Verapamil antiarrhythmics

Verapamil. Verapamil hydrochloride (see Table 1) is a synthetic papaverine [58-74-2] C2qH2 N04, derivative that was originally studied as a smooth muscle relaxant. It was later found to have properties of a new class of dmgs that inhibited transmembrane calcium movements. It is a (+),(—) racemic mixture. The (+)-isomer has local anesthetic properties and may exert effects on the fast sodium channel and slow phase 0 depolarization of the action potential. The (—)-isomer affects the slow calcium channel. Verapamil is an effective antiarrhythmic agent for supraventricular AV nodal reentrant arrhythmias (V1-2) and for controlling the ventricular response to atrial fibrillation (1,2,71—73). 

After po dosing, verapamil s absorption is rapid and almost complete (>90%). There is extensive first-pass hepatic metabolism and only 10—35% of the po dose is bioavahable. About 90% of the dmg is bound to plasma proteins. Peak plasma concentrations are achieved in 1—2 h, although effects on AV nodal conduction may be apparent in 30 min (1—2 min after iv adrninistration). Therapeutic plasma concentrations are 0.125—0.400 p.g/mL. Verapamil is metabolized in the liver and 12 metabolites have been identified. The principal metabolite, norverapamil, has about 20% of the antiarrhythmic activity of verapamil (3). The plasma half-life after iv infusion is 2—5 h whereas after repeated po doses it is 4.5—12 h. In patients with liver disease the elimination half-life may be increased to 13 h. Approximately 50% of a po dose is excreted as metabolites in the urine in 24 h and 70% within five days. About 16% is excreted in the feces and about 3—4% is excreted as unchanged dmg (1,2). 

All antiarrhythmic dra are used cautiously in patients with renal or hepatic disease. When renal or hepatic dysfunction is present, a dosage reduction may be necessary. All patients should be observed for renal and hepatic dysfunction. Quinidine and procainamide are used cautiously in patients with CHF. Disopyramide is used cautiously in patients with CHF, myasthenia gravis, or glaucoma, and in men with prostate enlargement. Bretylium is used cautiously in patients with digitalis toxicity because the initial release of norepinephrine with digitalis toxicity may exacerbate arrhythmias and symptoms of toxicity. Verapamil is used cautiously in patients with a history of serious ventricular arrhythmias or CHF. Electrolyte disturbances such as hypokalemia, hyperkalemia, or hypomagnesemia may alter the effects of the antiarrhythmic dru . Electrolytes are monitored frequently and imbalances corrected as soon as possible... 

When two antiarrhythmic dragp are administered concurrently the patient may experience additive effects and is at increased risk for drug toxicity. When quinidine and procainamide are administered with digitalis, tiie risk of digitalis toxicity is increased. Hiarmacologic effects of procainamide may be increased when procainamide is administered with quinidine When quinidine is administered with the barbiturates or cimetidine, quinidine serum levels may be increased. When quinidine is administered with verapamil, there is an increased risk of hypotensive effects. When quinidine is administered with disopyramide, there is an increased risk of increased disopyramide blood levels and/or decreased serum quinidine levels. 

Ondrias, K., Misik, V., Gergel, D. and Stasko, A. (1989). Lipid peroxidation of phosphatidylcholine liposomes depressed by the calcium channel blockers nifedipine and verapamil and by the antiarrhythmic-antihypoxic drug stobadine. Biochim. Biophys. Acta 1003, 238-245. 

Antiarrhythmics (e.g., disopyramide, flecainide, and others) P-Blockers (e.g., propranolol, metoprolol, atenolol, and others) Calcium channel blockers (e.g., verapamil and others)... 

Verapamil (Class IV antiarrhythmic drug) is an effective agent for atrial or supraventricular tachycardia. A Ca++ channel blocker, it is most potent in tissues where the action potentials depend on calcium currents, including slow-response tissues such as the SA node and the AV node. The effects of verapamil include a decrease in heart rate and in conduction velocity of the electrical impulse through the AV node. The resulting increase in duration of the AV nodal delay, which is illustrated by a lengthening of the PR segment in the ECG, reduces the number of impulses permitted to penetrate to the ventricles to cause contraction. 

Indications. Verapamil is used as an antiarrhythmic drug in supraventricular tachyarrhythmias. In atrial flutter or fibrillation, it is effective in reducing ventricular rate by virtue of inhibiting AV-conduction. Verapamil is also employed in the prophylaxis of angina pectoris attacks (p. 308) and the treatment of hypertension (p. 312). Adverse effects Because of verapamil s effects on the sinus node, a drop in blood pressure fails to evoke a reflex tachycardia Heart rate hardly changes bradycardia may even develop. AV-block and myocardial insufficiency can occur. Patients frequently complain of constipation. 

Verapamil possesses antiarrhythmic, antianginal, and hypotensive activity. It reduces the myocardial need of oxygen by reducing contractibility of the myocardium and slowing the freqnency of cardiac contractions. It canses dilation of coronary arteries and increases... 

Drugs that may affect disopyramide include antiarrhythmics, beta blockers, cisapride, clarithromycin, erythromycin, fluoroquinolones, hydantoins, quinidine, thioridazine, rifampin, verapamil, and ziprasidone. Drugs that may be affected by disopyramide include quinidine, anticoagulants, and digoxin. 

Antiarrhythmic activity (verapamil, possibly also diltiazem) impairment of AV conduction and to a lesser degree also that of sinus node activity. 

Reduction of the left ventricular outflow obstruction and antiarrhythmic activity underlying the beneficial effect of verapamil. 

Fig. 6. Influences of different types of antiarrhythmic agents (Vaughan-William s classification) on the shape of cardiac action potentials. First row Class I-agents action potentials of ventricular myocardial cells. Second row (from left to right) Action potential of SA-node cells influence of a )0-hlocker (class II). Action potential of ventricular myocardial cells influence of a class Ill-antiarrhythmic. Action potential of AV nodal cells influence of a class IV-antiarrhythmic (verapamil, diltiazem).

The class IV-antiarrhythmics are the calcium antagonists, but remain limited to verapamil and possibly also diltiazem. The dihydropyridines (nifedipine and related compounds) are unsuitable for antiarrhythmic therapy. The antiarrhythmic activity of verapamil and diltiazem is based upon the impairment of AV conduction and heart rate. A few compounds may be considered to act as antiarrhyth-mics, but they are not included in the Vaughan-Williams classification. 

Verapamil (Isoptin, Covera), in addition to its use as an antiarrhythmic agent, has been employed extensively in the management of variant (Prinzmetal s) angina and effort-induced angina pectoris (see Chapters 17 and 19). It selectively inhibits the voltage-gated calcium channel that is vital for action potential genesis in slow-response myocytes, such as those found in the sinoatrial and A-V nodes. 

The antiarrhythmic actions and uses of diltiazem (Cardizem see Chapter 19) are similar to those of verapamil. Diltiazem is effective in controlling the ventricular rate in patients with atrial flutter or atrial fibrillation. The pharmacology of diltiazem is discussed in detail in Chapter 19. 

These drugs, of which verapamil is the prototype, were first introduced as antianginal agents and are discussed in greater detail in Chapter 12. Verapamil and diltiazem also have antiarrhythmic effects. The dihydropyridines do not share antiarrhythmic efficacy and may precipitate arrhythmias. 

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