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    Skeletal Muscle Relaxants 3 Pha 2013

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    Skeletal Muscle Relaxants and Neuromuscular Blocking Agents can be categorized as either centrally or peripherally acting. Peripherally acting agents include neuromuscular blocking drugs (NMBDs) which can be depolarizing like succinylcholine or non-depolarizing. Non-depolarizing NMBDs include aminosteroids, benzylisoquinolines, and others. They work by competitively blocking acetylcholine receptors. Spasmolytics reduce muscle tone and spasms through various mechanisms like GABA, calcium channel, or alpha-2 adrenergic receptor agonism. Common examples discussed are baclofen, tizanidine, d

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    Skeletal Muscle Relaxants 3 Pha 2013

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    r0ben1n
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    Skeletal Muscle Relaxants and Neuromuscular Blocking Agents can be categorized as either centrally or peripherally acting. Peripherally acting agents include neuromuscular blocking drugs (NMBDs) which can be depolarizing like succinylcholine or non-depolarizing. Non-depolarizing NMBDs include aminosteroids, benzylisoquinolines, and others. They work by competitively blocking acetylcholine receptors. Spasmolytics reduce muscle tone and spasms through various mechanisms like GABA, calcium channel, or alpha-2 adrenergic receptor agonism. Common examples discussed are baclofen, tizanidine, d

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    dr.heshiar. muscle relaxant

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    Skeletal Muscle Relaxants and Neuromuscular Blocking Agents can be categorized as either centrally or peripherally acting. Peripherally acting agents include neuromuscular blocking drugs (NMBDs) which can be depolarizing like succinylcholine or non-depolarizing. Non-depolarizing NMBDs include aminosteroids, benzylisoquinolines, and others. They work by competitively blocking acetylcholine receptors. Spasmolytics reduce muscle tone and spasms through various mechanisms like GABA, calcium channel, or alpha-2 adrenergic receptor agonism. Common examples discussed are baclofen, tizanidine, d

    Copyright:

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    94 views37 pages

    Skeletal Muscle Relaxants 3 Pha 2013

    Uploaded by

    r0ben1n
    Skeletal Muscle Relaxants and Neuromuscular Blocking Agents can be categorized as either centrally or peripherally acting. Peripherally acting agents include neuromuscular blocking drugs (NMBDs) which can be depolarizing like succinylcholine or non-depolarizing. Non-depolarizing NMBDs include aminosteroids, benzylisoquinolines, and others. They work by competitively blocking acetylcholine receptors. Spasmolytics reduce muscle tone and spasms through various mechanisms like GABA, calcium channel, or alpha-2 adrenergic receptor agonism. Common examples discussed are baclofen, tizanidine, d

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    Skeletal Muscle Relaxants

    Skeletal Muscle Relaxants


    Centrally acting Diazepam Baclofen Tizanidine
    Peripheral acting NMBD Dantrolene

    Neuromuscular Blocking Agents

    History
    1596: Sir Walter Raleigh - Arrow poison Ourai from creepers 1811: Sir Benjamin Brodie - Curares paralysing effects 1825: Charles Waterton - Curare in donkeys 1850: Claude Bernard - Motor endplate

    History
    1942: Curare 1947: Gallamine 1949: d-Tubocurarine 1951: SCh 1960: Pancuronium 1964: Alcuronium 1970s: Fazadinium 1980: Atracurium 1992: Mivacurium 1994: Rocuronium 1995: Cis-atracurium 2000: Rapacuronium

    Neuromuscular Blockers

    Motor neuron

    ACHEsterase

    Skeletal Muscle

    Synthesis & storage Mobilization Release

    Nicotinic Receptor at adult NMJ


    ACh Epsilon / Gamma Alpha

    Alpha Ion Channel

    Beta

    ACh

    Delta

    In fetal & denervated receptors: Gamma replaces Epsilon

    AChR blocking agents


    Non competitive Competitive Local anaesthetics, Non-depolarizing agents depolarizing agents, Block of one or both Acetylcholine Ach binding sites Plug the channel & Affinity more at alphaprevent ion movement epsilon site

    Pharmacokinetics

    Absorption
    1- Oral ( not absorbed ) 2- IV ( rapid onset, fast distribution & predictable
    elimination. 3- S/C or IM (unpredictable absorption, high dose required)

    Distribution
    Vol. of distribution: Positively charged quaternary ammonium compounds remain ionized (water soluble ) Prolonged use may increases Vd up to 10 fold. Protein binding Albumin & Gamma globulins

    Drug Succinylcholine Mivacurium Atracurium Cis-atracurium Vecuronium

    Metabolism 98 - 99 % 95 99 % 70 90 % 70 90 % 30 40 % (Hepatic)

    Renal <2% <5% 10 30 % 10 30 % 40 % (metabolites)

    Biliary --Laudanosin Laudanosin 10 20 % (metabolites)

    Pancuronium
    Rocuronium

    10 20 % (Hepatic) Minimal (Hepatic)

    60 80 %
    30 40 %

    10 %

    60 %

    Clinical use of neuromuscular blockers Muscle relaxation during surgical procedures Endotracheal intubation Maintain controlled ventilation

    Clinical problems associated with neuromuscular blockers


    Potentiated by inhaled anesthetics (Isoflurane) Potentiated by aminoglycosides and calcium channel blockers Can block autonomic ganglia at higher doses Respiratory paralysis

