Certain metabolic modulators (eg, trimetazidine) are known as pFOX inhibitors because they partially inhibit the fatty acid oxidation pathway in myocardium. Because metabolism shifts to oxidation 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 tissue. (Ranolazine was initially assigned to this group of agents, but it lacks this action at clinically
TABLE 12–6 New drugs or drug groups under investigation for use in angina.
Direct bradycardic agents, eg, ivabradine
Inhibitors of slowly inactivating sodium current, eg, ranolazine
Metabolic modulators, eg, trimetazidine
Nitric oxide donors, eg, L-arginine
Potassium channel activators, eg, nicorandil
Protein kinase G facilitators, eg, detanonoate
Rho-kinase inhibitors, eg, fasudil
Sulfonylureas, eg, glibenclamide
Xanthine oxidase inhibitors, eg, allopurinol relevant concentrations.) Trimetazidine does inhibit LC-3KAT at achievable concentrations and has demonstrated efficacy in stable angina. However, it is not approved for use in the USA.
Perhexiline was found to benefit some patients with angina decades ago but was abandoned because of reports of hepatotoxicity and peripheral neuropathy. However, pharmacokinetic studies suggested that toxicity was due to variable clearance of the drug, with extremely high plasma concentrations in patients with deficient CYP2D6 activity. This drug may shift myocardial metabolism from fatty acid oxidation to more efficient glucose oxidation (compared with trimetazidine). Because it does not involve vasodilation, it may be useful in patients refractory to ordinary medical therapy if plasma concentration is carefully controlled. Perhexiline is currently approved in only a few countries (not the USA).
So-called bradycardic drugs, relatively selective If sodium channel 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 blockers. The lack of effect on gastrointestinal and bronchial smooth muscle is an advantage of ivabradine, and it is approved for use in angina and heart failure outside the USA. In the USA, it is approved for heart failure and is used off-label for angina in combination with β blockers.
The Rho kinases (ROCK) 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. It is investigational in angina.
Allopurinol represents another type of metabolic modifier. Allopurinol inhibits xanthine oxidase (see Chapter 36), an enzyme that contributes to oxidative stress and endothelial dysfunction in addition to reducing uric acid synthesis, its mechanism of action in gout. Studies suggest that high-dose allopurinol (eg, 600 mg/d) prolongs exercise time in patients with atherosclerotic angina. The mechanism is uncertain, but the drug appears to improve endothelium-dependent vasodilation. Allopurinol is not currently approved for use in angina.