Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5406_Библиотеки_им_академика_М_И_Перельмана.pdf
132 Pharmaceutical Chemistry
Example: Digoxin or Lanoxin acts as a cardiac glycoside drug which helps to increase
force and strength of myocardial contraction, cardiac output, more efficient pumping of
heart, reduces heart size, helping it function more efficiently, and removes and eliminates
body fluids accumulated in tissues. It has many adverse effects such as anorexia, nausea,
vomiting, headache, drowsiness, weakness, confusion, increasing salivation, etc.
6.2.1.1 Classification of Cardiac Glycosides
1. Cardenolides
2. Bufadenolides
Me
Me
OH
HO
Digitoxigenin
(Cardenolide prototype)
Me
Me
OH
HO
Bufalin
(Bufadienolide prototype)
OH
HO
HO
O
HO
O
O
OH
Me
Me
OH
HO
Digoxigenin
O
O
Me
O
CH
OH
HO
Me
O
O
Fig. 6.1: Major cardenolide and bufadienolide aglycones
HO
O
O
MeO
OH
Strophanthidin
O
O
HO
Me
Lanatoside C
Me
O
O
HO
O
O
HO
HO
HO
OH
Me
O
O
Me
Me
OH
Gitoxigenin
HO
OH
Me
OH
Me
OH
Oubagenin
O
O
O
OH
O
O
O
The cardiac glycosides are mostly obtained from the plant origin (known as cardenolides),
which contains a 5-membered D,E-unsaturated lactone ring, whereas those obtained from
animal origin (known as bufadienolides) contains a 6-membered lactone ring with two
Cardiovascular Drugs 133
conjugated double bonds (generally referred to as D-pyrone) (Fig. 6.1). Bufadienolides are
commonly known as toad poison because several of them are found in the skin secretion of
toad species.
The most important glycosides are listed in Table 6.1.
Table 6.1: Plants and major glycosides
Plant name Glycosides
Digitalis purpurea Digitoxin, Digoxin
Digitalis lanata Digoxin, Lanatosides, Deslanoside
Strophanthus gratus Ouabain
6.2.1.2 Mode of Action
Mode of action of these drugs exerts a positive inotropic effect on the heart. Glycosides
+
inhibit membrane-bound Na
leading to increase in intracellular Na
increases intracellular Ca
+
pumping of both Na
and K+ and thus the cumulative effect helps to increase in the Ca2+
, K+-activated adenosine triphosphatase at the cellular level,
+
2+
levels. Inhibition of the cellular enzyme also decreases outward
which exchanges with extracellular Ca2+ and thus
pool available for excitation-contraction coupling.
6.2.2 Antiarrhythmic Agents
Antiarrhythmic drugs or antidysrhythmic drugs or antifibrillatory drugs may be defined
as the drugs that are capable of reverting any irregular cardiac rhythm or rate to normal.
Antiarrhythmic drugs are used to treat the affected rhythm and the normal heart rate
known as arrhythmias (abnormal rhythms of the heart). Abnormal heart rate may be
caused by the disorder in the mechanical activity of the heart. In each myocardial cell of
the heart during each beat, the mechanical activity arises due to a specific sequence of
electrical activation, beginning with sinoatrial (SA) node while ending with depolarization
of the ventricle. Thus, abnormal heart rate may arise due to alteration in the conduction
automaticity refractory period of the myocardial cells in the heart.
These agents have some specific properties:
(i) Highly efficient in controlling supraventricular and ventricular arrhythmias
symptoms.
(ii) They have good effect on myocardial oxygen consumption.
(iii) They can be found in oral as well as intravenous activities.
6.2.2.1 Classification of Antiarrhythmic Agents
Singh-Vaughan Williams classification of antiarrhythmic agents is as follows:
+
6.2.2.1.1 Class-I: Membrane stabilizing agents (Na
channel blockers): This class of drugs
is found to interfere directly with depolarization of the cardiac membrane. Class-I drugs
are also sub-classified as follows:
134 Pharmaceutical Chemistry
(a) Class-IA: Prolongs action potential duration, e.g., Quinidine, Procainamide,
Disopyramide, Moricizine, etc.
(b) Class-IB: Shortens action potential duration, e.g., Lidocaine, Phenytoin, Tocainide,
Mexiletine, etc.
(c) Class-IC: Have no effect on action potential duration (i.e., slow phase
O-depolarization), e.g., Encainide, Flecainide, Indecainide, Propaferone, etc.
