. It includes pharmacological measures
(antihypertensive medication) and hygienic-dietary measures (reducing salt and animal fat
consumption, smoking cessation, reducing excess weight, avoiding sedentary lifestyle).
Blood pressure is directly proportional to cardiac output and peripheral vascular resistance.
Physiologically, in the regulation of the blood pressure values, most of them intervene:
sympathetic vegetative nervous system, volemia and the renin-angiotensin aldosterone
system. The kidney (involved in regulating volemia) and vasoactive substances such as
endothelin and nitric oxide (NO) released by the vascular endothelium also play an important
role. Endothelin produces a strong vasoconstriction and nitric oxide vasodilation.
Antihypertensive drugs act by influencing one or more mechanisms involved in the
regulation of TA. According to the main mechanism of action, antihypertensive are classified
into:
 Medications that reduce sympathetic control:
• sympatholytic with the central action (clonidine, alpha-methyldopa, etc.);
• ganglioplegic (trimetaphan);
• neurosympatholytic (guanetidine, reserpine, etc.)
• alpha adrenergic blockers (prazosin);
• beta adrenergic blockers (propranolol, metoprolol, atenolol, carvedilol, etc);
 Direct vasodilators (hydralazine, diazoxide, minoxidil);
 Calcium channel blockers (nifedipine, diltiazem, verapamil, etc.);
 Drugs that interfere with the renin-angiotensin-aldosterone system
• Angiotensin conversion enzyme inhibitors (captopril, enalapril, etc.);
• angiotensin AT1 receptor antagonists - (losartan, valsartan, candesartan, etc.);
• Renin antagonists (aliskiren);
• β-adrenergic blockers.
 Medications that lower blood volume - diuretics.
1. Medications that reduce sympathetic control

These drugs reduce sympathetic control over the cardiovascular system by acting at various
anatomic levels.
1.1. Sympatholytic with central action
Centrally sympatholytic drugs are drugs that directly or indirectly stimulate central
presynaptic α2-adrenergic receptors, with inhibitory effect on peripheral sympathetic control.
Clonidine stimulates central α2 adrenergic receptors from the bulbous and hypothalamic
structures, decreasing peripheral sympathetic tone and blood pressure. It also acts on non-
adrenergic receptors, respectively imidazoline receptors (I1 receptors). It reduces blood flow
to the cerebral and splanchnic area, but without decreasing renal blood flow and glomerular
filtration, which recommends the use of clonidine in patients that associate hypertension with
renal failure. It does not decrease peripheral resistance and does not produce orthostatic
hypotension.
As adverse reactions, it frequently causes sedation, drowsiness, constipation, dry mouth due
to inhibition of salivary secretion by central mechanism. It is contraindicated in patients who
associate depressive psychosis (may reactivate psychosis).
Methyldopa is analogous to DOPA. It penetrates the brain and substitutes DOPA in the
metabolic chain, causing the synthesis of alpha-methylnoradrenaline (false neurotransmitter)
that stimulates central α2-adrenergic receptors, with the inhibition of the peripheral
sympathetic activity. It is used in hypertensives with renal failure. It may be associated with
furosemide and vasodilators. It is also indicated in hypertension in pregnancy.
As adverse reactions, it produces: sedation, drowsiness, depression, nightmares, dizziness.
Moxonidine and Rilmenidine lower blood pressure, especially as a result of the action of the
imidazoline (I1) receptors in the bulb. Associate weaker central agonist α2 effect.
1.2. Ganglioplegics
Ganglioplegics (trimetaphan) act by blocking nicotine receptors from sympathetic and
parasympathetic vegetative ganglia and decrease the blood pressure with pronounced
orthostatic character. Sensitization of the heart to the action of catecholamines occurs,
increasing the risk of myocardial ischemia and arrhythmias. The sudden paralysis of the
sympathetic and parasympathetic vegetative ganglia explains the numerous adverse reactions
and the limitation of the clinical use of these drugs.
1.3. Neurosympatholytics
Neurosympatholytics act at the presynaptic component of peripheral sympathetic synapses,
decrease the availability of catecholamines in the synaptic cleft and the blood pressure.
Guanethidine enters the presynaptic terminations, by the same transport mechanism that
ensures the recovery of noradrenaline, stabilizes the presynaptic membrane and produces a
"presynaptic block", preventing the release of noradrenaline from sympathetic endings.
Guanethidine produces a marked hypotension, with a pronounced orthostatic character. It is
reserved for cases of severe hypertension or not responding to other treatment.
Reserpine prevent the recovery of noradrenaline in the storage vesicles. Remained in the
cytoplasm of presynaptic termination, noradrenaline is largely metabolized by the MAO, thus
decreasing the availability of the neurotransmitter. In the central nervous system, synaptic
deposits of dopamine and serotonin also decrease, which explains other effects of reserpine
(sedation-depression, extrapyramidal disorders). The hypotensive effect is slow. As side
effects: sedation, depressive states, nasal congestion, pyrosis, diarrhea, xerostomia, taste
changes, pain and / or swelling of the salivary glands, rarely bleeding of the buccal mucosa.
1.4. Alpha-adrenergic blockers
Adrenergic α-blockers produce vasodilation by blocking α1 receptors.
Non-selective α-adrenergic blockers, phentolamine and phenoxybenzamine, are used in the
treatment of secondary hypertension in pheochromocytoma. The combination with β-
adrenergic blockers is required to counteract the effects of catecholamines on the heart.
In the treatment of essential hypertension, selective α1-blockers, such as prazosin, doxazosin,
terazosin, are currently used.
Prazosine blocks postsynaptic α1 adrenergic receptors in the vascular smooth muscle without
affecting presynaptic alpha2 receptors. As a result, presynaptic α2 receptors may be triggered
by norepinephrine released into the synaptic cleft. By blocking the α1 receptors it produces
arterial vasodilation (with decreased peripheral resistance) and venodilation (with decreased
venous return), which explains the usefulness of prazosin and in the treatment of heart failure.
Renal circulation is unaffected. It is used in the medium and severe forms of hypertension,
generally being associated with a diuretic, possibly with other antihypertensives.
Prazosin acts as an antagonist also at the level of α1 receptors located in the prostate capsule,
improving the symptoms secondary to prostate adenoma. It is advantageous in hypertensive
men who associate benign prostatic hyperplasia.
As side effects it can produce orthostatic hypotension, headache, nausea, xerostomia,
polyarthralgia. Rarely, it may aggravate the clinical status of hypertensives that associate
angina pectoris of effort, which is why in such patients the association with a β blocker is
indicated.
Doxazosin is an α1 selective blocker, with a prazosin-like effect and longer duration of
action. It is indicated in the treatment of hypertension and symptomatology of prostate
adenoma.
1.5. Β-adrenergic blockers
Beta-adrenergic blockers are drugs that lower blood pressure in particular by inhibiting renin
(β1-adrenergic) secretion. It associates cardiac depression (with decreased heart rate). They
can be given alone or in combination with a diuretic and or vasodilator. In the case of
association with vasodilators, they have the advantage that they prevent reflex tachycardia. It
is indicated in all forms of hypertension. They are useful in hypertension associated with
ischemic heart disease and / or arrhythmia. It is also recommended in young people with
hypertension due to adrenergic hyperactivity.
Adverse reactions are due to decreased sympathetic beta-adrenergic control and consist of:
worsening heart failure, bradycardia, and in the case of non-selective beta-blockers,
bronchoconstriction and aggravation of peripheral ischemia are added. Administration of β-
blockers to diabetics under hypoglycemic medication (insulin preparations or oral
antidiabetics) requires caution, as they may promote hypoglycemic reactions and mask the
symptoms of hypoglycemia.
Propranolol, a non-selective β-blocker, without intrinsic sympathomimetic activity and with
quinidine membrane effect, is the oldest drug in the group and has long been used as an
antihypertensive agent. Is contraindicated in patients who associate asthma or peripheral
vascular-spastic disorders.
Atenolol is a β1 blocker. It is excreted renal. In patients with renal impairment, dose
reduction is required.
Metoprolol, a β1 blocker with relative selectivity (equipotent with propranolol as a β1
blocker, but 50-100 times lower than a β2 blocker), is advantageous in hypertensives that
associate asthma, diabetes, peripheral vascular disease.
Bisoprolol a selective β1 compound, metabolized by the liver, with a long half-life and once
per day administration.
Nebivolol is a selective β1 blocker that associates vasodialator effect. Vasodilation is the
result of increased NO release at the endothelial level. Produces a significant decrease in
peripheral vascular resistance. It has a long half-life, it is given once a day.
Carvedilol, a blocker of the β1 and α1 adrenergic receptors, is rarely used as an
antihypertensive, and remains a leading adrenergic blocker in the treatment of compensated
heart failure.
Labetalol blocks β1, β2 and α1 receptors. The decrease in blood pressure occurs by reducing
peripheral vascular resistance, without significant change in heart rate. It is indicated in the
treatment of pheochromocytoma and of some hypertensive emergencies.

2. Direct vasodilators

Direct vasodilators (musculotropes) produce relaxation of the arteriolar smooth muscle by

direct mechanism, with decreased peripheral resistance and venous return. Some compounds
also produce venodilation. The decrease in peripheral vascular resistance determines
compensatory mechanisms mediated by baroreceptors, the sympathetic vegetative system, the
renin-angiotensin-aldosterone system, with hydro-saline retention and reflex-induced
tachycardia.
Hydralazine produces decreased diastolic blood pressure through arteriolar vasodilation. Due
to the compensatory mechanisms, it is necessarily associated with a sympatholytic (common
β-blocker) and a diuretic. As side effects it can cause: headache, nasal congestion, nausea,
anorexia, xerostomia, palpitations. After prolonged administration, polyneuritis (pyridoxine
treatment) and lupoid syndrome appear.
Minoxidil is a highly effective antihypertensive agent with oral administration. It acts by
opening the potassium channels in the membrane of smooth vascular muscle cells. Adverse
reactions can sometimes be severe - tachycardia, hydrosaline retention with oedema,
headache. It promotes hair growth, producing hypertrichosis in women. In men this effect
may be useful in the treatment of alopecia, using local applications with minoxidil.
Diazoxide is a substance with a structure similar to thiazide diuretics, which produces
arteriolar vasodilation but has no diuretic action. In the first half hour, patients may have
orthostatic hypotension, so it is recommended to maintain clinostatism during this period. It
is used only in some hypertensive emergencies, injected intravenously quickly.
Sodium nitroprusside acts both by stimulating guanylate-cyclase in the smooth muscle cell of
the vascular wall and by releasing nitric oxide. Blood pressure drops rapidly (within 1-10
minutes), but the effect is short-lived. It is given in venous infusion, in hypertensive
emergencies, under medical supervision with blood pressure monitoring.
3. Calcium channel blockers

Calcium channel blockers lower blood pressure due to arterial vasodilation and / or heart
depression.
Dihydropyridines (nifedipine, amlodipine, felodipine) act predominantly in vessels, with
consequent decrease in peripheral resistance. In addition, it would also have an anti-
atherogenic effect, by preventing calcium overload of the arterial wall.
Phenylalkylamines (verapamil) work mainly on the calcium channels in the myocardial cell
membrane.
Benzothiazepines (diltiazem) have intermediate action between dihydropyridines and
phenylalkylamines.
Calcium channel blockers can be used in hypertensives that associate renal failure, diabetes,
asthma. They may be associated with other categories of antihypertensive drugs. However,
phenylalkylamine-β blockers or benzothiazepine-β blockers, however, require caution.
Nifedipine is the first compound in the dihydropyridine category used in therapy. It can now
be used in the form of delayed preparation in the treatment of mild or medium hypertension.
Amlodipine is a dihydropyridine that is commonly used in therapy, as antihypertensive or
antianginal.
Felodipine, lacidipine, lercanidipine are new generation long-acting dihydropyridines that are
better tolerated.
Nicardipine is indicated in the treatment of hypertensive emergencies, administered
intravenously, initially in slow bolus, then in venous infusion.
Diltiazem produces vasodilation and cardiac depressant effects; is used as antihypertensive.
Verapamil is indicated especially in patients with hypertension that associate cardiac
arrhythmia and / or ischemic heart disease. It is contraindicated in the presence of heart
failure, bradycardia, atrio-ventricular block. The association with β-blockers requires caution
because they associate the same type of adverse reactions. Combination with digoxin may
antagonize the positive inotropic effect of digoxin and increase the risk of bradycardia. As an
adverse reaction, it frequently causes constipation, headache.

4. Renin-angiotensin-aldosterone system inhibitors

4.1. Angiotensin converting enzyme inhibitors ACEIs

Angiotensin converting enzyme inhibitors (ACEIs) prevent the formation of angiotensin II as
a result of inhibiting the conversion enzyme. Decreasing the amount of angiotensin II causes
dilation of the arterioles, decreasing total peripheral resistance and blood pressure. At the
same time, the secretion of aldosterone decreases and the amount of bradykinin increases (the
conversion enzyme metabolizes bradykinin, in which case it is called kininase II). Increasing
the amount of bradykinin has both direct and vasodilatory consequences, as well as the
formation of increased amounts of PGE2 and prostacyclin.
ACEIs work on both the endocrine-type renin-angiotensin system (represented by
juxtaglomerular secreted renin and plasma angiotensin), as well as on local renin-angiotensin
systems in the myocardium and other tissues. As a result, ACEIs have other beneficial
effects, useful in the treatment of heart failure, of patients with acute myocardial infarction
and diabetic nephropathy (improves low renal function and reduces proteinuria).
The administration of ACEIs in hypertension can be done alone or in combination with other
antihypertensives.
Adverse reactions produced by ACEIs are: hypotension, dry cough (may require stopping
conversion enzyme inhibitors); bronchospasm, nasal obstruction, rashes, angioneurotic
edema (increased risk in patients with a history of angioneurotic edema of other etiology and
those in the black race); renal failure (in patients with bilateral renal artery stenosis or single
kidney), hyperkalemia (due to decreased aldosterone secretion and favored by the association
of potassium-sparing diuretics).
Captopril, the first ACEI used in therapy (since 1977), has a rapid but short-term effect,
which involves administering 2-3 doses per day.
Enalapril is transformed into an active form (enalaprilat) in the liver, acting as a prodrug.
Absorption is not influenced by the presence of food and the duration of action is longer than
in the case of captopril.
Currently many other conversion enzyme inhibitors are used – lisinopril, perindopril,
quinapril.
4.2. Angiotensin receptor antagonists
Angiotensin receptor antagonists used in medical practice block AT1 receptors, thus
preventing the effects of angiotensin II. The effects of angiotensin II are achieved by the
specific action of the membrane angiotensin receptors - AT1 and AT2. The action of AT1
receptors is responsible for: vasoconstriction, aldosterone release, inhibition of renin release,
increased noradrenaline release; involvement in angiogenesis, influence of vascular
permeability, production of cardiovascular hypertrophy. AT2 receptor function is less well
known, with data suggesting beneficial cardiovascular effects (antiproliferative effect).
The first compound used in medical practice as antihypertensive was losartan, with
antihypertensive effect due to blocking of AT1 receptors. Currently, other antagonists
(blockers) of AT1 receptors - valsartan, telmisartan, candersartan, irbesartan are commonly
used in HTA secretion. These substances are also known as "sartans".
Angiotensin receptor antagonists have all ACEIs effects. As they do not inhibit the
conversion enzyme (kininase II), they do not produce cough and may be a treatment
alternative in patients who have ACEIs intolerance. At appropriate doses, they have other
indications: treatment of heart failure; performing "kidney protection" in patients with
diabetes (albuminuria decreases); acute myocardial infarction, for cardioprotective effect.
In the treatment of high blood pressure, it is possible to resort to the combination of sartans
with other antihypertensives, including with a conversion enzyme inhibitor.
4.3. The renin antagonists
Aliskiren is the first compound of the category of renin antagonists used as antihypertensive.
It binds to the active site of renin (S3bp), producing direct inhibition of plasma renin activity
and blocking the renin-angiotensin-aldosterone system.
5. Diuretics as antihypertensive

Diuretics act as antihypertensives by decreasing the volume and implicitly of the cardiac
output, by saline depletion and possibly by direct vasodilating action. It is used as
antihypertensives especially hydrochlorothiazide, indapamide, and in more severe forms
furosemide. Anti-aldosterone diuretics (spironolactone, triamterene) may be associated with
these diuretics to potentiate the diuretic effect or to prevent hypokalemia.
Hydrochlorothiazide is usually given once per daily, in the morning, with breaks of 1-2 days
a week, to prevent secondary hyperaldosteronism and hypokalemia. It is contraindicated in
hypertensives that associate diabetes, gout or kidney failure.
Indapamide is a thiazide diuretic. It produces vasodilation at low doses and associates weak
diuretic action that increases with the dose. It is commonly used in the treatment of
hypertension. It is not contraindicated in diabetics.
Furosemide is a loop diuretic. It can be given orally in more severe forms of HTA or if there
are contraindications to thiazides. The injection form is used in hypertensive emergencies.
The anti-aldosterone diuretics, represented by spironolactone, have a modest antihypertensive
effect, antagonizing the effect of aldosterone, interfering with the K + / Na + exchange, with
the re-absorption of potassium ("potassium-sparing diuretics") and the elimination of sodium
and water. They may be associated with thiazide diuretics or loop diuretics. The association
with IEC or angiotensin receptor blockers requires caution, due to the risk of hyperkalemia.
Antihypertensive drugs LP

Antihypertensive medication, used in the treatment of hypertension (HTA), comprises drugs

that lower blood pressure, acting through different pharmacodynamics mechanisms.
 Medications that reduce sympathetic control:
• sympatholytic with the central action (clonidine, alpha-methyldopa, etc.);
• ganglioplegic (trimetaphan);
• neurosympatholytic (guanetidine, reserpine, etc.)
• alpha adrenergic blockers (prazosin);
• beta adrenergic blockers (propranolol, metoprolol, atenolol, carvedilol, etc);
 Direct vasodilators (hydralazine, diazoxide, minoxidil);
 Calcium channel blockers (nifedipine, diltiazem, verapamil, etc.);
 Drugs that interfere with the renin-angiotensin-aldosterone system
• Angiotensin conversion enzyme inhibitors (captopril, enalapril, etc.);
• angiotensin AT1 receptor antagonists - (losartan, valsartan, candesartan, etc.);
• Renin antagonists (aliskiren);
• β-adrenergic blockers.
 Medications that lower blood volume - diuretics.

Medications that reduce sympathetic control

Sympatholytic with central action
Clonidine stimulates central α2 adrenergic receptors from the bulbous and hypothalamic
structures, decreasing peripheral sympathetic tone and blood pressure. It also acts on non-
adrenergic receptors, respectively imidazoline receptors (I1 receptors).
Methyldopa is analogous to DOPA. It penetrates the brain and substitutes DOPA in the
metabolic chain, causing the synthesis of alpha-methylnoradrenaline (false neurotransmitter)
that stimulates central α2-adrenergic receptors, with the inhibition of the peripheral
sympathetic activity.
Ganglioplegics
Ganglioplegics (trimetaphan) act by blocking nicotine receptors from sympathetic and
parasympathetic vegetative ganglia and decrease the blood pressure with pronounced
orthostatic character.
Neurosympatholytics – Guanethidine and Reserpine
Neurosympatholytics act at the presynaptic component of peripheral sympathetic synapses,
decrease the availability of catecholamines in the synaptic cleft and the blood pressure.

Alpha-adrenergic blockers
Adrenergic α-blockers produce vasodilation by blocking α1 receptors.
Prazosine blocks postsynaptic α1 adrenergic receptors in the vascular smooth muscle without
affecting presynaptic alpha2 receptors. It is used in the medium and severe forms of
hypertension, generally being associated with a diuretic, possibly with other
antihypertensives.
Rp. Prazosin tablets 2 mg
I pack
Ds. Orally, 1 tablet 3 time per day
1.5. Β-adrenergic blockers
Beta-adrenergic blockers are drugs that lower blood pressure in particular by inhibiting renin
(β1-adrenergic) secretion. It associates cardiac depression (with decreased heart rate). They
can be given alone or in combination with a diuretic and or vasodilator. In the case of
association with vasodilators, they have the advantage that they prevent reflex tachycardia. It
is indicated in all forms of hypertension. They are useful in hypertension associated with
ischemic heart disease and / or arrhythmia. It is also recommended in young people with
hypertension due to adrenergic hyperactivity.

Rp. Carvedilol, tablets 2.5 mg

I pack
Ds. Orally, 1 tablet/day

Rp. Nebivolol, tablets 5 mg

I pack
Ds. Orally, 1 tablet/day, in the morning
Direct vasodilators
Direct vasodilators (musculotropes) produce relaxation of the arteriolar smooth muscle by
direct mechanism, with decreased peripheral resistance and venous return. Some compounds
also produce venodilation. The decrease in peripheral vascular resistance determines
compensatory mechanisms mediated by baroreceptors, the sympathetic vegetative system, the
renin-angiotensin-aldosterone system, with hydro-saline retention and reflex-induced
tachycardia.

Calcium channel blockers

Calcium channel blockers lower blood pressure due to arterial vasodilation and / or heart
depression.
Dihydropyridines (nifedipine, amlodipine, felodipine) act predominantly in vessels, with
consequent decrease in peripheral resistance. In addition, it would also have an anti-
atherogenic effect, by preventing calcium overload of the arterial wall.
Phenylalkylamines (verapamil) work mainly on the calcium channels in the myocardial cell
membrane.
Benzothiazepines (diltiazem) have intermediate action between dihydropyridines and
phenylalkylamines.

Rp. Amlodipine, tablets 5 mg

I pack
Ds. Orally, 1 tablet/day, in the evening

Renin-angiotensin-aldosterone system inhibitors

Angiotensin converting enzyme inhibitors ACEIs
Angiotensin converting enzyme inhibitors (ACEIs) prevent the formation of angiotensin II as
a result of inhibiting the conversion enzyme. Decreasing the amount of angiotensin II causes
dilation of the arterioles, decreasing total peripheral resistance and blood pressure. At the
same time, the secretion of aldosterone decreases and the amount of bradykinin increases.
Rp. Enalapril, tablets 10 mg
I pack
Ds. Orally, 1 tablet in the morning and 1 tablet in the evening
Angiotensin receptor antagonists
Angiotensin receptor antagonists used in medical practice block AT1 receptors, thus
preventing the effects of angiotensin II. The effects of angiotensin II are achieved by the
specific action of the membrane angiotensin receptors - AT1 and AT2. The action of AT1
receptors is responsible for: vasoconstriction, aldosterone release, inhibition of renin release,
increased noradrenaline release; involvement in angiogenesis, influence of vascular
permeability, production of cardiovascular hypertrophy.
These substances are also known as "sartans".

5. Diuretics as antihypertensive

Diuretics act as antihypertensives by decreasing the volume and implicitly of the cardiac
output, by saline depletion and possibly by direct vasodilating action. It is used as
antihypertensives especially hydrochlorothiazide, indapamide, and in more severe forms
furosemide. Anti-aldosterone diuretics (spironolactone, triamterene) may be associated with
these diuretics to potentiate the diuretic effect or to prevent hypokalemia.
Rp. Indapamide, tablets 2,5 mg
I pack
Ds. Orally, 1 tablet/day
Antiparasitic agents

This class includes a whole range of chemotherapeutics with specific action on parasites such as
Plasmodium, Entamoeba, Trichomonas, Giardia and with action against worms that can parasitize
the human intestine.

Antimalarial agents

They are chemotherapeutic with selective action on Plasmodium parasites - Plasmodium

falciparum, Plasmodium malariae, Plasmodium ovale, Plasmodium vivax – which are the etiological
agent of malaria.
Based on chemical structure, antimalarials were divided into several groups: 4-aminoquinoline
derivatives: chloroquine; 8 aminoquinoline derivatives: primachine; diaminopyrimidines:
pyrimethamine and trimethoprim; quinoline derivatives: quinine and mefloquine.
Antimalarials act in different phases of the development and multiplication of the parasite with
hematic schizontocidal action (chloroquine, mefloquine, quinine, artemisinins), tissue
schizontocide (primachine, pyrimethamine) or gametocide (primachine, pyrimethamine,
chloroquine). The latter can be used for epidemiological prophylaxis of the disease.
Chloroquine is used in the curative or prophylactic treatment of malaria. Its plasmodicidal action
is due to DNA binding, with consequent inhibition of nucleic acid and protein synthesis. It
accumulates in high concentrations in parasitic erythrocytes, which explains its selective action.
Chloroquine has anti-inflammatory properties, and can be used in the treatment of rheumatoid
arthritis. It is usually given orally, but can also be given by injection. Chloroquine is indicated in the
acute stage of malaria to eradicate erythrocyte forms of the parasite. It is generally well tolerated,
but digestive side effects or liver disorders may occur.
Hydroxychloroquine is very similar to chloroquine, having antimalarial and anti-inflammatory
properties.
Primachine has a plasmodicidal action against parasites in the liver and against sexual forms in the
blood. It acts similarly to chloroquine. It is indicated for the eradication of liver forms and for the
prevention of malaria relapses. In high doses, it can cause toxic methemoglobinemia. It can also
cause idiosyncratic haemolytic anemia in patients with glucose-6-phosphate dehydrogenase
deficiency.
Pyrimethamine acts by inhibiting plasmodia dihydrofolate reductase, blocking the formation of
tetrahydrofolic acid. Its association with a sulfamide (sulfadoxine or sulfadiazine) or a sulfone
(dapsone) is synergistic, as the two chemotherapies combined sequentially block some stages of
folic acid formation (sulfamide and sulfone inhibit dihydropteroate synthetase). This also reduces
the risk of developing resistance. The above-mentioned combinations can be administered orally in
the treatment and prophylaxis of malaria with Plasmodium falciparum. In high doses,
pyrimethamine can cause megaloblastic anemia and leukopenia.
Proguanil is a biguanide derivative that acts similarly to pyrimethamine.
Mefloquine has marked hematic schizontocidal action, being effective, even in a single therapeutic
dose, against polychemoresistant Plasmodium falciparum.
Quinine is an alkaloid in the bark of the Cinchona tree that acts as a gametocide by interfering with
protein synthesis due to DNA binding. Quinine has also other actions, weak analgesic and
antipyretic effect, local anesthetic, cardiac and hypotensive depressant, motor terminal plate
excitability depressant. It is to be chosen in severe malaria, in which it is administered
intravenously. It causes hypotension and severe arrhythmias after intravenous injection, and in
high doses or in idiosyncrasies may develop an acute cinchonism manifested by tinnitus, vertigo,
deafness, headache, vision problems, nausea, diarrhea, fever, various rashes. Occasionally, it can
cause blood dyscrasias.

Chemotherapeutics active in amoebiasis, trichomoniasis and

giardiasis

Metronidazole is a synthetic chemotherapeutic derived from 5-nitroimidazole; is active against

Entamoeba histolytica, Trichomonas vaginalis, Giardia intestinalis. It also has bactericidal action
against Gram-negative anaerobic bacilli (Bacteroides, Helicobacter), against Gram-positive
anaerobic cocci (Peptostreptococcus) and against most clostridia (including C. difficile).
Metronidazole is activated intracellularly by reducing its nitro group under the action of enzymes
specific to anaerobic pathogenic microorganisms (protozoa, bacteria). Intermediate compounds are
formed that act bactericidal by damaging the DNA, proteins and cell membranes of pathogenic
microorganisms.
Metronidazole is well absorbed after oral administration and is well distributed in tissues, including
CSF, brain, abscesses. It has a relatively short half-life (T1 / 2) of 7.5 hours.
It is the main active chemotherapeutic in acute amoebic dysentery, removing parasites localized
intestinal and extraintestinal, in vaginal trichomoniasis (used systemically in a single dose (2
grams) or 250mg 3 times a day for 3-7 days, but also intravaginally), in giardiasis (oral treatment,
three days), it is also of first choice in anaerobic abdominal or central nervous system infections in
combination with aminoglycosides (gentamicin) or beta-lactams (ampicillin, amoxicillin). It is
effective in diarrhea caused by Clostridum difficile and in Helicobacter pylori infections in patients
with gastric or duodenal ulcers.
Metronidazole relatively frequently causes digestive disorders (anorexia, nausea, unpleasant
metallic taste), in high doses it can cause toxic neurological disorders (peripheral neuritis, vertigo,
ataxia, epileptic seizures), may color urine red-brown. Alcohol consumption is contraindicated
during treatment with metronidazole, as disulfiram-like reactions (flush, nausea, vomiting,
dizziness, tachyarrhythmias) may occur. Due to possible teratogenic effects, its administration
during pregnancy is not indicated.
Tinidazole, ornidazole, nimorazole are derivatives of nitroimidazole with properties similar to
metronidazole, but with a longer T1/2, 12-14 hours, and a higher safety profile.
Diloxanide furoate is an amoebicidal active only on cysts in the intestinal lumen. It is indicated in
asymptomatic amoebic intestinal infections. It is generally well tolerated.
Clioquinol has intestinal antiseptic properties and is active against amoebic cysts in the intestinal
lumen. It can cause iodism. It is contraindicated in hyperthyroidism. Diododohydroxyquinoline
(iodoquinol) is similar to clioquinol.
Chloroquine, widely used as an antimalarial, is also an active amoebicidal, being effective in
hepatic amoebiasis, due to accumulation in the liver after oral administration.
Paromomycin is an aminoglycoside antibiotic with amoebicidal properties, being used in intestinal
amoebiasis and sometimes in the treatment of tapeworms. Its digestive absorption is minimal, so it
has no systemic effects. By injection, it is used in visceral leishmaniasis.
Mepacrine is useful in giardiasis, especially in cases that are resistant to other treatments. It
accumulates in tissues, from where it is slowly released and excreted in the urine. May color skin
yellow and nails brown (reversible effects).

