12- SKM RELAXANTS.ppt

Neuromuscular blockers SKELETAL MUSCLE RELAXANTS Learning Objectives • Explain Neuromuscular junction: NMJ • Describe Two types of skeletal muscle relaxants and their subtypes: – Neuromuscular blockers • Non-depolarizing (Competitive) blockers • Depolarizing blockers – Spasmolytic Drugs • Central...

Neuromuscular blockers SKELETAL MUSCLE RELAXANTS Learning Objectives • Explain Neuromuscular junction: NMJ • Describe Two types of skeletal muscle relaxants and their subtypes: – Neuromuscular blockers • Non-depolarizing (Competitive) blockers • Depolarizing blockers – Spasmolytic Drugs • Centrally Acting • Directly-Acting • Enumerate Drugs for Acute Muscle Spasm Two Types of Drugs • Neuromuscular blockers: – Interfere with transmission at the neuromuscular end plate – Uses: surgical procedures, ICU, GA - tracheal intubation • Spasmolytics: – Traditionally called “centrally acting” muscle relaxants – reduces spasticity in a variety of painful conditions – Uses: chronic back pain, painful fibromyalgias Neuromuscular junction Nicotinic Ach receptor: nAChR Skeletal muscle relaxation and paralysis • By interruption at several sites: the pathway from the central nervous system (CNS) to: – myelinated somatic nerves – unmyelinated motor nerve terminals – nicotinic acetylcholine receptors – motor end plate – muscle membrane and – intracellular muscular contractile apparatus NMJ blockade • Blockade of end plate function: by two basic mechanisms• Pharmacologic blockade: – Antagonist or NM blocking drugs: nondepolarizing NM blocking drugs – Prototype of this class is d-tubocurarine • The second type of blockade: Depolarizing type – An excess of a depolarizing agonist: such as acetylcholine – Prototype of this class is succinylcholine NM blocking agents: Classification • Non-depolarizing (Competitive) blockers: – Long acting: d-Tubocurarine, Pancuronium – Intermediate acting: Atracurium, Rocuronium – Short acting: Mivacurium • Depolarizing blockers: – Succinylcholine, Decamethonium 8 NM blockers: end plate channel Depolarizing Blocker • Neuromuscular block by over stimulation: – so that the end plate is unable to respond to further stimulation • Two sequential events: – Phase 1(depolarization block): • Maintained depolarization produces Na channel inactivation(so no repolarisation of next generation of action potentials) – Phase 2 (desensitization block): • Block is due to desensitization of Ach Receptors Depolarizing Blocker_2 • Succinylcholine: – More effect on NMJ and – less on autonomic ganglia – Releases histamine from mast cells – Anticholinesterase: do not reverse the paralysis in Phase I – may prolong the block Depolarizing Blocker_3 • Order of paralysis: – Neck, limbs  face, jaws, eyes  pharynx trunk respiratory • Used for short term procedures • ADRs: – Respiratory paralysis – Hyperkalemia – Malignant hyperthermia Nondepolarizing Blockers • Mechanism of Action – Reversible competitive antagonists – these compounds have two charged heads (e.g., quaternary ammonium) separated by a “thick” organic moiety (e.g., steroid nucleus) • Block can be reversed by anti-AChE agents – Neostigmine, pyridostigmine • Order of paralysis: – fingers, eyes limbs neck face trunk respiratory 13 Nondepolarizing Blockers_2 • Hypokalemia: potentiate their effects • New born are sensitive to these drugs • Myasthenia patients are also sensitive to paralysis • Adverse effects: – Bronchospasm – Hypotension • Inhalational anesthetics: Potentiation • Antibiotics: Aminoglycosides, tetracyclineenhances Nondepolarizing Blockers_3 • Pancuronium: – 5 times potent than d- tubocurarine. – Long onset - 2.9 min and DOA- 110 min • Atracurium: – DOA – 45 min, good tolerable in kidney and liver diseases • Rocuronium: – rapid onset- 1min and DOA - 55 min • Mivacurium: – onset 1.8 minutes, DOA - 20 minutes Uses of Neuromuscular Blocking Drugs • Surgical Relaxation • Tracheal Intubation • Control of Ventilation • Treatment of Convulsions Spasticity: Stretch Reflex Arc • Spinal injury • Cerebral palsy • Multiple sclerosis • Stroke Spasmolytic agents: MOA Spasmolytic Drugs: Centrally Acting • Baclofen: Oral, intrathecal – GABAB agonist: • MOA: causes membrane hyper-polarization via increased K+ conductance (cause presynaptic inhibition by reducing calcium influx and reduces the release of excitatory transmitter in both brain and spinal cord) – Decreases release: • Glutamate, substance P – Uses: • Severe spasticity-cerebral palsy, multiple sclerosis, stroke – S/E: • Sedation, muscleweakness Spasmolytic Drugs: Centrally Acting_2 • Diazepam: – MOA: • Facilitates GABAergic transmission in central nervous system - central sedation • Increases interneuron inhibition of primary motor afferents in spinal cord – Uses: • Chronic spasm due to cerebral palsy, stroke, spinal cord injury • acute spasm due to muscle injury Spasmolytic Drugs: Centrally Acting_3 • Tizanidine – MOA: α2-Adrenoceptor agonist in the spinal cord • Re-inforces both presynaptic and postsynaptic inhibition of reflex motor output – Uses: • Spasm due to multiple sclerosis, stroke, amyotrophic lateral sclerosis – S/E: • Weakness, sedation, hypotension Spasmolytic Drugs: DirectlyActing • Dantrolene: – MOA: • Blocks RyR1 Ca2+ release channels in the sarcoplasmic reticulum of skeletal muscle • Reduces actin-myosin interaction - weakens in skeletal muscle contraction – Uses: • IV: Malignant hyperthermia • Oral: Spasm due to cerebral palsy, spinal cord injury, multiple sclerosis – S/E: Muscle weakness Drugs for Acute Muscle Spasm • Cyclobenzaprine: by oral route – MOA: • act in the brain stem, possibly by interfering with polysynaptic reflexes that maintain skeletal muscle tone • has marked sedative and antimuscarinic actions – S/E: • Confusion, visual hallucinations – Uses: • Acute spasm due to muscle injury, inflammation • Other drugs : Chlorphenesin Notes