chapter
Calcium channel blockers
Pages 20

Additive hypotensive and negative inotropic effects. General anaesthetics tend to be myocardial depressants and vasodilators; they also ↓ sinus automaticity and AV conduction

Monitor BP and ECG closely

CALCIUM CHANNEL BLOCKERS

ANAESTHETICS – LOCAL Case reports of severe ↓ BP when bupivacaine epidural was administered to patients on calcium channel blockers

Additive hypotensive effect; both bupivacaine and calcium channel blockers are cardiodepressant; in addition, epidural anaesthesia causes sympathetic block in the lower limbs, which leads to vasodilatation and ↓ BP

Monitor BP closely. Preload intravenous fluids prior to the epidural

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CARDIOVASCULAR DRUGS CALCIUM CHANNEL BLOCKERS

BLOCKERS

calcium channel blockers

NSAIDs cause sodium retention and vasoconstriction at possibly both renal and endothelial sites

Monitor BP at least weekly until stable

CALCIUM CHANNEL BLOCKERS

OPIOIDS Diltiazem prolongs the action of alfentanil

Diltiazem inhibits CYP3A4mediated metabolism of alfentanil

Watch for the prolonged action of alfentanil in patients taking calcium channel blockers; case reports of delayed extubation in patients recovering from anaesthetics involving large doses of alfentanil in patients on diltiazem

CALCIUM CHANNEL BLOCKERS

ANTIARRHYTHMICS

CALCIUM CHANNEL BLOCKERS

AMIODARONE Risk of bradycardia, AV block and ↓ BP when amiodarone is co-administered with diltiazem or verapamil

Additive negative inotropic and chronotropic effect. Also, amiodarone inhibits intestinal P-gp, which ≠ the bioavailability of diltiazem and verapamil

Monitor PR, BP and ECG closely; watch for heart failure

CALCIUM CHANNEL BLOCKERS

DISOPYRAMIDE Risk of myocardial depression and asystole when disopyramide is co-administered with verapamil, particularly in the presence of heart failure

Disopyramide is a myocardial depressant like verapamil and can cause ventricular tachycardia, ventricular fibrillation or torsades de pointes

Avoid co-administering verapamil with disopyramide if possible. If single-agent therapy is ineffective, monitor PR, BP and ECG closely; watch for heart failure

CALCIUM CHANNEL BLOCKERS

FLECAINIDE Risk of heart block and ↓ BP when flecainide is co-administered with verapamil. A single case of asystole has been reported

Additive negative inotropic and chronotropic effect

Monitor PR, BP and ECG at least weekly until stable; watch for heart failure

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Mechanism Precautions

and ↓ availability of diltiazem

Postulated that diltiazem inhibits metabolism of moracizine, while moracizine ≠ metabolism of diltiazem; the precise mechanism of interaction is uncertain at present

Monitor PR, BP and ECG; adjust the doses of each drug accordingly

CALCIUM CHANNEL BLOCKERS

ANTIBIOTICS

CALCIUM CHANNEL BLOCKERS

MACROLIDES ≠ plasma concentrations of felodipine when co-administered with erythromycin; cases of adverse effects of verapamil (bradycardia and ↓ BP) with both erythromycin and clarithromycin

Erythromycin inhibits CYP3A4mediated metabolism of felodipine and verapamil. Clarithromycin and erythromycin inhibit intestinal P-gp, which may ≠ the bioavailability of verapamil

Monitor PR and BP closely; watch for bradycardia and ↓ BP. Consider reducing the dose of calcium channel blocker during macrolide therapy

CALCIUM CHANNEL BLOCKERS

RIFAMPICIN Plasma concentrations of calcium channel blockers may be ↓ by rifampicin

Rifampicin induces CYP3A4mediated metabolism of calcium channel blockers. It also induces CYP2C9-mediated metabolism of verapamil and induces intestinal P-gp, which may ↓ the bioavailability of verapamil

Monitor BP closely; watch for ↓ effect of calcium channel blockers

CALCIUM CHANNEL BLOCKERS

QUINUPRISTIN/ DALFOPRISTIN

Plasma levels of nifedipine may be ≠ by quinupristin-dalfopristin

Quinupristin inhibits CYP3A4mediated metabolism of calcium channel blockers

Monitor BP closely; watch for ↓ BP

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CARDIOVASCULAR DRUGS CALCIUM CHANNEL BLOCKERS

CALCIUM CHANNEL BLOCKERS

BUSULFAN ≠ plasma concentrations of busulfan and ≠ risk of toxicity of busulfan such as veno-occlusive disease and pulmonary fibrosis, when co-administered with diltiazem, nifedipine or verapamil