Anthelmintic chemotherapeutics

Anthelmintic chemotherapeutics are active against various worms that parasitize the human gut
and other tissues and organs.
Mebendazole is a synthetic benzimidazole derivative with broad-spectrum anthelmintic
properties. It is active on nematodes: Trichiuris trichiuria, Ankylostoma duodenale, Trichinella
spiralis, Ascaris lumbricoides, Enterobius vermicularis. It is electively captured by sensitive
parasites which it immobilizes and kills. It irreversibly inhibits the process of glucose uptake,
decreases the amount of glycogen, which prevents the formation of ATP, with cytotoxic
degeneration of microtubules.
Mebendazole after oral administration is absorbed in a very small proportion (10%). It is
transformed into inactive metabolites at the first hepatic passage and has a T1/2 of 2-6 hours.
It is to be chosen in the treatment of trichocephalosis, hookworm, ascaridiosis and oxyurase. It is
advantageous in cases of multiple infestation. In high doses it is indicated in inoperable
echinococcosis and in hepatic hydatid cysts. Under normal dosing conditions it is free of systemic
toxicity. It is contraindicated during pregnancy and in children under two years.
Albendazole is also a benzimidazole derivative. It is a broad-spectrum anthelmintic active against
nematodes, but also against many cestodes - Echinococcus granulosus, Cysticercosis. It can also kill
the eggs of Ascaris, Ankylostoma, Trichiuris. It works similarly to mebendazole.
After oral administration it is absorbed inconsistently. It undergoes a phenomenon of first hepatic
passage and transforms into the active metabolite - albendazole sulfoxide. It has a T1/2 of 8-12
hours. The sulfoxide metabolite is widely distributed in tissues, CSF and hydatid cysts.
It is a larvicide in hydatid disease (Echinococcus granulosus), cysticercosis, roundworm and
hookworm disease, where it can kill the eggs of these parasites. It is given on an empty stomach
when used against parasites in the intestinal lumen and after a high-fat meal (increase digestive
absorption) to kill parasites in the tissue.
It is the first choice in pinworm infections, where it is practically 100% effective after a single dose
of 400mg. This dose can be repeated every 2 weeks. It has similar indications to mebendazole.
Albendazole is also useful in the treatment of cutaneous or visceral migrating larvae as well as
intestinal capillaries.
It has virtually no side effects at usual doses and in short treatments of 1-3 days. In longer
treatments, it can give abdominal pain, fatigue, increased liver transaminases.
Thiabendazole is a thiazolyl-benzimidazole. It has a vermicidal effect and a wide spectrum, being
active both on various nematodes that parasitize the intestine and on the larval, migrating forms of
Strongyloides. Inhibits fumarate reductase, causing paralysis of worms. It also has anti-
inflammatory, analgesic and antipyretic action, as well as immunomodulatory effects through
action on T lymphocytes. It is also active in cutaneous migrans larvae, in which case it is
administered locally or orally for 2 days.
It is rapidly absorbed after oral administration and is fully metabolised. It has a higher toxicity than
albendazole, which is why it is less used today.
Pirantel pamoate is an active derivative against nematodes (Ascaris lumbricoides, Enterobius
vermicularis, Ankylostoma duodenale, Necator americanus, Trichostrongylus orientalis).
Intoxicates intestinal worms and produce their spastic paralysis due to depolarization of the motor
terminal plate, consequent inhibition of cholinesterase and release of acetylcholine. It is not active
on tissue migratory forms or on eggs. It is absorbed slightly from the intestine, where it achieves
high concentrations. It is of choice in ascaridiosis and oxyurase, in a single dose, which can be
repeated after two weeks.
Pirvini embonate is acts especially toxic against Enterobius vermicularis, which it paralyzes and
kills. It is not absorbed after oral administration, so it achieves high concentrations in the intestinal
mucosa and has no systemic toxicity. Color the feces in red.
Piperazine is active against Ascaris lumbricoides and Enterobius vermicularis. It causes flaccid
paralysis of worms by hyperpolarizing the membrane of muscle cells, eliminating parasites from
the intestine. Is less used today because of side effects (neurological disorders) and the need for
several days treatment. It is contraindicated in renal failure and epilepsy. It is also not associated
with pirantel because there is an antagonism between them.
Levamisole is an aminothiazole derivative. It is active against many nematodes, especially Ascaris
lumbricoides. It causes paralysis of worms by inhibiting fumarate reductase. It can be used as
associatetherapy of rheumatoid arthritis and other chronic inflammatory conditions. It is
completely absorbed from the intestine and is metabolized mostly by the liver. It is given orally, in a
single dose, in the therapy of ascariasis.
Niclosamide is a very active vermicide against cestodes: Taenia saginata, Taenia solium,
Botryocephalus, Hymenolepis nana. Inhibits oxidative phosphorylation and stimulates ATPase of
sensitive parasites. Intoxicated worms become vulnerable to intestinal proteases and are
eliminated in the feces. Niclosamide is insoluble, so it is not absorbed in the gut. It is very well
supported. It sometimes causes minor digestive disorders.
Other anthelmintics active especially against filariasis and trematodes are: diethylcarbamazine,
ivermectin, praziquantel.
 ANTITHROMBOTIC DRUGS

Antithrombotic drugs are a group of drugs used in the prophylactic and curative
treatment of thromboembolic disorders.
Vascular thrombosis can be arterial or venous.
• arterial thrombosis - an endothelium injury triggers platelet aggregation with
white thrombus formation.
• venous thrombosis - the coagulation process is activated by the blood stasis,
with the formation of the red thrombus.
In the case of thrombosis from the level of the valvular or vascular prostheses, both the
platelet aggregation and the coagulation process are involved, with obliteration and reduction
of local circulation or risk of embolism.
Fibrinolysis is the process of activation of plasminogen in plasmine, which hydrolyzes
fibrin and some coagulation factors (including fibrinogen) with clot lysis.
Antithrombotic drugs may be:
- anti-platelets
- anticoagulants
- fibrinolytic.

Anti-platelet drugs
Anti-platelet drugs inhibit platelet functions and prevent white thrombus formation. In
arterial thrombosis there is an injury of the vascular endothelium (atheroma plaques) which
causes the increase of platelet adhesivity and aggregability. As a result of these processes,
thromboxane A2 (TXA2), ADP, Platelet Activating Factor - PAF begins to be released, with
exposure of glycoprotein receptors IIb / IIIa (GP IIb / IIIa), from which fibrinogen binds, a
process that activates platelet aggregation and white thrombus formation. TXA2 promotes
platelet adhesivity and has vasoconstrictor action. Prostacyclin (prostaglandin I2; PgI2) is
formed in the normal vascular endothelium, and has an anti-aggregating and vasodilating
effects.
Anti-platelets drugs may have several mechanisms of action.
- inhibition of cyclooxygenase (acetylsalicylic acid)
- inhibition of ADP-induced aggregation (ticlopidine, clopidogrel)
- blocking membrane glycoprotein receptors – GP IIb / IIIa (abciximab, tirofiban)
- blocking thromboxane A2 receptors (terutroban)
The main indication is prophylaxis of arterial thrombosis in patients with ischemic
heart disease, acute myocardial infarction, bypass, angioplasty, history of stroke.
 Acetylsalicylic acid has a long-lasting anti-aggregating effect. It blocks irreversibly by
acetylation the platelet cyclooxygenase 1 (COX 1), decreasing TXA2 synthesis, inhibiting
platelet aggregation and prolonging bleeding time. The platelet anti-aggregating effect is
manifested at low doses of acetylsalicylic acid (75-300mg). At higher doses (500 mg)
endothelial cyclooxygenase is also inhibited, limiting the anti-aggregating effect by decreasing
prostacycline synthesis.
It is indicated in the treatment and prophylaxis of acute myocardial infarction, stroke,
peripheral arteriopathy. It is well tolerated, with few adverse reactions - digestive bleeding in
people with ulcer, gastritis. It is contraindicated in case of allergy to salicylates, recent
bleeding, ulcer.
Ticlopidine irreversibly inhibits platelet receptors for ADP, inhibiting adhesivity and
platelet aggregation.
It is indicated in the prophylaxis of arterial thrombosis (patients at risk or a history of
stroke or acute myocardial infarction), in patients with peripheral arteriopathy, hemodialysis,
coronary stent angioplasty.
Produces haematological adverse reactions: thrombocytopenia, neutropenia,
agranulocytosis, bleeding. Monitoring of the hemogram within the first 2-3 months of
treatment is required. Neutropenia may be severe, but is reversible if is stopped the treatment.
It can also cause diarrhea, nausea, abdominal pain, ulcer. Contraindications - bleeding,
ulceration, liver failure.
Clopidogrel irreversibly inhibits ADP receptors - subtype P2Y12 in platelets with
irreversible inhibition of platelet functions. Adverse reactions of clopidogrel are lower than
ticlopidine. It is indicated in the treatment and prophylaxis of acute myocardial infarction or
ischemic stroke and in patients with stent coronary angioplasty. Clopidogrel is a prodrug that
is activated in the liver via the cytochrome P 450 pathway. The antithrombotic effect is
maintained for 7-10 days after discontinuation of treatment. Contraindications: active bleeding
lesions (gastric or duodenal ulcer, cerebral hemorrhage), liver failure. Due to metabolism in
cytochrome P450, drug interactions are possible.
Prasugrel irreversibly inhibits P2Y12 platelet receptors with antiplatelet effects. It is a
prodrug, which is activated by hepatic metabolism in cytochrome P450.
Ticagrelor reversibly blocks the P2Y12 receptor. As P2Y12 receptor binding is
reversible, platelet activity returns rapidly after stopping treatment.
Glycoprotein receptor antagonists IIb / IIIa - Abciximab, Eptifibatide, Tirofiban, are
substances that inhibit platelet functions by blocking long-acting membrane glycoprotein IIb /
IIIa receptors, used in the treatment of coronary syndromes.
Dipiridamol has anti-platelet effect by inhibiting platelet phospho-diesterase, with
subsequent increase in platelet cAMP concentration and inhibition of adenosine reuptake and
metabolism.
Cilostazole inhibits platelet phosphodiesterase and produces also vasodilation.
 Anticoagulants

Anticoagulants are drugs that prevent the coagulation process: indirect thrombin
inhibitors (heparins, direct factor Xa inhibitors), direct thrombin inhibitors and coumarin
anticoagulants.

Indirect thrombin inhibitors - heparin

Heparin binds to antithrombin III (alpha2 plasma globulin), increases its inhibitory
effect on factor Xa and increases the ability of antithrombin III to inactivate thrombin (factor
IIa).
Unfractionated heparin - standard heparin or conventional heparin has
glycosaminoglycan-like molecule; the anticoagulant effect is produced by the pentazaharidic
sequence. It binds to antithrombin III, which physiologically inhibits coagulation factors IIa,
IXa and Xa, which increase its activity about 1000 times. It has a rapid, intense, short-term
effect, in vivo and in vitro. The in vitro anticoagulant effect is used in the collection of blood
samples
Heparin in high doses inhibits platelet aggregation, promoting bleeding; clarifies
lipemic plasma - increases the release of lipoprotein lipase from tissues with triglyceride lysis.
It has a polar molecule and is inactivated in the intestine. It is administered intravenously or
subcutaneously. It cannot be administered intramuscularly, as it produces hematomas. It has a
short half-life (30-60 minutes). Urinary elimination, partially inactive; caution is advised in
patients with renal impairment. It can be used in pregnancy because it does not cross the
placenta
Adverse reactions: bleeding, thrombocytopenia, decreased mineralocorticoid hormone
synthesis, osteoporosis, allergic reactions.
Overdose of heparin is treated with protamine sulfate, which chemically inactivates
heparin.
Contraindications: thrombocytopenia, hemophilia, thrombocytopenic purpura, active
gastric or duodenal ulcer, intracranial hemorrhage, abortion, genital bleeding, endocarditis,
heparin hypersensitivity, recent surgery, uncontrolled hypertension.
Heparin sodium salt may be administered intravenously by infusion or
subcutaneously. Verification of the efficacy and safety of the treatment is performed by
monitoring APTT (activated partially thromboplastin time )which should be maintained at
values 1.5-2.5 times higher than normal.
Indications: prophylaxis of venous thrombosis, pulmonary thromboembolism,
acute coronary syndromes and in some cases of acute peripheral ischemia.
 Heparin calcium salt is administered subcutaneously in the prophylaxis of
thromboembolic disorders.
Low molecular weight heparins (enoxaparin, dalteparin, nadroparin, reviparin,
tinzaparin) are obtained by depolymerization of heparin. It stimulates antithrombin III and
inhibits factor Xa. Are administered subcutaneously and have a long half-life (16-18 hours).
Adverse reactions, especially the risk of bleeding, are lower. Are used in the treatment of
venous thrombosis, pulmonary thromboembolism, acute myocardial infarction, prophylaxis of
venous thrombosis in patients undergoing surgery, immobilized.
Fondaparine selectively inhibits factor Xa; does not inhibit thrombin activity, does not
influence platelet activity and does not alter coagulation assays. It is administered
subcutaneously in acute myocardial infarction, pulmonary thromboembolism, deep vein
thrombosis or for thrombosis prophylaxis after surgery.
Idraparin is a preparate similar to fondaparine, with a longer half-life
Sulodexid has antithrombotic action by inhibiting factor Xa. It inhibits platelet
adhesivity, normalizes blood viscosity, activates lipoprotein lipase, and can normalize
increased plasma lipid concentrations.
Direct inhibitors of factor Xa – rivaroxaban, apixaban – are selective inhibitors of
factor Xa, without inhibitor effect on thrombin (factor IIa) and without effect on platelets. Are
indicated in the prevention of venous thromboembolism, prevention of stroke in patients with
chronic atrial fibrillation.

Direct thrombin inhibitors

It binds directly to the active site of thrombin and inhibits its effects. It can be given
parenterally (lepirudin, bivalirudin, agatorban) or orally (ximelgatran, dabigatran).
Hirudin is a natural substance that irreversibly inhibits thrombin. It has high toxicity -
it is administered only locally in the treatment of hematomas.
Lepirudine is administered injectable in the treatment of thrombosis.
Bivalirudine is a synthetic derivative of hirudin, which also inhibits platelet activation.
It is given intravenously to patients with acute coronary syndrome who undergo invasive
therapy.
Argatroban is useful in patients with heparin-induced thrombocytopenia.
Dabigatran is a thrombin inhibitor, which is administered orally. It is indicated for
thromboembolic accidents prophylaxis in hip or knee surgery and stroke in patients with
chronic atrial fibrillation. Adverse reactions: gastrointestinal disorders (nausea, vomiting),
bleeding especially in elderly patients. Contraindications: severe renal failure, active bleeding,
severe hepatic failure, pregnancy and lactation.
 Coumarinic anticoagulants

Coumarin anticoagulants - antivitamins K - inhibit hepatic activation of vitamin K

dependent coagulation factors - IIa, VIIa, IXa, Xa. They block epoxireductase, inhibit the
restoration of vitamin K's active form, and thus inhibit the activation of coagulation factors.
These anticoagulants are active only in vivo. The anticoagulant effect slowly settles, after 24-
72 hours, during which time the consumption of the vitamin K-dependent factors in the plasma
occurs, and it persists for 2-10 days after the discontinuation of the treatment, the interval
needed to restore the coagulation factors.
Pharmacokinetics: are well absorbed in the digestive tract, bind 90-99% on albumin
(90-99%) and are metabolized by the liver, cross the placenta and passes into breast milk.
Indications: curative treatment of thrombophlebitis and prophylaxis of
thromboembolism in patients with chronic atrial fibrillation or in those with mechanical
valve prostheses. Are administered orally and the INR (international normalized ratio)
is monitored.
Adverse reactions: bleeding through overdose or interactions with drugs or food. The
increased risk of bleeding is also due to the prolonged effect of oral anticoagulants. In the case
of bleeding by overdosage of oral anticoagulants, vitamin K, fresh plasma or prothrombin
complex concentrate is given. Hepatic disorders (insufficient synthesis of coagulation factors),
heart failure (through liver stasis), vitamin K deficiency, hyperthyroidism increase the effect
of anticoagulants.
Contraindications: hemorrhagic syndromes, ulcer, hypertension with stroke,
pregnancy, liver failure, severe kidney failure. Combination with heparin, anti-platelets drug,
NSAIDs, amiodarone, cimetidine, some antibiotics (penicillin, cephalosporins, erythromycin)
increases the effect of coumarin anticoagulants with high risk of bleeding.
The decrease of the anticoagulant effect occurs when it is combined with enzyme
inducing drugs (barbiturates, rifampicin, griseofulvin, carbamazepine), by increasing the
hepatic metabolism of the anticoagulant. All of these interactions require careful monitoring of
anticoagulant treatment Interactions with some foods. Foods rich in vitamin K (broccoli,
cauliflower, soy, spinach, cabbage, green salad, liver, black tea, fish oil) decrease the
anticoagulant effect, and the consumption of alcohol or certain vegetables and spices (garlic,
ginger, ginseng extract) or Ginkgo biloba) increases the anticoagulant effect. Acenocoumarol
has high potency; the effect is installed 24-36 hours after the first dose and maintained 36-72
hours after stopping treatment. Warfarin - the effect settles slower (about 37-60 hours) and
stays up to 5-7 days.
 Fibrinolytic drugs

Fibrinolytics (thrombolytics) are drugs that lysate fibrin clot by activating plasminogen
in plasmin.
Plasminogen can be activated in plasmin intrinsically by coagulation, dependent on
factor XII of coagulation, by extrinsic pathway through tissue plasminogen activator, urokinase
or exogenous drug activators.
Fibrinolytic drugs bind to the plasminogen in the fibrin clot, lyses fibrin and loosens
the thrombus, with re-permeabilization and reperfusion. Thrombolysis is effective in the first
hours-days of thrombosis.
Indications: acute myocardial infarction, pulmonary embolism, deep vein
thrombosis and peripheral arterial occlusion, large vein thrombosis (superior vena cava).
The recovery of the ischemic area is greater as the fibrinolytic administration becomes earlier.
For acute myocardial infarction, the results are optimal if the administration is done within the
first 4 hours after the onset of the infarction.
The most common adverse reaction of fibrinolytics is hemorrhage, in which case it is
necessary to interrupt fibrinolytic treatment, administer plasma infusions, and if necessary
administer antifibrinolytic drugs such as aminocaproic acid or aprotinin. Invasive maneuvers
should be avoided.
They are contraindicated in the case of a history of strokes, recent head trauma, brain
tumors, untreated hypertension, active gastric or duodenal ulcer, coagulopathies.
Fibrinolytics are given intravenously.
Streptokinase is a protein obtained from the filtrate of beta-hemolytic streptococcus
cultures. It interacts with plasminogen, transforms plasminogen into plasma and has a
thrombolytic effect. Adverse reactions: bleeding, hypotension by vasodilation, allergic
reactions.
Anistreplase - (acylated plasminogen-streptokinase-activator complex; APSAC) is
administered intravenously, attaches to fibrin chains, and produces proteolysis.
Urokinase directly activates plasminogen, transforming it into plasmin. The presence
of fibrin may increase its activity. It is not antigenic.
Alteplase (t-PA; tissue plasminogen activator) has high selectivity for fibrin, with poor
plasma proteolysis.
Reteplase - r-PA (recombinant plasminogen activator) is a recombinant plasminogen
activator that converts plasminogen into plasma, with consecutive thrombus lysis.
Tenecteplaza is a recombinant plasminogen activator with increased specificity for
fibrin from thrombus, converting plasminogen from thrombus into plasmin.
 ANTITHROMBOTIC DRUGS

Antithrombotic drugs may be:

- anti- platelets
- anticoagulants
- fibrinolytic.

ANTI-PLATELET DRUGS

Anti-platelet drugs inhibit platelet functions and prevent white thrombus formation.
In arterial thrombosis there is an injury of the vascular endothelium (atheroma plaques)
which causes the increase of platelet adhesivity and aggregability.
Anti-platelets drugs may have several mechanisms of action
- inhibition of cyclooxygenase (acetylsalicylic acid)
- inhibition of ADP-induced aggregation (ticlopidine, clopidogrel)
- blocking membrane glycoprotein receptors – GP IIb / IIIa (abciximab, tirofiban)
- blocking thromboxane A2 receptors (terutroban)
The main indication is prophylaxis of arterial thrombosis in patients with ischemic heart
disease, acute myocardial infarction, bypass, angioplasty, history of stroke.
Acetylsalicylic acid has a long-lasting anti-aggregating effect. It blocks irreversibly by
acetylation the platelet cyclooxygenase 1 (COX 1), decreasing TXA2 synthesis, inhibiting
platelet aggregation and prolonging bleeding time. The platelet anti-aggregating effect is
manifested at low doses of acetylsalicylic acid (75-300mg).
It is indicated in the treatment and prophylaxis of acute myocardial infarction, stroke,
peripheral arteriopathy. It is well tolerated, with few adverse reactions - digestive bleeding in
people with ulcer, gastritis. It is contraindicated in case of allergy to salicylates, recent
bleeding, ulcer.

Rp. Acetylsalicylic acid tablets 75 mg

I pack
Ds. orally, 1 tablet every 8 hours

Ticlopidine irreversibly inhibits platelet receptors for ADP, inhibiting adhesivity and
platelet aggregation.

Rp. Ticlopidine tablets 250 mg

I pack
Ds. orally, 1 tablet every 12 hours

Clopidogrel irreversibly inhibits ADP receptors - subtype P2Y12 in platelets with

irreversible inhibition of platelet functions. Adverse reactions of clopidogrel are lower than
ticlopidine. It is indicated in the treatment and prophylaxis of acute myocardial infarction or
ischemic stroke and in patients with stent coronary angioplasty.

Rp. Clopidogrel tablets 75 mg

I pack
Ds. orally, 1 tablet per day
 ANTICOAGULANTS

Anticoagulants are drugs that prevent the coagulation process: indirect thrombin
inhibitors (heparins, direct factor Xa inhibitors), direct thrombin inhibitors and coumarin
anticoagulants.

Indirect thrombin inhibitors - heparin

Heparin binds to antithrombin III (alpha2 plasma globulin), increases its inhibitory
effect on factor Xa and increases the ability of antithrombin III to inactivate thrombin (factor
IIa).
Unfractionated heparin - standard heparin or conventional heparin has
glycosaminoglycan-like molecule; the anticoagulant effect is produced by the pentazaharidic
sequence. It binds to antithrombin III, which physiologically inhibits coagulation factors IIa,
IXa and Xa, which increase its activity about 1000 times. It has a rapid, intense, short-term
effect, in vivo and in vitro. The in vitro anticoagulant effect is used in the collection of blood
samples

Heparin sodium salt may be administered intravenously.

Rp. Heparin sodium ampoules 5000 IU

XII ampuoles
Ds. i.v., 1 ampoule every 4 hours, with the control of APTT

Indications: prophylaxis of venous thrombosis, pulmonary thromboembolism, acute

coronary syndromes and in some cases of acute peripheral ischemia
Heparin calcium salt is administered subcutaneously in the prophylaxis of
thromboembolic disorders.
Low molecular weight heparins (enoxaparin, dalteparin, nadroparin, reviparin,
tinzaparin) are obtained by depolymerization of heparin. It stimulates antithrombin III and
inhibits factor Xa. Are administered subcutaneously and have a long half-life (16-18 hours).
Adverse reactions, especially the risk of bleeding, are lower. Are used in the treatment of
venous thrombosis, pulmonary thromboembolism, acute myocardial infarction, prophylaxis of
venous thrombosis in patients undergoing surgery, immobilized.

Enoxaparine - Clexane

Rp. Clexane syringes 4,000 IU

VII syringes
Ds. Injectable subcutaneous, 4,000 IU once daily

• In moderate risk patients, enoxaparin sodium treatment should be maintained for a

minimal period of 7-10 days whatever the recovery status (e.g. mobility). Prophylaxis
should be continued until the patient no longer has significantly reduced mobility.
• In patients at high risk of thromboembolism, the recommended dose of enoxaparin
sodium is 4,000 IU (40 mg) once daily given by SC injection preferably started 12 hours
before surgery. If there is a need for earlier than 12 hours enoxaparin sodium preoperative
prophylactic initiation (e.g. high risk patient waiting for a deferred orthopaedic surgery),
 the last injection should be administered no later than 12 hours prior to surgery and
resumed 12 hours after surgery.
• For patients who undergo major orthopaedic surgery an extended thromboprophylaxis up
to 5 weeks is recommended.
• For patients with a high venous thromboembolism (VTE) risk who undergo abdominal or
pelvic surgery for cancer an extended thromboprophylaxis up to 4 weeks is
recommended.

Direct inhibitors of factor Xa – rivaroxaban, apixaban – are selective inhibitors of

factor Xa, without inhibitor effect on thrombin (factor IIa) and without effect on platelets. Are
indicated in the prevention of venous thromboembolism, prevention of stroke in patients with
chronic atrial fibrillation.

Rp. Eliquis tablets 5 mg

I pack
Ds. orally, one tablet every 12 hours

Apixaban – Eliquis, tablets 2.5 and 5 mg

To prevent stroke and systemic embolism in nonvalvular atrial fibrillation -
indicated 5 mg PO BID

Direct thrombin inhibitors

Dabigatran (Pradaxa) is a thrombin inhibitor, which is administered orally. It is

indicated for thromboembolic accidents prophylaxis in hip or knee surgery and stroke in
patients with chronic atrial fibrillation.

Rp. Pradaxa, capsules 110 mg

I pack
Ds. orally, one capsule daily

Coumarinic anticoagulants

Coumarin anticoagulants - antivitamins K - inhibit hepatic activation of vitamin K

dependent coagulation factors - IIa, VIIa, IXa, Xa. They block epoxy reductase, inhibit the
restoration of vitamin K's active form, and thus inhibit the activation of coagulation factors.
These anticoagulants are active only in vivo. The anticoagulant effect slowly settles, after 24-
72 hours, during which time the consumption of the vitamin K-dependent factors in the plasma
occurs, and it persists for 2-10 days after the discontinuation of the treatment, the interval
needed to restore the coagulation factors.

Acenocumarol - Sintrom

Rp. Sintrom tablets 4 mg

I pack
Ds orally, one tablet daily
Antiviral drugs

Currently available antiviral drugs have only a virustatic effect. They prevent the spread of the viral
infection from one cell to another and thus prevent the progression of the disease.
The molecular mechanism of the antiviral drugs is very different from one drug to another:
- Some antivirals prevent the virion entering the host cell. So are some anti-HIV drugs
such as enfuvirtide and maraviroc.
- Other drugs, such as amantadine and rimantadine, two anti-influenza antivirals, inhibit
the release of nucleic acids into the host cell. They bind to some special proteins, called M2
proteins, located in the lipid shell of the virion and which act as channels for hydrogen ions.
Hydrogen ions pass through these channels and increase the internal acidity of the virion, a fusion
of hemagglutinin molecules takes place and viral genetic material is released inside the cell.
Amantadine and rimantadine, by modifying the activity of the M2 protein, prevent this process.
- It is also possible to inactivate the integration of viral DNA into the DNA of the host
cell, as in the case of raltegravir, an anti-HIV drug that inhibits integrase, an enzyme of viral origin
involved in the integration of provirus into the DNA of the host cell.
- Some antiviral drugs prevent the assembly of virions. Thus, for example, some anti-HIV
drugs inhibit viral protease, an enzyme of viral origin that lyses the precursors of HIV-enveloping
proteins by turning them into common capsid components. In this way, envelope proteins are no
longer formed and virions can no longer assemble in the cytoplasm of the host cell, due to the lack
of essential components.
- There are antiviral drugs that prevent the release of virions from the host cell. Thus,
for example, oseltamivir and zanamivir, two influenza antivirals inhibit neuraminidase, a viral
enzyme involved in the release of virions from the host cell. The receptor for attaching influenza
virus to the host cell is sialic acid normally contained in the host cell membrane. In order for virions
to be released from the host cell, an enzyme of viral origin, called neuraminidase, lyses membrane
sialic acid. If neuraminidase is inactivated, the viruses bind to the sialic acid in the host cell
membrane and can no longer be released from it.
- However, most antiviral drugs inhibit the formation of viral nucleic acids. These drugs
are usually analogues of nitrogenous bases or sometimes nucleoside analogues.
In all cases, antiviral drugs bind specifically and inhibit the activity of a particular protein that is
either viral or viral in origin, ie synthesized by the host cell as a result of information entered in the
viral genome. This ensures the specificity of action of antiviral drugs. However, such specific viral
molecules usually differ from one virus to another, which makes the spectrum of activity of antiviral
drugs generally narrow.
In addition to antiviral chemotherapeutics, other treatments may be used to cure and prophylaxis
of viral infections: vaccination, administration of specific antibodies to the virus causing the
infection, administration of interferons.
Antivirals active against the flu virus

A number of antiviral drugs are active against influenza viruses. Some of these drugs, such as
amantadine and rimantadine, prevent the release of viral genetic material into the host cell after
the virion enters the host cell due to its binding to sialic acid, the receptor for influenza virus. The
mechanism of action probably consists in inhibiting the activity of M2 protein, a protein located on
the inner surface of the lipid shell of the virus and which functions as an ion channel for hydrogen
ions. Hydrogen ions passing through this ion channel increase the pH inside the virion which causes
a fusion of hemagglutinin molecules resulting in the release of virion genetic material inside the
host cell. Other drugs, such as oseltamivir and zanamivir, prevent the release of virions from the
host cell. The mechanism of action is to inhibit the activity of a viral enzyme called neuraminidase.
This enzyme lyses sialic acid from the membrane of the host cell, which facilitates the release of
virions from the cell. By inhibiting neuraminidase activity, membrane sialic acid fixes virions to the
host cell so that they are no longer released to infect new cells.
Amantadine is also active against rubella virus and some tumor viruses, but is not usually used for
these indications. Amantadine also promotes dopaminergic transmission at the nigrostriatal level,
being useful as an antiparkinsonian, but this effect is leading also to side effects. Rimantadine has a
higher potency than amantadine and seems to be better tolerated. Oseltamivir is an apparently
well-supported oral antiviral. The main side effects consist of gastric irritation with the possible
production of nausea, vomiting, abdominal discomfort.
The main way to prevent the flu is vaccination.
The flu vaccine is usually very well tolerated. Sometimes, however, it can cause a slight discomfort
that mimics a flu. Extremely rarely it can cause some usually reversible neurological disorders. In
most cases, the flu vaccine is prepared on the embryonated egg and, depending on the degree of
purification performed by the manufacturer, can cause allergic phenomena in people with egg
protein allergy.

