Summary
Synopsis
Although verapamil is a well-established treatment for angina, cardiac arrhythmias and cardiomyopathies, this review reflects current interest in calcium antagonists as antihypertensive agents by focusing on the role of verapamil in hypertension. Verapamil is a phenylalkylamine derivative which antagonises calcium influx through the slow channels of vascular smooth muscle and cardiac cell membranes. By reducing intracellular free calcium concentrations, verapamil causes coronary and peripheral vasodilation and depresses myocardial contractility and electrical activity in the atrioventricular and sinoatrial nodes. Verapamil is well suited for the management of essential hypertension since it produces generalised systemic vasodilation resulting in a marked reduction in systemic vascular resistance and, consequently, blood pressure.
Evidence from clinical studies supports the role of oral verapamil as an effective and well-tolerated first-line treatment for the management of patients with mild to moderate essential hypertension. Clinical studies have shown that verapamil is more effective the higher the pretreatment blood pressure and some authors have found a more pronounced antihypertensive effect in older patients or in patients with low plasma renin activity. Sustained release verapamil formulations are available for oral administration which, as a single daily dose, are as effective in lowering blood pressure over 24 hours as equivalent doses of conventional verapamil formulations given 3 times daily.
As a first-line antihypertensive agent, oral verapamil is equivalent to several other calcium antagonists, β-blockers, diuretics, angiotensin-converting enzyme (ACE) inhibitors and other vasodilators, and is not associated with many of the common adverse effects of these treatments. Verapamil may be preferred as an alternative first-line antihypertensive treatment to diuretics in elderly patients because it has similar efficacy in these patients without causing the adverse effects commonly linked with diuretic treatment. Furthermore, because verapamil does not cause bronchoconstriction, it may be used in preference to β-blockers in patients with asthma or chronic obstructive airway disease. Reflex tachycardia, orthostatic hypotension or development of tolerance is not evident following verapamil administration. As a second- or third-line treatment for patients refractory to established antihypertensive regimens, verapamil produces marked blood pressure reductions when combined with diuretics and/or ACE inhibitors, β-blockers and vasodilators such as prazosin. Combined treatment with β-blockers may produce severe cardiac depression, particularly if intravenous doses of each drug are used and should not be initiated in patients with existing myocardial depression.
Adverse effects occur in about 9% of all patients treated with verapamil and necessitate withdrawal of treatment in about 1%. Constipation, the most common adverse effect, has been reported in up to 38% of patients in clinical trials, but only 2% of patients receiving verapamil require withdrawal of treatment as a result of this effect. Peripheral oedema, flushing, dizziness and headache are manifestations of verapamil’s vasodilatory effects and are usually minor and rare. Cardiovascular adverse effects occur in less than 1% of hypertensive patients and include bradycardia, hypotension and palpitations.
Thus, clinical evidence to date suggests that verapamil is an effective and well-tolerated first-line antihypertensive treatment and, in addition, offers substantial clinical benefits as a second- or third-line treatment in refractory hypertension.
Pharmacodynamic Properties
Like other calcium antagonists, verapamil inhibits the slow inward current of calcium in normal cardiac tissues, and in the atrioventricular and sinoatrial nodes. Electrophysiological studies have shown that oral and intravenous verapamil prolong conduction through the atrioventricular node by up to 33% without impeding intra-atrial or intraventricular conduction. Although in patients with abnormal sinus node function verapamil may cause sinus arrest or sinoatrial block, the drug has little effect on normal sinus rhythm.
In hypertensive patients, oral and intravenous doses of verapamil lower mean arterial blood pressure at rest and after exercise. However, oral verapamil does not usually have a blood pressure lowering effect in normotensive subjects. Following a single 160mg oral dose maximum antihypertensive effects are seen after about 1.5 to 2 hours and may last for at least 4 hours. Intravenous verapamil 5 to 10mg produces an immediate reduction in blood pressure which is maintained for about 10 minutes in hypertensive patients.
This marked antihypertensive effect is achieved primarily by peripheral vasodilation via a reduction in systemic vascular resistance. Most studies have shown that the fall in systemic vascular resistance is not associated with a change in cardiac output because of the counterbalancing negative inotropic and chronotropic effects of verapamil. However, in patients with heart failure (left ventricular ejection fraction < 35%) the vasodilating action of verapamil may not be sufficient to overcome its negative inotropic and chronotropic effects, resulting in decreased cardiac output.
Verapamil does not appear to significantly alter heart rate compared with β-blockers, which decrease heart rate, and dihydropyridine calcium antagonists such as nifedipine and nicardipine, which have been shown to increase heart rate.
Intravenous verapamil reduces coronary vascular resistance by about 24% in patients with coronary artery disease, by dilating both large and small coronary vessels. Thus coronary blood flow is increased, providing a potential benefit for such patients.
Verapamil has a variable effect on hepatic blood flow and portal pressure. Verapamil inhibits platelet aggregation induced by collagen, adrenaline (epinephrine) and adenosine diphosphate (ADP) but has little or no effect on renal function, plasma lipid concentrations or the secretion of glucose regulatory hormones.
