Presentation on theme: "INDIRECT CHOLINOMIMETICS Pharmacology Department"— Presentation transcript:
1INDIRECT CHOLINOMIMETICS Pharmacology Department Prof. Hanan HagarPharmacology Department
2Indirect acting cholinomimetic drugs What students should know:Classification of indirect acting cholinomimeticsMechanism of action, kinetics, dynamics and uses ofanticholinesterasesAdverse effects & contraindications of anticholinesterasesSymptoms and treatment of organophosphates toxicity.
3Indirect cholinomimetics (also called anticholinesterases) Mechanism of action:Anticholinesterases prevent hydrolysis of Ach by antagonizing cholinesterase thus increase Ach concentrations and actions at the cholinergic receptors (both nicotinic and muscarinic).
7Reversible indirect cholinomimetics Short acting, reversibleDrugs as EdrophoniumAlcoholforms weak hydrogen bond with cholinesteraseIntermediate acting, reversibleCarbamates estersbinds to two sites of cholinesterase enzymeAll polar except physostigminePhysostigminePyridostigmineNeostigmine
8Irreversible indirect cholinomimetics Very long acting, Phosphate esterse.g. Ecothiophate – Isoflurophatevery long duration of actionform very stable covalent bond with cholinesteraseAll phosphates are lipid soluble except ecothiophate which is polar.
9Pharmacological effects of anticholinesterases ALL Anticholinesterases have muscarinic and nicotinic actions (N & M actions) and some have CNS effects (only lipid soluble drugs).
10Pharmacological effects of anticholinesterases Muscarinic actionsNicotinic actionsCNS actions:Excitation, convulsion, respiratory failure, comaonly for lipid soluble anticholinesterasesphysostigmine & phosphate ester exceptEcothiophate.
11Muscarinic actions Cholinergic actions Organs Contraction of circular muscle of iris (miosis)(M3)Contraction of ciliary muscles for near vision (M3)Decrease in intraocular pressureEyebradycardia ( heart rate ) (M2)Release of NO (EDRF)HeartendotheliumConstriction of bronchial smooth musclesIncrease bronchial secretion M3LungIncreased motility (peristalsis)Increased secretionRelaxation of sphincter M3GITContraction of musclesRelaxation of sphincter M3Urinary bladderIncrease of sweat, saliva, lacrimal, bronchial, intestinal secretions M3Exocrine glands
12Nicotinic actions Neuromuscular junction Therapeutic dose: muscle contractionToxic dose: relaxation or paralysis.Ganglia: stimulation of sympathetic and parasympathetic gangliaAdrenal medulla release of catecholamines (A & NA).
13Indirect Cholinomimetics EdrophoniumReversible anticholinesterasealcoholPolarNOT absorbed orally (given by injection)attach mainly to anionic site of cholinesterase by weak hydrogen bond.Has short duration of action (5-15 min.)Used for diagnosis of myasthenia gravis
17Indirect Cholinomimetics (Organophosphorous compounds) EcothiophateMechanismIrreversible anticholinesteraseBinds to cholinesterase by strong covalent bond.Have very long duration of actionAging make bond extremely stableAll are highly lipid soluble except ecothiophateUsed for glaucoma.
18Organophosphates toxicity Sever bradycardia, hypotension.bronchospasm.Increased GIT motility cramps & diarrhea.CNS effects convulsion, coma and respiratory failure.Initial twitching of skeletal muscles muscle weakness & paralysis.
19Treatment of organophosphate toxicity Support respirationCholinesterase reactivators (Oximes)Atropine ( to block muscarinic & central actions).
20OXIMESPralidoxime (PAM)cholinesterase reactivatorActs by regeneration of cholinesterase enzyme.reactivates recently inhibited enzymes before aging.UsesI.V. over min for organophosphate intoxication.
21Donepezil Anticholinesterase drugs. Given orally. used for treatment of dementia ofAlzheimer’s disease.