Antivirals active against the herpes virus

A number of antiviral drugs are active against herpes virus, varicella-zoster virus and
cytomegalovirus. They generally act by insertion into the forming nucleic acid chain by stopping its
elongation and specifically inhibiting viral polymerase. The specificity for viral polymerase is not
very good and because of that, some of these drugs, in non-clinical research, have been shown to be
mutagenic, teratogenic, carcinogenic or myelosuppressive. Most of them (acyclovir, penciclovir,
ganciclovir) become active by their successive phosphorylation to the triphosphate form, which
inhibits viral polymerase. The first phosphorylation, which generates the monophosphate form, is
performed by a viral kinase while the other two phosphorylations are performed by host cell
enzymes. Because of that the drugs are concentrated in the active form only in the virally infected
cells.
Acyclovir is converted intracellularly to monophosphate by a kinase of viral origin. It is absorbed
slightly from the digestive tract, about 10-20%, but a precursor of it, valaciclovir is absorbed much
better and is converted in the body into acyclovir. Administered systemically, by injection or orally,
as acyclovir or valaciclovir, acyclovir is more effective than administered topically. It is used
topically in facial or genital herpes. In severe forms, including herpetic meningitis, it can be given
systemically, intravenously or orally. Acyclovir decreases the intensity of symptoms and especially
shortens the course of the disease. The most important side effects consist of digestive irritation,
nausea or vomiting, very rarely renal failure or neurotoxicity, especially with intravenous
administration of acyclovir, and local application of irritation at the site of administration,
sometimes with itching.
Famciclovir and penciclovir have the same spectrum of antiviral activity as acyclovir. Penciclovir
has a bioavailability of 5% after oral administration, but famciclovir is well absorbed and converted
in the body to penciclovir.
Ganciclovir is somewhat similar to the previous drugs, but is more active against cytomegalovirus
than against herpes viruses or varicella-zoster virus. Digestive absorption is reduced and is usually
used for intravenous administration. Valganciclovir is a prodrug that is well absorbed and rapidly
converted to ganciclovir. Ganciclovir and valganciclovir are used in the treatment or prophylaxis of
cytomegalovirus infections in immunocompromised patients and in patients with bone marrow or
organ transplants. The main adverse reaction is myelosuppression and, less frequently,
neurotoxicity.
Foscarnet inhibits the DNA polymerase of herpes viruses, varicella-zoster virus and
cytomegalovirus, but also the reverse transcriptase of HIV. It does not require intracellular
phosphorylation which makes it active against the viruses resistant to the above antivirals, if the
resistance is due to a kinase mutation that phosphorylates these drugs. It is nephrotoxic and
neurotoxic.
Cidofovir specifically inhibits the polymerase of herpes viruses and cytomegalovirus. It does not
require intracellular phosphorylation. It is absorbed slightly from the digestive tract, requiring
intravenous administration, and is eliminated from the body by renal excretion, both by glomerular
filtration and by tubular secretion. It is used to treat retinitis caused by cytomegalovirus in AIDS
patients. The main adverse reaction is nephrotoxicity which can be prevented to some extent by the
combination of probenecid, which decreases tubular cidofovir secretion.
Idoxuridine and trifluridine are non-specific inhibitors of DNA polymerase. It is used topically in the
treatment of herpes infections.
Docosanol is a long-chain saturated alcohol. It appears to inhibit the penetration of the virion into
the host cell by preventing coalescence between the membrane of the host cell and the lipid shell of
the virion. It is used in local administration in the form of ointments.

Antivirals against HIV

Are antivirals active against the HIV virus that causes AIDS. They are also known as antiretroviral
drugs. Some of these drugs are nucleoside reverse transcriptase inhibitors such as zidovudine,
didanosine, stavudine, zalcitabine, lamivudine, emtricitabine, abacavir and tenofovir. They
are inserted into the nucleic acid chain in formation which stops elongation and also inhibits
reverse transcriptase activity. Others are non-nucleoside reverse transcriptase inhibitors such
as nevirapine, delavirdine, etravirine and efavirenz. They bind to reverse transcriptase and
inhibit its activity without inserting into the forming DNA strand. A third category acts as viral
protease inhibitors, such as saquinavir, indinavir, ritonavir, nelfinavir, fosamprenavir,
lopinavir, atazanavir, tipronavir, and duranavir. These prevent the protein precursors of the
components of the viral envelope forming, thus preventing the virions assembling in the cytoplasm
of the host cell. Some of the reverse transcriptase inhibitors are active in vitro and against hepatitis
B virus.
Two other new groups of drugs active against HIV have emerged in the last decade. Some of these
drugs inhibit the penetration of the virion into the host cell. Virion penetration into the host cell
appears to be a relatively laborious phenomenon involving a viral fusion protein denoted gp160
and consisting of two parts, a small protein, gp41, through which it is anchored by the virion and a
larger portion. , gp120, which at one end binds to the CD4 cellular protein, the receptor for the HIV
virus, and at the other end strengthens its attachment by fixing, depending on the type of virus,
either to the CCR5 cytokine receptor or to the cytokine receptor CXCR4. Efuvirtide binds to the
viral protein gp41 and thereby prevents the binding of the viral protein gp120 to the CD4 cellular
protein, thereby preventing the virion from entering the host cell. Another drug, maraviroc
prevents the coupling between gp120 and the CCR5 receptor. Maraviroc prevents the entry into the
host cell only of viruses that enhance binding on CD4 protein via the CCR5 receptor, not of viruses
that enhance binding on CD4 protein via the CXCR4 receptor. Finally, there is the possibility of
inhibiting the integration of the provirus into the genome of the host cell. This is how
raltegravir, an inhibitor of integrase, a viral enzyme responsible for integrating provirus into the
genome of the host cell, works. None of these last 3 drugs develop cross-resistance with other anti-
HIV drugs.
All these drugs have a virustatic effect and prevent the spread of the infection from one cell to
another, thus delay the evolution of the viral infection.
Adverse reactions to these drugs are common and serious. Some produce severe haematological
phenomena such as anemia or neutropenia (zidovudine), neurotoxic phenomena (stavudine,
zalcitabine and didanosine), toxic damage to the pancreas (didanosine), etc. From a
pharmacokinetic point of view, protease inhibitors are also very potent inhibitors of cytochrome
P450 and may decrease the metabolism of other drugs concomitant administered.

Other antivirals

Ribavirin is a nucleoside inhibitor of many polymerases, being active against several types of
viruses, both DNA and RNA, including influenza A and B viruses, parainfluenza viruses, respiratory
syncytial virus, Lassa fever virus, HIV virus, viruses that produce hepatitis. It is mainly indicated in
the treatment of respiratory syncytial virus infections (aerosols), Lassa fever (intravenous), chronic
hepatitis C (intravenously or orally). In chronic hepatitis C it is estimated that ribavirin
administered alone has poor results but the efficacy increases greatly in combination with
interferons α, possibly β. In combination with interferon, there are studies showing that ribavirin
may also be effective in chronic hepatitis B and D. Adverse reactions include bronchospasm,
haemolytic anemia. The drug has been shown to be teratogenic in animals, but no human data are
available. In any case, pregnancy and breastfeeding are contraindications.
In addition to ribavirin, a number of antiretroviral drugs, including lamivudine and tenofovir, are
also used to treat chronic viral hepatitis B.
Telbivudine appears to be a specific antagonist of hepatitis B virus polymerase (reverse
transcriptase) and entecavir selectively inhibits hepatitis B virus polymerase (reverse
transcriptase). Entecavir is hepatotoxic. Adefovir is an inhibitor of the transcription of many
viruses but is only used in the treatment of hepatitis B virus infections. It is nephrotoxic.

Interferons

Interferons were originally discovered as endogenous molecules that interfere with viral infection.
Subsequently, antitumor and antiproliferative properties were described. There are three types of
interferons, one produced by leukocytes, denoted α, another produced by fibroblasts, denoted by β
and a third by stimulated T cells, denoted by γ. Interferons α and β are mainly attributed to
antiviral properties, while interferon γ is mainly attributed to immunomodulatory properties.

In reality, the range of molecules called interferon is much wider. They are, in fact, a class of
cytokines consisting of proteins and glycoproteins with a molecular weight between 15 kDa and 27
kDa, produced and secreted in vivo by various cells in response to viral infection or other stimuli.
Different genes encoding interferon synthesis and even several genes for the same type of
interferon have been described.
Interferons act at the cell level through specific receptors that alter nuclear transcription via the
JAK-STAT system. Two types of receptors have been described, one for interferons α and β, called
type I, and a second for interferon γ, called type II.

The spectrum of antiviral activity is broad including herpes viruses, varicella-zoster,

cytomegalovirus, hepatitis B virus, C and probably other hepatitis. The mechanism probably
consists in inhibiting viral replication. As an antitumor, interferon γ or type II probably acts by
prolonging the multiplication cycle of tumor cells and depleting some metabolites.
The side effects are relatively numerous. The most common is probably a flu-like syndrome that
responds to paracetamol. Other more common side effects: nausea, diarrhea, abdominal pain,
dermatological changes (alopecia, pruritus, dermatitis, dry skin), haematological disorders
(neutropenia).
The possibility of coupling interferon molecules with a polyethylene glycol (PEG) molecule
increases the duration of absorption after subcutaneous administration without decreasing
bioavailability and greatly increases the half-life.
 Antibacterial Chemotherapeutics

Antibacterial chemotherapeutics are substances that selectively kill bacteria that

infect the human (or animal) body, generally without affecting the cells of the macro
organism.
Some of the antibacterial chemotherapeutics kill the bacteria - bactericidal
antibiotics - penicillins, cephalosporins, aminoglycosides, etc. Others prevent bacteria
multiplication - bacteriostatic - thus leaving the body able to destroy them through natural
means of defense - tetracyclines, chloramphenicol, macrolides, sulfamides, etc.
Bactericidal chemotherapeutics are of two types:
- kills microbes only if they are in the multiplication phase - degenerative
bactericides - penicillins and cephalosporins.
- kills microbes regardless of whether they are in the multiplication phase or not
– absolute bactericides - aminoglycosides.
In medical practice, it is recommended not to associate degenerative bactericidal
antibiotics with bacteriostatic, because bacteriostatic antibiotics, preventing the
multiplication of microbes, no longer allow degenerative bactericidal chemotherapeutics
to act. Absolute bactericidal can be combined with bacteriostatic.
In microbial cultures, for any antibiotic there exists a dose that prevents the
multiplication of microbes - minimum bacteriostatic or inhibitory concentration (MIC) and
there are higher doses that kill the microbes - minimum bactericidal concentration (MBC).
The MBC/MIC ratio is called microbial tolerance. For chemotherapeutics considered
bactericidal, microbes have a low tolerance, MBC being close to MIC, so these
chemotherapeutics can be used in the therapy of infectious diseases in bactericidal doses.
For bacteriostatic chemotherapeutics, microbes have a high tolerance, MBC being so high
against MIC that these drugs can only be used in the treatment of infectious diseases in
bacteriostatic doses. There are also intermediate situations of antibacterial
chemotherapeutics. For example, erythromycin can be used at both bacteriostatic and
bactericidal doses.
In order to exert their selective action on microbes, antibacterial chemotherapeutics
are attached to certain particular vital structures in bacteria.
- Some antibacterial chemotherapeutics act on the bacterial wall, a resistance
structure located on the outside of bacterial cells. Penicillins bind to certain
bacterial proteins with a role in the synthesis of the bacterial wall - protein
binding penicillin, PBP, prevent their activity and inhibit the synthesis of the
 bacterial wall. Bacteria left without a wall are lysed, so these antibiotics are
bactericidal. Penicillins do not act on the preformed wall. They can only act
during the multiplication of bacteria when new bacteria have to synthesize their
bacterial wall. In this way penicillins are degenerative bactericidal antibiotics.
The selectivity of action is ensured by the fact that the cells of the
macroorganism do not have a cell wall.

- There are antibacterial chemotherapeutics that act on the cell membrane -

polymyxin B and colistin that have a detergent structure. They are inserted into
the cell membrane and modify its permeability with cell lysis - absolute type
bactericides. The selectivity of action is ensured by the fact that these drugs act
only on bacterial cell membranes with a specific phospholipid composition,
different from the phospholipid composition of the cell membranes of the
macroorganism.

- Other chemotherapeutics work on bacterial ribosomes. Bacterial ribosomes are

structures with a sedimentation constant of 80 S consisting of two subunits, one
with a sedimentation constant of 30 S and another with a sedimentation constant
of 50 S. There are some antibiotics that bind to either the 30 S subunit, either by
the 50 S subunit and prevent/reduce the synthesis of bacterial proteins -
tetracyclines, chloramphenicol, macrolides, lincomycin, clindamycin -
bacteriostatic antibiotics. Other antibiotics - aminoglycosides - bind to the 30 S
subunit of bacterial ribosomes, inhibit bacterial protein synthesis and alter RNA
transcription, with the synthesis of toxic proteins that kill bacteria – absolute
bactericidal effect.

- There are antibiotics that act on the functions of cellular DNA.

o Rifampicin inhibits bacterial DNA-dependent RNA polymerase and inhibits
bacterial protein synthesis.
o Quinolones inhibit gyrase, an enzyme that ensures the steric structure of
bacterial DNA and disrupts the synthesis of bacterial proteins.
The selective toxicity of antimicrobial chemotherapeutics means that there are
always microbes resistant to an antibiotic. A microbial species that produces a certain
antibiotic is resistant to that antibiotic - the natural resistance of microbes to antimicrobial
chemotherapy. The natural resistance of microbes to antimicrobial chemotherapeutics
results from the mechanism of action of antibiotics (penicillins, which inhibit the formation
of the bacterial wall, are not active against chlamydia, rickettsia or mycoplasmas, bacteria
that do not have a bacterial wall). However, there are situations in which certain microbial
species were initially sensitive or very sensitive to a particular antimicrobial
chemotherapeutic and later developed resistant strains - acquiring resistance, obtained
through genetic mutations and may be chromosomal - the gene encoding resistance is
located on the chromosomes, or extrachromosomal - the gene encoding resistance is
located in the plasmids.
- Chromosomal resistance is transmitted vertically from one generation to
another. This resistance is not transmitted between bacteria belonging to
different strains and disappears with the disappearance of that strain.

- Extrachromosomal resistance can be transmitted from one bacterium to

another and within bacteria belonging to different strains and even within
bacteria belonging to different species. Extrachromosomal resistance can be
transmitted by:
o conjugation - a bacterium sends to another bacterium an extension through
which the first bacterium transmits to the second a plasmid that may contain
a gene encoding resistance to a certain antibiotic (R factor) and the new
bacterium it also becomes resistant to that antibiotic. Through this
mechanism, microbial polyresistance (microbes resistant to several
antibiotics) can occur.
o transduction - a way of transmitting resistance through bacteriophages.
Bacteriophages are viruses that make bacteria sick and multiply inside
bacteria using the enzymatic baggage of the bacterium (the bacterial genome,
the DNA that encodes resistance to a particular antibiotic). When such a virus
infects a new bacterium, the bacterium thus infected becomes resistant to that
chemotherapeutic.
o transformation - bacteria incorporate free genetic material into the
environment, generally from dead bacteria. If the embedded material encodes
resistance to a particular antibacterial chemotherapeutic, the bacterium that
encapsulates it becomes resistant to that antibacterial chemotherapeutic. This
type of resistance transmission works in massive, possibly pluribacterial
infections, when there are many dead bacteria and a lot of free genetic
material in the environment.
Due to all these aspects, regardless of the antibiotic, there are sensitive microbes
and resistant microbes. The totality of microbes sensitive to a certain antibiotic constitutes
the spectrum of antimicrobial activity of the respective chemotherapeutic.
Depending on the number of microbial species sensitive to a particular antibacterial
chemotherapy, exist narrow-spectrum chemotherapeutics, active on a small number of
microbial species, such as penicillin G or aminoglycosides, and broad-spectrum
chemotherapeutics, active on a large number of microbial species, such as tetracyclines and
chloramphenicol. The term narrow spectrum refers only to the number of susceptible
microbial species and not to the type of susceptible microbes. Thus, penicillin and
aminoglycosides are narrow-spectrum antibiotics but do not have the same antimicrobial
spectrum (Table 1).

Table no. 1. Antibacterial spectrum. (I. G. Fulga, Antibioză, antibiotice, antibioterapie, Ed.
Med. Buc. 1989, p. 65)
Bacteria gram (+) gram gram (-) gram (-) Chlamydia
bacilli (+)cocci coci bacilli Rickettsia
Mycoplasm
a

Spectrum
Penicillin G /////////////////////////////////////////////////////////////////////
Aminoglycos ///////////////////////////////////////////////////////////////////////
ides
Broad /////////////////////////////////////////////////////////////////////////////////////////////////////////////
spectrum /////////
antibiotics

Over time, because of acquired resistance, the spectrum of antimicrobial activity is

progressively narrowing. The fact that the acquired resistance depends on the way in which
antimicrobial chemotherapeutics are used means that the resistance of microbes to
antibacterial chemotherapeutics may differ from a geographical area to another.
To choose an antibiotic for the treatment of an infection there is the possibility of
isolating the disease-causing microbe and determining its sensitivity to various
antimicrobial chemotherapeutics, for example by antibiogram, and choosing the most
active chemotherapeutic on the disease-causing microbe in each patient. However, only
information on the activity of the chemotherapeutic agent on the disease-causing microbe
is not sufficient to ensure therapeutic success. It is also necessary to know the
pharmacokinetics of the antibacterial chemotherapeutic to ensure that the antimicrobial
chemotherapeutic achieves active concentrations at the site of infection.
The pharmacokinetics of antibacterial chemotherapeutics are very different from
one drug to another.

Absorption. Some antibacterial chemotherapeutics, such as many penicillins,
are destroyed by hydrochloric acidity and are only active if administered
parenterally. Other chemotherapeutics, such as aminoglycosides, are polar and
are not absorbed from the digestive tract. Sometimes the digestive absorption of
antimicrobial chemotherapeutics is influenced by concomitantly administered
foods or drugs - tetracyclines form non-absorbable chelates with calcium,
magnesium, aluminum or iron ions.

Distribution. Most antibacterial chemotherapeutics achieve active

concentrations in most structures of the body, but there are situations in which
they do not enter certain areas of the body and are not active against infections
produced in these areas. Aminoglycosides have a polar structure and do not cross
the blood-brain barrier - they are not active in the treatment of bacterial
meningitis. There are situations in which antibiotics are concentrated in certain
areas of the body and will be preferred for the treatment of infections produced
in those areas. For example, ampicillin achieves 200 times higher concentrations
in the gallbladder than in the blood - very active in the treatment of infectious
cholecystitis; Chloramphenicol is concentrated in the lymph - very active in the
treatment of typhoid fever.

Elimination. It is done by urinary excretion, hepatic metabolism (or both in

various proportions). If the antibiotic has potentially toxic to the macro-
organism, in the event of a functional failure of the organ treating the drug, either
the antibacterial chemotherapeutic drug is avoided or, if absolutely necessary,
administered in lower doses and at longer intervals. The half-life of antibacterial
chemotherapeutics is generally short, so these drugs are given several times a
day, usually at regular intervals, once every 4-12 hours, depending on the half-
life. However, there are also antimicrobial chemotherapeutics that have a long
enough half-life to allow them to be administered once a day.

The side effects of antimicrobial chemotherapeutics are generally of three types:

toxic, allergic and biological or microbiological.

Toxic side effects. For each antibiotic there are target organs of toxicity.
Aminoglycosides are nephrotoxic and ototoxic, chloramphenicol is toxic to the
bone marrow, sulfamides may be toxic to the kidneys, ethambutol is toxic to the
optic nerve. It is generally indicated to avoid administering an antibiotic to a
patient who has a pathology of the target organ of the toxicity of that drug.

Allergic side effects occur only in certain people (atopic people) who
have been immunologically sensitized to that chemotherapeutic. Not all
antibiotics are equally allergenic. Among the most allergic anibacterial
antibiotics are penicillins and sulfamides. The most sensitizing route of
administration is the cutaneous mucosal route. Generally the allergy is
cross-linked to chemical groups of drugs (a person allergic to a certain
penicillin may be allergic to all penicillins).

Biological or microbiological side effects are side effects specific to

antimicrobial chemotherapeutics.
• By destroying certain microbes in the body, they produce
dysmicrobisms (reactions that occur when broad-spectrum
antibacterial chemotherapeutics are administered orally and the
saprophytic flora of the colon is destroyed). If the colon is
repopulated with a pathogenic microbe, an intestinal pathology
(diarrheal disease) may occur. If the repopulation of the colon is
done in a hospital environment, usually the repopulation is done
with a polyresistant microbe, with the appearance of severe
intestinal infections and difficult to treat - Clostridium difficile
infection or intestinal candidiasis.
• Another biological adverse reaction is the Herxheimer reaction,
which consists of a brutal worsening of the symptoms of the
disease at the beginning of treatment, due to the massive release
of bacterial endotoxins. This reaction can occur in many infections
with endotoxin-producing microbes (usually gram-negative
microbes) if given at high doses of chemotherapy, and can be
dangerous. To avoid this reaction, the treatment of massive
infections with endotoxin-producing microbes (syphilis, typhoid
fever, septicemia with gram-negative microbes, etc.) begins with
small doses that subsequently increase progressively.

Indications. Antibiotics are indicated in the treatment of infections with sensitive

microbes. In the treatment of an infection, the antibiotic must be chosen, which is active
against the disease-causing microbe, which penetrates and achieves active concentrations
at the site of infection and which is not toxic to any of the organs showing a possible
pathology in the patient to be treated. It is also important that the antibiotic is removed
from the body through a cleansing organ that is healthy for the patient to be treated.
Generally, antimicrobial chemotherapeutics are almost always administered for the acute
treatment of infections. The duration of treatment, with few exceptions, exceeds by a few
days the time of cure of the disease.

Beta-lactams

The category of beta-lactams includes compounds having a beta-lactam chemical

bond,

penicillins,

cephalosporins,

carbapenems,

monobactams,

tribactams and

beta-lactamase inhibitors.
Beta-lactams inhibit bacterial cell wall synthesis by binding irreversibly to a
transpeptidase, which cross-links peptidoglycans in the bacterial cell wall, causing lysis of
the bacteria. They are active only during cell division having degenerative bactericidal
effect.

Penicillins

Chemically, penicillins are based on 6-aminopenicillanic acid. Small changes in the

nucleus of penicillanic acid can lead to the ineffectiveness of the antibiotic. Destruction of
the C-N- bond in the beta-lactam nucleus converts penicillanic acid to penicilloic acid, with
no antibacterial activity. The link can be disrupted by several enzymes called
penicillinases, secreted by various microbes. Another important part of the chemical
structure of penicillins is the amide bond. It can also be disrupted by some bacterial
enzymes called amidases, which also inactivate the antibiotic but also this process has
industrial importance, being used to replace the natural radical in the structure with another
synthetic radical resulting synthetic derivatives. We can talk about natural penicillins and
semisynthetic penicillins.
Penicillins mechanism of action consist in inhibition of synthesis of bacterial
peptidoglycan macromolecular wall and activation of bacterial autolysis. Wall synthesis
takes place intracellularly and is a very complicated process, involving about 30 enzymes.
Penicillins are inhibitors of some of these enzymes called generic penicillin-binding
proteins (PBP). Penicillins of different classes can bind to one or more different PBPs. Due
to that different penicillins, if the respective compounds are acting on different PBPs, can
be associated in medical practice. Penicillins have a degenerative bactericidal action, being
active only on bacterial cells in active multiplication.

The antibacterial spectrum of penicillins varies from a class of penicillins to

another.

The pharmacokinetic properties are depending on the types of penicillins. For

example, benzylpenicillin has a very low bioavailability after oral administration because
it is inactivated by gastric acidity. Other penicillins are active in case of oral administration,
being relatively resistant to stomach hydrochloric acid (penicillin V). Penicillins are well
distributed in the sinuses, in the middle ear, in the respiratory tract, in the pharynx, in the
kidneys, liver, in the skin or mucous membranes. Most penicillins are excreted rapidly, as
active forms, by the kidneys, predominantly by active tubular secretion.
Penicillins are characterized by low toxicity. The most important and serious side
effects of penicillins are allergic reactions. Sensitization is crossed between penicillins, but
also with cephalosporins, in 10% of cases. Penicillin antigenicity is most often due to
penicillin metabolites (penicilloylamide – a major antigenic determinant; benzylpenicillin,
penicillanic acid, penicillic acid - minor determinants).
The most common are skin allergic reactions (urticaria, pruritus, rashes), Quincke's
edema, the most serious manifestation being anaphylactic shock. Some penicillins may
cause other allergic manifestations (interstitial nephritis, eosinophilia, vasculitis, or fever).
Sensitivity testing is freqvent.
Penicillins can also cause biological or microbiological side effects. A biological
adverse reaction is the Herxheimer reaction, which can occur in the first days of treatment
of syphilis with high-doses of penicillin and is produced by a massive release of endotoxins
by destroying a large amount of treponemes. Is manifested by fever, chills, headache,
myalgia, arthralgia, sometimes even reactivation of syphilitic lesions, lasting 1-3 days.
Prophylaxis can be done by starting of treatment with low doses of antibiotics.
Also can be mentioned as uncommon side effects after penicillins administration:
platelet aggregation after intravenous administration of high doses of penicillins,
hyperkalemia manifested by muscle spasms, coma, cardiac arrest after administration of
high doses of potassium penicillin, local irritation, pain or even necrosis after intramuscular
administration of penicillins, arterial or venous embolic events have also been reported
after parenteral administration.
Only very high doses of penicillin G (benzylpenicillin) can cause neurotoxicity
manifested by confusion, muscle fasciculations and convulsions especially in patients with
meningitis, epilepsy or uremia. For other penicillins, methicillin, nephrotoxicity can be
considered.
The group of penicillins include several substances grouped according to their
nature and their spectrum of activity. Thus, can be considered natural penicillins and
semisynthetic penicillins.

The class of natural penicillins includes:

• benzylpenicillin,
• benzanthinbenzylpenicillin,
• procainbenzylpenicillin,
• phenoxymethylpenicillin.
Substances belonging to this group have in common the narrow antibacterial
spectrum (Gram-positive and Gram-negative cocci, Gram-positive bacilli,
spirochetes and leptospires, actinomycetes, treponemes, borels). Compounds in the
benzylpenicillin group are inactivated by beta-lactamase, so they are not active against
bacterias that have gained resistance by synthesis of this enzyme.

Benzylpenicillin (penicillin G) is a natural penicillin. Its antibacterial spectrum is

narrow and although many bacterial have gained resistance. A number of germs have
remained very sensitive to penicillin G: streptococcus, pneumococcus, meningococcus,
Treponema pallidum, clostridia, tetanus bacillus, coal bacillus, actinomyces, bacteroides
(except Bacteroides fragilis), etc.
Benzylpenicillin and other natural penicillins have as treatment indications the
treatment of spreptococcal angina, anthrax, scarlet fever, prophylaxis of streptococcal
infections in patients with acute rheumatoid arthritis, treatment of erysipelas, gas gangrene,
syphilis or prophylaxis in animal bites.
Penicillin G is inactivated by the acidity of gastric juice. For this reason, the
antibiotic should only be given by injection.
 By introduction of a voluminous radical to the base nucleus the deposit penicillins
are obtained, benzathinebenzylpenicillin or benzathinpenicillin G. This type of penicillin
G is not soluble in water, they are injected intramuscularly and is slowly absorbed from the
injection site for 1-4 weeks. Serum concentrations of benzanthinbenzylpenicillin after
intramuscular injection are too low to cure an infectious disease (except for syphilis which
is cured with benzathinebenzylpenicillin), but are sufficient to prevent infections with a
microbe sensitive to penicillin G. Benzatinbenzylpenicillin is indicated as prophylaxis of
streptococcal infections in patients with a history of acute polyarticular rheumatism or is
used as curative treatment of syphilis.

Procainpenicillin G is a salt of benzylpenicillin with procaine. It is a retard form,

which is administered at 12 hours by intramuscular injections. It is less used because of a
marked risk of triggering allergies.

Another natural penicillin is penicillin V or phenoxymethylpenicillin. Penicillin V

has all the properties of penicillin G, with one exception: it is much more resistant to the
action of hydrochloric acid in the stomach and can be administered orally. Penicillin V is
administered exclusively orally in infections with penicillin-sensitive microbes, but is only
useful in mild or moderate infections.

• The group of semisynthetic penicillins includes several subclasses:

antistaphylococcal penicillins,
• broad-spectrum penicillins,
• antipioceanic penicillins,
• penicillins active mainly on enterobacteriaceae.

A first category of semisynthetic penicillins is antistaphylococcal penicillins. They

are also called penicillins "M"
They act on the same microbes as penicillin G, except that they cannot be destroyed
by penicillinase secreted by Staphylococcus aureus, so these penicillins are also active on
penicillinase-secreting staphylococci. The only indication for these penicillins is
staphylococcal infections.
Methicillin is not used today because it has a relatively weak activity and cannot be
administered orally because it is destroyed by hydrochloric acid in the stomach. In addition,
it can cause interstitial nephritis.
 Isoxazolylpenicillins, (oxacillin, cloxacillin, dicloxacillin, flucloxacillin,
naphthylline), are more active than methicillin and can be administered orally (additional
to injectable way).
As side effects are similar to penicillin but, in addition, they can cause jaundice to
the newborn and antenatal pregnancy, and nafcillin can cause neutropenia. These types of
penicillins are contraindicated in newborns and pregnant women in the third trimester of
pregnancy.

