Pharmacology Of NMJ + NMJ CIS Flashcards by Sarah Gillen

_________ 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

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__________ = sympathomimetic drug that facilitates the release of catecholamines from adrenergic nerve endings

Amphetamine

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_______ _______ is a bacterial toxin that enzymatically disables release of acetylcholine from cholinergic nerve endings

Botulinum toxin

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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

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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

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What type of NMJ blocking agent is curare?

Competitive (non-depolarizing)

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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

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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

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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

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What type of NMJ blocking agent is succinylcholine?

Non-competitive (depolarizing)

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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

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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

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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

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General poisoning due to ________ occurs after ingestion of various species of puffer fish. It is lethal even in small doses

Tetradotoxin

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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

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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

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What agent affecting the action nerve potential produces COMPLETE sensory block, and its effect on motor function differs with varying concentrations?

Bupivacaine

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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

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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

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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]

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A major cause of adverse reactions to ________ include excessive plasma levels, overdose, unintentional intravascular injection, or slow metabolic degradation

Bupivacaine

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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]

What are the 4 steps of NMJ neurotransmission to cause muscle contraction?

1. Axonal conduction 2. Junctional transmission; synthesis of ACh (skeletal muscle), storage of ACh, release of ACh, destruction of ACh 3. ACh signaling 4. Muscle contraction

What are the 4 steps of ACh junctional transmission from synthesis to destruction?

1. ACh synthesis 2. ACh storage into vesicles 3. ACh release 4. ACh destruction

What effect does botulinum toxin have on the NMJ?

It cleaves the SNARE complex, blocking fusion of the vesicles and plasma membrane causing a decrease in acetylcholine This leads to paralysis of muscles

What disorders can be treated with a cholinesterase inhibitor? What is the MOA?

Myasthenia gravis Dementia Alzheimer's Parkinson's Patients have decreased nicotinic ACh receptors on muscle cells. Giving this drug can increase the availability of ACh in the synapse

What effect does tetradotoxin have on the nerve action potential? What are some symptoms?

Affects the action potential prior to the NMJ. Causes no controlled movements. Inhibits voltage gated sodium channels which blocks axonal conduction Symptoms: weakness, dizziness, paresthesia, loss of reflexes, hypotension, generalized paralysis

What effect do local anesthetics have on the nerve AP?

Inhibit voltage gated Na+ channels which blocks axonal conduction

Name some examples of local anesthetic

Lidocaine Bupivacaine Procaine

What clinical effects is botox used for?

Temporary improvement of appearance of lines/wrinkles of face Prophylxis of chronic migraine headaches

Where does botulinum toxin come from and what are some symptoms?

Food-borne bacteria Symptoms: nausea, vomiting, abdominal pain, diarrhea, dry mouth

What effect does tetanus toxin have on the NMJ and what are the clinical signs of tetanus?

Blocks the fusion of synaptic vesicles by targeting VAMP/SNARE complex decreasing neurotransmitters at the NMJ Signs: spastic paralysis by blocking release of inhibitory neurotransmitters that serve to relax contracted muscles

What effect does curare alkaloids have on depolarization? Give an example of a curare alkaloid and what kind of signs does it produce?

Curare is an antagonist for ACh; competes with ACh for nACh receptor on the motor end plate Example: d-tubocurarine causes flaccid paralysis of skeletal muscle

What effect does succinyl choline have on depolarization?

Agonist for ACh in the NMJ. It binds to skeletal muscle nACh receptors and initially causes depolarization, but takes longer to break down by ACh esterase The continued depolarization leads to receptor blockage and paralysis. The receptor cannot be repolarized

What effect does Dantrolene have on contraction and what is it used to clinically treat?

It inhibits receptor in the SR of skeletal muscle cells. This decreases calcium release onto muscles which leads to decreased muscle contractions Clinical: treats malignant hyperthermia, spasticity associated with upper motor nerve disorders