Consultant. Vol. 42 No. 13

Calcium Channel Blocker-Drug Interactions: Strategies for Avoiding Untoward Effects

By TIMOTHY H. SELF, PharmD—Series Editor | November 1, 2002

University of Tennessee

Dr Self is professor of clinical pharmacy at the University of Tennessee Health Science Center in Memphis. He has 30 years of experience in a university medical center working with physicians in caring for patients, conducting clinical research, and teaching. He has authored over 200 publications, including more than 120 papers in peer-reviewed medical and clinical pharmacy/pharmacology journals. His clinical research abstracts have been presented at several American Thoracic Society international conferences as well as the American College of Chest Physicians and the American Academy of Asthma, Allergy, and Immunology.

Calcium channel blockers are commonly prescribed to treat several cardiovascular diseases and may be helpful in other conditions, such as migraine and bipolar disorder.¹ These agents are associated with numerous clinically significant drug interactions.^1-3 While some of these interactions, such as the effect of verapamil(Drug information on verapamil) on serum digoxin(Drug information on digoxin) concentrations, are well-known, others are not widely recognized— yet warrant attention.

My aim here is to heighten your awareness of these interactions to ensure optimal management as well as patient safety. I emphasize pharmacokinetic interactions.


	Table 1 —Examples of interactions with diltiazem and verapamil that increase serum concentrations of other drugs*

	Drug		Comment

	Carbamazepine^4,5		Monitor carbamazepine(Drug information on carbamazepine) levels when using this drug with diltiazem or verapamil; carbamazepine levels increase approximately 50%; neurotoxicity has been reported when carbamazepine was taken with diltiazem or verapamil

	Cyclosporine^3,6		Both diltiazem and verapamil can increase cyclosporine levels; some clinicians consider this interaction desirable as a strategy to decrease the cyclosporine dose and reduce cost if a calcium channel blocker is indicated

	Digoxin^7,8		Monitor digoxin levels; anticipate need to reduce digoxin dose (eg, by 50%) within the first week of initiation of verapamil therapy; effect is greater with concurrent cirrhosis; diltiazem may also elevate digoxin levels but usually not to a clinically significant degree

	Methylprednisolone⁹		Diltiazem can greatly increase methylprednisolone(Drug information on methylprednisolone) levels, which can result in adrenocortical suppression; this effect usually becomes clinically significant only during long-term methylprednisolone therapy

	Phenytoin⁵		Monitor phenytoin(Drug information on phenytoin) levels when giving concomitant verapamil or diltiazem; phenytoin toxicity is not as well documented as carbamazepine toxicity but is possible

	Quinidine¹⁰		Monitor quinidine(Drug information on quinidine) levels; interaction with verapamil causes a 33% decrease in oral quinidine clearance

	Statins (HMG-CoA reductase inhibitors)^11-16		Diltiazem and verapamil increase serum concentrations of simvastatin(Drug information on simvastatin)/simvastatin reductase inhibitors)11-16 acid; diltiazem also increases lovastatin(Drug information on lovastatin) levels; rarely, rhabdomyolysis has been reported; use low doses of simvastatin (20 mg) when diltiazem or verapamil is given concurrently; monitor creatine kinase levels and be alert for muscle tenderness; pravastatin(Drug information on pravastatin) does not interact with diltiazem or verapamil

	Tacrolimus¹⁷		Monitor tacrolimus(Drug information on tacrolimus) levels; anticipate need to reduce dose†

	Theophylline^3,18		Usually not clinically significant; monitor theophylline(Drug information on theophylline) levels, especially if these levels are in the upper therapeutic range when verapamil or diltiazem is started

	Triazolam¹⁹		Increased triazolam(Drug information on triazolam) levels and sedative effects; avoid combination therapy†

	HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A. *Examples only; consult references cited and drug interaction texts for further information. †This interaction has been documented with diltiazem; additional studies of interaction with verapamil are required.

