Pharmacology Of NMJ + NMJ CIS Flashcards
_________ is a drug/primary neurotransmitter at cholinergic nerve endings (preganglionic ANS, postganglionic parasympathetic, postganglionic sympathetic to thermoregulatory sweat glands, and somatic neuromuscular end plates
Acetylcholine
__________ = sympathomimetic drug that facilitates the release of catecholamines from adrenergic nerve endings
Amphetamine
_______ _______ is a bacterial toxin that enzymatically disables release of acetylcholine from cholinergic nerve endings
Botulinum toxin
What early neuromuscular blocking agent was one of the first used for muscular relaxation in general anesthesia and later led to the development of compounds like gallamine and pancuronium?
Curare
What are some of the ways that neuromuscular blockers are classified?
Mechanism of action Duration of action Speed of onset and offset of action Selectivity of action and safety margin Adverse effects
What type of NMJ blocking agent is curare?
Competitive (non-depolarizing)
Competitive (non-depolarizing) agents like curare operate by competing with ACh for binding to the receptor.
What type of paralysis do they cause?
Flaccid, relaxed paralysis
Competitive (non-depolarizing) agents like curare operate by competing with ACh for binding to the receptor.
What are some non-NMJ effects caused by these agents?
Ganglia, muscarinic blocking, histamine release
Competitive (non-depolarizing) agents like curare operate by competing with ACh for binding to the receptor.
How is this type of NMJ block reversed?
Acetylcholinesterase inhibitors
What type of NMJ blocking agent is succinylcholine?
Non-competitive (depolarizing)
What are the 2 phases associated with the MOA of non-competitive (depolarizing) NMJ blocking agents like succinylcholine?
Phase 1 block: membrane depolarization; transient fasciculations followed by paralysis
Phase 2 block: desensitization; membrane repolarizes, hyposensitive to ACh
T/F: Both competitive and non-competitive NMJ blocking agents can be reversed by administering acetylcholinesterase inhibitors
False; competitive inhibitors CAN be reversed by AChE inhibitors, but non-competitive CANNOT
What is the progression of paralysis due to blocking the NMJ? In what order do these muscles recover?
Small rapidly moving muscles (eyes, fingers), then limbs, the last is respiratory muscles
These are recovered in reverse order
General poisoning due to ________ occurs after ingestion of various species of puffer fish. It is lethal even in small doses
Tetradotoxin
What is the MOA of tetradotoxin?
Tetradotoxin blocks diffusion of sodium through sodium channels, thus preventing depolarization and propagation of action potentials in nerve cells
All of the observed toxicity of tetradotoxin is secondary to blockade of the _______ _________. It acts on the central and peripheral nervous systmes.
In recent studies using tetradotoxin therapeutically in conjunction with __________, local anesthetic effect can be prolonged.
However, clinical use of tetradotoxin may increase the incidence of toxicity
Action potential
Bupivacaine
What agent affecting the action nerve potential produces COMPLETE sensory block, and its effect on motor function differs with varying concentrations?
Bupivacaine
Which of the following would you use to provide motor blockade for caudal, epidural, or nerve block, but muscle relaxation may be inadequate for operations in which complete muscle relaxation is ESSENTIAL?
A. 0.25% Bupivacaine B. 0.5% Bupivacaine C. 0.75% Bupivacaine D. 0.5% Tetradotoxin E. 0.75% Tetradotoxin
B. 0.5% Bupivacaine
Which of the following agents would you use for caudal, epidural, or peripheral nerve block to produce incomplete motor block in which muscule relaxation is not important?
A. 0.25% Bupivacaine B. 0.5% Bupivacaine C. 0.75% Bupivacaine D. 0.5% Tetradotoxin E. 0.75% Tetradotoxin
A. 0.25% Bupivacaine
Which of the following would you use to produce complete motor block, especially when performing epidural block in abdominal operations requiring complete muscle relaxation?
A. 0.25% Bupivacaine B. 0.5% Bupivacaine C. 0.75% Bupivacaine D. 0.5% Tetradotoxin E. 0.75% Tetradotoxin
C. 0.75% Bupivacaine
[note that you would NOT use this for epidural anesthesia for obstetrical procedures]
A major cause of adverse reactions to ________ include excessive plasma levels, overdose, unintentional intravascular injection, or slow metabolic degradation
Bupivacaine
What are some drug interactions associated with bupivacaine?
