Metabolic therapy in the treatment of ischaemic heart disease: the pharmacology of trimetazidine

• Published in: Fundamental & clinical pharmacology 2003-04, Vol.17 (2), p.133-145
• Main Authors: Stanley, William C., Marzilli, Mario
• Format: Article
• Language: English
• Subjects: angina; Angina Pectoris - drug therapy; Antianginal agents. Coronary vasodilator agents; Biological and medical sciences; Carbohydrate Metabolism; Cardiovascular system; coronary artery disease; diabetes; Diabetes Complications; Diabetes Mellitus - metabolism; Energy Metabolism - drug effects; Fatty Acids - metabolism; glucose; Humans; lactate; Medical sciences; Myocardial Ischemia - complications; Myocardial Ischemia - drug therapy; Myocardial Ischemia - metabolism; myocardium; Myocardium - metabolism; Pharmacology. Drug treatments; Trimetazidine - pharmacology; Trimetazidine - therapeutic use; Vasodilator Agents - pharmacology; Vasodilator Agents - therapeutic use; Ventricular Dysfunction, Left - complications
• ISSN: 0767-3981; 1472-8206
• DOI: 10.1046/j.1472-8206.2003.00154.x

The primary result of myocardial ischaemia is reduced oxygen consumption and adenosine triphosphate (ATP) formation in the mitochondria, and accelerated anaerobic glycolysis, lactate accumulation and cell acidosis. Classic pharmacotherapy for demand‐induced ischaemia is aimed at restoring the balance between ATP synthesis and breakdown by increasing the oxygen delivery (i.e. with long acting nitrates or Ca2+ channel antagonist) or by decreasing cardiac power by reducing blood pressure and heart rate (i.e. with β‐blocker or Ca2+ channel antagonist). Animal studies show that fatty acids are the primary mitochondrial substrate during moderate severity myocardial ischaemia, and that they inhibit the oxidation of carbohydrate and drive the conversion of pyruvate to lactate. Drugs that partially inhibit myocardial fatty acid oxidation increase carbohydrate oxidation, which results in reduced lactate production and a higher cell pH during ischaemia. Trimetazidine (1‐[2,3,4‐trimethoxibenzyl]‐piperazine) is the first and only registered drug in this class, and is available in over 90 countries world‐wide. Trimetazidine selectively inhibits the fatty acid β‐oxidation enzyme 3‐keto‐acyl‐CoA dehydrogenase (3‐KAT), and is devoid of any direct haemodynamic effects. In double‐blind placebo‐controlled trials trimetazidine significantly improved symptom‐limited exercise performance in stable angina patients when used either as monotherapy or in combination with β‐blockers or Ca2+ channel antagonists. Given available evidence, trimetazidine is an excellent alternative to classic haemodynamic agents, and is unique in its ability to reduce symptoms of angina when used in patients resistant to a haemodynamic treatment as vasodilators, β‐blockers or Ca2+ channel antagonists.