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REVERSAL OF NEUROMUSCULAR BLOCKADE
DENNIS STEVENS MSN, CRNA, ARNPNOVEMBER 2005
FLORIDA INTERNATIONAL UNIVERSITYPHARMACOLOGY: NGR 6173
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OBJECTIVES Explain the mechanism of action of commonly
administered neuromuscular reversal agents.
Discuss the clinical pharmacologic characteristics
associated with cholinesterase inhibitors. Compare the effects that neuromuscular reversal agents
have on organ systems.
State the dosage recommendations for medications
associated with the reversal of neuromuscular blockade. Discuss how organ systems are affected by
anticholinergic agents.
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REFERENCES
Morgan, G.E., Mikhail, M.S., and Murray, M.J. (2002).Clinical Anesthesiology. (3rd Ed.). New York, NY:McGraw-Hill.
Nagelhout, J.J. and Naglaniczny, K.L. (2005). NurseAnesthesia. (3rd Ed.). St. Louis, MO: Elsevier-Saunders.
Stoelting, R.K. (1999). Pharmacology & Physiology inAnesthesia Practice. (3rd Ed.). Philadelphia, PA:
J.B. Lippincott Company.
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INTRODUCTION Cholinesterase inhibitors (anticholinesterases) are used
to reverse the effects of nondepolarizing neuromuscularblockers
Facilitates the speed of recovery from the skeletalmuscle effects associated with NDMRs Physostigmine is the prototype Derived from the Calabar bean Once used by West African tribes as a poison 1864: physostigmine isolated by Jobst and Hesse Precursor of organophosphates:
Insecticides
Nerve gas
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INTRODUCTION Commonly used cholinesterase inhibitors:
Neostigmine Edrophonium Pyridostigmine Physostigmine
Cholinergic receptors Nicotinic receptors Muscarinic receptors
Primary goal of muscle relaxant reversal is to maximizenicotinic transmission while minimizing muscarinic side
effects
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MECHANISM OF ACTION Neuromuscular transmission depends on acetylcholine
NDMRs compete with acetylcholine thereby blockingneuromuscular transmission
Reversal of blockade depends on gradual diffusion,redistribution, metabolism, and excretion of the NDMR
Pharmacologic reversal with administration of specificcholinesterase inhibitor agents
Neostigmine, pyridostigmine, and edrophonium inhibitsacetylcholinesterase which is responsible for the rapidhydrolysis of the neurotransmitter acetylcholine tocholine and acetic acid
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MECHANISM OF ACTION Inhibition of the hydrolysis of acetylcholine results in
greater availability at its sites of action
Pharmacological effects:
Competitive block at NMJ Inhibition of acetylcholinesterase Acceleration of the already established pattern of
spontaneous recovery Speeds time of recovery and allows for more prompt
wake up and recovery of protective reflexes
Administered during the time when spontaneousrecovery from neuromuscular blockade is occurring
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CLINICAL PHARMACOLOGICCHARACTERISTICS
Cholinesterase inhibitors can act at cholinergicreceptors of several other organ systems
Cardiovascular: Decreased heart rate Dysrhythmias
Pulmonary: Bronchospasm Increased bronchial secretions
Cerebral: Diffuse excitation
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CLINICAL PHARMACOLOGICCHARACTERISTICS
Gastrointestinal: Increased peristaltic activity Glandular secretions
Genitourinary: Increased bladder tone
Ophthalmologic:
Pupillary constriction Reversal of NDMR blockade requires only the nicotinic
cholinergic effects of the anticholinesterase drug.Muscarinic effects are attenuated or prevented by theconcurrent administration of anticholinergic agents
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NEOSTIGMINE Quaternary ammonium compound
Lipid insoluble; will not cross the blood-brain barrier
Two-fold mechanism of reversal: Inactivation of acetylcholinesterase Increase half life of acetylcholine at receptors
Dose: Maximum recommended dose 0.08 mg/Kg Dose should never exceed 5 mg
