Exam 4 - Lecture 37, Muscarinic antagonists and neuromuscular junction blockers

Muscarinic antagonist Neuromuscular, nAChR blockers (Depolarizing and non-depolarizing) ganglion blockers (little clinical use)

CNS, ANS pre- and postganglic neurons Coupled to Gaq

Myocardium, smooth muscle (SM), some neurons Coupled to Gai

common on effector cells (glandular and SM) Coupled to Gaq

Least prominent subtypes, CNS > PNS M4 = Gai and M5 = Gaq

MoA: Competitive antagonist of M1-5 receptors Medical Applications: can treat bradycardia, reduce saliva during surgery, Used for OOP poisoning, mydriatic in othalmology, IV atropine effective within minutes and lasts 30-60min, effect on central M receptors reduces Parkinsonian tremors Side effects: Tachycardiac, dry mouth, mydriasis, urinary retention and constipaton, crosses BBB OD: Antidote if physostigmine or pilocarpine

At low doses, atropine decreases heart rate because it inhibits presynaptic M2 receptors. It preferentially activates presynaptic receptors

Atropine is a ACh-antagonist, but its effects go beyond simple opposition of ACh, therefore its an inverse agonist M2 receptor has a baseline activity, and atropine bring its below that

Medical use: motion sickness and postoperative nausea GI-spasm, biliary spasm and IBS can do IM,SC or transdermal side effects: Similar to atropine, less severe Overdose: treat with physostigmine

Muscarinic antagonist FDA approved for excessive sweating and peptic ulcers Most commonly used with neostigmine during reversal of a NM blockade to mitigate side effects of neostigmine, such as bradycardia and reflect hypertension side effects: similar to atropine but does not cross BBB

depolarizes skeletal muscles

initiates and propagates action potentials

Nondepolarizing Depolarizing Inhibitors of ACh release

Antagonists that prevent the action of ACh (agonist) on nAChRs by occupying the receptor binding site Ex. Rocuronium

Agonists that have a longer half-life at the nAChR than ACh, leading to sustained depolarization of the muscle and inactivation of Nav channels causing phase 1 block Ex. Succinylcholine

ex. Botox Peptide toxins that prevent the Neurotransmitter vesicle machinery from releasing ACh into the synaptic cleft

naturally occurring causes slow skeletal muscle paralysis and histamine release Minimal medical utility because it also acts at ganglia, modern compounds safer Can be used to reduce painful neurotransmitter release following a-latrotoxin envenomation (black widow)

naturally occurring causes slow skeletal muscle paralysis and histamine release Minimal medical utility because it also acts at ganglia, modern compounds safer Can be used to reduce painful neurotransmitter release following a-latrotoxin envenomation (black widow)

** Not reversed by sugammadex **, use neostigmine Non-depolarizing neuromuscular blocker Derived from atracurium Facilitates placement of endotracheal tubes and relaxes skeletal muscle in surgery Hoffmann elimination, temp and plasma pH dependent, therefore increased temp speeds elimination Adverse effects: Hypotension and reflex tachycardia

** Reversed using sugammadex ** designed to be less potent than pancuronium aminosteroid non-depolarizing neuromuscular blocker facilitate tracheal intubation and relax skeletal muscle used for euthanasia/lethal injection w/ midazolam

** Reversed using sugammadex ** Curare mimic based on 2 ACh molecules, partially reversal w/ neostigmine aminosteroid non-depolarizing neuromuscular blocker facilitate tracheal intubation and relax skeletal muscle used for euthanasia/lethal injection w/ midazolam

Longer duration

Longer lasting, more potent

FDA approved in 2015, EU 2008 Reverses NMJ block by chelating amino steroid drugs Alternative to neostigmine and glycopyrrolate Can theoretically chelate other polar steroids, including oral contraceptives