6.2.2.1.2 Class-II: E-adrenergic blockers, e.g., Propranolol, Metoprolol, etc.
6.2.2.1.3 Class-III: Drugs that prolong the action potential duration, e.g., Amiodaron,
Bretylium tosylate, etc.
6.2.2.1.4 Class-IV: Ca-channel Blockers, e.g., Verapamil, Diltiazem, Nifedipine, etc.
6.2.2.1.5 Class-V: Antiarrhythmic drugs: These are also known as anion antagonists, e.g.,
Alimidine and Adenosine.
6.2.2.1.1 Class-I Antiarrhythmic Drugs
Class-I drugs are generally local anaesthetics acting on nerves and myocardial membranes
(show the greatest sensitivity) to slow conduction by inhibiting phase-0 of the action
potential. These drugs decrease the maximal rate of depolarization without changing the
resting potential, decrease conduction velocity, and also decrease spontaneous diastolic
depolarization in pacemaker cells which lead to suppress ectopic foci activity. They also
increase the excitability threshold and refractory period. The prolongation of the refractory
period tends to terminate re-entry of arrhythmias. This is sub-classified into Class-IA, IB, and
IC based on the primary pharmacologic effect by D.C. Harrison. Examples have been
shown in Fig. 6.2.
(a) Class-IA Antiarrhythmic drugs: Quinidine, Procainamide, Disopyramide
phosphate, Moricizine hydrochloride, etc., are common examples of this class.
Quinidine has a direct myocardial depressant action. It increases refractory period,
depresses contractility, depresses excitability and slows speed of conduction in
cardiac muscle. Procainamide is effective in promptly abolishing ventricular
premature depolarization and paroxysmal ventricular tachycardia and acts similar
to Quinidine. Disopyramide phosphate has both direct and indirect actions on the
heart, which resemble those of Quinidine. Moricizine hydrochloride is particularly
used for the patients suffering from impaired cardiac function and conduction
throughout the heart.
(b) Class-IB Antiarrhythmic drugs: Lidocaine, phenytoin, mexiletine hydrochloride,
and tocainide hydrochloride are the common examples of this class. Lidocaine,
similar to procaine, is an effective, clinically used, normally reserved for the
treatment of ventricular arrhythmias is, in fact, usually the drug of choice for
emergency treatment of ventricular arrhythmias. Mexiletine hydrochloride is most
useful in suppressing symptomatic ventricular arrhythmias. It is very similar to
lidocaine in its action, however, differs from lidocaine in its suitability for oral
administration, high systemic availability (90%) after ingestion and is metabolized
Cardiovascular Drugs 135
by hepatic route. Tocainide hydrochloride is another lidocaine congener, like
mexiletine in its electio-physiologic properties and antiarrhythmic action. Phenytoin
is most useful in treating ventricular arrhythmias associated with digitalis toxicity
or acute myocardial infarction (AMI).
(c) Class-IC Antiarrhythmic drugs: Flecainide acetate, Encainide hydrochloride,
Indecainide, Propafenone hydrochloride, etc., are common examples of this class.
Flecainide acetate is the first fluorine containing antiarrhythmic drug, used for
ventricular tachycardia and precipitation of cardiac arrest. The major metabolites,
m-O-dealkyl flecainide and m-O-dealkyl flecainide lactam, are inactive. Encainide
hydrochloride also has similar pharmacological action as Flecainide, however, its
action after long-term therapy seems to be affected by at least two active metabolites—
O-demetliylencainide and 3-methoxy-O-demethyl encainide. Encainide is twelve
times more active than quinidine. Indecainide is structurally similar to aprindine
and disopyramide. It has shown to be highly efficacious and a well treated
antiarrhythmic drug for the suppression of ventricular tachycardias. Propafenone
hydrochloride is useful in supraventricular and ventricular tachycardias and
tachyarrhythmias. It resembles the E-adrenoceptor blockers of aryloxypropanolamines. It is administered as a racemic mixture, wherein the R-enantiomer
possesses the antiarrhythmic activity and the S-enantiomer is a non-selective
E-adrenergic antagonist.
