Cholinergics Flashcards
Stimulation of muscarinic M1, M3, and M5 receptors results in what?
Activation of the IP3, diacylglycerol cascade to increase intracellular Ca++
Where are muscarinic receptors located?
All parasympathetic end organs and sweat glands and many CNS neurons
Where are nicotinic receptors located?
Skeletal muscle, autonomic ganglia, adrenal medulla
What are the effects of direct-acting muscarinic agonists?
Negative chronotropy/inotropy, release of NO in vessels (vasodilation and subsequent decreased BP), miosis (constriction of iris), bronchoconstriction, increased secretions, increased sweat, increased GI motility and secretion, relaxation of bladder sphincter
*remember these are all parasympathetic
Stimulation of muscarinic M2 and M4 receptors results in what?
Inhibition of cAMP production and/or activation of voltage-gated K+ channels (results in hyperpolarization in SA node and atrial cells)
Name the direct muscarinic agonists
ABC - acetylcholine, bethanechol, and carbachol
*bethanechol is badass because it doesn’t give a fuck about nicotinic receptors (the other two are also nicotinic agonists at high doses)
What are some general clinical uses for direct-acting cholinergic agonists?
Overcoming post-op paralytic ileus, urinary retention, and glaucoma
What are the contraindications to using direct-acting cholinergic agonists?
Asthma, heart conditions, peptic ulcer, GI/urinary tract obstruction, and hyperthyroidism (could get A fib)
What is the primary clinical use for carbachol?
Used in eyedrops as miotics for wide-angle type glaucoma treatment
Describe the mechanism of action of nicotine and its clinical relevance.
A potent nicotinic receptor agonist that is uncharged so it readily passes the BBB. It is used clinically for smoking cessation.
Why is nicotine addictive?
Because it activates the midbrain reward pathway increasing the release of dopamine particularly in the nucleus accumbens –> pleasure
Describe the side effects associated with nicotine.
Nausea/vomiting, CNS excitation, enhancement of short-term memory from increased attention, addiction and cravings, increased GI tone/activity, and increased HR/BP
Describe the mechanism of action and clinical use of varenicline.
It is a partial agonist at a4B2 nicotinic receptors, binding and activating them to lesser degree than nicotine. Used for smoking cessation. Don’t give to depressed/suicidal patients!
*If you wanna get clean from nicotine, you’ve gotta do your part(ial agonist)
Name and describe the general mechanism of action of indirect-acting cholinergic agonists.
Neostigmine, physostigmine, donepezil, and sarin.
They are all anticholinesterases, blocking metabolism of ACh to increase levels. *Sarin is a poison
What is the main clinical use of physostigmine?
A miotic agent to treat glaucoma.
*Can cross BBB
What is the main clinical use of donepezil?
Treatment for Alzheimer’s
*Crosses BBB
Increased ACh levels improve memory/cognition (effects are modest) and can cause insomnia (think of all the confused old people who don’t ever sleep)
What are the clinical uses of neostigmine?
Used for myasthenia gravis, paralytic ileus, and reverses vecuronium
*You won’t be paralyzed after I sting you with neostigmine
What are the effects of sarin?
SLUDGE
salivation lacrimation urination defecation GI distress emesis
(+the usual, pulm edema, twitching, resp paralysis, ataxia, confusion, convulsions, coma)
Describe the mechanism of action and clinical use of botulinum toxin.
Protein neurotoxin that blocks ACh release by cleaving SNAP-25 (the protein required to release ACh from vesicles) used for wrinkle reduction and muscle relaxation.
*SNAP you look 25 again!
Name the muscarinic antagonists and their clinical uses.
Atropine- preanesthetic medication (reduce secretions, relax bronchi), antispasmodic, antidiarrheal, treats sarin poisoning, and tx for bradycardia
Ipratropium- bronchodilation
Name the nicotinic antagonists.
SVT - succinylcholine, vecuronium, trimethaphan
*SVT? no nicotine for me!
Describe the mechanism of action and clinical use of trimethaphan.
It is the only clinically available ganglionic (a3) blocker. Used for acute dissecting aortic aneurysm to rapidly control BP and block reflexes
Describe the physiological effects of trimethaphan.
Vasodilation –> hypotension, venous dilation –> decreased CO, tachycardia, mydriasis (etc)
Big things to remember are listed because it treats acute dissecting aortic aneurysm so you don’t want high BP
Describe the mechanism of action and clinical use of vecuronium.
It is a competitive antagonist that binds to ACh recognition sites blocking ACh access. Used for muscle paralysis (lasts 1-1.5 hours) and can cause hypotension and histamine release
How can you reverse the effects of vecuronium?
Give neostigmine (often with atropine) which increases ACh levels at the NMJ eventually overcoming the blockade.
Describe the adverse effects associated with succinylcholine and thus what patients to avoid using it on.
Can cause malignant hyperthermia from Ca++ release (give dantrolene to block release from sarcoplasmic reticulum in skeletal muscle) and also increases K+ release which can cause hyerkalemia and arrhythmias. Thus avoid in renal failure, burn patients, patients w/ large areas of denervated muscle
How is succinylcholine metabolized and why is it relevant?
It is metabolized by cholinesterase. This is relevant because you DO NOT reverse it with neostigmine (remember that’s an anticholinesterase)
Describe the mechanism of action and clinical use of pralidoxime.
It can reactivate acetylcholinesterase and is used with atropine to treat sarin exposure.
What is the focus of Alzheimer’s treatment?
Focus is on anticholinesterases – mechanisms to increase ACh levels at CNS synapse.
