Calcium Antagonists

        The second major therapeutic approach to the treatment of angina is the use of calcium channel blockers. As stated earlier, calcium plays an important role in the regulation of many cellular processes including muscle contraction. The entry of extracellular Ca⁺² ions into the cytosol of myocardial cells and their release from intracellular storage sites is important for initiating the contraction of the myocardium. Calcium channel blockers reduce or prevent the increase of free cytosolic calcium ions by interfering with the transport of calcium ions through these pores.

    Structure

        There are three classes of calcium channel blockers available for anti-anginal action. These include the phenylalkylamines, the 1,4-dihydropyridines, and the benzothiazepines (figure below).

        To view the three-dimensional structures of these molecules click on the appropriate link below. (Highly recommended)

•     Nifedipine

•     Amlodipine

•     Nicardipine

•       Bepridil

•       Verapamil

•       Diltiazem

        The structural dissimilarity of these agents is apparent and serves to emphasize the fact the each is distinctly different from the others in its profile of effects.

        Metabolism

        The calcium channel blockers are rapidly and completely absorbed after oral administration as can be easily understood from their primarily hydrophobic structures. All these are highly protein bound (>90%) for the same reason.

        First-pass metabolism occurs extensively, especially for verapamil, leading to low bioavailability. The primary metabolites are N-demethylated and deacetylated products. Because of many N-methyl groups the number of metabolites produced are numerous. These metabolites are inactive.

        Typically the duration of action of these calcium channel blockers ranges from 4 - 8 h. However, amlodipine is the only agent that is active over a 24 h range and hence can be given once daily. The suggested reason for the longer duration of action of amlodipine is the lowered metabolism susceptibility due to the chlorine substitution in the phenyl ring.

        Biochemical Mechanism of Action

        Contraction of cardiac and other muscle occurs from a reaction between actin and myosin. The contractile process in the cardiac muscle involves a series of proteins including the troponins and tropomyosin. Free Ca⁺² ions bind to troponin C resulting in the exposure of binding sites on the actin molecule for interacting with myosin. (figure below)

       Thus the increase of free Ca⁺² ions within the cell initiates the process of contraction. Although the total intracellular [Ca⁺²] is more than 1 mM, the free [Ca⁺²] is usually less than 0.1 mM. Most of the Ca+2 is stored within intracellular organelles or is tightly bound to intracellular proteins. The dramatic increase in free [Ca⁺²] needed for contraction of cardiac muscles results from the activation of calcium channels on the cell membranes.

        These channels are selective for Ca⁺² ions. The channels are membrane bound proteins that transport extracellular Ca⁺² to the cytosol. There are several different types of calcium channels differing in location and function. Calcium antagonists act only on the L-type channel to produce their pharmacological effects. The L-channel are named on the basis of their long-lasting effects.

        The calcium channel blockers interact with the calcium channel protein. These blockers do not physically occlude the channel but rather bind to specific sites in the channel causing conformational changes that affect Ca⁺² movement.

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©2000 VCU School of Pharmacy
Revised: January 4, 2000
Questions or Comments : Dr. Umesh R. Desai