Cholinomimetics Flashcards
acetylcholine
looks like natural Ach, an ester, highly susceptible to cholinesterase, has moderate affinity for nicotinic receptors.
atropine is an antagonist
used as induction of miosis
methacholine
addition of beta-methyl group which lowers susceptibility to cholinesterase and lowers affinity for nicotinic receptors.
high antagonism by atropine
carbamoyl group increases resistance to cholinesterase
clinically used to diagnose asthma in patients who lack a history of wheezing – called the methacholine challenge test
contraindicated or risky conditions - unstable cardiac disease, MI or stroke
carbachol
not a target of cholinesterase, has both muscinaric and nicotinic effect
only used clinically as eye drops for glaucoma (opens canal of schleem) induction of miosis
bethanechol
not a target of cholinesterase, competitive with atropine, does not bind nicotinic receptor
increases secretions in GI, promotes GI motility, acts on detrusor muscle to promote microuritions.
contraindication in asmtha, GI obstruction, peptic ulcer disease, epilepsy, bradycardia, vasomotor instability, CAD, hypotension or parkinsonism
pilocarpine
unsusceptible to cholinesterase, high antagonism by atropine, does not bind nicotinic
neutral - can cross BBB
ophthalmic drops, half life is 1 hour; sjogren’s syndrome requires 4x the daily dosing, half life increased with renal impairment
causes - miosis, loss of accommodation, lowers intraocular pressure
treats - acute closed-angle glaucoma, chronic open-angle glaucoma and silagogue
nicotine - route of absorption, metabolization and excretion, uses
well absorbed from buccal mucosa, respiratory tract, skin and distributes to CNS and peripheral tissue
metabolized primarily by the liver, excreted mainly by the renal but pH dependent
nicotine has a biphasic effect - in small doses it causes rapid depolarization but in prolonged causes repolarization and a block -> convulsions and respiratory failure
uses - smoking cessation and ulcerative colitis
stimulates receptors in the CNS (mainly presynaptic neurons stimulating neurotransmitter release) and at neuromuscular junctions
varenicline - pharmacodynamics and kinetics, class and site of stimulation, contraindications and drug interactions
given orally with bioavailability, low plasma protein binding, drug is very miminally metabolized and is excreted primarily by the kidney
partial agonist - alpha4beta2 neuronal nAChR –> stimulates ventral tegmental area
high potential for neuropsychiatric events, increases risk for a CV in a patient with CV disease
interacts with nicotine, alcohol, Histamine H2R antagonisms, flouroquinoloe antibiotics
how do indirect-acting cholinometics work?
Inhbits acertylchinesterase causing the accumulation of acetylcholine -> accumulation increase potential for stimulation of excessive cholinergic receptors in the CNS and PNS depending on if it can cross the BBB
Short-acting noncovalent AchE inhibitor
Edrophonium
Reversible carbamate AchE inhibitors
Physostigmine, neostigmine and pyridostigmine
MOA - 2-step hydrolysis covalent carbamoylateed enzyme
Drug is hydrolyzed slowly increasing duration of action
Irreverisible organo-phosphates
Echothiophate, DFP, insecticide and nerve agent
These are poisons
Binds convalently and irreversibly to enzmye, extremely stable bond.
Edrophonium
Short-acting AchE inhibitor
Does not cross BBB, rapidly renal excretion, given IV or IM
only works in PNS
Used for: Myasthenia gravis, cholinergic crisis, myasthenic crisis and reverses neuromuscular block
Lasts about 10 min
How to differentiate between cholinergic crisis and myasthenia crisis?
If you were to give a little bit of edrophonium there would be a slight increase in muscle contraction if it is myasthenia crisis, in cholinergic crisis there would be no musclar strengthening
Physostigmine
Reversible carbamate AchE inhibitor
Antidote for anticholinergic toxicity - like atropine toxicity
Crosses BBB because it’s tertiary, hepatic metabolism, given IV or IM
Used for reversal of toxic, life-threatening delirium caused by toxicity of pure anticholinergic agents - atropine, jimson weed
Lasts 45-60 mins
can cause bradycardia, respiratory distress, and seizures if administered too rapidly.
Neostigmine
Reversible carbamate AchE inhibitor
Does not cross BBB, IV, IM or oral- direct nicotinic activity at NM junction, renal excretion
Uses - Myathenia gravis treatment, reversal Nm block, post-op ileus or urinary retention
Lasts for 2.5 to 4 hours
Pyridostigmine
Reversible carbamate AchE inhibitor
Can be given IV, IM or oral
Uses - myasthenia gravis treatment, reversal of neuromuscular block, pretreatment for Soman nerve gas exposure
Lasts 6 to 8 hours oral, 2-3 IV
Echothiophate
organophosphate AchE inhibitor
Used for chronic open angle glaucoma and post-surgically (eye surgery?), topical - eye drops
Lasts 100 hours
Malathion
organophosphate AchE inhibitor
Topical scabicide - head lice
Acute organophosphate toxicity
Presents with muscinaric, nicotinic and CNS effects
Happens in minutes after absorption
death from respiratory arrest due to paralysis, bronchorrhea or seizures
Treatment - remove toxic agent and clothing, wash skin, gastric lavage and respiratory/cardiovascular support.
Antidotes:
Atropine - antimuscinaric, binds and breaks phosphate bond pulling off organophosphate, effects CNS and PNS but ineffective at neuromuscular synapse
Pralidoxime - cholinesterase regenterator and can relieve respiratory muscle paralysis, effects PNS only
What are the signs and symptoms of cholinergic toxicity?
BUMBBELSS
Diarrhea Urination Miosis Bronchconstriction Bradycardia Excitation Lacrimation Salivation Sweating
Donepezil
Centrally-acting Ach-esterase inhibitor
100% biovialable, excreted renally and biliary
MOA - reversible, noncompetitive inhibition of central AChE
Others - Rivastigmine, Galantamine, tacrine (no longer on the market)
Donepezil - 70 hr half life, once daily dose, oral
given to Alzeimer’s patients - does not reverse symptoms but instead slightly increase cognition and slows decline to an extent.
What are the adverse effects of centrally acting AChE inhibitors?
Bradycardia, hypotension, insomnia or vivid dreams, nausea, anorexia, vomiting or diarrhea
cevimeline
synthetic derivative of pilocarpine
MOA - increased secretion of exocrine glands
high affinity for M3 R on lacrimal and salivary glands
alternative for treatment of xerostomia in patients with Sjogrens
half life of 5 hours with 3 times dosing
what are the drugs used to treat Alzhemier’s? which one is also used to in Parkinson’s patients?
donepezil - 70 hour half life, once daily oral dosing
rivastigmine - 1 hour half life oral at high doses - 2x daily, also a trandermal patch that still has effect up to 3 hours after removal - once daily
galantamine - oral tablet, available with extended release, half life 7 hours, 2x daily dosing, once with extended release formula
used for dementia - rivastigmine is used in PD pts as well
How to differentiate between cholinergic crisis and myasthenia crisis?
If you were to give a little bit of edrophonium there would be a slight increase in muscle contraction if it is myasthenia crisis, in cholinergic crisis there would be no muscular strengthening
cholinergic crisis - cholinomimetic/Ach toxictiy, excess vagal stimulation. often from the treatment of myasthenia gravis