Due to inhibition of CYP3A4mediated metabolism of busulfan by these calcium channel blockers. Busulfan clearance may be ↓ by 25%, and the AUC of busulfan may ≠ by 1500mol/L

Monitor clinically for veno-occlusive disease and pulmonary toxicity in transplant patients. Monitor busulfan blood levels as AUC of below 1500mol/L per minute tends to prevent toxicity

CALCIUM CHANNEL BLOCKERS

DOXORUBICIN ≠ serum concentrations and efficacy of doxorubicin when co-administered with verapamil, nicardipine and possibly diltiazem and nifedipine; however, no cases of doxorubicin toxicity have been reported

Uncertain; however, verapamil is known to inhibit intestinal P-gp, which may ≠ the bioavailability of doxorubicin

Watch for symptoms/signs of toxicity (tachycardia, heart failure and hand-foot syndrome)

CALCIUM CHANNEL BLOCKERS

EPIRUBICIN Cases of ≠ bone marrow suppression when verapamil is added to epirubicin

Uncertain at present Monitor FBC closely

CALCIUM CHANNEL BLOCKERS

ETOPOSIDE ≠ serum concentrations and risk of toxicity when verapamil is given to patients on etoposide

Verapamil inhibits CYP3A4mediated metabolism of etoposide

Watch for symptoms/signs of toxicity (nausea, vomiting and bone marrow suppression) in patients taking calcium channel blockers

CALCIUM CHANNEL BLOCKERS

IFOSFAMIDE ↓ plasma concentrations of 4-hydroxyifosfamide, the active metabolite of ifosfamide and risk of inadequate therapeutic response when it is co-administered with diltiazem, nifedipine or verapamil

Due to inhibition of the isoenzymatic conversion to active metabolites by diltiazem

Monitor clinically the efficacy of ifosfamide and ≠ the dose accordingly

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Mechanism Precautions

azem, nifedipine or verapamil. ≠ risk of toxicity (e.g. abdominal pain, constipation and dyspnoea) and of neurotoxicity (e.g. taste disturbances, dizziness, headache, paraesthesias and peripheral neuropathy)

Due to inhibition of hepatic metabolism of imatinib by the CYP3A4 isoenzymes by diltiazem

Monitor for clinical efficacy and for the signs of toxicity listed along with convulsions, confusion and signs of oedema (including pulmonary oedema). Monitor electrolytes and liver function, and for cardiotoxicity

CALCIUM CHANNEL BLOCKERS

IRINOTECAN Risk of ≠ serum concentrations of irinotecan with nifedipine. No cases of toxicity reported

Inhibition of hepatic microsomal enzymes but exact mechanism uncertain at present

Watch for symptoms/signs of toxicity (especially diarrhoea, an early manifestation of acute cholinergic syndrome)

CALCIUM CHANNEL BLOCKERS

PORFIMER ≠ risk of photosensitivity reactions with diltiazem

Attributed to additive effects Avoid exposure of skin and eyes to direct sunlight for 30 days after porfimer therapy

CALCIUM CHANNEL BLOCKERS

TRETINOIN ↓ plasma tretinoin levels and risk of ↓ anti-tumour activity when is co-administered with diltiazem, nifedipine or verapamil

Due to induction of CYP3A4mediated metabolism of tretinoin

Avoid co-administration if possible

CALCIUM CHANNEL BLOCKERS

VINCA ALKALOIDS 1. ≠ risk of bone marrow depression, neurotoxicity and ileus due to ≠ plasma concentrations of vinblastine when is co-administered with diltiazem, nifedipine or verapamil. 2. Verapamil ≠ vincristine levels; no cases of toxicity have been reported 3. ≠ plasma concentrations of vinorelbine and ≠ risk of bone marrow and neurotoxicity when co-administered with diltiazem, nifedipine or verapamil

1. Inhibition of CYP3A4-mediated metabolism of vinblastine and ↓ efflux of vinblastine due to inhibition of renal P-gp 2. ↓ clearance, but exact mechanism not known 3. Due to inhibition of CYP3A4-mediated metabolism of vinorelbine by these calcium channel blockers

1. Avoid concurrent use of CYP3A4 inhibitors and P-gp efflux inhibitors with vinblastine. Select an alternative drug of same group with ↓ effects on enzyme inhibition and P-gp inhibition 2. Watch for symptoms/signs of toxicity 3. Monitor for clinical efficacy and monitor FBC and for neurotoxicity (pain, numbness, tingling in the fingers and toes, jaw pain, abdominal pain, constipation and ileus)

