Introduction
Calcium channel blockers (CCBs) are a group of medications that use several different mechanisms to disrupt the flow of calcium through calcium channels. They were developed in the 1970s and are now widely used as antihypertensives and in heart failure, and also have uses as antiarrhythmics and in stable angina.
They can be divided into cardioselective agents (aka non-dihydropyridines), verapamil and diltiazem, and non cardioselective agents, (aka dihydropyridines) which are essentially all the other CCBs – most commonly – amlodipine, nifedipine, lercanidipine and felodipine. The non-cardioselective agents (sometimes referred to as vasoselective) have greater effect on peripheral smooth muscle and less effect on the myocardium, and thus avoid the negative inotropic effects of cardioselective agents.
- Verapamil is strongly cardioselective and not useful for hypertension
- Diltiazem has mixed effects
- Amlodipine, nifedipine, lercanidipine and felodipine are strongly vasoselective
It is important to remember this distinction because the cardioselective agents are generally contraindicated for use together with beta-blockers as there is a risk of heart block, bradycardia and heart failure – whereas the vasoselective agents are often routinely (and safely) used in conjunction with beta-blockers in patients with carious conditions (particularly stable angina).
Examples
Verapamil, diltiazem, nifedipine, amlodipine, felodipine
Uses
Calcium channel blockers (sometimes called calcium antagonists) are indicated in:
- Hypertension
- Recommended by NICE as first line therapy in patients over 55 or of black African origin, or second line therapy in other patients
- Can be combined with other agents (typically ACE-inhibitors or ARBs)
- Angina
- CCBs are first line agents for heart failure
- Both the cardioselective and vasoselective types can be used, but be wary in patients who may also have heart failure, where amlodipine is preferred and cardioselective agents may be contraindicated
- Often used in conjunction with a beta-blocker
- Beta-blocker plus calcium channel blocker is more effective than using either agent alone
- Do NOT prescribe a non-dihydropyridine CCB with a beta-blocker without specialist (i.e. cardiologist) advice
- Heart failure
- Generally only amlodipine should be used in heart failure
- Theoretically has beneficial effects in heart failure by reducing peripheral vasoconstriction and therefore the afterload.
- Other CCBs should generally be avoided in systolic heart failure.
- Verapamil and diltiazem can have a negative inotropic effect and should be avoided in left systolic dysfunction. It is thought that this negative inotropic effect outweighs the benefits of reduced afterload.
- Some arrhythmias
- Useful in SVTs (supraventricular tachyarrhythmias) and atrial fibrillation. Usually diltiazem or verapamil are used.
- May also be trialled in patients with symptomatic VEBs (ventricular ectopic beats)
- Other Uses
- May be used as migraine or cluster headache preventatives – especially verapamil
- May be used to treat Reynaud’s phenomenon – especially amlodipine and nifedipine
- Can be used topically as 2% diltiazem cream to reduce anal tone which can reduce pressure on anal fissure and help them to heal. It is also occasionally prescribed in a similar manner for external haemorrhoids
Mechanism
- Interfere with calcium uptake into cells through the ‘slow calcium channels’ – also know as L-type calcium channels
- This causes a reduction in intercellular calcium in cardiac and vascular cells
- In the blood vessels this causes smooth muscle relaxation
- In the cardiac cells this causes reduced myocardial contractility
- In His-Purkinje system in the heart – especially in the SA and AV nodes. These tissues depend on slow acting calcium currents to develop their action potentials. Fast response myocardial tissues (in the atria, ventricles and accessory pathways) instead depend on sodium channels
- In the myometrium 0- which cases a reduction in uterine contractility
- The non-dihydropyridines (cardioselective CCBs) are sometimes classified as class IV anti-arrhythmics because of their mechanism of action
- Calcium channel blockers thus block the slow calcium channels, and slow the rate of conduction through the SA and AV nodes (especially AV node).
- In clinical practice, this prolongs the PR interval, and reduces the sinus rate
- The extent of blockade is dose dependent – the higher the dose, the greater the blockade
- The reduced rate, contractility and afterload caused by calcium channel blockers reduces cardiac oxygen demand makes them useful for treating stable angina
- They also cause peripheral vasodilation, which can then in turn cause activation of the sympathetic nervous system
- Their effects vary widely depending on the exact calcium channel blockers used, unlike other drugs used for similar purposes – such as beta-blockers. This is due to their different vasodilatory effects, and thus differing sympathetic nervous system activation. Some agents barely activate the sympathetic nervous system at all, whilst other have a stronger effect, which can then counteract their effect on the SA and AV nodes
- Short acting calcium channel blockers (diltiazem and verapamil) are particularly selective for cardiac muscle, and are strongly negatively inotropic. They reduce cardiac output and slow the heart rate and should be avoided in heart failure.
- Dihydropyridine calcium channel blockers (e.g. amlodipine, felodipine, nifedipine) tend to affect vascular smooth muscle more than cardiac muscle, and are generally considered safe in heart failure.
- Abrupt withdrawal of calcium-channel blockers has been known to result in angina due to rebound vasoconstriction
Adverse Effects
- Generally calcium channel blockers are well tolerated
- Palpitations (probably due to reflex tachycardia), flushing and headaches can occur with vasoselective agents
- Verapamil can cause constipation
- Verapamil can also cause bradycardia, heart block and cardiac failure
- Diltiazem can cause any of the above
- Cardioselective agents have been reported to cause asystole and death when given with beta-blockers – avoid unless closely supervised by a cardiologist!
Prescribing
- Usually CCBs are given orally
- Verapamil is available IV and sometimes given via this route for acute arrhythmia
- Amlodipine has a half life of 35 hours and typically given as a once daily dose
- Verapamil, diltiazem and nifedipine have relatively short half lives (2-8 hours) and are available as standard release and modified release preparations
- Examples
- Amlodipine – for hypertension – 5-10mg OD
- Verapamil – for SVT – 40-160mg BD or TDS, or, 180-240mg MR OD or BD. IV dose is much smaller – typically 2.5 -10mg STAT – not commonly used.
- Diltiazem – for angina – 90mg MR OD
References
- Calcium channel blockers – patient.info
- Calcium channel blockers – Australian Medicines Handbook
- Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
- Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.
- Beers, MH., Porter RS., Jones, TV., Kaplan JL., Berkwits, M. The Merck Manual of Diagnosis and Therapy