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Skeletal muscle relaxants (2011) - drdhriti
 

Skeletal muscle relaxants (2011) - drdhriti

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A power point presentation on "Skeletal Muscle Relaxants" suitable for UG MBBS level students

A power point presentation on "Skeletal Muscle Relaxants" suitable for UG MBBS level students

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    Skeletal muscle relaxants (2011) - drdhriti Skeletal muscle relaxants (2011) - drdhriti Presentation Transcript

    • SKELETAL MUSCLE RELAXANTS DEPARTMENT OF PHARMACOLOGY, NEIGRIHMS SHILLONG, MEGHALAYA
    • Skeletal Muscle Functions From Muscle twitch to sustained contraction Muscle twitching refers to small, local, involuntary muscle contractions (twitching) that may appear like a shiver under the skin
    • The Neuromuscular Junction N N type Receptors
    • The Skeletal Muscle Contraction The complex actin-myosin interaction to cause contraction (Sliding filament theory)
    • The Ach Receptor (Intrinsic Ion Channel) Depolarization 5 subunits Normally ACh binds in alpha subunits (- ve charged) groups in receptors with its cationic head
    • Skeletal Muscle Relaxation, why clinically ???
      • In conjunction with GA:
        • Facilitate intubation of the trachea
        • Facilitate mechanical ventilation
        • Optimized surgical working conditions
    • Why Skeletal Muscle Relaxation – contd.
      • In Muscle spasm:
      • It is defined as a sudden involuntary contraction of one or more muscle groups and is usually an acute condition associated with muscle strain (partial tear of a muscle) or sprain
          • Musculoskeletal Injury
          • Low Back pain or neck pain
          • Sports Injury
          • Fibromyalgia, tension headaches
      • Involve afferent nociceptive input from damaged area
      • Excitation of alpha motor outflow
      • Tonic contraction of affected muscle
      • Build up of pain-mediating metabolites
    • Why Skeletal Muscle Relaxation – contd.
      • In Spasticity:
      • Spastic neurological conditions (Spasticity): It is a motorneurone disorder characterized by skeletal muscle rigidity, exaggerated tendon jerks and paralysis of affected muscles
      • Associated with Motor neuron conditions
        • Cerebral palsy, Stroke, Multiple sclerosis, Traumatic brain injury, Anoxia and Neurodegenerative disease
        • In many patients with these conditions, spasticity can be disabling and painful with a marked effect on functional ability and quality of life
    • Spastic disorders Danger: Chronic muscle spasm can result in muscle atrophy in the specific muscle or muscle group
    • What are SMRs ???
      • Definition: Skeletal Muscle Relaxants are the drugs that act
        • peripherally at neuromuscular junction
        • or muscle fiber itself
        • or, centrally in cerebrospinal axis to reduce muscle tone and /cause muscle paralysis
    • 1. Centrally acting 2. Neuromuscular Junction 3. Directly on muscle
    • Classification: Peripherally acting SMRs
      • Neuromuscular Blockers:
        • Nondepolarizing (Competitive) blockers:
          • Long acting: d-Tubocurarine, Pancuronium, Doxacurium, Pipecuronium, Gallamine and Metocurine
          • Intermediate acting: Vecuronium, Atracurium, Cisatracurium, Rocuronium, Rapacuronium
          • Short acting: Mivacurium
        • Depolarizing blockers: Succinylcholine (suxamethonium), Decamethonium
      • Directly acting: Dantrolene and quinine
    • History: From hunting in Jungles to Operation theatre
      • Curare: The arrow poison
      • Source: Chondrodendrone tomentosum and Strychnos toxifera
      • Derived from: "ourare“ meaning arrow poison in South American Indian
      • Tubocurarine name: Because of packing in “ hollow bamboo tubes”
    • What is Competitive - Nondepolarizing Block in Muscles then?
