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 beta-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 beta-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 beta-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, beta-blockers or Ca2+ channel antagonists.