Pharmacology of the Neuromuscular Junction [4] Flashcards Preview

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Flashcards in Pharmacology of the Neuromuscular Junction [4] Deck (8)
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1
Q

Outline the physiological events leading to contraction of skeletal muscle and describe potential drug targets for pharmacotherapy

A

Nerve action potential arrives at motor end plate. The AP depolarization is mediated via Na+ ion inward current through voltage -sensitive sodium channels (VSSC). AP depolarization opens voltage-sensitive calcium channels (VSCC) allowing Ca++ ion influx. Ca++ interaction with vesicle-associated membrane proteins (including synaptobrevin) then promotes membrane fusion and vesicular ACh release

Potential targets: VSSC (local anesthetics), VSCC (anti-seizure meds), Synaptobrevin (botox), ACh release (botox, black widow), Nm receptor (agnosist =SuCh antagnosit=curare)

2
Q

Describe how botulinum toxin and black widow spider venom affect cholinergic neurotransmission

A

Botulism toxin: lyses synaptobrevin to prevent the synaptic fusion and the subsequent release of ACh at the neuromuscular junction

Black widow spider venom: causes excessive clumping of ACh-containing vesicles, resulting in an explosive release of neurotransmitter into the synapse

3
Q

Explain what happens with brief versus prolonged stimulation of nicotinic cholinergic receptors.

A

Brief stimulation of these receptors leads to conductance of cations (mostly sodium) through the pore region of the receptor channel and depolarization results. If depolarization is sufficient, an action potential is fired (voltage-gated sodium channels open) and the muscle contracts. During depolarization the inactivation gates of voltage-gated sodium channels are closed, but these are reopened as the membrane repolarizes.

However, when there is prolonged depolarization, the membrane cannot repolarize and the inactivation gates do not reopen. As a result, the voltage-gated sodium channels can no longer conduct sodium and an action potential cannot be fired again. If this state of inactivity persists, the nAChR eventually becomes desensitized. Desensitization means that the nicotinic receptor still binds ACh, but does not couple to the opening of ion channels, so an action potential cannot be fired

4
Q

Describe the effects produced by selective antagonists of the nicotinic cholinergic receptor at the NMJ and explain their clinical usefulness

A

Antagonists for nAChRs at the NMJ competitively bind to the receptor, preventing ACh from binding and depolarizing the membrane. As a result, muscle contraction is inhibited.

Antagonists that are selective for the NMJ produce flaccid paralysis of the skeletal muscles. Muscles receiving the greatest innervation (“fast-twitch”) are paralyzed first.

NMJ nAChR antagonists are used clinically as an adjuvant to surgical anesthesia to relax skeletal muscles and to facilitate intubation by relaxing the muscles of the airway. These drugs are not absorbed from the GI tract, so they are generally administered intravenously.

5
Q

Describe the different properties of curare, atracurium, and rocuronium [nondepolarizing (competitive) neuromuscular blocking agents] that make them useful/not in different clinical situations useful.

A

All of these drugs act as competitive, nAChR antagonists at the NMJ.

Curare: Onset in 4-6min. Elminated by kidney. Duration of 80-120 min. Histamine release and Ganglionic nAChR inhibition

Atracurium: Onset in 2-4 min. Eliminated by spontaneous hydrolysis and plasma Che. Duration of 30-60min. Some histamine release and NO Ganglionic nAChR inhibition

Rocuronium: Onset in 1-2min. Eliminated by liver. Duration of 30-60min. NO histamine release or Ganglionic nAChR inhibition.

6
Q

Describe the properties that make succinylcholine distinct from other clinically used neuromuscular blocking agents

A

Succinylcholine is a depolarizing blocker, while the other blocking agents are competitive antagonists. The succinylcholine is not rapidly eliminated from the NMJ, causing a sustained depolarization that eventually leads to depolarization block, desensitization of the nAChR and flaccid muscle paralysis. This constitutes the Phase I block. After this block wears off, a curare-like (competitive antagonist) block remains. This is the Phase II block.

Succinylcholine is very useful clinically because its duration of action is around 8 minutes. So it can be titrated and adjusted on a near minute-to-minute basis

7
Q

Explain the effects of cholinesterase inhibitors in patients receiving nondepolarizing vs depolarizing neuromuscular blocking agents

A

In pts receiving….

Non-depolarizing: CAN be reversed by cholinesterase inhibitors (AChEIs) (i.e., the increase in synaptic ACh levels overcomes competitive block)

Depolarizing: SuCh is NOT hydrolyzed by AChE (but action is terminated by diffusion from synapse and subsequent degradation by pseudocholinesterase)

8
Q

Outline the management of organophosphate poisoning

A

Mechanic ventilation may be required

Pralidoxime regenerates the inactivated cholinesterase back to the active enzyme

Atropine for its CNS action and block of bradycardia and bronchospasm - bronchorrhea and respiratory secretions as well as other symptoms of “SLUDGE”

Diazepam to prevent or treat convulsions