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Trimetazidine is a piperazine derivative indicated for the symptomatic treatment of stable angina pectoris in patients inadequately controlled or intolerant to first line therapies.

Trimetazidine has been studied as a treatment for angina pectoris since the late 1960s. 7, 8 Acidic conditions, caused by anaerobic metabolism and fatty acid oxidation, in response to myocardial ischemia, activate sodium-hydrogen and sodium-calcium antiport systems.

The increased intracellular calcium decreases contractility.

It is hypothesized that trimetazidine inhibits 3-ketoacyl coenzyme A thiolase, which decreases fatty acid oxidation but not glucose metabolism, preventing the acidic conditions that exacerbate ischemic injury. 1, 10 However, evidence for this mechanism is controversial.

Trimetazidine is not

FDA approved.

However, it has been approved in France since 1978.

Trimetazidine is indicated for the symptomatic treatment of stable angina pectoris in patients inadequately controlled or intolerant to first line therapies.

Trimetazidine is indicated for the symptomatic treatment of stable angina pectoris in patients inadequately controlled or intolerant to first line therapies.

Patients should be counselled regarding the risk of use with reduced renal or hepatic function, worsening of extrapyramidal symptoms or other movement disorders, and risk of falls.

During myocardial ischemia, anaerobic metabolism takes over, increasing levels of lactic acid.

The decreased intracellular pH and increased concentration of protons activates sodium-hydrogen and sodium-calcium antiport systems, raising intracellular calcium concentrations, finally leading to decreased contractility.

This injury to the myocardium raises concentrations of catecholamines, which activate hormone sensitive lipase, and increasing fatty acid concentrations in plasma.

When the myocardium is repurfused, fatty acid oxidation becomes the dominant form of ATP production, maintaining an acidic pH, and further exacerbating the injury.

The mechanism of action of trimetazidine is not fully understood.

Trimetazidine may inhibit mitochondrial 3-ketoacyl coenzyme A thiolase, decreasing long chain fatty acid β-oxidation but not glycolysis in the myocardium. 1, 10 The decreased long chain fatty acid β-oxidation is compensated for by increased use of glucose, preventing a lowered myocardial pH, and further decreases in contractility. 1, 10 However, another study suggests that 3-ketoacyl coenzyme A thiolase may not be trimetazidine's target, and that this mechanism may be incorrect.

U 3-ketoacyl-CoA thiolase, mitochondrial inhibitor Humans.

In elderly patients, a 35 mg oral modified release tablet reaches a mean C max of 115 µg/L, with a T max of 2.0-5.0 hours, and a mean AUC 0-12 of 1104 h*µg/L.

In young, healthy patients, the same dose reaches a mean C max of 91.2 µg/L, with a T max of 2.0-6.0 hours, and an AUC 0-12h 720 h*µg/L.

The volume of distribution of trimetazidine is 4.8 L/kg.

Trimetazidine can be oxidized at the piperazine ring to form trimetazidine ketopiperazine.

Trimetazidine can also be

N-formylated, N-acetylated, or N-methylated at the piperazine ring to form N-formyltrimetazidine, N-acetyltrimetazidine, and N-methyltrimetazidine respectively.

Alternatively, trimetazidine can be demethylated at the 2, 3, or 4 position of the 2,3,4-trimethoxybenzyl moiety to form 2-desmethyltrimetazidine, 3-desmethyltrimetazidine, or 4-desmethyltrimetazidine.

The desmethyltrimetazidine metabolites can undergo sulfate conjugation or glucuronidation prior to elimination.

Hover over products below to view reaction partners Trimetazidine Trimetazidine Ketopiperazine N-formyl Trimetazidine N-acetyltrimetazidine N-methyltrimetazidine 2-desmethyltrimetazidine + 3-desmethyltrimetazidine + 4-desmethyltrimetazidine 4-desmethyltrimetazidine O-glucuronide 4-desmethyltrimetazidine O-sulphate 3-desmethyltrimetazidine O-glucuronide 3-desmethyltrimetazidine O-sulphate 2-desmethyltrimetazidine O-glucuronide 2-desmethyltrimetazidine O-sulphate.

Trimetazidine is 79-84% eliminated in the urine, with 60% as the unchanged parent compound. 3, 9 In a study of 4 healthy subjects, individual metabolites made up 0.01-1.4% of the dose recovered in urine.

In the urine, 2-desmethyltrimetazidine made up 0-1.4% of the recovered dose, 3.

• and 4-desmethyltrimetazidine made up 0.039-0.071% each, N-methyltrimetazidine made up 0.015-0.11%, trimetazidine ketopiperazine made up 0.011-0.4%, N-formyltrimetazidine made up 0.035-0.42%, N-acetyltrimetazidine made up 0.016-0.19%, desmethyl trimetazidine O-sulphate made up 0.01-0.65%, and an unknown metabolite made up0.026-0.67%.

In young, healthy subjects, the half life of trimetazidine is 7.81 hours. 3, 9 In patients over 65, the half life increases to 11.7 hours. 3, 9.

Trimetazidine clearance is strongly correlated with creatinine clearance.

In eldery patients with a creatinine clearance of 72 ± 8 mL/min, trimetazidine clearance was 15.69 L/h.

In young, healthy patients with a creatinine clearance of 134 ± 18 mL/min, trimetazidine clearance was 25.2 L/h.

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Data regarding overdoses of trimetazidine are not readily available.

Treat overdoses with symptomatic and supportive therapy.

The oral

LD in rats is 1700 mg/kg, and in mice is 1550 mg/kg.

The subcutaneous

LD in rats is 1500 mg/kg, and in mice is 410 mg/kg.