Dexpropranolol INN, Dexpropranolol Hydrochloride USAN,

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.

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 ;

CARDIOVASCULAR DRUGS

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 HAPTER 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.