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CARDIOVASCULAR DRUGS CALCIUM CHANNEL BLOCKERS

BLOCKERS

toremifene when is coadministered with diltiazem, nifedipine or verapamil

Due to inhibition of CYP3A4mediated metabolism of toremifene

Clinical relevance is uncertain. Necessary to monitor for clinical toxicities

CALCIUM CHANNEL BLOCKERS

CICLOSPORIN 1. Plasma concentrations of ciclosporin are ≠ when co-administered with diltiazem, nicardipine, verapamil and possibly amlodipine and nisoldipine. However, calcium channel blockers seem to protect renal function 2. Ciclosporin ≠ nifedipine levels

1. Uncertain; presumed to be due to impaired hepatic metabolism. Also, diltiazem and verapamil inhibit intestinal P-gp, which may ≠ the bioavailability of ciclosporin. Uncertain mechanism of renal protection 2. Uncertain effect of ciclosporin on nifedipine

1. Monitor ciclosporin levels and ↓ dose accordingly (possibly by up to 25-50% with nicardipine) 2. Monitor BP closely and warn patients to watch for signs of nifedipine toxicity

CALCIUM CHANNEL BLOCKERS

CORTICOSTEROIDS 1. Antihypertensive effects of calcium channel blockers are antagonized by corticosteroids 2. ≠ adrenal-suppressive effects of dexamethasone, methylprednisolone and prednisolone when co-administered with diltiazem, nifedipine or verapamil. This may ≠ the risk of infections and produce an inadequate response to stress scenarios

1. Mineralocorticoids cause sodium and water retention, which antagonizes the hypotensive effects of calcium channel blockers 2. Due to inhibition of metabolism of these corticosteroids

1. Monitor BP at least weekly until stable 2. Monitor cortisol levels and warn patients to report symptoms such as fever and sore throat

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Mechanism Precautions

Additive hypotensive effect. Aldesleukin causes ↓ vascular resistance and ≠ capillary permeability

Monitor BP at least weekly until stable. Warn patients to report symptoms of hypotension (light-headedness, dizziness on standing, etc.)

CALCIUM CHANNEL BLOCKERS

SIROLIMUS Plasma concentrations of sirolimus are ≠ when given with diltiazem. Plasma levels of both drugs are ≠ when verapamil and sirolimus are co-administered

Diltiazem and verapamil inhibit intestinal CYP3A4, which is the main site of sirolimus metabolism

Watch for side-effects of sirolimus when it is co-administered with diltiazem or verapamil; monitor renal and hepatic function. Monitor PR and BP closely when sirolimus is given with verapamil

CALCIUM CHANNEL BLOCKERS

TACROLIMUS Plasma concentrations of tacrolimus are ≠ when given with diltiazem, felodipine or nifedipine; however, they appear to protect renal function

Uncertain, but presumed to be due to inhibition of CYP3A4-mediated tacrolimus metabolism

Watch for side-effects of tacrolimus; monitor ECG, blood count and renal and hepatic function

CALCIUM CHANNEL BLOCKERS

ANTIDEPRESSANTS

CALCIUM CHANNEL BLOCKERS

LITHIUM Small number of cases of neurotoxicity when co-administered with diltiazem or verapamil

Uncertain, but thought to be due to an additive effect on neurotransmission

Monitor closely for side-effects

CALCIUM CHANNEL BLOCKERS

MAOIs ≠ antihypertensive effect of calcium channel blockers when co-administered with MAOIs

Additive hypotensive effects; postural ↓ BP is a side-effect of MAOIs

Monitor BP at least weekly until stable. Warn patients to report symptoms of hypotension (light-headedness, dizziness on standing, etc.)

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CARDIOVASCULAR DRUGS CALCIUM CHANNEL BLOCKERS

verapamil (oedema, flushing and ↓ BP) attributed to ≠ levels when co-administered with fluoxetine

Fluoxetine inhibits CYP3A4mediated metabolism of calcium channel blockers. It also inhibits intestinal P-gp, which may ≠ the bioavailability of verapamil

Monitor BP at least weekly until stable. Warn patients to report symptoms of hypotension (lightheadedness, dizziness on standing, etc.). Consider reducing the dose of calcium channel blocker or using an alternative antidepressant

CALCIUM CHANNEL BLOCKERS

ST JOHN’S WORT St John’s wort is associated with ↓ verapamil levels

St John’s wort induces CYP3A4, which metabolizes calcium channel blockers, and induces intestinal P-gp, which may ↓ the bioavailability of verapamil

