Neuromuscular Blocking Drugs

Question 1

What are alpha motor neurones?

Answer 1

Lower motor neurons whose cell bodies are found in the anterior horn of the spinal cord and whose axons travel in the body to innervate skeletal muscle

Question 2

Describe how impulses are transmitted across synapses.

Answer 2

1. Propagtion of action potential propagates along the presynaptic neurone until it reaches pre-synaptic terminal
2. Depolarisation of presynaptic membrane
3. Opening of coltage gated calcium channels
4. Calcium influx
5. Vesicle exocytosis
6. Neurotransmitter release into synaptic cleft and diffuses across synapse to post-synaptic membrane

NOTE: Each step results in the subsequent step

Question 3

What type of receptor is found at the neuromuscular junction?

Answer 3

Nicotinic acetylcholine receptors

• Ion-channel linked

REMEMBER: nAChR - different to ganglionic nAChR

• This allows drugs to be developed which are specifically targeted to skeletal muscle nAChRs

Question 4

Where are nicotinic ACh receptors found on the muscle fibre?

Answer 4

On the motor end-plate

• The motor end plate is roughly in the middle of the skeletal muscle fibre
• NOTE: NMJ = junction between motor neurone and muscle fibre

Question 5

What happens once ACh binds to the nicotinic receptors on the motor end-plate?

Answer 5

• ACh binding to the receptor causes opening of the ion channels and an influx of Na⁺
• This generates an end-plate potential
• This is a graded potential
• Therefore, the amount of depolarisation is dependent on:
  
  • Amount of acetylcholine released from the presynaptic neurone
  • Number of receptors stimulated on the motor end-plate
• Once the end plate potential reaches the threshold potential, it generates an action potential
  
  • AP - all or nothing
• AP propagates in both directions along the muscle fibre
• You get excitation-contraction coupling → muscle contraction

NOTE: Ion channel doesn’t stay open for long - closes very quickly so whole process can occur again (i.e. can be stimulateed to open again)

Question 6

Where is acetylcholinesterase found?

Answer 6

In the synaptic cleft

• ACh → choline + acetate
• Choline taken back up into pre-synaptic nerve terminal so it can be used in the re-synthesis of ACh

Question 7

Describe the structure of nicotinic acetylcholine receptors.

Answer 7

• They span the whole width of the lipid bilayer
  
  • They have both an intracellular and extracellular domain
• They consist of 5 subunits
  
  • There are always 2 alpha subunits, which ACh bind to and activate the receptor
    
    • So you need 2 molecules of ACh to activate each receptor - one for each subunit

Question 8

State different sites at which drugs can act to effect NM transmission

Answer 8

• Central process
  
  • Sensory neurones stimulate APs in the spinal cord and therefore motor neurone activation
• Conduction of nerve AP in motor neurone
• ACh release
• Depolarisation of motor end-plate → AP initiation
• Propagation of AP along muscle fibre and muscle contraction

These all act to reduce NM transmission and relax the skeletal muscles

Question 9

Name two drugs that are used as spasmolytics and describe their action.

Answer 9

• Diazepam
• Baclofen

They work to reduce the generation of APs in the spinal cord - centrally acting drugs

• They both facilitate GABA transmission
• GABA = chief inhibitory NT in CNS

Question 10

Give some examples of conditions in which spasmolytics may be used.

Answer 10

• Multiple sclerosis
• Stroke

These patients may have spasticity - this could be helped by treatment with spasmolytics

• Spasticity = increased, involuntary, velocity-dependent muscle tone that causes resistance to movement
  
  • Muscle tone is increased - i.e. muscle is more contracted
  • The faster you move the limb, the more the tone and the greater the resistance
• ​This makes the muscles more stiff and reduces their functionality
• Spasmolytics could help relax skeletal muscle to counteract the hypertonia

Question 11

How do local anaethetics (LAs) work?

Answer 11

Normal action:

• They work by blocking VGSCs
• When an LA is injected around a wound, they would act on the sensory neurones in that area to reduce the generation and propagation of APs to the CNS
• This contributes the their analgesic (pain relief) action

Action on motor neurones:

• If you inject the LA too close to a motor neurone, it can also block VGSCs and reduce AP conduction down motor neurone
• This can cause some muscle weakness due to relaxation (reduced tone)
• This is an unwanted effect on LAs

Question 12

State some drugs which inhibit ACh release.

Answer 12

• Hemicholinium
  
  • ​Blocks reuptake of choline which is needed for further ACh synthesis and release
• Ca²⁺ entry blockers
  
  • Block entry of Ca²⁺ into presynaptic terminal, therey preventing vesicle exocytosis
• Neurotoxins
  
  • Have various mechanisms of action in general
  • Botulinum toxin:
    
    • Interacts with and damages proteins involved in vesicle fusion with pre-synaptic membrane (a key step in vesicle exocytosis)
    • If this happens with respiratory muscles: respiratory muscle paralysis → respiratory failure and death

Question 13

Name another spasmolytic that has a different action to the ones that act centrally.