Broad-spectrum penicillins - aminopenicillins or "A" penicillins. They are

called broad-spectrum penicillins because, in addition to the microbes on which penicillin
G is active, they are also active on a number of Gram-negative bacilli, such as H. Influenzae
non B, Enterococcus fecalis, Bordetella tertussis, Vibrio chilarae. They are also used in
polychemotherapy protocols to eradicate Helicobacter pylori infection in patients with
gastric or duodenal ulcers.
Ampicillin, the first penicillin in this class, is indicated in the treatment of
meningitis in children, in Listeria infections, in dental infections, in enterococcal
endocarditis, in pneumococcal endocarditis, in the treatment of cholecystitis and
angiocolitis, in the prophylaxis of endocarditis and in urinary tract infections with sensitive
germs. Ampicillin is the 2nd treatment alternative to typhoid fever after chloramphenicol.
Ampicillin is resistant to hydrochloric acid and can be orally administered. It is
absorbed pretty well digestively, is slightly bound to plasma proteins, diffuses well at the
biliary, urinary and respiratory levels and in the inflamed meninges. It is excreted in the
urine and biliary.
As side effects it can destroy the saprophytic flora of the intestine, producing
intestinal dysmicrobism. Ampicillin also triggers allergic reactions (hives, anaphylactic
shock) or rash.
Amoxicillin, another broad-spectrum penicillin, has similar antibacterial properties
as amoxicillin but is much better absorbed from the digestive tract and does not cause
intestinal dysmicrobisms. Amoxicillin is administered orally, i.m. and i.v. It has a relatively
high frequency of rash especially in patients with infectious mononucleosis.
Ampicillin and especially amoxicillin are frequently associated with clavulanic
acid, a beta-lactamase inhibitor, which makes them active on penicillinase-secreting
staphylococci.
 Antipioceanic penicillins are active against Pseudomonas aeruginosa. Two
subclasses are included carboxypenicillins and ureidopenicillins.
Carbenicillin is belonging to carboxypenicillins. The antimicrobial activity of
carbenicillin is weaker than that of penicillin G. It is destroyed by penicillinase. Its main
indication remains pyocyanic infection. The activity spectrum of carboxypenicillins
includes aminopenicillin-sensitive germs to which are added Pseudomonas aeruginosa,
Enterobacter spp, indole-positive Proteus, Morganella, Serratia spp, Providentia spp and
other vibrios.
Ticarcillin, another carboxypenicillin, is indicated in infections with Gram-
negative bacilli (especially Pioceanic), resistant to other antibiotics and most often in
combination with aminoglycosides. Ticarcillin is administered i.v. By combining ticarcillin
with clavulanic acid (beta-lactamase inhibitor) its spectrum is broadened, the combination
being also active on Staphylococcus.
Temocillin, a ticarcillin derivative, is a beta-lactamase-resistant carboxypenicillin
and is indicated in the treatment of infections with multidrug-resistant Gram-negative
bacteria but especially in Enterobacteriaceae infections when administered by injection i.v.
Piperacillin, meslocillin and azlocillin belong to ureidopenicillins.
The spectrum of activity of this class includes mainly Enterobacteriaceae.
Inconstantly sensitive are Ps. Aeruginosa, N.gonorrhoae, Enterococcus faecium,
Acinetobacter, H. Influenzae. These drugs are active on germs that produce
cephalosporinases and germs that are resistant to aminopenicillins or generation I of
cephalosporins. From a kinetic point of view, the absorption of drugs in this class is zero
after oral administration. T1 / 2 is short. The diffusion is good in the tissues, especially in
the bone or in the inflamed meninges. It is excreted renally in active form and biliary
excreted in a proportion of 20-30%. Are indicated in meningitis produced by Gram-
negative bacillus, systemic infections with sensitive germs or prophylactic treatment after
colorectal or gynecological surgery. May cause neutropenia, nausea, diarrhea, increased
transaminases, prolonged bleeding, or allergic reactions.

Penicillins especially active on enterobacteriaceae are also known as

amidinopenicillins. They are antibiotics that have a narrow spectrum, represented mainly
by Gram-negative bacilli (Enterobacter, E.Coli, Proteus, Klebsiella, Salmonella, Shigella,
Citrobacter). Mecillinam is bacteriostatic at normal concentrations, but bactericidal at high
urinary concentrations. It is especially indicated in the treatment of urinary tract infections
with sensitive germs or in the treatment of typhoid or paratyphoid fever. Other compounds:
pivmecylinam (oral active), sulbenicillin.
 Cephalosporins

Cephalosporins (cephaems) are a group of beta-lactam antibiotics, similar to

penicillins in terms of chemical structure, mechanism of action and side effects. They are
derivatives of 7-aminocephalosporanic acid.
Cephalosporins act bactericidal, by a penicillin-like mechanism, by binding to
specific receptor proteins (PBPs), especially PBP3. The synthesis of the cell wall is
inhibited and the autolytic enzymes in the cell wall are activated.
According to microbiological criteria, cephalosporins are classified into five
generations (I, II, III, IV, V).
The first generation includes: cefalexin, cephalothin, cefradine, cefatrizin,
cefadroxil, cefazolin, cefapirin, cefazedone, cephaloglycine, cephalonium, cephaloridine,
cefazaflur, cefradoxin. The first four substances are administered orally, the others
parenterally. First-generation cephalosporins act primarily on Gram-positive cocci, Gram-
negative cocci, aerobic Gram-positive bacilli, and anaerobes and on Gram-negative aerobic
bacilli. Their antibacterial spectrum sums up the spectrum of penicillin, oxacillin and
ampicillin. They have a maximum effectiveness on pneumococcus, streptococcus,
meningococcus, methicillin-sensitive golden staphylococcus, and act less on the
penicillinase-secretor. In addition, they are active on H. influenzae, E. coli, Klebsiella
pneumoniae, Proteus mirabilis, Salmonella, Shigella, Pasteurella, N. gonorrhoae,
Corynebacterium diphtheriae, Actinomyces. From a kinetic point of view, the first
generation cephalosporins have a variable availability after oral administration (depending
on the compound). They diffuse little in the CSF and are therefore not used in the treatment
of meningitis. Are excreted in the urine in active form. Bronchial infections, skin infections
and prophylactic treatment after abdominal surgery are indications. As side effects may
occur allergies (in 5% of cases crossed with penicillins), leukopenia, thrombopenia,
phlebitis or thrombophlebitis (especially after cephalothin). Nephrotoxicity is to be
considered for cephaloridine and, less freqvent for cephalothin, and can be aggravated by
the association with aminoglycosides.
The second generation include: cefachlor, ceforuxime or zinnate, cefonicide,
cefamandole, cefminox, cefotiam, cefprozil, cefbuperazone, cefuzonam, but also
cefamycins such as cefoxitime or cefamethan, cefotethan. Cefuroxime and cefachlor are
active orally, the rest only parenterally. Their spectrum sums up the spectrum of penicillin
G + oxacillin + ampicillin + gentamicin + metronidazole. Compared to the first generation,
the second generation of cephalosporins cover a wider spectrum. From pharmacokinetic
point of view, variable T1/2, well diffusion into tissues except CSF, renal excretion in
active form and only a small amount is biliary excreted are to be considered.
Cephalosporins in this class are of choice in ENT, bronchopulmonary, gynecological, skin
and soft tissue infections, urinary tract infections and as a prophylactic treatment after
surgery. These compounds are better tolerated than those in the first generation. Increases
in transaminases, alkaline phosphatase, and bilirubin have been reported.
The third generation: cefotaxime, ceftriaxone, cefoperazone, ceftazidime,
cefixime, ceftibuten, cefetamet, cefpodoxima, cefcapen, cefdaloxin, cefdinir, cefditoren,
cefmenox, cefodiz, cefodiz, cefodiz, cefodiz. Similar to these structures are oxacefemas
such as latamoxef or flomoxef.
Are characterized by extended spectrum of activity on Gram-negative germs such
as Citrobacter, Klebsiella, Morganella, Salmonella, Shigella, Pasteurella, E.Coli, Proteus
mirabilis, vulgaris, H. influenzae. Serratia, Yersinia, Enterobacter, Klebsiella pneumoniae,
Ps.aeruginosa, Bacteroides, Acinetobacter, penicillin-resistant pneumococcus are
inconstantly sensitive. Legionella is resistant. From pharmacokinetic point of view,
absorption is variable after oral administration; T1/2 is variable from a compound to
another, good tissue diffusion even in CSF (are indicated in the treatment of meningitis
with sensitive germs), in general mainly renal eliminated as active form.
As side effects may cause allergic reactions, pseudocholecystitis, neutropenia,
eosinophilia, thrombocytosis. Cephalosporins with a methylthiotetrazole side chain, which
have a structure similar to oral anticoagulants, have similar actions, which can cause a
significant decrease in prothrombin activity. Cephalosporins that can cause such side
effects include cefoperazone and latamoxeph, which also has antiplatelet action.
Cefoperazone and cefmenoxime may cause disulfiram side effects. Most cephalosporins in
this class cause increases in transaminases and post-drug diarrhea. In addition,
superinfections may occur because many third-generation cephalosporins are ineffective
against some Gram-positive bacteria (especially methicillin-resistant staphylococci) and
enterococci, which may proliferate during therapy with such antibiotics.
Cephalosporins of this generation are reserve antibiotics, which are indicated in
severe infections, localized or generalized with sensitive germs.
Fourth-generation cephalosporins are cefepime, cefpiroma, cefosopran,
cefquinome. , substances that are only parenterally active.
Are more resistant to the action of beta-lactamases produced by S. aureus or
enterobacter. They have a good activity on enterobacteriaceae, P. aeruginosa, S. aureus and
Streptococcus pneumoniae. Cefepima has a selective action on PBP2, a high rate of
intrabacterial penetration, a high resistance to beta-lactamases, and a minimal risk of
inducing bacterial resistance. From pharmacokinetic point of view, are administered
parenterally only, T1/2 about 2 hours, excellent tissue diffusion in the respiratory tree, in
the peritoneal fluid, prostate, CSF, eliminated by the kidneys in active form. Side effects
are similar to those of generation III cephalosporins. They are indicated in severe intra-
abdominal infections in combination with metronidazole, in systemic or localized
nosocomial infections, in severe bacterial infections.
Fifth generation, ceftobiprol and ceftaroline. They are also known as
cephalosporins active anti methicillin-resistant Staphylococcus aureus (MRSA). Their
spectrum of activity includes Gram-positive cocci and aerobic Gram-positive bacilli,
enterobacteriaceae and Gram-negative bacilli (involved in respiratory infections). As
mechanism of action, they are acting on modified variants of PBP2. Are eliminated by the
kidneys in active form. Adverse reactions: similar to third generation cephalosporins. They
are especially indicated in soft tissue infections caused by MRSA or in pneumonia caused
by this germ.

Carbapenems

Carbapenems, compound with a beta-lactam nucleus, are resistant to most beta-

lactamases (penicillinases, cephalosporinases, but not metalobetalactamases).
Mechanism of action consist in inhibition of the bacterial wall synthesis by
binding to PBP1 and PBP2. They have a broad antibacterial spectrum, with differences
from a compound to another, acting on Gram-negative, Gram-positive cocci and bacilli,
aerobic and anaerobic germs.
From pharmacokinetic point of view, carbapenems have zero bioavailability after
oral administration. Their half-life is short in general (below one hour). Are fixed on
plasma protein in low percentage. Tissue diffusion is good (including CSF). Imipenem is
metabolised in the renal tubules by dihydropeptidase, therefore it is associated with
cilastatin which inhibits dihydropeptidase. Elimination is predominantly renal.
Resistance is explained by decreased permeability of the bacterial membrane, by
the existence of efflux pumps, and by the secretion by bacteria of carbapenemases that
inhibit the antibiotic.
Adverse reactions: allergic reactions (cross-allergic reactions with other
betalactamines in 30-50%), neurological toxicity (seizures), digestive disorders (diarrhea,
pseudomembranous colitis with Cl.difficile), increases in transaminases, bilirubin or
alkaline phosphatase, haematological disorders (eosinophilia, neutropenia,
thrombocytopenia and anemia).
Carbapenems are reserve antibiotics, indicated in severe infections with
microorganisms multidrug-resistant. Carbapenems induce cephalosporinase synthesis and
therefore the combination of cephalosporins is not recommended.
Imipenem, meropenem, ertapenem are examples of carbapenems. Also, some
other penems, similar to carbapenems, faropenem is an example, have been introduced in
medical practice. They are characterized by a broader antibacterial spectrum, are not
susceptible to renal dihydropeptidase and can be given orally.

Monobactams and tribactams

Monobactams are beta-lactam nucleus derivates. The antimicrobial spectrum is

narrow: aerobic Gram-negative cocci and bacilli, including Pseudomonas, and most
microorganisms that secrete beta-lactamases. Mechanism of action consist in inhibition of
the bacterial wall synthesis by binding to PBP3. Are resistant to penicillinases but are
inactivated by high level of cephalosporinases. Are indicated in severe infections with
aerobic Gram-negative bacilli.
Aztreonam is indicated in sepsis and urinary, pelvic, intra-abdominal and
respiratory infections with Gram-negative bacilli, even resistant to other antibiotics. It is
administered only parenterally, intramuscularly or intravenously. Adverse reactions: may
cause phlebitis and rash. Has a low immunogenic potential.
Tribactams are another group of beta-lactams. Sanfetrinem has a broad spectrum,
is active on Gram-positive and Gram-negative bacteria (including pyocyanic), aerobic and
anaerobic. It is resistant to the action of beta-lactamases and renal dihydropeptidase 1. Is
administered orally as a prodrug that releases sanfetrinem into the body.
 Beta-lactamase inhibitors

In this category are included compounds with beta-lactam structure that inhibit
penicillinases and cephalosporinases.
They have weak antibacterial activity.
They are associated with other beta-lactams and increase activity of the respective
antibiotics. May increase synthesis of cephalosporinases (eg, clavulanic acid).
Clavulanic acid, sulbactam and tazobactam are the main substances in this class.
Some of their associations with different beta-lactams are well known: augmentin =
clavulanic acid + amoxicillin; timentin = clavulanic acid + ticarcillin; sultamicillin =
ampicillin + sulbactam; sulperazone = sulbactam + cefoperazone; tazocillin = tazobactam
+ piperacillin.
 Drugs used in the treatment of gastric or duodenal ulcers

Antiulcer drugs act pathogenically, combating the imbalance between aggressive

factors on the gastro-duodenal mucosa - gastric-hydrochloric hypersecretion, biliary reflux,
H. pylori infection - and protective factors of the gastroduodenal mucosa - mucosal barrier,
bicarbonate secretion, bicarbonate secretion mucosal cells and healing of mucosal lesions.

Physiologically the stomach secretes a large amount of hydrochloric acid at a pH

around 1. Acid secretion is the result of the activity of the parietal cells of the fundic
epithelium. The parietal cells are provided with secretory ducts, incorporating a specific
transport system - H+ / K+-ATPase. This ATP-ase functions as a proton pump, transporting
hydrogen ions from the cytosol into the stomach lumen, instead of stoichiometrically with
potassium ions.

The secretory activity of parietal cells is stimulated physiologically by the intervention

of three main mechanisms: vagal nerve control, endocrine control - through gastrin - and
paracrine control - for example through histamine - .

The main role is played by histamine, which activates the adenylate cyclase / cAMP
system through specific H2 receptors. Vague and gastrin stimulate acid secretion in parietal
cells both through a direct intervention on them, an intervention involving M receptors and
gastrin receptors, respectively, and as a messenger Ca secondary ions, as well as indirect
through increased histamine release from paracrine cells and from mast cells. Both the
increase in cAMP and that of Ca2+ in the parietal cells determine the activation of H+ / K+-
ATPase with the increase of H+ secretion in the canal. The H+ required for this process come,
in part, from the dissociation of carbonic acid produced at the cytosolic level under the action
of carboanhydrase by the reaction between CO2 and H2O. At the same time, the activity of
the proton pump is accompanied by an increase in the permeability of the apical membrane
of the parietal cell for K+ and Cl-, which ultimately results in the formation of a large amount
of HCl in the secretory lumen.
 Prostaglandins, especially those of the E series, and somatostatin intervene with an
inhibitory role on acid secretion. Their regulatory intervention is performed through a
negative coupling with adenylate cyclase which results in a decrease in the availability of
cAMP in the parietal cell. Both prostaglandins and somatostatin are positively involved in
regulating mucus secretion, bicarbonate, as well as in maintaining mucosal trophicity by
regulating local blood flow.

The imbalance between aggressive and protective factors leads to the appearance of
ulcer disease.

H. pylori, by negatively influencing the protective factors of the mucosa, can

contribute to the appearance of gastric or duodenal ulcer.

In the treatment of ulcer disease are used: antacids; inhibitors of gastric acid secretion;
mucosal protectors; antimicrobial associations against H. pylori.

Many of the substances used as antiulcer drugs are also useful in the treatment of reflux
esophagitis and Zollinger Ellison syndrome.

Antacids

Antacids are weak bases whose action consists in neutralizing gastric acidity.
Secondary to an increase in gastric pH to values greater than 5, an inhibition of the
proteolytic activity of pepsin also occurs. As a result, antacids relieve ulcer pain and speed
up ulcer healing, being especially effective in duodenal ulcers. The most used are aluminum
and magnesium hydroxide, sodium bicarbonate and calcium carbonate as well as other
carbons, silicates and phosphates.

The efficacy of antacids depends on the ability to neutralize HCl, the water solubility
of the compound, the contact time between the antacid and gastric acid secretion and possibly
the physiological effects of the cations used.
 The emptying time of the stomach limits the effect of antacids to 15 - 60 min. under
the conditions of administration on an empty stomach. The presence of food or the association
with substances that slow down the emptying of the stomach (for example: atropine-like
parasympatholytic) increase the contact time while maintaining the antacid effect for 1-2
hours.

In addition to the effect of buffering gastric acidity, antacids can also cause changes
in gastric and intestinal motility. Thus, magnesium compounds increase gastrointestinal
motility and those of aluminum and calcium decrease it. The increase in gastric motility is
due in part to an increase in gastrin secretion due to the alkalization of the antral content.

Depending on the degree to which antacids are absorbed, in unchanged form, at the
intestinal level they are divided into non-systemic and systemic antacids.

Non-systemic antacids, at commonly used doses, do not alter the acid-base balance
because they form insoluble salts in the gut that are not absorbed. In high doses even non-
systemic antacids can be absorbed. They do not cause alkalosis but can alkalize urine.

Systemic antacids, due to intestinal absorption of baking soda, can cause metabolic
alkalosis and alkalization of urine. Metabolic alkalosis is favored by high doses of antacid
and the presence of renal failure. Under ingestion of large amounts of calcium and phosphates,
systemic antacids can cause calcium-alkali syndrome, characterized by alkalosis,
hypercalcemia, phosphate retention, calcium precipitation in the kidneys, and kidney failure.
Alkalization of urine, due to excessive administration of antacids, may promote the
development of nephrolithiasis.

Antacids can cause drug interactions. By changing the gastrointestinal pH they can
change the bioavailability of some drugs administered orally and by changing the urinary pH
they can influence the rate of renal cleansing of weak acids. In addition, compounds that alter
the rate of gastrointestinal transit may influence the absorption at this level of concomitantly
administered drugs. To avoid these interactions, it is recommended that an interval of
approximately 2 hours be allowed between the administration of the antacid and other drug
compounds.

Aluminum compounds. Aluminum hydroxide is the most widely used. It is a non-

systemic antacid with weak and slow action. The binding of bile acids from the refluxed bile,
aggressive for the gastric and esophageal mucosa, also contributes to the therapeutic benefit.

As side effects aluminum hydroxide can cause constipation due to inhibition of

gastrointestinal motility, insoluble aluminum salts can form obstructive concretions, due to
the formation of unabsorbable phosphates, prolonged treatment, can cause phosphate
deficiency and osteoporosis. Aluminum compounds can also cause, under conditions of renal
failure, encephalopathy and proximal myopathy.

In addition to drug interactions produced by alkalization of gastric contents and urine,

it should be borne in mind that aluminum hydroxide decreases the availability for absorption
of many drugs: isoniazid, some sulfamides, tetracycline, indomethacin, chlorpromazine,
digoxin, propranolol, anticholinergics away from the antacid dose).

Aluminum hydroxide is used as a gel in aqueous suspension, 5-30 ml each, or as a dry

gel, 0.5 g at a time.

Magnesium compounds. Magnesium hydroxide is a predominantly non-systemic

antacid, with rapid, intense and medium duration of action. In people without kidney failure,
there is no alkalosis, but the urine can become alkaline.

Magnesium ions have laxative properties (see “Laxatives and purgatives”). To prevent
this effect, it is advantageous to combine magnesium preparations with constipating antacids.
In the presence of renal failure, magnesium absorbed from the intestine - in small amounts
under normal conditions - can accumulate reaching toxic levels and causing central
depression.
For the antacid action, use the aqueous suspension (magnesium milk) or magnesium
hydroxide powder.

Magnesium oxide forms magnesium hydroxide in water having similar properties to

it.

Magnesium carbonate and magnesium trisilicate have a weaker, slower but longer
lasting antacid effect.

Calcium compounds. The prepared calcium carbonate or chalk is a predominantly

non-systemic antacid with relatively fast, intense and medium duration action.

Calcium ions, at the antral level, stimulate gastrin secretion, causing a rebound in acid
secretion (the phenomenon can be prevented by frequent administration of the antacid).

Calcium precipitates in the intestine, with constipating consequences and can

sometimes lead to the formation of fecal concretions. Calcium absorbed from the intestine
leads to a chronic increase in calcium that can become dangerous in the presence of kidney
failure. Excessive use can cause hypercalcaemia with alkalosis and calcinosis. It also
produces an increase in calcium which promotes the formation of kidney stones.

Sodium bicarbonate. It is a systemic antacid with fast, intense and short-acting action.
The administration of sodium bicarbonate causes a rapid increase in gastric pH to 7-8,
achieving an immediate therapeutic benefit. However, after the cessation of the effect, there
is a rebound of acid secretion.

Sodium bicarbonate is a soluble alkaline salt, so the risk of systemic alkalosis is

significant when the preparation is administered for long periods in large doses. It can
sometimes lead to calcium-alkali syndrome. It is recommended not to use it chronically to
avoid these side effects. Absorbed sodium may increase sodium and blood volume, making
the drug contraindicated in patients with heart failure, high blood pressure and / or kidney
failure. Sodium bicarbonate alkalizes urine.

Gastric secretion inhibitors

Many drugs reduce the acidic gastric secretion by intervening either in the mechanisms
of its regulation or on the metabolism of the parietal cell.

This group comprises: H2-histaminergic blockers, proton pump inhibitors,

parasympatholytic substances, prostaglandin analogs, somatostatin analogs and other
compounds.

H2-histaminergic blockers

H2 receptor blockers prevent the gastric excitatory effect of histamine, autacoid, which
is an indispensable final link in the control of the secretory activity of parietal cells. Acid
secretion stimulated by gastrin and, to a lesser extent, by muscarinic agonists, is also inhibited
by compounds of this class. These compounds have increased selectivity for H2 receptors and
have no or very poor effects on H1 receptors. Although H2 receptors also exist in other tissues
(vascular or bronchiolar smooth muscle) these substances do not produce significant
functional changes in them.

The therapeutic benefit is mainly due to the decrease in basal and nocturnal acid
secretion. It also inhibits gastric acid secretion stimulated by various mechanisms (food,
fictitious lunch, fundus distension, etc.). H2 receptor antagonists cause decreased volume,
peptic activity, and acidity of gastric secretion. A decrease in intrinsic factor secretion is also
produced, but unimportant in terms of vitamin B12 absorption.

In patients with peptic ulcer, H2 receptor antagonists relieve symptoms, decrease the
need for antacids, reduce the frequency of complications and speed healing. Prolonged
administration is useful for relapse prophylaxis. Prophylactic administration is useful for the
prevention of stress ulcers, those produced by the administration of non-steroidal anti-
inflammatory drugs (such as acetylsalicylic acid), by pyloric ligation, by
parasympathomimetics, etc.

From a structural point of view, the currently used compounds can be divided into:

- imidazoline derivatives (such as histamine): cimetidine,

- furan derivatives: ranitidine,
- thiazole derivatives: famotidine, nizatidine.

Bioavailability after oral administration is generally good, with a peak plasma

concentration reached after 1-2 hours. For most compounds, except nizatidine, due to
metabolism in the first hepatic passage, the bioavailability values after oral administration are
approximately 50%. Elimination is by both the kidney in unchanged form and by hepatic
metabolism. Renal or hepatic impairment generally necessitates dose reduction or adjustment
of administration.

H2-receptor blockers, like all substances that increase gastric pH, alter the digestive
absorption and bioavailability of many other drugs. Cimetidine inhibits the activity of
cytochrome P450, causing decreased hepatic metabolism of other concomitant drugs.
Ranitidine, famotidine or nizatidine produce insignificant or no such effect at all. Through
this mechanism, cimetidine increases the half-life of many drugs, including: phenytoin,
theophylline, phenobarbital, some benzodiazepines, cyclosporine, carbamazepine, calcium
channel blockers, propranolol, warfarin, tricyclic antidepressants, etc. when administered
concomitantly with the gastric secretion inhibitor. Cimetidine also increases the plasma
concentration of procainamide by decreasing its tubular secretion.

Therapeutic use of H2 blockers, especially cimetidine, may cause adverse reactions.

The frequency of their production is generally low and their severity is lower because H2
receptors are of little importance in other organs and, in addition, H2 blockers cross the blood-
brain barrier slightly. More common may be: headache, nausea, dizziness, myalgias, skin
rash, pruritus, lactation disorders. Drowsiness and confusion may occur in the elderly or in
patients with renal impairment. Prolonged administration of cimetidine can cause impotence,
decreased libido and gynecomastia. These adverse effects are due, at least in part, to the
inhibition of estradiol hydroxylation by the cytochrome P450. Pancytopenia, immune system
depression, hepatitis, anaphylactic shock, increased serum creatinine by inhibiting tubular
secretion have also been reported with reduced frequency. Rapid intravenous administration
may cause bradycardia.

In addition to therapeutic uses in duodenal and gastric ulcers, the drugs in this group
are also useful in the treatment of gastroesophageal reflux disease, an indication for which
nizatidine may be preferred because it combines a gastrointestinal exacerbation effect (in this
case it is more advantageous to take two doses in the morning. and in the evening), in the
treatment of Zollinger Ellison syndrome (higher doses are administered), in pre-anesthesia to
reduce the risk of aspiration of gastric acid, and in other situations where reduction of gastric
acidity is necessary (short loop syndrome, systemic mastocytosis with hyperhistamine etc.)

Proton pump inhibitors (H+ / K+ -ATPase)

This group includes substances that block the proton pump at the apical membrane of
parietal cells. H + / K + -ATPase inhibitors have specific effects (because H + / K + -ATPase
is found only in the parietal cell) and marked by decreased gastric acid secretion. Gastric
secretion volume, pepsin secretion, intrinsic factor and gastric emptying rate are not altered.

The main representatives of this class are benzimidazole derivatives, omeprazole

being the first drug in this series. From a pharmacological and therapeutic point of view, the
properties of these compounds are very similar, but there are also some differences.

H + / K + -ATP-ase inhibitors, which reach the secretory ducts of the parietal cell in
the blood, under the action of an intensely acidic environment, undergo a protonation process,
accumulate locally and are transformed into a sulfenamide, the biologically active form. For
this reason, these substances can be considered prodrugs. Sulfenamide covalently binds to
thiol groups of cysteine residues in the α subunit (on the canalicular surface) of H + / K + -
ATPase. Consequently, the proton pump is irreversibly blocked in the case of omeprazole.
Restoration of secretory activity involves the synthesis of new enzyme protein molecules.
Because the mean H + / K + -ATPase resynthesis time is 18 hours, the secretory activity of
parietal cells is inhibited for more than 24 hours, although the half-life of omeprazole is only
60 minutes. In the case of lansoprazole, the blockade of the proton pump is slowly reversible
by the intervention of glutathione, but this does not influence the duration of the effect.

Proton pump inhibitors are usually packaged in the form of enteric preparations for oral
administration or in injectable forms.

After oral administration of the first doses the bioavailability is good but reaches a
maximum only after a few days, due to the inhibition of gastric acid secretion by the action
of the drug. It is advantageous to combine with antacids. They are transported in the blood
bound to plasma proteins. Purification is done by hepatic metabolism and renal elimination
of metabolites.

Proton pump inhibitors are indicated in the treatment of duodenal ulcer and in the
treatment of gastric ulcer. In these situations, patients who have not responded to treatment
with H2 blockers are eligible. The combination of anti-H. pylori chemotherapy is
advantageous.

Omeprazole is used as a racemic mixture, the active form being the levogir isomer.
There are also preparations that contain only the levogira form (S-omeprazole). Omeprazole
is usually given in doses of 20 mg / day and lansoprazole 15-30 mg / day.

Reflux esophagitis is another indication of this group. In this case the efficacy being
higher compared to H2 blockers.