Pharmacokinetic Properties
Peak plasma verapamil concentrations of up to 336 µg/L are achieved within 1 to 2 hours of single oral doses of conventional verapamil 80 to 160mg in healthy volunteers but may be delayed up to 8 hours or more after a single oral dose of a sustained release preparation. However, similar mean plasma concentrations are achieved after equivalent daily doses of conventional and sustained release verapamil formulations, and bioavailability of sustained release verapamil formulations approaches that of conventional formulations.
Mean peak plasma concentration was 168 µg/L 1.2 hours after a single 80 or 120mg dose of conventional verapamil in hypertensive patients and 753 µg/L after 4 weeks of twice daily administration of conventional verapamil 120 to 240mg.
Although in both healthy volunteers and hypertensive patients over 90% of a single oral verapamil dose is absorbed, systemic bioavailability of the drug is limited to about 20% because of extensive first-pass hepatic extraction. Bioavailability is approximately doubled after repeated dosing, and is considerably increased in patients with hepatic cirrhosis but is unchanged in patients with renal failure.
Verapamil is widely distributed throughout the body, with an apparent volume of distribution in volunteers of 113 to 418L and 257 to 406L following intravenous and oral administration, respectively. Volume of distribution is further increased in various disease states such as liver cirrhosis. Verapamil is approximately 90% bound to plasma proteins and binding is independent of plasma concentration over a range of 35 to 1557 µg/L.
The primary metabolic pathways of verapamil are N-dealkylation and O-demethylation. The contribution of metabolites to the overall pharmacological effect is minimal as most metabolites are excreted as inactive conjugates. Norverapamil has about 20% of the pharmacological activity of the parent drug. Only 3% of a single verapamil dose is excreted in urine as unchanged drug, while approximately 70% of a single dose is excreted as metabolites in urine and 15% in faeces.
Verapamil clearance is subject to considerable interindividual variation and, as expected for a drug that undergoes extensive first-pass hepatic metabolism, clearance is reduced in patients with hepatic disease, and also in elderly patients. During chronic oral dosing with conventional verapamil formulations in volunteers and hypertensive patients verapamil clearance is reduced, with a corresponding increase in elimination half-life. The reasons for accumulation of verapamil during long term oral administration are not clear but a decrease in first-pass hepatic metabolism appears likely. It is evident that single dose pharmacokinetic data have limited use in predicting steady-state plasma verapamil concentrations.
Therapeutic Trials
In placebo-controlled studies, conventional or sustained release verapamil formulations administered in daily oral doses of 160 to 480mg consistently lower supine, standing and sitting blood pressures by up to 20% in patients with mild to moderate essential hypertension. 24-Hour blood pressure control is similar after 2 or 3 daily doses of a conventional verapamil formulation or a single dose of a sustained release formulation.
In comparative studies, verapamil has an equivalent effect on blood pressure to traditional first-line antihypertensive treatments. Compared with β-blockers, oral verapamil titrated from 240 to 480 mg/day is at least as efficacious as propranolol 80 to 480 mg/day, atenolol 50 to 100 mg/day, metoprolol 100 to 200 mg/day or pindolol 15 mg/day. During exercise, verapamil and propranolol have similar effects on blood pressure; both lower blood pressure without altering the pressor response to exercise but only propranolol decreases exercise tolerance in hypertensive patients.
Although data is limited, studies comparing the drug with diuretics provide evidence for the use of verapamil as an alternative first-line treatment, particularly in elderly hypertensive patients and in patients with low plasma renin activity. One study has shown that sustained release verapamil has similar antihypertensive efficacy to daily doses of bemetizide 25mg plus triamterene 50mg, hydrochlorothiazide 50mg plus amiloride 5mg, or thiabutazide 2.5mg plus spironolactone 25mg. Another 4-week study has shown that a conventional verapamil formulation at a dose of 320 mg/day reduces supine blood pressure by 26/18mm Hg, compared with bendrofluazide 5 mg/day which reduced blood pressure by 14/8mm Hg in hypertensive patients.
The antihypertensive effect of verapamil compares favourably with that of other calcium antagonists such as nicardipine, diltiazem, nifedipine and nitrendipine, and with other antihypertensive agents such as methyldopa or prazosin. However, comparative clinical trials with verapamil and other calcium antagonists such as felodipine, nisoldipine and isradipine are required to clarify the efficacy of verapamil in hypertension.
In patients refractory to traditional antihypertensive regimens, verapamil is an effective second-line treatment. For example, in patients with moderate to severe hypertension refractory to captopril 100 mg/day monotherapy, the addition of verapamil 320 mg/day significantly reduced systolic and diastolic blood pressures. Similarly, combined verapamil and prazosin treatment reduced blood pressure by up to 30/13mm Hg compared with either drug given alone, while treatment with a verapamil/chlorthalidone combination reduced diastolic blood pressure to below 95mm Hg in patients refractory to verapamil monotherapy. Although the antihypertensive effect of verapamil and a β-blocker is beneficial in hypertensive patients, this treatment combination should be avoided in patients with impaired cardiac function because of the risk of severe cardiac depression or asystole.
