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Medicinal Chemistry

Medicinal Chemistry

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These drugs are found to interfere directly with depolarization of the cardiac membrane. Quite
often they also exhibit local anaesthetic properties.

A few important members of this category are discussed below :

A. Quinidine Sulphate BAN, Quinidine Sulfate USAN,

Quinidine sulphate (2 : 1) (salt) dihydrate ; Cinchonan-9-ol, 6′-methoxy-, (9S)-, sulphate (2 : 1)
(salt), dihydrate ; BP ; USP ; Eur. P., Int. P., Ind. P. ;

SK-Quinidine Sulfate(R)

(SK and F) ; Quinidex(R)

(Robins)

Preparation

Quinidine sulphate may also be prepared from the mother liquors remaining after separation of
quinine from the extracts of Cinchona by a known process.

It is very effective in the suppression of atrial premature contractions and also in shielding the
recurrences of atrial fibrillation. However, it has been found to be effective moderately against ven-
tricular premature systoles and paroxysmal atrial tachycardia.

Dose : Initial, adult, oral, 200 to 800 mg after each 2 or 3 hours up to 5 g on the first day,
followed by 100 to 200 mg 3 to 6 times per day.

There are quite a few quinidine-like agents that are used frequently as membrane-stabilizing

drugs. For instance

B.Disopyramide INN, Disopyramide Phosphate BAN, USAN

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α-[2-(Diisopropylamino)-ethyl]-α-phenyl-2-pyridine-acetamide phosphate (1 : 1) ; 4-Di-
isopropylamino-2-phenyl-2-(2-pyridyl) butyramide phosphate (1 : 1) ; BP ; USP ;

Norpace(R)

(Searle)

Synthesis

Conversion of 4-diisopropylamino-2-phenyl-2-(2-pyridyl) butyronitrile to the corresponding amide
is caused by heating with concentrated sulphuric acid which on treatment with phosphoric acid yields
the official compound disopyramide phosphate.

Disopyramide phosphate is recommended orally as a prophylaxis of either unifocal or multifocal
premature ventricular contractions and ventricular tachycardia. It also exhibits both anticholinergic and
local anaesthetic properties.

Dose : Initial, adult, oral, 200 to 300 mg followed by 100 to 200 mg after every 6 hours.

C.Lorcainide INN, Lorcainide Hydrochloride BAN, USAN,

4′-Chloro-N-(1-isopropyl-4-piperidinyl)-2-phenyl-acetanilide monohydrochloride ;
Benzeneacetamide, N-(4-chlorophenyl)-N-1-(1-methylethyl)-4-piperidinyl-, monohydrochloride ;
Lorcainide Hydrochloride(R)

(Janssen Pharmaceutica, Belgium)

It is very effective particularly during chronic thearpy perhaps due to its inherent high first-pass

metabolism orally.

Dose : 100 mg 2 or 3 times per day.

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MEDICINAL CHEMISTRY

D.Procainamide INN, Procainamide Hydrochloride BAN, USAN,

p-Amino-N-[2-diethylamino)-ethyl] benzamide hydrochloride ; Benzamide, 4-amino-N-[2-
(diethylamino) ethyl]-, monohydrochloride ; BP ; USP ; Int. P., Ind. P. ;

Procan(R)

(Parke-Davis) ; Pronestyl(R)

(Squibb)

Synthesis

p-Nitro-N-[2-(diethylamino) ethyl] benzamide is obtained by the interaction of p-nitrobenzoyl
chloride and β-diethylamino ethylamine. The resulting product on reduction with tin and hydrochloric
acid gives the procainamide base which yields the official compound on passing a stream of hydrogen
chloride gas.

Procainamide is a class I anti-arrhythmic agent with actions similar to those of quinidine. It
depresses myocardial automaticity and excitability and increases the effective refractory period of the
atrium. It finds its application towards the suppression of ventricular extrasystoles and paroxysmal
ventricular tachycardia. It is also useful in the control and management of atrial fibrillation and prema-
ture atrial contractions.

Dose : Initial, adult, oral, for atrial dysrhythmias, 1.25 g, then 750 mg after 1 hour, followed by
500 mg to 1 g every 2 hours as required ; for ventricular dysrhythmias, 1 g followed by 250 to 500 mg
every 3 hours.

Lignocaine has already been discussed under ‘local anaesthetics’ and it is also found to possess
anti-arrhythmic actions. There are a few other synthetic compounds which exhibit lignocaine-like prop-
erties,
e.g., mexiletine hydrochloride ; tocainide which shall be discussed as under :

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E. Mexiletine INN, Mexiletine Hydrochloride BAN

1-Methyl-2-(2, 6-xylyloxy) ethylamine hydrochloride ; Mexitil(R)

(Boehringer Ingelheim, U.K.)

It belongs to the Class I anti-arrhythmic agent having properties very much alike to those of
lignocaine. Unlike lignocaine it may be administered orally. It is employed for the management and
control of ventricular arrhythmias.

Dose : Initial, oral, 400 to 600 mg, followed by 200 to 250 mg 3 or 4 times per day, starting 2
hours after the loading dose ; maintenance dose 600 to 800 mg daily in divided doses.

F. Tocainide INN, BAN, USAN,

Amino-2′, 6′-propionoxylidide ; Propanamide, 2-amino-N-(2, 6-dimethyl-phenyl) ; Tonocard(R)

(Merck)

It is used exclusively for the prevention and treatment of ventricular arrhythmias.

