Anaesthetics: Pharmacology - Skeletal muscle relaxants Flashcards
Describe the sequence of events in normal neuromuscular function
- Arrival of impulse at motor nerve terminal
- Ca2+ influx
- ACh release and diffusion into synaptic cleft
- 2x ACh bind a-B and d-a subunits of nicotinic receptor to induce channel opening
- Na+ influx and K+ efflux at motor end plate produces the end plate potential
- If stimulus is of sufficient magnitude, potential is propagated
- Excitation-contraction coupling occurs
What of the two mechanisms of neuromuscular blockade?
- Nondepolarising: via antagonism of ACh at nicotinic receptors
- Depolarising: via paradoxical effect of ACh excess
Describe the structure of nondepolarising muscle relaxants
Similar to ACh but conceals “double-acetylcholine” structure in one of two types of bulky, semi-rigid ring systems
Poor lipid solubility (and therefore CNS entry) due to presence of one or two quaternary nitrogens
Describe the mechanism of action of nondepolarising muscle relaxants. What level of receptor occupancy is required for full blockade? Is this effect surmountable?
Directly antagonises ACh at motor end plate, and at larger doses can enter pore of nicotinic receptor channel to produce more intense blockade
Full blockade requires 90% receptor occupancy
Because they act as competitive antagonists, effect is surmountable (e.g. with AChE inhibitors)
Describe the pharmacokinetics of nondepolarising muscle relaxants
Absorption: poor oral absorption (hydrophilic), must be given parenterally
Distribution: rapid initial distribution with slower elimination phase, Vd 80-140ml/kg; only slightly larger than blood volume due to hydrophilic and ionised nature, therefore inability to cross cell membranes, and poor peripheral binding; poor entry into CNS
Metabolism/elimination: duration of action correlates with elimination pathway; longer duration/elimination (>35mins) when excreted by kidney, shorter (20-25mins) when hepatic
Describe the difference in duration of action and elimination of longer-, intermediate-, and short-acting nondepolarising muscle relaxants. Give two examples of each
Longer-acting: eliminated by kidney, duration of action >35mins, e.g. d-tubocurarine (40% renal) and pancuronium (80% renal)
Intermediate-acting: eliminated by liver, duration of action 20-35mins, e.g. rocuronium and vecuronium (both 75-90% hepatic)
What is Hoffmann elimination and which neuromuscular blocking agent does it apply to? What is the clinical significance of this phenomenon?
Hoffmann elimination is a form of spontaneous breakdown which occurs with atracurium
Produces laudanosine, a metabolite that is slowly metabolised by the liver with a t1/2 of 50mins, and that crosses the BBB and can cause toxicity (seizures, increase in volatile anaesthetic requirement)
Why is cisatracurium widely used where atracurium is not?
Cisatracurium is less toxic as it has less dependence on hepatic inactivation, and produces less laudanosine and systemic histamine release
How are steroidal muscle relaxants metabolised and what is the clinical significance of this?
Metabolised to 3-hydroxy, 17-hydroxy, or 3,17-hydroxy metabolites
3-hydroxy metabolites are active with ~40-80% of potency of parent drug and a longer t1/2
Can accumulate with prolonged administration (e.g. in ICU) and cause prolonged paralysis
What are the effects of nondepolarising muscle relaxants on skeletal muscle?
Initial motor weakness followed by flaccid, unexcitable muscles
Larger muscles are more resistant to blockade and recover more quickly: diaphragm is the last muscle to be paralysed and the first to recover
No adverse effects if ventilated appropriately
What are the effects of the various nondepolarising muscle relaxants on CVS? Specifically mention pancuronium, tubocurarine and atracurium
Vecuronium, cistatracurium and rocuronium have little if any effects
Pancuronium causes moderate tachycardia and increased CO without change in TPR (primarily via vagolytic mechanisms)
Tubocurarine (and atracurium to lesser extent) causes hypotension due to systemic histamine release, which can be prevented by pre-medication with an antihistamine
Tubocurarine also causes ganglionic block with larger doses
What are the effects of nondepolarising muscle relaxants on the respiratory system?
Tubocurarine can cause bronchospasm due to systemic histamine release
What underlies the increased risk of aspiration and decreased hypoxic drive that follows neuromuscular blockade with a nondepolarising agent?