Verapamil also has a beneficial effect as a third-line antihypertensive treatment. In patients with severe hypertension refractory to their existing treatment with a diuretic and ACE inhibitor, blood pressure fell by 37/22mm Hg after at least 7 months of triple therapy with an ACE inhibitor, diuretic and verapamil.
Verapamil has been used with varying success in other hypertensive states. Patients with pulmonary hypertension had reduced pulmonary arterial pressure and vascular resistance after orally or intravenously administered verapamil, but adverse effects on right ventricular function have also been reported. In patients with hypertension and angina pectoris, oral verapamil 480 mg/day has a similar antianginal and antihypertensive effect to propranolol 320 mg/day. Verapamil has also been shown to be effective in hypertension secondary to renal disease, in hypertension in pregnancy, and as an intravenous formulation in hypertensive crises.
Adverse Effects
The overall incidence of adverse effects associated with verapamil treatment is about 9% and treatment is withdrawn in approximately 1% of patients. In over 4200 hypertensive patients treated with sustained release verapamil 240 to 480 mg/day, adverse effects were reported in 11.3% of patients and treatment was withdrawn in 3.2% of patients. The most common adverse effect in verapamil-treated patients is constipation which occurs in up to 37.6% of patients, but this is rarely serious and necessitates withdrawal of treatment in approximately 2% of treated patients. Other non-cardiac adverse effects which occurred in hypertensive patients treated with verapamil are headache (1.5%), dizziness (3.7%), fatigue (1%), flushing (1%) and nausea (1%). Cardiac adverse effects (bradycardia, palpitations and orthostatic hypotension) occurred in less than 1% of hypertensive patients; however cardiac adverse effects including first- and second-degree heart block, ventricular fibrillation and conduction disturbances have been reported during verapamil treatment for other cardiac disorders. Cardiac conduction disturbances are more common in patients with severely impaired cardiac function, of in patients receiving recent or concurrent β-blocker therapy.
Other adverse effects which have occurred infrequently and have a possible causal relationship to verapamil treatment include impotence, hepatotoxicity, central nervous system disorders and skin disorders. The abrupt withdrawal of verapamil after long term treatment was not associated with a rebound phenomenon in over 400 patients who had suffered a recent myocardial infarction and were treated for 6 months with oral verapamil.
Dosage and Administration
In patients with essential hypertension oral verapamil as a conventional formulation should be started at 80mg 3 times daily and titrated up to 160mg 3 times daily. Lower doses, starting at 40mg 3 times daily, may be used in elderly patients and in patients with hepatic dysfunction. The manufacturers’ recommended daily dose of oral sustained release verapamil preparations for the treatment of hypertension is 240mg once daily, although sometimes 120mg once daily may be sufficient in elderly patients. In general, doses are titrated up to 480 mg/day in 2 divided doses, but higher doses (up to 720 mg/day) have been used in some patients.
Intravenous verapamil 5 to 10mg (0.075 to 0.15 mg/kg bodyweight) administered over 2 minutes is recommended if an immediate antihypertensive effect in adults is required. If necessary, 5 to 10 mg/h can be administered via a drip infusion. Intravenous doses of 0.1 to 0.3 mg/kg bodyweight are recommended in patients aged under 15 years.
Intravenous verapamil should not be administered within a few hours of an intravenous β-blocker because of the risk of cardiac depression. Oral combination treatment with β-blocking agents has been administered without causing severe adverse effects in patients with preserved cardiac function.
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Various sections of the manuscript reviewed by: L. Corea, Cardiology Clinic, University of Perugia, Perugia, Italy; L.X. Cubeddu, Division of Clinical Pharmacology, University of North Carolina, Chapel Hill, North Carolina, USA; A. Doyle, Department of Medicine, University of Melbourne, Fitzroy, Victoria, Australia; W.H. Frishman, Montefiore Medical Center, Jack D. Weiler Hospital of the Albert Einstein College of Medicine, Bronx, New York, USA; J.S. Horvath, Renal and Hypertension Unit, Royal Prince Albert Hospital, Camperdown, New South Wales, Australia; C. Kawai, Faculty of Medicine, Kyoto University, Kyoto, Japan; J. Lam, Institute of Cardiology of Montréal, Montréal, Québec, Canada; G.R.J. Lewis, Napier Hospital, Napier, New Zealand; Y. Nakamura, Faculty of Medicine, Kyoto University, Kyoto, Japan; E.B. Raftery, Northwick Park Hospital and Clinical Research Centre, Harrow, Middlesex, England; J. van Harten, Centre for Bio-Pharmaceutical Sciences, Division of Pharmacology, Sylvius Laboratories, Leiden, The Netherlands.
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McTavish, D., Sorkin, E.M. Verapamil. Drugs 38, 19–76 (1989). https://doi.org/10.2165/00003495-198938010-00003
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DOI: https://doi.org/10.2165/00003495-198938010-00003