Calcium-channel blockers (CCBs) were developed in the 1970s and are now widely used.
Mode of action
CCBs all inhibit inward movement of calcium ions through the slow channels of active membranes, especially in:
- Cells of the myocardium (negative inotropic effect/myocardial depression).
- Cells within the His-Purkinje system of the heart (impairment of atrioventricular conduction).
- Cells of vascular smooth muscle (dilatation of coronary and peripheral arteries).
- Cells of the myometrium (reduce uterine contractile activity)
Because the various drugs differ in the relative affinity for these sites, a different balance of therapeutic effects is seen and hence differing indications, efficacy, contra-indications and side-effects. There are three subclasses of CCB:
- Nifedipine - has more affinity for vascular smooth muscle and less for other sites; hence, its value in Raynaud's disease. It rarely precipitates heart failure, as negative inotropic effects are offset by reduction in afterload. Longer-acting preparations should only be used for hypertension and angina (rarely).
- Nicardipine - is similar to nifedipine in its effects on smooth muscle and is used for angina prophylaxis and hypertension. It is not licensed for use in Raynaud's disease.
- Amlodipine and felodipine - are also similar to nifedipine and do not adversely affect myocardial contractility (with the risk of heart failure). They 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).
- Lacidipine, lercanidipine, and isradipine - again, are similar in effect to nifedipine but are only indicated for hypertension.
- 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).
Side-effects of all dihydropyridine CCBs relate to vasodilatation and may improve after a few days (headache, flushing). Ankle swelling, which may only partly respond to diuretics, is also common.
These are used in angina and effects include reduced myocardial oxygen demand and reversal of coronary vasospasm with minimal peripheral vasodilation. Examples include:
- Verapamil - is very negatively inotropic. However, it also impairs atrioventricular 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 contra-indicated with beta-blockers. It is a 'rate-limiting' CCB.
These are intermediate between the above two and have both cardio-depressant and vasodilatory effects. Examples include:
- 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. It is a 'rate-limiting' CCB.
- Raynaud's phenomenon.
- Supraventricular tachycardias, including atrial fibrillation.
- Ischaemic neurological deficit after subarachnoid haemorrhage.
- Delay of preterm labour.
- Prophylaxis for cluster headache.
Evidence of efficacy
- CCBs, along with beta-blockers, are first-line treatment for stable angina.
- Consensus that CCBs are effective in reducing symptoms in stable angina.
- No significant differences, compared with beta-blockers, in frequency of angina, exercise duration, mortality and quality of life.
- Exercise-induced angina is more effectively reduced with amlodipine than atenolol, and the combination is even better.
- Lowering blood pressure prevents strokes and coronary heart disease. CCBs are a key therapeutic choice in the major guidelines for the treatment of hypertension.
- Nifedipine is the mainstay of medical treatment.
- Nifedipine has been shown to reduce frequency and severity of attacks in primary Raynaud's disease but is associated with expected adverse effects (see 'Common adverse effects', below).
- The evidence base for amlodipine and diltiazem is not strong.
- 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.[6, 7]
- Most experience of CCBs to prevent premature labour has been with nifedipine.
- Compared with betamimetics, CCBs are more effective at postponing birth, with fewer side-effects for women and some short-term benefits for the baby.CCBs may have benefits over oxytocin receptor antagonists and magnesium sulfate but further research is required.
- No CCB is licensed for tocolysis.
- 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. It has been reported to cause bradycardia and atrioventricular block so further research is needed.
Common adverse effects
These can be predicted from the type of CCB and mode of action, as already illustrated. Examples include:
- Heart failure
- Heart block
Vascular smooth muscle
Cautions and contra-indications
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.
- Avoidance of grapefruit juice with felodipine, lacidipine, lercanidipine, nicardipine, nifedipine, nimodipine and verapamil. This may affect metabolism.
- Sudden withdrawal of CCBs may exacerbate angina.
These are best considered under each individual drug.
Monitoring and follow-up
This will be determined largely by the condition being treated. Blood pressure and electrocardiography monitoring may be warranted but are best decided upon an individual basis.
Further reading and references
Angina; NICE CKS, October 2015 (UK access only)
Hypertension - not diabetic; NICE CKS, October 2015 (UK access only)
Raynaud's phenomenon; NICE CKS, April 2014 (UK access only)
British National Formulary (BNF); NICE Evidence Services (UK access only)
Management of stable angina; NICE Clinical Guideline (July 2011)
ESC Guidelines on the Management of Stable Coronary Artery Disease; Eur Heart J 201334:2949–3003
Lawes CM, Bennett DA, Feigin VL, et al; Blood pressure and stroke: an overview of published reviews. Stroke. 2004 Apr35(4):1024.
Pope J; Raynaud's phenomenon (primary). BMJ Clin Evid. 2013 Oct 102013:1119.
Supraventricular Arrhythmias; European Society of Cardiology Guideline (2003)
Siu CW, Lau CP, Lee WL, et al; Intravenous diltiazem is superior to intravenous amiodarone or digoxin for achieving ventricular rate control in patients with acute uncomplicated atrial fibrillation. Crit Care Med. 2009 Jul37(7):2174-9
Gaspar R, Hajagos-Toth J; Calcium channel blockers as tocolytics: principles of their actions, adverse effects and therapeutic combinations. Pharmaceuticals (Basel). 2013 May 236(6):689-99. doi: 10.3390/ph6060689.
Flenady V, Wojcieszek AM, Papatsonis DN, et al; Calcium channel blockers for inhibiting preterm labour and birth. Cochrane Database Syst Rev. 2014 Jun 56:CD002255. doi: 10.1002/14651858.CD002255.pub2.
Cohen AS, Matharu MS, Goadsby PJ; Electrocardiographic abnormalities in patients with cluster headache on verapamil therapy. Neurology. 2007 Aug 1469(7):668-75.
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