Trizedon OD

Trizedon OD Mechanism of Action



Full Prescribing Info
Pharmacotherapeutic group: Other cardiovascular antianginal drug. ATC code: C01EB15.
Pharmacology: Pharmacodynamics: Mechanism of action: By preserving energy metabolism in cells exposed to hypoxia or ischaemia, trimetazidine prevents a decrease in intracellular ATP levels, thereby ensuring the proper functioning of ionic pumps and transmembrane sodium-potassium flow whilst maintaining cellular homeostasis.
Trimetazidine inhibits β-oxidation of fatty acids by blocking long-chain 3-ketoacyl-CoA thiolase, which enhances glucose oxidation. In an ischaemic cell, energy obtained during glucose oxidation requires less oxygen consumption than in the β-oxidation process. Potentiation of glucose oxidation optimizes cellular energy processes, thereby maintaining proper energy metabolism during ischaemia.
Pharmacodynamic effects: In patients with ischaemic heart disease, trimetazidine acts as a metabolic agent, preserving the myocardial high-energy phosphate intracellular levels. Anti-ischemic effects are achieved without concomitant haemodynamic effects.
Clinical efficacy and safety: Clinical studies on trimetazidine have demonstrated its efficacy and safety in the treatment of patients with chronic angina, either alone or when the benefit from other antianginal medicinal products was insufficient. In a 426-patients randomized, double blind, placebo-controlled study (TRIMPOL-II), trimetazidine (60 mg/day) added to metoprolol 100 mg daily (50 mg b.i.d) for 12 weeks significantly improved statistically exercise tests parameters and clinical symptoms as compared to placebo: total exercise duration +20.1s, p= 0.023, total workload +0.54 METs, p=0.001, time to 1-mm ST-segment depression +33.4s, p=0.003, time to onset of angina +33.9s, p<0.001, angina attacks/week -0.73, p=0.014 and short acting nitrates consumption/week, -0.63, p=0.032, without hemodynamic changes.
In a 223 patients randomized, double blind, placebo-controlled study (Sellier), one 35 mg trimetazidine modified release tablet (b.i.d.) added to 50 mg atenolol (o.d.) for 8 weeks produced a significant increase (+34.4s, p=0.03) in the time to 1-mm ST-segment depression in exercise tests, in a sub-group of patients (n=173), when compared to placebo, 12 hours after taking the drug. A significant difference was also evidenced for the time to onset of angina pectoris (p=0.049). No significant difference between groups could be found for the other secondary endpoints (total exercise duration, total workload and clinical endpoints).
In a 1962 patients three-month randomised, double-blinded study (Vasco study) on top of atenolol 50 mg/d, two dosages of trimetazidine (70 mg/d and 140 mg/d) were tested versus placebo. In the overall population, including both asymptomatic and symptomatic patients, trimetazidine failed to demonstrate a benefit on both ergometric (total exercise duration, time to onset of 1mm ST and time to onset angina) and clinical endpoints. However, in the subgroup of symptomatic patients (n= 1574) trimetazidine (140 mg) significantly improved total exercise duration (+23.8 s versus +13.1 s placebo; p=0.001) and time to onset of angina (+46.3 s versus +32.5 s placebo; p=0.005).
In a 165 patients three-month randomised, double-blind acceptability study on top of both routine antianginal therapies and secondary prevention therapy, the safety profile of trimetazidine 80 mg once daily was shown to be similar to that of trimetazidine MR 35 mg bid. No unexpected adverse event was reported and the study showed no concern regarding the once daily intake of trimetazidine 80 mg.
Pharmacokinetics: Absorption: After oral administration of trimetazidine 80 mg OD capsule, trimetazidine PK profile is flat with a peak of trimetazidine concentration reached around 14 hours after drug intake. Over dosing interval i.e. 24 hours the plasma concentration remains for 15 hours at levels above or equal to 75% of the maximum concentration.
Steady state is reached by the third dose intake (3 days).
Food intake has no effect on trimetazidine PK after administration of the 80 mg MR formulation.
Distribution: The volume of distribution is 4.8 l/kg; protein binding is low (16%).
Elimination: Trimetazidine is primarily eliminated in the urine, mainly as unchanged form. The elimination half-life is on average 7 hours in healthy young volunteers and 12 hours in elderly (more than 65 years).
Total clearance of trimetazidine mainly consists of renal clearance which is directly correlated to creatinine clearance and, to a lesser extent, of liver clearance which is reduced with age.
Toxicology: Preclinical safety data: Chronic toxicity studies conducted by the oral route in dogs (5 to 40 and rats (5 to 200, showed a good safety profile.
Neither embryo-foetotoxic effect nor teratogenicity were detected in mice and in rabbits. A general study on reproduction and embryogenesis in 3 generations of rats showed no anomalies.
The genotoxic potential was thoroughly assessed with in vitro studies including the evaluation of the mutagenic and clastogenic potential and one in vivo study. All tests were negative.
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Already a member? Sign in
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Already a member? Sign in