Cholinesterase Inhibitors Flashcards
Cholinesterases
-acetylcholinesterase
-plasma cholinesterase
Acetylcholinesterase
-located in synapses
-substrate selective for ACH
plasma cholinesterase
-located in plasma
-selective for ACH, succinylcholine, local anesthetics
AChE
-highest turnover rate of any mammalian enzyme
-hydrolyze ACH 5000x/sec
Hydrolysis of ACh by AChE
-requires water
-cleaves ester
= choline + inactivated enzyme
-attack with H20 = reactivated enzyme
cholinesterase inhibitors
-anticholinesterase agents
-reversible or irreversible
-muscarinic or nicotinic effect
Reversible anticholinesterase agents
-alcohol (edrophonium)
-carbamates (physostigmine, neostigmine, pyridostigmine)
-donepezil (aricept)
Irreversible anticholinesterase agents
-organophosphates
-echothiophate (glaucoma)
-sarin (nerve gas)
-malathion (pesticide, lice)
Acetylcholinesterase inhibitors
-quarternary ammonium alcohol
-simplest structure
-bind anionic site and block ACh binding
-reversible
-non-covalent
Carbamates
-quarternary or tertiary ammonium groups
-reversible
-covalent modification to AChE
-more slowly hydrolyzed than ACh
Inhibition of AChE by neostigmine
-positive charge binds anionic site
-ester at esteratic site
slide 21
Therapuetic AChE inhibitors
-inhibit AChE
-noncovalent reversible
-endorphonium
-pyridostigmine
-neostigmine
edorphonium
-very short acting
-diagnosis fo myathenia gravis (skeletal muscle weakness)
pyridostigmine
-used in treatment of MG
-reversal of nondepolarizing neuromuscular blockade
-pretreatment for potential nerve gas exposure (occupy AChE so nerve gas has nowhere to go)
neostigmine
-used for MG, reversal of nondepolarizing neuromuscular bloackade
-post-op urinary retention
Physostigmine
-inhibt AChE
-CAN cross BBB
-antidote to antimuscarinic poisoning
Problems with therapeutic AChE inhibitors
excessive cholinergic receptor activation
Isofluorophate and echothiophate (Organophosphates)
-irreversible
-covalent modification of AChE
-longer acting
-used in treatment of glaucoma
-most are TOXIC
Echothiophate
-therapeutic organophosphate AChE inhibitor
-long acting
-essential irreversible
echothiopate clinical use
-originally for glaucoma
-better drugs now tho
problems with organophosphate AChE inhibitor therapeutics
-excessive cholinergic receptor activation
-including miosis
Sarin and Soman AChE inhibitors
-nerve gasses
-irreversible
-covalent modification to AChE
Malathion and diazinon (organophophates)
-insecticides
-irreversible
-covalent
-rapidly inactivated in mammals
Biotransformation of MALATHION
-Cyt P450 in insects to malaoxon
-carboxyesterase in mammals and birds to inactivate it
Pralidoxamine Chloride
-antidote for pesticide or nerve gas poisoning (AChE poisoning)
-most effective if given within few hours of exposure
Regeneration of AChE by Pralidoxime
-before aging occurs
-attack phosphate and release phosphate
-slide 37
Pralidoxime (2-PAM)
-AChE inhibitor antiddote)
-hydrolyze organophosphate if treated before aging occurs
-regenerate AChE
-does not cross BBB
Atropine
-block access to muscarinic receptor (ANTAGONIST)
-CANT BLOCK ACTION AT NICOTINIC RECEPTORS
slide 39
slide 39
Alzheimer’s disease
-atrophy of brain
-widening of sulci and thinning of gyri
-improper processing of B-amyloid precursor protein leads to toxic form that promotes apoptosis
-plaques and tangles
-loss of cholinergic neurons in brain
Drugs to treat alzheimers
-donepezil
-rivastigmine
-galantamine
-memantine
Donepezil
-bind to anionic site
-block ACh binding
-reversible
-non-covalent
-enhance cognitive ability
-does not slow progression
Rivastigmine (exelon)
-reversible carbamate AChe inhibitor
-enhance cognitive ability by increasing cholinergic function
-lose effectiveness as disease progresses
-nausea, vomiting, anorexia
-new and better one: epastigmine
Galantamine
-reversible competitive AChE inhibitor
-extract from daffodil bulbs
-lose effectiveness as disease progresses
-may be nicotinic receptor agonist
-inhibitors of P450 enzymes will increase galantamine bioavailability
Mematine
-NMDA receptor antagonist
-NDMA receptors activated by glutamate in CNS
-maybe too much glutamate?
-glutamate regulators improve condition
-may slow progression of disease
-moderate to severe
-favorable adverse effect profile
Slide 45 review
slide 45 review
Cholinergic Agonist side effects
-DUMBBELS
-use caution in pateints with asthma, coronary insufficiency, peptic ulcer
-cardiovascular and respiratory
Cholinergic side effects
-SLUD
-Salivation
-Lacrimation
-Urination
-Defecation
-also:
-increased sweating
-decreased heartrate
-pupils constrict
-CNS activation
Astma and COPD contraindications to PSNS drugs
increase bronchoconstriction
Coronary defeciency contraindications to PSNS drugs
further lower heart rate
peptic ulcer contraindications to PSNS drugs
would increase acid secretion
obstruction of the urinary/ GI tract contraindications to PSNS drugs
if increased contraction does not remove obstruction
Epilepsy contraindications to PSNS drugs
-M1Rs
-CNS penetrable drugs (pilocarpine, physostigmine)
Cholinergic receptor antagonist treatment
Atropine
reversible AChE inhibitor treatment
2-PAM (pralidoxime)
