Neuromuscular blocking drugs

Question 1

What nervous system do neuromuscular blocking drugs affect?

Answer 1

Somatic nervous system

Question 2

Describe the somatic nervous system

Answer 2

See diagram - single cholinergic motor neurone innervating skeletal muscle

Question 3

Where is the cell body of a motor neurone?

Answer 3

In the ventral horn of the spinal cord

Question 4

Describe neuromuscular transmission?

Answer 4

See slides:
Synthesis of ACh
Action potential
Release of ACh
Stimulate nicotine receptors on muscle. Type 1 receptor ionotropic - Na+ enters depolarisation = end plate potential
ACh is broken down - choline and acetate
Choline pump moved back into presynaptic nerve terminal

Question 5

What is the end plate potential dependent on?

Answer 5

1) the amount of ACh
2) number of nicotinic receptors there

It is a graded potential - at all normal environment the end plate potential are sufficient enough to generate an action potential. -55mV = action potential

Question 6

How sub units are there in the nicotinic receptors?

Answer 6

there are 2 alpha sub units
5 subunits in total
alpha x2
beta x1
gamma x1
delta x1

Question 7

What are the two groups of neuromuscular blocking drugs? Give examples

Answer 7

1) Non depolaring (Competitive antagonists) - tubocurarine and atracurium
2) Depolarising (agonists) - suxamethonium = succinylcholine

They work post synaptically

Question 8

How many molecules of ACh are required to stimulate a nicotinic receptor?

Answer 8

2 ACh

they each bind onto one alpha subunit

Question 9

What are the different sites which neuromuscular blocking drugs can act and what drugs can act at these different sites?

Answer 9

Central processes –> Spazmolytics (Diazepam, Baclofen)
Conduction of nerve AP in motor neurone –> LA
ACh release –> Hemicholinium, Ca2+ entry blockers, neurotoxins (botulinin toxin)
Depolarisation of motor end-plate; AP initiation –> Tubocurarine, suxamethonium
Propagation of AP along muscle fibre + muscle contraction –>Spasmolytics (Dantrolene - works via reducing the release of intracellular calcium in the SR stores)

Everything causes skeletal muscle relaxation

Question 10

What do NM blocking drugs do not affect what?

Answer 10

Consciousness
Pain sensation

NB. We always assist respiration (until drug inactive or antagonised) when NM blocking drugs are used. Put them on a ventilator

Question 11

What is the structural similarities between tubocurarine and ACh?

Answer 11

quaternary ammonium group

High affinity no efficacy = antagonist

Question 12

What are the structural similarities between ACh and suxamethonium?

Answer 12

Suxamethonium consists of two ACh molecules joined tail to tail
Effective agonist

Question 13

Describe the method of action of suxamethonium

Answer 13

It is a depolarising blocker - creates an extended end plate depolarisation which gives rise to a depolarisation block = Phase 1 block

Essential what happens the nicotinic receptor becomes over stimulated so it shuts down. The suxamethonium stays in the synaptic cleft for much longer than ACh resulting in this over stimulation. It is not broken down as quickly.

Classic symptom of suxamethonium block is fasiculations –> flaccid paralysis

Question 14

Describe the pharmacokinetics of suxamethonium

Answer 14

Route of administration = I.V (highly charged)
Duration of paralysis = about 5 mins (short)
Metabolised by pseudo-cholinesterase in liver & plasma (see cholinomimetics liver)

Question 15

What are the 2 main uses of suxamethonium?

Answer 15

Endotracheal intubation

Muscle relaxant for ECT (Electroconvulsive therapy)

Question 16

What are the unwanted effects of suxamethonium?

Answer 16

• Post-operative muscle pains: due to early fasiculations
• Bradycardia: direct muscarinic actions of suxamethonium on heart. Usually atropine is there to block any any agonist effects on muscarinic receptors
• Hyperkalaemia: Soft tissue injury or burns (this tissues have increased the number of nicotinic receptors which means there is a greater overal potassium efflux. Upregulation of nicotinic receptors and supersensitisation to suxamethonium) –> ventricular arrhythmias/cardiac arrest
• Increase intraoccular pressure: avoid suxamethonium in patients with eye injuries or glaucoma. This is due to the fact hexamethonium may cause the contraction of the extraoccular muscles of the eye

Question 17

Describe tubocurarine

Answer 17

It is a non-depolarising NM blocker which is a naturally occurring quaternary ammonium compound.

Question 18

What is the method of action of tubocurarine?

Answer 18

Competitive nAChR antagonist (against ACh)

70-80% block of the nicotinic receptors is necessary

Question 19

What are tubocurarines effects?

Answer 19

Tubocurarine –> Flaccid paralysis

Order of effects:
1) Extrinsic muscles of the eye (double vision)
2) Small muscles of face, limbs and pharynx
3) Respiratory muscles
Then recovery happens in reverse

Question 20

What are the uses of tubocurarine?

Answer 20

1) relaxation of skeletal muscles during surgical operations (=less anaesthetic) for abdominal surgery
2) Permit artificial ventilation. It causes relaxation of resp muscles so artificial ventilation can be used

N.B the actions of non-depolarising blockers can be revered by anticholinesterases - Neostigmine (+atropine - given to reverse any effects that maybe caused by the increased levels of ACh acting on muscarinic receptors). Because ACh is no longer being broken down it surmounts the tubocurarine (remember its an competitive antagonist)

Question 21

Describe the pharmacokinetics of tubocurarine

Answer 21

Route of administration = I.V (highly charged)
Does not cross BBB or placenta
Duration of paralysis = 1-2 hours (long)
Not metabolised
Excretion = 70% urine, 30% bile (you must take care if there is renal or hepatic function impairment) If there is impairment that means the action of tubocurarine is going to be extended. Atracurium is used (15min - doesn’t require liver of renal function; it breaks down in the plasma)

Question 22

What are the unwanted effects of tubocurarine?

Answer 22

If you have to give a high concentration of tubocurarine you may get some overlap onto the ganglionic nicotinic receptors (resulting in ganglion block). It also causes histamine release from the mast cells (due to tubocurarine being slightly basic).

Hypotension

• Ganglion block (decreased TPR caused by block on the sympathetic side)
• Histamine release from mast cells (histamine is a vasodilator stimulates H1 receptors on vascualture)

Tachycardia (may cause arrhytmias)

• Reflex (in response to hypotension)
• Blockade of vagal ganglia

Bronchospasm
Excessive secretions (bronchial & salivary)
^ Both caused by histamine release

Apnoea (always assist respiration)