skeletal muscle relaxants lecture 9

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skeletal muscle relaxants lecture 9
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  1. Two types of skeletal muscle relaxants:
    • I. Neuromuscular blocking agents
    • §Non-depolarizing neuromuscular blockers
    • §Depolarizing neuromuscular blockers
    • §Botulinum toxins
    • §Interfere with neurotransmission at neuromuscular junction
    • §Lack central nervous system activity
    • §Primarily used as adjuncts in general anesthesia during surgery
    • to achieve muscle relaxation
    • to facilitate intubation of respiratory tract
    • II. Spasmolytic drugs
    • §Mostly act in central nervous system, “centrally acting” muscle relaxantsPrimarily used to treat muscle spasticity caused by CNS disorders
  2. Pathophysiology of spascitiy: Higher level control of stretch reflex:
    • 1. After entering spinal cord, every sensory signal travels to two destinations:
    • 1). Spinal cord to elicit local cord reflexes
    • 2). Higher levels of nervous system to control the extent
    • of muscle contraction and coordinate body movement
    • § Cerebral cortex
    • § Brain stem
    • § Higher levels of spinal cord
    • 2. High levels of nervous system integrate sensory information
    • and send output to cord motor neurons through two pathways:
    • 1). Descending excitatory pathways
    • 2). Descending inhibitory pathways
    • 3. The balance between the two pathways is crucial for normal
    • motor function
    • 4. Imbalance between the two pathways results in spasticity
    • 1). Enhanced excitatory pathways
    • 2). Diminished inhibitory pathways
    • these two cause hyperexcitability
  3. GABA is the major ______ neurotransmitter and inolved in descending __________ pathways
    inhibitory, inhibitory
  4. Action of GABA:
    • 1. GABA acts through binding to GABA receptors
    • 2. Two types of GABA receptors:
    • 1). GABAA receptor: GABA-gated Cl- channel
    • § Binding of GABA to GABAA on post-synaptic neurons opens Cl- channels
    • § Cl- influx hyperpolarizes neuronal membrane, making it more difficult to depolarize and thus reducing neuronal excitability
    • 2). GABAB receptor: G-protein coupled receptor
    • § Presynaptic GABAB Receptors: binding of GABA blocks Ca2+ channels, inhibiting the release of excitatory neurotransmitters
    • § Postsynaptic GABAB receptors: binding of GABA opens K+ channels, K+ efflux results in membrane hyperpolarization
  5. Action of spasmolytic drugs:
    • 1. Increase or mimic the activity of GABA, enhancing activity of descending inhibitory pathways
    • 2. Inhibit excitatory neurotransmitter release: a2-adrenegic agonists
    • 3. Directly act on muscle contractile machinery: dantrolene
  6. Treatment of spasticity:
    • 1. Relieve discomfort and improve activities of daily living
    • 2. Multimodal approach
    • 1). Physical and occupational therapy
    • 2). Medications:
    • §Spasmolytics
    • §Nonsteroidal anti-inflammatory drugs: e. g. acetaminophen, reduce pain and inflammation
    • §Corticosteroids: reduce inflammation
    • 3). Surgery: might be necessary in case of severe muscle spasticity
  7. Classification of spasmolytic drugs:
    • I. Direct-acting Muscle Relaxants
    • Dantrolene (Dantrium)
    • Botulinum Toxin
    • II. Centrally Acting Spasmolytic Drugs
    • § Drugs Increasing GABA Activity:
    • Baclofen (Lioresal)
    • Gabapentin (Neurontin)
    • § a2-adrenergic Agonists:
    • Tizanidine (Zanaflex)
    • § Benzodiazepines:
    • Diazepam (Valium)
    • § Drugs for Acute Local Muscle Spasm:
    • Carisoprodol (Soma)
    • Chlorzoxazone (Paraflex)
    • Cyclobenzaprine (Flexeril)
    • Metaxalone (Skelaxin)
    • Methocarbamol (Robaxin) Orphenadrine (Norflex)
  8. Dantrolene:
    • 1. Mechanism of Action
    • 1). Normal contractile response involves release of Ca2+ from sarcoplasmic reticulum, and Ca2+ is required for the interaction of actin with myosin which generates muscle contraction
    • 2). Ca2+ is released from sarcoplasmic reticulum via ryanodine receptor (RyR) channel
    • RyR1: skeletal muscle sarcoplasmic reticulum
    • RyR2: cardiac and smooth muscle sarcoplasmic reticulum3). Dantrolene binds to RyR1, blocking opening of the channel and thus Ca2+ release
    • 2. Indications:
    • 1). Spasticity in stroke, cerebral palsy, spinal cord injury and multiple sclerosis
    • 2). Treatment of malignant hyperthermia: IV administration
    • 3. Pharmacokinetics:
    • 1). Slow and incomplete oral absorption (about 30%)
    • 2). Plasma half-life about 8 hours
    • 3). Metabolized by liver and excreted in urine
    • 4. Adverse Effects:
    • 1). Generalized muscle weakness (due to reduction in muscle strength)
    • 2). Drowsiness, sedation
    • 3). Hepatic toxicity may occur, liver function monitoring is required
  9. Botulinum Toxin:
    Botulinum toxin type A (Botox)
    Botulinum toxin type B (Myobloc)
    • 1. Purified from toxins produced by Clostridium Botulinum.