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NEOSTIGMINE Onset: 5-10 minutes Duration: 45-90 minutes Recommended anticholinergic: glycopyrrolate
Reported to cross placenta resulting in fetal bradycardia Most commonly used reversal agent; may increase
incidence of PONV May be used to treat myasthenia gravis, urinary bladder
atony, and paralytic ileus Has been used as an adjunct to intrathecal anesthesia Pediatric and elderly patients appear to be more sensitive
to its effects
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EDROPHONIUM Quaternary ammonium compound
Limited lipid solubility
Available with atropine as a combination drug (Enlon-Plus)
Dose: 0.5-1.0 mg/Kg
Most rapid onset of action; within 5 minutes
Duration: 30-60 minutes Recommended anticholinergic: atropine
Not recommended for deep block
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PYRIDOSTIGMINE Used in the treatment of myasthenia gravis
Long acting acetylcholinesterase inhibitor
Dose: 0.1-0.4 mg/kg
Slow onset: 10-20 minutes
Duration: 60-120 minutes
Recommended anticholinergic: glycopyrrolate
Not frequently used in anesthesia
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PHYSOSTIGMINE Tertiary amine
Lipid-soluble and freely passes the blood-brain barrier
Can cause confusion and lethargy
Used to counteract the delirium caused bybenzodiazepines and barbiturates
Dose: 0.01-0.03 mg/Kg
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COMPETETIVE BLOCKADE Competition between NDMR and acetylcholine for the
motor end plate receptor at the neuromuscular junction
Greater concentration gains control of the receptor site
Recurarization was a problem with long acting NDMRs
whose effects outlasted the clinical effects of theanticholinesterase agents
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ELIMINATION All acetylcholinesterase inhibitors are excreted to some
extent by the kidneys
Neostigmine: 25% Edrophonium: 75%
Elimination half-life of neostigmine:
70-80 minutes in patients with normal renal function 181 minutes in anephric patients
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ANTICHOLINERGICS Glycopyrrolate
Atropine
Scopolamine Anticholinergics are esters of an aromatic acid
combined with an organic base In clinical doses only muscarinic receptors are blocked Administered to attenuate the peripheral muscarinic
effects of acetylcholinesterase inhibitors Acetylcholinesterase inhibitors must be administered
with an anticholinergic Several organ systems are affected
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SYSTEMIC EFFECTS Cardiovascular:
Blockade of muscarinic receptors in the SA node resultsin increased heart rate
Atrial dysrhythmias and nodal rhythms occasionally occur Respiratory:
Inhibits secretions of the respiratory tract mucosa Relaxes bronchial smooth musculature
Cerebral: Can cause various CNS effects ranging from stimulation
to depression Physostigmine reverses these actions
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SYSTEMIC EFFECTS Gastrointestinal:
Salivary secretions markedly reduced
Prolonged gastric emptying time Ophthalmic:
Causes mydriasis and cyclopegia
Genitourinary:
May decrease ureter and bladder tone Thermoregulation:
Inhibition of sweat glands
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PHARMACOLOGIC CHARACTERISTICS
Naturally occurring tertiary amine anticholinergic drugs:
Atropine and scopolamine
Semisynthetic quaternary ammonium derivative: Glycopyrrolate
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DOSAGE RECOMMENDATIONS Neostigmine 0.5-0.8 mg/Kg with equal portion of
glycopyrrolate (0.2 mg glycopyrrolate per 1mgneostigmine). Maximum dose neostigmine 5 mg.
Edrophonium 0.5-1 mg/Kg with atropine 0.014 mg per1 mg of edrophonium. If glycopyrrolate administered(0.007 mg glycopyrrolate per 1 mg of edrophonium)should be given several minutes prior to edrophonium
to avoid bradycardia. When administering reversal agents to pediatric
patients, always give the anticholinergic, wait for aresponse, then give the acetylcholinesterase inhibitor.