Trimetazidine

Pathophysiology: What happens during myocardial ischemia

To fully understand the mechanism of action of the drug, it is necessary to examine the metabolic disorders that occur in the heart muscle during oxygen deprivation. Under ischemic conditions, the following pathological cascade is triggered:

• Energy starvation: ATP molecule synthesis drops sharply.
• Ionic imbalance: due to energy deficiency, the function of ATP-dependent potassium channels is disrupted. This leads to a global failure of the transmembrane transport of key ions: potassium, sodium, and calcium.
• Acidosis: attempting to compensate for the energy shortage, the cell enhances anaerobic glycolysis, which inevitably leads to acidification of the intracellular environment.
• Cytotoxicity: fatty acid oxidation is activated, triggering a massive accumulation of free radicals that directly destroy cardiomyocytes.

Mechanism of action (Pharmacodynamics)

The pharmacodynamics of trimetazidine is based on the optimization of cellular energy metabolism. The site of action of the drug is located inside the mitochondria.

1. Enzyme inhibition: the drug selectively blocks the enzyme 3-ketoacyl-CoA thiolase.
2. Biochemical shift: blocking this enzyme leads to the suppression of $\beta$-oxidation of fatty acids. In response, cardiomyocyte metabolism switches to an alternative pathway: glucose oxidation.
3. End result: the glucose cleavage process requires significantly less oxygen to synthesize the exact same amount of ATP. This ensures a more efficient energy production under hypoxic conditions.

Cellular effects and clinical outcome

Restoration of intracellular ATP stores triggers a chain of positive changes in tissues:

• Normalization of ionic homeostasis: ion pump function resumes, pathological cell overload with sodium and calcium ions decreases, and potassium concentration normalizes. The main outcome is improvement of myocardial contractility.
• Combating acidosis: activation of aerobic glycolysis significantly reduces intracellular acidification.
• Cytoprotection: inhibition of fat oxidation naturally decreases the production of destructive free radicals.

In clinical practice, it is important to note that trimetazidine does not affect general hemodynamics (does not change blood pressure or heart rate) or myocardial blood supply. In patients with angina pectoris, it reduces the frequency of attacks, increases exercise tolerance, and decreases the need for nitrates.

Pharmacokinetics and place in therapy

The drug (also known by the brand name Preductal) is well absorbed from the gastrointestinal tract and easily crosses histohematogenous barriers. Its plasma protein binding is extremely low, about 1%. It is weakly metabolized and excreted predominantly by the kidneys. At the standard dosing regimen (20 mg three times daily), a steady therapeutic concentration in the blood is achieved within 24 hours.

In modern medicine, trimetazidine is used as part of combination therapy for coronary artery disease (CAD). For the prevention of severe complications, such as myocardial infarction, it is prescribed concomitantly with:

• Antiplatelet agents (acetylsalicylic acid, clopidogrel);
• Lipid-lowering agents (statins: simvastatin, pravastatin).

The treatment is well tolerated; side effects are rare and mostly limited to mild gastrointestinal disorders.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Pathophysiology of myocardial ischemia: the role of ATP-dependent potassium channels in ionic homeostasis.
• Biochemistry of energy metabolism: a detailed comparison of $\beta$-oxidation of fatty acids and glucose oxidation.
• Mechanisms of free radical formation during hypoxia and their cytotoxic effects.
• Pharmacology of adjunctive CAD therapy: mechanisms of action of antiplatelet agents and statins.
• Differences between aerobic and anaerobic glycolysis under ischemic conditions.

Other topics in the section "Cardiovascular Drugs"

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.