    • 2. Blocks ACh release from storage vesicles and inhibits neuromuscular transmission. Local injection causes muscle relaxation
    • 3. Indications
    • §Treatment of local muscle spasm: muscles of face, eyes, hands
    • §Treatment of generalized spasticity due to central nervous system disorders
    • §Used to relieve symptoms of Parkinson’s disease: tremor, excessive salivation
    • §Used in cosmetics to reduce facial wrinkles
    • 4. Adverse effects: dry mouth and dysphagia
  10. Baclofen:
    • 1. Mechanism of Action
    • 1). GABAB receptor agonist
    • 2). Binds to GABAB receptors on post-synaptic neurons, resulting in increased K+ efflux and membrane hyperpolarization
    • 3). Binds to GABAB receptors on presynaptic terminal of excitatory neurons, reducing the release of excitatory neurotransmitters by blocking Ca2+ influx
    • 2. Indications
    • 1). Spasticity in multiple sclerosis and spinal cord injuries
    • 2). Off label uses:
    • §Intractable low back pain
    • §Treatment of trigeminal neuralgia
    • §Reduction of rigidity in patients with Parkinson’s disease
    • §Migraine headache
    • 3. Pharmacokinetics
    • 1). Rapid and complete oral absorption, limited CNS penetration
    • 2). Intrathecal administration: used to control severe spasticity and muscle pain that are not responsive to oral medication
    • 3). Short plasma half-life of 3-4 hours4). Primarily eliminated by kidney in unchanged form
    • 4. Adverse Effects
    • 1). Drowsiness, sedation, fatigue
    • 2). Sudden withdrawal from chronic administration may induce seizure,
    • withdrawal should be done slowly
    • 3). Intrathecal administration may cause excessive somnolence, respiratory depression.
    • Abrupt withdrawal may result in acute hyperspasticity, high fever, delirium
  11. Gabapentin:
    • 1. Is an amino acid, structurally similar to GABA
    • 2. First introduced for treatment of partial seizure, also effective as a spasmolytic agent in patients with multiple sclerosis
    • 3. Does not directly act on GABA receptors, but increases release of GABA
    • 4. Readily absorbed orally, short plasma half-life of 5 – 8 hours
    • 5. Is not metabolized and eliminated unchanged in urine
    • 6. Common adverse effects: somnolence, dizziness, headache, tremor
  12. Tizanidine:
    • 1. Mechanism of Action
    • 1). Centrally acting a2-adrenoceptor agonist
    • 2). Binds to a2 receptors , decreasing release of excitatory neurotransmitters in spinal cord, resulting in presynaptic and postsynaptic inhibition of reflex motor output
    • 3). Inhibits nociceptive (e.g. pain) transmission in spinal dorsal horn
    • 2. Indications:
    • Treatment of spasm due to stroke, multiple sclerosis and amyotrophic lateral sclerosis
    • 3. Pharmacokinetics:
    • 1). Complete oral absorption, plasma half-life of 2 – 3 hours
    • 2). Metabolized by hepatic cytochrome P450 enzyme (CYP1A2), excreted in urine and feces
    • 4. Adverse Effects:
    • 1). Hypotension, especially when used in combination with other antihypertensive drugs
    • 2). Drowsiness, dizziness, sedation
    • 3). Dry mouth, fatigue
    • 5. Drug Interactions:
    • 1). Cytochrome P450 1A2 inhibitors: such as Fluvoxamine, Ciprofloxacin increase the plasma concentration of tizanidine
    • 2). Oral contraceptives: reduce tizanidine clearance by 50%
  13. Diazepam: benzodiazepine sedative-hypnotics:
    • 1. Mechanism of Action
    • 1). Binds to GABAA receptors in brain and spinal cord
    • 2). Causes Cl- influx and hyperpolarization of Postsynaptic neurons, thus reducing neuronal excitability
    • 2. Indications:
    • 1). Chronic spasm due to cerebral palsy, stroke, spinal cord injury
    • 2). Acute spasm due to local muscle trauma
    • 3. Pharmacokinetics:
    • 1). Well absorbed, long plasma half-life of 1- 3 days
    • 2). Metabolized by liver microsomal cytochrome P450 enzymes
    • 3). Conjugated metabolites eliminated in urine
    • 4. Adverse Effects:
    • 1). Sedation and cognitive impairment
    • 2). Sudden cessation after chronic treatment may result in withdrawal syndrome: anxiety, agitation and insomnia
  14. Drugs for acute local muscle spasm:
    • Carisoprodol (Soma)
    • Chlorzoxazone (Paraflex)
    • Cyclobenzaprine (Flexeril)
    • Metaxalone (Skelaxin)
    • Methocarbamol (Robaxin)
    • Orphenadrine (Norflex)
    • 1. Act in CNS, probably at the level of brain stem
    • 2. Mechanism of action is not clear, probably via sedative properties
    • 3. Relief acute muscle spasm caused by local tissue trauma or muscle strains, not effective in treating muscle spasm due to CNS disorders
    • 4. Adverse effects include sedation, drowsiness, vertigo, anticholinergic activity

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