Monitor BP regularly for at least the first 2 weeks of initiating St John’s wort

CALCIUM CHANNEL BLOCKERS

TCAs ≠ plasma concentrations of TCAs when co-administered with diltiazem and verapamil. Reports of cardiotoxicity (first-and seconddegree block) when imipramine is given with diltiazem or verapamil

Uncertain, but may be due to a combination of ↓ clearance of TCAs (both diltiazem and verapamil are known to inhibit CYP1A2, which has a role in the metabolism of amitriptyline, clomipramine and imipramine) and ≠ intestinal absorption (diltiazem and verapamil inhibit intestinal P-gp, which may ≠ amitriptyline bioavailability)

Monitor ECG when commencing or altering treatment

CALCIUM CHANNEL BLOCKERS

ANTIDIABETIC DRUGS

CALCIUM CHANNEL BLOCKERS

INSULIN Single case reports of impaired glucose intolerance requiring ≠ insulin requirements with diltiazem and nifedipine

Uncertain at present Evidence suggests that calcium channel blockers are safe in diabetics; monitor blood glucose levels when starting calcium channel blockers

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Mechanism Precautions

hypoglycaemic episodes

Inhibition of CYP3A4-mediated metabolism of repaglinide

CALCIUM CHANNEL BLOCKERS

ANTIEPILEPTICS

CALCIUM CHANNEL BLOCKERS

BARBITURATES ↓ plasma concentrations of felodipine, nifedipine, nimodipine, nisoldipine and verapamil with phenobarbital

Phenobarbital induces CYP3A4, which metabolizes calcium channel blockers. It also induces intestinal P-gp, which may ↓ the bioavailability of verapamil

Monitor PR and BP closely; watch for ≠ BP

CALCIUM CHANNEL BLOCKERS

CARBAMAZEPINE 1. Diltiazem and verapamil ≠ plasma concentrations of carbamazepine (cases of toxicity) 2. ↓ plasma concentrations of felodipine, nifedipine and possibly nimodipine and nisoldipine

1. Diltiazem and verapamil inhibit CYP3A4-mediated metabolism of carbamazepine. They also inhibit intestinal P-gp, which may ≠ the bioavailability of carbamazepine 2. Carbamazepine, in turn, induces CYP3A4, which metabolizes calcium channel blockers

1. Monitor carbamazepine levels when initiating calcium channel blockers, particularly diltiazem and verapamil 2. Monitor PR and BP closely; watch for ≠ BP when starting carbamazepine in patients already on calcium channel blockers

CALCIUM CHANNEL BLOCKERS

PHENYTOIN 1. Phenytoin levels are ≠ by diltiazem and possibly nifedipine and isradipine 2. ↓ plasma concentrations of diltiazem, felodipine, nisoldipine, verapamil and possibly nimodipine

1. Postulated to be due to inhibition of CYP3A4-mediated metabolism of phenytoin. Diltiazem is also known to inhibit intestinal P-gp, which may ≠ the bioavailability of phenytoin 2. Phenytoin induces CYP3A4, which metabolizes calcium channel blockers

1. Monitor phenytoin levels when initiating calcium channel blockers, particularly diltiazem and verapamil 2. Monitor PR and BP closely; watch for ≠ BP when starting phenytoin in patients already on calcium channel blockers

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CARDIOVASCULAR DRUGS CALCIUM CHANNEL BLOCKERS

Primidone induces CYP3A4, which metabolizes calcium channel blockers

Monitor PR and BP closely; watch for ≠ BP

CALCIUM CHANNEL BLOCKERS

SODIUM VALPROATE Nimodipine levels may be ≠ by valproate

Uncertain at present Monitor BP at least weekly until stable. Warn patients to report symptoms of hypotension (light-headedness, dizziness on standing, etc.)

CALCIUM CHANNEL BLOCKERS

ANTIFUNGALS – FLUCONAZOLE, ITRACONAZOLE, KETOCONAZOLE, POSACONAZOLE

Plasma concentrations of dihydropyridine calcium channel blockers are ≠ by fluconazole, itraconazole and ketoconazole. Risk of ≠ verapamil levels with ketoconazole and itraconazole. Itraconazole and possibly posaconazole may ≠ diltiazem levels

The azoles are potent inhibitors of CYP3A4 isoenzymes, which metabolize calcium channel blockers. They also inhibit CYP2C9-mediated metabolism of verapamil. Ketoconazole and itraconazole both inhibit intestinal P-gp, which may ≠ the bioavailability of verapamil. Diltiazem is mainly a substrate of CYP3A5 and CYP3A5P1, which are inhibited by itraconazole. Around 75% of the metabolism of diltiazem occurs in the liver and the rest in the intestine. Diltiazem is a substrate of P-gp (also an inhibitor but unlikely to be significant at therapeutic doses), which is inhibited by itraconazole, resulting in ≠ bioavailability of diltiazem

