Neuromuscular Blocking Agents and Other Muscle Relaxants

VMED 5223 George M. Strain

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

Uses of neuromuscular blocking agents
‡ By intravenous or systemic administration:
± Adjuvant in surgical anesthesia to obtain relaxation of skeletal muscle ± ³Balanced´ anesthesia ± to minimize anesthetic use without compromising analgesia ± To assist in intubation (esp. succinylcholine) ± Corneal or retinal surgeries to obtain relaxation of extraocular muscles (cisatracurium) ± Therapy of spastic disorders

‡ By topical administration:
± Mydriasis in birds (vecuronium)

Steps in neuromuscular transmission

Outline of Drug Classes Acting On Muscle Function
‡ Neuromuscular blocking drugs
± Competitive (non-depolarizing) ± Depolarizing

‡ Centrally acting muscle relaxant drugs (spasmolytics) ‡ Peripherally acting skeletal muscle relaxants

Classes of neuromuscular blocking agents
‡ Competitive (non-depolarizing) neuromuscular blocking agents (prototype: d-tubocurarine/curare) ‡ Depolarizing neuromuscular blocking agents (prototype: succinylcholine)

Competitive neuromuscular blocking agents
‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ d-tobocurarine Gallamine (Flaxedil) Alcuronium (Alloferin) Pancuronium (Pavulon) Atracurium (Tracrium) Cisatracurium (Nimbex) Vecuronium (Noncuron) Doxacurium (Neuromax)

Blue = greatest veterinary use

Competitive neuromuscular blocking agents
‡ d-tubocurarine - slight hypotension; histamine (HA) release (problem in asthma); limited use. ‡ Gallamine triethiodide (Flaxedil) - tachycardia; no HA release; crosses placental barrier. ‡ Alcuronium chloride (Alloferin) - similar to curare, shorter lasting; slight hypotension and tachycardia. ‡ Pancuronium bromide (Pavulon) - long-acting; slight tachycardia and hypertension. ‡ Atracurium besylate (Tracrium) - intermediate-acting; safe in liver and kidney disease; bradycardia may result during surgical manipulations, esp ophthalmologic, ENT, or laparoscopy (treat with atropine or glycopyrrolate); precipitates in alkaline pH; can cause HA release at higher doses. Probably most used in veterinary medicine.

Competitive neuromuscular blocking agents
‡ Cisatracurium besylate (Nimbex) - one of 10 isomers of atracurium; 3X potency; immediate onset of action; used in ophthalmologic surgeries. ‡ Vecuronium bromide (Noncuron) - intermediateacting; lack of CV or HA-releasing effects; drug of choice when CV stability required; mydriasis in birds. ‡ Doxacurium chloride (Nuromax) - long-lasting, most potent agent known; minimal CV or HA-releasing effects; not currently used in veterinary medicine.

Effect of competitive blocking agents on skeletal muscle
‡ First: motor weakness ‡ Then flaccid motor paralysis ‡ Sequence of paralysis
± Small, rapidly moving muscles first ± Then large muscle masses ± Then toes, jaw, eyes, ears, limbs, neck and trunk. ± Finally, intercostal muscles and diaphragm paralyzed

Competitive blockade reversed by neostigmine (Ns)

Effect of competitive blockers on cardiovascular system
‡ Decreased blood pressure - due to histamine release ‡ Increased heart rate (baroreceptor reflex)

Competitive blockers contd.
‡ Onset of action slow ‡ Duration of action short initially, with residual effect ‡ (Cumulative with repeated doses) ‡ Poorly absorbed from GI tract ‡ Termination of action: hepatic metabolism/ renal excretion. ‡ Accumulation may occur in patients with renal insufficiency

Competitive blockers cont¶d.
‡ Action enhanced or potentiated by:
± Acidosis ± Aminoglycoside antibiotics (inhibition of ACh release«membrane stabilization) ± Volatile anesthetics (membrane stabilizers)

Competitive blockers cont¶d.
‡ Action antagonized by cholinesterase inhibitors (neostigmine, edrophonium), tetanic stimulation ‡ Coagulability of blood decreased (due to release of heparin from mast cells)

