Cholinesterase Inhibitors Flashcards by Brooke Thornburg

Cholinesterases

-acetylcholinesterase
-plasma cholinesterase

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Acetylcholinesterase

-located in synapses
-substrate selective for ACH

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plasma cholinesterase

-located in plasma
-selective for ACH, succinylcholine, local anesthetics

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AChE

-highest turnover rate of any mammalian enzyme
-hydrolyze ACH 5000x/sec

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Hydrolysis of ACh by AChE

-requires water
-cleaves ester
= choline + inactivated enzyme
-attack with H20 = reactivated enzyme

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cholinesterase inhibitors

-anticholinesterase agents
-reversible or irreversible
-muscarinic or nicotinic effect

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Reversible anticholinesterase agents

-alcohol (edrophonium)
-carbamates (physostigmine, neostigmine, pyridostigmine)
-donepezil (aricept)

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Irreversible anticholinesterase agents

-organophosphates
-echothiophate (glaucoma)
-sarin (nerve gas)
-malathion (pesticide, lice)

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Acetylcholinesterase inhibitors

-quarternary ammonium alcohol
-simplest structure
-bind anionic site and block ACh binding
-reversible
-non-covalent

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Carbamates

-quarternary or tertiary ammonium groups
-reversible
-covalent modification to AChE
-more slowly hydrolyzed than ACh

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Inhibition of AChE by neostigmine

-positive charge binds anionic site
-ester at esteratic site
slide 21

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Therapuetic AChE inhibitors

-inhibit AChE
-noncovalent reversible
-endorphonium
-pyridostigmine
-neostigmine

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edorphonium

-very short acting
-diagnosis fo myathenia gravis (skeletal muscle weakness)

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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)

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neostigmine

-used for MG, reversal of nondepolarizing neuromuscular bloackade
-post-op urinary retention

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Physostigmine

-inhibt AChE
-CAN cross BBB
-antidote to antimuscarinic poisoning

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Problems with therapeutic AChE inhibitors

excessive cholinergic receptor activation

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Isofluorophate and echothiophate (Organophosphates)

-irreversible
-covalent modification of AChE
-longer acting
-used in treatment of glaucoma
-most are TOXIC

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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

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)