Complete neuromuscular blocking agent with shortest duration of action
Ans. c (Mivacurium) (Ref. Anaesthesia by Ajay Yadav, 2nd/pg. 90)Mivacurium is a nondepolarizing neuromuscular blocking agent with a short duration of action. Mivacurium is indicated as an adjunct to anesthesia to facilitate endotracheal intubation and to induce skeletal muscle relaxation in the surgical field.Neuromuscular blocking agentsAcetylcholineNicotinic Cholinergic Receptor# Release- Mechanism: Ca2+ entry and halting of K+ exit at presynaptic terminal -ACh release- Inhibitors of ACh release: Mg2+ blocks Ca2+ channels of presynaptic neurons in heart | ACh release- Promoters of ACh release: |-aminopyridine blocks K+ channels of presynaptic neurons | ACh release# Metabolism - In Blood: Butyrylcholinesterase, pseudocholinesterase or plasma cholinesterase (identical enzymes)- In neuromuscular cleft: Acetylcholinesterase- Dibucaine : Dibucaine acts to inhibit normal acety Icholinesterase, and therefore will be unable to inhibit abnormal acetylcholinesterase. Persons w/abnl acetylcholinesterases have dibucaine value at approx 50, instead of 80-90 for normal acetylcholinesterases# Structrure- Composed of b subunits, where ACh binds the a subunits# Location- Presynaptic neuron in neuromuscular junction: causes positive feedback on ACh release, usually constitutes a negative feedback mechanism. Postsynaptic neuron in neuromuscular junction: causes propagation of action potential to myofibrilsOverview of Neuromuscular Blocking Agents# Depolarizing drugs - Noncompetitive depolarization of nicotinic cholinergic receptor - Not effective in Myasthenia Gravis pts since there is a |in postsyn ACh receptors & therefore not enough receptors to activate# Non-depolarizing Drugs- Competitive blockade of nicotinic-cholinergic receptors- Not effective in Eaton-Lambert pts since there is an | in postsyn ACh receptors & not enough non-depolarizing drug to inhibit all# Reversal of Muscle Relaxant Activity- AChesterase inhibitors only for non-depolarizing drugs, but inhibitors have no selectivity for NMJ & will inhibit AChesterases in heart & plasma -| non depolarizing in plasma must give an anti-muscarinic to prevent heart effects- Recombinant pseudocholinesterase for pts w/atypical cholinesteraseMivacurium & rocuronium can be used as muscle relaxant in 'rapid sequence induction'.Skeletal Muscle RelaxantsSubclassMechanism of actionEffectsClinical applicationsPharmacokinetics, toxicities, interactionsDepolarizing neuromuscular blocking agentSuccinylcholineAgonist at nicotinic acetylcholine (ACh) receptors, especially at neuromuscular junction depolarizes may stimulate ganglionic nicotinic ACh and cardiac muscarinic ACh receptorsInitial depolarization causes transient contractions, followed by prolonged flaccid paralysis depolarization is then followed by repolarization that is also accompanied by paralysisPlacement of tracheal tube at start of anesthetic procedure rarely, control of muscle contractions in status epilepticusRapid metabolism by plasm cholinesterase normal duration, 5 min arrhythmias hyperkalemia transient increased intrabdominal, intraocular pressure postoperative muscle painNondepolarizing neuromuscular blocking agentsd-TubocurarineCompetitive antagonist at ACh receptors, especially at neuromuscular junctionsPrevents depolarization by ACh, causes flaccid paralysis can cause histamine release with hypotension weak block of cardiac muscarinic Ach receptorsProlonged relaxation for surgical procedures superseded by newer nondepolarizing agentsRenal excretion duration, 40-60 min toxicities: histamine release hypotension prolonged agentsCisatracuriumSimilar to tubocurarineLike tubocurarine but locks histamine release and antimuscarnic effectsProlonged relaxation of surgical procedures relaxation of respiratory muscles to facilitate mechanical ventilation in intensive care unitNot dependent on renal or hepatic function duration 25-45 min toxicities: Prolonged apnea but less to than atacuriumRocuroniumSimilar to cisatracuriumLike cisatracurium but slight antimuscarinic effectLike cisatracurium useful in patients with renal impairmentHepatic metabolism duration 20-35 min Toxicities: like cisatracuriumMivacurium: Rapid onset, short duration (10-20 min); metabolized by plasma cholinesteraseVecuronium: Intermediate duration; metabolized in liverCentrally acting spasmolytic drugsBaclofenGABA agonist, facilitates spinal inhibition of motor neuronsPre- and postsynaptic inhibition of motor outputSevere spasticity due to cerebral palsy, multiple sclerosis, strokeOral, intrathecal toxicities: sedation, weaknessCyclobenzaprinePoorly understood inhibition of muscle stretch reflex in spinal cordReduction in hyperactive muscle reflexes antimuscarinic effectsAcute spasm due to muscle injury inflammationHepatic metabolism duration 4-6 h toxicities: strong antimuscarinic effectsChlorphenesin, methocarbamol, orphenadrine, other: Like cyclobenzaprine with varying degrees of antimuscarinic effectDiazepamFacilitates GABAergic transmission in central nervous systemIncreases interneuron inhibition of primary motor afferents in spinal cord central sedationChronic spasm due to cerebral palsy, stroke, spinal cord injury acute spasm due to muscle injuryHepatic metabolism duration 12-24 hTizanidinea2-Adrenoceptor agonist in the spinal cordPresynaptic and postsynaptic inhibition of reflex motor outputSpasm due to multiple sclerosis, stroke, amyotrophic lateral sclerosisRenal and hepatic elimination duration, 3-6 h toxicities: Weakness, sedation hypotensionDirect-acting muscle relaxantsDantroleneBlocks RyRl Ca2+ release channels in the sarcoplasmic reticulum of skeletal muscleReduces actin-myosin interaction weakness skeletal muscle contractionIV: Malignant hyperthermia Oral spasm due to cerebral palsy spinal cord injury multiple sclerosisIV, oral duration, 4-6 h Toxicities: Muscle weakness.Mivacurium. another isoquinoline compound, has the shortest duration of action of all nondepolarizing muscle relaxants. However, its onset of action is significantly slower than that of succinylcholine. In addition, the use of a larger dose to speed the onset can be associated with profound histamine release leading to hypotension, flushing, and bronchospasm. Clearance of mivacurium by plasma cholinesterase is rapid and independent of the liver or kidney. However, because patients with renal failure often have decreased levels of plasma cholinesterase, the short duration of action of mivacurium may be prolonged in patients with impaired renal function. Although mivacurium is no longer in widespread clinical use, an investigational ultra-short-acting isoquinoline nondepolarizing muscle relaxant, gantacurium, is currently in phase III clinical testing. This novel compound has a very rapid onset and short duration of action
Rocuronium
Pipecuronium
Mivacurium
Pancuronium
Muscle Relaxant