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

November 1, 2002

Article

Calcium channel blockersare commonly prescribedto treat severalcardiovascular diseasesand may be helpful inother conditions, such as migraineand bipolar disorder.1 These agentsare associated with numerous clinicallysignificant drug interactions.1-3While some of these interactions,such as the effect of verapamil onserum digoxin concentrations, arewell-known, others are not widely recognized-yet warrant attention.

Calcium channel blockersare commonly prescribedto treat severalcardiovascular diseasesand may be helpful inother conditions, such as migraineand bipolar disorder.¹ These agentsare associated with numerous clinicallysignificant drug interactions.^1-3While some of these interactions,such as the effect of verapamil onserum digoxin concentrations, arewell-known, others are not widely recognized-yet warrant attention.

My aim here is to heighten yourawareness of these interactions to ensureoptimal management as well aspatient safety. I emphasize pharmacokineticinteractions.

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

Drug

Comment

Carbamazepine

Monitor 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

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

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

Methylprednisolone

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

Phenytoin

Monitor phenytoin levels when giving concomitant verapamil or diltiazem; phenytoin toxicity is not as well documented as carbamazepine toxicity but is possible

Quinidine

Monitor quinidine levels; interaction with verapamil causes a 33% decrease in oral quinidine clearance

Statins (HMG-CoA reductase inhibitors)

Diltiazem and verapamil increase serum concentrations of simvastatin/simvastatin reductase inhibitors)11-16 acid; diltiazem also increases 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 does not interact with diltiazem or verapamil

Tacrolimus

Monitor tacrolimus levels; anticipate need to reduce dose†

Theophylline

Usually not clinically significant; monitor theophylline levels, especially if these levels are in the upper therapeutic range when verapamil or diltiazem is started

Triazolam

Increased 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 OFDRUG METABOLISM
Diltiazem and verapamil inhibitthe metabolism of several drugs; exam-ples of these interactions are listed inTable 1. These 2 calcium channelblockers inhibit the cytochrome P-450isoenzyme CYP 3A4^1,2as well as drugtransport via P-glycoprotein. The lattereffect results in increased serum concentrationsof drugs such as digoxin.Dihydropyridine calcium channel blockers(eg, nifedipine) generally do not inhibitthe metabolism of other drugs.

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

Drug

Comment

Anticonvulsants

Serum felodipine and nisoldipine concentrations dramatically reduced in patients receiving phenytoin; felodipine levels also decreased with carbamazepine and 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

Rifampin

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

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

Erythromycin

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

Itraconazole

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

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

EFFECTS OF OTHER DRUGSON CALCIUM CHANNELBLOCKERS
Inducers of drug metabolism,such as rifampin, increase the clearanceof verapamil, diltiazem, and dihydropyridinecalcium channel blockers(Table 2).^1,2 On the other hand,inhibitors of drug metabolism (eg,erythromycin) may decrease theclearance of calcium channel blockers(Table 3)^.1,2

PHARMACODYNAMICINTERACTIONS
Although the emphasis here ison pharmacokinetic interactions,pharmacodynamic interactions alsodeserve mention. Abernethy andSchwartz¹ have provided a usefulsummary of pharmacodynamicinteractions.

If other cardiovascular drugs areused concomitantly with calciumchannel blockers, be alert for additivepharmacologic effects. For example,the use of verapamil or diltiazem concurrentlywith amiodarone inhibitsatrioventricular conduction and sinusnodefunction more than therapywith either calcium channel blockeralone.

References:

