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Central Spasmolytics
- Reduce spasticity in CNS (muscle relaxation)
- Treat chronic back pain and painful fibromyalgia
- Antispasmodics- act on CNS and affect skeletal muscle
- Antispastics- act on CNS and affect skeletal muscle
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Peripheral Spasmolytics
- Antispasmodics- act on GI tract and affect smooth muscle
- Antispastics- dantrolene (spasmolytic) has no significant CNS effects
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Neuromuscular blockers
- Skeletal muscle relaxants cause muscle paralysis at the neuromuscular junction (end plate)
- Nicotinic ACh receptor neurotransmission
- Peripheral action
- Adjunct during general anesthesia
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Fibromyalgia
Widespread musculoskeletal pain accompanied by fatigue, sleep, memory and mood issues
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Spasmolytic Drugs
- Spasticity- an increase in tonic stretch reflexes and flexor muscle spasms (ie, increased basal muscle tone) together with muscle weakness
- Disease conditions:
- - Skeletal muscle disorders
- - Spinal injury
- - Cerebral palsy
- - Multiple sclerosis
- - Stroke
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DIAZEPAM
- Enhance inhibitory neurotranmission
- Benzodiazepines facilitate the action of GABAA in the spinal cord
- Produces sedation at the doses required to reduce muscle tone
- Spasmolytic midazolam: limited clinical experience
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BACLOFEN
- Gablofen: an orally active GABAB agent, INC inhibitory transmission
- INC K+ conductance → DEC Ca2+ influx → presynaptic inhibition
- DEC pain in patients with spasticity (may DEC the release of substance P)
- Less sedation (differ from diazepam)
- Less reduction in muscle strength (differ from dantrolene)
- Rapidly and completely absorbed after oral administration
- Half-life: 3-4 hours
- Adverse effects: drowsiness, increased seizure activity (must withdraw very slowly); Excessive somnolence, respiratory depression, coma
- Long-term intra-thecal baclofen therapy for severe spastic disorders
- Other use: low back pain; migraine headaches; craving in recovering alcoholics
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TIZANIDINE
- α2 agonists (as clonidine)
- Less cardiovascular effects (differ from clonidine)
- Cause both pre-and post-synaptic inhibition (spinal cord)
- Nociceptive transmission in the spinal dorsal horn
- Adverse effects: drowsiness, hypotension, dizziness, dry mouth, asthenia, and hepatotoxicity.
- Linear pharmacokinetics, adjust dose in pts with liver or kidney problems
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DANTROLENE
- Skeletal muscle RyR channel (RyR1)
- Cardiac muscle and smooth muscle: a different RyR channel (RyR2).
- Major adverse effects are generalized muscle weakness, sedation, and occasionally hepatitis.
- The treatment of malignant hyperthemia
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Botulinum Toxin A
- Neurotoxic protein produced by the bacterium Clostridium botulinum
- By inhibiting the release of acetylcholine from presynaptic motor neurons
- Heavy chain binds to receptor and enters cell; light chain causes irreversible blockade;
- Slow on set (4-7 days) and prolonged action (~ 2-3 months)
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CNS Muscle relaxants (CNS antispasmodics)
- Centrally active drugs: eg, cyclobenzaprine, metaxalone
- Relief of acute muscle spasm (local tissue trauma or muscle strains)
- Act primarily at the level of the brainstem.
- Ineffective for cerebral palsy
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Carisoprodol
- Soma: muscle relaxant, CNS depressant
- Used for the treat acute, painful musculoskeletal conditions in adults (only for 2-3 wks)
- Metabolized in the liver by CYP2C19 to form meprobamate
- MOA: Slight depression of all neurons at synaptic junctions in CNS
- Its metabolite, meprobamate (antianxiety, CNS depressant), has barbiturate like effects on GABA-A
- CI- Hx of acute intermittent porphyria or hypersensitivity to carbamate such as meprobamate
- ADR- drowsiness, dizziness; sedation, somnolence, abuse, dependence, seizure and withdrawal seizures, confusion
- DI- Additive with other CNS depressants (Alcohol, benzodiazepines, opioids, tricyclic antidepressants)
- - CYP2C19 inhibitors- omeprazole or fluvoxamine
- - CYP2C19 inducers- rifampin or St. John’s Wort, Low dose aspirin
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Cyclobenzaprine
- Flexeril
- very potent(5 mg), extended-release formulation
- Blocks nerve impulses (or pain sensations) to brain for Txt of skeletal muscle pain or injury
- MOA: Act on the locus coeruleus (in brainstem) to increase NE release, through affecting fibers to inhibit α motor neurons in the ventral horn of the spinal cord
- ADR- Atropine like effects (dry mouth, constipation, urinary retention, blurred vision); somnolence, confusion
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chlorzoxazone
- Paraflex
- Liver toxicity
- Sedative properties; malaise
- Inhibits muscle spasm by affecting the spinal cord and subcortical areas of the brain
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Metaxalone
- Skelaxin
- CNS depressant, less sedative
- No direct action on the contractile mechanism of striated muscle, motor end plate, or nerve fiber
- ADR- GI upset, N/V, dizziness, somnolence, HEMOLYTIC AMEMIA, Leucopenia, Jaundice
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Methocarbamol
- Robaxin- similar to metaxalone
- ADR- Itching, rash, GI upset, nystagmus, vertigo, blurred vision, arrhythmia, hypotension, leucopenia
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Orphenadrine
- Norflex- relieve pain and discomfort caused by strains, sprains, and other muscle injuries with its analgesic properties
- ADR- Syncope, dry mouth, blurred vision, arrhythmia, hypotension, leucopenia, liver toxicity
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Antispasmodics for Irritable Bowel Syndrome (GI tract smooth muscle)
- Nonspecific Antagonists of Muscarinic Receptor
- Tertiary amine
- - Dicyclomine (Bentyl)
- - Hyoscyamine (Levsin)
- Quaternary ammonium compounds
- - Glycopyrrolate (Robinul): less CNS side effects
- - Methscopolamine (Pamine): less CNS side effects
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NEUROMUSCULAR BLOCKING DRUGS
- Prototype drug- d-tubocurarine and succinylcholine
- Receptor target of neuromuscular blocking drugs- Muscular Nicotinic Acetylcholine Receptors
- Antagonist blocking (non-depolarizing neuromuscular blocking)
- - Rocuronium (steroid derivatives)
- - Atracurium- metabolite Laudanosine may cause seizures (monitoring)
- - Mivacurium- Shortest duration of action
- - INC histamine release (hypotension, flushing, and bronchospasm)
- Agonist blocking- excess of depolarization (succinylcholine, AChE inhibitor)
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