Pharmacology - Neuromuscular Blockade

Question 1

How can neuromuscular blocking agents be classified?

Answer 1

Depolarising
Partial agonists that bind the post-synaptic nAChR to induce depolarisation, but then hold it open in an inactivated state - Suxamethonium

Non-depolarising
Competitively inhibit pre- and post-synaptic nAChR at the NMJ
75% of receptors need to be occupied before clinical impact seen

Benzylisoquinoliniums
Atracurium
Tubocurarine
Mivacurium

Aminosteroids
Rocuronium
Vecuronium
Pancuronium (long acting)

Question 2

Discuss Suxamethonium

Answer 2

Class and uses
Depolarising muscle relaxant
Bis-choline ester of succinic acid, a polar, quaternary amine compound

Used for rapid favourable muscle relaxation conditions for intubation, and for ECT.

Presentation
Clear, colourless solution for injection of 50mg/ml, must be stored at 4°C

Dose
Paediatric 1-2mg/kg IV, 3-4mg/kg IM
Adult 1-1.5mg/kg IV

Mechanism of action
Partial agonist at nAChR, binding both alpha subunits, causing the ion channel to open & the cell to depolarise, with muscle fasciculation. It is not broken down by cholinesterases at the NMJ, occupying the binding site and causing flaccid paralysis until the muscle dissociates. Broken down by plasma psuedocholinesterases.

Effects & Side Effects
Cardiovascular - bradycardia (stimulation of nodal muscarinic receptors, particularly after a second dose and in children), ventricular arrhythmias
GI - Increased gastric & lower oesophageal tone, no increased risk of regurgitation
Neurological - Transient rise in IO pressure (8-10mmHg, countered by co-administration with thiopentone), avoid in open-globe injuries
Metabolic - Hyperkalaemia (contraindicated >24hrs after significant burn or muscular dystrophies due to upregulation of extra-junctional AChR, causing excessive potassium release)
MSK - Muscle pains & fasciculations, can be reduced through co-administartion of a small dose of non-depolarising blocker
Relatively common cause of anaphylaxis
Malignant hyperthermia
Suxamethonium apnoea
Pharmacokinetics
Absorption - Given IV or IM
Distribution - Polar molecule, low Vd
Metabolism - Rapidly hydrolysed to succinylmonocholine and choline - so rapidly that only 20% of the IV dose reaches the NMJ. Succinylmonocholine is hydrolysed again to succinic acid and choline
Excretion - Approx 5-10% excreted in urine

Repeated doses of Suxamethonium cause a phase II block - with characteristics similar to non-depolarising agents - reduced twitch height, fade, and post-tetanic potentiation

Question 3

What is suxamethonium apnoea?

Answer 3

Reduced pseudocholinesterase activity prevents suxamethonium from being broken down as rapidly as expected, resulting in prolonged paralysis. Genetic or acquired.

Genetic
Four alleles on chromosome 3
Usual (>95% of population homozygotes, 4% heterozygous resulting in prolonged paralysis of over 10 minutes)
Atypical
Fluoride resistant
silent
Acquired
Any condition with reduced pseudocholinesterase activity (Liver, kidney, heart failure, thyrotoxicosis, pregnancy, some cancers)

Drugs may also reduce the activity of pseudocholinesterase
Lithium, lidocaine, neostigmine, COCP, Ketamine

Testing and diagnosis
Dibucaine test - This LA test inhibits pseudocholinesterase, but not the abnormal variants. The percentage of inhibition by dibucaine is called the dibucaine number, and the lower the number, the lower the proportion of normal pseudocholinesterase, and hence the longer the paralysis

Treatment
FFP
Supportive care

Question 4

Discuss Rocuronium

Answer 4

Class and uses
Aminosteroid non-depolarising neuromuscular blocking agent

Fast-onset muscle relaxation to facilitate intubation & surgery

Presentation
10mg/ml clear colourless solution, stored at 4°C

Dose
0.6mg/kg for routine intubation (2 minutes to peak intubating conditions)
1.2mg/kg for RSI (60-90 seconds)

Mechanism of action
Competitive inhibition of pre- and post-synaptic nAChR at the NMJ

Effects & Side Effects
Slight tachycardia at high doses

Pharmacokinetics
Absorption - IV or IM
Distribution - Polar, small Vd - low potency means larger dose given & faster onset
Metabolism - Small amount of hepatic metabolism
Excretion - Unchanged in bile, small amount in urine

Reversal - Neostigmine or Sugammadex

Question 5

Discuss Vecuronium

Answer 5

Class and uses
Monoquaternary aminosteroid non-depolarising neuromuscular blocker

Used for intubation and surgery

Presentation
10mg lyophylised powder with mannitol and NaOH, reconstituted with 5ml of water to produce 2mg/ml solution

Dose
0.1mg/kg, with intubation conditions after 1.5-2mins

Mechanism of action
Non-depolarising competitive nAChR blocker at the NMJ

Effects & Side Effects
No significant CVS effect or histamine release

Pharmacokinetics
Absorption - IV or IM
Distribution - Polar, small Vd
Metabolism - Hepatic metabolism
Excretion - Urine & bile

Question 6

How does neostigmine work, why is it given with glycopyrrolate?

Answer 6

Neostigmine inhibits acetylcholinesterase, reducing the breakdown of acetylcholine in the NMJ.

Dose 0.04mg/kg

This increases the amount of ACh available to compete at the nACh receptor, reversing the effect of non-depolarising neuromuscular blockade.

It also causes ACh buildup at muscarinic receptors, and parasympathetic symptoms - bronchospasm, diarrhoea, salivation, and bradycardia. These are countered with an antimuscarinic agent, such as glycopyrrolate

Question 7

Compare the pharmacodynamic properties of non-depolarising neuromuscular blockers

Answer 7

Rocuronium
0.6 | fast | medium
Mivacurium
0.2 | medium |short
Vecuronium
0.1 | medium | medium
Atracurium
0.5 | medium | medium
Pancuronium
0.1 | medium | long

Intubating dose (mg/kg)
Speed of onset
Duration

Question 8

Describe pancuronium

Answer 8

Aminosteroid non-depolarising neuromuscular blocking agent with two quaternary amine groups

Dose is 0.1mg/kg, taking around 2 minutes to peak intubating conditions.

Long acting (45 minutes)

Acts as a vagolytic, causing some tachycardia. No histamine release

Question 9

Discuss Atracurium

Answer 9

Class and uses
Benzylisoquinolinium non-depolarising neuromuscular blocker

Muscle relaxation to facilitate intubation and surgery

Presentation
10mg/ml clear colourless solution, which should be stored at 4°C.
Mixture of 10 isomers
Cis-atracurium is enantiopure

Dose
0.5mg/kg IV for atracurium, less for cis-atracurium, intubating conditions within 2 minutes.

Mechanism of action
Competitive inhibition of nAChR at the NMJ

Effects & Side Effects
Cardiovascular - hypotension (histamine release)
Respiratory - bronchospasm (histamine release)
MSK - Accelerates muscle breakdown during long infusions on ITU

Pharmacokinetics
Absorption - given IV
Distribution - Polar, small Vd
Metabolism - Organ-independent pathways:
Non-enzymatic Hofmann elimination (45%), with spontaneous degradation to laudanosine, faster in alkaline and warmer environments
Ester hydrolysis (55%), producing laudanosine, faster in acidic environments
Excretion - Renal

The more potent cis-atracurium is given in smaller doses, meaning slower onset (Bowman’s principle)

Cis-atracurium produces less histamine and less laudanosine, mainly undergoing Hofmann elimination