Monitor PR, BP and ECG, and warn patents to watch for symptoms/signs of heart failure

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Mechanism Precautions

co-administered with sulfinpyrazone

Uncertain, but presumed to be due to ≠ hepatic metabolism

Monitor PR and BP at least weekly until stable. Watch for poor response to verapamil

CALCIUM CHANNEL BLOCKERS

ANTIHYPERTENSIVES AND HEART FAILURE DRUGS

≠ hypotensive effect Additive hypotensive effect; may be used therapeutically

Monitor BP at least weekly until stable. Warn patients to report symptoms of hypotension (light-headedness, dizziness on standing, etc.)

CALCIUM CHANNEL BLOCKERS

ALPHA-BLOCKERS ≠ efficacy of alpha-blockers; ≠ risk of first-dose ↓ BP with alfuzosin, prazosin and terazosin

Additive hypotensive effect; may be used therapeutically

Watch for first-dose ↓ BP when starting either drug when the patient is already established on the other; consider reducing the dose of the established drug and starting the new agent at the lowest dose and titrating up

VERAPAMIL CENTRALLY ACTING ANTIHYPERTENSIVES

Reports of two cases of complete heart block when clonidine was given to a patient on verapamil

Additive effect; both drugs are known to rarely cause AV dysfunction

Monitor ECG closely when co-administering

CALCIUM CHANNEL BLOCKERS

ANTIMALARIALS – MEFLOQUINE

Risk of bradycardia Additive bradycardic effect; mefloquine can cause cardiac conduction disorders, e.g. bradycardia. Also a theoretical risk of Q-T prolongation with co-administration of mefloquine and calcium channel blockers

Monitor PR closely

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CARDIOVASCULAR DRUGS CALCIUM CHANNEL BLOCKERS

Inhibition of CYP3A4-mediated metabolism of darifenacin

Avoid co-administration (manufacturer’s recommendation)

BLOCKERS

DRUGS – LEVODOPA

Additive hypotensive effect Monitor BP at least weekly until stable. Warn patients to report symptoms of hypotension (light-headedness, dizziness on standing, etc.)

CALCIUM CHANNEL BLOCKERS

ANTIPLATELET AGENTS – ASPIRIN

↓ antihypertensive effect with aspirin; effect not noted with lowdose aspirin

Aspirin may cause sodium retention and vasoconstriction at possibly both renal and endothelial sites

Monitor BP closely when high-dose aspirin is prescribed

CALCIUM CHANNEL BLOCKERS

ANTIPSYCHOTICS

CALCIUM CHANNEL BLOCKERS

ANTIPSYCHOTICS ≠ antihypertensive effect Dose-related ↓ BP (due to vasodilatation) is a side-effect of most antipsychotics, particularly phenothiazines

Monitor BP especially during initiation of treatment. Warn patients to report symptoms of hypotension (light-headedness, dizziness on standing, etc.)

CALCIUM CHANNEL BLOCKERS

CLOZAPINE Plasma concentrations of clozapine may be ≠ by diltiazem and verapamil

Diltiazem and verapamil inhibit CYP1A2-mediated metabolism of clozapine

Watch for side-effects of clozapine

CALCIUM CHANNEL BLOCKERS

SERTINDOLE Plasma concentrations of sertindole are ≠ by diltiazem and verapamil

Diltiazem and verapamil inhibit CYP3A4-mediated metabolism of sertindole

Avoid co-administration; raised sertindole concentrations are associated with an ≠ risk of prolonged Q-T interval and therefore ventricular arrhythmias, particularly torsades de pointes

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Mechanism Precautions

inhibitors

Protease inhibitors inhibit CYP3A4-mediated metabolism of calcium channel blockers. Also, ritonavir inhibits CYP2C9mediated metabolism of verapamil, and ritonavir and saquinavir both inhibit intestinal P-gp, which may ≠ the bioavailability of verapamil

Monitor PR, BP and ECG closely; ↓ dose of calcium channel blocker if necessary (e.g. the manufacturers of diltiazem suggest starting at 50% of the standard dose and titrating to effect)

CALCIUM CHANNEL BLOCKERS

ANXIOLYTICS AND HYPNOTICS

CALCIUM CHANNEL BLOCKERS

ANXIOLYTICS AND HYPNOTICS

≠ hypotensive effect Additive hypotensive effect; anxiolytics can cause postural ↓ BP

