Calcium channel blockers are drugs which disrupt the transfer of calcium ions through calcium channels. Examples include amlodipine, diltiazem, nifedipine and verapamil. They are frequently used in the treatment of hypertension and ischemic heart disease, where they decrease blood pressure, or lessen chest pain in patients suffering from angina pectoris. Verapamil is also used in the prevention of migraine. In terms of pharmacology of calcium channel blockers, they belong to two main classes: dihydropyridine and non-dihydropyridine. Unwanted effects include headache, flushing, dizziness, palpitations (with dihydropyridines), bradycardia and heart block (non-dihydropyridines).
Pharmacology of Calcium Channel Blockers
Calcium channel blockers are drugs predominantly used in the treatment of hypertension and angina pectoris. Calcium is an essential element for excitation-contraction coupling of muscle cells, the levels of which have profound pharmacological influence.
The drugs were first identified by the German pharmacologist Albrecht Fleckenstein in 1964, a man who – later in 1991 – was awarded the distinguished Albert Einstein World Award of Science. Calcium channel blockers have since gone on to become one of the most prescribed classes of drug used in the treatment of cardiovascular illness.
Mechanism of Action
The mechanism by which calcium channel blockers work is complex. The excitation-contraction coupling of cardiac cells occurs through voltage-dependent calcium channels – channels which are, incidentally, also found on skeletal and smooth muscle. Calcium channel blockers therefore have the following four effects:
- Increase arterial diameter - they do not affect venous diameter.
- Lessen the force of cardiac contraction.
- Slow both the conduction of electrical activity and heartbeat.
- Reduce aldosterone production and, consequently, blood pressure.
Calcium channel blockers can reduce aldosterone production because calcium channels are also present on the zona glomerulosa of the adrenal gland. Both L-type and T-type calcium channels are found in cardiovascular tissues.
- L-type channels are long-acting, high-threshold activated, but slowly inactivated. Almost all therapeutic CCBs express their effect through L-type channels.
- T-type channels are transient, low-threshold activated, but quickly inactivated – channels which are predominantly found in the sinoatrial and atrioventricular nodes.
The vast majority of calcium channel blockers are lipophilic compounds. They are well absorbed from the gut lumen and undergo variable first-pass metabolism.
Nifedipine is inactivated by such metabolism, whereas diltiazem and verapamil are metabolised to less potent metabolites. Half-lives vary, but tend to oscillate between 2 and 12 hours depending on which calcium channel blocker. Duration of action is increased with modified-release formulations.
Verapamil may also be administered intravenously, while nifedipine is also available as a topical formulation. Amlodipine differs from other calcium channel blockers in that it does not undergo first-pass metabolism. It also has a high volume of distribution and slower liver metabolism – both of which result in a considerably longer half-life of between 1 and 2 days.
Arterial dilation causes headache, flushing and dizziness – though tolerance often occurs with frequent use. Patients with poor left ventricular function who take calcium channel blockers are at an increased risk of precipitating heart failure.
Amlodipine does not, though, suppress cardiac contractility – and is linked to peripheral oedema and fatigue. Dihydropyridines – such as amlodipine and nifedipine – may cause tachycardia and palpitations.
Non-dihydropyridines – such as verapamil and diltiazem – may cause bradycardia and heart block. Verapamil is also associated with gingival hyperplasia and gut-related effects, such as constipation.
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