Anesthesia Pharmacology:  Neuromuscular Blocking Agents and Muscle Relaxants

Depolarization Neuromuscular Blockade

Succinylcholine (Anectine)

• Time course

  • Rapid onset (30-60 seconds) -- IV.

  • Short duration of action: 3-5 minutes.

• Applications

  • 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.

•  Phases -- Phase I

  •  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.

• Phases -- Phase II

  • 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

• Time course/Duration of Action:  Succinylcholine (Anectine)

  •  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.

• Drugs which may prolong succinylcholine (Anectine) action due to effects on pseudocholinesterase

  • Insecticides.

  • Nitrogen mustard, cyclophosphamide (Cytoxan) causes plasma cholinesterase inhibition.

  • Metoclopramide (Reglan) (10 mg IV).

  • High estrogen levels (parturients).

•  Resistance to succinylcholine (Anectine)

  •  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).

•  Atypical Pseudocholinesterase (plasma cholinesterase)

  •  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.

• Clinical consequences of atypical cholinesterase on neuromuscular-blockade duration

  • 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.

• Succinylcholine (Anectine) side effects

  • Succinylcholine (Anectine): major side effect categories

    Hyperkalemia	Arrhythmias	Myalgia	Increased intraocular pressure
    Increased ICP (intracranial pressure)	Skeletal muscle contractions	Myoglobinuria	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.  

  • Cardiac arrhythmias:

    • Classification:

      • Sinus bradycardia

      • Junctional rhythm

      • Sinus arrest

    • Mechanism:

      •  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)

    •   Risk factors:

      • Muscular dystrophy (clinically unrecognized).

      • Severe skeletal muscle trauma.

      • Skeletal muscle atrophy following denervation.

      • Unhealed third degree burns.

      • Other factors/considerations:

        • 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:

        •  Hyperkalemia.

        •  Rhabdomyolysis.

        •  Cardiac arrest.

      • Muscular dystrophies:

        •  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).

        • Clinical Implications:

          • 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

      • Neck (pharyngitis).

      • Back.

      • Abdominal muscles.

    • 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.

  • Increased Intragastric Pressure

    • 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.

      • Associated risk:

        • 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).

  • Increased Intraocular Pressure

    • 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).

    • Excessively-long skeletal muscle contraction i.e. masseter jaw rigidity

      • Halothane (Fluothane)-succinylcholine (Anectine) sequence is associated with masseter jaw rigidity/incomplete jaw relaxation in children.

        • Considered normal; frequency would be about 4%.

        • Clinical Challenge:

          • 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.