Newer Antianginal Drugs

NEWER ANTIANGINAL DRUGS

Because of the high prevalence of angina, new drugs are actively sought for its treatment. Some of the drugs or drug groups currently under investigation are listed in Table 12–6.

Ranolazine is a newer antianginal drug that appears to act byreducing a late sodium current (I_Na) that facilitates calcium entry via the sodium-calcium exchanger . The resulting reduction in intracellular calcium concentration reduces cardiac contractility and work. Ranolazine is approved for use in angina in the USA.

Certain metabolic modulators (eg, trimetazidine) are known as pFOX inhibitors because they partially inhibit the fatty acid oxida-tion pathway in myocardium. Because metabolism shifts to oxida-tion of fatty acids in ischemic myocardium, the oxygen requirement per unit of ATP produced increases.

Partial inhibition of the enzyme required for fatty acid oxidation (long-chain 3-ketoacyl thiolase, LC-3KAT) appears to improve the metabolic status of ischemic tis-sue. (Ranolazine was initially assigned to this group of agents.). Trimetazidine is not approved for use in angina in the USA. A much older drug, allopurinol, represents another type of metabolic modifier. Allopurinol inhibits xanthine oxidase , an enzyme that contributes to oxidative stress and endothelial dysfunc-tion. A recent study suggests that high-dose allopurinol prolongs exercise time in patients with atherosclerotic angina.

So-called bradycardic drugs, relatively selective I_f sodium chan-nel blockers (eg, ivabradine), reduce cardiac rate by inhibiting the hyperpolarization-activated sodium channel in the sinoatrial node. No other significant hemodynamic effects have been reported. Ivabradine appears to reduce anginal attacks with an efficacy similar to that of calcium channel blockers and β block-ers. The lack of effect on gastrointestinal and bronchial smooth muscle is an advantage of ivabradine, and Food and Drug Administration approval is expected.

The Rho kinases comprise a family of enzymes that inhibit vascular relaxation and diverse functions of several other cell types. Excessive activity of these enzymes has been implicated in coronary spasm, pulmonary hypertension, apoptosis, and other conditions. Drugs targeting the enzyme have therefore been sought for possible clinical applications. Fasudil is an inhibitor of smooth muscle Rho kinase and reduces coronary vasospasm in experimental animals. In clinical trials in patients with CAD, it has improved performance in stress tests.