cholinergics

cholinergic system

carry Ach neurotransmitter

all preganglionic of ANS (sympathetic + parasympathetic)

only postganglionic fibers in parasympathetic

acetylcholine

metabolized in synaptic junction by acetyl cholinesterase

acts through nicotinic/muscarinic receptors

actions are opposite to epinephrine

nicotinic receptors

Nm + Nn

ligand gated ion channels

open when Ach binds

rapid response

muscarinic receptors

M1, M2, M3

G protein coupled receptors (GPCRs)

trigger intracellular cascade > slow response

M1 receptor

found on CNS neurons > CNS effects

Gq type receptor

M2 receptor

found on heart

reduces HR, force of contraction, CO, BP

Gi type receptor

M3 receptor

smooth mm contraction > diarrhea, bronchospasm, urination

gland secretion > salivation, sweating, gastric acid + tracheo-bronchial secretions

pupil - miosis

ciliary mm contraction

Gq type receptor

Nn receptor

on ganglia - stimulate postganglionic fibers

Nm

on skeletal mm end plate - contract skeletal mm

cholinergic agonists

drugs that mimic/increase Ach actions

adverse effects = exacerbated, physio effects of excess Ach in body

direct cholinergic agonists

mimic effects of Ach + act at Ach receptors

acetylcholine, bethanechol, pilocarpine, carbachol, methacholine

bethanechol

muscarinic agonist

stimulates M3 receptors > incr bowel movements + bladder contracts for elimination

used in pts w/ paralytic ileus (typically post-op) or urinary retention (nonobstructive)

pilocarpine

muscarinic agonist

alkaloid - lipid soluble + penetrates cornea wall

can reduce dryness of mouth

used for glaucoma or Sjogren's syndrome

indirect cholinergic agonists

aka acetylcholinesterase inhibitors

incr Ach lvls + action at synapses

neostigmine, phyysostigmine, pyridostigmine, edrophonium, tacrine, donepezil, ecothiophate, malathion, parathion, sarin

reversible cholinesterase inhibitors

short acting, AchE reactivated after some time to break down Ach as usual

used for Myasthenia gravis + Alzheimer's

neostigmine, phyysostigmine, pyridostigmine, edrophonium, tacrine, donepezil, rivastigmine, galantamine

irreversible cholinesterase inhibitors

long acting, enzyme reactivation takes long time/doesn't happen

leads to persistent Ach action

often used as insecticides/war gases

ecothiopate - clinically useful for glaucoma

malathion, parathion - organophosphorus poisoning

myasthenia gravis tx

AchE inhibitors (indirect cholinesterase inhib)

Neostigmine (IV) - acute cases

Pyridostigmine (oral) - longer duration for maintenance/long term therapy

edrophonium

shortest acting AchE inhibitor - 5 min

used to make diagnosis of MG

differentiates myasthenic vs cholinergic crisis (Tensilon test)

if pt mm weakness improved after edrophonium = positive for MG

myasthenic crisis

an acute exacerbation of disease caused by inadequate amount of meds, infection fatigue or stress.

cholinergic crisis

due to excess rx (overtreatment) > weakness due to nicotinic depolarization blockade of MEP

alzheimer's tx

due to loss of cholinergic neurons

AchE inhibitors

tacrine, galantamine, rivastigmen, doneprazil

OP poisoning

acute toxic effects of irreversible cholinesterase inhibitors

phosphorylation (irreversible inhibition) of enzyme >> excess Ach

stimulates muscarinic receptors > miosis, blurred vision, bradycardia, salivation, sweating, urination, bronchial constriction, vomiting, diarrhea

OP poisoning tx

support ventilation + circulation

gastric lavage + administer activated charcoal

use atropine (or pralidoxime)

severe - hemoperfuse + mech ventilation

atropine

muscarinic receptor blocker (anticholinergic)

CANNOT control nicotinic effects of OP poisoning

IV large dose until mydriasis, tachycardia, mouth dry

HR > 90 + monitor pupil size

pralidoxime

AchE reactivator

hydrolyzes drug bound enzyme

give at earliest possible before "24h" aging of enzyme - tht makes it irreversible

anticholinergic drugs

aka cholinergic blockers or parasympatholytics

drugs that block Ach action

allow sympathetic system to dominate (mimics adrenergics)

2 types: muscarinic or nicotinic receptor blockers

muscarinic receptor blockers

Atropine

Homatropine (short acting form of atropine)

Tropicamide (shortest acting form of atropine)

Cyclopentolate

Pirenzepine

Scopolamine

Benztropine

Ipratropium bromide, tiotropium

Glycopyrrolate

Dicyclomine

tropicamide

muscarinic antagonist

mydriatic

cyclopegia in refractory testing (loss of accomodation)

benztropine

for drug induced Parkinsonism

ipratropium bromide

for COPD/bronchial asthma

not much systemic absorption, less side effects

pirenzepine

peptic ulcers

scopolamine

prevent motion sickness

glycopyrrolate

pre-anesthetic to reduce bronchial secretions

dicyclomine

treats GI spasm

helps spasmodic abdominal pain

muscarinic blockers for overactive bladder

oxybutynin, darifenacin, solifenacin

atropine poisoning

"dry as bone, hot as hare, blind as bat, red as beet, mad as a hatter"

dry mouth, mydriasis, tachycardia, hot/flushed skin, agitation, delirium, death

tx: physostigmine