      • They have affinity but no IA for N M receptors (Antagonist)
      • They have N+ atoms and get attracted to the ACh receptor site – but cannot bring conformational change like Ach
      • No EPP generation in nerve endings
      • However, can only act on closed channels – no action on already opened channels
        • But after sometime EPP falls to critical value – no propagation of AP and thus no contraction
      • Action can be overcome by increased Ach or clinically done by Neostigmine
      • They also block prejunctional Ach receptors on motor nerve endings – FADE PHENOMENON
        • Twitches turn to depressed on repetitive stimulation
    • Mechanism of action of non-depolarizing neuromuscular blockers Na Ca K ACh ACh Normal transmission 1- resting 2- active Non depolarizing neuromuscular blockade
      • Low doses:
      • competitive
      • antagonist of Ach
      • Action reversed by
      • Ach esterase inhibitors
      • Large doses:
      • Ion channel is blocked
      • More weakness of
      • neuromuscular
      • transmission
      • Action could not be
      • reversed by
      • Ach esterase inhibitors
      Other actions: Can block pre-junctional sodium channels and interfere with mobilization of Ach at nerve endings
    • Nondepolarizing Block in Muscles
    • Non-depolarizing - clinically
      • Intravenous administration of tubocurarine, 0.1–0.4 mg/kg, will initially cause motor weakness, followed by the skeletal muscles becoming totally flaccid and unexcitable to electrical stimulation
      • Larger muscles (eg, abdominal, trunk, paraspinous, diaphragm) are more resistant to blockade and recover more rapidly than smaller muscles (e.g. facial, foot, hand)
      • Diaphragm is usually the last muscle to be paralyzed
      • Assuming that ventilation is adequately maintained, no adverse effects occur
      • When administration of muscle relaxants is discontinued, recovery of muscles usually occurs in reverse order
    • Depolarizing Block - Succinylcholine
      • Affinity and sub-maximal intrinsic activity for N M receptors
        • Classically 2 (two) phases can be describe
          • Phase I block
          • Phase II block
      • Phase I block:
        • Depolarize the muscle end plate by opening Na+ channel (like Ach)
        • Initially, twitching and fasciculation occur – partial IA (transient depolarization) and repetitive excitation (chest and abdomen)
        • But, unlike Ach do not dissociate rapidly from end plate region (resistant to AChE) – only to liver and plasma ChE
        • Na+ channels get deactivated – No action of Ach to produce MAP – Flaccid paralysis
    • Succinylcholine – contd.
      • Phase II block:
        • In spite of presence of depolarizing agent, muscles repolarize again as physiological phenomenon (priming)
        • But cannot generate fresh depolarization – most probably due to desensitization of Ach receptors
        • Resembles antagonist like action on muscles – like tubocurarine (non-depolarizing block)
        • Can partially reversed by AChE
    • What Anesthetists do ?
      • Assessment of neuromuscular block by stimulation of the ulnar nerve
      • Important for Induction, recovery (reversal drug amount) from anaethesia and also in ICU patients
      • Monitored from compound action potentials or muscle tension developed in the adductor pollicis (thumb) muscle
      • Protocols - “train of four” and the “double burst”
      • Train of four (TOF) – four supramaximal electrical stimuli are applied at 2Hz and strength of contractions are recorded
      • TOF ratio is 1 at recovery
      • Non-depolarizing agents show – fading phenomenon
      • Depolarizing agents in phase I shows no fading and TOF is 1, but in phase II shows fading phenomenon
    • Train-of-four Monitoring
    • Other Actions of NM blockers
      • Autonomic ganglia:
        • Partial blockade of ganglia (N N type of receptor)
        • Results in fall in BP and tachycardia
      • Histamine release:
        • Hypotension
        • Bronchospasm, excess bronchial and salivary secretion
      • CVS: Fall in BP due to
        • Ganglion blockade, histamine release and reduced venous return
        • Heart increased – vagal ganglion blockade
      • (All newer NDP agents have negligible effects on BP and Heart rate)
      • Succinylcholine may cause cardiac arrhythmias
    • Pharmacokinetic of N M blockers
      • Polar quaternary compounds - Not absorbed orally, do not cross cell membranes, low Vd and do not cross BBB or placental barrier – always given IV or IM
      • Muscles with high blood flow affected earlier
      • Redistribution to non-muscular tissues occur and action may persist longer than half life
      • Drugs metabolized in plasma/liver – short half-life (Vecuronium, atracuronium, rocuronium etc.) – 20-40 min.
