Trimetazidine

Trimetazidine is an antianginal agent belonging to the Fatty acid oxidation inhibitors.

Trimetazidine is used in the symptomatic treatment of stable angina pectoris.

Trimetazidine is rapidly absorbed from the gastrointestinal tract with a volume of distribution of 4.8 L/kg with plasma protein binding of 16% and gets partially metabolized in the liver (<40% metabolized) into 8 metabolites with unknown activity and gets excreted via urine (79-84%; >60% as unchanged drug) with elimination half-life: Approx 5-6 hours (immediate-release tab); 7 hours (modified-release tab and prolonged-release cap).

The Tmax of Trimetazidine was about <2 hours (immediate-release tab); 2-6 hours (modified-release tab); approx 14 hours (prolonged-release cap)and Cmax was about 91.2 µg/L.

The common side effects are dizziness, drowsiness, headache, weakness, Nausea, strong irregular heartbeat, swelling, and dizziness upon standing.

Trimetazidine is available in a dosage form, such as tablets.

Trimetazidine is available in Japan, Russia, France, and India.

Trimetazidine inhibits β-oxidation of fatty acids by blocking long-chain 3-ketoacyl-CoA thiolase, with the effect of enhancing glucose oxidation, resulting in the more efficient production of ATP with less oxygen demand. It prevents a decrease in intracellular ATP levels by preserving energy metabolism in cells exposed to ischemia or hypoxia, thus ensuring the proper functioning of ionic pumps and transmembrane Na-K flow without changing hemodynamic parameters.

Trimetazidine is available in a dosage form, such as a tablet.

Trimetazidine tablets were taken orally with or without food.

Trimetazidine is used in the symptomatic treatment of stable angina pectoris.

Trimetazidine selectively inhibits long-chain 3-ketoacyl coenzyme A thiolase, an enzyme responsible for mitochondrial beta-oxidation of long-chain fatty acids. Trimetazidine also increases pyruvate dehydrogenase activity, binds to the mitochondrial membrane, directly inhibits cardiac fibrosis, and improves the mechanical resistance of the sarcolemma.

Trimetazidine is approved for its use in the following clinical indications:

Stable angina

Adult: As adjunctive therapy for the symptomatic treatment of patients who are inadequately controlled by or intolerant of 1st-line antianginal therapies: As conventional tab: 20 mg bid. As modified-release tab: 35 mg bid. A prolonged-release cap: 80 mg once daily.

Trimetazidine is available in various dosage strengths: 20mg, 35 mg, and 80 mg.

Trimetazidine is available in a dosage form, such as a tablet.

• CrCl 30-60 mL/minute:
• Immediate-release tablet: Initial and maximum dose: 20 mg twice daily
• Modified release tablet: Initial and maximum dose: 35 mg once daily (preferably in the morning)
• CrCl <30 mL/minute: Use is contraindicated

Trimetazidine is approved for the treatment of Angina pectoris

Eat plenty of fruits, vegetables, and whole grains. Choose lean proteins, such as skinless chicken, fish, and beans. Eat non-fat or low-fat dairy products, such as skim milk and low-fat yogurt. Avoid foods that contain high levels of sodium (salt).

Trimetazidine may be contraindicated in the following.

Parkinson’s disease, parkinsonian symptoms, restless leg syndrome, tremors, and other related movement disorders.

Severe renal impairment (CrCl <30 mL/min). Lactation.

This medicine is not recommended for use in pregnant women unless absolutely necessary. All the risks and benefits should be discussed with the doctor before taking this medicine.

Salt Substitutes: Those who are taking Trimetazidine should avoid sodium, calcium, and magnesium-rich foods. The salts may reduce the blood-pressure-lowering effect of Trimetazidine.

The adverse reactions related to the molecule Trimetazidine can be categorized as

• Common Adverse Effects: Haemorrhage, potential risk of transmission of infection, embolism including pulmonary or cholesterol embolism, infusion reactions (e.g., fever, chills, rigors). Rarely allergic reactions (e.g., bronchospasm, rash). Gastrointestinal disorders: Gingival bleeding, gastrointestinal or retroperitoneal hemorrhage, nausea, vomiting.
• Less Common Adverse Effects: Headache, and dizziness. Skin and subcutaneous tissue disorders: Rash, urticaria, pruritus.
• Rare Adverse Effects: Palpitations, extrasystoles, tachycardia, arterial hypotension, orthostatic hypotension, and flushing.

The clinically relevant drug interactions of Trimetazidine are briefly summarized here.

Trimetazidine should be used with caution with sedatives or hypnotics (buspirone), strong painkillers, some allergy medications (chlorphenamine), certain antidepressants (fluoxetine and lithium), medicines to lower blood pressure (methyldopa), medicines to treat Parkinson’s disease (levodopa, pramipexole, ropinirole), medicines to treat epilepsy (phenobarbital, carbamazepine, phenytoin, rifampicin, primidone, oxcarbazepine, ethosuximide, valproate).

Symptoms: Hypertension, acute heart failure, bradycardia, heart block, AV block, cardiogenic shock, bronchospasm, trouble breathing and consciousness, coma, nausea, vomiting, generalized convulsions, cyanosis (manifest in 20 minutes – 2 hours after taking metoprolol).

Treatment: gastric lavage, the symptomatic therapy: atropine sulfate injection (IV fast 0.5-2 mg) if bradycardia and a violation of AV conduction; glucagon (1-10 mg IV, then IV infusion 2-2.5 mg / h) and dobutamine in the case of reduction of myocardial contractility; agonists (noradrenaline, adrenaline, etc.) when arterial hypotension; diazepam (IV slowly) to eliminate seizures; beta-agonists inhalation or IV jet injection of aminophylline to relieve broncho spastic reactions; cardio acceleration.

Pharmacodynamics:

Trimetazidine is indicated for the symptomatic treatment of stable angina pectoris in patients inadequately controlled or intolerant to first-line therapies. Patients should be counseled regarding the risk of use with reduced renal or hepatic function, worsening of extrapyramidal symptoms or other movement disorders, and risk of falls

Pharmacokinetics:

• Absorption

In elderly patients, a 35 mg oral modified release tablet reaches a mean Cmax of 115 µg/L, with a Tmax of 2.0-5.0 hours, and a mean AUC0-12 of 1104 h*µg/L. In young, healthy patients, the same dose reaches a mean Cmax of 91.2 µg/L, with a Tmax of 2.0-6.0 hours, and an AUC0-12h 720 h*µg/L.

• Distribution:

The volume of distribution: 4.8 L/kg. Plasma protein binding: 16%.

• Metabolism:

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 positions 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.

• Elimination

Trimetazidine is 79-84% eliminated in the urine, with 60% as the unchanged parent compound. 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%.