Cholinergic Agonists Flashcards by joelle wasikowski

m1 receptor tissue

postganglionic

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m1 receptor response

depolarization

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m2 receptor tissue

heart

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m2 receptor response

inhibition

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m3 receptor tissue

smooth muscles, exocrine glands, endothelium

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m3 receptor response

contraction, secretion, relaxation

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which receptor does acetylcholine have the highest affinity for?

muscarinic

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acetylcholine biosynthesis

choline into nerve terminal
acetylcholine + choline
transported into storage vesicle by VAT
Ca goes up in cell, vesicles fuse and ACh released (this can be blocked by botox)
ACh binds to receptors and is terminated by AChE

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muscarinic agonist heart effects

M2 leads to decrease in HR, conduction, and force

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muscarinic agonist exocrine glands effect

M3 increase in secretion (tears, saliva, sweat)

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muscarinic agonist smooth muscle effect

M3 increase in contraction

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muscarinic agonist sphincter effect

M3 relaxation

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muscarinic agonist CNS effects

M1 tremor, hypothermia, increased locomotor activity, improved cognition

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direct acting cholinergic receptors structure

esters (like acetylcoa)

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chemical modifications to direct acting cholinergic agonist

add beta methyl, add carbamate

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modification effect on activity and sensitivity to AChE

beta methyl increse muscarinic decrease nicotinic, adding either will decrease sensitivity to AChE

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what are alkaloids

natural product, stereochemistry, selective

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pilocarpine target

muscarinic agonist

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pilocarpine use

for dry mouth (xerostemia/sjorgens), promote sweating, urination, salivation, glaucoma (increase outflow)

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why are antimuscarinic drugs contraindicated in glaucoma?

STRONG side effects

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methacholine

muscarinic agonist
provocative test for hyperactive airways

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carbachol

muscarinic agonist
ocular (surgery, glaucoma)

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bethanechol

muscarinic agonist
GI stimulation, treatment of urinary retention

PSNS side effects

diarrhea, urination, miosis, bradycardia, bronchoconstriction, emesis, lacrimation, salivation, sweating

PSNS cautions

asthma, COPD, coronary insufficiency, peptic ulcer

nicotinic receptor structure

ionotropic (Na ion channels)

nicotinic receptor neurotransmitters

acetylcholine and nicotine

nicotinic receptors location in body

Nm: skeletal muscle endplate Nn: autonomic ganglia, brain (CNS)

nicotine effects

alerting, dopamine release (addictive), hypertension, tachycardia, seizures

varenicline (Chantix)

nicotinic partial agonist produces low amounts dopamine and blocks nicotine binding EFFECTIVE but side effect suicide (boxed warning)

types of cholinesterases

acetylcholinesterase, plasma cholinesterase

acetylcholinesterase location and selectivity

synapses, ACh selective

plasma cholinesterase location and selectivity

plasma (non neuronal), ACh, succinylcholine, local anesthetics

acetylcholinesterase activity esteric and anionic site

esteric site = acetyl , anionic site = choline serine attaches to acetyl, choline released water nuc attacks acetyl and then releases it enzyme is reactivated!

AChE inhibitors general structure

quarternary ammonium alcohol or carbamate, organophosphate

edrophonium

reversible and noncovalent Myasthenia Gravis

AChE inhibitors carbamates

reversible and covalent more slowly hydrolyzed than ACh carbamates just chills for a sec

pyridostigmine

reversible and noncovalent treatment MG, potential nerve gas exposure

neostigmine

reversible and covalent treatment MG, post op urinary retention

what is a problem with AChE inhibitors?

exessive cholinergic receptor activation

AChE inhibitors organophosphates

irreversible, covalent, longer acting, most are toxic

echothiophate

organophosphate irreversible covalent originally for glaucoma, not used now

sarin

organophosphate irreversible covalent nerve gases

malathion/diazinon

organophosphate irreversible covalent insecticide rapidly inactivated in mammals

malathion biotransformation in insects vs adults

insects: cyp450 converts s to o to become toxic mammals: esterase hydrolyzes functional group to become inactive

aging effect organophosphates

bind covalently to serine, functional group dealkylated, water can not hydrolyze the remaining group (this is irreversible aging)

aging antidote

2-PAM

antidote for pesticide or nerve poisoning, effective if given quick before aging occurs hydrolyzes the organophosphate combined with atropine

Alzheimer's Disease

loss of cholinergic neurons in the brain

donepezil

symptoms of Alzheimers does not slow progression of disease binds anionic site

rivastigmine

symptoms Alzhemiers reversible carbamate loses effectiveness as disease progresses

galantamine

symptoms alzhemiers reversible competitive inhibitor loses effectiveness as disease progresses

memantamine

symptoms alzheimers may slow progression!!

SLUD

salivation, lacrimation, urination, defecfation

cholinergic side effects treatment

atropine (2PAM if irreversible)

physostigmine

antimuscarinic poisioning