INHIBITION OF DRUG METABOLISM
Diltiazem and verapamil inhibit the metabolism of several drugs; exam- ples of these interactions are listed in Table 1. These 2 calcium channel blockers inhibit the cytochrome P-450 isoenzyme CYP 3A4^1,2as well as drug transport via P-glycoprotein. The latter effect results in increased serum concentrations of drugs such as digoxin. Dihydropyridine calcium channel blockers (eg, nifedipine(Drug information on nifedipine)) generally do not inhibit the metabolism of other drugs.


	Table 2 — Examples of drug interactions that decrease calcium channel blocker levels*

	Drug		Comment

	Anticonvulsants^20-22		Serum felodipine(Drug information on felodipine) and nisoldipine(Drug information on nisoldipine) concentrations dramatically reduced in patients receiving phenytoin; felodipine levels also decreased with carbamazepine and phenobarbital(Drug information on phenobarbital); avoid these combinations if possible; anticipate need for higher doses of felodipine or nisoldipine and monitor response to therapy if phenytoin, carbamazepine, or phenobarbital must be given concurrently; possible reduction in verapamil concentrations caused by phenytoin requires further investigation

	Rifampin²³		Verapamil and diltiazem serum concentrations are dramatically reduced (below the level of detection) for typical oral dosage range; nifedipine levels and pharmacologic effects are also greatly reduced†; other appropriate cardiovascular agents are preferred when rifampin is required

	*Examples only; consult references cited and drug interaction texts for further information. †Studies of interaction with other dihydropyridines are needed; anticipate that the effect of the calcium channel blocker will be markedly decreased because of rifampin.


	Table 3 — Examples of drug interactions that increase calcium channel blocker levels*

	Drug		Comment

	Cimetidine^1,2		Monitor for heightened effects, especially with dihydropyridine calcium channel blockers; in some patients, the dose of the calcium channel blocker may need to be reduced

	Erythromycin²⁴		Felodipine levels increase; monitor blood pressure and be alert for adverse effects; anticipate need to reduce felodipine dose; note that grapefruit juice or unprocessed grapefruit also raises felodipine levels, especially in elderly patients^25-27

	Itraconazole²⁸		Felodipine levels increase; monitor blood pressure and heart rate; anticipate need to reduce dose of felodipine or other dihydropyridines with concurrent administration of itraconazole(Drug information on itraconazole) and possibly other azole antifungals (eg, ketoconazole(Drug information on ketoconazole) and nisoldipine²⁹)

	*Examples only; consult references cited and drug interaction texts for further information.

EFFECTS OF OTHER DRUGS ON CALCIUM CHANNEL BLOCKERS
Inducers of drug metabolism, such as rifampin, increase the clearance of verapamil, diltiazem, and dihydropyridine calcium channel blockers (Table 2).^1,2 On the other hand, inhibitors of drug metabolism (eg, erythromycin(Drug information on erythromycin)) may decrease the clearance of calcium channel blockers (Table 3)^.1,2

PHARMACODYNAMIC INTERACTIONS
Although the emphasis here is on pharmacokinetic interactions, pharmacodynamic interactions also deserve mention. Abernethy and Schwartz¹ have provided a useful summary of pharmacodynamic interactions.

If other cardiovascular drugs are used concomitantly with calcium channel blockers, be alert for additive pharmacologic effects. For example, the use of verapamil or diltiazem concurrently with amiodarone(Drug information on amiodarone) inhibits atrioventricular conduction and sinusnode function more than therapy with either calcium channel blocker alone.

