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yr 2 lcrs - pharm > 10 - Neuromuscular Blocking Drugs > Flashcards

10 - Neuromuscular Blocking Drugs Flashcards

1
Q

How do signals travel through the somatic nervous system?

A

Motor neurone cell body in ventral horn of spinal cord

Single axon projects outwards

Innervates a skeletal muscle

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2
Q

What type of neurons exist in the somatic nervous system?

A

Motor neurones

They are cholinergic

i.e. they release ACh onto the skeletal muscle

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3
Q

How do Action Potentials get transmitted to skeletal muscle in the somatic nervous system?

A

Acetyl CoA + Choline > ACh

  • via cholineacetyl transferase (CAT)
  • this enzyme is only in cholinergic neurones

ACh loaded into vesicles via vesicular pumps

Action potential arrives in terminal

Depolarisation of nerve terminal

Calcium influx into pre-synaptic nerve terminal

Exocytotic release of ACh from vesicles in pre-synaptic bulb into synaptic cleft

ACH diffuses onto post-synaptic membrane of skeletal muscle fibre

Stimulates nicotinic ACh receptors (type 1 which has five subunits) on post-synaptic membrane on skeletal muscle fibre
- these muscle type receptors are different to ganglionic neuronal nAChRs

Receptor changes conformation and opens a cation channel for 1-2ms (transient opening)

Na+ enters skeletal muscle fibre (and some K+ leaves and some Ca2+ enters)

Skeletal muscle fibre becomes depolarised

End Plate Potential (EPPs) is the initial depolarisation. This is a graded potential.

When EPP reaches -50mv (approximately), this stimulates the Action Potential in the skeletal muscle fibre

Action Potential shoots in both directions down the skeletal muscle fibre

Causes Excitation-Contraction Coupling

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4
Q

What do End Plate Potentials in skeletal muscle fibres depend on?

A

Dependent on:

  • number of nicotinic receptors
  • amount of ACh
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5
Q

What’s the main difference between an Action Potential and an End Plate Potential?

A

End Plate Potential
- graded

Action Potential
- all or nothing

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6
Q

How is ACh removed from a cholinergic synapse?

A

Break down by Acetylcholinesterase

This enzyme sits in the cleft, bound to the basement membrane

ACh into choline and acetic acid

Very rapid breakdown

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7
Q

What happens to the products of ACh breakdown in the synaptic cleft?

A

CHOLINE

- pumped back into pre-synaptic nerve terminal and used to make more ACh

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8
Q

How are we able to develop drugs with a degree of selectivity for nAChRs in the somatic nervous system?

A

There are multiple types of nAChR with slightly different pharmacology

Therefore, drugs can be developed which affect the muscle type nAChRs without completely affecting the neuronal type nAChRs.

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9
Q

What 2 groups are Neuromuscular junction blocking drugs split into?

A

NON-DEPOLARISING (COMPETITIVE ANTAGONISTS)

DEPOLARISING (AGONISTS)

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10
Q

Give examples of Competitive (Non-Depolarising) neuromuscular blocking drugs.

A 
Tubocurarine
Gallamine
Pancuronium
Alcuronium
Atracurium
Vecuronium
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11
Q

Give an example of Depolarising neuromuscular blocking drug.

A

Suxamethonium

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12
Q

How large are nicotinic receptors?

A

Have a large span

Have a significant extracellular and intracellular domain

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13
Q

How many subunits do nicotinic receptors have?

A

5 subunits

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14
Q

What part of nicotinic receptors does ACh bind to?

A

The alpha subunits of the receptor

There are 2 alpha subunits

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15
Q

How many molecules of ACh are needed to stimulate a nAChR?

A

2

Because there are 2 alpha subunits that make up the receptor

And ACh binds to these alpha subunits

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16
Q

What happens when ACh binds to the alpha subunits of the nAChR?

A

The channel opens within the receptor

The small bridge closing the channel off opens up due to conformational change in the receptor

There is a massive influx of Na+ through the receptor

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17
Q

Which drugs act on central processes?

A

Spasmolytics

e. g.
- Diazepam (Valium)
- Baclofen

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18
Q

Which drugs act on conduction of nerve AP in the motor neurone?

A

Local Anaesthetics

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19
Q

Which drugs act on ACh release?

A

Hemicholinium

Ca2+ Entry Blockers

Neurotoxins

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20
Q

Which neuromuscular blocking drugs act on depolarisation of motor end-plate AP initiation?

A

Turnocurarine

Suxamethonium

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21
Q

Which drugs act on propagation of AP along muscle fibre and muscle contraction?

A

Spasmolytics

e. g.
- Dantrolene

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22
Q

How do Diazepam and Baclofen work as Spasmolytic drugs?