Patients taking MAOIs or TCAs may produce severe, prolonged hypertension
Concurrent use of these agents should generally be avoided and careful patient monitoring is essential
What are the 2 agents discussed in class that affect vesicular acetylcholine release?
Botulinum toxin
Tetanus toxin
What produces botulinum toxin?
Clostridium botulinum, a gram-positive anaerobic bacteria
The clinical syndrome of botulism can occur following ingestion of contaminated food. What is its mechanism of action?
BTX prevents the release of acetylcholine from axon endings at the NMJ and thus causes flaccid paralysis
[BTX is endocytosed, its light chain cleaves specific SNARE proteins necessary for ACh vesicle to fuse with membrane, so it cannot be released]
What makes botulism toxin a good weapon?
Extreme potency and lethality
Ease of production
Difficult to distinguish intential exposures
Expensive, long-term care needed for recovery
What produces tetanus toxin?
Tetanus toxin is an extremely potent neurotoxin produced by the vegetative cell of Clostridium tetani in anaerobic conditions, causing tetanus
Tetanus toxin is the neurotoxin that causes ________; it travels through nerve cells to the ____ ______ and causes severe muscle cramps
Lockjaw
Spinal cord
_______ _______ are non-depolarizing agents that compete with acetylcholine, a chemical that carries info between nerve and muscle cells, and blocks transmission of that information
Curare alkaloids
___________ is a competitive, non-depolarizing blocking agent that is 5x more potent than tubocurarine but with reduced histamine release as well as a lack of ganglionic blockade
Pancuronium
________ is a competitive, non-depolarizing blocking agent that also has some muscarinic blocking activity
Gallamine
_________ is a competitive non-depolarizing blocking agent that is short-acting and undergoes hydrolysis by acetylcholinesterase
Mivacurium
_________ is a competitive non-depolarizing blocking agent other than Mivacurium that undergoes hydrolysis by AChE
Atracurium
What drug acts as a depolarizing muscle relaxant and may be used to induce anesthesia or when a tube must be inserted in the trachea?
Succinylcholine
What is the mechanism of action of succinylcholine?
Affects depolarization; keeps muscles from contracting, leading to paralysis of muscles of the face and those used to breathe and move
Succinylcholine keeps muscles from contracting, leading to paralysis of muscles of the face and those used to breathe and move. What are some adverse effects associated with succinylcholine?
Postoperative pain Jaw rigidity Excessive salivation Hypotension Rash
[there are also many drugs known to interact with succinylcholine; risk of acute rhabdomyolosis with hyperkalemia followed by ventricular arrhythmias, cardiac arrest, and death in those found to have undiagnosed muscle myopathies like DMD]
What are the clinical uses for agents that inhibit acetylcholinesterase?
Dementia associated with Alzheimer or Parkinson’s
Myasthenia gravis
Nerve gas and organophosphate pesticide exposure
Reversal of neuromuscular blockade during anesthesia
What are some agents known to inhibit acetylcholinesterase?
Short acting (alcohol): edrophonium
Intermediate acting (carbamates): Neostigmine, pyridostigmine, physostigmine
Long acting (organophosphates): echothiophate, malathion, parathion, sarin
What agent is used in the treatment of severe high body temperature (malignant hyperthermia), and clinical spasticity resulting from upper motor neuron disorders like spinal cord injury, stroke, cerebral palsy, or MS?
Dantrolene (aka Dantrium or Revonto)
Dantrolene is an agent characterized by its ability to affect muscle contraction. What is its mechanism of action?
Muscle relaxant - restores a normal level of calcium in the muscles which helps to prevent or reduce severe high body temperature
Dantrolene is a muscle relaxant that restores a normal level of calcium in the muscles which helps to prevent or reduce severe high body temperature. What are some adverse effects associated with Dantrolene?
Drowsiness, bloody/black tarry stool, dark urine, confusion, constipation
[many drugs are known to interact with Dantrolene as well]