REFERENCES:
1. Abernethy DR, Schwartz JB. Calcium-antagonist drugs. N Engl J Med. 1999;341:1447-1457.
2. Flockhart DA, Tanus-Santos JE. Implications of cytochrome P450 interactions when prescribing medication for hypertension. Arch Intern Med. 2002;162: 405-412.
3. Hunt BA, Self TH, Lalonde RL, Bottorff MB. Calcium channel blockers as inhibitors of drug metabolism. Chest. 1989;96:393-399.
4. Brodie MJ, MacPhee GJA. Carbamazepine neurotoxicity precipitated by diltiazem. Br Med J. 1986;292: 1170-1171.
5. Bahls FH, Ozuna J, Ritchie DE. Interactions between calcium channel blockers and the anticonvulsants carbamazepine and phenytoin. Neurology. 1991;41:740-742.
6. Lindholm A, Henricsson S. Verapamil inhibits cyclosporin metabolism. Lancet. 1987;1:1262-1263.
7. Schwartz JB, Keefe D, Kates RE, et al. Acute and chronic pharmaodynamic interaction of verapamil and digoxin in atrial fibrillation. Circulation. 1982;65: 1163-1170.
8. Verschraagen M, Koks CH, Schellens JH, Beijnen JH. P-glycoprotein system as a determinant of drug interactions: the case of digoxin-verapamil. Pharmacol Res. 1999;40:301-306.
9. Varis T, Backman JT, Kivisto KT, Neuvonen PJ. Diltiazem and mibefradil increase the plasma concentrations and greatly enhance the adrenal suppressant effect of oral methylprednisolone. Clin Pharmacol Ther. 2000;67:215-221.
10. Edwards DJ, Lavoie R, Beckman H, et al. The effect of coadministration of verapamil on the pharmacokinetics and metabolism of quinidine. Clin Pharmacol Ther. 1987;41:68-73.
11. Kantola T, Kivisto KT, Neuvonen PJ. Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther. 1998;64:177-182.
12. Mousa O, Brater C, Sundblad KJ, Hall SD. The interaction of diltiazem with simvastatin. Clin Pharmacol Ther. 2000;67:267-274.
13. Yeo KR, Yeo WW, Wallis EJ, Ramsay LE. Enhanced cholesterol reduction by simvastatin in diltiazem- treated patients. Br J Clin Pharmacol. 1999;48: 610-615.
14. Peces R, Pobes A. Rhabdomyolysis associated with concurrent use of simvastatin and diltiazem. Nephron. 2001;89:117-118.
15. Kanathur N, Mathai MG, Byrd RP, et al. Simvastatin-diltiazem drug interaction resulting in rhabdomyolysis and hepatitis. Tenn Med. 2001;94:339-341.
16. Azie NE, Brater DC, Becker PA, et al. The interaction of diltiazem with lovastatin and pravastatin. Clin Pharmacol Ther. 1998;64:369-377.
17. Hebert MF, Lam AY. Diltiazem increases tacrolimus concentrations. Ann Pharmacother. 1999;33:680-682.
18. Sirmans SM, Pieper JA, Lalonde RL, et al.
Effect of calcium channel blockers on theophylline disposition. Clin Pharmacol Ther. 1988;44:29-34.
19. Kosuge K, Nishimoto M, Kimura M, et al. Enhanced effect of triazolam with diltiazem. Br J Clin Pharmacol. 1997;43:367-372.
20. Capewell S, Freestone S, Critchley JA, et al. Reduced felodipine bioavailability in patients taking anticonvulsants. Lancet. 1988;2:480-482.
21. Michelucci R, Cipolla G, Passarelli D, et al. Reduced plasma nisoldipine concentrations in phenytointreated patients with epilepsy. Epilepsia. 1996;37:1107- 1110.
22. Woodcock BG, Kirsten R, Nelson K, et al. A reduction in verapamil concentrations with phenytoin. N Engl J Med. 1991;325:1179.
23. Strayhorn VA, Baciewicz AM, Self TH. Update on rifampin interactions III. Arch Intern Med. 1997;157: 2453-2458.
24. Bailey DG, Bend JR, Arnold JM, et al. Erythromycin-felodipine interaction: magnitude, mechanism, and comparison with grapefruit juice. Clin Pharmacol Ther. 1996;60:25-33.
25. Lundahl J, Regardh CG, Edgar B, Johnsson G. Effects of grapefruit juice ingestion—pharmacokinetics and hemodynamics of intravenously and orally administered felodipine in healthy men. Eur J Clin Pharmacol. 1997;52:139-145.
26. Dresser GK, Bailey DG, Carruthers SG. Grapefruit juice–felodipine interaction in the elderly. Clin Pharmacol Ther. 2000;68:28-24.
27. Bailey DG, Dresser GK, Dreeft JH, et al. Grapefruit- felodipine interaction: effect of unprocessed fruit and probable active ingredients. Clin Pharmacol Ther. 2000;68:468-477.
28. Jalava K, Olkkola KT, Neuvonen PJ. Itraconazole greatly increases plasma concentrations and effects of felodipine. Clin Pharmacol Ther. 1997;61: 410-415.
29. Heinig R, Adelmann HG, Ahr G. The effect of ketoconazole on the pharmacokinetics, pharmacodynamics and safety of nisoldipine. Eur J Clin Pharmacol. 1999;55:57-60.

