Neuromuscular Blocking Agents Dr. Ahmed Haki Ismael

Neuromuscular Blockers Competitive Antagonists of the Nicotinic Receptor e.g. curare (d-tubocurarine), vecuronium, pancuronium, atracurium, etc… Depolarizing Blockers e.g. succinylcholine, decamethonium

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). 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 Concepts

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 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.

D-tubocurarinepancuronium Vecuronium Decamethonium Succinylcholine Depolarizing Blockers Competitive Blockers

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

Curares - Chondrodendron e Strychnos Strychnos toxifera

West 1932

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

Neuromuscular blockers differ from each other in: Mechanism of action Duration of action Speed of onset and offset of action Selectivity of action and safety margin Adverse effects

AgentPharmacological Properties Onset time (min) Duration (min) Elimination SuccinylcholineUltrashort acting; Depolarizing Plasma cholinesterase D-tubocurarineLong duration; Competitive Renal and liver AtracuriumIntermediate duration; Competitive Plasma cholinesterase MivacuriumShort duration; Competitive Plasma cholinesterase PancuroniumLong duration; Competitive 4-6 Renal and liver RocuroniumIntermediate duration; competitive 1-2 Renal and liver Classification of Blockers

Muscle AP Nerve AP Left Leg Muscle Stimulation Right Leg Nerve Stimulation Right Leg Muscle Stimulation Site of Action of d-Tubocurarine

G: gallamine; TC: tubocurarine; NEO: neostigmine; S: succinylcholine. Non-depolarizing Block

Depolarizing Block C10:decamethonium TC:tubocurarine NEO:neostigmine S:succinylcholine

CompetitiveDepolarizing Effect of previous d- tubocurarine AdditiveAntagonistic Effect of previous decamethonium None/antagonisticMay be additive Efect of cholinesterase inhibitors ReverseNo antagonism Effect on motor end plate Elevated threshold to Ach; no depolarization Partial, persisting depolarization Initial excitatory effectNoneTransient fasciculations Effect of KCl or tetatnus on block Transient reversal No antagonism Comparison of Competitive and Depolarizing Blocking Agents

Dual Block by Depolarizing Agents C10: decamethonium; NEO: neostigmine; TC: tubocurarine NEO reversed the blockade by C10.

Depolarizing Blocker Competitive Blockade Competitive Blocker Noncompetitive Blockade (desensitization) (electrogenic Na pump) (direct channel block) Changing Nature of Neuromuscular Blockade

Sequence of Paralysis Fingers, orbit (small muscles) limbs Trunk neck IntercostalsDiaphragm Recovery in Reverse

Other Effects of Neuromuscular Blockers Action at Autonomic Ganglia e.g. d-tubocurarine blocks, succinylcholine may stimulate newer agents have less ganglionic effects Histamine Release e.g. d-tubocurarine bronchospasm, bronchial and salivary secretions

Adverse Effects/Toxicity Hypotension Decreased tone and motility in GI tract Depolarizing agents can cause increased K efflux in patients with burns, trauma, or denervation and lead to hyperkalemia Prolonged apnea (many reasons, check for pseudochlinesterase genetic polymorphism) Malignant hyperthermia (succinylcholine + halothane especially) Sinus bradycardia/junctional rhythm (with succinylcholine)

Systolic BP % Change in Systolic BP with d-Tubocurarine as a Function of Dose and Depth of Anesthesia Increasing Dose of d-tubocurarine Increasing Depth (% Halothane) 0.25% 0.5% 0.75% 6 mg/m 2 12 mg/m 2 18 mg/m 2

Influence of Type of Anesthetic on Enhancement of Neuromuscular Blockade By d-Tubocurarine

HR CO SVRMAP Hemodynamic Effects of d-Tubocurarine and Pancuronium

Drug Interactions Cholinesterase Inhibitors (antagonize competitive and enhance depolarizing) Inhalational Anesthetics (synergistic) Aminoglycoside Antibiotics (synergistic) Calcium Channel Blockers (synergistic)

Therapeutic Uses Adjuvant in surgical anesthesia Orthopedic procedures for alignment of fractures To facilitate intubations – use one with a short duration of action In electroshock treatment of psychiatric disorders