Verapamil, the first clinically useful member of this group, was the result of attempts to synthesize more active analogs of papaverine, a vasodilator alkaloid found in the opium poppy. Since then, dozens of agents of varying structure have been found to have the same fundamental pharmacologic action (Table 12–5). Three chemically dissimilar calcium channel blockers are shown in Figure 12–4. Nifedipine is the prototype of the dihydropyridine family of calcium channel blockers; dozens of molecules in this family have been investigated, and several are currently approved in the USA for angina, hypertension, and other indications.
The calcium channel blockers are orally active agents and are characterized by high first-pass effect, high plasma protein
TABLE 12–4 Properties of several voltage-activated calcium channels.
1Antianginal drug withdrawn from market.2Channel types associated with sperm flagellar activity may be of the Catsper 1–4 variety.3Synthetic snail peptide analgesic (see Chapter 31).4Antiseizure agent (see Chapter 24).DHPs, dihydropyridines (eg, nifedipine); sFTX, synthetic funnel web spider toxin; ω-CTX, conotoxins extracted from several marine snails of the genus Conus; ω-aga-IIIA and ω-aga-IVA, toxins of the funnel web spider, Agelenopsis aperta; SNX-482, a toxin of the African tarantula, Hysterocrates gigas.
binding, and extensive metabolism. Verapamil and diltiazem are verapamil and diltiazem appear to bind to closely related but not also used by the intravenous route. identical receptors in another region of the same subunit. Binding of a drug to the verapamil or diltiazem receptors allosterically affects dihydropyridine binding. These receptor regions are stere- oselective, since marked differences in both stereoisomer-binding
A. Mechanism of Action affinity and pharmacologic potency are observed for enantiomers The voltage-gated L type is the dominant type of calcium channel of verapamil, diltiazem, and optically active nifedipine congeners. in cardiac and smooth muscle and is known to contain several Blockade of calcium channels by these drugs resembles that drug receptors. It consists of α1 (the larger, pore-forming sub-of sodium channel blockade by local anesthetics (see Chapters 14 unit), α2, β, γ, and δ subunits. Four variant α1 subunits have and 26). The drugs act from the inner side of the membrane and been recognized. Nifedipine and other dihydropyridines have bind more effectively to open channels and inactivated channels. been demonstrated to bind to one site on the α1 subunit, whereas Binding of the drug reduces the frequency of opening in response
TABLE 12–5 Clinical pharmacology of some calcium channel-blocking drugs.
FIGURE 12–4 Chemical structures of several calcium channel-blocking drugs.
to depolarization. The result is a marked decrease in transmembrane calcium current, which in smooth muscle results in long-lasting relaxation (Figure 12–3) and in cardiac muscle results in reduction in contractility throughout the heart and decreases in sinus node pacemaker rate and atrioventricular node conduction velocity. * Although some neuronal cells harbor L-type calcium channels, their sensitivity to these drugs is lower because the channels in these cells spend less time in the open and inactivated states.
Smooth muscle responses to calcium influx through ligand-gated calcium channels are also reduced by these drugs but not as markedly. The block can be partially reversed by elevating the concentration of calcium, although the levels of calcium required are not easily attainable in patients. Block can also be partially reversed by the use of drugs that increase the transmembrane flux of calcium, such as sympathomimetics.