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Interaction Detail
Warning:
Concurrent use of VERAPAMIL and BETA-ADRENERGIC BLOCKERS may result in hypotension, bradycardia.

Clinical Management:
If concurrent therapy is required, monitor cardiac function and blood pressure carefully, particularly in patients predisposed to heart failure.

Onset:
Rapid

Severity:
Major

Documentation:
Good

Probable Mechanism:
additive cardiovascular effects, decreased metabolism of some beta blockers

Summary:
Verapamil and beta blockers both have direct negative inotropic effects, slow AV conduction, and will possibly potentiate hypotension, bradycardia, congestive heart failure, and conduction abnormalities (Prod Info Covera HS, 2003). Cardiac risk is increased by left ventricular dysfunction, aortic stenosis, or large doses of either drug (McCourty et al, 1988; Zatuchni, 1985; Winniford et al, 1985). The reaction has occasionally been reported with ophthalmic beta blockers (Pringle & MacEwen, 1987). Pharmacokinetic interactions observed have generally not been of a clinically significant magnitude.

Literature:
Adverse effects that may occur with combined verapamil and beta blocker therapy are often associated with conduction problems (9% of patients), dyspnea or heart failure (8% of patients), hypotension or dizziness (5% of patients), and lethargy (2% of patients). The cardiovascular adverse effects led to treatment withdrawal in 5% to 8% of patients who received the combination. Intravenous verapamil combined with beta blocker therapy is contraindicated, and oral verapamil combined with beta blocker therapy should only be used in patients who do not have impaired left ventricular function (Brouwer et al, 1985). Pharmacodynamic interactions with propranolol, atenolol, metoprolol, and pindolol have been reported, with the most marked effects occurring with propranolol (Bailey & Carruthers, 1991; Keech et al, 1988). It is likely that such interactions may occur with all beta blocking drugs, particularly in at-risk patients. Concomitant therapy with oral atenolol and oral verapamil resulted in increased steady-state atenolol plasma levels in some patients during chronic oral maintenance therapy. More than a 100% increase in the atenolol area under the concentration-time curve (AUC) was observed in some of the ten patients in the study. However, the group comparisons did not achieve statistical significance (Keech et al, 1988). An interaction with metoprolol has also been reported (Keech et al, 1986). No significant pharmacokinetic interaction was seen between verapamil and propranolol (Murdoch et al, 1991). Nine healthy volunteers received single oral doses of R-verapamil 120 mg or placebo with talinolol 50 mg during a randomized, crossover study. Coadministration of R-verapamil decreased the maximum concentration (Cmax) of
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talinolol from 149 ng/mL to 95 ng/mL and also decreased the area under the concentration-time curve (AUC) from 0 to 24 hours from 945 ng/h/mL to 721 ng/h/mL. The renal clearance of talinolol remained unaffected. Verapamil is extensively metabolized and is a substrate of both P-glycoprotein and cytochrome P450 3A isoenzymes. Talinolol is also a P-glycoprotein substrate. The ability of verapamil to decrease the oral bioavailability of talinolol is most likely dose dependent (Schwarz et al, 1999). A 72-year-old female developed intractable cardiogenic shock during combination therapy with verapamil and atenolol for recurrent supraventricular arrhythmia. The patient had coronary atherosclerosis, liver cirrhosis, and bradycardia-tachycardia syndrome. A pacemaker was implanted and verapamil therapy was subsequently initiated. Cardiogenic shock was triggered with the addition of atenolol to her treatment regimen two weeks after implantation. An unsuccessful attempt was made to increase aortic pressure by high dose catecholamines and counterpulsation. Immediate elevation of aortic pressure occurred after intravenous administration of calcium chloride. The patient recovered and was discharged two weeks later (Sakurai et al, 2000). Both verapamil and beta-blockers have direct negative inotropic effects, slow AV conduction, and can potentiate hypotension, bradycardia, congestive heart failure, and conduction abnormalities (Prod Info Betagon, 2000).

Reference(s):
Bailey DG & Carruthers SG: Interaction between oral verapamil and beta-blockers during submaximal exercise: relevance of ancillary properties. Clin Pharmacol Ther 1991; 49:370-376. Brouwer RM, Follath F & Buhler FR: Review of the cardiovascular adversity of the calcium antagonist beta-blocker combination: implications for antihypertensive therapy. J Cardiovasc Pharmacol 1985; 7(suppl 4):S38-S44. Keech AC, Harper RW, Harrison PM et al: Extent and pharmacokinetic mechanisms of oral atenolol-verapamil interaction in man. Eur J Clin Pharmacol 1988; 35:363-366. Keech AC, Harper RW, Harrison PM et al: Pharmacokinetic interactions between oral metoprolol and verapamil for angina pectoris. Am J Cardiol 1986; 58:551-552. McCourty JC, Silas JH, Tucker GT et al: The effect of combined therapy on the pharmacokinetics and pharmacodynamics of verapamil and propranolol in patients with angina pectoris. Br J Clin Pharmacol 1988; 25:349-357. Murdoch DL, Thomson GD, Thompson GG et al: Evaluation of potential pharmacodynamic and pharmacokinetic interactions between verapamil and propranolol in normal subjects. Br J Clin Pharmacol 1991; 31:323-332. Pringle SD & MacEwen CJ: Severe bradycardia due to interaction of timolol eye drops and verapamil. Br Med J Clin Res Ed 1987; 294:155-156. Product Information: Betagon(R), mepindolol. Schering S.p.A., Milan, Italy, 01/2000. Product Information: Covera HS(R), verapamil. Pharmacia Corporation, Chicago, IL, 03/2003. Sakurai H, Kei M, Matsubara K et al: Cardiogenic shock triggered by verapamil and atenolol - a case report of therapeutic experience with intravenous calcium. Jpn Circ J 2000; 64:893-896. Schwarz UI, Gramatte T, Krappweis J et al: Unexpected effect of verapamil on oral bioavailability of the betablocker talinolol in humans. Clin Pharmacol Ther 1999; 65:283-290. Winniford MD, Fulton KL & Hillis LD: Symptomatic sinus bradycardia during concomitant propranolol-verapamil administration. Am Heart J 1985; 110:498. Zatuchni J: Bradycardia and hypotension after propranolol HCl and verapamil. Heart Lung 1985; 14:94-95. Copyright 2013 Truven Health Analytics Inc.

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