NEUROMUSCULAR BLOCKING AGENTS

Key Concept Muscle relaxation does not ensure unconsciousness, amnesia, or analgesia Neuromuscular blocking agents are used to improve conditions for tracheal intubation, to provide immobility during surgery, and to facilitate mechanical ventilation. Depolarizing muscle relaxants act as acetylcholine (ACh) receptor agonists, whereas nondepolarizing muscle relaxants function as competitive antagonists. Depolarizing muscle relaxants are not metabolized by acetylcholinesterase, they diffuse away from the neuromuscular junction and are hydrolyzed in the plasma and liver by another enzyme, pseudocholinesterase (nonspecific cholinesterase, plasma cholinesterase, or butyrylcholinesterase).

Key concept. Cont. With the exception of mivacurium, nondepolarizing agents are not significantly metabolized by either acetylcholinesterase or pseudocholinesterase. Reversal of their blockade depends on redistribution, gradual metabolism, and excretion of the relaxant by the body, or administration of specific reversal agents (eg, cholinesterase inhibitors) that inhibit acetylcholinesterase enzyme activity. Compared with patients with low enzyme levels or heterozygous atypical enzyme in whom blockade duration is doubled or tripled, patients with homozygous atypical enzyme will have a very long blockade (eg, 4–6 h) following succinylcholine administration. Succinylcholine is considered contraindicated in the routine management of children and adolescents because of the risk of hyperkalemia, rhabdomyolysis, and cardiac arrest in children with undiagnosed myopathies

Key concept. Cont. Normal muscle releases enough potassium during succinylcholine-induced depolarization to raise serum potassium by 0.5 mEq/L. Although this is usually insignificant in patients with normal baseline potassium levels, a life-threatening potassium elevation is possible in patients with burn injury, massive trauma, neurological disorders, and several other conditions Doxacurium, pancuronium, vecuronium, and pipecuronium are partially excreted by the kidneys, and their action is prolonged in patients with renal failure. Atracurium and cisatracurium undergo degradation in plasma at physiological pH and temperature by organ-independent Hofmann elimination. The resulting metabolites (a monoquaternary acrylate and laudanosine) have no intrinsic neuromuscular blocking effects

Key concept. Cont. Hypertension and tachycardia may occur in patients given pancuronium. These cardiovascular effects are caused by the combination of vagal blockade and catecholamine release from adrenergic nerve endings Long-term administration of vecuronium to patients in intensive care units has resulted in prolonged neuromuscular blockade (up to several days), possibly from accumulation of its active 3-hydroxy metabolite, changing drug clearance, or the development of a polyneuropathy Rocuronium (0.9–1.2 mg/kg) has an onset of action that approaches succinylcholine (60–90 s), making it a suitable alternative for rapid-sequence inductions, but at the cost of a much longer duration of action.

History of neuromuscular blocking agents Early 1800’s – curare discovered in use by South American Indians as arrow poison 1932 – West employed curare in patients with tetanus and spastic disorders 1942 – curare used for muscular relaxation in general anesthesia 1949 – gallamine discovered as a substitute for curare 1964 – more potent drug pancuronium synthesized

Milestones of Neuromuscular Blockade in Anesthesia 1942 introduction of dTc in anesthesia 1949 Succinylcholine, gallamine metocurine introduced 1958 Monitoring of NMF with nerve stimulators 1968 Pancuronium 1971 introduction of TOF 1982 Vecuronium,Pipecurium,atracurium 1992 Mivacurium 1994 Rocuronium 1996 Cisatracurium 2000 Rapacurium introduced and removed

Morphological aspects of function

Morphological aspects of function Neuro-muscular junction Synapses at neuro-muscular junction

Depolarizing Blockers

Succinylcholine “Except when used for emergency tracheal intubation or in instances in clinical practice where immediate securing of the airway is necessary, succinylcholine is contraindicated in children and adolescent patients.”

Succinylcholine Advantages Disadvantages Rapid onset Hyperkalemia (burns,massive trauma,denervation.…) Short Duration I.M. injection Cardiac Dysrhythmias Masseter Spasm Malignant Hyperthermia Myalgias Prolonged effect

Succinylcholine: Increased intragastric pressure Intraocular pressure G-E junction opens at pressures > 28cm H20 transient increase up to 40 cm H20 Defasciculate, abolishes the rise Intraocular pressure Prevention: defasciculate, benzodiazepam, lidocaine,acetazolamide, deep anesth. at laryngoscopy Drug of Choice? for the “Glaucoma” and “full stomach” Recommendations: SUX if possible, priorize, Airway first. If SUX is used: sedate and defasciculate transient increase of 8mm Hg ; peaks at 2-4 min due to contraction of extra-ocular muscles

Succinylcholine: Prolonged Apnea after…. Aetiology 1. Disease States Hepatic Cirrhosis (reduced 50%) renal disease (50%), returns to normal after renal transplant malignancy (bronchogenic, GI) Burns 2. Iatrogenic echothiopate anticholinesterases pancuronium pheneizine (MAO inhibitor) glucocorticoids (estrogens) organophosphates (insecticides) cytotoxic drugs (cyclophosphamide)

Pancronium Bis-quaternary Aminosteroid High potency therefore slow onset Long acting No or slight increase on blood pressure Vagolytic Renal clearance

Cis-Atracurium one of the stereo isomers of atracurium (15%) 3 X more potent than atracurium slow onset, intermediate duration eliminated by Hoffman degradation Laudanosine as a metabolite non-organ elimination doses of 5 X ED95 (0.05mg/kg) no histamine release CV stability

Reversal of Neuromuscular Blockade Anticholinesterases: Edrophonium Neostigmine Atropine is added to block the muscarinic effect of the anticholinestrases

Anticholinesterases Unwanted side effects Autonomic Nausea and vomiting Neostigmine > Edrophonium ? Edrophonium (0.5-1.0 mg/kg) with Atropine ( 7-15 ug/kg) Neostigmine (40-70 ug/kg) with Glycopyrolate (0.7-1.0mg)

Difficulty reversing block Right dose? Intensity of block to be reversed? Choice of relaxant? Age of patient? Acid-base and electrolyte status? Temperature? Other drugs?

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