Trimetazidine

Trimetazidine is a drug for angina pectoris sold under many brand names.[1] Trimetazidine is described as the first cytoprotective anti-ischemic agent developed and marketed by Laboratoires Servier (France). Trimetazidine is an anti-ischemic (anti-anginal) metabolic agent, which improves myocardial glucose utilization through inhibition of fatty acid metabolism, also known as fatty acid oxidation inhibitor.

Trimetazidine
Clinical data
Trade namesVastarel[1]
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • UK: Controlled Drug
  • US: Schedule IV
Pharmacokinetic data
Bioavailabilitycompletely absorbed at around 5 hours, steady state is reached by 60th hour
Protein bindinglow (16%)
Metabolismminimal
Elimination half-life7 to 12 hours
Excretionmainly renal (unchanged), exposure is increased in renal impairment – on average by 4-fold in subjects with severe renal impairment (CrCl <30 ml/min)
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.023.355
Chemical and physical data
FormulaC14H22N2O3
Molar mass266.336 g/mol g·mol−1
3D model (JSmol)
 NY (what is this?)  (verify)

Medical uses

Trimetazidine is usually prescribed as a long-term treatment of angina pectoris, and in some countries (including France) for tinnitus and dizziness. It is taken twice a day. In 2012 European Medicines Agency (EMA) finished a review of benefits and risks of trimetazidine and recommended restricting use of trimetazidine-containing medicines just as an additional treatment of angina pectoris in case of inadequate control by or intolerance to first-line antianginal therapies.[2]

Controlled studies in angina patients have shown that trimetazidine increases coronary flow reserve, thereby delaying the onset of ischemia associated with exercise, limits rapid swings in blood pressure without any significant variations in heart rate, significantly decreases the frequency of angina attacks, and leads to a significant decrease in the use of nitrates.

It improves left ventricular function in diabetic patients with coronary heart disease. Recently, it has been shown to be effective in patients with heart failure of different etiologies.[3][4]

Other pharmaceutical uses

Trimetazidine is among the performance enhancing drugs prohibited in athletics by the World Anti-Doping Agency. In 2014, Chinese Olympic champion swimmer Sun Yang was caught with a urine test and banned by the Chinese Swimming Association for 3 months.[5]

Adverse effects

Trimetazidine has been treated as a drug with a high safety and tolerability profile.[6] It interacts with monoamine oxidase inhibitors.

There is scarce information about trimetazidine's effect on mortality, cardiovascular events or quality of life. Long term randomized controlled trials comparing trimetazidine against standard anti-anginal agents, using clinically important outcomes would be justifiable.[6] Recently, an international multicentre retrospective cohort study has indeed shown that in patients with heart failure of different etiologies, the addition of trimetazidine on conventional optimal therapy can improve mortality and morbidity.[7]

EMA recommends that doctors should no longer prescribe trimetazidine for the treatment of patients with tinnitus, vertigo or disturbances in vision.[2] The recent EMA evaluation also revealed rare cases (3.6/1 000 000 patient years) of Parkinsonian (or extrapyramidal) symptoms (such as tremor, rigidity, akinesia, hypertonia), gait instability, restless leg syndrome, other related movement disorders, majority of patient recovered within 4 months after treatment discontinuation, therefore, doctors are advised not to prescribe the medicine either to patients with Parkinson disease, parkinsonian symptoms, tremors, restless leg syndrome or other related movement disorders, nor to patients with severe renal impairment.[2]

Mechanism of action

Trimetazidine inhibits beta-oxidation of fatty acids by blocking long-chain 3-ketoacyl-CoA thiolase, which enhances glucose oxidation.[8] In an ischaemic cell, energy obtained during glucose oxidation requires less oxygen consumption than in the beta-oxidation process. Potentiation of glucose oxidation optimizes cellular energy processes, thereby maintaining proper energy metabolism during ischaemia. 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.[9]

