Calcium Channel Blockers

Indications for Use

Dihydropyridine calcium-channel blockers include amlodipine, felodipine, lacidipine, lercanidipine, nicardipine, nimodipine and nifedipine. Amlodipine is often used as a first line calcium channel blocker in hypertension, and has been found to reduce hospitalisations for angina and revascularisation procedures in patients with coronary artery disease. Nimodipine is frequently used in aneurysmal subarachnoid haemorrhage to prevent ischaemic neurological deficits, with treatment typically lasting 21 days. Nifedipine is commonly used to treat hypertension in pregnancy.

Non-dihydropyridine calcium channel blockers include verapamil and diltiazem, also known as phenylalkylamines and benzothiazepines, respectively. Verapamil is also indicated in secondary prevention of reinfarction after an acute myocardial infarction as an alternative to beta-blockers. Both agents are used to control heart rate in patients with supraventricular tachyarrhythmias (SVT) such as atrial fibrillation or flutter; however, verapamil is more likely to be used in this indication due to higher cardioselectivity.  

Verapamil and diltiazem are classified as a class IV antidysrhythmic drug under the Vaughan Williams classification, They act by prolonging the plateau phase and reducing conduction through calcium channel blockade.

Mechanism of Action

CCBs inhibit L-type voltage gated calcium channels by binding to the ɑ1 subunit, inhibiting transmembrane influx of calcium ions into cardiac and vascular muscle. L-type voltage gated calcium channels are found on the plasma membrane of many cells and are the main calcium source for contraction in smooth and cardiac muscle. 

Dihydropyridine CCBs are more selective for vascular smooth muscle, where they cause a direct relaxation of arterial smooth muscle leading to an antihypertensive effect. 

Non-dihydropyridine CCBs are more selective for the heart (with verapamil being the most cardio selective) and can also be used in the treatment of arrhythmias. They slow conduction in the sinoatrial and atrioventricular (AV) nodes, slowing the heart and causing a partial AV block, treating a SVT. In angina, non-dihydropyridines work by reducing myocardial contractility and therefore oxygen demand.

Nimodipine increases cerebral perfusion via arterial dilatation and reduces cerebral vasospasm following subarachnoid haemorrhage. 

By TeachMeSeries Ltd (2026)

Fig 1: Blockade of Calcium-Induced Calcium Release from Cardiomyocytes by Calcium Channel Blockers

Pharmacokinetics

The only intravenous CCB available is verapamil which can be used in the acute management of arrhythmias, however adenosine is generally preferred due to its more favourable safety profile.

CCBs are extensively metabolised, often demonstrating low bioavailability. Due to this, in hepatic impairment exposure to CCBs is often increased. 

Amlodipine has a long half life, meaning once daily dosing can achieve an appropriate therapeutic response, conversely all of the other CCBs have shorter half lives, requiring either more frequent dosing or use of modified release (MR) preparations. There are several different long acting preparations of nifedipine and diltiazem available and these may not be interchangeable, therefore prescribing should be by brand. 

The pharmacokinetics of commonly prescribed CCBs are described in the table below:

Contraindications

Most of the contraindications for the use of CCBs are related to cardiac conditions, however use is also contraindicated in shock and lercanidipine is contraindicated in severe renal impairment (GFR <30ml/min).

Cardiac conditions

• CCBs can precipitate heart failure (except amlodipine), therefore are contraindicated in heart failure with reduced ejection fraction (EF) or in a history of impaired left ventricular function
  • Dihydropyridines rarely worsen heart failure however they should not be initiated in people with uncontrolled heart failure, amlodipine can be used with caution in patients with stable heart failure. 
• Verapamil is contraindicated in Wolff-Parkinson-White syndrome and in ventricular dysrhythmias.
• Diltiazem and verapamil are contraindicated in 2nd or 3rd degree atrioventricular block
• CCBs should be avoided within 1 month of myocardial infarction (MI). All except amlodipine can increase mortality after MI when left ventricular dysfunction or pulmonary congestion co-exist. 

