Nursing Pharmacology Chapter 20:  Neuromuscular Blockers

Depolarization Neuromuscular Blockade

Succinylcholine (Anectine)

• Time course:

  • Rapid onset (30-60 seconds) following IV administration

  • 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 ofSuccinylcholine (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) -- 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): 80minutes

  • 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 affects the liver disease [reduced synthesis] or enzyme inhibition due to anticholinesterases} 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 may be 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)

          • Clinical Implications:

            • Probable small percentage of pediatric patients present with undiagnosed myopathy -- alternative to succinylcholine (Anectine) use -- a nondepolarizing neuromuscular-blocking agent

      •  Myalgia is a postoperative succinylcholine (Anectine) skeletal muscle effect.

        • Most common localization

          • Neck (pharyngitis)

          • Back

          • Abdominal muscles

      • Possibly due to succinylcholine (Anectine)-induced skeletal muscle fiber contractions {affect 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

        • Thought to be related to intensity of succinylcholine (Anectine)-induced muscle fasciculation {intragastric pressure increases 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). permission requested

•   Excessively-long skeletal muscle contraction: masseter jaw rigidity

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

    • Considered normal; frequency -- 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.