Drugs acting at the skeletal neuromuscular junction

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Neuropharmacology – BIOL 20782

Dr. Liz FitzgeraldTel. x 55495Email. elizabeth.m.fitzgerald@manchester.ac.uk

Chemical – involve neurotransmitter AP may/may not rlse sufficient neurotransmitter for post- synaptic cell to reach threshold

Electrical – direct contact between cells (gap junctions) AP always propagated to next cell

Types of Synapses

Most synapses between neurones, and all synapses between neurones and other cells involve chemical synapses

Skeletal Neuromuscular Junction (SNMJ)

Fast chemical synapse = Cholinergic synapse

Neurotransmitter = acetylcholine (ACh)

Receptor = nicotinic ACh receptor (nAChR)

1. Neuromuscular blocking drugs - non-depolarising drugs - depolarising drugs - inhibitors of acetylcholine (ACh) synthesis/ release

2. Drugs that enhance cholinergic transmission

- inhibitors of cholinesterase - stimulants of ACh release

1. Cholinergic transmission at the skeletal neuromuscular junction (SNMJ)

- physiology of the SNMJ

- synthesis/release of acetylcholine (ACh) - nicotinic AChRs 2. Drugs blocking neuromuscular transmission

3. Drugs that enhance cholinergic transmission

The motor end plates at the distal ends of the axon terminal filaments of a motor nerve. The plates represent the nervous contribution to the neuromuscular junctions. The axon terminal filaments are the segmented lines leading to the plates. The segmented appearance of the nerve fibers is due to presence of the Schwann cells around the fibers and the nodes of Ranvier between the Schwann cells.The plates shown here are "ending" [innervating] on teased skeletal muscle fibers.

Neuromuscular Junction Motor End Plates [100x]

Neuromuscular Junction (Frog)

www.zoology.ubc.ca

Activation of ion channels at a neuromuscular junction

Presynaptic

Postsynaptic

At the SNMJ……

ACh binds nAChRs opening of cation channels (net influx Na+) rapid localised depolarisation at motor endplate (endplate potential, epp) initiates an action potential in the muscle fibre muscle contraction.

Only 1 nerve fibre supplies each muscle fibre but epp amplitude > sufficient for action potential

Transmission even when epp reduced 70-80 % - large margin of safety!

Model of nAChR

At the SNMJ,

ACh binds to the subunit (2 binding sites), 2 molecules of ACh are required to open the channel

1 vesicle contains enough ACh to bind ~3000 receptors2 mols. ACh bind nAChR, min. ~6000 molecules AChper vesicle

Av. depolarisation at SNMJ is 40 mV (postsynaptic potential per vesicle = 1 mV) at least 40 vesicles released and ~120,000 receptors activated at the SNMJ

In reality, ~ 300 vesicles rlsed high safety margin

Acetylcholine synthesis and release

www.starklab.slu.edu

Cholineacetyltransferase

H+

Neuromuscular blocking drugs

Used as an adjunct to surgical procedures to induce paralysis, e.g. intubation for anaesthesia

1. Postsynaptic action – interfere with action of ACh (site of action of most clinically important drugs) - Non-depolarising blockers (antagonists at nAChRs + some also block ion channels)

- Depolarising blockers (agonists at nAChRs)

2. Presynaptic action – inhibit ACh synthesis/release

Depolarising blocker

Non-depolarising blockers

“Curare” – mixture of naturally occurring plant alkaloids used as arrow poison by South American Indians.

1856 – Claude Bernard showed that “curare”caused paralysis by blocking neuromusculartransmission.

Tubocurarine – Main constituent of “curare”. Now rarely used clinically.

Synthetic drugs:

Gallamine – 1st useful synthetic drug but can cause tachycardia & 100% renal excretion (to be avoided in patients with poor renal function). Superceded by drugs with fewer side-effects, e.g. Pancuronium, Vecuronium, Atracurium

1.Non-depolarising blockers(Postsynaptic)

Non-depolarising blockers

- Competitive antagonists at nAChRs.- 70-80% of nAChRs must be blocked before transmission fails.- Degree of block varies according to… stimulation frequency temperature cholinesterase inhibition etc.

NB. Some drugs also block presynaptic autoreceptors inhibit ACh release during repetitive stimulation of the motor nerve.

Mechanism of action

Fig 10.6 – new Rang

Effects of non-depolarising blockers

Mainly a result of motor paralysis (some drugs also have significant autonomic effects).

Order in which muscles affected:Extrinsic eye muscles > small muscles of face > limbs andpharynx > respiratory muscle.

Conciousness + pain normal, even when paralysis complete

Unwanted effects

Tubocurarine - arterial pressure, mainly via ganglion block - blocking postsynaptic action of ACh by blockingneuronal nAChRs. Also due to release of histamine from Mast cells bronchospasm (common to many strongly basic drugs)

Other drugs, e.g. vecuronium, lack these side-effects, cause < hypotension.

Gallamine, pancuronium – block muscarinic AChRs (particularly in heart tachycardia)

Pharmacokinetic aspects

Non-depolarising neuromuscular blockers are mainly used in anaesthesia – muscle relaxation.

Given intravenously but differ in rates of onset and recovery.

Table 10.7New Rang

Non-depolarising blockers:- Most metabolised by liver/ excreted unchanged in urine.Exceptions:- atracurium (hydrolyses spontaneously in plasma)mivacurium (hydrolysed by plasma cholinesterase)

Duration of action 15 min > 1-2 h

Route of elimination important –gallamine – impaired renal/hepatic function can dangerously prolong paralysis in patients with renal failure.

atracurium – chemically unstable @ physiological pH short duration of action. Action becomes significantly briefer during respiratory alkalosis caused by hyper-ventilation.