Monitor BP at least weekly until stable. Warn patients to report symptoms of hypotension (lightheadedness, dizziness on standing, etc.). Consider reducing the dose of calcium channel blocker or using an alternative antidepressant

DILTIAZEM, VERAPAMIL BZDs Plasma concentrations of midazolam and triazolam are ≠ by diltiazem and verapamil

Diltiazem and verapamil inhibit CYP3A4-mediated metabolism of midazolam and triazolam

↓ the dose of BZD by 50% in patients on calcium channel blockers; warn patients not to perform skilled tasks such as driving for at least 10 hours after a dose of BZD

CALCIUM CHANNEL BLOCKERS

BUSPIRONE Plasma concentrations of buspirone are ≠ by diltiazem and verapamil

Diltiazem and verapamil inhibit CYP3A4-mediated metabolism of buspirone

Start buspirone at a lower dose (2.5 mg twice daily suggested by the manufacturers) in patients on calcium channel blockers

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CARDIOVASCULAR DRUGS CALCIUM CHANNEL BLOCKERS

BLOCKERS

conduction defects and heart failure

Additive hypotensive effect; may be used therapeutically

Monitor PR, BP and ECG at least weekly until stable. Warn patients to report symptoms of hypotension (light-headedness, dizziness on standing, etc.)

DIHYDROPYRIDINES BETA-BLOCKERS Rare cases of severe ↓ BP and heart failure when nifedipine and nisoldipine are given to patients on beta-blockers

Uncertain why this severe effect occurs

Monitor PR, BP and ECG at least weekly until stable. Warn patients to report symptoms of hypotension (light-headedness, dizziness on standing, etc.)

DILTIAZEM BETA-BLOCKERS ≠ hypotensive and bradycardic effects: cases of severe bradycardia and AV block when both drugs are administered concurrently in the presence of pre-existing heart failure or conduction abnormalities

Additive effects on conduction; diltiazem causes bradycardia, sinoatrial block and AV block. Also, diltiazem inhibits CYP1A2mediated metabolism of propanolol

Monitor PR, BP and ECG at least weekly until stable. Warn patients to report symptoms of hypotension (light-headedness, dizziness on standing, etc.)

VERAPAMIL BETA-BLOCKERS 1. Risk of cardiac arrest when parenteral verapamil is given to patients on beta-blockers 2. Risk of bradycardias when both are given orally

Additive effect. Also, verapamil inhibits CYP1A2-mediated metabolism of propanolol

1. Do not administer intravenous verapamil to patients taking betablockers 2. Monitor ECG and BP carefully when both are given orally

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Mechanism Precautions

DILTIAZEM, VERAPAMIL THEOPHYLLINE ≠ theophylline levels with diltiazem and verapamil. Mostly not clinically significant but two cases of theophylline toxicity with verapamil have been reported

Uncertain, but thought to be due to inhibition of CYP1A2-mediated metabolism of theophylline

Be aware of the small possibility of theophylline toxicity when commencing calcium channel blockers; check levels if any problems occur, and consider either reducing the dose of theophylline or using an alternative calcium channel blocker

NIFEDIPINE THEOPHYLLINE Clinically non-significant ↓ theophylline levels with nifedipine, but there are case reports of theophylline toxicity after starting nifedipine

Uncertain; probably due to alterations in either metabolism or volume of distribution of theophylline

Be aware of the small possibility of theophylline toxicity when commencing calcium channel blockers; check levels if any problems occur, and consider either reducing the dose of theophylline or using an alternative calcium channel blocker

CALCIUM CHANNEL BLOCKERS

CALCIUM CHANNEL BLOCKERS

Co-administration of nifedipine and diltiazem leads to ≠ plasma concentrations of both drugs

Uncertain, but presumed mutual inhibition of CYP3A isoformmediated metabolism

Monitor PR, BP and ECG at least weekly until stable. Warn patients to report symptoms of hypotension (light-headedness, dizziness on standing, etc.)

CALCIUM CHANNEL BLOCKERS

CARDIAC GLYCOSIDES

VERAPAMIL DIGOXIN 1. Verapamil causes an ≠ in serum digoxin levels, and there have been case reports of significant toxicity 2. ≠ AV block when digoxin is co-administered with verapamil

1. Verapamil seems to inhibit P-gp-mediated renal and biliary clearance of digoxin. Inhibition of intestinal P-gp would also ≠ the bioavailability of digoxin 2. Additive effect

1. It is recommended to ↓ digoxin doses by 33-50% when starting verapamil; monitor digoxin levels and watch for symptoms/signs of toxicity 2. Monitor ECG closely when co-administering digoxin and verapamil, especially when verapamil is being given parenterally