Answer 13

Dantrolene

• It works in the skeletal muscle fibres themselves
• Reduced the release of Ca^₂₊ from the sarcoplasmic reticulum

Question 14

What do neuromuscular blocking drugs do?

Answer 14

Block NM transmission at the NMJ (i.e. the motor-end plate which is specific to the NMJ)

• They have a post-synaptic action

Question 15

State the three main neuromuscular blocking drugs.

Answer 15

• Tubocurarine
• Atracurium
• Suxamethonium (otherwise known as succinylcholine)

Question 16

What are the two types of neuromuscular blocking drugs? Give examples of drugs for each type

Answer 16

Depolarising e.g:

• Tubocurarine
• Atracurium

Non-depolarising e.g:

• Suxamethonium

Question 17

State some characteristics of neuromuscular blocking drugs.

Answer 17

• Do not affect consciousness
• Do not affect pain sensation
• When giving these drugs you always assist respiration because of its effect on the respiratory muscles
  
  • i.e. It would cause relaxation of the respiratory muscles which would mean you would struggle to self-ventilate

Question 18

Describe the difference in structure between non-depolarising and depolarising NM blockers?

Answer 18

Tubocurarine (non-depolarising):

• Has quarternary ammonium groups, similar to ACh
  
  • These similarities allow it to bind to nicotinic receptor (i.e. has affinity)
  • BUT it has no efficacy
• Non-depolarising agents in general:
  
  • Rigid, bulky molecules with limited movement around their bonds (free rotation)
    
    • This makes them good receptor blockers

Suxamethonium (depolarising):

• Made up of two acetylcholine molecules that are linked together
  
  • As it is made up of two acetylcholine molecules it can binds to the two alpha subunits and activate the receptor
  • Therefore it has a good efficacy - good stimulator of the nicotinic receptor
• Agonists in general:
  
  • More free rotation

Question 19

Describe the mechanism of action suxamethonium.

Answer 19

• Suxamethonium is a nicotinic receptor agonist so it can activate muscle fibres
  
  • Initally you will see this as fasciculations (twitching of individual muscle fibres) as the suxamethonium begins to stimulate the nicotinic receptors
• However, it is not metabolised as rapidly as ACh
• So it remains in the synapse and can activate nicotinic receptors on the motor end-plate for longer
• Therefore, it causes an extended end plate depolarisation leading to a depolarisation block of the NMJ
• Also known as a phase 1 block
• Receptors are essentially being overstimulated, so the receptor response shuts down
  
  • This results in flaccid paralysis
    
    • Muscles relax due to depolarisation block so you have a lack of muscle tone → muscles can’t contract → prevents movement

Question 20

What is the route of administration of suxamethonium?

Answer 20

IV

• As it is highly charged it would not be very easily absorbed through the GI tract into the bloodstream

Question 21

What is the duration of paralysis of suxamethonium?

Answer 21

5 mins - short-acting NM blocker

Question 22

How is suxamethonium metabolised?

Answer 22

It is metabolised by pseudocholinesterase in the liver and plasma

NOTE: Pseudocholinesterase metabolises a variety of choline esters (non-specific)

Question 23

What are some uses of suxamethonium?

Answer 23

Endotracheal intubation

• Relaxes the muscles of the airways which makes it easier to insert a tube into the trachea

Muscle relaxant for electroconvulsive therapy (ECT)

• ECT is a treatment for severe clinical depression
• Essentially with this, you are passing electrical currents through the brain to induce seizures
• Therefore, it is important to use a muscle relaxant to prevent motor symptoms that you would normally get from seizures such as jerking, in order to prevent musculoskeletal injury

Question 24

State and explain four unwanted effects of suxamethonium.

Answer 24

Post-operative muscle pains

• This sometimes occurs due to the initial fasciculations

Bradycardia

• This is due to the direct muscarinic action on the heart
• Because suxamethonium is a ACh agonist, it can mimic ACh and can have parasympathetic effects on the heart by acting on muscarinic receptors
• But this effect tends to be prevented as atropine (competitive muscarinic antagonist) is included in thepre-medication
  
  • Pre-medication given before GA
  • Suxamethonium (a muscle relaxant) can be given with GA

Hyperkalaemia

• Soft tissue injury or burns can lead to ventricular arrhythmias or cardiac arrest
• If there is a burn or some soft tissue injury, you will lose some of the neurones innervating the muscle and so you get upregulation of the receptors in the skeletal muscle = deinnervation supersensitivity
  
  • So, there will be more receptors on the muscle fibre for suxamethonium to act on and activate
  • This results in bigger influx of sodium and bigger efflux of potassium through the nicotinic receptor
  • Therefore, you get hyperkalaemia which leads to the arrythmia and cardiac arrest – disrupts normal electrical activity of the heart
• So in burns patients or patients with soft tissue damage, use a non-depolarising NM blocker

Raised Intraocular Pressure

• AVOID for eye injuries and glaucoma
• Due to increased contraction of the extraocular muscles

Question 25

State some characteristics of tubocurarine.

