CALCIUM-CHANNEL BLOCKERS

2011

CALCIUM-CHANNEL BLOCKERS are agents that literally block or close any of the many types of calcium channels. However, in common usage the term is mainly used to describe a class of drugs finding increasing application in therapeutics (also called calcium antagonists or calcium-entry blockers) typified by the dihydropyridines (DHPs). In a more general usage of the term, there are many different classes of calcium-channel blockers, and many types of calcium channels. See CALCIUM-CHANNEL ACTIVATORS.

First, in the cell membrane, the voltage-gated calcium channels are of at least six types — termed L, N, T, P, Q, R — that may be differentiated by electrophysiological, molecular cloning and pharmacological criteria. The L- and N-channels are high-voltage activated, voltage-dependent and undoubtedly of great importance in normal physiology; L mainly in smooth, cardiac and skeletal muscle (and some neurons), but N only in neurons. T-channels are important in repetitive activity in cardiac SA node of the heart, neurons and some endocrine cells. The remainder have been found more recently in neurons. These channels are products of different genes, but they all share great structural similarity — both with respect to each other, and to voltage-gated K+ and Na+ channels. The individual pharmacology of each of these six ion channels resides largely in the α1-subunit (which includes a voltage-sensing sequence); but even this is heterogeneous within a given channel (for the L-channel there are at least six different genes). Calcium is vital to the function of every cell type, and plays multiple roles ranging from charge-carrier across the membrane, to near-universal final intracellular-mediation of contraction, secretion or cell growth. Calcium-channel blockers can be used for therapeutic effect (or for analytical purposes) without endangering the function of every cell, partly by reason of the extreme diversity of the ctpsubunits. For instance, there is considerable selectivity of action between blockers of the N-channel (blocked by ω-conotoxin GVIA, a peptide toxin from a marine snail), whereas DHP and related blockers are much more active at L-channels. There are only rather nonselective blockers for the T-channels, e.g. octanol, Ni2+, amiloride, flunarizine. The beta-channels are characterized by their sensitivity to ω-agatoxin IVA (a funnel web spider toxin (FTX)), and are also blocked by to-agatoxin III A and ω-conotoxin MVIIC. The Q-channel is blocked by ω-agatoxin IVA and ω-conotoxin MVIIC.

In clinical practice, there is further selectivity of drug action at the L-channels, in part originating from the fact that there seem to be separate, but adjacent, binding sites for different chemical classes of calcium antagonists. Of the L-channel blockers, some chemical families are more active on the smooth muscle of the cardiovascular system (e.g. nifedipine and most other DHPs), whereas others are more cardioactive (e.g. verapamil). Some further details of these differences are given at the VASODILATOR entry. This selectivity has been attributed to there being different binding sites on the a,-subunits (closely located by molecular biology mutation techniques) for the dihydropyridines (e.g. nifedipine, nitrendipine. nimodipine), benzothiazepines (e.g. diltiazem) and phenylalkylamines (e.g. verapamil) groups. Latterly, further chemical groups of L-channel blockers have been developed that may afford some selectivity for uterine, gastrointestinal or airways smooth muscle (including some indolizinesulphones, e.g. fantofarone and mixed calcium-/sodium-channel blockers, e.g. lifarizine). A further factor contributing to some degree of selectivity follows from the fact that L-channel blockers show use-dependence through binding more strongly to the inactivated mode; a consequence of which might be that more electrophysio-logically active, and often pathological, states would be more sensitive to the blocking action of some L-channel blockers, and so would to some extent be self-regulating.

Clinically, the main uses of the L-channel calcium-channel blockers include a direct smooth muscle relaxant action as vasodilators and for effects on heart muscle (see smooth MUSCLE RELAXANTS; VASODILATORS), leading to their widespread use as antihypertensives (e.g. amlopidine, isradipine, nicardipine, nifedipine, verapamil), in ANTIANGINAL AGENTS (e.g. amlopidine, diltiazem, nicardipine, nifedipine, verapamil), as ANTIARRHYTHMIC AGENTS (e.g. verapamil), as vasodilators to treat peripheral vascular disease or Raynaud’s phenomenon (e.g. nifedipine), in the prevention of ischaemic damage following subarachnoid haemorrhage (nimodipine), and as ANTIMIGRAINE AGENTS in prophylaxis against attacks (e.g. nifedipine, verapamil).

Yet other drugs affect intracellular calcium channels of the endoplasmic or sarcoplasmic reticulum, e.g. inositol triphosphate receptor channels, which open in response to InsP3 itself and certain other inositol phosphates antagonized by heparin. The various ryanodine receptor channels, are activated by low concentrations of ryanodine, but antagonized by high concentrations of ryanodine and by ruthenium red. The ryanodine receptor in skeletal muscle has a mutant form (on an autosomal dominant gene) which can be triggered by halothane and suxamethonium chloride to precipitate the dangerous condition of malignant hyperthermia. The muscle rigidity of this condition, and some other muscle rigidity states, can be treated clinically by blocking the receptors with dantrolene. These and other intracellular sites may well represent important future targets for drug action.

Turning to ligand-gated channels, less is known about channel-blocking mechanisms. Some possible sites are outlined at the calcium-channel activators entry. Blocking agents may work by indirect, possibly allosteric, interactions with intrinsic ion channels (e.g. ruthenium red at the capsaicin receptor, or glycine at the NMDA glutamate receptor). Others work through a direct-coupled G-protein action (e.g. N-type calcium channel-closure through opioid or α2-adrenoceptor activation).