Pharma

• Skeletal Muscle Relaxants


  Drugs that reduce skeletal muscle tone
• Learning outcomes


  • Identify skeletal muscle relaxants, their sites and mechanisms of action
  • Identify the main side effects of the skeletal muscle relaxants
  • Recognize malignant hyperthermia and the drugs used to control this condition
• Neuromuscular blockers


  • Depolarizing blockers
  • Competitive blockers
• Neuromuscular blockers


  • Aminoglycosides
  • Magnesium
  • Botulinum toxins
• Somatic nerve


  Site of action for skeletal muscle relaxants
• Skeletal muscle relaxants site of actions


  • Peripheral acting: neuromuscular blockers
  • Central acting: e.g. baclofen and diazepam
  • Direct acting: dantrolene
• Spasmolytics


  Relieve spasm
• Antispastic


  Relieve spasticity
• Spasm


  Muscle tone caused by musculoskeletal conditions as back and neck pain, tetanus and fibromyalgia
• Spasticity


  Muscle tone caused by spinal problems as cerebral palsy, multiple sclerosis, stroke, spinal cord injuries
• Spasm treated by


  • cyclobenzaprine
  • orphenadrine
• Spasticity treated by


  • baclofen
  • tizanidine
  • diazepam
  • dantrolene
  • botulinum toxin
• Mechanisms of centrally acting muscle relaxants


  • Reduce skeletal muscle tone by selective action on the cerebrospinal axis, without altering consciousness
  • Selectively depress spinal and supraspinal polysynaptic reflexes involved in regulation of muscle tone
  • Polysynaptic pathways in the ascending reticular formation which are involved in wakefulness are also depressed, though to a smaller extent
  • Cause sedation
  • No effect on neuromuscular transmission and on muscle fibers but reduce rigidity, upper motor neuron spasticity and hyperreflexia
• Classification of centrally acting muscle relaxants


  • Mephenesin congeners: mephenesin, carisoprodol, chlorzoxazone, metaxalone, methocarbamol
  • Benzodiazepines: diazepam, clonazepam, trizolam
  • GABA derivatives: baclofen, gabapentin, pregabalin
  • Central α2 agonists: tizanidine
• Mephenesin


  The first drug discovered as a muscle relaxant, not used clinically due to side effects
• Carisoprodol


  Carbamate derivative, for muscle spasm, mechanism unknown but may be due to CNS depression and alteration of pain perception, one metabolite is meprobamate (anxiolytic), sedative, anxiolytic, analgesic, side effects include drowsiness, dizziness, abuse
• Methocarbamol


  Carbamate derivative, for muscle spasm, mechanism similar to carisoprodol (CNS depression), less sedative and longer duration than mephenesin, can be given orally or IV (tetanus), combined with analgesics, side effects include dizziness, drowsiness, urine discoloration
• Chlorzoxazone (Myofen)


  Pharmacologically similar to mephenesin but with longer duration and better tolerated orally, mechanism unknown but works primarily in spinal cord and subcortical areas of the brain to inhibit multi-synaptic reflex arcs involved in producing and maintaining skeletal muscle spasm, combined with analgesics, side effects include dizziness, drowsiness, hepatotoxicity
• Orphenadrine (Norflex)


  Anticholinergic drug, closely related to diphenhydramine, the first agent used in Parkinson's disease, for muscle spasm, mechanism unknown but may be due to anticholinergic effect in brain stem, combined with analgesics, side effects include dry mouth, constipation, urine retention
• Cyclobenzaprine (Multi-Relax)


  Related to tricyclic antidepressants, has anticholinergic activity, mechanism unknown but may be due to 5-HT2 antagonism, for muscle spasm, side effects include dry mouth, drowsiness, fatigue, headache
• Diazepam (Valium)


  Benzodiazepine, generally anxiolytic, sedative, hypnotic, anticonvulsant and spasmolytic, enhances GABA (GABA A) transmission supraspinally, can be given orally or IV/IM, for muscle spasm and spasticity, more sedative action than muscle relaxation, particularly valuable in tetanus and spinal injuries
• Baclofen


  For muscle spasticity (cerebral palsy, multiple sclerosis, spinal cord injuries), can be given orally or intrathecally, GABA B agonist which depress both polysynaptic and monosynaptic reflexes in the spinal cord, side effects include hypotension and tachycardia
• Gabapentin, pregabalin


  Centrally acting muscle relaxants
• Tizanidine


  New skeletal muscle relaxant, congener of clonidine, for muscle spasm and spasticity, central alpha 2 agonist which inhibits release of excitatory amino acids like aspartate in the spinal interneurons, while facilitating the inhibitory amino acid glycine, inhibits polysynaptic reflexes, reduces muscle tone and frequency of muscle spasms without reducing muscle strength, effective orally, side effects include hypotension, sedation, dry mouth, hepatotoxicity
• Dantrolene


  Interferes with release of calcium from its stores in skeletal muscles (sarcoplasmic reticulum), affects excitation-contraction coupling, cardiac and smooth muscles are not affected, used in treatment of malignant hyperthermia, can be given IV or orally (absorption is slow and incomplete), penetrates the brain causing some sedation
• Therapeutic uses of skeletal muscle relaxants


  • Neurological spastic disorders (multiple sclerosis, cerebral palsy, spinal injury, hemiplegia and paraplegia)
  • Malignant hyperthermia
• Adverse effects of skeletal muscle relaxants


  • Muscle weakness (the dose limiting toxicity)
  • Sedation (less than centrally acting muscle relaxants)
  • Diarrhea
  • Liver toxicity (long term)
• Malignant hyperthermia


  Inability to bind calcium by sarcoplasmic reticulum in some patients due to genetic defect, autosomal dominant mutation of calcium channels RYR1, triggered by general anesthesia as halothane and neuromuscular blockers as succinylcholine, symptoms include increased calcium release, intense muscle spasm, severe rise in body temperature