cholinergic agonist Flashcards
types of cholinesterases
acetylcholinesterase and plasma cholinesterase
acetylcholinesterase
-located in synapses
-substrate selectivity: ACh
plasma cholinesterase
-located in plasma (non neuronal)
-substrate selectivity: ACh, succinylcholine, local anesthetics (procaine)
cholinesterase and hydrolysis of ACh
-AChE has the highest turnover rate of any known mammalian enzyme
-AChE hydrolyzes ACh molecules with a turnover time of 150 microseconds, ~5,000 times per second!
-The reaction requires water. Three amino acid residues that form a catalytic triad (esteric site)
anticholinesterase reversible agents
-Alcohol: edrophonium
-carbamates: Physostigmine, neostigmine, pyridostigmine
-others: donepezil (aricept)
anticholinesterase irreversible agents
-organophosphates: echothiophate (used in glaucoma), sarin (nerve gas, chemical warfare agents), malathion (pesticide, head lice)
acetylcholinesterase inhibitor edrophium
-tensilon
-quaternary ammonium alcohol
-simplest structure
-bind to anionic site and block ACh binding
-reversible
-non-covalent
acetylcholinesterase inhibitor neostigmine, pyridostigmine, and physostigmine
-carbamates
-quaternary or tertiary ammonium groups
-reversible
-covalent modification to AChE
-more slowly hydrolyzed than ACh
action of AChE inhibitors: edrophonium, neostigmine, pyridostigmine
-inhibition of acetylcholinesterase:
-Edrophonium via noncovalent, reversible
-“stigmines” as substrates that are more slowly hydrolyzed than ACh
-Does NOT readily cross BBB
clinical use of neostigmine
- Used for MG, reversal of nondepolarizing neuromuscular blockade,
- post-op urinary retention
problems of Edrophonium, Neostigmine, Pyridostigmine
excessive cholinergic receptor activation
action of physostigmine
Inhibition of acetylcholinesterase:
“stigmines” as substrates that are more slowly hydrolyzed than ACh
clinical use of edrophonium
very short-acting (minutes); diagnosis of Myasthenia Gravis (MG) (skeletal muscle weakness due to loss of skeletal muscle nicotinic receptors because of autoimmune disease)
clinical use of pyridostigmine
-Used in the treatment of MG, reversal of nondepolarizing neuromuscular blockade,
pretreatment for potential nerve gas exposure (occupy AChE so that nerve gas has nowhere to go)
clinical use of physostigmine
Physostigmine (can cross blood-brain barrier): Antidote to antimuscarinic poisoning
problems of physostigmine
excessive cholinergic receptor activation
isofluorophate and echothiophate
-organophosphates (most are toxic)
-irreversible
-covalent modification to AChE
-longer acting
-used in the treatment of glaucoma
action of echothiphate
inhibiton of acetylcholinesterase: long-acting (essentially irreversible)
problem of echothiophate
Excessive cholinergic receptor activation (including miosis)
sarin and soman
-organophosphate
-nerve gases
-irreversible
-covalent modification to AChE
clinical use of echothiophate
-Originally for glaucoma (increase ACh and enhance muscarinic activation and subsequent outflow of aqueous humor)
-Not used currently due to availability of better drugs
malathion and diazinon
-organophosphate
-insecticides
-irreversible
-covalent modification to AChE
-rapidly inactivated in mammals
biotransformation of insecticides
malathion to malaoxon by Cyt P450 and insects
antidote for AChE “poisoning”
-pralidoxine chloride
-antidote for pesticide or nerve gas poisoning
-most effective if given within a few hours of exposure
action of pralidoxime (2-PAM)
-Strong nucleophile – will hydrolyze organophosphate IF TREAT BEFORE AGING OCCURS – this will regenerate acetylcholinesterase DOSE NOT CROSS THE BLOOD-BRAIN BARRIER (thus combine with the
muscarinic receptor antagonist atropine)
Alzheimer’s
-most common cause of dementia after age 50
-atrophy of the brain
-widening of sulci and thinning of gyri
-improper processing of beta-amyloid precursor protein leads to toxic form beta A42 that promotes apoptosis
-loss of cholinergic neurons in the brain
clinical use of pralidoxime (2 PAM)
treatment of organophosphate toxicity
drugs for alzheimer
-donepezil (aricept)
-rivastigmine (exelon)
-galantamine (razadyne)
-memantine: donepezil and memanthine (namzaric)
treatment of alzheimers by donepezil
-bind to anionic site and block ACh binding
-reversible, so non covalent
-enhances cognitive ability
-does not slow the progression of the disease
-approved to treat all stages of Alzheimers
treatment of alzheimers by rivastigmine
-reversible carbamate AChE inhibitor
-enhances cognitive ability by increasing cholinergic function
-loses effectiveness as disease progresses
-side effects: nausea, vomiting, anorexia, and weight loss
-newer long-acting carbamate eptastigmine
treatment of alzheimers by memantine
-N-methyl-D-asparate (NMDA) receptor antagonist
-NMDA receptors are activated by glutamate in the CNS in areas associated with cognition and memory
-neuronal loss Alzheimer’s may be related
to increased activity of glutamate
-Glutamate regulators to improve memory,
attention, reason, language and the ability
to perform simple tasks
-May slow progression of the disease,
approved for moderate-to-severe disease
-Favorable adverse effect profile
DUMBBELs
Diarrhea
Urination
Miosis
Bradycardia
bronchoconstriction
emesis
lacrimation
salivation and sweating
SLUD
salivation
lacrimation
urination
defecation
contraindication to the use of parasympathomimetic drugs for asthma and COPD
increase bronchoconstriction
contraindication to the use of parasympathomimetic drugs on coronary deficiency
further lower heart rate
contraindications to the use of parasympathomimetic drugs on peptic ulcar
would increase acid secreation
contraindications to the use of parasympathomimetic drugs on construction of the urinary or GI tract
if increased contraction does not remove an obstruction
Contraindication to the use of parasympathomimetic drugs on epilepsy
M1Rs
CNS penetrable drugs