A

Work in the treatment of spasticity (too much tension in muscles)

Such as in:

  • Multiple Sclerosis
  • Following a stroke
  • Cerebral Palsy

Act centrally in spinal cord

Reduce outflow of APs to skeletal muscle by acting on GABA system

Promotes relaxation

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23
Q

How do Local Anaesthetics work?

A

They block VSSCs

Prevent APs from sensory pain neurones to the brain

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24
Q

How Ca2+ Entry Blocking drugs act to relax skeletal muscles?

A

Reduce Ca2+ entry into pre-synaptic nerve terminal

Reduce ACh release into cleft

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25
Q

How can Neurotoxins cause paralysis and respiratory arrest?

A

Interfere with ACh release

Paralysis of respiratory muscles

Difficult to breathe

26
Q

What is the most potent neurotoxin?

A

Botulinum Toxin

  • gets into pre-synaptic terminal
  • prevents ACh release
27
Q

How does Dantrolene act as a Spasmolytic?

A

Good at treating spasticity

Works within skeletal muscle fibre

Reduces release of Ca2+ from sarcoplasmic reticulum stores

Less severe muscle contraction

28
Q

Where do Neuromuscular Blocking Drugs act?

A

Post-synaptically

  • work at the level of the receptor on the skeletal muscle fibre
29
Q

What is another name for Suxamethonium?

A

Succinylcholine

30
Q

Do neuromuscular blocking drugs affect consciousness?

A

No they do not affect consciousness

They also do not affect pain sensation

31
Q

What must you always do whilst a patient is being given neuromuscular blocking drugs?

A

Always assist respiration

Until the drug is inactive or antagonised

32
Q

Compare the chemical structure of ACh to Tubocurarine

A

COMPETITIVE AGENT
NON-DEPOLARISING AGENT
nAChR ANTAGONIST

Has affinity for nAChR but no efficacy

Big, bulky structure with limited rotation around their bonds

Both have a quaternary ammonium group with methyl groups attached

33
Q

Compare the chemical structure of ACh to Suxamethonium

A

DEPOLARISING AGENT
nAChR AGONIST

Has affinity and efficacy for nAChR

If you split Suxamethonium in half, you get two molecules of ACh

Both have a quaternary ammonium group with methyl groups attached

34
Q

What is the difference between Suxamethonium stimulating an nAChR and ACh stimulating it?

A

Only need one molecule of Suxamethonium to stimulate the nAChR as it is 2 molecules of ACh attached together. Therefore, it can bind to both alpha subunits of a nAChR at once.

35
Q

What is the only clinically used Depolarising Neuromuscular Blocking drug?

A

Suxamethonium

36
Q

What is the mechanism of action of Suxamethonium?

A

Extended End Plate Depolarisation on the skeletal muscle fibre

Gives rise to a ‘Depolarisation’ or ‘Phase 1’ Block

Overstimulates the nAChR by flooding the synaptic cleft

Suxamethonium is broken down much more slowly than ACh (5 mins as opposed to 1-2ms)

37
Q

What is the duration of paralysis with Suxamethonium?

A

5 mins (short)

38
Q

What notable symptom is caused by Suxamethonium administration?

A

Fasciculations (small muscle twitches)

Individual fibres twitching

Shortly after this, there is flaccid paralysis due to overstimulation of nAChRs

39
Q

How is Suxamethonium administers?

A

I.V.

It is a highly charged molecule therefore is not very lipid soluble

40
Q

How is Suxamethonium metabolised?

A

By Pseudo-Cholinesterase

In the liver and plasma

41
Q

How is Suxamethonium utilised clinically?

A

Endotracheal Intubation
- e.g. for a bronchoscopy

Muscle Relaxant for ECT
- for people who don’t respond to antidepressants

42
Q

In which people may Suxamethonium have an action for a few hours rather than its normal 5 minutes?

A

In people who have a genetic deficiency of pseudo-cholinesterase

About 1 in 3000 people

43
Q

What is ECT?

A

ECT (Electroconvulsive Therapy) is a treatment that involves sending an electric current through the brain to trigger an epileptic seizure to relieve the symptoms of some mental health problem.

44
Q

What are some of the unwanted effects of Suxamethonium?

A

POST-OPERATIVE MUSCLE PAINS
- Due to initial fasciculations causing slight muscle tearing

BRADYCARDIA

  • Direct muscarinic action on heart
  • Can stimulate the muscarinic receptors on the heart
  • Howver, Atropine is used a predmedication to block any overstimulation of the muscarinic receptor

HYPERKALAEMIA

  • Watch especially if person has soft tissue injury or burns
  • May give rise to ventricular arrhythmias/ cardiac arrest

RAISED INTRA-OCULAR PRESSURE

  • Increased contraction of muscles around the eye
  • Avoid for eye injuries/glaucoma
45
Q

Why is Suxamethonium not given to people with burns/soft tissue injuries?