Dose : 500 to 750 mg administered slowly through IV.
There are a few compounds which may be conveniently grouped together under the miscellane-

ous category.

G. Dexpropranolol INN, Dexpropranolol Hydrochloride USAN,

(+)-(R)-1-Isopropylamino-3-(1-naphthyloxy) propan-2-ol hydrochloride ; 2-Propanol, 1-[(1-
methylethyl)-amino]-3-(1-naphthalenyloxy)-, hydrochloride ;

Dexpropranolol Hydrochloride(R)

(ICI Pharmaceuticals, U.K.) ;

Besides possessing similar membrane-stabilizing effects like propranolol, it also exerts little
beta-adrenoreceptor blocking activity.

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MEDICINAL CHEMISTRY

5.1.1.Mechanism of Action of Membarne-Stabilizing Agents
The mechanism of action of certain membrane-stabilizing agents are described here under :

5.1.1.1.Quinidine

The bioavailability of quinidine seems to be governed solely on a combination of metabolism
and P-gp* efflux. It has been demonstrated that the bioavailabilities of quinidine gluconate and quinidine
sulphate
are 70-75% and 80-85%, respectively. Interestingly, once the ‘drug’ gets absorbed, it is sub-
jected to the hepatic first-pass metabolism and is found to be plasma-protein bound to the extent of
almost 85%, having an elimination half-life of nearly 6 hours. The ‘drug’ is largely metabolized in the
liver, and the renal excretion of the ‘unchanged drug’ is also substantially appreciable i.e., nearly 10%-
15%. The two predominant metabolites are the corresponding hydroxylated derivatives, namely : (a) o-
Demethylquinidine ;
and (b) Oxydihydroquinoline, as given below :

o-Demethylquinidine (a)

Oxydihydroquinidine (b)

[Obtained by hydroxylated structural

[Obtained by oxidation of the ‘vinyl’

analogues at the ‘Quinoline Ring’]

function at the ‘Quinuclidine Ring’]

Interestingly, the aforesaid metabolites (a) and (b) essentially retain only about 33% of the phar-
macological activity in comparison to that of quinidine. Furthermore, it has been observed that the
quinidine, which being a P-gp substrate, invariably checks the renal tubular secretion of digoxin via
the P-gp efflux pump route, thereby giving rise to an enhanced plasma concentration for digoxin.

5.1.1.2.Disopyramide

Though its antiarrythmic features are quite identical to those of quinidine and procainamide,
yet there exist certain exceptions with regard to its specific antimuscarinic activities which are found to
be much more marked and pronounced ; and strategically manifested at the two prominent extracardiac
and intracardiac sites.

Salient Features.The various salient features of the ‘drug’ are :

1.Minimises cardiac automaticity in non nodal cells.

2.Enhances the functional refractory period and minimises the relative refractory period in
atrial as well as ventricular cells.

3.Lowers the responsiveness of particularly the myocardial cells to the electrical stimulation.

4.Minimises the ensuing conduction velocity and enhances the stimulus threshold.

*P-gp : P-Glycoprotein ;

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5.Both at the SA-node and AV-node, its inherent direct myocardial depressant pharmacological
actions are adequately opposed by its antimuscarinic property. Hence, at a dosage regimen
varying between low to intermediate doses, specfically, it can caused essentially sinus
tachycardia in certain subjects ; besides, decreasing AV-nodal capability to afford a second-
degree block
of considerably high frequency atrial impulses that eventually pass through
directly to the ventricle. Perhaps, that is why such patients that do have particularly
supraventricular tachyarrythmias, are normally digitalized before being treated with
disopyramide.

The drug is practically absorbed completely when administered orally, having the bioavailability
extending upto 90%. About 50% of the drug gets usually excreted parctically unchanged in the urine
having a biological half-life of 5 to 7 hours in subjects with both adequate cardiac output and almost
normal renal function. A small fraction ~ 10% is usually secreted into bile. Its thereapeutic plasma levels
normally vary between 2-4 mcg. mL–1

. Lastly, it has been demonstrated with adequate evidence that a

substantial portion of a dose gets eliminated by N-monodealkylation.

5.1.1.3.Procainamide

The ‘drug’ is found to depress myocardial contractility and hence, may produce hypotension ; it
must be given to patients very cautiously those who are having a clear cut history of heart-failure,
valvular disease or aortic stenosis. It possesses an antimuscarinic action on the atrioventricular node
which may ultimately negate its direct depressant action on that node.

It is practically absorbed completely from the oral route, and the peak-plasma levels are accom-
plished within a span of 1-2 hours, where it is protein bound to the extent of 15%. Its volume of distribu-
tion is approximately 2 mL . g–1

. About 50 to 60% of the drug gets eliminated by the renal excretion
(along with the tubular secretion). Importantly, it gets metabolized to N-acetylprocainamide, which is
an active metabolite, and can be accumulated.

5.1.1.4.Tocainide Hydrochloride
It has been established that the total body clearance of tocainide hydrochloride stands at 166

mL. min–1

only thereby suggesting that the hepatic clearance is not to an appreciable extent. By virtue of
the fact that the drug has very low hepatic clearance, the prevailing hepatic extraction ratio should be
quite small ; and hence, the drug is most unlikely to afford a sizable first pass effect. It gets hydrolyzed
in a manner very much akin to lidocaine ; and as such its metabolites are active.

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