Medical Pharmacology Chapter 20: Neuromuscular Blocking Agents and Muscle Relaxants
Depolarization Neuromuscular Blockade
Rapid onset (30-60 seconds) -- IV.
Short duration of action: 3-5 minutes.
Skeletal muscle relaxation, facilitating intubation.
Mechanism of Action
Succinylcholine (Anectine) binds to nicotinic cholinergic receptors.
Promotes post synaptic membrane depolarization causing a relatively long-term depolarization (compared acetylcholine) due to reduced synaptic breakdown.
Blockade occurs because depolarized membrane is unresponsive to subsequent acetylcholine-receptor interaction.
Depolarization component is the phase I blockade.
Prolonged phase I blockade may be associated with potassium transport (from inside cell out): which may increase serum potassium by 0.5 mEq/L.
Properties of phase I blockade:
Reduced amplitude; sustained response to continuous electrical stimulation.
Reduced contractile-response to single twitch stimulus.
Enhanced neuromuscular-blockade following anticholinesterase drug administration.
Train-of-four (TOF) ratio of > 0.7 (the height of the 4th twitch to that of the 1st twitch); a measure of presynaptic membrane effects.
When the single twitch height has recovered to about 100%, the train-of-four ratio is about 70%.
No post-tetanic facilitation.
Skeletal muscle fasciculations are associated with initial (onset) succinylcholine (Anectine) action.
Continued succinylcholine (Anectine) administration results in a transition from endplate depolarization to endplate repolarization..
However, this repolarization state is not susceptible to acetylcholine depolarization provided succinylcholine (Anectine) remains present.
Blockade, even following repolarization, has led to the description of phase II block as "a desensitization blockade".
Transition from a phase I to a phase II blockade may be rapid (following a succinylcholine (Anectine) dose of 2-4 mg/kg IV).
Phase II onset: initial manifestation -- tachyphylaxis with need to increase succinylcholine (Anectine) infusion rate or to administer larger doses.
Various degrees of phase I & phase II blockade may coexist.
Mainly phase I: anticholinesterases enhance neuromuscular-blockade.
Mainly phase II: anticholinesterases antagonize phase II blockade.
Small doses of edrophonium (Tensilon) (0.1-0.2 mg/kg, IV) may be useful in discriminating phase I vs. phase II block
Duration of action determined by plasma cholinesterase-mediated succinylcholine (Anectine) hydrolysis
Plasma cholinesterase: hepatic enzyme.
Initial succinylcholine (Anectine) metabolite: succinylmonocholine (very weak neuromuscular-blocking)
Plasma cholinesterase activity determines the amount of succinylcholine (Anectine) reaching the endplate (most succinylcholine (Anectine) is hydrolyzed by plasma enzyme).
Factors influencing plasma cholinesterase (pseudocholinesterase) activity:
Reduced hepatic enzyme synthesis.
The presence of atypical (genetic) plasma cholinesterase which exhibits reduced succinylcholine (Anectine) hydrolytic capacity.
Liver disease (severe).
Drug effects, e.g. neostigmine (Prostigmin) -- a carbamylating cholinesterase inhibitor.
Nitrogen mustard, cyclophosphamide (Cytoxan) causes plasma cholinesterase inhibition.
Metoclopramide (Reglan) (10 mg IV).
High estrogen levels (parturients).
Genetic: increased plasma cholinesterase activity.
Obesity -- more plasma cholinesterase activity.
Pharmacodynamic effects, e.g. myasthenia gravis.
In myasthenia gravis: reduced number of nicotinic, neuromuscular junctional receptors -- the target for the drug succinylcholine (Anectine).
Consequence: prolonged neuromuscular-blockade (1-3 hours) following normal succinylcholine (Anectine) dosage.
Dibucaine (Nupercainal, generic)-related cholinesterase variant: most important.
Dibucaine is an amide local anesthetic that inhibits wild type plasma cholinesterase by 80%; however, it inhibits atypical enzyme by only 20%.
If dibucaine (Nupercainal, generic) number equals 80: normal cholinesterase
If dibucaine (Nupercainal, generic) number equals 20: homozygous for atypical cholinesterase, frequency = 1/3200.
1 mg/kg IV succinylcholine (Anectine): > three hours duration
25% recovery of single twitch response following 0.03 mg/kg IV (small dose) mivacurium (Mivacron): 80 minutes.
For heterozygous atypical plasma cholinesterase patients (frequency: 1/480) -- dibucaine (Nupercainal, generic) number equals 40-60.
Moderately prolonged duration: as long as 30 minutes following succinylcholine (Anectine).