Omeprazole and the other medicines in the group are the first choice in the treatment
of Zollinger Ellison syndrome, in which case the doses used are higher than those used in the
treatment of antiulcer ulcers.
 Omeprazole and lansoprazole are generally well tolerated even at high doses used in
the treatment of Zollinger Ellison syndrome. Adverse reactions reported include
gastrointestinal disorders (nausea, diarrhea, abdominal colic), central nervous system
disorders (headache, dizziness, somnolence), rash, temporary increases in hepatic
aminotransferases. Due to the increase in gastric pH, prolonged treatment may promote the
development of digestive tract infections or nosocomial pneumonia. Increased gastrin
secretion, due to lack of hydrochloric acid, can lead to parietal cell hyperplasia and even the
development of carcinoid tumors, effects that have been shown in laboratory animals.
Although no such reactions have been reported in humans, long-term treatment should be
performed with caution and under close supervision considering the tumor risks associated
with hypergastrinemia and elevated gastric nitrosamines in hydrochloric acid conditions.

Both omeprazole and lansoprazole, in very high doses, inhibit the hepatic cytochrome
P450 system and decrease the metabolism of some co-administered drugs. Through this
mechanism, omeprazole interacts with phenytoin, diazepam and warfarin. Their concomitant
administration with omeprazole requires dose reduction and close clinical monitoring.

Parasympatholytic substances

Parasympatholytics (muscarinic receptor antagonists) decrease basal secretion and

secretion stimulated by nerve mechanisms (cephalic phase and partially gastric phase) of
hydrochloric acid in parallel with decreased volume of gastric secretion. Muscarinic
antagonists also inhibit pepsin and gastrin secretion (see 10. Cholinergic system). These
effects have led to the selection of non-selective parasympatholytics (amines or quaternary
ammonium derivatives) in the treatment of ulcer disease. Parasympatholytics decrease the
rate of emptying the stomach, which is an advantage in duodenal ulcers, but not in gastric
ulcers. This effect is useful in the conditions of the association of parasympatholytics with
antacids, increasing the period of contact of the antacid with the gastric juice and implicitly
the therapeutic benefit. Parasympatholytics also cause a decrease in the secretion of mucus
and bicarbonate, which is a disadvantage in terms of their use as antiulcer.

Non-selective muscarinic antagonists (atropine and related compounds) are effective

in the treatment of duodenal ulcer and gastric ulcer, and can be used in both curative and
prophylactic treatment.

These compounds are disadvantageous in patients with reflux esophagitis because due
to the decrease in the speed of emptying the stomach and the relaxation of the lower
esophageal sphincter, it favors gastroesophageal reflux. In high-dose Zollinger-Ellison
syndrome, non-selective parasympatholytics are also disadvantageous due to significant
systemic adverse reactions.

Atropine, an alkaloid with an amine structure, has a less selective and short-lived
gastric antisecretory effect, it is currently rarely indicated in ulcerative disease. As an
antiulcer, 0.5 - 1 mg is administered orally 3-4 times a day. Belladonna preparations in
equivalent doses may also be used.

Adverse reactions are common and result in reduced treatment compliance. Among
the most common side effects are: dry mouth, visual disturbances (photophobia, inability to
accommodate), constipation, difficulty urinating, tachycardia.

Glaucoma, prostate adenoma, pyloric stenosis are situations that contraindicate the
administration of atropine or related non-selective muscarinic antagonists.

Pirenzepine and telenzepine are compounds with more selective anticholinergic

action for gastric acid secretion. This is due to the selective blockade, at usual doses, of M1
receptors in the ganglion cells of the gastric intramural plexus and in the presynaptic
cholinergic terminations (see 10. Cholinergic system).

Therapeutically, pirenzepine and telenzepine are useful in duodenal or gastric ulcer,

50 mg administered orally 2-3 times a day for pirenzepine and 3 mg / day, orally, for
telenzepine.
 Due to the hydrophilic nature of these compounds, digestive absorption is limited, it
binds little to plasma proteins, crosses the blood-brain barrier insignificantly (they do not
cause central nervous system reactions). Pirenzepine is eliminated slowly by bile, stool and
renal secretion unchanged.

Undesirable effects are rarer and less important. However, dry mouth, accommodation
disorders, rashes may occur. Narrow-angle glaucoma, renal failure, prostate adenoma are
contraindications.

Prostaglandin analogues

The gastric mucosa secretes mainly prostaglandins E2 and I2 which, like

prostaglandins E1, inhibit acid gastric secretion and have cytoprotective properties due to
increased bicarbonate and mucus secretion. Under the action of these autacoids, in addition,
the protective capacity of the mucus and the regenerative capacity of the mucosa are improved
due to the improvement of the local circulation. The antisecretory effect is due to the action
of specific receptors on parietal cells, resulting in inhibition of adenylate cyclase and
decreased cellular cAMP.

Synthetic analogues of these prostaglandins decrease stimulated acid secretion and,

less, basal acid secretion. Compounds in this class are useful in the treatment of duodenal
ulcer, gastric ulcer, hemorrhages secondary to ulcer, gastritis or esophagitis. However, the
main therapeutic use is in the prophylaxis of iatrogenic ulcers caused by long-term
administration of non-steroidal anti-inflammatory drugs.

After oral administration, absorption occurs rapidly, with a maximum plasma

concentration of approximately 30 minutes.
 Side effects that may occur during the administration of synthetic prostaglandin
derivatives include: diarrhea, nausea, flatulence, abdominal pain, sometimes colic, headache,
dizziness.

Because these compounds also have oxytocic effects they are contraindicated in
pregnant or possibly pregnant women. Advanced cerebral atherosclerosis and coronary heart
disease require caution due to the hypotensive effect of prostaglandin E1 derivatives. Caution
is also required in renal and hepatic impairment.

Misoprostol is a derivative of PGE1. It is administered internally in a dose of 0.4 - 0.8

mg / day fragmented in 2 - 4 doses.

Enprostil is a PGE2 derivative with misoprostol-like properties. It must not be

combined with cimetidine because it lowers its plasma concentration.

Somatostatin analogues

Somatostatin, a hormone secreted by the hypothalamus and pancreatic D cells,

inhibits the secretion of peptides from the gastroenteropancreatic endocrine system (gastrin,
serotonin, VIP, glucagon, insulin), the secretion of growth hormone and growth hormone-
releasing hormone.

Therapeutically, octreotide, a synthetic octapeptide analog of somatostatin, is used.

Octreotide is indicated as a symptomatic treatment in acromegaly and in various

gastroenteropancreatic endocrine tumors (vipoma, glucagon, gastrinoma - Zollinger Ellison
syndrome).

In Zollinger Ellison syndrome, in which case the combination with H2 blockers is

advantageous, it decreases acid hypersecretion, eliminates diarrhea and other symptoms due
to gastrin hypersecretion. In addition to inhibiting gastrin secretion, the inhibitory activity of
parietal cell secretion (which has membrane receptors for somatostatin, negatively coupled to
the adenylate cyclase / cAMP system) also contributes to the therapeutic benefit.

Octreotide is given by injection subcutaneously. Absorption occurs rapidly, the

maximum plasma concentration is reached after 30 minutes. Elimination is biliary in
unchanged form, the plasma half-life is approximately 1.5 hours.

Anorexia, nausea, vomiting, flatulence, abdominal pain, diarrhea may occur as side
effects. May alter glucose tolerance, insulin-dependent diabetic patients may cause
hypoglycaemia, glycemic control is required. Rarely, hepatitis, increased liver enzymes,
hyperbilirubinemia, increased incidence of gallstones may occur. Locally, at the injection site,
it causes irritation with pain and inflammation.

Octreotide decreases the bioavailability after oral administration of cimetidine and

cyclosporine.

Other substances that may inhibit gastric secretion.

This group includes antigastric substances and carbohydrase inhibitors.

Antigastrinic substances in this group are included substances with more or less
selective antigastrinic action. Due to the blockade of gastrin receptors in parietal cells,
compounds in this class have gastric antisecretory properties, generally of modest intensity.
They are used sparingly in the treatment of active ulcers in gastritis to control iatrogenic
gastric irritation, usually in combination with antacids.

Proglumide, an isoglutamic acid derivative, is an antagonist of gastrin and

cholecystokinin receptors. It is used sparingly, given orally 400 mg 3 times daily before
meals.
 Carbohydrase inhibitors, compounds in this group are characterized by the ability to
inhibit carbohydrase, an enzyme involved in the formation of hydrogen ions necessary for the
production of hydrochloric acid in parietal cells. Through this mechanism these compounds
could inhibit basal acid gastric secretion and that stimulated by histamine, insulin or
pentagastrin. In patients with gastric or duodenal ulcer, they lead to pain relief and speed up
the healing of the lesion. The efficacy in the treatment of ulcer disease is lower compared to
that of H2 blockers or parasympatholytics and the risk of severe side effects is higher.

Acetazolamide is a heterocyclic sulfonamide with antiulcer properties, probably of

limited efficacy, which also has a weak diuretic effect and alkalizes urine, lowers intraocular
pressure (indicated in glaucoma) and has and has antiepileptic properties.

As an antiulcer, it is administered orally, 20 - 25 mg / kg per day.

Side effects with acetazolamide may include side effects: extremity paresthesia,
asthenia, drowsiness, muscle aches, rarely allergic reactions and blood dyscrasias.

In diabetics or those with acidosis, administration should be done with caution, under
close supervision, or avoided. Acetazolamide is contraindicated in those with severe renal or
adrenal insufficiency and in those with an allergy to sulfonamide compounds.

Protectors of the gastroduodenal mucosa

This group comprises drugs whose antiulcer therapeutic benefit is mainly due to a
cytoprotective action and the favoring of protection and defense factors in the gastric or
duodenal mucosa.

Bismuth salts and sucralfate are included in this group.

Bismuth salts have weak effects of neutralizing gastric acidity but increase the
secretion of mucus and bicarbonate, decrease the proteolytic activity of pepsin and form in
the acidic environment a crystalline deposit adherent to the protein residues on the surface of
the ulcer that prevents the retrodiffusion of hydrogen ions and aggression. peptic. An
important role is attributed to the antibacterial action against H. pylori. An action to stimulate
the secretion of prostaglandins with cytoprotective effects has also been described. Through
all these mechanisms, bismuth salts become useful as a curative medication, especially in
duodenal ulcers and less in gastric ulcers. Some derivatives may also be useful in the
treatment of reflux esophagitis.

Derivatives with a low bismuth content such as colloidal bismuth subcitrate and
bismuth subsalicylate, administered orally in 2 or 4 doses, half an hour before meals, are
currently used. The combination with antacids is disadvantageous.

A small part of the administered bismuth is absorbed, but most remains in the intestine
and is eliminated as insoluble salts in the feces. Absorbed bismuth is excreted in saliva, urine
or bile.

Bismuth compounds should not be combined with tetracycline because their

bioavailability decreases after oral administration.

Severe side effects such as ataxia, myoclonic encephalopathy or osteodystrophy are

rare in currently used compounds. Blackening of the stool or sometimes the tongue, nausea,
vomiting, transit changes may occur.

Bismuth preparations are contraindicated in patients with renal impairment (there is a

risk of accumulation of bismuth in the body) and during pregnancy. Bismuth subsalicylate is
contraindicated in people allergic to salicylates.

Sucralfate has a complex molecule made of sucrose octasulfate coupled with

aluminum hydroxide.

The substance, insoluble in water, in acidic medium releases aluminum and

polymerizes three-dimensionally forming a viscous gel, adherent to the mucosal surface and
especially at the level of the ulcerous lesion. The adhesion capacity is higher in the case of
duodenal ulcer lesions than in the gastric ones. It is the main mechanism for producing the
antiulcer effect. In addition, the stimulation of cytoprotective prostaglandin formation, pepsin
adsorption, increased mucus secretion and improvement of its composition, favoring the
formation of epithelial growth factor, mechanisms whose influence by sucralfate is uncertain,
have been described. However, the therapeutic benefit is also due to the fixation by sucralfate
of bile salts that reflux from the duodenum and whose importance in the pathogenesis of
gastric ulcer is certain.

Sucralfate is indicated mainly in duodenal ulcers but also in gastric ulcers as a curative
treatment or for the prophylaxis of recurrences. It is also indicated in the prophylaxis of stress
ulcers and can bring therapeutic benefits to patients with gastroesophageal reflux disease.

Adverse effects that may occur during treatment are rare. It can most often cause
constipation. Dry mouth, nausea, vomiting, headache, rash occur less frequently. Aluminum
poisoning may occur with prolonged, high-dose treatment in patients with renal impairment.
It can produce precipitates of aluminum phosphate in the gut, as described for aluminum
compounds. However, the risk of hypophosphataemia is generally low.

When co-administered with other drugs, sucralfate may reduce their bioavailability
due to their adsorption. Among the drugs with which it produces such interactions may be
noted: tetracyclines, cimetidine, phenytoin, digoxin, theophylline, amitriptyline,
fluoroquinolones. A clear interval of 2 hours should be allowed between the administration
of such substances and the time of administration of sucralfate.

In the treatment of active ulcer sucralfate is administered in a dose of 1 g one hour

before each meal. As a prophylactic treatment, two doses of 1 g each one hour before meals
are sufficient. Antacids like food, due to decreased gastric acidity, prevent the activation of
sucralfate. A minimum of 30 minutes should be allowed between sucralfate and antacids.
 Antibacterial associations against H. pylori

H. pylori is a gram-negative bacillus that frequently colonizes the mucus on the surface
of the gastric epithelium. The bacillus produces inflammatory gastritis and decreases the
ability of the mucosa to defend factors that are incriminated in the pathogenesis of ulcer
disease, gastric lymphoma and gastric adenocarcinoma.

Because most ulcer patients have H. pylori infection, eradication of the bacillus is
considered a useful way to treat and prevent ulcers. Removal of the bacillus promotes the
healing of the ulcerative lesion, increases the therapeutic benefit achieved by the
administration of H2 blocker or blockers of the proton pump and, especially, decreases the
risk of ulcer recurrence.

Because the bacillus develops resistance rapidly, antibacterial treatment is done using
therapeutic combinations. Associated are: bismuth salts (also attributed anti-H. pylori
properties), metronidazole or tinidazole and tetracycline or amoxicillin or clarithromycin (see
72. Antimicrobial chemotherapeutics). Anti-H. pylori combinations are administered in
combination with antisecretory medication, usually H2 blockers or proton pump blockers for
a short period of time, after which antisecretory treatment is continued for up to 6 months.
 PROKINETICS

Prokinetics are drugs that act by stimulating the motility of the digestive tract,
favoring the movement of the food bowl / feces in the oro-anal (aboral) direction.

Prokinetics are generally used in the treatment of gastric hypomotility, by removing

the sensation of epigastric discomfort, nausea, vomiting. It is also used in the treatment of
esophageal reflux with associated symptoms (pyrosis, dyspnea, cough, phonation disorders,
or asthma). Prokinetics also have anti-vomiting action.

Prokinetics that have an intensive action on the large intestine are used especially in
irritable bowel syndrome with a predominance of constipation. They are also used in regular
constipation.

Normal intestinal motility depends on the proper functioning of the enteric nervous
system which is closely correlated with the vegetative nervous system but also with the central
nervous system. There is also an endocrine component represented by the hormones and
enteric autacoids.

The enteric nervous system is spread from the distal esophagus to the anal area. Most
enteric neurons are found in the Meissner submucosal plexus and the Auerbach myenteric
plexus.

The enteric nervous system can function autonomously against influences from the
vegetative nervous system or the central nervous system. Normal peristalsis but also anti-
peristalsis can be initiated by the release of serotonin in the enterochromaffin cells of the
digestive mucosa in contact with the food bowl.

Serotonin released in small amounts stimulates primary afferent intrinsic neurons,

which will transmit the signal to interneurons in the myenteric plexus, which further transmit
the signal to excitatory neurons at the proximal end of the digestive tract and inhibitory
neurons at the distal end of the same segment. Thus, the proximal segment is contracted and
the distal segment is relaxed with the advancement of the food bowl in the aboral direction.
The main neurotransmitter in the excitatory neuron is acetylcholine and in the inhibitory
neuron it is considered to be NO, but ATP, VIP - vasoactive intestinal peptides are also
involved.

Excess serotonin released from enterochromaffin cells (for example when are used
cytotoxic as anticancer drugs) can stimulate vagal terminations with the production of the
vomiting reflex.

The prokinetic action is based on antidopaminergic, cholinergic and serotonergic

mechanisms. Regarding serotonergic mechanisms, prokinetic / anti-vomiting or vomiting
effects can be obtained depending on the type of serotonergic receptors stimulated. Thus,
stimulation of 5-HT4 receptors leads to prokinetic effects and stimulation of 5-HT3 receptors
leads to vomiting effects. Blocking 5-HT3 serotonergic receptors can block the vomiting
reflex but can also be useful in stimulating digestive motility in the aboral sense. Another
possible mechanism for stimulating motility in the stomach or gallbladder is to stimulate the
receptors of enteric hormones such as motiline or cholecystokinin receptors.

Prokinetics are metoclopramide, domperidone, prokaloprid, motilin receptor

stimulants - erythromycin, cholinomimetics - betanecol, reversible anticholinesterases -
neostigmine.

Metoclopramide stimulates the motility of the stomach and small intestine without
affecting the motility of the colon. In addition, increases the tone of the lower esophageal
sphincter, prevents the relaxation of the upper part of the stomach and relax the pylorus. It
also has anti-vomiting effects. It is mainly a dopaminergic antagonist, but also a 5-HT4
agonist, 5-HT3 antagonist at the level of enteric vagal terminations but also at the central
nervous level, and possibly a substance that sensitizes smooth muscles to acetylcholine
released by neurons in the myenteric plexus. The combination of anticholinergics is
disadvantageous because it prevents the prokinetic effect of metoclopramide.
 It is used in gastroesophageal reflux disease where it achieves symptomatic benefits.
It is also used in gastroparesis, in this case accelerating gastric emptying, in procedures that
involve duodenal intubation or imaging (radiological). The most important use is to relieve
nausea and vomiting from gastrointestinal disorders.

It is administered orally 30 minutes before meals and at bedtime (for esophageal reflux
disease), also intrarectally, intramuscularly or intravenously.

The effect after internal administration appears in 30-60 minutes, being quickly
absorbed but with an important first liver pass metabolization. It is also distributed in the
CNS. The elimination is done by liver metabolism but also by renal elimination in unmodified
form.

Metoclopramide has side effects similar to classic neuroleptics: extrapyramidal effects

- dystonia, parkinsonian syndrome (which occurs after a few weeks of treatment and
disappears upon discontinuation of treatment), tardive dyskinesia, galactorrhea,
gynecomastia, amenorrhea. Other side effects include drowsiness, nervousness, headache,
diarrhea. It can accelerate the intestinal passage of some drugs by reducing their
bioavailability (digoxin).

Metoclopramide is contraindicated in patients with tardive dyskinesia, Parkinson

disease, mechanical ileus, bleeding or gastrointestinal perforations, pheochromocytoma,
epilepsy, after surgery with pyloroplasty or digestive anastomoses.

Domperidone has metoclopramide-like properties, increasing gastric and small

intestine motility. It has no effect on stimulating the movements of the colon. It is also anti-
vomiting. Unlike metoclopramide, its mechanism of action is predominantly represented by
antagonization of peripheral D2 receptors; does not cross the blood-brain barrier.

After internal administration it has a low bioavailability due to the first liver pass
metabolism. It is eliminated in the form of metabolites in the feces.
 Because it does not cross the blood-brain barrier, it does not interfere with Parkinson's
disease medication. It produces headaches and has few central nervous effects: it influences
body temperature, increases prolactin secretion with galactorrhea, amenorrhea, gynecomastia
(acts in areas where the blood-brain barrier is missing).

Prucalopride is a specific agonist of 5-HT4 receptors. Increases the motility of the

small intestine and colon. It is indicated in the symptomatic treatment of chronic constipation
in women in whom laxatives have not caused adequate relief. The most common side effects
are headache and gastrointestinal symptoms (abdominal pain, nausea or diarrhea).

Neostigmine is a reversible acetylcholinesterase inhibitor that may increase the rate of

emptying of the stomach, small intestine or colon. It is used especially in cases of acute
distension of the large intestine. In intravenous administration, it promptly leads to the
evacuation of gas and feces in most patients. It has side effects characteristic of
cholinomimetics such as: hypersalivation, nausea, vomiting, diarrhea and bradycardia.
Bilateral vagotomy prevents the gastric and small intestine effects of neostigmine.

Betanecol is a non-selective muscarinic agonist that stimulates receptors (especially

M3 type) in smooth muscle cells and at the synapses in the myenteric plexus. It has limited
uses in the treatment of esophageal reflux and gastroparesis.

Motilin receptor stimulants such as erythromycin and other macrolides are used in
the treatment of diabetic gastroparesis. Due to the risk of selection of macrolide-resistant
colonic germs, such as Clostridium difficile (which causes pseudomembranous colitis), it is
used in short-term treatments.
 ANTISPASMODICS

Antispasmodics are a therapeutic group that includes substances that can prevent
smooth muscle spasms. They can relieve the pain associated with colic and cause a delay in
emptying the contents of the cavitary organs from the gastrointestinal, biliary, urinary, female
genital tract.

These substances are used in the treatment of digestive, biliary, urinary colic, for the
prophylaxis or control of drug-induced smooth muscle spasms (for example by the
administration of morphine) and in the treatment of dysmenorrhea. Two syndromes that are
relatively well defined clinically benefit from the administration of antispasmodics: irritable
bowel syndrome and overactive bladder syndrome.

Depending on the mechanism of effect production, antispasmodics are divided into

two classes: neurotropic antispasmodics and musculotropic antispasmodics.

Neurotropic antispasmodics

The substances in this group act as antagonists of muscarinic receptors and produce
smooth muscle relaxation by blocking parasympathetic innervation. These compounds
relax the smooth gastrointestinal, biliary, urinary and bladder muscles. The effects on the
female genital tract are less important. For the antispasmodic effect, natural alkaloids with
parasympatholytic effects such as atropine and scopolamine can be used, but, especially,
derivatives with amine structure or quaternary ammonium of them are used.

Parasympatholytics are indicated in the treatment of digestive spasms (produced by

insulin, morphine, parasympathomimetic or produced by ulcer, functional dyspepsia,
inflammatory or functional disorders of the small intestine, irritable bowel syndrome, etc.),
biliary or urinary spasms of various etiologies (opioid spasms).
 After oral administration, bioavailability is good for amine compounds. Quaternary
ammonium derivatives are slightly absorbed from the digestive tract due to their polar
structure.

They produce atropine-type side effects (constipation, xerostomia, vision problems,

urination disorders, tachycardia), which are more common in case of injectable
administration.

As an antispasmodic, atropine can be administered orally or injected subcutaneously.

Among the derivatives with amine structure more widely used in the treatment of digestive
colic are: piperidolate, dicycloverine.

Butylscopolamine (administered internally or injected intramuscularly or

intravenously), oxyphenonium, methanthelin, propantheline, cimetropium, otilonium are
quaternary ammonium compounds used as antispasmodics. For urinary tract disorders can be
used as antispasmodics oxybutynin, tolterodine (non-selective antimuscarinics); darifenacin,
solifenacin (antimuscarinic with selectivity against M3 receptors). Due to the relaxation of
the bladder and the favoring the contraction of the bladder sphincter, they are indicated in
hyperactive bladder syndrome, in infantile enuresis or in spastic paraplegia.

Mirabegron is a new antispasmodic in urinary tract disorders that has a different

mechanism of action - stimulating β3 adrenergic receptors in the smooth muscles of the
urinary tract. Stimulation of β3 adrenergic receptors leads to relaxation of the muscles of the
bladder wall. Tachycardia is a common side effect of this drug, probably by stimulating
cardiac β-adrenergic receptors.
 Musculotropic antispasmodics

The antispasmodic effect of these substances is produced by direct action on the

visceral smooth muscles. Musculotropic antispasmodics may stimulate the physiological
mechanisms of muscle relaxation or may have the opposite effect on the mechanisms of
smooth muscle contraction. A mechanism for muscle relaxation occurs by guanylate cyclase
stimulation by NO (nitric oxide), with the release of cGMP which can lead to the opening of
K+ channels with cellular hyperpolarization and, consequently, inhibition of actin- myosin
interaction. Another mechanism is the activation of cAMP with the stimulation of protein
kinase A, phosphorylation of some intracellular proteins that reduce the intracellular Ca2+
concentration and lead to cellular hyperpolarization by inhibiting the actin-myosin
interaction.

Papaverine, an opium alkaloid, has antispasmodic and musculotropic vasodilating

effects. The antispasmodic effect is due to the inhibition of phosphodiesterase in smooth
muscle cells (with accumulation of cAMP) and inhibition of Ca2+ channels.

It can be administrated internally, intramuscularly or intravenously. It is used in

erectile dysfunction in intracavernous administration.

Causes as side effects: tachycardia, facial congestion, hypotension, drowsiness,

dizziness, sweating, constipation. In intravenous administration can cause arrhythmias, heart
block, sudden death.

Mebeverine, a synthetic derivative, is useful in the treatment of irritable bowel

syndrome. It is administered internally.

Drotaverine may be useful as an antispasmodic in patients with spastic digestive and

biliary disorders. Because it also produces vasodilation and β1-receptor inhibition, it may be
useful in the treatment of vasculospastic syndromes (including those with coronary spasms).
It is administered internally, by injection intramuscularly or intravenously.
 Trimebutine is an agonist of peripheral opioid receptors acting on the colonic muscles
either as an antispasmodic (inhibits colonic motility if previously stimulated) or as a
prokinetic (favors colonic peristaltic movements if transit is slow). It is useful in the treatment
of irritable bowel syndrome.

Pinaveril is a Ca2+ channel blocker useful in irritable bowel syndrome.

Organic nitrates can be used in esophageal spasms, which cause pain similar to those
caused by coronary spasms. Their mechanism of action is the relaxation of the esophageal
smooth muscles by releasing NO with the consequent stimulation of guanilate cyclase.
 ANTIEMETIC DRUGS

Antiemetics are drugs that can relieve nausea and prevent vomiting.

Nausea and vomiting can occur in many situations such as: administration of drugs
(especially anticancer chemotherapeutics), general anesthesia, infectious or non-infectious
gastrointestinal disorders, pregnancy, motion sickness, etc.

The vomiting reflex is a complex process coordinated by the vomiting center located
at the level of the solitary tract in the bulb. It receives afferents from the vomiting
chemoreceptor area located in the postrema area, from the vestibular apparatus, cerebral
cortex, thalamus and hypothalamus and from the gastrointestinal tract and other viscera. The
postrema area is poorly protected by the blood-brain barrier which makes the chemoreceptor
area accessible to emetogenic substances.

Although incompletely elucidated, it is known that a number of neurotransmitters are

involved in the onset and vomiting. Thus, dopamine acts through D2 receptors, serotonin
through 5-HT3 receptors, histamine through H1 receptors, acetylcholine through M1
muscarinic receptors and enkephalins through δ and κ receptors have a pro-emetic effect
while µ-type receptors appear to produce antiemetic effects.

Currently, with different therapeutic indications, as antiemetics are used:

antidopaminergic substances, ant serotonergic substances, cannabinoids, antihistamines,
antimuscarinic substances, to which can be added glucocorticoids and benzodiazepines.
 Antihistamines used as antiemetic drugs

H1 receptor antagonists are useful in the prophylaxis of motion sickness, in vestibular

disorders of Menière's disease, in vomiting in pregnancy and in vomiting produced by drugs
(opioids, general anesthetics). The antiemetic effect is produced probably by a H1 receptors
inhibition and an anticholinergic action in the vomiting center and in the vestibular nuclei.
Therapeutic use of such compounds may cause side effects such as sedation, drowsiness,
atropine disorders (dry mouth, etc.). Among the antihistamines used as antiemetics are:
promethazine, diphenhydramine, pheniramine, cyclizine, buclizine, meclosin.

D2 dopaminergic receptor antagonists

A number of compounds, from different structural classes, act as antiemetics mainly

by blocking dopaminergic D2 receptors predominantly in the vomiting-triggering
chemoreceptor area. Such substances are useful to treat postoperative and postanesthetic
vomiting, in uremia, radiotherapy, in drug-induced vomiting, including that produced by
anticancer chemotherapeutics. Efficacy is improved by combination with glucocorticoids.

Phenothiazines, neuroleptics used as antiemetics, are generally well tolerated. May

cause drowsiness, orthostatic hypotension, rarely extrapyramidal disorders. Hepatic or renal
disfunction as well as cerebral atherosclerosis require caution in use. Chlorpromazine,
Proclorperazine, Thietylperazine oral, intrarectal or intramuscular injection may be used.

Butyrophenones - haloperidol, droperidol - have properties similar to

phenothiazines with the advantage of less important sedative and hypotensive effects but with
a higher risk of extrapyramidal syndrome.

Substituted benzamides - metoclopramide, trimethobenzamide - are useful as

antiemetics under the same conditions as neuroleptics. The antiemetic effect of these
compounds is due to the blockade of D2 receptors in the triggering chemoreceptor area, the
blockade of 5-HT3 receptors and a prokinetic action in the gastrointestinal tract. As an
antiemetic, metoclopramide can be administered internally, injected intramuscularly or
subcutaneously, or, if necessary, injected intravenously.

Among benzimidazole derivatives, domperidone is the most widely used compound

as an antiemetic. It has metoclopramide-like properties.

Anticholinergics

Scopolamine, a structurally similar alkaloid to atropine, has parasympatholytic and

psychomotor depressant properties.

As an antiemetic it is predominantly useful in the prophylaxis of motion sickness. It is

administered cutaneous in the form of transdermal systems, which are applied retro
auricularly. It produces sedation and atropine-type side effects (dry mouth, constipation,
vision problems, etc.). It is contraindicated in patients with glaucoma or prostate adenoma.

5-HT3 receptor antagonists

5-HT3 receptor antagonists are effective in the treatment of drug-induced vomiting

(especially as a result of chemotherapy) and radiotherapy-induced vomiting. Such substances
are generally considered as reserve antiemetics.

Ondansetron and granisetron are the most commonly used compounds, they can be
administered orally or by injection.

As side effects may cause: headache, drowsiness, constipation, dizziness, visual

disturbances (in case of intravenous administration).

