12- SKM RELAXANTS.pdf

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 •...

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 mechanismsPharmacologic 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: • Depolarizing blockers: – – – – Long acting: d-Tubocurarine, Pancuronium Intermediate acting: Atracurium, Rocuronium Short acting: Mivacurium Succinylcholine, Decamethonium 0 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: • • Used for short term procedures ADRs: – – – – Neck, limbs respiratory face, jaws, eyes Respiratory paralysis Hyperkalemia Malignant hyperthermia pharynx trunk Nondepolarizing Blockers • Mechanism of Action • Block can be reversed by anti-AChE agents • Order of paralysis: – – – – Reversible competitive antagonists these compounds have two charged heads (e.g., quaternary ammonium) separated by a “thick” organic moiety (e.g., steroid nucleus) Neostigmine, pyridostigmine fingers, eyes limbs neck face trunk respiratory 0 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, tetracycline- enhances Nondepolarizing Blockers_3 • Pancuronium: • Atracurium: • Rocuronium: • Mivacurium: – – – – – 5 times potent than d- tubocurarine. Long onset - 2.9 min and DOA- 110 min DOA – 45 min, good tolerable in kidney and liver diseases rapid onset- 1min and DOA - 55 min 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: Directly-Acting • 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