Brand names

Trimetazidine is distributed under many brand names: 3 Kat, Adexor, Aiyiling, Angimax, Angimet, Anginox, Angintriz, Angiozil, Angirel, Angirid, Angitrim, Angivas, Angivent, Antoris, ApoTrimet, Apstar, Atanol, Bustidin, Cardimax, Carvidon, Curime, Cyto-Protectin, Cytogard, Dilatan, Dimesar, Domisin, Energotrim, Feelnor, Idaptan, Imovexil, Intervein, Invidon, Kardin, Liomagen, Matenol, Metacard, Metacardia, Metagard, Metazydyna, Mezitan, Miozidine, Moduxin, Neotri, Novazidine, Portora, Prectazidine, Predizin, Predozone, Preductal, Predutrim, Preduxl, Protevasc, Rimecor, Setal, Sitorel, Tacirel, Tazidinol, Tazz, TevaTrim, TMZ, Triacyt, Tricardia, Tricoz, Triguard, Trimductal, Trimecard, Trimeductan, Trimektal, Trimeluzine, Trimepect, Trimerel, Trimet, Trimetacor, Trimetaratio, Trimetazidin, Trimetazidinã, Trimetazidine, Trimetazidinum, Trimetazigen, Trimetazydyna, Trimezar, Trimpol, Trizedon, Trizid, Trizidine, Tryme, Vascotasin, Vascotazin, Vashasan, Vasorel, Vasotrim, Vaspycar, Vastar, Vastarel, Vastazid, Vastinan, Vastinol, Vastor, Vestar, Vosfarel, Whilst, Ze Wei Er, Zidimet, Zidin, Zidmetin, Zilutra, and Zimetin.[1]

References
  1. "Trimetazidine – International brands". Drugs.com. Retrieved 7 May 2017.
  2. "European Medicines Agency recommends restricting use of trimetazidine-containing medicines" (pdf). Press release. European Medicines Agency. 2012-06-12.
  3. Fragasso G, Palloshi A, Puccetti P, Silipigni C, Rossodivita A, Pala M, Calori G, Alfieri O, Margonato A (September 2006). "A randomized clinical trial of trimetazidine, a partial free fatty acid oxidation inhibitor, in patients with heart failure". J. Am. Coll. Cardiol. 48 (5): 992–8. doi:10.1016/j.jacc.2006.03.060. PMID 16949492.
  4. Tuunanen H, Engblom E, Naum A, Någren K, Scheinin M, Hesse B, Juhani Airaksinen KE, Nuutila P, Iozzo P, Ukkonen H, Opie LH, Knuuti J (September 2008). "Trimetazidine, a metabolic modulator, has cardiac and extracardiac benefits in idiopathic dilated cardiomyopathy". Circulation. 118 (12): 1250–8. doi:10.1161/CIRCULATIONAHA.108.778019. PMID 18765391.
  5. "Sun Yang, el chico malo de la natación que gana todo pero al que nadie quiere". yahoo.es. 22 July 2019.
  6. Ciapponi A, Pizarro R, Harrison J (2005). "Trimetazidine for stable angina". Cochrane Database Syst Rev (4): CD003614. doi:10.1002/14651858.CD003614.pub2. PMID 16235330. (Retracted, see doi:10.1002/14651858.cd003614.pub3. If this is an intentional citation to a retracted paper, please replace {{Retracted}} with {{Retracted|intentional=yes}}.)
  7. Fragasso G, Rosano G, Baek Hong S, Sisakian H, Di Napoli P, Alberti L, Calori G, Kang SM, Sahakyan A, Vitale C, Marazzi G, Margonato A, Belardinelli R. "Effect of partial acid oxidation inhibition with trimetazidine on mortality and morbidity in heart failure: results from an international multicentre retrospective cohort study." Int J Cardiol. 2013; 163: 320–5.
  8. Kantor PF, Lucien A, Kozak R, Lopaschuk GD (March 2000). "The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase". Circ. Res. 86 (5): 580–8. doi:10.1161/01.RES.86.5.580. PMID 10720420.
  9. Stanley WC, Marzilli M (April 2003). "Metabolic therapy in the treatment of ischaemic heart disease: the pharmacology of trimetazidine". Fundam Clin Pharmacol. 17 (2): 133–45. doi:10.1046/j.1472-8206.2003.00154.x. PMID 12667223.

Further reading
  • Sellier P, Broustet JP (2003). "Assessment of anti-ischemic and antianginal effect at trough plasma concentration and safety of trimetazidine MR 35 mg in patients with stable angina pectoris: a multicenter, double-blind, placebo-controlled study". Am J Cardiovasc Drugs. 3 (5): 361–9. doi:10.2165/00129784-200303050-00007. PMID 14728070.
  • Génissel P, Chodjania Y, Demolis JL, Ragueneau I, Jaillon P (2004). "Assessment of the sustained release properties of a new oral formulation of trimetazidine in pigs and dogs and confirmation in healthy human volunteers". Eur J Drug Metab Pharmacokinet. 29 (1): 61–8. doi:10.1007/BF03190575. PMID 15151172.
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