Dibucaine (Nupercainal, generic) analysis only measures enzyme capability for succinylcholine (Anectine) hydrolysis--
Reduced active enzyme (due to effects associated with liver disease reflected in reduced enzyme synthesis or enzyme inhibition due to the presence of anticholinesterase)} will affect succinylcholine (Anectine) duration, but not be detected by dibucaine (Nupercainal, generic) analysis
Miller, R.D., Skeletal Muscle Relaxants, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 434-449. Stoelting, R.K., "Neuromuscular-Blocking Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 182-219 White, P. F. "Anesthesia Drug Manual", W.B. Saunders Company, 1996.
Increased intraocular pressure
Increased ICP (intracranial pressure)
Skeletal muscle contractions
Increased intragastric pressure
Note: Many succinylcholine (Anectine) side effects may be reduced by prior administration of non-paralyzing doses of nondepolarizing neuromuscular-blocking agents
This pre-treatment does not reduce the extent of potassium release caused by succinylcholine (Anectine)
Small children are extremely sensitive to succinylcholine given that the parasympathetic system develops in advance of the sympathetic system. Should intubation not be successful following a single succinylcholine dose, the tendency to give a second dose should be resisted since the second dose may precipitate cardiac arrest.
Direct activation by succinylcholine (Anectine) of muscarinic, cardiac cholinergic receptors.
Cardiac Effects: most likely following a second succinylcholine (Anectine) dose, administered about five minutes following the initial dosage.
Atropine pre-treatment does not prevent bradycardia following a second succinylcholine (Anectine) dose.
Other autonomic effects:
Succinylcholine (Anectine) activates ganglionic cholinergic receptors producing:
Increased heart rate
Increased systemic blood-pressure
Hyperkalemia following succinylcholine (Anectine)
Muscular dystrophy (clinically unrecognized).
Severe skeletal muscle trauma.
Skeletal muscle atrophy following denervation.
Unhealed third degree burns.
Succinylcholine (Anectine)-mediated potassium release secondary to severe abdominal infection.
Potassium release following denervation (begins within four days, may last six months or more).
Pre-treatment with subparalyzing doses of nondepolarizing blockers is not effective in preventing or affecting the extent of potassium release following succinylcholine (Anectine).
Male children with undiagnosed myopathy appear predisposed to succinylcholine (Anectine)-induced:
Most common form of muscular dystrophy (frequency 1/3300 male births): Duchenne's muscular dystrophy.
Diagnosis not possible until 2-6 years of age.
Becker muscular dystrophy (X-linked; (frequency: 1/33,000 male births), less common then Duchenne's dystrophy).
Probable small percentage of pediatric patients present with undiagnosed myopathy. As an alternative to succinylcholine (Anectine), a nondepolarizing neuromuscular-blocking agent may be used.
Myalgia may be a postoperative succinylcholine (Anectine) skeletal muscle effect.
Most common localization
This skeletal muscle effect is possibly due to succinylcholine (Anectine)-induced skeletal muscle fiber contractions as this effect may be reduced by prior treatment with non-paralyzing doses of tubocurarine.
Vecuronium (Norcuron) when used in place of succinylcholine (Anectine) does not prevent myalgia following laproscopy.
Succinylcholine (Anectine) frequently increases intragastric pressure.
This increase is thought to be related to intensity of succinylcholine (Anectine)-induced muscle fasciculation.
The intragastric pressure increases can be prevented by previous administration of nondepolarizing agent.
Possible gastric fluid passage into esophagus, pharynx, and long.
gastroesophageal sphincter more likely to open at pressures > 28 cm H2O.
Rarely seen in children, probably due to limited muscle fasciculation associated with succinylcholine (Anectine).
Succinylcholine (Anectine): transient increase beginning 2-4 minutes after administration and lasting about 5-10 minutes.
Possible risk: in open eye injury (unsubstantiated by research}; however, this concern may limit use of succinylcholine (Anectine) in this patient population.
Masseter Jaw Anatomy
Images obtained from "The Structural and Functional Anatomy of Mastication" by Paul Surtees, B.Sc; The Victoria University of Manchester (1999).
Halothane (Fluothane)-succinylcholine (Anectine) sequence is associated with masseter jaw rigidity/incomplete jaw relaxation in children.
Considered normal; frequency would be about 4%.
Normal response vs. masseter jaw rigidity prodromal for malignant hyperthermia.
Miller, R.D., Skeletal Muscle Relaxants, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 434-449; .Stoelting, R.K., "Neuromuscular-Blocking Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 182-219; White, P. F. "Anesthesia Drug Manual", W.B. Saunders Company, 1996.