NMB General Concepts
Drugs and factors that diminish NMB.
Anti-convulsants (phenytoin, carbamezapine) Frusemide in high dose. Hyperkalaemia. Hypercalcaemia. Burns. Paresis or hemiplegia. Steroids. Azathioprine.
What physicochemical property do all neuromuscular blockers share?
At least one quaternary ammonium with at least one positively charged nitrogen atom which binds the alpha subunit of the nicotinic receptor.
What is the primary determinant of the onset and offset of NMBDs at certain muscle groups? (SAQ 2003A8)
Blood flow, followed by fiber type and muscle size. Onset - Laryngeal>diaphragm>adductor pollicis. Offset - D>L>AP L and D also have fast twitch fibers with higher density of receptors at NMJ, so more resistant to onset and are offset more rapidly. AP blockade may still exist after recovery of L and D. See graph.
How does respiratory acidosis effect NMB duration?
Prolongs the duration.
How does hypercalcaemia effect NMB duration?
Shortens the duration.
How does hyperkalaemia effect NMB duration?
Shortens the duration.
How does hypomagnesaemia effect NMB duration?
Shortens the duration.
Drugs and factors that prolong NMB.
Volatiles. Aminoglucosides. Local anaesthetics. Cardiac dysrhythmics. Frusemide. Magnesium. Lithium. Cyclosporin. Hypothermia. Hypokalaemia. Female. Dantrolene.
What is the dibucaine number for a normal person?
80
What percentage of receptors need to be antagonized to establish block?
80-90%
Approximate autonomic margins of safety of nondepolarizing neuromuscular blockers*
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Clinical autonomic effects of neuromuscular blocking drugs
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Dose response of Rocuronium under 1 MAC of various volatiles.
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Draw a picture of the binding of a NDNMB agent at the nicotinic receptor.
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Draw the NMJ nicotinic receptor demonstrating binding sites of Acetylcholine
1. Five subunit protein pentameric structure with 2 alpha, beta, gamma and epsilon subunits. 2. Several million receptors at each post-synaptic membrane 3. At least 400,000 open per action potential
Outline the Physicochemical and Pharmacokinetic properties of Nondepolarizing muscle relaxants.
1. Highly ionized due to quaternary ammonium groups. 2. Water soluble at p H 7.4. 3. Limited lipid solubility and therefore small Vd. 4. Do not cross BBB, are not reabsorbed in the renal tubules, poor oral bioavailability and do not cross the placenta. 5. Pharmacokinetics are affected by age, co-administration of other drugs, renal and hepatic disease.
Outline the effects of NMB's on Histamine release.
1. Involves mast cell degranulation, but is NOT IgE mediated. 2. Mainly involves the skin and connective tissue mainly involved manifesting as flushing and mild hypotension. 3. Bronchospasm is rare. 4. Histamine release usually occurs with high doses such as in intubating doses. 5. More common with the Benzylisoquinoloniums than the Bisquaternary aminosteroids. Suxamethonium is the strongest. Rocuronium strongest of the steroidals. 6. Can be prevented by pretreatment with antihistamines. 7. Histamine demonstrates tachyphylaxis to subsequent doses of NMB.
Draw and label a picture of the NMJ.
1. Resting membrane potential -90 mV 2. Three types of N-AChR, two post synaptic, junctional and extra-junctional, and one presynaptic. Extrajunctional only relevant in NMJ dysfunction or disease such as denervation or myopathy. Receptors proliferate and contribute to acute hyperkalaemia when stimulated by Sux. 3. ACh is a quaternary ammonium ester. 4. Released into synapse in "quanta" (5-10,000 molecules). 5. Quanta a randomly released in small quantities producing MEP's. 6. Release of Ach - cAMP and calcium-dependent process.
List factors effecting the speed of onset of NMB drugs. (SAQ 2004A2).
1. Route of administration (CVC, IV, IM) 2. Dose administered. 3. Type of NMB administered 4. Rate of administration. 5. Priming dose prior to intubation. 6. Other drugs - sedatives and hypnotics, aminoglycosides, LA's 7. High cardiac output states. 8. Pregnancy and the elderly. 9. Myasthenia Gravies
Describe acetylcholine synthesis and metabolism
1. Synthesised from acetylation of choline by Choline acetylase. 2. Acetylcholinesterase hydrolyses ACh rapidly to acetic acid and choline
What is the rate of Anaphylaxis or Anaphylactoid reactions in anaesthesia?
1:1000 to 1:25,000. 60% Neuromuscular blocking agents. 17% Latex. 15% Antibiotics.
Which classes of antibiotics potentiate neuromuscular blockade?
Aminoglycosides, lincomycin, clindamycin. Polymyxins - Colistin.
What is the ED95 in NMB?
Dose needed to acheive 95% supression of the single twitch height response in the Adductor Pollicis muscle in 50% of subjects.
Which peripheral muscle best reflects the blockade of the L?
Orbicularis oculi, high blood flow and fast twitch fibers.
List causes of prolonged NMB after 4 hours procedure. (SAQ 2006A6).
Pharmacokinetic 1. Absorption - repeated dose, overdose without monitoring, wrong drug. 2. Distribution - Prolonged infusion of Vec could lead to accumulation in lipid tissues, 3. Metabolism - Hepatic failure - increased activity of aminosteroids - Roc, Vec, and Panc. Decreased plasma cholinesterase synthesis - increased Sux, Mivac. Hypothermia slows metabolism and Hoffman. Acidosis decreases Hoffman, increases NDNMB affinity for receptor. Pseudocholinesterase Deficiency leads to prolonged Mivacurium effect. 4. Elimination - Renal Failure - increased Panc, Roc and active metabolites of Vec. Pharmacodynamic. 1. Electrolyte disturbances - HypoK, HyperMg, HypoCa 2. Acidosis 3. Drug interactions - see list above. 4. Neuromuscular disease - MG, Eaton Lambert Muscular Dystrophy. Also 1. Failure to reverse properly, wrong dose, out of date drug.