Other antiemetics in this class are: tropisetron, allosetron, azasetron.

 ANTI-DIARRHEA DRUGS

Diarrhea, repeated fecal emissions with soft or liquid feces, can have multiple etio-
pathogenic causes: infectious or inflammatory digestive syndromes, osmotic causes,
malabsorption, excessive secretion of factors that stimulate peristalsis and intestinal
secretions, etc.

An important role in the treatment of severe diarrhea, which leads to significant hydro-
electrolytic losses, is played by rehydration and increased salt intake. To limit water and
electrolyte depletion as well as to improve patient comfort, the administration of symptomatic
antidiarrheals is useful. Symptomatic antidiarrheals, in mild cases, may be sufficient on their
own.

Symptomatic antidiarrheals should not be used or should be discontinued in diarrhea

with bloody feces, high fever or systemic damage through intestinal toxins due to the risk of
aggravation of the existing condition.

Opioids used as antidiarrheals

Opium and some opium alkaloids - morphine, codeine - have antidiarrheal properties.
Such substances inhibit the secretory activity in the digestive tract, cause a decrease in
gastroduodenal motility, increase the tone of the pyloric, ileocecal and anal sphincters and
inhibit the anal defecation reflex. Digestive effects occur at lower doses than analgesics and
are produced by stimulating µ-type opioid receptors in the digestive smooth muscle or in the
myenteric plexus but also through other mechanisms (cholinergic and serotonergic).

Opioids are indicated symptomatically in the control of severe diarrhea that does not
subside with other antidiarrheals, in patients with ileostomy or colostomy.

The use of natural derivatives as antidiarrheals is limited by the risk of addiction. This
risk is low or absent in the case of synthetic or semi-synthetic derivatives. Nausea, vomiting,
abdominal pain, constipation, dizziness, histaminergic reactions are the most commonly
reported adverse reactions.

Opioids are contraindicated in patients with severe ulcerative colitis (risk of toxic
megacolon), in pseudomembranous colitis (caused by Clostridium difficile), in acute
infectious diarrhea, in patients with subocclusive syndrome or intestinal occlusion, in the
presence of jaundice or in hepatitis. Use in children is not recommended. Combination with
alcohol or other central nervous system depressants is also not recommended.

Opium is used as an antidiarrheal in the form of opium tincture.

Codeine, the methylated derivative of morphine, is useful as an antidiarrheal

administered internally.

Diphenoxylate, a piperidine derivative used as an antidiarrheal, is administered

internally. Administered in large doses can be addictive.

Loperamide, another synthetic piperidine derivative that has no central effects, is used
as an antidiarrheal for internal administration. It has properties similar to diphenoxylate but
the effects are more intense and longer lasting. It is better supported and does not develop
addiction.

Racecadotril acts by inhibiting enkephalinase, an enzyme that degrades enkephalins.

It has antidiarrheal properties by inhibiting the secretion of water and electrolytes in the
intestine. Unlike opioid receptor agonists, it can be given to children, including infants, in
individualized doses based on body weight and age. Treatment should be combined with oral
rehydration. It has no effect on intestinal motility and does not cause constipation as an
adverse reaction. It does not cause side effects in the central nervous system.
 Parasympatholytics used as antidiarrheals

Parasympatholytics, by blocking the stimulatory cholinergic influences in the digestive

tract, cause a decrease in gastrointestinal motility and decrease secretions. Due to these
changes, muscarinic antagonists may be useful in the treatment of mild to moderate cases of
diarrhea.

They can be used as antidiarrheals atropine or synthetic derivatives -

butylscopolamine, propantheline.

5-HT3 receptor antagonists

In addition to antiemetic effects, blocking 5-HT3 receptors has an antipropulsive effect on the
muscles of the colon, especially on the muscles of the left colon.

Alosetron is a 5-HT3 antagonist effective as an antidiarrheal in irritable bowel

syndrome with severe diarrhea in women. It has not been determined whether alosetron is
effective in men. Also, no substances with the same mechanism of action (ondansetron,
granisetron, palonosetron, which are used as antiemetics) in the treatment of diarrhea have
been studied.

Compounds that increase the viscosity of the intestinal contents and have
adsorbent and protective properties

Kaolin, a naturally hydrated aluminum silicate, has antidiarrheal effects due to its
ability to adsorb toxins, fermentation products and intestinal putrefaction, and increases the
viscosity of the intestinal contents. It is administered internally before meals. It should be
taken at a distance from other medicines because kaolin can reduce their digestive absorption.
 It is contraindicated in patients with obstructive disorders of the digestive tract.

Medicinal charcoal, an activated charcoal, is useful for diarrhea treatment, abdominal

distension, flatulence and in the treatment of drug intoxications. The effects are due to the
adsorbent capacity of the compound.

Teduglutide

Teduglutide is a substance similar to GLP-2 - glucagon-like peptide-2. It is indicated

in patients who have short bowel syndrome and who are dependent on parenteral nutrition.
The drug administered subcutaneously improves the absorption of fluids and nutrients in the
intestine (decreasing the symptoms caused by insufficient absorption of nutrients, including
diarrhea) and decreases the amount of nutrients required for parenteral administration.
 LAXATIVES AND PURGATIVES

Laxatives and purgatives are drugs that promote the elimination of feces. The laxative
effect refers to the elimination of soft and formed feces and the purgative effect refers to the
elimination of multiple feces of liquid and semi-liquid consistency. There is a possibility that
a medicine in this class may have a laxative effect at low doses and a purgative effect at high
doses. The laxative or purgative effect is due to the acceleration of feces elimination or
increased water content of feces, through mechanisms such as: direct stimulation of intestinal
motility, increased active water secretion or its attraction by osmotic forces in the intestinal
lumen, increased secretion of electrolytes.

The indications for laxatives and purgatives are limited. They can be used in functional
constipation or in irritable bowel syndrome with a predominance of constipation. Purgatives
can be used to empty the intestinal contents before surgery on the colon, morphofunctional
examinations of the colon - colonoscopy, radiological examination, in some food or drug
intoxications.

Repeated use, without a doctor's recommendation, may exacerbate constipation, as the

peristalsis of the emptied bowel is no longer stimulated by the contents, further favoring the
abuse of laxatives or purgatives. Laxatives and purgatives are contraindicated in case of
appendicitis and, in general, in the presence of abdominal pain, as they can cause serious
accidents. They are also contraindicated in case of intestinal obstruction.
 Volume Laxatives

This group of laxatives includes indigestible plant fibers and substances with
polysaccharide structure, which increase the volume of intestinal contents and, consequently,
peristalsis. Their effect occurs after 1-3 days of treatment. Laxatives are preferred in
conditions of functional constipation, in patients with anorexia or dietary restrictions, which
do not allow a sufficient intestinal content to support peristalsis.

Methylcellulose, agar (agar), Psyllium seeds, flax seeds, ingested together with
water, act as volume laxatives.

Osmotic purgatives

Various salts, administered orally, have a purgative or laxative effect, depending on

the dose. They are not absorbed, remain in the intestine where they retain water through
osmosis and increase peristalsis.

Saline purgatives are used when rapid bowel movements are needed - before
radiological examination, endoscopy or bowel surgery, as in some intoxications.

Highly concentrated solutions have an irritating effect, causing nausea and vomiting.
They can also cause dehydration.

Sodium sulfate, magnesium sulfate, magnesium citrate, magnesium hydroxide can be

used as saline purgatives.

There are other substances that act by retaining water in the intestine by osmotic forces
- macrogoles and lactulose.

The most commonly used macrogols (polyethylene glycols) for laxative purposes are
macrogol 4000 (forlax) or macrogol 3350 (miralax). Mixtures of sodium sulphate and
macrogol 4000 (fortrans) are used for purgative purposes for radiological or endoscopic
examination of the intestine as well as for the preparation of the colon for surgery.

Lactulose is a synthetic disaccharide that acts as a laxative or purgative by retaining

water in the intestine by osmotic forces but also by stimulating intestinal motility.

It is indicated in habitual constipation and in patients with hepatic encephalopathy

(acids resulting from the degradation of lactulose decrease the amount of ammonia that
reaches the systemic circulation reducing the risk of this complication of cirrhosis, which is
considered to be caused by ammonia produced by intestinal bacteria diffused by the blood-
brain barrier).

Purgatives stimulating of intestinal motility

These drugs stimulate the propulsive movements of the small intestine or colon. The
effect is due to mucosal irritation, with the onset of reflexes mediated by the submucosal
plexus, which is why they are also known as irritating purgatives. In addition, it promotes the
secretion of electrolytes and water in the intestine, increasing the volume and giving a soft or
semi-liquid consistency to the intestinal contents. Castor oil is obtained from the seeds of
Ricinus comunis. It rarely causes intestinal colic. It can trigger labor when given to pregnant
women near term.

Bisacodil is a diphenylmethane derivative with irritating laxative (low dose) and

purgative (high dose) properties.
 Laxatives by softening the stool

These laxatives directly soften the feces and facilitate the progression of the intestinal
contents. Sodium docusate has a weak laxative effect, which is evident after 2-3 days of
treatment. It acts as a surfactant, facilitating the penetration of water and fats into the fecal
bowl. It is administered orally or rectally. Oral paraffin oil softens the stool.

Laxatives with action on specific receptors

These drugs produce a laxative effect by interfering with specific pharmacological

receptors: µ-type opioid receptors, 5-HT4 serotonergic receptors or ClC-2 chlorine channels
(named after the gene that encodes them).

Methylnaltrexone is a µ-opioid receptor antagonist that can counteract the

constipation produced by opioid agonists. Because it does not cross the blood-brain barrier,
methylnaltrexone bromide acts as a peripheral antagonist of the µ-opioid receptor, without
influencing the analgesic effects on the central nervous system produced by opioid agonists.
Frequently causes gastrointestinal disorders - abdominal pain, nausea, increased intestinal
transit to diarrhea, flatulence and injection site reactions.

Prucaloprid, a drug with an agonist action on serotonergic 5-HT4 receptors, has dose-
dependent laxative or purgative effects.

Lubiprostone, a derivative of prostaglandin E1, acts as an agonist on a specific

chlorine channel (ClC-2) on the surface of gastrointestinal epithelial cells, increasing the
secretion of chlorine and water. It is used as a laxative in habitual constipation and in irritable
bowel syndrome with a predominance of constipation. As side effects it frequently causes
nausea, increased intestinal transit to diarrhea, headache, distension and abdominal pain.
 Drugs used in the treatment of gastric or duodenal ulcers

GASTRIC SECRETION INHIBITORS

Many drugs reduce the acidic gastric secretion by intervening either in the
mechanisms of its regulation or on the metabolism of the parietal cell.

This group comprises:

• H2-histaminergic blockers,
• proton pump inhibitors,
• parasympatholytic substances,
• prostaglandin analogs,
• somatostatin analogs and other compounds.

H2-histaminergic blockers
H2 receptor blockers prevent the gastric excitatory effect of histamine, autacoid,
which is an indispensable final link in the control of the secretory activity of parietal cells.
Acid secretion stimulated by gastrin and, to a lesser extent, by muscarinic agonists, is also
inhibited by compounds of this class. These compounds have increased selectivity for H2
receptors and have no or very poor effects on H1 receptors. Although H2 receptors also
exist in other tissues (vascular or bronchiolar smooth muscle) these substances do not
produce significant functional changes in them.

Rp. Ranitidine tablets 150 mg

I pack
Ds. Orally, 2 tablets per day, in the evening.
 Proton pump inhibitors (H+ / K+ -ATPase)
This group includes substances that block the proton pump at the apical membrane
of parietal cells. H + / K + -ATPase inhibitors have specific effects (because H+ / K+ -
ATPase is found only in the parietal cell) and marked by decreased gastric acid secretion.
Gastric secretion volume, pepsin secretion, intrinsic factor and gastric emptying rate are
not altered.

Rp. Omeprazol capsules 20 mg

I pack
Ds. Orally, 1 capsule per day

PROKINETICS
Prokinetics are drugs that act by stimulating the motility of the digestive tract,
favoring the movement of the food bowl / feces in the oro-anal (aboral) direction.

Prokinetics are generally used in the treatment of gastric hypomotility, by removing

the sensation of epigastric discomfort, nausea, vomiting. It is also used in the treatment of
esophageal reflux with associated symptoms (pyrosis, dyspnea, cough, phonation
disorders, or asthma). Prokinetics also have anti-vomiting action.

Metoclopramide stimulates the motility of the stomach and small intestine without
affecting the motility of the colon.

• in addition, increases the tone of the lower esophageal sphincter,

• prevents the relaxation of the upper part of the stomach
• relaxes the pylorus.
• It has also anti-vomiting effects.
• It is mainly a dopaminergic antagonist, but also a 5-HT4 agonist, 5-HT3
antagonist at the level of enteric vagal terminations but also at the central
nervous level, and possibly a substance that sensitizes smooth muscles to
 acetylcholine released by neurons in the myenteric plexus. The combination
of anticholinergics is disadvantageous because it prevents the prokinetic
effect of metoclopramide.
• It is used in gastroesophageal reflux disease where it achieves symptomatic
benefits.
• It is also used in gastroparesis, in this case accelerating gastric emptying, in
procedures that involve duodenal intubation or imaging (radiological).
• The most important use is to relieve nausea and vomiting from
gastrointestinal disorders.

It is administered orally 30 minutes before meals and at bedtime (for esophageal

reflux disease), also intrarectally, intramuscularly or intravenously.

Rp. Metoclopramid tablets 10 mg

I pack
Ds. Orally, 1 tablet 30 minutes before meal

ANTISPASMODICS

Antispasmodics are a therapeutic group that includes substances that can prevent
smooth muscle spasms. They can relieve the pain associated with colic and cause a delay
in emptying the contents of the cavitary organs from the gastrointestinal, biliary, urinary,
female genital tract.
 Neurotropic antispasmodics
The substances in this group act as antagonists of muscarinic receptors and
produce smooth muscle relaxation by blocking parasympathetic innervation.

These compounds relax the smooth gastrointestinal, biliary, urinary and bladder
muscles. Parasympatholytics are indicated in:

• the treatment of digestive spasms (produced by insulin, morphine,

parasympathomimetic or produced by ulcer, functional dyspepsia,
inflammatory or functional disorders of the small intestine, irritable bowel
syndrome, etc.),
• biliary or urinary spasms of various etiologies (opioid spasms).

Rp. Butylscopolamine tablets 10 mg

I pack
Ds. Orally, 1 tablet 4 times per day

Musculotropic antispasmodics
The antispasmodic effect of these substances is produced by direct action on the
visceral smooth muscles. Musculotropic antispasmodics may stimulate the physiological
mechanisms of muscle relaxation or may have the opposite effect on the mechanisms of
smooth muscle contraction.

Drotaverine may be useful as an antispasmodic in patients with spastic digestive

and biliary disorders. Because it also produces vasodilation and β1-receptor inhibition, it
may be useful in the treatment of vasculospastic syndromes (including those with coronary
spasms). It is administered internally, by injection intramuscularly or intravenously.

Rp. Drotaverine, tablets 40 mg

I pack
Ds. Orally, 1 tablet every 8 hours
 ANTIVOMITING DRUGS
Antivomiting are drugs that can relieve nausea and prevent vomiting.

Antihistamines used as antivomiting

H1 receptor antagonists are useful in:

• the prophylaxis of motion sickness,

• in vestibular disorders of Menière's disease,
• in vomiting in pregnancy
• in vomiting produced by drugs (opioids, general anesthetics).

The antiemetic effect is produced probably by a H1 receptors inhibition and an

anticholinergic action in the vomiting center and in the vestibular nuclei. Therapeutic use
of such compounds may cause side effects such as sedation, drowsiness, atropine disorders
(dry mouth, etc.). Among the antihistamines used as antiemetics are: promethazine,
diphenhydramine, pheniramine, cyclizine, buclizine, meclosin.

Rp. Promethazine tablets 30 mg

I pack
Ds. Orally, 1 tablet 3 times per day

D2 dopaminergic receptor antagonists

A number of compounds, from different structural classes, act as antiemetics mainly
by blocking dopaminergic D2 receptors predominantly in the vomiting-triggering
chemoreceptor area. Such substances are useful to treat postoperative and postanesthetic
vomiting, in uremia, radiotherapy, in drug-induced vomiting, including that produced by
anticancer chemotherapeutics. Efficacy is improved by combination with glucocorticoids.
 Rp. Metoclopramide injectable solution
III ampoules
Ds. Inj i.m., 1 ampoule every 8 hours

Rp. Metoclopramid tablets 10 mg

I pack
Ds. Orally, 1 tablet every 6 hours

ANTI-DIARRHEAL DRUGS
Diarrhea can have multiple etipathogenic causes: infectious or inflammatory
digestive syndromes, osmotic causes, malabsorption, excessive secretion of factors that
stimulate peristalsis and intestinal secretions, etc.

Opioids used as antidiarrheals

Opium and some opium alkaloids - morphine, codeine - have antidiarrheal
properties. Such substances inhibit the secretory activity in the digestive tract, cause a
decrease in gastroduodenal motility, increase the tone of the pyloric, ileocecal and
anal sphincters and inhibit the anal defecation reflex. Digestive effects occur at lower
doses than analgesics and are produced by stimulating µ-type opioid receptors in the
digestive smooth muscle or in the myenteric plexus but also through other mechanisms
(cholinergic and serotonergic).

Opioids are indicated symptomatically in the control of severe diarrhea that does
not subside with other antidiarrheals, in patients with ileostomy or colostomy.

Loperamide, a synthetic opioid that has no central effects, is used as an

antidiarrheal for internal administration. It has properties similar to diphenoxylate but the
effects are more intense and longer lasting. It is better supported and does not develop
addiction.

Rp. Loperamid capsules 2 mg

I pack
Ds. Orally, initially 2 capsules and then, 1 capsule after each diarrheic
stool, maxim 8 capsules per day

Laxatives and purgatives

Laxatives and purgatives are drugs that promote the elimination of feces.

The laxative effect refers to the elimination of soft and formed feces and the
purgative effect refers to the elimination of multiple feces of liquid and semi-liquid
consistency.

There is a possibility that a medicine in this class may have a laxative effect at low
doses and a purgative effect at high doses.

The laxative or purgative effect is due to the acceleration of feces elimination or

increased water content of feces, through mechanisms such as: direct stimulation of
intestinal motility, increased active water secretion or its attraction by osmotic forces
in the intestinal lumen, increased secretion of electrolytes.

Rp. Bisacodil tablets 5 mg

I pack
Ds. Orally, 1 tablet per day
 DIURETICS

Diuretics are drugs which generally increase production of urine (diuresis).

Diuretics, by a direct renal action, increase Na+ excretion (natriuresis) by the kidney and
the excreted Na+ is followed osmotically by water.

The diuretic effect is produced by a direct action on the cells of the nephron, for
most of the diuretics, or indirectly, by modifying the content of the filtrate.

The most important indications for diuretics are:

• mobilization of edemas,
• antihypertensive therapy,
• therapy of congestive heart failure,
• prophylaxis of renal failure - in circulatory failure (shock).

In the group of diuretics are included several compounds belonging to different

structures and acting by different mechanisms. Considering the mechanism of action, the
main categories of diuretics are:

• loop diuretics
• thiazides
• carbonic anhydrase inhibitors
• potassium-sparing diuretics,
• osmotic diuretics,
• antidiuretic hormone (ADH) antagonists
 Loop diuretics

The loop diuretics, such as furosemide and bumetanide - as sulfonamide type - and
ethacrynic acid - as compound included in this group with non-sulfonamide structure -
have a very powerful diuretic effect and can cause 15–25% of filtered Na+ to be excreted.
Most of the compounds in the group are suitable for oral and i.v. administration.
After oral administration of furosemide, a strong diuresis occurs within 1 hour but persists
for only about 4 hours.
The site of action of these agents is the thick ascending limb of Henle’s loop,
where they inhibit Na+/K+/2Cl− cotransport and, as a result, the excretion of these
electrolytes together with water and excretion of Ca2+ and Mg2+ is significantly increased.
The effect of loop diuretics is present even in case of renal failure with creatinine
clearance reduction.
Therapeutic indications of loop diuretics, in addition to those described above, are:
• pulmonary edema (they are venodilators and have a rapid effect in acute left
ventricular failure),
• in renal failure with creatinine clearance reduction (< 30 ml/min)
refractoriness to thiazide,
• prophylaxis of acute renal hypovolemic failure,
• cerebral edema
• acute glaucoma crisis.
o For all these indications i.v. administration is preferred.
As unwanted effects, the loop diuretics can produce:

hypokalemia, as a consequence of an increased secretion of K+ in the
connecting tubule and the collecting duct because more Na+ becomes
available for exchange against K+, effects which are more intense compering
with thiazides;

hyperglycemia

hyperuricemia - which may precipitate gout in predisposed patients
(sulfonamide diuretics compete with urate for the tubular organic anion
secretory system), effect which is less significant than for thiazides.
In addition, the loop diuretics can produce as particular side effects hearing loss and
enhanced sensitivity to nephrotoxic agents. These effects were described in case of high
doses administered at patients with renal failure.
 Thiazides

Thiazides are less powerful than loop diuretics but are preferred in treating
uncomplicated hypertension. They are better tolerated than loop diuretics.
In this category are included thiazides as hydrochlorothiazide and
bendroflumethiazide are and related drugs as chlortalidone and indapamide which have
different structure.
As pharmacodynamics, they bind to the Cl- site of the distal tubular Na+/Cl- co-
transport system, inhibiting its action and causing natriuresis with loss of sodium and
chloride ions in the urine.
Effects of thiazides on Na+, K+, H+ and Mg2+ balance are qualitatively similar to
those of loop diuretics, but smaller in magnitude. In contrast to loop diuretics, however,
thiazides reduce Ca2+ excretion, which may be advantageous in older patients at risk of
osteoporosis.
Co-administration with loop diuretics has a synergistic effect, because the loop
diuretic delivers a greater fraction of the filtered load of Na+ to the site of action of the
thiazide in the distal tubule.
Thiazide diuretics have a vasodilator action which is for therapy benefit when they
are considered for long term administration in the treatment of hypertension and heart
failure.
Thiazide diuretics are useful in diabetes insipidus, where they reduce the volume of
urine by reducing the ability of the kidney to excrete hypotonic urine.
From pharmacokinetic point of view, thiazides and related drugs are effective orally.
All are excreted in the urine, mainly by tubular secretion, and they compete with uric acid
for the organic anion transporter.
Thiazides are indicated in therapy of:

hypertension,

heart failure,

edemas,

diabetes insipidus

prophylaxis of recurrent kidney calcium stone formation in idiopathic
hypercalciuria.
As unwanted effects, hypokalemia, loss of Mg+, hyperuricemia, hypochloremic
alkalosis, and erectile dysfunction can be considered. In addition, with a rear incidence,
idiosyncratic reactions (rashes, blood dyscrasias) can occur.
 Carbonic anhydrase inhibitors

Carbonic anhydrase inhibitors act predominantly in the proximal convoluted tubules

where they decrease Na+ reabsorption because fewer H+ ions are available for the Na+/H+
antiporter and, as a result, excretion of Na+ and H2O increases.
Acetazolamide is an example in the group.
Carbonic anhydrase inhibitors are less indicated as diuretics in present because their
diuretic effect is self-limiting due to decreasing of extracellular bicarbonate. The main
indications for drugs in this class include:

acute glaucoma,

acute mountain sickness

epilepsy.
As diuretics acetazolamide has to be administered in high doses which can produce
significant side effects.
The main possible side effects are:
• hyperchloremic metabolic acidosis,
• renal stones,
• potassium wasting,
• drowsiness,
• nervous system toxicity,
• paresthesia
• hypersensitivity reactions.
These drugs are contraindicated at patients with cirrhosis because they decrease
renal elimination of NH4+ and can lead to hyperammonemia and hepatic encephalopathy.
 Potassium-sparing diuretics

In this category are included:

- mineralocorticoid (aldosterone) receptor antagonists (spironolactone and its
metabolite canrenone),
- amiloride dependent Na+ channel blockers (triamterene and amiloride).

Mineralocorticoid (aldosterone) receptor antagonists are weak diuretics. Their

effect is directly related to the aldosterone blood concentration.
Potassium-sparing diuretics influence Na+ absorption (and K+ secretion) in the
collecting tubules and ducts, process regulated by aldosterone, and reduce Na+ absorption.
They significantly increase Na+/K+ ratio in urine.
The potassium-sparing diuretics are indicated to prevent K+ loss which can be
produced by other diuretics. They are indicated in treatment of heart failure, hypertension,
hyperaldosteronism (primary or secondary to hepatic cirrhosis and secondary to nephrotic
syndrome).
Spironolactone is orally administered, is well absorbed from the gut and
metabolized by the liver. Despite its plasma half life is short, the diuretic effect is persistent
because it is maintained by canrenone, the spironolactone metabolite.
As side effects, spironolactone can produce:
• hyperkalemia (close monitoring of plasma electrolytes is to be considered
and association with other drugs which can increase K+ in plasma is to be
avoided),
• gastrointestinal upset
• in addition to these, spironolactone can produce gynecomastia and
impotence due to its activity on progesterone and androgen receptors in other
organs.
Triamterene and amiloride act on the collecting tubules and collecting ducts,
inhibiting Na+ reabsorption by blocking especial luminal sodium channels named
amiloride dependent sodium channels and decreasing K+ excretion.
They are mainly administered in association with other diuretics (loop diuretics or
thiazides) to counteract K+ loss.
They are orally administered, usually well absorbed from gastrointestinal tract and
partially metabolized by the liver and partially unchanged excreted in urine.
As side effect, the main one consists in hyperkalemia. Gastrointestinal disturbances
and idiosyncratic reactions are rare.
 Osmotic diuretics

Osmotic diuretics (e.g. mannitol, sorbitol) are inert substances which are filtered at
glomerular level and increase osmolality of tubular fluid in proximal convoluted tubule
and loop of Henle and so reduce passive reabsorption of H2O.
They are parenterally administered. Mannitol is not metabolized and is excreted by
glomerular filtration.
Osmotic diuretics are indicated in:
• the prophylaxis of renal hypovolemic failure,
• the mobilization of brain edema,
• the treatment of acute glaucoma attacks.
As side effects, mannitol can transitorily increase extracellular volume which can
aggravate hypertension or cardiac failure and can lead to acute pulmonary edema,
headache, nausea, and vomiting. Also, dehydration, hyperkalemia, and hypernatremia can
occur. If administered at patients with renal dysfunction can produce hyponatremia (the
compound is retained intravascular and extract water from cells).

Antidiuretic hormone (ADH) antagonists

Congestive heart failure and syndrome of inappropriate ADH secretion (SIADH)

can lead to ADH excess and water retention associated with hyponatremia.
Vaptans, nonpeptide acting as ADH receptor antagonists have been studied.
Conivaptan (currently available only for intravenous use) exhibits activity against both
V1a and V2 receptors and lixivaptan and tolvaptan (the oral agents) are selectively active
against the V2 receptor.
In addition, two nonselective agents, lithium and demeclocycline, a tetracycline,
have anti-ADH effects linked to their capacity to reduce the formation of cyclic adenosine
monophosphate (cAMP) in response to ADH. The effect is associated with many side
effects.
Antidiuretic hormone antagonists are used to manage syndrome of inappropriate
ADH secretion (SIADH) when water restriction has failed to correct the abnormality.
Lithium carbonate has been used to treat this syndrome with unpredictable response.
Demeclocycline appears to have a more predictable result with less toxicity.
 As side effects, if serum Na+ is not monitored closely, ADH antagonists can cause
severe hypernatremia and nephrogenic diabetes insipidus. Both lithium and
demeclocycline have been reported to cause acute renal failure. Long-term lithium therapy
may also cause chronic interstitial nephritis.
Demeclocycline should be avoided in patients with liver disease and in children
younger than 12 years.
 Diuretics

CLINICAL USES

Diuretics have a wide range of clinical uses, including:

• hypertension (HTN),
• heart failure,
• edematous states,
• renal dysfunction,
• hypercalcemia,
• nephrolithiasis,
• glaucoma
• mountain sickness.

Although they are classed as diuretics, recognize that both loops and thiazides
cause significant vasodilation, an action that contributes to their clinical effectiveness,
especially in HTN and heart failure.

Hypokalemia and Alkalosis

Diuretics that block Na reabsorption at segments above the CT will increase sodium
load to the collecting tubules and ducts ("downstream"). This results in increased loss of
K + → hypokalemia, and in the case of both loop and thiazide diuretics the associated loss
of H+ results in alkalosis

LOOP DIURETICS

Actions
Ethacrynic acid and Furosemide
Loop diuretics inhibit the Na/K/2Cl cotransporter on the luminal membrane of the
thick ascending loop (TAL).
Normally, Na+ reabsorbed via the Na/K/2Cl transporter is transported back into
the blood by a Na/K-ATPase exchange mechanism and by a Na/C1 cotransporter, the
excess Cl- returning to the blood via passive diffusion.
Inhibition of the Na/K/2Cl cotransporter decreases intracellular K+ levels →↓
back-diffusion of K+ →↓ positive potential →↓ reabsorption of Ca2+ and Mg2+.

Thus, loop diuretics increase urinary levels of Na+, K+, Ca2+, Mg2+, and C1-.
 Clinical Uses
• acute pulmonary edema,
• acute renal failure,
• heart failure,
• hypercalcemic states,
• hypertension,
• refractory edemas.

Adverse Effects

Allergies,

alkalosis,

hypocalcemia,

hypokalemia,

hypomagnesemia,

hyperuricemia,

hypovolemia,

ototoxicity enhanced by aminoglycosides.

Rp. Furosemide, tablets 40 mg

I pack
Ds. Orally, 1 tablet 2 times per week

THIAZIDES

Actions
Hydrochlorothiazide, indapamide are organic acids that are both filtered and
secreted and that inhibit the NaCl cotransporter on the luminal membrane of the distal
convoluted tubule (DCT).