REFERENCES:1. Abernethy DR, Schwartz JB. Calcium-antagonistdrugs. N Engl J Med. 1999;341:1447-1457.
2. Flockhart DA, Tanus-Santos JE. Implications ofcytochrome P450 interactions when prescribing medicationfor 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 neurotoxicityprecipitated by diltiazem. Br Med J. 1986;292:1170-1171.
5. Bahls FH, Ozuna J, Ritchie DE. Interactionsbetween calcium channel blockers and the anticonvulsantscarbamazepine and phenytoin. Neurology.1991;41:740-742.
6. Lindholm A, Henricsson S. Verapamil inhibitscyclosporin metabolism. Lancet. 1987;1:1262-1263.
7. Schwartz JB, Keefe D, Kates RE, et al. Acute andchronic pharmaodynamic interaction of verapamiland digoxin in atrial fibrillation. Circulation. 1982;65:1163-1170.
8. Verschraagen M, Koks CH, Schellens JH, BeijnenJH. P-glycoprotein system as a determinant ofdrug 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 concentrationsand greatly enhance the adrenal suppressanteffect of oral methylprednisolone. Clin PharmacolTher. 2000;67:215-221.
10. Edwards DJ, Lavoie R, Beckman H, et al. Theeffect of coadministration of verapamil on the pharmacokineticsand metabolism of quinidine. ClinPharmacol Ther. 1987;41:68-73.
11. Kantola T, Kivisto KT, Neuvonen PJ. Erythromycinand verapamil considerably increase serumsimvastatin and simvastatin acid concentrations. ClinPharmacol Ther. 1998;64:177-182.
12. Mousa O, Brater C, Sundblad KJ, Hall SD. Theinteraction of diltiazem with simvastatin. Clin PharmacolTher. 2000;67:267-274.
13. Yeo KR, Yeo WW, Wallis EJ, Ramsay LE. Enhancedcholesterol reduction by simvastatin in diltiazem-treated patients. Br J Clin Pharmacol. 1999;48:610-615.
14. Peces R, Pobes A. Rhabdomyolysis associatedwith concurrent use of simvastatin and diltiazem.Nephron. 2001;89:117-118.
15. Kanathur N, Mathai MG, Byrd RP, et al.Simvastatin-diltiazem drug interaction resultingin rhabdomyolysis and hepatitis. Tenn Med.2001;94:339-341.
16. Azie NE, Brater DC, Becker PA, et al. The interactionof diltiazem with lovastatin and pravastatin.Clin Pharmacol Ther. 1998;64:369-377.
17. Hebert MF, Lam AY. Diltiazem increases tacrolimusconcentrations. Ann Pharmacother. 1999;33:680-682.
18. Sirmans SM, Pieper JA, Lalonde RL, et al.
Effect of calcium channel blockers on theophyllinedisposition. Clin Pharmacol Ther. 1988;44:29-34.
19. Kosuge K, Nishimoto M, Kimura M, et al. Enhancedeffect of triazolam with diltiazem. Br J ClinPharmacol. 1997;43:367-372.
20. Capewell S, Freestone S, Critchley JA, et al. Reducedfelodipine bioavailability in patients taking anticonvulsants.Lancet. 1988;2:480-482.
21. Michelucci R, Cipolla G, Passarelli D, et al. Reducedplasma nisoldipine concentrations in phenytointreatedpatients with epilepsy. Epilepsia. 1996;37:1107-1110.
22. Woodcock BG, Kirsten R, Nelson K, et al. Areduction in verapamil concentrations with phenytoin.N Engl J Med. 1991;325:1179.
23. Strayhorn VA, Baciewicz AM, Self TH. Update onrifampin 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. ClinPharmacol Ther. 1996;60:25-33.
25. Lundahl J, Regardh CG, Edgar B, Johnsson G.Effects of grapefruit juice ingestion-pharmacokineticsand hemodynamics of intravenously and orallyadministered felodipine in healthy men. Eur J ClinPharmacol. 1997;52:139-145.
26. Dresser GK, Bailey DG, Carruthers SG. Grapefruitjuiceâfelodipine interaction in the elderly. ClinPharmacol Ther. 2000;68:28-24.
27. Bailey DG, Dresser GK, Dreeft JH, et al. Grapefruit-felodipine interaction: effect of unprocessed fruitand probable active ingredients. Clin Pharmacol Ther.2000;68:468-477.
28. Jalava K, Olkkola KT, Neuvonen PJ. Itraconazolegreatly increases plasma concentrations and effectsof felodipine. Clin Pharmacol Ther. 1997;61:410-415.
29. Heinig R, Adelmann HG, Ahr G. The effect ofketoconazole on the pharmacokinetics, pharmacodynamicsand safety of nisoldipine. Eur J Clin Pharmacol.1999;55:57-60.