Verapamil (Brand names: Isoptin, Calan, among others) belongs to a group of medicines called calcium channel blockers. The heart muscle and the muscle in the blood vessel walls need calcium to contract and tighten. Verapamil stops calcium from getting into these muscles.
 BRAND NAMES
 MECHANISM OF ACTION
Verapamil is a calcium channel blocker that exerts its pharmacologic effects by modulating the influx of ionic calcium across the cell membrane of the arterial smooth muscle as well as in conductile and contractile myocardial cells.
The mechanism of action of Verapamil as an antianginal agent includes the following two mechanisms:
- Relaxation and prevention of coronary artery spasm: Verapamil dilates the main coronary arteries and coronary arterioles, both in normal and ischemic regions, and is a potent inhibitor of coronary artery spasm. This property increases myocardial oxygen delivery in patients with coronary artery spasm and is responsible for the effectiveness of Verapamil in vasospastic (Prinzmetal's or variant) as well as unstable angina at rest.
- Reduction of oxygen utilization: Verapamil regularly reduces the total peripheral resistance (afterload) against which the heart works both at rest and at a given level of exercise by dilating peripheral arterioles. This unloading of the heart reduces myocardial energy consumption and oxygen requirements and probably accounts for the effectiveness of Verapamil in chronic stable effort angina.
Electrical activity through the AV node depends, to a significant degree, upon calcium influx through the slow channel. By decreasing the influx of calcium, Verapamil prolongs the effective refractory period within the AV node and slows AV conduction in a rate-related manner. This property accounts for the ability of Verapamil to slow the ventricular rate in patients with chronic atrial flutter or atrial fibrillation.
Verapamil exerts antihypertensive effects by decreasing systemic vascular resistance, usually without orthostatic decreases in blood pressure or reflex tachycardia; bradycardia (rate less than 50 beats/min) is uncommon (1.4%).
Type 1 Diabetes:
Researchers from the University of Alabama, Birmingham, found that verapamil completely reversed type 1 diabetes in mice, and they expect to test the drug on humans in 2015. Patients with type 1 Diabetes are unable to produce insulin and the blood is overcome with sugar. In the presence of high blood sugar a protein called TXNIP is overproduced in the pancreas's beta cells, causing their death and inhibiting the body's natural production of insulin. the research showed that, in mouse models, verapamil lowers TXNIP levels in the pancreas's beta cells, leading to the eradication of diabetes in the mice.
- Angina at rest including:
- Vasospastic (Prinzmetal's variant) angina
- Unstable (crescendo, pre-infarction) angina
- Chronic stable angina (classic effort-associated angina)
- In association with digitalis for the control of ventricular rate at rest and during stress in patients with chronic atrial flutter and/or atrial fibrillation
- Prophylaxis of repetitive paroxysmal supraventricular tachycardia
Verapamil is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug.
Initial: 80-120 mg three times a day, increasing at daily or weekly intervals to a maximum of 480 mg/day. However, 40 mg three times a day may be warranted in patients who may have an increased response to verapamil (eg, decreased hepatic function, elderly, etc).
The dosage in digitalized patients with chronic atrial fibrillation ranges from 240 to 320 mg/day in divided (t.i.d. or q.i.d.) doses. The dosage for prophylaxis of PSVT (non-digitalized patients) ranges from 240 to 480 mg/day in divided (t.i.d. or q.i.d.) doses. In general, maximum effects for any given dosage will be apparent during the first 48 hours of therapy
The usual initial monotherapy dose in clinical trials was 80 mg three times a day (240 mg/day). Daily dosages of 360 and 480 mg have been used but there is no evidence that dosages beyond 360 mg provided added effect. Consideration should be given to beginning titration at 40 mg three times per day in patients who might respond to lower doses, such as the elderly or people of small stature. The antihypertensive effects of Verapamil are evident within the first week of therapy. Upward titration should be based on therapeutic efficacy, assessed at the end of the dosing interval.
- Severe left ventricular dysfunction
- Hypotension (systolic pressure less than 90 mm Hg) or cardiogenic shock
- Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker)
- Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker)
- Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (eg, Wolff-Parkinson-White, Lown-Ganong-Levine syndromes) (see WARNINGS)
- Patients with known hypersensitivity to verapamil hydrochloride
 WARNINGS AND PRECAUTIONS
Cytochrome inducers/inhibitors In vitro metabolic studies indicate that verapamil is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9, and CYP2C18. Clinically significant interactions have been reported with inhibitors of CYP3A4 (e.g., erythromycin, ritonavir) causing elevation of plasma levels of verapamil while inducers of CYP3A4 (e.g., rifampin) have caused a lowering of plasma levels of verapamil.