Thiazides increase urinary levels of Na, K, and Cl ions but decrease levels of Ca2+.

Clinical Uses

Thiazides are widely used in

• HTN and heart failure with proven long-term efficacy.
Their actions are improved by Na restriction. Their activity is reduced at low GFR.
• Also used in edematous states (+/- loops), including pulmonary edema,
recurrent calcium nephrolithiasis, and diabetes insipidus (ADH resistance),
including that due to lithium.
 Adverse Effects

Allergies,

alkalosis,

hypokalemia,

hypercalcemia,

hyperuricemia,

hypovolemia,

hyperglycemia,

hyperlipidemia (↑ LDL-C and TGs, not indapamide)

sexual dysfunction.

Rp. Indapamide, tablets 2.5 mg

I pack
Ds. Orally, 1 tablet per day

K+ SPARING AGENTS

Actions
Spironolactone, amiloride, and triamterene act at the level of the collecting tubules
and ducts. These are weak diuretics because most of the filtered Na+ is reabsorbed before
reaching the CT.
The CT determines final urinary Na+ concentration and is a major site of secretion
of K+ ions and protons.
Spironolactone (aldosterone receptor antagonist) and amiloride and triamterene
+
(Na channel blockers) prevent the above effects, leading to minor effects on Na'
reabsorption but major effects on the retention of K ions and protons. Thus, they cause
small increases in urinary Na+ and marked decreases in urinary K+, resulting in
hyperkalemia and acidosis.

Clinical Use
Spironolactone
In hyperaldosteronism, as an adjunctive with other diuretics in HTN and in heart
failure.
Rp. Spironolactone, tablets 25 mg
I pack
Ds. Orally, 1 tablet per day
Drugs for Heart Failure
Heart failure is due to defects in cardiac contractility (the "vigor" of heart muscle),
leading to inadequate cardiac output.
Compensation in heart failure is offset by specific drugs that can:
↓ preload-diuretics, ACEIs, AT receptor antagonists, and vasodilators.
↓ afterload-ACEIs, AT antagonists, and vasodilators.
↑ contractility-digitalis, beta agonists.

ACE INHIBITORS

ACEIs block formation of AII and inhibit bradykinin metabolism →↓ aldosterone →↓

fluid retention -→↑ vasodilation →↓ preload and afterload.
ACEIs are now the primary drugs used for management of heart failure. AT antagonists
appear to have similar efficacy.
Ex: Enalapril, Lisinopril, Trandolapril

Rp. Enalapril, tablets 10 mg

I pack
Ds. Orally, 1 tablet in the morning and 1 tablet in the evening

CARDIAC GLYCOSIDES

Cardiac glycosides exert positive inotropic actions on the heart. Their initial action is to
inhibit cardiac membrane Na+/K+-ATPase →↓ Na+/Ca2+ exchange →↑ Ca2+ in SR →↑
Ca2+ release and binding to troponin → tropomyosin moves →↑ actin and myosin
interaction +↑ contractile force.
Binding of digitalis to the "pump" is inhibited by K+, so hyperkalemia decreases the
effects and hypokalemia may increase the effects and cause toxicity

Clinical Uses

Digoxin is the most widely used cardiac glycoside.

In addition to use in heart failure, the vagomimetic properties of digoxin may be used
prophylactically in supraventricular tachyarrhythmia (SVTs), including atrial fibrillation.

Toxicity

Early signs: anorexia and nausea with ECG changes (↓ QT interval, T-wave inversion,
PVBs, bigeminy). Later CNS effects: disorientation, visual effects (halos), and
hallucinations. Severe cardiac toxicity:AV block, and ventricular tachycardia or VF.
Management includes adjustment of electrolytes, use of antiarrhythmic (lidocaine,
phenytoin), use of digitalis Fab antibodies, and pacemakers.
Toxicity is increased by ↓ K (diuretics), ↓ Mg, ↑ Ca and by quinidine, NSAIDs,
amiodarone, verapamil, sympathomimetics, and some antibiotics (e.g., erythromycin).
Avoid digitalis in Wolff-Parkinson-White arrhythmias.

Rp. Digoxin, tablets 0.25 mg

I pack
Ds. Orally, 1 tablet per day, 5 days per week
 HEMATOPOIETIC GROWTH FACTORS

Hematopoietic growth factors are natural substances that play a role in the growth and
development of hematopoietic cells. Some of these have been reproduced by genetic
engineering on an industrial scale and are used as medicines.

The stimulants of erythropoiesis

Erythropoietin is the growth factor specific for hematopoietic cells, with colony
forming units (erythrocytes, CFU-E), very important in the production of red blood cells;
decreased erythropoietin formation causes anemia.
Human erythropoietin obtained through genetic engineering is called epoetin, the first
synthesized being epoetin alfa. Currently, there are several types of epoetin noted in Greek
letters (alpha, beta, gamma), which differ only by the method of manufacture, without any
pharmacodynamic or pharmacokinetic differences between the compounds.
The effect of epoetin is maximal in patients with erythropoietin deficiency and is
dependent on the existence of CFU-E colonies.
Indications:
- anemia with erythropoietin deficiency in patients with chronic renal failure.
- anemia caused by some antiviral or anticancer drugs.
- anemia in children born prematurely.
- preoperative - avoiding anemia through intraoperative blood loss.

Adverse reactions: worsening of hypertension, with hypertensive encephalopathy,

seizures and stroke, thrombosis.

Darbepoietin is a longer half-life synthesis molecule than erythropoietin, which allows

lower frequency administration. It has the same therapeutic indications and side effects as
epoetin.
 Myelopoiesis stimulants
Stimulating factor of granulocyte colonies (G-CSF) - filgrastim and lenograstim.
Indications: Increased granulocyte count in case of severe neutropenia - some cancers,
bone marrow transplant, blood collection before chemotherapy, febrile neutropenia caused by
chemotherapy.
Side effects. Mild to moderate bone pain, which results in common analgesics such as
paracetamol, increased serum uric acid, alkaline phosphatase and lactic dehydrogenase,
splenomegaly.
Pegfilgrastim is a synthesis molecule consisting of the filgrastim molecule to which a
polyethylene glycol (PEG) molecule has been associated, a process generally known as PEG-
ilar (read pegylation). This PEG-ilar has greatly increased the molecular weight of filgrastim,
preventing its glomerular filtration. In practice, it is given in case of granulocytopenias , in
single dose, it persists in the body until, under its effect, the number of granulocytes increases,
after which it is eliminated from the body by the granulocytes formed under its
pharmacodynamic effect.

Stimulating factor of granulocyte and macrophage-forming colonies (GM-CSF) -

sargramostim, molgramostim.
GM-CSF is useful for increasing the production of cells derived from granulocyte,
erythrocyte, monocyte and macrophage-forming colonies (CFU-GEMM) when needed. Good
results were obtained in patients with bone marrow autotransplantation, which produced a
remarkable improvement in the evolution of the disease. Also, sargramostim may be useful in
the treatment of blood dyscrasias produced by some drugs such as anticancer drugs or some
anti-AIDS medications, especially if blood discretions involve decreasing the number of
colonies forming figured elements of the blood (for example, anemia by decreasing the number
of E-CFU).

Thrombopoiesis stimulants
The most important regulator of thrombopoiesis is thrombopoietin.
Romiplostim binds to the thrombopoietin receptor that activates it as well as
physiological thrombopoietin and increases platelet number. The drug is administrated in
subcutaneous injections once a week. It is slowly absorbed from the site of administration,
distribution in the body is limited, and elimination from the body is done on average in a few
days, the faster the platelet count is higher. Thrombotic adverse reactions, thrombocythemia,
splenomegaly, have been reported. It is used mainly in the treatment of patients with severe
idiopathic thrombocytopenic purpura.
 Eltrombopag has an affinity for the thrombopoietin receptor. Unlike romiplostim,
however, eltrombopag does not attach to the extracellular binding site of thrombopoietin to the
thrombopoietin receptor, but rather to the transmembrane segment of the receptor, but manages
to activate the thrombopoietin receptor, and increases platelet counts. Adverse effects include
headache, digestive disorders, paresthesia, cataract and other eye disorders, various infections,
benign and malignant tumors. It is authorized for the treatment of severe idiopathic
thrombocytopenic purpura.

There are other factors capable of stimulating platelet formation, including interleukins
6 and 11 (IL-6 and IL-11).
Oprelvekin has the same amino acid sequence as IL-11. Increases platelet count after
approximately 7 days of treatment, this increase is maintained for another 7 days after stopping
treatment, then returns to baseline in approximately 14 days after stopping administration. As
adverse reactions it can cause tachycardia and even severe cardiac arrhythmias, edema, pleural
effusion, fever. It is indicated in the treatment of severe thrombocytopenia produced by
anticancer treatment.
 Respiratory System

- Drugs used to treat asthma

- Drugs used to treat cough
- Expectorants
- Surfactant

Drugs used to treat asthma

This therapeutic group includes substances useful in the prophylactic or curative treatment of
bronchial asthma, being effective for the control of various clinical forms of asthma.
In the production and maintenance of respiratory inflammation, bronchospasm and viscous
bronchial hypersecretion (components incriminated in asthma), multiple pathogenic mechanisms
are involved; agglomeration of various inflammatory cells and chemical produced by them,
epithelial lesions, increased permeability of capillaries, neurovegetative imbalances.
Currently, in the treatment of asthma, mainly substances with bronchodilator action and
substances with anti-inflammatory action at bronchial level are used. In addition to such
substances, in asthma, depending on the clinical situation, various therapeutic measures may be
useful: avoiding exposure to allergens and trigger factors, specific desensitization, administration
of antibiotics, administration of expectorants, oxygen therapy, treatment of acidosis.
Substances with bronchodilator action currently used can be divided, according to the mechanism
of action, into: sympathomimetic bronchodilators, parasympatholytic bronchodilators and
musculotropic bronchodilators.
With anti-inflammatory action, glucocorticoids are mainly used in the treatment of asthma. Mast
cell degranulation inhibitors are used in the prevention of asthma attacks. To these therapeutic
groups are added leukotriene receptor antagonists and lipoxygenase inhibitors.
Calcium channel blockers, nitric oxide-releasing compounds or potassium channel-releasing
compounds are currently being studied for possible bronchodilator effects.
Sympathomimetics bronchodilator

Sympathomimetics are among the most active substances in the treatment and prophylaxis of
asthma attacks. Such compounds are included in most antiasthmatic treatment protocols.
The therapeutic benefit in asthma is mainly due to the stimulation of β2 adrenergic receptors that
cause bronchodilation. Also, at the pulmonary level, β2 adrenergic stimulation also produce
increased mucociliary clearance, inhibition of cholinergic neurotransmission, maintenance of
small vessel integrity as well as inhibition of mast cell degranulation. The formation and / or
release of histamine, leukotrienes, prostaglandins from mast cells, basophils and, possibly, other
lung cells is prevented. However, these actions do not significantly influence the chronic
background inflammation.
Beta2-adrenergic effects are produced as a result of adenylate cyclase stimulation and
consequent increase in intracellular cAMP. Cyclic adenylate via a protein kinase increases Na +,
K + - membrane ATPase activity and decreases cytoplasmic Na + levels. Consecutively, the Na
+ / Ca2 + exchange is activated, with the decrease of the available intracellular Ca2 +. Decreased
intracellular Ca2 + leads to relaxation of the bronchial smooth muscles and inhibition of mast cell
degranulation.
Sympathomimetics used as antiasthmatics have different affinities for adrenergic receptors.
Sympathomimetics with α and β adrenergic actions - such as adrenaline - with beta actions (both
β1 and β2) are used, but without alpha actions - for example isoprenaline - or selective β2 agonists
- for example salbutamol, phenoterol, etc. - the latter have the advantage of a reduced risk of side
effects.
Another aspect with important repercussions in the therapeutic use of sympathomimetic
bronchodilators is the duration of action of the compound. Adrenaline and isoprenaline, with a
short duration of action, are used only for the curative treatment of asthma attacks, while
salbutamol, terbutaline and phenoterol, with a medium duration of action, are advantageous both
for the treatment of asthma crisis and for their prophylaxis. Salmeterol, which has a long duration
of action, is used exclusively prophylactically.
Sympathomimetic bronchodilators are prepared in forms for inhalation, internal administration or
injection.
Inhalation can be useful both curatively and prophylactically, contributes to bronchoselectivity and
reduces the importance of systemic side effects. This is the most common mode of administration
of β2 sympathomimetics.
Internal administration may be useful in the case of long-term prophylactic treatment for asthma
attacks, especially when aerosols cannot be used. In this case the effect is installed more slowly
but is longer lasting. The main disadvantage is the higher risk of side effects compared to aerosols
(achieved plasma concentrations are much higher which can lead to loss of β2 selectivity).
The injection, subcutaneously or intramuscularly, is mainly used to stop the asthma attack. It can
also be useful in severe asthma in order to achieve the maximum possible bronchodilation. Side
effects are common and can be severe.
The use of sympathomimetics in the treatment of asthma can lead to side effects. Their number,
frequency and intensity are all the greater as the substance used has a lower selectivity for β2
adrenergic receptors. As already shown, the route of administration of the compound is also
important in terms of adverse reactions.
Sympathomimetics can cause vasoconstriction and hypertension (α adrenergic effects), cardiac
stimulation with tachyarrhythmias, palpitations and angina attacks (β1 adrenergic effects),
vasodilation, relaxation of the uterus, stimulation of striated muscles, increase in blood glucose
(β2 effects). Sympathomimetics can also produce psychomotor stimulation with β adrenergic
anxiety and nervousness. Headache, dizziness or fine trembling of the fingers are other side
effects that can be caused by sympathomimetics.
A problem of chronic treatment with β2 stimulants is the decrease in the duration of the
bronchodilator effect over time, less the decrease in its intensity. Tolerance is mainly due to the
decrease in the number of adrenergic receptors by inhibiting their synthesis (down regulation).
Cortisones quickly restore (in 6-8 hours) this reactivity.
In some asthma patients, the administration of selective β2 sympathomimetics may initially lead
to a decrease in arterial blood oxygen saturation. This undesirable effect is the consequence of
the imbalance between ventilation and perfusion - the arterioles, dilated by beta2-adrenergic
action, provide an increased amount of blood to the alveoli, still insufficiently ventilated, if the
bronchodilation is not sufficiently operative. The adrenaline that produces vasoconstriction does
not cause an imbalance between ventilation and infusion.
The presence of tachyarrhythmias, angina pectoris, myocardial infarction, hypertension,
hyperthyroidism, diabetes mellitus in asthmatic patients requires caution in administration or
contraindicates the administration of sympathomimetics. The elderly are also a social category to
which these substances should be administered with caution.
The antiasthmatic sympathomimetics currently used belong to three structural groups:
catecholamines, resorcinols and saligenins.
The differences between the three structural categories are due to substituents on the phenolic
nucleus.
Also, the size of the substituents on the amino group is important for the action on different
adrenergic receptors. Increasing the size of the substituent increases the selectivity for β or β2
adrenergic receptors.
Catecholamines - adrenaline, isoprenaline, isoetarine - due to the polar character of the
substituents, pass hard through the membranes (intestinal absorption is poor, the blood-brain
barrier passes a little). Internally administered catecholamines are largely inactivated by sulfation
in the intestine, and the small amount absorbed is practically completely degraded by methylation
to the oxidril group at position 3. This explains the ineffectiveness of the oral route. The duration
of action is short for both injected adrenaline and for preparations introduced by inhalation, due
to inactivation in the body by tissue uptake and metabolism by COMT and MAO.
Resorcinols - orciprenaline, terbutaline, phenoterol; have 2 oxidril groups substituted at positions
3 and 5 of the benzene nucleus - have higher selectivity for β2 receptors. The molecule is more
stable which makes the availability after oral administration better and prolongs the duration of
the effect.
Saligenins - salbutamol, have a -CH2OH substituent in position 3 and a -OH group in position 4.
They have intense β2 adrenergic actions. The molecule is stable, which gives the possibility of
oral administration and prolongs the effect.
Adrenaline (epinephrine) is used for the asthma attack treatment by subcutaneous
administration. It can also be administered in aerosols. In both cases the effect settles quickly and
is short-lived.
Isoprenaline - synthetic catecholamine with predominantly beta-adrenergic action – administered
by inhalation can be used as a symptomatic treatment of asthma attack or other bronchospasm
(in bronchitis, bronchiectasis with emphysema). The effect occurs quickly and lasts 1 / 2-2 hours.
Orciprenaline (the resorcinol analog of isoprenaline) has a more lasting effect. It is used for crisis
prophylaxis administered by inhalation. The therapeutic benefit occurs quickly and lasts 3-4 hours.
It can also be administered internally (the effect appears after 15-30 minutes and lasts about 4
hours).
Terbutaline (tertiary analogue of orciprenaline) has a higher beta2 selectivity and a slightly more
lasting effect. It can be inhalatory administered, the effect is installed after 5-30 minutes and lasts
3-6 hours. In the case of oral administration the effect occurs after 1/2 hour and lasts 4-8 hours.
Administered by injection subcutaneously the effect is evident after 6-15 minutes and is
maintained for 1.5-4 hours. Administered by inhalation is indicated for the treatment and
prophylaxis of moderate asthma attacks. Oral administration is appropriate when crisis are
frequent or dyspnea is continuous. Injectable administration is recommended for the emergency
treatment of asthma attacks.
Clenbuterol (a terbutaline analogue that has two Cl- substituents instead of phenolic oxidils) has
a partial agonist effect on β2 adrenergic receptors. Clenbuterol has high potency and medium
duration effect. It is given orally or by inhalation.
Phenoterol (a resorcinol derivative) has a more lasting bronchodilator effect. It is administered
inhaler for crisis prophylaxis or internally.
Salbutamol (a saligenin derivative) has a selective β2 action and a relatively long-lasting effect.
It can be administered inhaler or internally. In the case of inhalation administration,
bronchodilation is evident after 15 minutes and is maintained for 3-4 hours; after internal
administration the effect begins in 30 minutes and lasts 3-4 hours. Aerosols are useful in asthma
of medium intensity. In asthma with continuous dyspnea, internal administration is recommended.
Salmeterol (a salbutamol-like compound) has a relatively slow and long-lasting effect. The effect
occurs 10-20 minutes after inhalation and lasts about 12 hours. It is advantageous for the long-
term prophylaxis of asthma attacks, but not stop crisis once produced. The long duration of the
effect is explained by the stable fixation of the side chain at a site on the β2 adrenergic receptor
close to its active site. Inhalatory administration.
Parasympatholytics bronchodilators

Parasympatholytics inhibit direct the reflex vagal mediated bronchoconstriction, with important
effect on large bronchia. It also inhibits the mast cell degranulation produced by acetylcholine.
The effects are produced by blocking of muscarinic cholinergic receptors and altering the balance
of intracellular cyclic nucleotides in favor of cGMP.
Atropine is not used as antiasthma drug because, in clinical conditions, the bronchodilator effect
occurs at high doses, difficult to tolerate.
Ipratropium (a synthetic anticholinergic substance) administered in aerosols has a
bronchodilator effect of moderate intensity, which installs slightly slower than for
sympathomimetics and is relatively durable; mucociliary clearance, volume and viscosity of
tracheobronchial secretions are not significantly altered. The effects are due to blockage of
respiratory muscarinic receptors.
The therapeutic benefit is important in asthmatics in whom bronchospasm has an important vagal
reflex component, the compound being indicated mainly in reflex asthma. Patients with a weak
response to β2 adrenergic stimulants and those with contraindications to them as well as chronic
bronchitis (due to the important vagal reflex component) are other indications of the compound.
Ipratropium has a polar molecule and is slightly absorbed through the tracheobronchial mucosa.
It is taken up by the mucociliary escalator and swallowed at the level of the pharynx. It is not
absorbed from the digestive tract and is eliminated by feces. Reduced absorption explains the
limitation of the effect on the bronchial system and lack of atropine-type systemic side effects.
It is administered inhalatory in the form of dosed pressurized aerosols. Ipratropium is generally
well tolerated. Side effects: dry mouth, bitter taste, constipation caused by direct action on the
digestive tract. In patients with narrow-angle glaucoma or prostate adenoma, however, caution is
required due to the theoretical risk of uncontrolled digestive absorption due to possible mucosal
damage. The phenoterol-ipratropium combination is advantageous due to the synergistic
bronchodilator action of the two components. In this situation, the bronchodilator effect affects
both the small bronchia (through the β2 adrenergic agonist) and the large bronchia (through
ipratropium). There are commercial preparations (berodural, ipratropium / salbutamol) containing
the same combination that are administered in aerosols and are indicated especially for the
elimination of dyspnea attacks during periods of asthma exacerbation.
Oxytropium has properties similar to those of ipratropium. It is administered inhaler.
Musculotropic bronchodilators

Theophylline (caffeine-like xanthine alkaloid) relaxes the smooth muscles of the bronchia and
other smooth muscles, stimulates the myocardium, stimulates HCl gastric secretion, increases
diuresis and excites the central nervous system.
It can be used in the treatment of asthma as such or in the form of an aminophylline that is more
soluble and has a higher bioavailability after oral administration.
Theophylline has a bronchodilator effect (less intense than for sympathomimetics) and may be
effective in patients in whom sympathomimetics have become inactive. The relaxation of the
bronchia is due to a direct action on the smooth muscles. In addition to bronchodilation, the
stimulation of mucociliary clearance is favorable.
In addition to these effects, theophylline is effective in bronchial asthma and has an anti-
inflammatory and immunomodulatory effect (attributed to reducing the action of LTD4 on specific
receptors and blocking the release of proinflammatory substances from mast cells by adenosine)
and a central stimulant effect that may have favorable consequences in nocturnal asthma
(increasing respiratory volume and reactivity of respiratory centers to carbon dioxide). Removing
fatigue and increasing diaphragm contractility can also be beneficial. Hemodynamic effects of the
compound (increases myocardial contractile force, decreases preload and decreases venous
filling pressure, dilates pulmonary arteries) may also be favorable in asthmatic patients.
Side effects: anorexia, nausea, gastric irritation, palpitations, headache, nervousness, insomnia.
Excessive doses can cause tachycardia, arrhythmias, convulsions. Rapid intravenous injection
may cause skin congestion, hypotension, severe arrhythmias, precordial pain, nausea and
vomiting, marked restlessness, seizures. Cases of sudden death have been reported during i.v.
injection.
Theophylline is contraindicated in patients with epilepsy, acute myocardial infarction and
theophylline allergy. Gastroduodenal ulcer is a relative contraindication. Use in cardiac,
hypertensive, hyperthyroid, hepatic disease, elderly and newborns requires caution.
Do not administer concomitantly with other xanthine preparations. The combination with
ephedrine or other sympathomimetics increases the risk of toxic reactions.
Mast cell degranulation inhibitors

This therapeutic group includes substances able to prevent the release and / or production of
chemical mediators of the inflammatory process by mast cells and other cells involved in
inflammation of the bronchial mucosa and which are prophylactically effective in asthma,
especially allergic. Mast cell degranulation inhibitors are not useful as a curative treatment for
asthma attacks once triggered.
Chromoglycic acid is used as a medicine in the form of sodium cromoglycate (disodium salt). It
acts as an antiasthmatic due to its anti-allergic and anti-inflammatory properties.
Administered before antigenic contact, it prevents the onset of an allergic asthma attack. It also
prevents seizures caused by effort, cold and irritants. Chronic administration in patients with mild
or moderate asthma improves lung function and avoids dyspnea attacks caused by antigen
exposure and effort. The frequency and intensity of crisis decreases, the need for
sympathomimetic bronchodilators or glucocorticoids may be reduced. Therapeutic benefits are
obtained in most patients with allergic asthma, especially in children. Full effectiveness is
manifested after 3-4 weeks of treatment. In patients with intrinsic asthma or asthmatic bronchitis,
the effectiveness is lower.
Chromoglycic acid is also useful in allergic rhinitis and topical allergic conjunctivitis. Administered
internally, it can be useful in various food allergies, as well as in patients with systemic
mastocytosis and gastrointestinal disorders. Chromoglycate stabilizes the membrane of lung
mast cells and inhibits the release of histamine from them as well as the excessive formation of
leukotrienes by leukocytes, mast cells and tracheal epithelium, triggered by IgE in allergic asthma.
These effects are attributed to a decrease in the availability of calcium ions in sensitized mast
cells, phosphorylation of a specific protein, and inhibition of phosphodiesterase by increasing the
amount of cyclic adenylate. Some actions of platelet aggregation factor - PAF - (accumulation of
eosinophils in the lungs and bronchospasm) are also prevented under the action of
chromoglycate. The chromoglycate passes little through the biological membranes. After internal
administration it is absorbed insignificantly. It is also slightly absorbed after inhalation. The
absorbed drug is excreted unchanged in bile and urine. The half-life is short. Adverse reactions
have been reported: nausea, unpleasant taste, arthralgia, urticaria, eosinophilic lung infiltration,
dysuria. Administered inhaler may cause: transient bronchospasm, cough, wheezing (due to local
irritation) which can be prevented or treated by administration of a parasympatholytic or
sympathomimetic bronchodilator. Very rarely, severe anaphylactic or anaphylactoid reactions
may occur.
Nedocromil (a derivative of chromoglic acid) has similar properties to chromoglic acid but a
higher potency. It is indicated, in combination, in mild and moderate forms of asthma, also as an
alternative to beta-adrenergic stimulants or orally administered theophylline. It is also used in
rhinitis and allergic conjunctivitis, administered locally. Side effects have been reported:
headache, bitter taste, nausea, abdominal discomfort, usually minor and transient.
Ketotifen has antianaphylactic and antihistamine properties. At the respiratory level it has
properties similar to the chromoglic acid to which is added the prolonged blockade of H1-type
histaminergic receptors which may contribute to the antiasthmatic effect.
Ketotifen is almost completely absorbed from the intestine. About half of the amount absorbed is
inactivated at the first hepatic passage. It is mostly metabolized.
The drug has not been shown to be effective in intrinsic asthma and exercise asthma.
Side effects: sedation and drowsiness, dry mouth, nausea, anorexia, epigastralgia, constipation,
rarely dizziness, weight gain. The combination with sedatives and hypnotics is not recommended
(potentiation of central depression). Co-administration of ketotifen and oral antidiabetics may
cause thrombocytopenia.

Glucocorticoids in asthma

Glucocorticoids are very effective in asthma, but are an alternative therapeutic, considering the
high risk of side effects.
It causes a spectacular improvement in clinical and lung function, restores reactivity to
sympathomimetics. The effect is obvious in patients who do not respond to bronchodilators and
in severe cases of asthma.
The therapeutic benefit is mainly due to the anti-inflammatory action as well as the ability of these
compounds to inhibit the formation of many important chemicals in the pathogenesis of asthma.
Oral preparations are appropriate in chronic asthma refractory to bronchodilators. Prednisone is
usually used. Side effects and contraindications are common to cortisone. The main problem of
long-term treatment is the depression of adrenal cortex function, which causes many patients,
who are recommended glucocorticoids with the intention of a limited cure, to become
corticosteroid-dependent. Therefore, the use of this medication in chronic asthma requires
discernment and medical supervision.
Intravenous injections, with relatively rapid action, are indicated in severe asthma attacks.
Respiratory tests begin to improve after 2 hours after injection and the effect is clinically evident
after 6-12 hours. High doses are recommended, given early and for a short time. Water-soluble
preparations such as hydrocortisone hemisuccinate are used.
Intramuscular injections, with slow and prolonged action, are advantageous for cures for several
weeks, when the disease worsens or in patients who require oral treatment but do not cooperate.
Methylprednisolone acetate or triamcinolone acetonide may be used. These glucocorticoids
cause the usual side effects of cortisone medication. Because it achieves active blood
concentrations for a long time, the risk of depression of adrenal pituitary function is high, so such
cures should be occasional (except for patients already corticosteroid-dependent).
Cortisone inhalation preparations, in the form of aerosols, such as beclomethasone
dipropionate, have a limited action on the bronchi. They are useful for the prophylaxis of asthma
attacks and the avoidance of exacerbations in chronic asthma, allowing the avoidance of
cortisone systemically. They are much better tolerated compared to systemic preparations with a
minimal risk of corticosteroid dependence or other glucocorticoid-specific side effects. However,
they can cause some side effects such as promoting the development of oropharyngeal
candidiasis and can cause dysphonia. In addition, exacerbation of asthma may sometimes occur
upon discontinuation of inhaled glucocorticoids, necessitating resumption of treatment and
gradual dose reduction.

Leukotriene antagonists and lipoxygenase inhibitors

Leukotrienes, especially LTD4 and LTE4 (peptidyloleukotrienes known as SRS-A, the slow-
reactive substance of anaphylaxis) are important autacoids in the pathogenesis of asthma, having
proinflammatory and bronchoconstrictor effects. Impairment of the synthesis or action of such
substances appears to be an important possibility in the drug control of asthma.
Montelukast and Zafirlukast are competitive antagonists of peptidyloleukotrienes, blocking their
receptors. They are administered internally for the prolonged prophylaxis of mild or moderate
asthma attacks. The effectiveness and risk of side effects are not fully evaluated.
Zileutone inhibits 5-lipoxygenase, an enzyme involved in the synthesis of leukotrienes. The
substance inhibits the production of leukotrienes involved in bronchospasm (LTC4 and LTD4) as
well as LTB4, an autacoid with chemotaxic action and leukocyte activation in the bronchial
mucosa. It is indicated as a long-term prophylactic treatment in mild-to-moderate asthma. It is
administered internally. Leukotriene antagonists and lipoxygenase inhibitors are especially
indicated as a prophylactic treatment for asthma induced by acetylsalicylic acid or other non-
steroidal anti-inflammatory drugs.

