VERAPAMIL HCL

Chemistry - A calcium channel blocking agent, verapamil HCl occurs as a bitter-tasting, nearlywhite, crystalline powder. It is soluble in water and the injectable product has a pH of 4 - 6.5.

Storage, Stability, Compatibility

Verapamil HCl tablets should be stored at room temperature(15-30°C); the injectable product should be stored at room temperature (15-30°C) and be protectedfrom light and freezing.
Verapamil HCl for injection is compatible when mixed with all commonly used intravenoussolutions. However a crystalline precipitate may form if verapamil is added to an infusion line with0.45% sodium chloride with sodium bicarbonate running. Verapamil is reported to be compatiblewith the following drugs: amikacin sulfate, aminophylline, ampicillin sodium, ascorbic acid, atropinesulfate, bretylium tosylate, calcium chloride/gluconate, carbenicillin disodium, cefamandole naftate, cefazolin sodium, cefotaxime sodium, cefoxitin sodium, cephapirin sodium, chloramphenicolsodium succinate, cimetidine HCl, clindamycin phosphate, dexamethasone sodium phosphate, diazepam, digoxin, dobutamine HCl (slight discoloration due to dobutamine oxidation), dopamine
HCl, epinephrine HCl, furosemide, gentamicin sulfate, heparin sodium, hydrocortisone sodiumphosphate, hydromorphone HCl, insulin, isoproterenol, lidocaine HCl, magnesium sulfate, mannitol, meperidine HCl, metaraminol bitartrate, methicillin sodium, methylprednisolone sodium succinate, metoclopramide HCl, morphine sulfate, multivitamin infusion, nitroglycerin, norepinephrinebitartrate, oxytocin, pancuronium Br, penicillin G potassium/sodium, pentobarbital sodium, phenobarbital sodium, phentolamine mesylate, phenytoin sodium, potassium chloride/phosphate, procainamide HCl, propranolol HCl, protamine sulfate, quinidine gluconate, sodium bicarbonate, sodium nitroprusside, ticarcillin disodium, tobramycin sulfate, vasopressin, and vitamin B complexw/C.
The following drugs have been reported to be physically incompatible with verapamil: albumininjection, amphotericin B, hydralazine HCl, nafcillin sodium, and trimethoprim/sulfamethoxazole.
Compatibility is dependent upon factors such as pH, concentration, temperature, and diluents usedand it is suggested to consult specialized references for more specific information.

Pharmacology - VERAPAMIL HCL

A slow-channel calcium blocking agent, verapamil is classified as a class IVantiarrhythmic drug. Verapamil exerts its actions by blocking the transmembrane influx of extracellular calcium ions across membranes of vascular smooth muscle cells and myocardial cells. Theresults of this blocking is to inhibit the contractile mechanisms of vascular and cardiac smoothmuscle. Verapamil also has inhibitory effects on the cardiac conduction system and these effectsproduce its antiarrhythmic properties. Electrophysiologic effects include increased effectiverefractory period of the AV node, decreased automaticity and substantially decreased AV nodeconduction. On ECG, heart rate and RR intervals can be increased or decreased, PR and A-Hintervals are increased. Verapamil has negative effects on myocardial contractility and decreasesperipheral vascular resistance.

Uses, Indications

Veterinary experience with this agent is still rather limited, but in dogs verapamil is indicated for supraventricular tachycardias and possibly for the treatment of atrial flutter orfibrillation.