      • Drugs excreted in urine – longer half-life (dTC and pancuronium) – 60-120 min.
      • Succinylcholine succinylmonocholine succinic acid + choline
      • In some – genetically determined abnormality and deficient pseudocholinesterase paralysis & apnoea
    • Individual compounds - Succinylcholine
      • Advantages:
      • Most commonly used SMR for ET intubation
      • Good intubation conditions – relax jaw, separated vocal chords with immobility, no diaphargmatic movements
      • Quick onset of action (1 – 2 min)
      • Used as continuous infusion occasionally
      • Disadvantages:
        • Cardiovascular: BP, HR and arrhythmias
        • Fasciculation
        • Muscle pain
        • Increase intraocular pressure
        • Increase intragastric pressure
        • Increase intracranial pressure
        • Hyperkalemia: K+ efflux from muscles, life threatening in CHF, patient with diuretics etc.
        • Malignant hyperthermia
        • Not indicated below 8 years of age
    • What is Malignant hyperthermia
      • Rare genetically determined reaction to susceptible persons having abnormal RyR receptor Ca+ channel
      • Caused by Halothane and manifests as high temperature due to persistent muscle contraction – increased intracellular Ca+
      • Succinylcholine accentuates this condition
      • Treatment:
        • Rapid external cooling – ice pack
        • Bicarbonate infusion
        • 100% oxygen inhalation
        • Injection of dantrolene: Dirtect acting muscle relaxant
    • What is succinylcholine apnoea?
      • A condition where muscles paralysed for an increased length of time and cannot breathe adequately at the end of an anaesthetic
      • Can be – inherited or spontaneous in a person with no family history
        • In inherited – reduced level of plasma cholinesterase
        • In acquired – normal level but reduced enzyme activity (Pregnancy, Hypothyroidism, Liver disease, Renal disease , Carcinomatosis)
      • Management:
        • Anaesthetize the patient and ventilate
        • Monitor the NM transmission (TOF)
        • patient should remain ventilated and anaesthetized until breathing spontaneously
        • Frozen plasma is infused
        • Family members should be tested by blood test and tagged if positive
    • Individual Compounds – contd.
      • Pancuronium:
      • Steroidal compound 5 times more potent than dTC
      • No cardiac or respiratory toxicity (little ganglion blockade)
      • Low histamine release – no bronchospasm or flushing
      • Long duration of action – reversal required
      • Preferred only in long surgeries
      • Vecuronium:
      • Congener of Pancuronium
      • Slow onset but prolonged action
      • CVS stability – no histamine release
      • Spontaneous and Quick recovery
      • Mostly commonly used
    • Individual Compounds – contd.
      • Atracurium:
        • Competitive blocker and less potent than pancuronium
        • Reversal not required
        • Non-enzymatic spontaneous degradation in addition to cholinesterase
        • Preferred in elderly and neonates
      • Rocuronium: Non-depolarizing agent
        • Rapid and immediate action
        • Alternative to SCh for tracheal intubation
        • Also acts as maintenance relaxant and no reversal required
        • Rapid intubation condition 60 – 90 seconds
        • Also used in ICU for mechanical ventilation
    • Neuro-muscular blockers - Interactions
      • Thiopentone Sodium – same syringe
      • General anaesthetics – potentiate blockers
      • Anticholinesterases – Neostigmine
      • Antibiotics – Aminoglycosides
      • Calcium Channel blockers – potentiate blockers (Verapamil)
      • Diuretics – hypokalemia
    • Neuro muscular blockers - uses
      • Adjuvant to General anaesthesia
      • Assisted ventilation
      • Convulsion and trauma from electroconvulsive therapy
      • Tetanus
      • Status epilepticus
      Vocal cord
    • Directly acting relaxants - Dantrolene
      • Different from neuromuscular blockers, no action on NM transmission
      • MOA – Ryanodine receptors (RyR) calcium channels – prevents depolarization – no intracellular release of Ca++
      • Absorbed orally, penetrates brain and produces sedation, metabolized in liver, excreted in kidney. T1/2 8-12 hrs.