Anti-IGE monoclonal antibodies

Omalizumab, is useful in patients with severe chronic asthma who do not respond to beta-
stimulant treatment with high-dose inhaled glucocorticoids. Omalizumab reduces bronchial
inflammation and reduces the frequency and severity of seizures. The indication of choice is for
patients with demonstrated IgE-mediated hypersensitivity. The drug is given subcutaneously
twice a week.
Drugs used to treat cough

Are medicines that can reduce/calm the cough. Their effect is mainly due to the depression of the
cough reflex (cough center). Some antitussives also have a peripheral action, at the airway
mucosa.
Antitussives are a symptomatic medication useful in all situations when the cough is harmful
(unproductive cough that tires the patient).
The antitussive treatment must take into account that the cough reflex also has a defensive
character, representing an important mechanism for cleaning and draining the tracheobronchial
tree, especially in the case of subjects with lung infections.
Opium and morphine are active antitussives, depressing the cough center. They are used
sparingly because they have important side effects: risk of addiction, respiratory depression,
favored bronchospasm, thickening of tracheobronchial secretion, paralysis of vibrating cilia. They
may be useful in special situations, where it is desirable to combine antitussive action with intense
analgesic and sedative effect (patients with lung cancer, rib fractures, pneumothorax, heart attack,
hemoptysis).
Codeine, the methylated derivative of morphine, has a marked antitussive effect. Like morphine,
it depresses breathing, dries bronchial secretions, promotes bronchospasm, causes constipation,
but has the great advantage that the potential for developing addiction is much lower. It is
administered orally, being the most widely used antitussive.
It has an analgesic action of moderate intensity, for which it is sometimes associated with
antipyretic analgesics, especially acetylsalicylic acid.
Codeine should be avoided in patients with marked respiratory failure. Use in young children
requires caution (high doses may cause seizures).
Noscapine, an isoquinoline alkaloid from opium (related to papaverine), has an antitussive action,
is weakly bronchodilator, stimulates breathing. It has no analgesic properties, does not cause
addiction.
Dextromethorphan is commonly used in antitussive associations but its effectiveness as an
antitussive is considered to be poor. It acts as an opioid receptor antagonist and by antagonizing
NMDA receptors centrally. Administered in high doses it has an increased risk of tolerance and
dependence. It can also cause hallucinations when given in high doses.
Benzonate is a local anesthetic that works by inhibiting peripheral receptors involved in producing
the cough reflex. As side effects may cause: dysphagia, dizziness, severe allergic reactions in
patients allergic to paraaminobenzoic acid (a metabolite of benzonate). Administered in large
doses may cause seizures and cardiac arrest.
Clofedanol, a synthetic compound, is a relatively weak antitussive, but slightly more durable than
codeine.
Moguistein, a peripheral-acting compound that opens K + ATP-dependent channels,
theobromine, a methylxanthine derivative that inhibits phosphodiesterases, guaifenesin, a
compound indicated primarily as an expectorant, baclofen, a selective GABAB receptor
antagonist, are compounds that have been shown to be effective. significant antitussives
compared to placebo and which may be indicated in particular circumstances in patients with
upper respiratory infections.
Studies have recently begun for new antitussives such as compounds that antagonize TRPV1
(Transient Receptor Potential V1) and TRPA1 (Transient Potential Receptor A1) receptors that
are activated by compounds such as capsaicin, bradykinin or H +, substances known as cough
agents.

Expectorants

The expectorant action is due either to the stimulation of the secretory activity of the glands of the
tracheobronchial mucosa, or to the direct fluidification of the mucous secretions.
Secretostimulating expectorants are stimulating the activity of the serous glands in the
bronchial mucosa and increasing plasma transudation at this level. Some, administered orally,
have a weak irritating action on the gastric mucosa, triggering a reflex tracheobronchial
hypersecretion. Others are absorbed, then partially eliminated through the mucosa of the airways,
acting directly on the secretory cells.
The therapeutic efficacy of these classical expectorants is relatively poor.
Ammonium chloride and other ammonium salts reflexively stimulate bronchial secretion. It
also has weak acidifying and diuretic properties. Ammonium chloride can cause nausea and
vomiting. It is contraindicated in patients with ammonia intoxication - in uremia and severe hepatic
impairment - in conditions of acidosis and severe respiratory failure.
Potassium iodide and sodium iodide stimulate reflex and direct bronchial secretion. They are
used especially in chronic bronchitis. The spectrum of pharmacological actions of iodine also
includes: influencing thyroid function, promoting the healing of chronic inflammatory processes,
antiseptic properties. As side effects, iodine can cause stomach irritation with nausea and
vomiting. Prolonged administration or the first doses of idiosyncrasies can cause minor toxic
phenomena, known as iodism: oculonasal catarrh, headache, acneiform eruptions. Iodine
interferes with thyroid tests for a long time (several months) and rarely promotes goiter
development. It should be avoided in patients with pulmonary tuberculosis, because, due to its
irritating and congestive action, they can promote the activation of the disease.
Gaiacol, potassium gaiacolsulfonate and guaifenesin have poor expectorant action.
Secretolytic expectorants act directly on bronchial secretions, fluidizing them. This group
comprises mucolytic substances, surfactants and moisturizers.
Mucolytics act on mucous secretion, loosening various types of bonds responsible for the
aggregation of proteoglycemic macromolecules that form the skeleton of mucus, with consecutive
fluidization and relief of sputum.
N-acetylcysteine is a mucolytic with a thiol structure. The expectorant effect is due to the -SH
group, which disrupt the inter- and intracaternary disulfide bridges of the mucosal aggregate,
forming new -S-S- bonds between the drug and the mucoprotein fragments. It is administered
internally, injected intramuscularly or slowly intravenously, in aerosols or in direct instillations,
being indicated in hypersecretory syndromes with respiratory tree loading: bronchopulmonary
infections, chronic obstructive pulmonary disease, cystic fibrosis.
In particular, acetylcysteine is also used in the treatment of acute paracetamol intoxication. In this
case it is administered as an intravenous infusion, at a total dose of 300 mg / kg, over 20 hours.
It acts as a hepatoprotector by increasing glutathione levels and preventing the formation of
hepatotoxic metabolites of paracetamol.
Brutal fluidization of secretions can cause bronchial flooding in patients unable to expectorate
(which requires bronchoaspiration). Acetylcysteine should be used with caution in asthmatics as
it may promote bronchospasm.
Carbocysteine, methylcysteine, erdosteine are N-acetylcysteine-like derivatives but
considered to have lower expectorant efficacy.
Bromhexine, a synthetic compound with a quaternary ammonium structure, has mucolytic
properties. The effect is probably exerted by means of lysosomal enzymes, whose activity
increases at the mucosal surface. Bromhexine is administered orally, by injection subcutaneously,
intramuscularly or intravenously or by inhalation, and is indicated in bronchitis and bronchiectasis.
Administered internally it can cause nausea. The solution for injection should not be mixed with
alkaline preparations (glucocorticoids, ampicillin, etc.).
In all cases, hydration of the patient is essential.
Surfactant

The surfactant, lowers the surface tension at the contact surface between air and water, allowing
the alveoli to open and the lungs to expand during inspiration and to avoid the collapse of the
alveoli and the collapse of the lungs during exhalation. In addition, it prevents the passage of
fluids from the interstitium and capillaries to the lumen of the alveoli.
In the therapy are available preparations of natural surfactant and synthetic surfactant intended
primarily for the prophylaxis and treatment of respiratory distress syndrome in immature
newborns. The clinical effects in newborns with pulmonary immaturity consist of increased
oxygenation, sometimes marked, which may occur in the first minutes and a significant
improvement in the arterial O2 / alveolar O2 ratio.
The main side effect of surfactant treatment is an increased risk of pulmonary haemorrhage (by
an unknown mechanism). An increased risk of intracranial haemorrhage has also been reported.
The administration of the surfactant must be done with great caution, because the surfactant
effect implies the possibility of overdistension of the lungs, hyperoxia and hypocabnia. Other
undesirable phenomena that may occur during administration are: bradycardia, vasoconstriction
and pallor or hypotension, transient apnea.
 Respiratory System

- Drugs used to treat asthma

- Drugs used to treat cough
- Expectorants
- Surfactant

Drugs used to treat asthma

Sympathomimetics bronchodilator

Sympathomimetics are among the most active substances in the treatment and prophylaxis of
asthma attacks. Such compounds are included in most antiasthmatic treatment protocols.
The therapeutic benefit in asthma is mainly due to the stimulation of β2 adrenergic receptors that
cause bronchodilation. Also, at the pulmonary level, β2 adrenergic stimulation also produce
increased mucociliary clearance, inhibition of cholinergic neurotransmission, maintenance of
small vessel integrity as well as inhibition of mast cell degranulation. The formation and / or
release of histamine, leukotrienes, prostaglandins from mast cells, basophils and, possibly, other
lung cells is prevented. However, these actions do not significantly influence the chronic
background inflammation.
Salbutamol (a saligenin derivative) has a selective β2 action and a relatively long-lasting effect.
It can be administered inhaler or internally. In the case of inhalation administration,
bronchodilation is evident after 15 minutes and is maintained for 3-4 hours; after internal
administration the effect begins in 30 minutes and lasts 3-4 hours. Aerosols are useful in asthma
of medium intensity. In asthma with continuous dyspnea, internal administration is recommended.
Rp. Salbutamol tablets 4 mg
I pack
Ds. Orally, 1 tablet every 8 hours

Rp. Salbutamol ampoules 0.5 mg

VI ampoules
Ds. Inj. Subcutaneous, 1 ampoule every 4 hours

Rp. Salbutamol pressurized metered-dose aerosol canister

I canister
Ds. Inhalator, 1 puff every 6 hours
Salmeterol (a salbutamol-like compound) has a relatively slow and long-lasting effect. The effect
occurs 10-20 minutes after inhalation and lasts about 12 hours. It is advantageous for the long-
term prophylaxis of asthma attacks, but not stop crisis once produced. The long duration of the
effect is explained by the stable fixation of the side chain at a site on the β2 adrenergic receptor
close to its active site. Inhalatory administration.
Rp. Salmeterol pressurized metered-dose aerosol canister
I canister
Ds. Inhalator, 1 puff every 12 hours

Parasympatholytics bronchodilators

Parasympatholytics inhibit direct the reflex vagal mediated bronchoconstriction, with important
effect on large bronchia. It also inhibits the mast cell degranulation produced by acetylcholine.
The effects are produced by blocking of muscarinic cholinergic receptors and altering the balance
of intracellular cyclic nucleotides in favor of cGMP.
Atropine is not used as antiasthma drug because, in clinical conditions, the bronchodilator effect
occurs at high doses, difficult to tolerate.
Ipratropium (a synthetic anticholinergic substance) administered in aerosols has a
bronchodilator effect of moderate intensity, which installs slightly slower than for
sympathomimetics and is relatively durable; mucociliary clearance, volume and viscosity of
tracheobronchial secretions are not significantly altered. The effects are due to blockage of
respiratory muscarinic receptors.

Rp. Ipratropium pressurized metered-dose aerosol canister

I canister
Ds. Inhalator, 1 puff every 8 hours

Rp. Berodual pressurized metered-dose aerosol canister

I canister
Ds. Inhalator, 1 puff every 12 hours
(Berodual=salbutamol + ipratropium)
Mast cell degranulation inhibitors
This therapeutic group includes substances able to prevent the release and / or production of
chemical mediators of the inflammatory process by mast cells and other cells involved in
inflammation of the bronchial mucosa and which are prophylactically effective in asthma,
especially allergic. Mast cell degranulation inhibitors are not useful as a curative treatment for
asthma attacks once triggered.
Chromoglycic acid is used as a medicine in the form of sodium cromoglycate (disodium salt). It
acts as an antiasthmatic due to its anti-allergic and anti-inflammatory properties.
Nedocromil (a derivative of chromoglic acid) has similar properties to chromoglic acid but a
higher potency. It is indicated, in combination, in mild and moderate forms of asthma, also as an
alternative to beta-adrenergic stimulants or orally administered theophylline. It is also used in
rhinitis and allergic conjunctivitis, administered locally. Side effects have been reported:
headache, bitter taste, nausea, abdominal discomfort, usually minor and transient.
Ketotifen has antianaphylactic and antihistamine properties. At the respiratory level it has
properties similar to the chromoglic acid to which is added the prolonged blockade of H1-type
histaminergic receptors which may contribute to the antiasthmatic effect.
Rp. Ketotifen tablets 1 mg
I pack
Ds. orally, 1 tablet every 12 hours

Glucocorticoids in asthma

Glucocorticoids are very effective in asthma, but are an alternative therapeutic, considering the
high risk of side effects.
It causes a spectacular improvement in clinical and lung function, restores reactivity to
sympathomimetics. The effect is obvious in patients who do not respond to bronchodilators and
in severe cases of asthma.
The therapeutic benefit is mainly due to the anti-inflammatory action as well as the ability of these
compounds to inhibit the formation of many important chemicals in the pathogenesis of asthma.
Oral preparations are appropriate in chronic asthma refractory to bronchodilators. Prednisone is
usually used. Side effects and contraindications are common to cortisone. The main problem of
long-term treatment is the depression of adrenal cortex function, which causes many patients,
who are recommended glucocorticoids with the intention of a limited cure, to become
corticosteroid-dependent. Therefore, the use of this medication in chronic asthma requires
discernment and medical supervision.
Rp. Prednison tablets 5 mg
I pack
Ds. Orally, 1 tablet every day in the morning.
Cortisone inhalation preparations, in the form of aerosols, such as beclomethasone
dipropionate, have a limited action on the bronchi. They are useful for the prophylaxis of asthma
attacks and the avoidance of exacerbations in chronic asthma, allowing the avoidance of
cortisone systemically. They are much better tolerated compared to systemic preparations with a
minimal risk of corticosteroid dependence or other glucocorticoid-specific side effects. However,
they can cause some side effects such as promoting the development of oropharyngeal
candidiasis and can cause dysphonia. In addition, exacerbation of asthma may sometimes occur
upon discontinuation of inhaled glucocorticoids, necessitating resumption of treatment and
gradual dose reduction.
Rp. Beclomethasone metered-dose aerosol canister
I canister
Ds. Inhalator, 1 puff every 12 hours

Leukotriene antagonists and lipoxygenase inhibitors

Leukotrienes, especially LTD4 and LTE4 (peptidyloleukotrienes known as SRS-A, the slow-
reactive substance of anaphylaxis) are important autacoids in the pathogenesis of asthma, having
proinflammatory and bronchoconstrictor effects. Impairment of the synthesis or action of such
substances appears to be an important possibility in the drug control of asthma.
Montelukast and Zafirlukast are competitive antagonists of peptidyloleukotrienes, blocking their
receptors. They are administered internally for the prolonged prophylaxis of mild or moderate
asthma attacks. The effectiveness and risk of side effects are not fully evaluated.
Rp. Montelukast tablets
I pack
Ds. Orally, 1 tablet per day

Anti-IGE monoclonal antibodies

Omalizumab, is useful in patients with severe chronic asthma who do not respond to beta-
stimulant treatment with high-dose inhaled glucocorticoids. Omalizumab reduces bronchial
inflammation and reduces the frequency and severity of seizures. The indication of choice is for
patients with demonstrated IgE-mediated hypersensitivity. The drug is given subcutaneously
twice a week.
Drugs used to treat cough

Are medicines that can reduce/calm the cough. Their effect is mainly due to the depression of the
cough reflex (cough center). Some antitussives also have a peripheral action, at the airway
mucosa.
Antitussives are a symptomatic medication useful in all situations when the cough is harmful
(unproductive cough that tires the patient).
The antitussive treatment must take into account that the cough reflex also has a defensive
character, representing an important mechanism for cleaning and draining the tracheobronchial
tree, especially in the case of subjects with lung infections.
Opium and morphine are active antitussives, depressing the cough center. They are used
sparingly because they have important side effects: risk of addiction, respiratory depression,
favored bronchospasm, thickening of tracheobronchial secretion, paralysis of vibrating cilia. They
may be useful in special situations, where it is desirable to combine antitussive action with intense
analgesic and sedative effect (patients with lung cancer, rib fractures, pneumothorax, heart attack,
hemoptysis).
Codeine, the methylated derivative of morphine, has a marked antitussive effect. Like morphine,
it depresses breathing, dries bronchial secretions, promotes bronchospasm, causes constipation,
but has the great advantage that the potential for developing addiction is much lower. It is
administered orally, being the most widely used antitussive.
It has an analgesic action of moderate intensity, for which it is sometimes associated with
antipyretic analgesics, especially acetylsalicylic acid.
Codeine should be avoided in patients with marked respiratory failure. Use in young children
requires caution (high doses may cause seizures).
Noscapine, an isoquinoline alkaloid from opium (related to papaverine), has an antitussive action,
is weakly bronchodilator, stimulates breathing. It has no analgesic properties, does not cause
addiction.
Dextromethorphan is commonly used in antitussive associations but its effectiveness as an
antitussive is considered to be poor. It acts as an opioid receptor antagonist and by antagonizing
NMDA receptors centrally. Administered in high doses it has an increased risk of tolerance and
dependence. It can also cause hallucinations when given in high doses.
Benzonate is a local anesthetic that works by inhibiting peripheral receptors involved in producing
the cough reflex. As side effects may cause: dysphagia, dizziness, severe allergic reactions in
patients allergic to paraaminobenzoic acid (a metabolite of benzonate). Administered in large
doses may cause seizures and cardiac arrest.
Rp. Codeine, tablets 15 mg
I pack
Ds. Orally, 1 tablet every 6 hours
Expectorants

The expectorant action is due either to the stimulation of the secretory activity of the glands of the
tracheobronchial mucosa, or to the direct fluidification of the mucous secretions.
Secretostimulating expectorants are stimulating the activity of the serous glands in the
bronchial mucosa and increasing plasma transudation at this level. Some, administered orally,
have a weak irritating action on the gastric mucosa, triggering a reflex tracheobronchial
hypersecretion. Others are absorbed, then partially eliminated through the mucosa of the airways,
acting directly on the secretory cells.
The therapeutic efficacy of these classical expectorants is relatively poor.
Mucolytics act on mucous secretion, loosening various types of bonds responsible for the
aggregation of proteoglycemic macromolecules that form the skeleton of mucus, with consecutive
fluidization and relief of sputum.
Carbocysteine, methylcysteine, erdosteine are N-acetylcysteine-like derivatives but
considered to have lower expectorant efficacy.
Bromhexine, a synthetic compound with a quaternary ammonium structure, has mucolytic
properties. The effect is probably exerted by means of lysosomal enzymes, whose activity
increases at the mucosal surface. Bromhexine is administered orally, by injection subcutaneously,
intramuscularly or intravenously or by inhalation, and is indicated in bronchitis and bronchiectasis.
Administered internally it can cause nausea. The solution for injection should not be mixed with
alkaline preparations (glucocorticoids, ampicillin, etc.).
In all cases, hydration of the patient is essential.

Rp. Erdomed capsules

I pack
Ds. Orally, 1 capsule every 12 hours
Surfactant

The surfactant, lowers the surface tension at the contact surface between air and water, allowing
the alveoli to open and the lungs to expand during inspiration and to avoid the collapse of the
alveoli and the collapse of the lungs during exhalation. In addition, it prevents the passage of
fluids from the interstitium and capillaries to the lumen of the alveoli.
In the therapy are available preparations of natural surfactant and synthetic surfactant intended
primarily for the prophylaxis and treatment of respiratory distress syndrome in immature
newborns. The clinical effects in newborns with pulmonary immaturity consist of increased
oxygenation, sometimes marked, which may occur in the first minutes and a significant
improvement in the arterial O2 / alveolar O2 ratio.
The main side effect of surfactant treatment is an increased risk of pulmonary haemorrhage (by
an unknown mechanism). An increased risk of intracranial haemorrhage has also been reported.
The administration of the surfactant must be done with great caution, because the surfactant
effect implies the possibility of overdistension of the lungs, hyperoxia and hypocabnia. Other
undesirable phenomena that may occur during administration are: bradycardia, vasoconstriction
and pallor or hypotension, transient apnea.
 Anemia treatment

Hematopoiesis, the process of blood cells formation in the bone marrow, requires
iron, vitamin B12 and folic acid, as well as hematopoietic growth factors.
Anemia is a decrease in the number of red blood cells and the amount of hemoglobin
(Hb) in the blood below the accepted normal values.
The most common cause is the iron deficiency that causes hypochromic and
microcytic anemia - iron deficiency anemia.
Deficiency of vitamin B12 or folic acid produces megaloblastic erythropoiesis, with
asynchronous maturation between nucleus and cytoplasm - megaloblastic anemia.

Iron - iron deficiency anemia

Iron is found in the body, extracellularly and intracellularly, in the hem group of
hemoglobin, myoglobin, or in deposit form of transferrin, ferritin or hemosiderin, in the
amount of about 4 grams.
- 70% in hemoglobin
- 10% in myoglobin
- 10-20% in deposits (ferritin and hemosiderin) and in plasma transferrin.
Iron is absorbed into the proximal duodenum and jejunum. Daily absorption is 5-10%
of ingested iron, ie 0.5-1 mg / day but can increase up to 30% depending on the body's needs.
Iron from products with animal origin is direct absorbed in hem form, which is taken
up by a transporter - HCP1 (hem carrier protein 1) from the luminal surface of intestinal cells
and released at the erythrocyte level.
Iron from vegetable products is absorbed very hard.
Iron deposits are found especially in the liver, spleen and hematopoietic marrow in
the form of ferritin and hemosiderin, where iron is released according to the needs of the
body.
There are no specific iron removal mechanisms.
The iron requirement in iron deficiency anemia can be calculated according to the
hemoglobin value. For the recovery of each gram of missing hemoglobin, 150 mg of iron is
required, to which 400 - 1000 mg of iron will be added to restore the deposits.
Treatment is done with oral or injectable iron compounds along with the treatment of
the cause (bleeding, malabsorption syndromes). Iron compounds are also administered
prophylactically during pregnancy, in children during the growing period.
Within 5-10 days after the onset of iron treatment, the reticulocyte crisis appears,
hemoglobin and serum iron begin to increase and deposits are gradually restored.
Oral iron preparations are most often used in the treatment of iron-deficiency anemia,
in the form of the most easily absorbed ferrous salts - ferrous sulphate, ferrous gluconate,
administered before meals. Vitamin C promotes intestinal absorption of iron.
The most common adverse reactions during oral iron preparations administration are
gastrointestinal adverse reactions: gastric irritation, nausea, epigastric pain, intestinal transit
disorders - constipation by fixation of hydrogen sulphide at low doses or diarrhea by
gastrointestinal irritation at doses and coloring of faeces in black.
Iron injectable compounds are used only when oral administration is not possible
(absorption deficiency, inflammatory bowel disease, gastric ulcer). Iron can be administered
intravenously or intramuscular. Specific adverse reactions for injectable administration of
iron are allergic reactions - rash, bronchospasm, anaphylactic shock.
 Acute iron intoxication is very severe; nausea, vomiting, abdominal pain, bloody
diarrhea, dyspnea and shock with severe metabolic acidosis, coma are specific for acute iron
overdose. Deferoxamine (iron chelator) is used to treat the overdose.
Chronic iron intoxication - hemochromatosis occurs as a result of excessive iron
deposition in the myocardium, liver and pancreas causing insufficiency of these organs.

Vitamin B12 and folic acid - megaloblastic anemia

Vitamin B12 (cobalamin) is a co-factor in 2 biological reactions:

- homocysteine - methionine synthesis.
- transformation of methyl malonyl-CoA into succinyl-CoA
Synthesis of methionine. Vitamin B12 transfers the methyl group from N-methyl
tetrahydrofolate to homocysteine which is converted to methionine; N-methyl-
tetrahydrofolate is converted to tetrahydrofolate (the active form of folic acid).
Tetrahydrofolate is the precursor of some important co-factors in the synthesis of DNA. In
the absence of vitamin B12, tetrahydrofolate cannot be formed and DNA synthesis will be
disturbed.
The absence of vitamin B12 blocks the conversion of N-methyl-tetrahydrofolate into
tetrahydrofolate, the precursor of some very important co-factors in DNA synthesis.
Deficiency of tetrahydrofolate blocks the conversion of uridylate into thymidylate required
for DNA synthesis. N-methyl-tetrahydrofolate accumulates, the formation of tetrahydrofolate
- the "folate trap" decreases, and desynchronization of nucleus-cytoplasmic maturation,
typical for megaloblastic anemia, occurs. The metabolism of vitamin B12 interferes with the
metabolism of folic acid at this level, explaining why megaloblastic anemia can be partially
corrected also with high doses of folic acid.
Transformation of methyl malonyl-CoA into succinyl-CoA. This reaction is important
for the synthesis of myelin sheath. Deficiency of vitamin B12 leads to accumulation of
methyl malonyl-CoA and methylmalonic acid. Plasma and urinary dosage of methylmalonic
acid is useful for diagnostic of megaloblastic anemia through vitamin B12 deficiency.
Deficiency of myelin sheath formation will also cause significant neurological damage,
which can be corrected only by vitamin B12 administration.
Vitamin B12 comes from animal sources; daily absorption is 1-5 mcg and is
conditioned by the presence of the intrinsic factor (Castle) produced by the gastric parietal
cells. The complex vitamin B12 - intrinsic factor is absorbed in the ileum. Vitamin B12 is
stored in the liver - 3000 - 5000 mcg. The daily requirement of vitamin B12 is 2 mcg,
megaloblastic anemia occurring after approximately 5 years of deficiency.
Causes of megaloblastic anemia due to vitamin B12 deficiency are:
- inadequate intrinsic factor secretion (Biermer anemia, gastrectomy, congenital
absence of intrinsic factor)
- malabsorption syndrome (Crohn's disease, intestinal resections)
- particular diets (vegetarianism).
Vitamin B12 deficiency can cause megaloblastic anemia and neurological lesions -
peripheral neuritis type with paresthesia, muscle weakness, severe neurological disorders.
Vitamin B12 administered intramuscularly or subcutaneously rapidly corrects megaloblastic
anemia. The reticulocyte crisis occurs 5-10 days after the start of treatment and recent
neurological lesions are corrected within a few weeks; old neurological lesions are
irreversible.
Folic acid is found in vegetables (but is destroyed by boiling), meat and eggs; it is
completely absorbed at the level of the proximal junction in the form of N-methyl-
tetrahydrofolate which will be transformed into tetrahydrofolate at the cellular level.
Tetrahydrofolate is involved in the synthesis of thymidylate, used in DNA formation.
The enzymes involved in the synthesis of thymidylate are destroyed by drugs such as
methotrexate, trimethoprim, 5-fluorouracil; therefore, folic acid is recommended during
treatment with these drugs to prevent megaloblastic anemia.
The folate deficiency is manifested by megaloblastic anemia without neurological lesions and
is corrected quickly after folic acid administration - oral preparations.
 Anemia treatment - LP

Anemia is a decrease in the number of red blood cells and the amount of hemoglobin
(Hb) in the blood below the accepted normal values.
The most common cause is the iron deficiency that causes hypochromic and
microcytic anemia - iron deficiency anemia.
Deficiency of vitamin B12 or folic acid produces megaloblastic erythropoiesis, with
asynchronous maturation between nucleus and cytoplasm - megaloblastic anemia.

Iron - iron deficiency anemia

Iron is found in the body, extracellularly and intracellularly, in the hem group of
hemoglobin, myoglobin, or in deposit form of transferrin, ferritin or hemosiderin, in the
amount of about 4 grams.
Iron is absorbed into the proximal duodenum and jejunum. Daily absorption is 5-10%
of ingested iron, ie 0.5-1 mg / day but can increase up to 30% depending on the body's needs.
Iron from products with animal origin is direct absorbed in hem form, which is taken
up by a transporter - HCP1 (hem carrier protein 1) from the luminal surface of intestinal cells
and released at the erythrocyte level.
Iron from vegetable products is absorbed very hard.
The iron requirement in iron deficiency anemia can be calculated according to the
hemoglobin value. For the recovery of each gram of missing hemoglobin, 150 mg of iron is
required, to which 400 - 1000 mg of iron will be added to restore the deposits.

Treatment for a patient with anemia – Hb=9g/dl

Target Hb=15g/dl
To restore the normal Hb value we need: 150x6=900 mg Iron
To restore the deposits we can consider we need 600 mg (is mandatory to check the
Iron deposit and then calculate the iron requirement to restore)
Total amount of iron to correct the anemia in this case is 1500 mg

Can be used Venofer 20 mg iron / ml, ampoules 5 ml solution for injection, iv

administration
One millilitre of solution contains 20 mg of iron. Each 5 ml ampoule of Venofer
contains 100 mg iron – for complete treatment are necessary 15 ampoules

Rp. Venofer, ampoules 5 ml

XV ampoules
Ds inj iv, 2 ampoules, 3 times per week

Or, for oral administration – Ferrograd C – a combination Iron + vitamin C 1 pill/day

(vitamin C favorise the intestinal iron absorbtion; each pill of Ferrograd C has approximately
100 mg iron. In case of oral administration, the treatment is longer comparing with iv
administration because the maxim absorbtion is 30% from the administrated dose – 30 mg
iron/day.

Rp. Ferrograd C, tablets

III packs
Ds. orally, 1 tablet per day, before meal
 Vitamin B12 and folic acid - megaloblastic anemia

Vitamin B12 administered intramuscularly or subcutaneously rapidly corrects megaloblastic

anemia.

Rp. Vitamin B12, ampoules injectable solution, 1mg/1ml

XXV
Ds. inj im, initially 1 ampoule on alternate days for two weeks, then 1 ampoule
weekly until the blood count is normal
Maintenance: 1000 micrograms every two to three months

Folic acid is found in vegetables (but is destroyed by boiling), meat and eggs; it is
completely absorbed at the level of the proximal junction in the form of N-methyl-
tetrahydrofolate which will be transformed into tetrahydrofolate at the cellular level.

Rp. Folic acid, tablets 5 mg

II packs
Ds. orally, 1 tablet per day