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CARDIOVASCULAR DRUGS CALCIUM CHANNEL BLOCKERS

NICARDIPINE, NISOLDIPINE

These calcium channel blockers are thought to ↓ renal excretion of digoxin

Monitor digoxin levels carefully

CALCIUM CHANNEL BLOCKERS

DIGITOXIN Plasma concentrations of digitoxin may be ≠ by diltiazem and verapamil

Uncertain at present Watch for digitoxin toxicity

VERAPAMIL CNS STIMULANTS – MODAFINIL

May cause ↓ verapamil levels if CYP1A2 is the predominant metabolic pathway and alternative metabolic pathways are either genetically deficient or affected

Modafinil is a moderate inducer of CYP1A2 in a concentrationdependent manner

Be aware

CALCIUM CHANNEL BLOCKERS

DIURETICS

CALCIUM CHANNEL BLOCKERS

DIURETICS ≠ hypotensive effect Additive effect Monitor BP at least weekly until stable. Warn patients to report symptoms of hypotension (light-headedness, dizziness on standing, etc.)

CALCIUM CHANNEL BLOCKERS

POTASSIUM-SPARING DIURETICS

≠ serum concentrations of eplerenone when given with diltiazem and verapamil

Calcium channel blockers inhibit CYP3A4-mediated metabolism of eplerenone

Restrict dose of eplerenone to 25 mg/day. Monitor serum potassium concentrations closely; watch for hyperkalaemia

CALCIUM CHANNEL BLOCKERS

DUTASTERIDE Plasma concentrations of dutasteride may ≠ when co-administered with diltiazem or verapamil

Uncertain, but postulated that it may be due to inhibition of CYP3A4-mediated metabolism of dutasteride

Watch for side-effects of dutasteride

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Mechanism Precautions

effects), and ≠ bioavailability of isradipine, lacidipine, lercanidipine, nicardipine, nifedipine, nimodipine and verapamil (without reported adverse clinical effects)

Postulated that flavonoids in grapefruit juice (and possibly Seville oranges and limes) inhibit intestinal (but not hepatic) CYP3A4. They also inhibit intestinal P-gp, which may ≠ the bioavailability of verapamil

Avoid concurrent use of felodipine and nisoldipine and grapefruit juice

CALCIUM CHANNEL BLOCKERS

H2 RECEPTOR BLOCKERS

CALCIUM CHANNEL BLOCKERS

CIMETIDINE ≠ levels of calcium channel blockers, especially diltiazem and nifedipine

Inhibition of CYP3A isoformmediated metabolism

Monitor BP at least weekly until stable; watch for ↓ BP. Consider reducing the dose of diltiazem and nifedipine by up to 50%

CALCIUM CHANNEL BLOCKERS

FAMOTIDINE Reports of heart failure and ↓ BP when famotidine is given with nifedipine

Additive negative inotropic effects Caution when co-administering famotidine with calcium channel blockers, especially in elderly people

DILTIAZEM, NIFEDIPINE, VERAPAMIL

5-HT1 AGONISTS – ALMOTRIPTAN, ELETRIPTAN

≠ plasma concentrations of almotriptan and risk of toxic effects of almotriptan, e.g. flushing, sensations of tingling, heat, heaviness, pressure or tightness of any part of the body, including the throat and chest, dizziness

Almotriptan is metabolized mainly by CYP3A4 isoenzymes. Most CYP isoenzymes are inhibited by diltiazem to varying degrees, and since there is an alternative pathway of metabolism by MAO-A, toxicity responses vary between individuals

CSM has advised that if chest tightness or pressure is intense, the triptan should be discontinued immediately and the patient investigated for ischaemic heart disease by measuring cardiac enzymes and doing an ECG. Avoid concomitant use in patients with coronary artery disease and in those with severe or uncontrolled hypertension

CALCIUM CHANNEL BLOCKERS

IVABRADINE ≠ levels with diltiazem and verapamil

Uncertain Avoid co-administration

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CARDIOVASCULAR DRUGS CALCIUM CHANNEL BLOCKERS

CALCIUM CHANNEL BLOCKERS

ANION EXCHANGE RESINS Colestipol ↓ diltiazem levels Colestipol binds diltiazem in the intestine

Monitor for poor response to diltiazem. Separating doses of diltiazem and colestipol does not seem to ↓ this interaction

CALCIUM CHANNEL BLOCKERS

STATINS ≠ plasma levels of atorvastatin, lovastatin and simvastatin; case reports of myopathy when atorvastatin and simvastatin are co-administered with diltiazem or verapamil

