Calcium channel blockers

Drug interaction

Calcium channel blockers

DrugPharmacodynamicPharmacokineticImplications
AlcoholAdditive effect on BPVerapamil and diltiazem inhibit the metabolism and increase ethanol plasma levels. Alcohol may increase the rate of diltiazem release from the prolonged release preparation.The effects of alcohol may be exaggerated. Avoid alcohol in patients receiving these CCBs
Alpha-adrenergic blockers:
- Prazosin
- Terazosin
Exert an additive hypotensive effect with verapamilVerapamil may increase the plasma concentrations of prazosin and terazosin with an additive hypotensive effect.Close monitoring of blood pressure
AnestheticsDiltiazem and verapamil potentiate the depression of cardiac contractility, AV block, bradycardia and hypotension produced by general anesthetics.The combination should be avoided.
AntiarrhythmicsIncrease the risk of bradycardia, AV block, hypotension and heart failure. Coadministration of verapamil with either disopyramide or flecainide increases the risk of myocardial depression and asystole.Nifedipine decreases the plasma levels of quinidine
Diltiazem and verapamil increase quinidine plasma levels Verapamil may decrease the clearance of flecainide
The combination should be made with caution. Monitor clinical, hemodynamic and ECG changes.
Diltiazem and verapamil are antiarrhythmics and its co-prescription with other antiarrhythmics is not recommended
Anti-H2 agents:
- Cimetidine
- Ranitidine
They may potentiate the antihypertensive effect of nifedipineCimetidine decreases hepatic blood flow and metabolism and increases the plasma levels of diltiazem, nifedipine, nisoldipine, nitrendipine and verapamilReduce the dose of the CCB and monitor BP. Replace cimetidine and ranitidine by famotidine or nizatidine. Amlodipine do not interact with cimetidine
Anti-hypertensivesAdditive vasodilator responseMonitor BP. Reduce the dosage of other antihypertensives to avoid the risk of hypotension
Antineoplastic drugsVerapamil reduces the resistance to doxorrubicinCyclophosphamide, vincristine, procarbazine, doxorubicin and cisplatin reduce the absorption of verapamilIncrease the dose of verapamil. Use another CCB.
AspirinCoadministration of diltiazem and verapamil with aspirin may increase the risk of bleeding.Caution with this combination. Monitor the bleeding risk
Azole antifungals:
- Fluconazole, Itraconazole, Ketoconazole, Posaconazole, Voriconazole
They inhibit CYP3A4 and increase the plasma levels of CCBsAppropriate dosage adjustment of the CCB is needed.
The starting dose of atorvastatin should be 10 mg od and the maximum dose 20 mg od.
BenzodiazepinesThe effects of midazolam and triazolam are markedly increased by diltiazem or verapamilDiltiazem and verapamil inhibit CYP3A4 and increase the plasma levels of midazolam and triazolamSpecial care in patients treated with these short-acting benzodiazepines. This interaction does not occur with diazepam. Diltiazem does not interact with temazepam.
Beta-blockersAdditive effects on BP (hypotension), heart rate (bradycardia), AV conduction and/or cardiodepressant effects when combined with verapamil or diltiazem.Diltiazem increases the bioavailability of oral propranolol.
Verapamil may increase the plasma concentrations of metoprolol and propranolol.
Coadministration of β-blockers with DHP-CCBs is usually well tolerated.
This combination should be administered under close medical (ECG) supervision, particularly at the beginning of treatment.
Verapamil is best combined with atenolol or nadolol that are excreted by renal route than with β-blockers that are metabolized in the liver (carvedilol, metoprolol, propranolol).
IV β-blockers should not be given in patients treated with diltiazem or verapamil.
Bile-acid binding resinsReduce the bioavailability of diltizem and verapamilMonitor the response to CCBs. Separate the doses of CCB and resins by about 2 hours.
BoceprevirThe maximum dose of atorvatatin should be limited to 40 mg.
BuspironeDiltiazem increases the AUC and the elimination time of buspironeDose adjustments are needed.
Calcium saltsAntagonize the antiarrhythmic effects of CCBsMonitor for a reduced response when large doses of calcium are given