BLOG FOR CONSULTANTLIVE

Send us your blogs! Contact us for more information if you are interested in writing a post or becoming a blogger.

TOPIC INDEX

Developmental/Genetic

Nutritional/Metabolic

ABOUT OUR BLOGGERS

	On Health and Mental Health Erik R. Vanderlip, MD, is a senior fellow and acting instructor in the University of Washington Department of Psychiatry. As a dually-trained family physician and psychiatrist, Dr Vanderlip is active in national health system redesign efforts with a particular interest in newer models of the medical home. He practices family medicine in a hybrid primary care clinic within a mental health center in Seattle.
	The HIV-AIDS Observer Rodger D. MacArthur, MD, is Professor of Medicine, Wayne State University, Department of Internal Medicine, Division of Infectious Diseases and Director and Site Principal Investigator, Wayne State University HIV/AIDS Clinical Research Unit.
	Speaking of Pain Steven A. King, MD, MS, is in the private practice of pain medicine in New York, and he is Clinical Professor of Psychiatry at the New York University School of Medicine, New York.
	Tales Doctors Tell David T Nash, MD, is Clinical Professor of Medicine at Upstate Medical Center in Syracuse, New York. The author of more than 250 peer-reviewed clinical articles, Dr Nash has practiced cardiology in Syracuse for over 50 years. He is a Fellow of the National Lipid Association.
	Primary Care Matters Gregory W. Rutecki, MD, is Professor of Medicine at the University of South Alabama College of Medicine in Mobile. He is section editor of the hypertension topic center on this web site.
	Practice Makes Perfect Pamela Wible, MD, pioneered the first community-designed ideal medical clinic in America. An expert in patient-centered care, Dr Wible helps citizens design cutting-edge clinics and hospitals nationwide. Her model is taught in medical schools and featured in Harvard School of Public Health's newest edition of Renegotiating Health Care. Dr. Wible is a medical reporter for the Oregonian, has been interviewed by CNN, ABC, CBS, and is a frequent guest on NPR.

FROM PHYSICIANS PRACTICE

Five Steps to Improving Patient Access
Judy Capko, May 21, 2013
Patient access is getting increased attention through reform initiatives. Here are five steps you can take to make sure patients get appropriate access to care in your office.

Growing HIPAA Threat – Ignore Windows XP at Your Own Peril
Marion K. Jenkins, May 21, 2013
Chances are good that you have some major ticking software time bombs lurking in your medical practice's computer environment, namely Windows XP and Server 2003.

Finding Physician Work-Life Balance in the Small Moments
Jennifer Frank, MD, May 21, 2013
At my practice and at home, things are always busy. There's laundry or homework, or a patient with needs.

Three Areas to Reduce Costs at Your Medical Practice
Greg Mertz, May 19, 2013
By taking a hard look at reducing costs for staffing, overhead, and technology at your medical practice, you may see increased physician compensation.

Dos and Don’ts for Starting a Physician Blog
Michael Woo-Ming, MD, May 18, 2013
Starting a physician blog can provide your medical practice with marketing benefits, but it's important to do it right.

Calcium Channel Blocker-Drug Interactions: Strategies for Avoiding Untoward Effects

Join the Conversation