Uncertain, but postulated to be due to inhibition of CYP3A4mediated metabolism of statins in the intestinal wall. Also, diltiazem and verapamil inhibit intestinal P-gp, which may ≠ the bioavailability of statins

Watch for side-effects of statins. It has been suggested that the dose of simvastatin should not exceed 20 mg when given with verapamil, and 40 mg when given with diltiazem

CALCIUM CHANNEL BLOCKERS

MAGNESIUM (PARENTERAL)

Cases of profound muscular weakness when nifedipine is given with parenteral magnesium

Both drugs inhibit calcium influx across cell membranes, and magnesium promotes movement of calcium into the sarcoplasmic reticulum; this results in muscular paralysis

Do not administer calcium channel blockers during parenteral magnesium therapy

CALCIUM CHANNEL BLOCKERS

MUSCLE RELAXANTS

CALCIUM CHANNEL BLOCKERS

DEPOLARIZING ≠ effect of suxamethonium with parenteral, but not oral, calcium channel blockers

Uncertain; postulated that ACh release at the synapse is calcium dependent; ↓ calcium concentrations at the nerve ending may ↓ ACh release, which in turn prolongs the nerve blockade

Monitor nerve blockade carefully, particularly during short procedures

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Mechanism Precautions

channel blockers; the effect is less certain with oral therapy. In two cohort studies, vecuronium requirements were halved in patients on diltiazem. Nimodipine does not seem to share this interaction

Uncertain; postulated that ACh release at the synapse is calcium dependent; ↓ calcium concentrations at the nerve ending may ↓ ACh release, which in turn prolongs the nerve blockade

Monitor nerve blockade carefully in patients on calcium channel blockers, particularly near to the end of surgery, when muscle relaxation may be prolonged and difficult to reverse

CALCIUM CHANNEL BLOCKERS

BACLOFEN AND TIZANIDINE

≠ hypotensive effect with baclofen of tizanidine. Risk of bradycardia with tizanidine

Additive hypotensive effect. Tizanidine has a negative inotropic and chronotropic effect

Monitor BP at least weekly until stable. Warn patients to report symptoms of hypotension (light-headedness, dizziness on standing, etc.)

CALCIUM CHANNEL BLOCKERS

DANTROLENE Risk of arrhythmias when diltiazem is given with intravenous dantrolene. Risk of ↓ BP, myocardial depression and hyperkalaemia when verapamil is given with intravenous dantrolene

Uncertain at present Extreme caution must be exercised when administering parenteral dantrolene to patients on diltiazem or verapamil. Monitor BP and cardiac rhythm closely; watch for hyperkalaemia

CALCIUM CHANNEL BLOCKERS

NITRATES ≠ hypotensive effect Additive effect Monitor BP at least weekly until stable. Warn patients to report symptoms of hypotension (light-headedness, dizziness on standing, etc.)

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Oestrogens cause sodium and fluid retention

Monitor BP at least weekly until stable; routine prescription of oestrogens in patients with ≠ BP is not advisable

CALCIUM CHANNEL BLOCKERS

ORLISTAT Case report of ≠ BP when orlistat was started for a patient on amlodipine

Uncertain at present Monitor BP at least weekly until stable

CALCIUM CHANNEL BLOCKERS

PERIPHERAL VASODILATORS

CALCIUM CHANNEL BLOCKERS

CILOSTAZOL ≠ plasma concentrations and efficacy of cilostazol with diltiazem, verapamil and nifedipine

These calcium channel blockers inhibit CYP3A4-mediated metabolism of cilostazol

Avoid co-administration

CALCIUM CHANNEL BLOCKERS

MOXISYLYTE (THYMOXAMINE)

≠ hypotensive effect Additive hypotensive effect Monitor BP at least weekly until stable. Warn patients to report symptoms of hypotension (light-headedness, dizziness on standing, etc.)

CALCIUM CHANNEL BLOCKERS

PHOSPHODIESTERASE TYPE 5 INHIBITORS

≠ hypotensive action particularly with sildenafil and vardenafil

Additive effect; phosphodiesterase type 5 inhibitors cause vasodilatation

Warn patients of the small risk of postural ↓ BP

CALCIUM CHANNEL BLOCKERS

POTASSIUM CHANNEL ACTIVATORS

≠ hypotensive effect Additive effect Avoid co-administration of nicorandil with phosphodiesterase type 5 inhibitors. With other drugs, monitor BP closely

CALCIUM CHANNEL BLOCKERS

PROSTAGLANDINS – ALPROSTADIL

≠ hypotensive effect Additive hypotensive effect Monitor BP at least weekly until stable. Warn patients to report symptoms of hypotension (light-headedness, dizziness on standing, etc.)