MeO
F
3CH2
HO
Me
Lidocaine
CO
N
N
Quinidine Procainamide
H
N
NEt
O
Me
O
N
H
OCH2CF
Flecainide
O
NH
O
2
HN
Phenytoin
H
N
3
CHMe
H
N
NEt
Me
HC
2
2
2
H
N
O
MeO
Fig. 6.2: Class-I antiarrhythmic drugs
Me
O
N
H
Encainide
2
N
CONH
N
Disopyramide
Me
O
Me
Mexiletine
NH
Me
N
O
O N
2
2
H2N
Me
H
N
Me
Tocainide
O
Indecainide
N
S
Moricizine
O
Me
NH
2
Me
NHMe
NHCOOEt
136 Pharmaceutical Chemistry
6.2.2.1.2 Class-II Antiarrhythmic Drugs
These drugs are also known as ǃ-receptor antagonists and are a good example of
antihypertensive agents as well. These drugs block the role of the sympathetic nervous
system in the genesis of certain cardiac arrhythmias. Their dominant electrophysiological
effect is to depress adrenergically enhanced Ca-ion influx through E-receptor blockade. At
higher doses, these drugs may also exhibit anaesthetic properties, which cause decreased
excitability, decreased conduction velocity, and a prolonged effective refractory period. In
normal therapeutic situations, the E-blocking effects are more important than any local
anaesthetic effects. These drugs may have E-receptor antagonists which exert their
antiarrhythmic activity through their selective blockers of E-receptors. They depress
automaticity, prolong atrioventricular (AV) conduction, reduce heart rate, and also
decrease contractility. These drugs are primarily effective in the treatment of
tachyarrhythmias caused by increased sympathetic activity. Propranolol, Acebutolol,
Esmolol and Sotalol are the common examples of this class of drugs (Fig. 6.3). Propranolol
LVWKHFODVV,,SURWRW\SHǃDGUHQHUJLFEORFNHUDQGXVHGIRUORQJWHUPWUHDWPHQWRIFDUGLDF
arrhythmias and also useful in the ventricular arrhythmias that arise due to enhanced
adrenergic stimulation (example: from emotional stress, heavy exercise). Sotalol is a much
safer drug than amiodarone and is used for supraventricular and ventricular arrhythmias
while Esmolol is used for the treatment of supraventricular tachycardias. E
-selective
1
adrenergic receptor blocker Acebutolol and its principal metabolite N-acetylacebutolol
(also known as diacetolol) are used to control ventricular pressure beats.
Me
Sotalol
O
N
H
Acebutolol
Me
O O
S
OH
H
O
Me
O
N
H
N
Me
Me
OH
H
N
Fig. 6.3: Class-II antiarrhythmic drugs
O
Me
O
O
Esmolol
O
OH
OH
Propranolol
H
Me
N
Me
N
H
6.2.2.1.3 Class-III Antiarrhythmic Drugs
Class-III drugs cause a homogeneous prolongation of the duration of the action potential.
This results in the prolongation of the effective refractory period. It is believed that most
of Class-III antiarrhythmic agents act through phase 3 of the action potential by blocking
K-ion channels. For example, bretylium belongs to the class of quaternary ammonium
compounds, used for ventricular arrhythmias that are refractory to other therapy. Another
example, Amiodarone hydrochloride is highly lipid soluble and an iodinated benzofuran
Cardiovascular Drugs 137
derivative and suppresses premature ventricular contractions and ventricular tachycardia
(Fig. 6.4). Its use is reserved for the treatment of life threatening ventricular arrhythmias
refractory to other treatment.
Br
MeEtO3S
N
Me
O
Me
O
Me
I
NEt
2
O
Bretylium tosylate
Fig. 6.4: Class-III Antiarrhythmic drugs
Amiodarone
I
6.2.2.1.4 Class-IV Antiarrhythmic Drugs: Ca-ion Channel Blockers
These drugs selectively block the slow inward current carried by Ca-ions, so called Ca-ion
channel blockers. Generally, it is believed that the inward current in cardiac cell is involved
in the genesis of certain types of cardiac arrhythmias. These drugs cause an extension of
the refractory period in the antiventricular-node (AV-node) and the atria, a decrease in
spontaneous diastolic depolarization and atrioventricular conduction. Thus, these are
very potent and effective drugs for treating supraventricular arrhythmias because they
block the conduction of premature impulses at the AV-node. For example, Verapamil is a
potent drug of choice for supraventricular tachycardia and arterial fibrillation (Fig. 6.5).
Br
MeEtO3S
N
Me
Bretylium tosylate
O
Me
O
Amiodarone
Fig. 6.5: Class-IV antiarrhythmic drug
Me
I
I
NEt
2
O
6.2.2.1.5 Class-V Antiarrhythmic Drugs: Anion Antagonists
Alinidine and adenosine are the common drugs of this class. Alinidine is an elective
bradycardiac agent. It might restrict anionic membrane currents. Adenosine is used to
treat paroxysmal supraventricular tachyarrhythmias, including those associated with
bypass pathways (Fig. 6.6).
