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Metrifonate Supervized by: Dr: Hanan Hajar Prepared by: Marzuga S. Monikher Chemistry Metrifonate • Metrifonate is an • organophosphorus compound Non-enzymatically converted to 2,2dichlorovinyl dimethyl phosphate [DDVP] which is the active metabolite Dichlorovos Mechanism Of Action • irreversible cholinesterase inhibitor • Equal selectivity for butyryl cholinesterase (BChE) and acetyl cholinesterase (AChE) • Prolonged action at cholinergic receptor due to blocking of the hydrolysis of Ach Pharmacological Action • Metrifonate exhibits binding activity at nicotinic receptors sites and no activity at muscurinic site producing significant inhibition of brain [chE] activity • Metrifonate affecting the cognitive, behavioral and global function Pharmacokinetic • Dosing: According to the body weight metrifonate is administered orally once daily – Loading dose for 2 weeks [2 mg/kg] – Maintenance dose for 10 weeks [0.65 mg/kg] This course of treatment causing 70% inhibition of AchE level Pharmacokinetic • Absorption: It is rapidly and almost completely absorbed, leading to increase in brain Ach levels within 1 hour of oral administration it undergoes little protein binding <15% • Metabolism: It is a prodrug biotransformation of mertifonate occurs independently of the hepatic cytochrome P450 It is slowly and non-enzymatically transformed to DDVP which is PH dependent Serum t½ is 2 hours Pharmacokinetic Variable Duration of enzyme inhibition Metrifonate Long Dosage frequency Once daily Dosage adjustment needed No Drug discontinuation because of adverse effects [% patients] 8 to 9 % Interaction with drugs metabolized by P450 isoenzyme No Pharmacokinetic • Excretion: – 80% is excreted in urine – 1-3% is excreted unchanged in the liver Uses • Mertrifonate has a 30-years history as treatment for schistosomiasis • in late 1980s it was concedered as a potential treatment for AD on the basis of its anticholinesterase properties Adverse Effects • Diarrhea • Leg cramps • Rhinorrhea • Vomiting abdominal discomfort • Muscle weakness Toxicity and Drug Interactions • Because of the:-1. short t½ 2. low plasma protein binding 15% 3. leak the involvement of P450 in metabolism ======== Toxicity and drug interaction risk is unlikely