Pharmacokinetics - VERAPAMIL HCL

In humans, about 90% of a dose of verapamil is rapidly absorbed after oraladministration, but because of a high first-pass effect, only about 20-30% is available to the systemic circulation. Patients with significant hepatic dysfunction, may have considerably higherpercentages of the drug bioavailable. Food will decrease the rate and extent of absorption of thesustained-release tablets, but less so with the conventional tablets.
Verapamil's volume of distribution is between 4.5-7 L/kg in humans and has been reported to beapproximately 4.5 L/kg in dogs. In humans, approximately 90% of the drug in the serum is boundto plasma proteins. Verapamil crosses the placenta and milk levels may approach those in theplasma.
Verapamil is metabolized in the liver to at least 12 separate metabolites, with norverapamil beingthe most predominant. The majority of the amount of these metabolites are excreted into the urine.
Only 3-4% is excreted unchanged in the urine. In humans, the half-life of the drug is 2-8 hoursafter a single IV dose, but it can increase after 1-2 days of oral therapy (presumably due to asaturable process of the hepatic enzymes). Serum half-lives of 0.8 hours and 2.5 hours have beenreported in the dog.
Contraindications/Precautions - Verapamil is contraindicated in patients with cardiogenic shockor severe CHF (unless secondary to a supraventricular tachycardia amenable to verapamil therapy), hypotension (<90 mmHg systolic), sick sinus syndrome, 2nd or 3rd degree AV block, digitalis-intoxicated, or if patient is hypersensitive to verapamil.
IV verapamil is contraindicated within a few hours of IV beta-adrenergic blocking agents (e.g., propranolol) as they both can depress myocardial contractility and AV node conduction. Use of thiscombination in patients with wide complex ventricular tachycardia (QRS > 0.11 seconds) can causerapid hemodynamic deterioration and ventricular fibrillation.
Verapamil should be used with caution in patients with heart failure, hypertrophic cardiomyopathy, and hepatic or renal impairment. Toxicity may be potentiated in patients with hepatic dysfunction. Itshould be used very cautiously in patients with atrial fibrillation and Wolf-Parkinson-White(WPW) syndrome as fatal arrhythmias may result.

Adverse Effects, Warnings

While clinical experience with verapamil is limited, the followingadverse reactions may occur: hypotension, bradycardia, tachycardia, exacerbation of CHF, peripheral edema, AV block, pulmonary edema, nausea, constipation, dizziness, headache or fatigue.
Overdosage - Symptoms of overdosage may include bradycardia, hypotension, junctional rhythms, and 2nd or 3rd degree AV block.
If overdose is secondary to a recent oral ingestion, emptying the gut and charcoal administrationmay be considered. Treatment is generally supportive in nature; vigorously monitor cardiac andrespiratory function. Intravenous calcium salts (1 ml of 10% solution per 10 kgs of body weight)have been suggested to treat the negative inotropic symptoms, but may not adequately treatsymptoms of heart block. Use of fluids, and pressor agents (e.g dopamine, norepinephrine, etc)may be utilized to treat hypotensive symptoms. The AV block and/or bradycardia can be treatedwith isoproterenol, norepinephrine, atropine, or cardiac pacing. Patients who develop a rapid ventricular rate after verapamil due to antegrade conduction in flutter/fibrillation with WPW syndrome, have been treated with D.C. cardioversion, lidocaine, or procainamide.

Drug Interactions

beta-adrenergic blockers (e.g., propranolol) and verapamil both are negative cardiac inotropes and chronotropes. If given concurrently, these effects may be additive andsignificantly affect cardiac function.
Verapamil activity may be adversely affected by Vitamin D or calcium salts.
Cimetidine may increase the effects of verapamil.
Verapamil may increase the blood levels of digoxin or digitoxin. Monitoring of "dig" serumlevels recommended if using concurrently.
The neuromuscular blocking effects of nondepolarizing muscle relaxants may be enhanced byverapamil.
Quinidine effects may be altered and hypotension may occur in patients also receiving verapamil.
Rifampin may significantly reduce the effects of oral verapamil; these effects may persist for several days after rifampin is discontinued.
Verapamil may increase serum levels of theophylline and lead to toxicity. Verapamil may displace highly protein bound agents (e.g., warfarin) from plasma proteins.
Calcium channel blockers may increase intracellular vincristine by inhibiting the drug's outflowfrom the cell.