Calcium channel blockersDiltiazem can be combined with DHPs in patients with resistant coronary artery vasospasmDiltiazem increases nifedipine plasma levelsMonitor for increased nifedipine effects
CarbamazepineIncrease carbamazepine toxicity (nausea, visual disturbances, dizziness, or ataxia)Some CCBs (diltiazem) can inhibit CYP3A4 and increases carbamazepine plasma levelsMonitor the plasma levels and reduce the dosage of carbamazepine
ClonidineCases of bradycardia and complete AV block when diltiazem or verapamil and clonidine are combinedNo interaction exist between nifedipine and clonidine
ColchicineCases of myopathy, including rhabdomyolysis, when atorvastatin and colchicine are co-administeredVerapamil inhibits CYP3A4 and P-gp and increases the exposure to colchicineThis combination is not recommended.
Corticosteroids (methylprednisolone)Diltiazem can increase methylprednisolone levels through inhibition of CYP3A4 and P-gpMonitor the patient when initiating methylprednisolone treatment. Adjustment of the methylprednisolone dose may be necessary.
Cytochrome P450 3A inducers:
- Barbiturates
- Efavirenz
- Rifampin
- St John's wort)
Decrease the effects of CCBsThey increase the metabolism and decrease the plasma levels of CCBsIncrease the doses of CCBs as appropriate. Patients should be carefully monitored where initiating or discontinuing the inducer.
Dabigitran etexilateVerapamil increases the Cmax and AUC of dabigatran when both drugs are coadministred. However, no chages are observed when verapamil was administered 2 hours after dabigatran etexilateClose clinical surveillance is recommended when both drugs are combined, particularly in patients at risk of bleeding (mild to moderate renal impairment)
Dantrolene (I.V.)The combination with verapamil increases the risk of hypotension, myocardial depression and hyperkalemia. Ventricular fibrillation when combined with verapamilThis combination should be avoided.
DigoxinIncreased risk of bradycardia and AV blockBepridil, nifedipine, nitrendipine, nisoldipine and verapamil inhibit digoxin clearance, reduce its volume of distribution and increase digoxin plasma levels. Diltiazem does not interact with digoxin.Monitor digoxin plasma levels and the ECG. reduce the maintenance dose of digoxin.
DofetilideIncreases the risk of arrhythmiasCCBs increase dofetilide plasma levelsThe combination is contraindicated.
DiureticsAdditive antihypertensive effectsReduce the dosage as appropriate to avoid the risk of hypotension.
EzetimibeThe risk of muscular events increases with concomitant use of ezetimibe and atorvastatinClinical monitoring is recommended.
FentanylDiltiazem and verapamil increase or prolong their effects and may cause potentially fatal respiratory depressionDiltiazem and verapamil inhibit CYP3A4 increasing fentanyl exposureThe doses of fentanyl should be carefully monitored, and adjusted as needed
FibratesIncreased risk of muscular adverse effectsUse the lowest dose of atorvastatin. Patients should be appropriately monitored
FluoxetineIt increases the adverse effects of CCBsFluoxetine reduces the clearance and increases CCB plasma levelsReduce the dose of CCBs if necessary
Grapefruit juiceInhibits CYP3A4 and increases the plasma levels of felodipine, nicardipine, nifedipine, nimodipine, nitrendipine, nisoldipine and verapamilAvoid grapefruit juice. Amlodipine and diltiazem plasma levels are only minimally affected.
HalofantrineIncreased risk of QT interval prolongation and ventricular arrhythmiasVerapamil and diltiazem inhibit CYP450 3A4 and increase halofantrine plasma levelsMonitor the ECG for 8-12 hours after completion of therapy
Hepatitis C protease inhibitor
- Boceprevir
The maximum dose of atorvatatin should be limited to 40 mg.
Imipramine Increased risk of hypotension, AV block and cardiodepressionDiltiazem and verapamil decrease the clearance of imipramine and increase its plasma levelsMonitor the patients for increased imipramine toxicity (tachycardia, dry mouth, sedation) and ECG (AV block). Reduce the dosage of diltiazem/verapamil
Immunosuppressants:
- Ciclosporin
- Everolimus
- Sirolimus
- Tacrolimus
Increase the adverse effects of the immunosupressantsDiltiazem, nicardipine, nifedipine and verapamil inhibit the metabolism of the immunosuppressants and increase their plasma levels.
Diltiazem and verapamil increase the oral absorption and exposure to everolimus