      • Dose: 25-100 mg 4 times daily
      • Uses: UMN disorders – paraplegia, hemiplegia, cerebral palsy and malignant hyperthermia (drug of choice 2.5 – 4 mg/kg))
      • Adverse effects – Sedation, malaise, light headedness, muscular weakness, diarrhoea and hepatotoxicity
    • Centrally acting Muscle relaxants
      • Drugs that reduce skeletal muscle tone by selective action on cerebrospinal axis
      • Depress the spinal and supraspinal reflexes of muscle tone
      • Also depresses polysynaptic reflexes of ascending reticular formation – wakefulness disturbed (sedation)
      • No effect on NM junction but reduce UMN spasticity and hyperreflexia
    • Centrally acting Vs Peripherally acting
      • Centrally acting
      • Decrease muscle tone but no reduction in power
      • Polysynaptic reflexes in CNS
      • CNS depression
      • Orally and parenterally
      • Spastic conditions, muscle spasm
      • Peripherally acting
      • Cause muscle paralysis
      • Block NM transmission
      • No CNS effect
      • Given IV
      • Short term surgical procedures
    • Centrally acting Muscle relaxants
      • Classification:
      • Mephenesin congeners – Mephenesin, Carisoprodol, Chlorzoxazone, Methocarbamol and Chlormezanone
      • Benzodiazepines – Diazepam, lorazepam, Clonazepam and others
      • GABA derivative – Baclofen
      • Central α -2 agonist - Tizanidine
    • Centrally acting Muscle relaxants – contd.
      • Mephenesin (Relaxyl/medicreme)
        • Modulation of reflexes in spinal internuncial neurone
        • Cannot be used systemically
        • Irritant rather than relaxant – topical preparations
      • Carisoprodol, Chlorzoxazone (Mobizox), Methocarbamol (Robinax/Robiflam) and Chlormezanone – similar but can be used orally
    • Benzodiazepines as muscle relaxant
      • Very potent centrally acting muscle relaxant – supraspinal
      • Mechanism of action is via “GABA A receptor Cl- complex” enhancement – inhibitory in nature
      • Diazepam and Clonazepam are the most potent ones
      • Diazepam is the prototype of BZDs
    • GABA A -Benzodiazepine receptor-chloride channel complex
    • Baclofen (β-parachlorophenyl GABA)
      • Mechanism of action: GABA B agonist
      • hyperpolariztion of neurones by increasing K+ conductance and alteration of Ca++ flux
      • Does not affect to Cl- conductance
      • Site of action: spinal chord – depresses polysynaptic and monosynaptic reflexes
      • Clinical effects: decreased hyperreflexia; reduced painful spasms; reduced anxiety
      • Dose: orally 5 mg three times daily, gradually increase to 20 mg four times daily or higher
        • intrathecally initially 50 mcg/day increase to 300-800 mcg/day
    • Individual Compounds - Tizanidine
      • Mechanism of action: alpha-2 receptor agonist – inhibits the release of excitatory amino acids in spinal interneurones
      • Clinical effects: reduced tone, spasm frequency, and hyperreflexia
      • Doses: tizanidine initial 4 mg three times daily increase to 36 mg/day; clonidine initial 0.1 mg twice daily increase to 2.4 mg/day
    • Uses of Centrally acting relaxants
      • Acute muscle spasms
      • Backache and neuralgias
      • Anxiety and tension
      • Spastic neurological disorders
      • Tetanus
      • Electroconvulsive therapy
      • Orthopaedic manipulations
    • What to Remember !!
      • Skeletal Muscle Relaxants - Classification
      • Mechanism of non-depolarizing
      • Mechanism of Depolarizing – Phase 1 and phase 2
      • Uses of SMRs
      • Mechanism and treatment of Succinylcholine apnoea and malignant hyperthermia
      • Few Drug Interactions of SMRs
      • Centrally acting Muscle relaxants – Names and uses
    • Some Questions ???
      • Write Short Notes on:
        • Succinylcholine
        • Atracurium
        • Dantrolene
        • Tizanidine
        • Baclofen
      • Clinical Cases:
        • Outline the cause, pathogenesis, clinical features and treatment of succinylcholine apnea
    • Thank you