Cautions and Adverse Effects

Cautions and adverse effects of CCBs are varied:

Heart

• Vasodilation may result in reduced cardiac output therefore CCBs should be used cautiously in cardiac outflow obstruction e.g. aortic stenosis / obstructive hypertrophic cardiomyopathy 
• Sudden withdrawal may be associated with myocardial ischaemia 

Endocrine

• Diltiazem may increase blood glucose levels, so should be used cautiously in diabetes

Respiratory 

• Diltiazem can cause bronchospasm, so should be used cautiously in asthma. 

Liver

• Caution in hepatic impairment, likely leading to increased exposure, especially diltiazem and verapamil which are extensively metabolised in the liver.

Renal

• Reduced renal perfusion has been reported with diltiazem leading to acute renal failure
• Lercanidipine can cause cloudy peritoneal effluent for patients undergoing peritoneal dialysis

Gastrointestinal 

• Calcium channel blockers have an inhibitory effect on intestinal motility therefore should be used with caution in patients at risk of developing intestinal obstruction or ileus. Verapamil commonly causes constipation. 

Other

• Diltiazem is not recommended in patients with acute porphyria. 
• Peripheral oedema, specifically ankle swelling can occur with dihydropyridine CCBs. This effect is dose-dependent and is not related to generalised fluid retention, but is due to precapillary vasodilation.
• Dizziness, headache, flushing and somnolence; interestingly CCBs may reduce migraine frequency.
• Mild gingivitis may occur with CCBs, this can be reversed with good oral hygiene 

Interactions 

CCBs can cause an enhanced hypotensive effect with other anti-hypertensive medications, TCAs, MAOIs and beta blockers. Whereas the hypotensive effects of CCBs can be inhibited by non-steroidal anti-inflammatories (NSAIDs).

Non-dihydropyridine CCBs should not be prescribed with beta blockers unless under specialist supervision due to the risk of heart failure and bradycardia. Furthermore there is an increased risk of bradycardia and AV block when amiodarone is administered with non-dihydropyridines.

Non-dihydropyridines

Verapamil and diltiazem are inhibitors of CYP3A4 and P-gp, therefore drugs which are substrates for CYP3A4 and/or P-gp may have increased exposure when given concomitantly. 

This can lead to the following effects:

Increased levels of P-Gp substrates: colchicine, dabigatran, digoxin, apixaban, rivaroxaban, methylprednisolone.

Increased levels of CYP substrates: carbamazepine, colchicine, phenytoin, ivabradine, sirolimus, tacrolimus, ciclosporin, midazolam, methylprednisolone, simvastatin, atorvastatin, lomitapide. When given alongside statins, verapamil should be started at the lowest possible dose. 

Reduced exposure to CCBs with enzyme inducers such as carbamazepine, phenobarbital, primidone, phenytoin, rifampicin, St Johns Wort

Increased exposure to CCBs with enzyme inhibitors such as clarithromycin and erythromycin

Other interactions of note are as follows:

• Verapamil is contraindicated with ivabradine
• Verapamil may increase digoxin levels, due to displacement of digoxin at tissue-binding sites, P-gp inhibition and reduced renal excretion. 
• Diltiazem is contraindicated alongside dantrolene infusion (risk of ventricular fibrillation) and with lomitapide (risk of elevated lomitapide levels and deranged LFTs)

Dihydropyridines 

Like non-dihydropyridines, dihydropyridine CCBs are metabolised by CYP3A4 therefore levels may be increased when administered with strong/moderate CYP3A4 inhibitors (including grapefruit) and reduced with strong CYP3A4 inducers. 

Interactions of clinical significance: 

• CCBs + Grapefruit / Grapefruit juice: avoid
• Amlodipine + simvastatin: increased simvastatin levels are reported (77% increase in exposure) – the dose of simvastatin should be limited to 20mg for patients also taking amlodipine. 
• Felodipine + strong CYP3A4 inhibitors and inducers: avoid 
• Lercanidipine + strong inhibitors of CYP3A4/ciclosporin (increased plasma levels of ciclosporin and felodipine)/grapefruit: contraindicated
• Lercanidipine + CYP3A4 inducers: not recommended
• Lercanidipine + digoxin: increase digoxin maximum plasma levels. 
• No interaction is expected when lercanidipine is administered in the morning and simvastatin at night. 
• Nimodipine + strong CYP3A4 inducers: not recommended 
• Nimodipine + strong CYP3A4 inhibitors: blood pressure monitoring is recommended due to an expected increase in nimodipine levels. 

References

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