Neuromuscular blocking drugs

Question 1

Which nervous system do neuromuscular drugs target?

Answer 1

Somatic Nervous System

(Not ANS- no involvement of the sympathetic and the parasympathetic)

Question 2

Describe the somatic system in terms of their neurones and which neurotransmitter they use

Answer 2

It is a single axon- they innervate skeletal muscle

they are motor neurones

Neurotransmitter: ACh

Receptor- bind to nicotinic receptors

Question 3

Which nerves are the longest nerves?

Answer 3

Sciatic nerves

Question 4

How is ACh released into the synaptic cleft?

Answer 4

1. ACh are produced in the pre-synaptic cleft. Formed by the reaction between choline and Acetyl CoA (via the choline acetyl transferase enzyme)
2. ACh are packaged in vesicles. they wait for an action potential
3. Depolarisation of nerve causes opening of ca channels (voltage sensitive).
4. Ach exocytoses into the cleft and diffuses to the membrane of skeletal muscle (end plate region).
5. Ach interacts with receptors here and they are nicotinic receptors.

Question 5

Describe the structure of the nicotinic receptors that the ACh binds to and what happens once ACh binds

Answer 5

The receptors have 5 subunits which changes conformation and causes an influx of sodium in the endplate and causes an endplate potential (EPP)- it is a graded potential- depends on how much Ach and how many receptors there are.

If there are enough EPPs, then an action potential is fired. Shoots off down both ways down the skeletal fibres. Innervated the end plate region and this causes the excitation and contraction of the skeletal muscle.

Question 6

What happens to the ACh that is still bound to the nicotinic receptor?

Answer 6

It is removed and recycled by the anticholinesterase enzyme.

it is broken down into choline and acetate. The choline can be taken up and used again to form ACh.

Question 7

What is the subunit composition of muscle-type nicotinic receptors?

Answer 7

2 alpha

beta

gamma

epsilon

Question 8

What is the importance of the alpha subunits?

Answer 8

Nicotinic receptors span the whole membrane of the skeletal muscle.

ACh only binds to the alpha and this is what opens the receptor.

This is what causes the influx of sodium (and some loss of potassium).

these receptors have a large extracellular domain and slightly smaller intracellular domain.

Question 9

what are the different sites of neuromuscular blocking drug action?

Answer 9

• Central processes
• Conduction of nerve AP in motor neurone
• ACh release
• Depolarisation of motor end-plate and AP initiation
• Propagation of AP along muscle fibre and muscle contraction.

Question 10

give an example of a type of neuromuscular blocking drug that acts on central processes

Answer 10

Spasmolytics

Question 11

What is the action of spasmolytics?

Answer 11

They dissolve spacisity- work in the CNS (spinal cord) to reduce the degeneration. They are GABAergic drugs. They reduce neuromuscular transmission by central actions within the nerve cells, relieving the spasm of the nerve cells.

Question 12

Give some examples of spasmolytics

Answer 12

e.g. diazepam, Valium or baclofen.

Question 13

Give an example of a type of neuromuscular blocking drug that targets the conduction of nerve AP in motor neurone

Answer 13

Local anaesthetics

Question 14

Describe the action of local anaesthetics

Answer 14

They reduce generation of propagation of APs- blocking sodium channels and inhibiting the influx of sodium. Contributes to analgesic (painkiller) action. They can reduce some of the APs down motor fibres too so there can be skeletal muscle weakness. But not usually the case, because you try and inject where the sensory terminals are.

Question 15

Give an example of some types of neuromuscular blocking drugs that target ACh release

Answer 15

Hemicholium

…

Also calcium channel blockers and neurotoxins

Question 16

Describe the action of hemicholium

Answer 16

Reduce ACh release by blocking Ca entry into the pre-synaptic release- vesicles of ACh cannot enter the synaptic cleft.

Question 17

Actions of botulinin as a neuromuscular blocking drug

Answer 17

Proteinases in botulinin (toxin) that targets proteins and disrupts the release process of ACh- can lead to respiratory arrest. Used in Botox to paralyse muscles

Question 18

Give a type of neuromuscular blocking drug that will prevent the propagation of AP along the muscle fibre and prevent muscle contraction

Answer 18

Spasmolytics

Question 19

Which spasmolytic will prevent the propagation of APs and contraction of muscles specifically?

Answer 19

Dantrolene

Question 20

Describe the actions of dantrolene

Answer 20

Reduces the ca release from the sarcoplasmic reticulum so end muscle cannot contract

Question 21

There are 2 types of neuromuscular blocking drugs that stop the depolarising of the motor end-pate/ AP initiation- what are they and give examples for each one

Answer 21

1. NON- DEPOLARISING = Tubocarine and atracurium (competitive antagonists)
2. DEPOLARISING = suxamethonium (nicotinic receptor agonists)

Question 22

Why can’t the depolarising/ non-depolarising blockers not be used as LAs?

Answer 22

They do not affect consciousness or pain sensation.