HMG-CoA reductase inhibitors The use of HMG-CoA reductase inhibitors that are CYP3A4 substrates in combination with verapamil has been associated with reports of myopathy/rhabdomyolysis. Co-administration of multiple doses of 10 mg of verapamil with 80 mg simvastatin resulted in exposure to simvastatin 2.5-fold that following simvastatin alone. Limit the dose of simvastatin in patients on verapamil to 10 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required as verapamil may increase the plasma concentration of these drugs.
Aspirin In a few reported cases, co-administration of verapamil with aspirin has led to increased bleeding times greater than observed with aspirin alone.
Grapefruit juice Grapefruit juice may increase plasma levels of verapamil.
Alcohol Verapamil may increase blood alcohol concentrations and prolong its effects.
Beta-blockers Verapamil should not be combined with a beta-blocker due to high risk of bradycardia and heart-block
Digitalis Clinical use of verapamil in digitalized patients has shown the combination to be well tolerated if digoxin doses are properly adjusted. However, chronic verapamil treatment can increase serum digoxin levels by 50% to 75% during the first week of therapy, and this can result in digitalis toxicity. In patients with hepatic cirrhosis, the influence of verapamil on digoxin kinetics is magnified. Verapamil may reduce total body clearance and extrarenal clearance of digitoxin by 27% and 29%, respectively. Maintenance and digitalization doses should be reduced when verapamil is administered, and the patient should be reassessed to avoid over- or under-digitalization. Whenever over-digitalization is suspected, the daily dose of digitalis should be reduced or temporarily discontinued. On discontinuation of CALAN use, the patient should be reassessed to avoid under-digitalization.
Antihypertensive agents Verapamil administered concomitantly with oral antihypertensive agents (e.g., vasodilators, angiotensin-converting enzyme inhibitors, diuretics, beta-blockers) will usually have an additive effect on lowering blood pressure. Patients receiving these combinations should be appropriately monitored. Concomitant use of agents that attenuate alpha-adrenergic function with verapamil may result in a reduction in blood pressure that is excessive in some patients. Such an effect was observed in one study following the concomitant administration of verapamil and prazosin.
- Disopyramide: Until data on possible interactions between verapamil and disopyramide are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration.
- Flecainide: A study in healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects on myocardial contractility, AV conduction, and repolarization. Concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction.
- Quinidine: In a small number of patients with hypertrophic cardiomyopathy (IHSS), concomitant use of verapamil and quinidine resulted in significant hypotension. Until further data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy should probably be avoided.
The electrophysiologic effects of quinidine and verapamil on AV conduction were studied in 8 patients. Verapamil significantly counteracted the effects of quinidine on AV conduction. There has been a report of increased quinidine levels during verapamil therapy.
- Nitrates: Verapamil has been given concomitantly with short- and long-acting nitrates without any undesirable drug interactions. The pharmacologic profile of both drugs and the clinical experience suggest beneficial interactions.
- Lithium: Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil-lithium therapy; lithium levels have been observed sometimes to increase, sometimes to decrease, and sometimes to be unchanged. Patients receiving both drugs must be monitored carefully.
- Carbamazepine: Verapamil therapy may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side effects such as diplopia, headache, ataxia, or dizziness.
- Rifampin: Therapy with rifampin may markedly reduce oral verapamil bioavailability.
- Phenobarbital: Phenobarbital therapy may increase verapamil clearance.
- Cyclosporine: Verapamil therapy may increase serum levels of cyclosporine.
- Theophylline: Verapamil may inhibit the clearance and increase the plasma levels of theophylline.
- Inhalation anesthetics: Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, should each be titrated carefully to avoid excessive cardiovascular depression.
- Neuromuscular blocking agents: Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly.
- Telithromycin: Hypotension and bradyarrhythmias have been observed in patients receiving concurrent telithromycin, an antibiotic in the ketolide class.
- Clonidine: Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with verapamil. Monitor heart rate in patients receiving concomitant verapamil and clonidine.
