REVERSAL OF NEUROMUSCULAR BLOCKADE

DENNIS STEVENS MSN, CRNA, ARNP NOVEMBER 2005 FLORIDA INTERNATIONAL UNIVERSITY PHARMACOLOGY: NGR 6173

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.

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). Nurse Anesthesia. (3rd Ed.). St. Louis, MO: Elsevier-Saunders. Stoelting, R.K. (1999). Pharmacology & Physiology in Anesthesia Practice. (3rd Ed.). Philadelphia, PA: J.B. Lippincott Company.

INTRODUCTION

Cholinesterase inhibitors (anticholinesterases) are used to reverse the effects of nondepolarizing neuromuscular blockers Facilitates the speed of recovery from the skeletal muscle 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

INTRODUCTION

Commonly used cholinesterase inhibitors: Neostigmine Edrophonium Pyridostigmine Physostigmine Cholinergic receptors Nicotinic receptors Muscarinic receptors Primary goal of muscle relaxant reversal is to maximize nicotinic transmission while minimizing muscarinic side effects

MECHANISM OF ACTION

Neuromuscular transmission depends on acetylcholine NDMRs compete with acetylcholine thereby blocking neuromuscular transmission Reversal of blockade depends on gradual diffusion, redistribution, metabolism, and excretion of the NDMR Pharmacologic reversal with administration of specific cholinesterase inhibitor agents Neostigmine, pyridostigmine, and edrophonium inhibits acetylcholinesterase which is responsible for the rapid hydrolysis of the neurotransmitter acetylcholine to choline and acetic acid

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 spontaneous recovery from neuromuscular blockade is occurring

CLINICAL PHARMACOLOGIC CHARACTERISTICS

Cholinesterase inhibitors can act at cholinergic receptors of several other organ systems Cardiovascular: Decreased heart rate Dysrhythmias Pulmonary: Bronchospasm Increased bronchial secretions Cerebral: Diffuse excitation

CLINICAL PHARMACOLOGIC CHARACTERISTICS

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 the concurrent administration of anticholinergic agents

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

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

EDROPHONIUM

Quaternary ammonium compound Limited lipid solubility Available with atropine as a combination drug (EnlonPlus) 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

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

PHYSOSTIGMINE

Tertiary amine Lipid-soluble and freely passes the blood-brain barrier Can cause confusion and lethargy Used to counteract the delirium caused by benzodiazepines and barbiturates Dose: 0.01-0.03 mg/Kg

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 the anticholinesterase agents

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

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

SYSTEMIC EFFECTS

Cardiovascular: Blockade of muscarinic receptors in the SA node results in 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

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

PHARMACOLOGIC CHARACTERISTICS

Naturally occurring tertiary amine anticholinergic drugs: Atropine and scopolamine Semisynthetic quaternary ammonium derivative: Glycopyrrolate

DOSAGE RECOMMENDATIONS

Neostigmine 0.5-0.8 mg/Kg with equal portion of glycopyrrolate (0.2 mg glycopyrrolate per 1mg neostigmine). Maximum dose neostigmine 5 mg. Edrophonium 0.5-1 mg/Kg with atropine 0.014 mg per 1 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 a response, then give the acetylcholinesterase inhibitor.