Cholinomimetics

Question 1

acetylcholine

Answer 1

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

Question 2

methacholine

Answer 2

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

Question 3

carbachol

Answer 3

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

Question 4

bethanechol

Answer 4

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

Question 5

pilocarpine

Answer 5

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

Question 6

nicotine - route of absorption, metabolization and excretion, uses

Answer 6

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

Question 7

varenicline - pharmacodynamics and kinetics, class and site of stimulation, contraindications and drug interactions

Answer 7

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

Question 8

how do indirect-acting cholinometics work?

Answer 8

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

Question 9

Short-acting noncovalent AchE inhibitor

Answer 9

Edrophonium

Question 10

Reversible carbamate AchE inhibitors

Answer 10

Physostigmine, neostigmine and pyridostigmine

MOA - 2-step hydrolysis covalent carbamoylateed enzyme

Drug is hydrolyzed slowly increasing duration of action

Question 11

Irreverisible organo-phosphates

Answer 11

Echothiophate, DFP, insecticide and nerve agent
These are poisons

Binds convalently and irreversibly to enzmye, extremely stable bond.

Question 12

Edrophonium

Answer 12

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

Question 13

Physostigmine

Answer 13

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.

Question 14

Neostigmine

Answer 14

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

Question 15

Pyridostigmine

Answer 15

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

Question 16

Echothiophate

Answer 16

organophosphate AchE inhibitor

Used for chronic open angle glaucoma and post-surgically (eye surgery?), topical - eye drops
Lasts 100 hours

Question 17

Malathion

Answer 17

organophosphate AchE inhibitor

Topical scabicide - head lice

Question 18

Acute organophosphate toxicity

Answer 18

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

Question 19

What are the signs and symptoms of cholinergic toxicity?

Answer 19

BUMBBELSS

Diarrhea
Urination 
Miosis 
Bronchconstriction 
Bradycardia
Excitation
Lacrimation
Salivation
Sweating

Question 20

Donepezil

Answer 20

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.

Question 21

What are the adverse effects of centrally acting AChE inhibitors?

Answer 21

Bradycardia, hypotension, insomnia or vivid dreams, nausea, anorexia, vomiting or diarrhea

Question 22

cevimeline

Answer 22

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

Question 23

what are the drugs used to treat Alzhemier’s? which one is also used to in Parkinson’s patients?

Answer 23

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

Question 24

How to differentiate between cholinergic crisis and myasthenia crisis?

Answer 24

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