NH
2
Cl
N
N
HN
Cl
Alimidine
Fig. 6.6: Class-V antiarrhythmic drugs
N
HO
N
N
N
O
Adenosine
OH
OH
138 Pharmaceutical Chemistry
6.2.3 Antianginal Agents
‘Angina’ a Greek word, means ‘to choke’ and the term is especially used for pain or
discomfort in the heart. Our body always demands perfect metabolic conditions of the
heart for oxygen that can regulate the blood supply properly. Sometimes the metabolic
demand is not perfect or fluctuating; at that time, the blood supply is not proper and thus
can create discomfort or pain in the heart. Angina may arise in various forms like sudden,
severe pain, and pain in left shoulder or left arm which can be converted later into severe
atherosclerosis. You can see from Fig. 6.7 the kinds of pain related to the heart. In typical
angina the pain is generally induced by emotion, exercise and eating. Nitroglycerine-like
compounds initially help in relieving the symptoms of angina, but now other classes of
drugs (ǃ-adrenergic blocking agents & Ca-channel blockers) are equally as effective.
Chest pain
Cardiac Non-cardiac
Ischemia Non-ischemic
- Coronary
atherosclerosis
- Coronary spasm
- Pericarditis
- Aortic dissection
- Cardiomyopathies
Fig. 6.7: Kinds of pain
Pulmonary
Psychogenic
- Depression
- Anxiety
Gastrointestinal
(Esophagial spasm)
Neuromusculoskeletal
The antianginal drugs are directed mainly for alleviating and preventing anginal attacks
by dilating the coronary artery and these are also sub-classified as follows.
6.2.3.1 Classification of Antianginal Drugs
6.2.3.1.1 Nitrates and Nitrites
These act by the formation of free radical nitric oxide (NO), and activate the guanylate
cyclase. Nitric oxide forms a reductive nitrothiol intermediate which activates a soluble
cytosolic form of the enzyme guanylate cyclase. Thus, cyclic guanosine monophosphate
(cGMP) formation is thereby increased which increases the synthesis of guanosine
3’,5’-monophosphate and activates a protein kinase which later mediates dephosphorylation
of myosin responsible for the maintenance of the contractile state in smooth muscles. These
are sub-classified on the basis of their chemical structure as follows:
(a) Nitrates: e.g., Nitroglycerin, Erythritol tetranitrate, Trolnitrate phosphate,
Isosorbide dinitrate, Pentaerythritol tetranitrate, Mannitol hexanitrate, etc.
(b) Nitrites: e.g., Amyl nitrite, Sodium nitrite, Nitroprusside sodium, etc.
Cardiovascular Drugs 139
6.2.3.1.2 Ca-ion Channel Blockers
These drugs act by selectively inhibiting the Ca-ion influx into the heart muscles and
inhibit calcium ion influx into the vascular smooth muscle. It dilates the main coronary
arterioles, and by inhibiting coronary artery spasm, they increase myocardial oxygen
delivery in patients with Prinzmetal’s angina. These are sub-classified on the basis of their
chemical structures:
(a) Aryl alkyl amine derivative: e.g., Verapamil.
(b) Benzothiazepine: e.g., Diltiazem.
(c) Dihydropyridine derivative: e.g., Nifedipine, Nimodipine, Nitrendipine,
Nicardipine, Amlodipine, Felodipine, and Isradipine.
(d) Newer second generation alkyl amine derivative: e.g., Bepridil.
6.2.3.1.3
E-Adrenergic Antagonist
These drugs decrease the sympathetic stimulation of the heart and thus reduce the heart
rate and decrease myocardial contractibility. These effects, in turn, decrease the oxygen
requirements of the myocardium, both during exercise and at rest, viz., Propranolol (see
also antihypertensives).
6.2.3.1.4 Miscellaneous Coronary Vasodilators
E.g., Dipyridamol, Cyclandelate and Papaverine (Fig. 6.8).