A

Damage

People have less innervation to skeletal muscle due to damage of soft issue

Therefore, skeletal muscle puts out more nicotinic receptors (upregulation)

This is deinnervation supersensitivity of skeletal muscle fibres

If patient is given Suxamethonium, more Na+ influx into fibres and more K+ efflux

This K+ efflux may be enough to cause hyperkalaemia

46
Q

Where was Tubocurarine found and what type of compound is it?

A

Naturally occurs in a South American plant (used as arrow poison)

It is a quaternary ammonium compound (alkaloid)

47
Q

What is the mechanism of action of Tubocurarine?

A

Competitive nAChR antagonist

Has affinity but no efficacy

48
Q

What percentage of block of nAChRs is needed for Tubocurarine to be effective?

A

70-80%

Significantly reduces End Plate Potential

49
Q

What is the difference between the original Tubocurarine compound and its the synthetic drug range that has been created based upon its mechanism of action?

A

The synthetic drugs have a different duration of action to Tubocurarine

50
Q

What are the effects of Tubocurarine?

A

Flaccid Paralysis

Muscles that are paralysed in order:

  • Extrinsic eye muscles causing double vision
  • Small muscles of face, limbs, pharynx
  • Respiratory muscles

These muscles recover in the reverse order

51
Q

What are the clinical uses of Tubocurarine?

A

Relaxation of skeletal muscles during surgical operations (esp. big abdominal muscles)

  • therefore require less anaesthetic
  • operation is safer
  • patient can be brought around much quicker

Permit artificial ventilation

52
Q

How can the actions of non-depolarising neuromuscular blocking drugs be reversed?

A

Can be reversed using anticholinesterases

e.g. Neostigmine (raises levels of ACh in the synaptic cleft, overcoming block caused by Tubocurarine/other drugs)

Some Atropine is also given to reverse any effects on muscarinic receptors

53
Q

How is Tubocurarine administered?

A

I.V.

It is highly charged due to ammonium groups and is therefore not very soluble

54
Q

Why does Tubocurarine not cross the BBB or the placenta?

A

Because it is highly charged due to its quaternary ammonium group

55
Q

How long is the duration of paralysis caused by Tubocurarine?

A

1-2 hours (long)

56
Q

Why does Tubocurarine stop working after 1-2 hours?

A

It is not metabolised

Therefore, it is excreted in its complete form.

  • 70% in urine
  • 30% in bile
57
Q

Why is it important to note whether people have impaired renal or hepatic function when administering Tubocurarine?

A

This is because it is not metabolised and therefore has to be excreted to halt it s effects in the body.

The duration of Tubocurarine would be extended.

58
Q

What drug would be given instead of Tubocurarine to a patient with impaired renal or hepatic function, and why?

A

Atracurium

Because it’s duration of action is 15 minutes as opposed to 1-2hours.

Therefore, its duration of action is not determined by its excretion like Tubocurarine.

59
Q

How is Atracurium stopped from functioning in the body?

A

It has a chemically unstable compound.

It is hydrolysed in the plasma into two inactive fragments.

This occurs spontaneously over 15-20 minutes.

60
Q

What are some of the unwanted effects of Tubocurarine?

A

2 MAIN EFFECTS:

GANGLION BLOCK

  • some overlap onto ganglionic nicotinic receptors
  • there is a degree of selectivity for muscle type nicotinic receptors
  • but high dose of tubocurarine may overlap onto neuronal type ganglionic nicotinic receptors

HISTAMINE RELEASE
- from mast cells
- due to Tubocurarine
THESE 2 EFFECTS CAN CAUSE:

Hypotension

  • Ganglion blockade on the autonomic sympathetic side decreases TPR
  • Also due to histamine release from mast cells, histamine is a vasodilator by stimulating H1 receptors on vasculature

Tachycardia

  • reflex initially due to the hypotension
  • blockade of vagal ganglia by removing brake on the heart
  • can lead to arrhythmias

Bronchospasm
- due to histamine release

Excessive Secretions

  • bronchial and salivary
  • due to histamine release

Apnoea

  • always assist respiration
  • due to blocking the respiratory muscles
61
Q

Which physiological process is mostly likely to be interfered with by the clinical use of neuromuscular blocking drugs?

A

Respiration

62
Q

What form of paralysis is caused by use of a non-depolarising neuromuscular block?

A

Flaccid Paralysis

yr 2 lcrs - pharm (44 decks)

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