Competitive blockers cont¶d.
‡ Undesirable effects - histamine release, cardiovascular effects ‡ Therapeutic advantages - no fasciculation, no CNS effects

Depolarizing neuromuscular blocking agents
‡ Succinylcholine (suxamethonium, Scoline) ‡ Rocuronium (Zemuron) ‡ Mivacurium (Micacron)

Depolarizing neuromuscular blocking agents
‡ Succinylcholine (suxamethonium; Scoline) - rapid and short-lasting block, used to facilitate intubation (mostly in humans); used illegally in bow hunting. In an emergency can be given IM, but slower and less predictable action. Can cause bradycardia (prevent with atropine), hyperkalemia, anaphylaxis, or malignant hyperthermia in genetically predisposed subjects. Dogs, cattle, sheep sensitive; horses and pigs less so. Initial response (Phase I block) is depolarizing block; with time becomes Phase II block, similar to non-depolarizing blocking drugs. ‡ Rocuronium bromide (Zemuron) - succinylcholine alternative developed for human use. ‡ Mivacurium chloride (Micacron) - succinylcholine alternative developed for human use.

Depolarizing blocking agents
‡ Phase I block ± depolarizing block of motor end-plate ‡ Phase II blockcompetitive block of motor end-plate/ partially susceptible to reversal by cholinesterase inhibitors

NS inhibition of SCh metabolism by AChE

Depolarizing agents cont¶d.
‡ Effect on skeletal ‡ Effect on muscle - fasciculation, cardiovascular system: weakness, paralysis increased blood pressure, increased or decreased heart rate (due to stimulation of parasympathetic and/or sympathetic ganglia)

Depolarizing agents cont¶d.
‡ Onset of action rapid (1 minute) ‡ Termination of action: metabolized by plasma pseudocholinesterase and liver. ‡ Duration of action short; however may ‡ With SCh, initial metabolite is revert to phase II succinylmonocholine, block weaker, predominately competitive blocking action.

Depolarizing agents cont¶d.
‡ Action enhanced or potentiated by neostigmine and organophosphates (cholinesterase inhibitors), isoflurane. ‡ Undesirable side effects
± muscle fasciculation, hyperkalemia (important in patients with congestive heart failure) ± Phase II block

Depolarizing agents cont¶d.
‡ Undesirable side effects cont¶d.
± May trigger malignant hyperthermia in genetically susceptible patients (dyspnea,
tremor and stiffness, extreme hyperthermia, and rapid postmortem rigor mortis)

± Muscarinic actions at high doses

‡ Advantages - short duration of action, little histamine release


Centrally Acting Muscle Relaxants (Spasmolytics)

Centrally acting muscle relaxants (spasmolytics)
‡ Used in defective neuronal control of muscle activity ± in Scottish terriers (Scotty cramp), Dalmatians, and Labs ‡ Spasms associated with intervertebral disc disease ‡ Spasms associated with tetanus or strychnine toxicosis ‡ Adjunct to anesthesia for muscle relaxation (guaifenesin) ‡ Do not abolish voluntary muscle control

Centrally acting muscle relaxants (spasmolytics)
‡ Veterinary use:
± Guaifenesin (Guailaxin) ± Methocarbamol (Robaxin) ± Diazepam (Valium)

‡ Human use:
± Cyclobenzaprine (Flexeril) ± Carisoprodol (Soma) ± Chlorzoxazone (Parafon Forte DSC; Paraflex) ± Baclofen (Lioresal)

Centrally acting muscle relaxants (spasmolytics)
‡ Act in CNS, either spinal cord and/or lower brain ‡ Act on interneurons, E and Kmotor neurons, or descending motor pathways ‡ Diazepam (Valium) - acts on CNS benzodiazepine receptors to facilitate GABAA inhibitory effects. ‡ Baclofen (Lioresal) ± GABA analog

Peripherally Acting Skeletal Muscle Relaxants

Peripherally acting skeletal muscle relaxants
‡ Dantrolene (Dantrium) - blocks release of calcium from the sarcoplasmic reticulum ‡ No effect on cardiac or respiratory muscle ‡ Used to treat:
± urethral obstruction due to increased external urethral tone (esp. sphincter) ± malignant hyperthermia