 PREGNANCY AND LACTATION
Pregnancy Category C (US). Reproduction studies have been performed in rabbits and rats at oral doses up to 1.5 (15 mg/kg/day) and 6 (60 mg/kg/day) times the human oral daily dose, respectively, and have revealed no evidence of teratogenicity. In the rat, however, this multiple of the human dose was embryocidal and retarded fetal growth and development, probably because of adverse maternal effects reflected in reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery.
Nursing mothers: Verapamil is excreted in human milk. Because of the potential for adverse reactions in nursing infants from verapamil, nursing should be discontinued while verapamil is administered.
 SIDE EFFECTS
The following reactions to orally administered verapamil occurred at rates greater than 1.0% or occurred at lower rates but appeared clearly drug-related in clinical trials in 4,954 patients:
|Bradycardia (HR <50/min)||1,4 %|
|AV block total (1°, 2°, 3°)||1,2 %|
|2° and 3°||0,8 %|
 RELATED LINKS
|ACE inhibitors||Benazepril (Lotensin) • Captopril (Capoten) • Cilazapril • Delapril • Enalapril (Renitec, Vasotec) • Fosinopril (Monopril) • Lisinopril (Prinivil, Zestril) • Moexipril (Univasc) • Perindopril (Aceon) • Quinapril (Accupril) • Ramipril (Altace, Triatec) • Trandolapril (Mavik) • Zofenopril (Bifril, Zopranol)|
|Angiotensin II receptor antagonist||Azilsartan (Edarbi) • Candesartan (Atacand) • Eprosartan (Teveten) • Irbesartan (Aprovel, Avapro, Karvea) • Losartan (Cozaar) • Olmesartan (Benicar, Olmetec) • Telmisartan (Micadis) • Valsartan (Diovan, Tareg)|
|Renin inhibitors||Aliskiren (Rasilez, Tekturna)|
|Alpha-1 blockers||Doxazosin (Cardura) • Prazosin (Minipress) • Terazosin (Hytrin)|
|Alpha-2 agonists (centrally acting)||Clonidine (Oral route) • Clonidine (Transdermal) (Catapresan) • Guanfacine (Tenex) • Methyldopa (Aldomet)|
|Calcium channel blockers||Dihydropyridines||Amlodipine (Norvasc) • Barnidipine (Vasexten) • Felodipine (Plendil) • Isradipine (Dynacirc) • Lacidipine (Lacipil, Motens) • Lercanidipine (Zanidip) • Manidipine • Nicardipine • Nifedipine (Adalat) • Nisoldipine • Nitrendipine|
|Benzothiazepine||Diltiazem (Cardizem, Taztia XT, Tiazac, Tildiem)|
|Phenylalkylamine||Gallopamil • Verapamil (Calan)|
|Beta blockers||Beta1 selective (cardioselective)||Acebutolol (Sectral) • Atenolol (Tenormin) • Betaxolol (Kerlon) • Bisoprolol (Concor) • Celiprolol (Cordiax) • Metoprolol (Betaloc, Lopressor, Toprol-XL) • Nebivolol (Bystolic, Lobivon, Nebilox)|
|Nonselective (Beta1 and Beta2 blockers)||Oxprenolol (Trasitensin) • Propranolol (Inderal) • Timolol (Blocadren)|
|Nonselective (Beta1, Beta2 and Alpha1 blockers)||Carvedilol (Dilatrend) • Labetalol (Trandate)|
|Beta blocker with intrinsic sympathomimetic activity (ISA)||Acebutolol (Sectral) • Celiprolol (Cordiax)|
|Lipophilic Beta blockers||Propranolol (Inderal) • Metoprolol (Betaloc, Lopressor, Toprol-XL) • Oxprenolol (Trasitensin)|
|Diuretics||Carbonic anhydrase inhibitors||Acetazolamide (Diamox)|
|Loop diuretics||Bumetanide • Etacrynic acid • Furosemide (Lasix) • Piretanide • Torasemide (Demadex)|
|Thiazide diuretics||Chlorothiazide (Diuril) • Hydrochlorothiazide (Esidrex)|
|Thiazide-like diuretics||Chlortalidone (Hygroton) • Indapamide (Lozol, Lozide) • Metolazone|
|Potassium-sparing diuretics|| Epithelial sodium channel blockers: Amiloride (Midamor) • Triamterene (Dyrenium) |
Aldosterone receptor antagonists: Potassium canrenoate • Eplerenone (Inspra) • Spironolactone (Aldactone)
|Combination therapy||Amiloride/Hydrochlorothiazide (Moduretic) • Spironolactone/Hydrochlorothiazide (Aldactazide)|