Download Metrifonate

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