    Depolarizing Agents

    Succinylcholine (1951)
    The only depolarizing NMBA currently used It has short onset (< 1 min) & short duration (5 10 min) Both N2 atoms are quaternary (+ ve) IV injection small fraction reaches NMJ ED 95 is 0.35 0.5 mg/kg (dose = 1mg/kg) Depolarizing effect within 20-40 sec (fasciculations) followed by relaxation (< 60 sec)

    Succinylcholine Side effects


    1- Stimulation of muscarinic AChR
    Sinus bradycardia, even sinus arrest

    2- Ganglionic stimulation
    Increased heart rate , hypertension

    3- Allergic Reactions 4- Myalgia (Prevented by precurarization, Benzo,


    Lido, Ca)

    5- Raised Intra Cranial Pressure , Intra Ocular Pressure and Intra Gastric Pressure .

    Succinylcholine
    contraindications

    Neuromuscular disease Denervation (after 2 days) Immobilization (after 3 days) Burns (after 2 days) Allergy to SCh

    Non-depolarizing agents

    Non-depolarizing agents
    Bind to one or both Alpha units of AChRs Competitive antagonism of Ach Dynamic binding (repeated association & dissociation). Presynaptic receptors also blocked. 90 % receptor block: complete block

    Non-depolarizing agents

    Aminosteroids Pancuronium Vecuronium Rocuronium Rapacuronium Benzylisoquinolines Atracurium Cis-atracurium Mivacurium d - Tubocurarine

    Pancuronium
    Bis-quarternary aminosteroid Competitive antagonist at pre/post-synaptic nicotinic ACh NMJ receptor. Long acting Low lipid solubility, 80% excreted unchanged in urine 40% undergoes hepatic metabolism to active metabolites, 50% as potent at NMJ In liver failure, increase elimination t1/2 Vagolytic effect on cardiac muscarinic May precipitate myocardial ischaemia.

    Rocuronium
    Mono quaternary amminosteroid

    Rapid onset (1 - 2 min) and short duration (20-35 min) Largely excreted unchanged (upto 50%) in bile in 2 hrs (>30% renal excretion in 24 hrs) Prolonged action in renal, hepatic diseases and old age Absence of histamine release Slight vagolytic action

    Cis-atracurium
    Purified form of one of 10 steroisomers of atracurium, 5 times more potent Similar to atracurium except slow onset, very little histamine. Onset of action 3 - 5 min & duration 20-35 min 77% Hoffman degradation at normal pH to inactive metabolities. 17% renal clearance

    Mivacurium
    Only non-depolarizer with short duration Onset 2 3 min, duration 12 20 min Hydrolyzed by plasma cholinesterase (88 % rate of SCh) 7% unchanged in urine Inactive metabolites Antagonism: Spontaneous recovery, ? Reversal with neostigmine, Edrophonium for deep block

    Doxacurium
    Benzylisoquinoline Most recent Long onset & prolonged duration No histamine release No cardiovascular effects Excreted mainly in the urine & the bile

    Spasmolytics

    Spasmolytics
    Spasticity is characterized by an increase in tonic stretch reflexes and flexor muscle spasms ( increase basal muscle tone) together with muscle weakness Chronic neurologic diseases
    - Cerebral Palsy, Multiple Sclerosis and stroke

    Acute Injury
    - Spinal cord damage, muscle inflammation Goal of therapy: Reduce spasticity and pain, while retaining function

    Spasmolytics
    Benzodiazepines (Diazepam, etc.) GABAA Receptors CNS and Spinal Cord Side Effects: Sedation
    Cl H3 C N N O

    Diazepam (Valium)

    Spasmolytics
    GABAB receptor agonist H2 N CO2H Activation of K+ channels CNS and Spinal cord Less sedation than BZDs Intrathecal pumps now used in chronic Cl conditions Baclofen Warning for severe withdrawal syndrome from intrathecal use Side effects : Altered mental status, hyperpyrexia, exaggerated spasticity, muscle rigidity, and rhabdomyolysis

    Spasmolytics
    N S N H N Cl N N H

    Tizanidine (Zanaflex)

    - Alpha 2 adrenergic receptor agonist Congener of clonidine Presynaptic inhibition of motor neurons 1/10 - 1/50th potency as clonidine in lowering blood pressure Side Effects: Drowsiness, hypotension, dry mouth

    Spasmolytics
    Drugs used to treat acute local muscle spasm
    These drugs acts primarily at the level of brainstem Carisoprodol Chlorphenesin Chlorzoxazone Cyclobenzaprine Metaxalone Orphenadrine

    Spasmolytics
    Dantrolene Sodium (Dantrium)
    O 2N O O H C N N NNa+ O

    Interferes with excitation-contraction coupling Reduces release of Ca++ from the sarcoplasmic reticulum (blocks contraction) Uses: Cerebral palsy, multiple sclerosis and Malignant Hyperthermia Side Effects: Muscle weakness, sedation, rare hepatitis

    Spasmolytics
    Botulinum Toxin
    Local injection of botulinum toxin is a useful treatment for generalized spastic disorders eg, cerebral palsy . It is also useful for ophthalmological and cosmetic treatment of skin wrinkles around the eyes and mouth.

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