CH2ONO
CHONO
CHONO
CH2ONO
Erythritol
tetranitrate
2
2
2
2
Me Me
N
H
Nitrendipine
CH
CHONO
CHONO
CHONO
CHONO
CH2ONO
Mannitol
hexanitrate
NO
2
CO2EtMeO2C
ONO
2
2
2
2
2
2
2
MeO2C
Me Me
O2NO
O
O
ONO
2
Isosorbide
dinitrate
NO
2
O Me
N
O
N
H
Nicardipine
Fig. 6.8: Various coronary vasodilators
ONO
Amyl nitrite
MeO
MeO
Me Me
Nifedipine
NC
NC
Fe
NC
Nitroprusside
sodium
CHMe
NC
Verapam li
NO
CO2MeMeO2C
N
H
CN
CN
2
2
NO
-2
2Na
N
Me
NaONO
Sodium
Nitrite
OMe
OMe
Cl
Cl
CO2EtMeO2C
Me Me
N
H
Felodipine
6.2.4 Antihypertensive Agents
Antihypertensive agents control the blood pressure by several mechanisms. Examples:
Diuretics (Hydrochlorothiazide and Furosemide) help increase Na and water excreation
140 Pharmaceutical Chemistry
by kidneys. E-Adrenergic blockers (Propranolol, Metoprolol and Atenolol) help to decrease
cardiac output and peripheral vascular resistance. ACE-inhibitors (Captopril, Enalapril
and Lisinopril) are used to block an enzyme in the kidneys which reduces vasoconstriction
and stimulates water excretion. Ca-ion channel blockers (Verapamil, Nifedipine and
Amiodipine) help to prevent entry of Ca-ion into cardiac and smooth muscle cells which
result in vasodilation and lowering of blood pressure. D-Adrenergic blockers (Doxazosin,
Terazosin and Prazosin) results in vasodilation as well as in decreasing the blood pressure.
6.2.4.1 Classification of Antihypertensives agents
6.2.4.1.1 Adrenoceptor Blocking Agents
(a) D-Adrenergic antagonist: Prazosin (Piperazinylquinazoline derivative) is the most
selective D
than for D
potent than Prazosin but retains its specificity for D
-antagonist and its affinity for D1-receptors is about 1000-fold greater
1
-receptors. Prazosin is structurally similar to Terazosin which is less
2
-receptors. Tolazoline and
1
Phentolamine, both are non-selective D-adrenergic antagonist. They are toxic and
stimulate gastrointestinal smooth muscles and also increase gastric acid secretion.
These agents (Fig. 6.9) are also sub-classified as follows.
(i) Piperazinylquinazoline derivatives, e.g., Prazosin, Terazosin.
(ii) Imidazoline derivatives, e.g., Tolazoline, Phentolamine.
H
N
N
O
Me
Phentolamine
OH
H
N
N
Tolazoline
MeO
MeO
N
NH
Prazosin
O
MeO
MeO
O
O
N
N
N
N
2
Terazosin
NH
Fig. 6.9: D-Adrenergic antagonist
N
N
N
2
(b) E-Adrenoceptor antagonists: Propranolol is an aryloxypropranolamine and
non-selective ǃ-adrenergic antagonist. In aqueous solution propranolol decomposes
with oxidation of the isopropylamino side chain, leading to discoloration of the
solution.
Highly lipophilic propranolol is generally used in the treatment of hypertension,
cardiac arrhythmias. It gets metabolized in the liver. The major metabolite of
Propranolol is 4-hydroxypropranolol, which also shows E-adrenergic blocking
activity. It is often effective in supraventricular tachyarrhythmia, e.g., Propranolol,
Atenolol, Metoprolol, etc. (Fig. 6.10).
Cardiovascular Drugs 141
O
Propranolol
O
N
H
OH
OH
NH
O
Hepatic Metabolism
N
H
2
Fig. 6.10: E-Adrenoceptor antagonists
4-Hydroxypropranolol
O
OH
O
Me
N
H
MetoprololAtenolol
O
OH
OH
N
H
(c) D,E-Adrenoceptor antagonists: Labetalol is a non-selective E-blocker that acts as a
competitive antagonist at both D
- and E-adrenergic receptors. Labetalol decreases
1
blood pressure more rapidly than other E-blockers and is also used in the treatment
of hypertension (Fig. 6.11).
Me
N
H
OH
Labetalol
Fig. 6.11: D,E-Adrenoceptor antagonists
OH
CONH
2
(d) Centrally acting agents: D-Methyldopa is converted into D-methyl noradrenaline
(which acts as a false neurotransmitter) and thus activates central D-receptor and
reduces the blood pressure. Clonidine, originally developed as a nasal decongestant,
is also used in the treatment of all grades of hypertension. There are two major
metabolites of Clonidine: p-Hydroxyclonidine and its O-glucuronide, viz.,
Methyldopa, Clonidine, Guanabenz, Guanfacine, etc. (Fig. 6.12).
NH
HO
HO
Methyldopa
NH
Me
COOH
2
N
Cl
NH
Cl
Clonidine
Fig. 6.12: Centrally acting agents
Cl
Cl
Guanabenz
NH
N
N
NH
2
Cl
2
Guanfacine
H
NH
N
NH
O
Cl
2