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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
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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
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GABA is the major ______ neurotransmitter and inolved in descending __________ pathways
inhibitory, inhibitory
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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
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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
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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
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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)
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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
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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
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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
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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
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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%
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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
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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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