Neuromuscular blocking drugs

Question 1

what neurotransmitters are used in the somatic nervous system?

Answer 1

Ach

-goes onto skeletal muscles

Question 2

how does nACHR differ in NMJ?

Answer 2

The NMJ nAChR is different in structure to the ganglionic (ANS) nAChR and so we can produce selective drugs just for the somatic nervous syste

Question 3

describe NM transmission

Answer 3

NM transmission – 
production of ACh using CAT 
AP propagation 
Ca2+ influx 
ACh exocytosis 
ACh binds to receptors and Na+ influx 
ACh esterase breaks down ACh à recycling by uptake.

Question 4

what are 3 most important NM-blocking drugs?

Answer 4

o Competitive – tubocurarine, atracurium.

o Depolarising – suxamethonium.

Question 5

what are the subunits in the nicotinic acetylcholine receptor?

Answer 5

There are 5 subunits in the receptor; a1, a2, b, d, g.

Question 6

which subunit receptor does ACh bind to?

Answer 6

ACh only binds to the alpha receptors.

Question 7

describe the density of these receptors on the motor-end plate

Answer 7

The density of these receptors on the motor-end plate is VERY high.

Question 8

what is the difference between the extracellular and intracellular domains?

Answer 8

There is a large extracellular domain and a slightly smaller intracellular domain.

Question 9

give examples of spasmolytics 
\+ 
where do spasmolytics act 
\+
what do they do?

Answer 9

e.g. Diazepam, Baclofen.
o Target central processes within the nerve cell.
o Spasmolytics relieve spasm of the muscles

Question 10

local anaesthetics

where do they act?

Answer 10

Inhibit the influx of sodium and so reduce the propagation of the AP along the nerve.

Question 11

Hemicolinium,
where do they act +
what do they do?

Answer 11

Hemicolinium, Ca2+-entry blockers, neurotoxins.

o Inhibit re-uptake of choline.

Question 12

Tubocurarine, suxamethonium.

where do they act

Answer 12

o These react on the post-synaptic membrane.

Question 13

Spasmolytics – e.g. Dantrolene.

where do they act/hat do they do?

Answer 13

PROPAGATION OF AP ALONG MUSCLE FIBRE + MUSCLE CONTRACTION

Question 14

what are the two types of postsynaptic NM blocking drugs?

Answer 14

non-depolarising

depolarising

Question 15

give examples of non-depolarising postsynaptic NM blocking drugs

Answer 15

competitive antagonists
o Tubocurarine.
o Atracurium.

Question 16

give examples of depolarising

Answer 16

agonists - cause depolarising block
Suxamethonium/Succinylcholine.
-this is so good at stimulating due to its very similiar structure to Ach

Question 17

what are the key points to remember about post-synaptic neuromuscular blocking drugs?

Answer 17

§ These drugs do NOT affect consciousness or pain sensation.
§ Respiration must ALWAYS be assisted when taking these drugs (until the drug is inactive or is antagonised).

Question 18

what is the method of action of suxamethonium?

Answer 18

o Causes a long (takes a long time to break down in the synaptic cleft) depolarising block.
o Also causes fasciculations (brief twitches of muscle fibres) à flaccid (loss of tone) paralysis.

Question 19

what are the pharmokinetics of suxamethonium?

Answer 19

o Administration – IV (it is highly charged and so IV is best ROA).
o Duration of paralysis is short (~5 minutes).
o Metabolised by a pseudo-cholinesterase in the liver and plasma.

Question 20

what are the uses of suxamethonium?

Answer 20

o Intubation – relaxes vocal chords.

o Muscle relaxant for ECT (ElectroConvulsive Therapy

Question 21

what are the unwanted effects of suxamethonium?

Answer 21

o Post-op muscle pains.
o Bradycardia – direct muscarinic action of the heart.
o Hyperkalaemia – soft tissue injuries or burns à ventricular arrhythmias/MI.
o Increase in IOP – thus avoid for glaucoma patients.

Question 22

what are the methods of actions of tubocuraine?

Answer 22

(non-depolarising NM blocker)
o A competitive nAChR antagonist.
o A block of 70-80% is necessary to cause effect of skeletal muscle relaxation.

Question 23

what are the effects of tubocuraine?

Answer 23

o Tubocurarine à flaccid paralysis.
o The flaccid paralysis then affects the muscles in a particular order:
§ Extrinsic eye muscles (double vision).
§ Small muscles of the face, limbs and pharynx.
§ Respiratory muscles.
o The recovery of this effect then works backwards and rewinds the effects.
§ I.E. eye muscles are blocked first and recover last!

Question 24

what are the uses for tubocurarine?

Answer 24

o Relaxation of skeletal muscles during surgical operations (so less anaesthetic needed).
o Permits artificial ventilation – as it relaxes the respiratory muscles.

Question 25

how can the effects of non-depolarising NM blockers be reversed?

Answer 25

The effects of non-depolarising NM blockers can then be reversed using anticholinesterases (e.g. neostigmine)

Question 26

what are the pharmacokinetics behind using non-depolarising NM blockers?

Answer 26

§ Pharmacokinetics:
o Administered via IV as highly charged.
o Does NOT cross BBB or placenta – so can be used in pregnant women for example.
o Paralysis lasts a LONG time (~40-60mins).
o NOT metabolised, it is excreted – 70% urine, 30% bile – care needed if renal or hepatic function impaired.

§ Atracurium – lasts 15mins and is chemically unstable so can be used in patients with renal or hepatic impairment.

Question 27

what are the unwanted effects of non-depolarising NM blockers such as tubocurarine?

Answer 27

Causes a ganglion block and histamine release:
§ Hypotension – ganglion blockade lowers TPR and histamine release causes vasodilation.
§ Tachycardia – reflex tachycardia (hypotension) and also due to blockade of vagal ganglia.
§ Bronchospasm, excessive secretions – histamine release causing bronchoconstriction.
§ Apnoea – thus ALWAYS assist respiration.