Trimetazidine

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Trimetazidine
Trimetazidine.svg
Systematic (IUPAC) name
1-(2,3,4-trimethoxybenzyl)piperazine
Clinical data
Trade names Vastarel
AHFS/Drugs.com International Drug Names
Legal status CD (Schedule I) (UK)
Routes Oral
Pharmacokinetic data
Bioavailability completely absorbed at around 5 hours, steady state is reached by 60th hour
Protein binding low (16%)
Metabolism minimal
Half-life 7 to 12 hours
Excretion mainly 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 5011-34-7 N
ATC code C01EB15
PubChem CID 21109
ChemSpider 19853 YesY
UNII N9A0A0R9S8 YesY
ChEMBL CHEMBL203266 YesY
Chemical data
Formula C14H22N2O3 
Mol. mass 266.336 g/mol
 N (what is this?)  (verify)

Trimetazidine is a drug for angina pectoris sold under the brand name Vastarel MR. Trimetazidine is described as the first cytoprotective anti-ischemic agent developed and marketed by Les 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.

Medical uses[edit]

Trimetazidine 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.[1]

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.[2][3]

Adverse effects[edit]

Trimetazidine has been treated as a drug with a high safety and tolerability profile.[citation needed] 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.[4] 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.[5]

EMA recommends that doctors should no longer prescribe trimetazidine for the treatment of patients with tinnitus, vertigo or disturbances in vision.[1] The recent EMA evaluation also revealed high potential for Parkinsonian (or extrapyramidal) symptoms (such as tremor, rigidity, akinesia, hypertonia), gait instability, restless leg syndrome, other related movement disorders, reversible after treatment discontinuation. As a consequence, 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.[1]

Mechanism of action[edit]

By preserving the energy metabolism in cells exposed to hypoxia or ischemia, trimetazidine prevents a decrease in intracellular adenosine triphosphate levels, thereby ensuring the proper functioning of ionic pumps and transmembranous sodium-potassium flow whilst maintaining cellular homeostasis. It also inhibits oxidation of fatty acid in blood vessels.[6]

Trimetazidine inhibits beta-oxidation of fatty acids by blocking long-chain 3-ketoacyl-CoA thiolase, which enhances glucose oxidation.[7] 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.[6]

Brand names[edit]

Distributed as: Vastarel MR, Vastarel 20 mg, Vastarel LM, Vastarel LP, Preductal MR, Тридуктан, Тридуктан МВ, Flavedon MR, Trivedon MR 35 mg (Cipla Ltd.), Flavedon 20 mg, Cardaptan, Idaptan, Carvidon MR and Trizedon MR. In the Philippines, a local brand is called Vestar. Also Carmetadin for World Medicine company.In Bangladesh, Angirid MR is the local brand by The ACME Laboratories Ltd.

References[edit]

  1. ^ a b c "European Medicines Agency recommends restricting use of trimetazidine-containing medicines" (pdf). Press release. European Medicines Agency. 2012-06-12. 
  2. ^ 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. 
  3. ^ 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. 
  4. ^ 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. 
  5. ^ 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.
  6. ^ a b 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. 
  7. ^ 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. 

Further reading[edit]

  • 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. 

External links[edit]