Calcium Channel Blockers

Calcium channel blockers (CCBs) were developed in the 1970s. They are now widely used.Those now available have quite disparate therapeutic effects, indications and adverse effects.

• Dihydropyridine CCBs (drugs ending in 'pine'):
  • Reduce systemic vascular resistance and arterial pressure but not in angina (except amlodipine)
• Phenylalkylamine CCBs (for example verapamil). Used in angina hence:
  • Reduce myocardial oxygen demand
  • Reverse coronary vasospasm
  • Minimal peripheral vasodilation
• Benzothiazepine CCBs (for example diltiazem):
  • Intermediate between 2 subclasses above
  • Have both cardio-depressant and vasodilatory effects

• Verapamil is very negatively inotropic, impairs a-v conduction so slowing heart rate and lowering blood pressure. As a consequence it is used for angina, hypertension and supraventricular tachycardias (SVTs) but can also precipitate heart failure, cause hypotension, exacerbate conduction disorders and is contraindicated with beta blockers.
• Nifedipine has more affinity for vascular smooth muscle and less for other sites. Hence it's value in Raynaud's Disease. It rarely precipitates heart failure as negative inotropic effects are offset by reduction in after load. Longer acting preparations should only be used for angina (rarely) and hypertension.
• Nicardipine is similarly effective on smooth muscle and used for angina prophylaxis and hypertension. It is not licensed for use in Raynaud's Disease.
• Amlodipine and felodipine similarly do not adversely affect myocardial contractility (with the risk of heart failure) and have a longer duration of action than nifedipine making them useful in hypertension and angina. All are valuable in angina associated with coronary vasospasm. Side effects relate to vasodilatation and may improve after a few days (headache, flushing).
• Isradipine, lacidipine, lercanidipine and nisoldipine again are similar in effect to nifedipine but except for nisoldipine (also used for angina) are only indicated for hypertension.
• Diltiazem is effective in angina and the longer acting formulation in hypertension. It is less negatively inotropic than verapamil but should still be used cautiously with beta-blockers.
• Nimodipine is similar to nifedipine but has an enhanced, selective effect on the cerebral arteries. This makes it useful for cerebral artery spasm and it is used solely for this purpose after subarachnoid haemorrhage (to prevent ischaemic deficit).

• Angina
• Hypertension
• Raynaud's phenomenon
• Supraventricular arrhythmias
• Ischaemic neurological deficit after subarachnoid haemorrhage
• Prophylaxis for cluster headache

See related articles on Angina, Management of Hypertension, Raynaud's, Cluster Headache.

• Angina:
  • Consensus that calcium-channel blockers are effective at reducing symptoms in stable angina.
  • No significant differences compared with beta-blockers in frequency of angina, exercise duration, mortality, quality of life.^1,2,3
  • No significant difference compared with isosorbide mononitrate in frequency of attacks or quality of life, but peripheral oedema more of a problem.⁴
• Hypertension:
  • Lowering blood pressure prevents strokes and ischaemic heart disease.⁵ Calcium channel blockers are a key therapeutic choice in the major guidelines for the treatment of hypertension.
• Raynaud's Disease:
  • Nifedipine and diltiazem are the mainstay of medical treatment.
  • Nifedipine has been shown consistently to reduce frequency and severity of attacks in Primary Raynaud's but is associated with expected adverse effects (see below).^6,7,8 In one typical study 19 out of 21 sufferers preferred nifedipine to placebo but 30% reported side effects.⁷
  • The evidence base for amlodipine and diltiazem is not strong.
• Supraventricular arrhythmias:
  • Intravenous verapamil and diltiazem have been found equally effective at reducing heart rate at 10 or 30 minutes compared with placebo in atrial flutter and atrial fibrillation but use of verapamil could be limited by hypotension.⁹
• Cluster headache:
  • Verapamil is used (unlicensed indication) to help reduce the severity of cluster attacks and there seems consensus from patient groups and clinicians that it is useful. Trials are needed.

Angina prophylaxis

• First choice when a beta blocker cannot be taken is monotherapy with one of the following:
  • Isosorbide mononitrate
  • A rate limiting calcium-channel blocker (verapamil or diltiazem)
  • Ivabradine
  • Long acting dihydropyridine calcium channel blocker (modified release nifedipine)
• Second choice is:
  • Dual therapy-CCB with a beta-blocker at maximum tolerated dose add:
    • Long acting dihydropyridine like nifedipine (beware the risk of bradycardia especially with diltiazem)
    • Verapamil is not recommended (because of an even greater risk of bradycardia and a risk of heart failure)
  • Dual therapy-CCB with nitrates:
    • If monotherapy gives inadequate control
    • When beta blockers cannot be taken

Hypertension

CCBs should be first choice in:

• Elderly patients with isolated systolic hypertension (dihydropyridine calcium-channel blocker)
• Hypertensive patients with Raynaud's phenomenon (dihydropyridine calcium-channel blocker)
• Hypertensive patients with angina (rate limiting calcium-channel blockers-verapamil or diltiazem)

• Hypertensives of African origin
• Patients over age 55

• Often useful according to hypertension guidelines

Raynaud's phenomenon

Nifedipine starting at 5 mg t.d.s. and going up to 20 mg t.d.s. is the drug of choice.

SVTs

There is as indicated above evidence of efficacy in atrial flutter and fibrillation for verapamil and diltiazem. Their place in the overall management of arrhythmias should be reviewed elsewhere.

Subarachnoid haemorrhage

Nimodipine is used in hospital with close monitoring for subarachnoid haemorrhage.

These can be predicted from the type of CCB and mode of action as already illustrated. Examples include:

• Myocardial effects:
  • Hypotension
  • Heart failure
• Conduction effects:
  • Heart block
  • Arrhythmias
• Vascular smooth muscle:
  • Flushing
  • Oedema
  • Headaches
  • Rashes
• Other effects:
  • Constipation
  • Rashes
  • Gynaecomastia
  • Photosensitivity

Again these can be predicted from the type of CCB and mode of action. Individual drug monographs need to be reviewed. Some examples include:

• Cardiovascular: shock, unstable angina, significant aortic stenosis, bradycardia, heart failure etc.
• Hepatic or renal impairment.
• Breast feeding, pregnancy.
• Avoidance of grapefruit juice with felodipine, isradipine, lacidipine, lercanidipine, nicardipine, nifedipine, nimodipine, nisoldipine and verapamil. This may affect metabolism.
• Sudden withdrawal of CCBs may exacerbate angina.

These are best considered under each individual drug.

This will be determined largely by the condition being treated. Side effects, blood pressure measurement and checks on renal and hepatic function should be reviewed regularly according to resources and clinical need.