There is subtle evidence of residual muscle paralysis that persists beyond clinically observed pharmacologic duration of effect
Which of the nondepolarising muscle relaxants has the most rapid time to onset?
Rocuronium with time to onset of 60-120secs
Why might you pre-medicate a patient with antihistamine prior to administering tubocurarine?
Decreases the risk of hypotension due to systemic histamine release with tubocurarine
Describe the structure of depolarising muscle relaxants
Similar to ACh: succinylcholine is 2x linked ACh molecules
Poor lipid solubility (and therefore CNS entry) due to presence of one or two quaternary nitrogens
Describe the mechanism of action of depolarising muscle relaxants
Two phases:
1. Phase I (depolarising)
- Binds to and opens nicotinic receptors causing Na+ influx and depolarisation
- This produces transient contraction of muscle motor units
- Succinylcholine is not metabolised effectively by AChE at the end-plate and so depolarisation persists and the membrane becomes unresponsive to subsequent impulses
- Because excitation-contraction coupling requires repolarisation (“repriming”) and repetitive firing, flaccid muscle paralysis results
- Phase II (desensitising)
- With continued exposure, membrane repolarises even in presence of succinylcholine (mechanism unclear but may be due to channel blockade rather than agonist effect)
- In this state the receptor is desensitised and requires a larger stimulus to become depolarised again
What is the effect of AChE inhibitors on nondepolarising vs depolarising muscle relaxants?
Nondepolarising: can overcome blockade
Depolarising: in phase I augments (not reverses) blockade by providing further depolarising stimulus, in late phase II receptor desensitisation can be overcome with sufficient ACh so AChE inhibitors can reverse blockade
Describe the pharmacodynamics of depolarising muscle relaxants
Absorption: poor oral absorption (hydrophilic), parenteral only
Distribution: does not cross BBB
Metabolism: broken down efficiently (and rapidly) by plasma (predominantly) and liver cholinesterases (e.g. pseudocholinesterase, butyrylcholinesterase); therefore short duration of action 5-10mins (dependent on succinylcholine diffusing away from NMJ as it is not metabolised by AChE)
What % of succinylcholine reaches the NMJ and what influences this? What is the clinical significance?
Only ~1% reaches NMJ, influenced by circulating levels of plasma cholinesterase
Succinylcholine action may be prolonged by genetic variant in plasma cholinesterase
Ability to metabolise succinylcholine can be measured as the “dibucaine number”
What are the effects of depolarising muscle relaxants on skeletal smooth muscle?
Initial transient muscle fasciculations (over chest and abdomen) within 30secs
Flaccid paralysis within 90secs
What are the effects of depolarising muscle relaxants on the CVS?
Stimulates autonomic receptors (including ganglionic nicotinic and in heart):
- Negative inotropy and chronotropy (reversible with anticholinergics, e.g. atropine)
- Bradycardia if second dose given <5mins after first
- Positive inotropy and chronotropy with large doses
- Can cause cardiac arrhythmias, especially when administered during halothene anaesthesia
Name five adverse effects of depolarising muscle relaxants and the mechanism of each
- Hyperkalaemia:
- K+ released during fasciculations
- Increased risk in patients with burns, trauma, closed head injury, and NMD due to proliferation of extrajunctional ACh receptors -> more K+ release, may be sufficient to cause cardiac arrest - Raised IOP:
- Mechanism unclear
- Not contraindicated in eye surgery unless anterior chamber is open (i.e. open globe injury) - Raised intragastric pressure (5-40cm H2O):
- Due to fasciculations
- Risk of emesis and aspiration
- Increased risk in patients with delayed gastric emptying (e.g. diabetes), trauma, oesophageal dysfunction, and obesity - Myalgia:
- Due to muscle fasciculations - Cardiac arrhythmia (especially during halotheme anaesthesia):
- Due to stimulation of autonomic receptors
How do inhaled (volatile) anaesthetics interact with nondepolarising muscle relaxants?
Potentiate neuromuscular blockade via the following mechanisms:
- CNS depression
- Increased muscle blood flow due to peripheral vasodilation, enhancing delivery of muscle relaxant to NMJ
- Decreased sensitivity of postjunctional membrane to depolarisation
List volatile anaesthetics in terms of most to least likely to interact with nondepolarising muscle relaxants
Isoflurane
Sevoflurane
Desflurane
Halothane
Nitrous oxide