Question 23

What do the depolarising/ non-depolarising blockers always need to be accompanied with?

Answer 23

Respiratory assistance- until the drug is inactive or antagonised.

Question 24

What is suxamethonium’s structure with relevance to ACh?

Answer 24

Suxamethonium is essentially two molecules of Ach. Freely rotation and can allow it to be an agonist- block it and has high efficacy.

Question 25

What is suxamethonium's method of action?

Answer 25

Administered IV- will diffuse into muscle and you will see muscle twitches initially (fasciculations) and then after a min, you generate flaccid paralysis (relaxation of skeletal muscles). Overstimulates receptors and therefore it shuts down. Extended depolarisation (massive stimulation) Suxamethonium not broken down as quickly as ACh and therefore acts as a competitive antagonist. Paralysis by muscarinic relaxation.

Question 26

Why is suxamethonium given as IV?

Answer 26

Need to be given IV as it very charged- paralysis is only 5 minutes. Suxamethonium is a short-acting Neuromuscular blocker. It is metabolised by pseudo-cholinesterases in the liver and plasma- gives rise to the short duration action.

Question 27

Give three clinical uses of suxamethonium

Answer 27

1. Endotracheal intubation- when you put a tube down trachea (maybe for further anaesthetics or investigation)- in order to relax the vocal cords. 2. Muscle relaxant for ECT (electroconvulsive therapy)- used in the treatment of depression. 3. Treatment for severe depression- effective in some people. Suxamethonium is a relaxant before ECT is given. It reduces the incidence for suicide.

Question 28

Give 4 unwanted side effects of suxamethonium

Answer 28

1. Post-operative muscle pains (due to fasciculations) 2. Bradycardia- due to muscarinic actions- not usually a problem as atropine is also given. 3. Hyperkalaemia- if there is soft tissue injury, you can damage sensory input, the reaction of the body is to put more nAChR there. Denervation supersensitivity. If these patients are given suxamethonium, there is a greater response with a great potassium efflux- can lead to ventricular faults and cardiac failure. Avoid the use of suxamethonium in burn patients and use something else 4. Can increase ocular pressure- avoid for eye injuries or pre-diagnosed glaucoma- use non-depolarising blockers.

Question 29

What is the structure of tubocurarine with respect of ACh?

Answer 29

End of ACh you have charged quaternary ammonium. Tubocurarine also has this. This similarity allows it also to bind and be a competitive antagonist. Big bulky molecules with little rotation, will not free up the receptor for ACh to bind.

Question 30

What are the effects of tubocurarine?

Answer 30

The initial effect of tubocurarine is flaccid paralysis --\>extrinsic eye muscles (double vision) --\> small muscles of face, limbs and pharynx --\> respiratory muscles The recovery is the reversal of these effect- i.e. eye muscles are the first to be blocked and recover last.

Question 31

What is tubocurarine's method of action?

Answer 31

It is a competitive nAChR antagonist. A block of 70-80% of the nAChR is needed for flaccid paralysis

Answer 32

There is a stimulation of the EPP but this will be insufficient for AP firing. AP will not carry through

Question 33

How is tubocurarine administered and describe the half-life

Answer 33

Administered IV (highly charged) Can be used in C section as does not cross placenta- does not cross BBB either. Acting for 1-2 hours- longer duration of paralysis Not metabolised but fully excreted- 70% in urine and 30% bile.

Question 34

What are 3 clinical uses of tubocurarine?

Answer 34

1. Relaxation of skeletal muscles- you can increase the dose of general anaesthetic; you can get the skeletal muscle relaxant. But you don’t want too much anaesthetic, so you use non-depolarising blockers during surgery. The patients will wake up faster. 2. Permits artificial ventilation- Given to people of ventilators so their respiratory muscles relax, and they are not working against the ventilators. 3. These non-depolarising drugs can be reversed by anticholinesterases. This can be used to raise the endogenous ACh level, you can overcome the tubocurarine block (as it is competitive)- you can bring a patient around quicker.

Question 35

What should you do if a patient with a renal or hepatic impariment needs to use tubocurarine?

Answer 35

If a patient has renal or hepatic impairment, the drug would be longer acting so you’d want to use an alternative. Use **atracurium**- unstable at physiological pHs. It breaks down spontaneously (hydrolysed in the plasma)- in 15 minutes is broken down.

Question 36

What are the unwanted effects of tubocurarine?

Answer 36

(Ganglion block- histamine release- leakage from mast cells, not a receptor-mediated response. Tubocurarine is SO BASIC) * Hypotension- reduction in TPR and reduction in BP. * Vasodilation- from histamine and reduction in BP * Tachycardia- can rise to arrhythmias- reflex to the drop in BP but also due to the blockade of vagal ganglia (the PNS)- therefore there will be an increase in HR * Bronchospasm and increase secretions (bronchial and salivary)- due to histamine release * Apnoea- always assist the respiration when you use neuromuscular blockers.