Answer 25

It is a naturally occurring ammonium compound *(alkaloid)* found in a South American plant *(arrow poison)* A range of synthetic drugs are now available

Question 26

Describe the mechanism of action of tubocurarine.

Answer 26

Tubocurarine is a **competitive** nicotinic acetylcholine **receptor antagonist** * You only need 70-80% block to achieve full relaxation of the muscles * If you block this proportion of the receptors then the end-plate potential generated will NOT reach the threshold potential * You will still get **some depolarisation** though *(small end-plate potential)*

Question 27

What is the result of tubocurarine administration? Describe the order of relaxation of skeletal muscles and the order in which they return back to normal when given tubocurarine.

Answer 27

Tubocurarine causes **flaccid paralysis** The skeletal muscles relax in a certain sequence and they get back to normal in the **opposite** order In order of first to relax: * Extrinsic eye muscles * Small muscles of the face, limbs and pharynx * Respiratory muscles

Question 28

State two uses of tubocurarine.

Answer 28

Relaxation of muscles during surgical operations - this means that less general anaesthetic is needed * *Anaesthetics are used for temporary loss of sensation* * *However, some GAs themselves also cause muscle relaxation* * *Therefore, if you use an additional muscle relaxant like tubocurarine, you will need a lower dose of the GA* Permit artificial ventilation * *If a patient's own breathing is irregular, you want to relax their own respiratory muscles so they are not doing anything* * *This will allow them to follow the rate of the ventilator and ventilate properly*

Question 29

How can the actions of NM blockers be reversed?

Answer 29

Give an **anticholinesterase** - e.g. **neostigmine** = reversible anticholinesterase (and _atropine_ with it) * *You increase the concentration of the acetylcholine so it can outcompete the non-depolarising blocker* * *By giving neostigmine you increase the acetylcholine concentration in all other cholinergic synapses* * *So you give some **atropine** (competitive muscarinic antagonist) with it so that it blocks the muscarinic receptor overstimulation*

Question 30

What is the route of administration of tubocurarine?

Answer 30

IV * As it is highly charged it would not be very easily absorbed through the GI tract into the bloodstream

Question 31

What is important to remember about the distribution of tubocurarine?

Answer 31

It does **not** cross the BBB or placenta

Question 32

What is the duration of paralysis of tubocurarine?

Answer 32

1-2 hours - **long-acting** NM blocker

Question 33

Describe the metabolism and excretion of tubocurarine? What could be a consequence of this and what is a possible solution?

Answer 33

It is **NOT** metabolised at all It is excreted in its unchanged form in: * Urine (70%) * Bile (30%) Therefore, if renal/hepatic function is impaired, you get a much _longer_ duration of action with tubocurarine administration * In this case you could use **atracurium as an al**

Question 34

What is an alternative to tubocurarine? When would you use it?

Answer 34

Alternative - **atracurium** Atracurium is chemically unstable so only has a duration of action of 15 minutes * *Tubocurarine is not metabolised so its duration of action depends on excretion, which depends on renal/hepatic function* * *Therefore, if renal/hepatic function is impaired, you get a much longer duration of action of tubocurarine* * *In this case you could use atracurium as an an alternative* *due to its shorter duration of action* * *It automatically breaks down in plasma as it is chemically unstable*

Question 35

State some unwanted effects of tubocurarine.

Answer 35

The unwanted effects are mainly due to: * Ganglion blockade * It could block some of the nicotinic receptors in the ganglia when you start increasing the concentration of tubocurarine * Selectivity decreases as concentration increases * Histamine release from mast cells * Tubocurarine is a very basic drug * Alkaline conditions cause histamine leakage out of the cell Unwanted effects: Hypotension * Blood pressure can drop due to ganglion blockade (blocking ANS → blocks SNS → prevents vasoconstriction → reduced TPR) * Histamine causes vasodilation → reduced TPR Tachycardia which may lead to arrythmias * Tachycardia is a reflex in response to the hypotension * Could also be due to the blockade of vagal *(i.e. parasympathetic)* ganglia * REMEMBER: all autonomic ganglia (parasympathetic _and_ sympathetic) have nicotinic ACh receptors Bronchospasm * Histamine causes bronchoconstriction * *Bronchospasm = sudden constriction* Excessive secretions (bronchial and salivary) * Caused by the histamine release Apnoea * Respiratory muscles are relaxed as they are skeletal muscles * This is why you always _assist respiration_ in someone who's taking tubocurarine