Cyclosporin inhibits CYP3A4 and increases the plasma levels of CCBs.
Frequent monitoring of BP and adjust the dose as appropriate.
The plasma levels of these drugs should be closely monitored.
Reduce the dose of immunosuppressants.
Cyclosporin plasma levels and renal function should be closely monitored. Amlodipine does not present this interaction.
IvabradineAdditional slowing of heart rate when coadministered with diltiazem or verapamilAvoid this combination
LithiumDiltiazem and verapamil increases the risk of lithium-induced neurotoxicityMonitor the plasma levels and neurotoxic effects of lithium. Dose adjustments are needed.
Macrolides:
- Chlarithomycin
- Erythomycin
- Telithromycin
Increase the effects of CCBs. Telithromycin produces hypotension and bradycardia when combined with verapamilMacrolides inhibit CYP3A4 and increases the bioavailability of some CCBs (verapamil)Reduce the dose of CCBs if these macrolides are prescribed.
The starting dose of atorvastatin should be 10 mg od and the maximum dose 20 mg od.
NefazodoneNefazodone inhibits the CYP 3A4 and increases plasma levels of nifedipineMonitor blood pressure when both drugs are coadministrated. Consider to reduce the dose of nifedipine
Neuromuscular blockersSome CCBs can reduce the release of acetylcholine and potentiate the neuromuscular blockade of pancuroniumRisk for an increased neuromucular blockade during surgery
NitratesAdditive vasodilator effects Increase the dosage of nitrates gradually. Monitor BP
PhenothiazinesAdditive vasodilator effectsIncreased risk of hypotension. Monitor BP
PhenytoinIncrease phenytoin toxicity (e.g., drowsiness, visual disturbances, change in mental status, seizures, nausea, or ataxia)Diltiazem and verapamil inhibit CYP3A4 and increase phenytoin plasma levels. Phenytoin induces CYP 3A4 and may decrease the plasma levels of nifedipine and verapamilMonitor the effects and plasma levels of phenytoin.
Increase the dose of nifedipine. Reduce the dose of nifedipine when phenytoin is discontinued.
PimozideIncreases the risk of proarrhythmiaDiltiazem and verapamil increase plasma levels of pimozide Avoid the combination
RanolazineDiltiazem and verapamil increase the plasma levels of ranolazineCareful dose titration of ranolazine is recommended
SildenafilCCBs increase its plasma levelsReduce the doses of these drugs
Statins
Atrovastatin
Lovastatin
Simvastatin
Increased incidence of muscular disordersDiltiazem, isradipine and verapamil inhibit CYP3A4 and increases the plasma levels of these statins.
Atorvastatin increases verapamil levels.
Treatment with simvastatin, atorvastatin or lovastatin in a patient taking verapamil should be started at the lowest possible dose and titrated upwards. Max dose of simvastatin: 10-20 mg/day.
Use fluvastatin, pravastatin, and rosuvastatin that are not metabolized by CYP3A4.
Caution when atorvastatin and verapamil are concomitantly administered.
SulfinpyrazoneAntagonizes the antihypertensive effect of verapamilReduce the plasma concentrations of verapamilAvoid the combination
TheophyllineCCBs increase the adverse effects of theophyllineDiltiazem and verapamil reduce its clearance and increase its plasma levelsMonitor theophylline plasma levels. The dose of diltiazem and verapamil should be adjusted if necessary.
TobaccoReduces the antianginal effect of CCBs Patient must stop smoking
VIH protease inhibitors:
- Atazanavir, Indinavir, Nelfinavir, Ritonavir, Saquinavir
-Saquinavir+ritonavir, darunavir+ritonavir, lopinavir+ritonavir, fosamprenavir+ritonavir
Prolong the PR interval of the ECG. Orthostatic hypotension with the combination of nelfinavir or ritonavir/indinavir and nifedipineThey increase the bioavailability of diltiazem and verapamil.Ritonavir and saquinavir should not be used with other agents that prolong the PR interval
The starting dose of atorvastatin should be 10 mg od and the maximum dose 20 mg od
WarfarinAtorvastatin (80 mg/day) causes a small decrease in prothrombin time which returned to normal within 15 days of treatment.Uncertain clinical meaning
Vitamin D (at high doses)May reduce the response to CCBsMonitor the effects of CCBs

Abbreviations

BP: blood pressure
CCB: calcium channel blocker
Cmax: peak plasma levels
I.V.: intravenously
AUC: area under the curve