IPAP 3-17 Pharm 2 Mod 1-1- Skeletal Muscle Relaxants

CNS DEPRESSANTS- ORPHENADRINE (Norflex) MOA: ***- Analog of diphenhydramine - ANTIHISTAMINE and ANTICHOLINERGIC properties - EUPHORIGENIC (opioid-like) and ANALGESIC properties; full mechanism is unknown Clinical Use: - Treatment of MUSCLE SPASMS associated with ACUTE PAINFUL MUSCULOSKELETAL conditions

Adverse Effects: ***- ANTICHOLINERGIC effects: dry mouth (1st to appear); tachycardia, urinary hesitancy or retention, blurred vision, nausea/vomiting, etc. - High risk for CONFUSION IN ELDERLY Contraindications: - GLAUCOMA, pyloric or duodenal obstruction, stenosing peptic ulcers - PROSTATIC HYPERTROPHY or obstruction of the bladder neck - MYASTHENIA GRAVIS

CENTRAL A2 AGONIST- TIZANIDINE (Zanaflex) MOA: ***- CENTRALLY ACTING A2 AGONIST (~clonidine) ***- REDUCES SPASTICITY by INCREASING PRESYNAPTIC INHIBITION OF MOTOR NEURONS - 1/10 to 1/15 of the blood pressure lowering ability as clonidine (DROPS BP) Clinical Use: ***- MUSCLE SPASTICITY ***- SHORT ACTING agent

Adverse Effects: ***- DROWSINESS is the most PROMINENT adverse effect • Start low and titrate the dose up (2mg TID) - Dry mouth ***-HYPOTENSION - asthenia, hepatoxicity - MUST ADJUST DOSAGE for patients with HEPATIC or RENAL IMPAIRMENT

CNS DEPRESSANTS- CYCLOBENZAPRINE (Flexeril) MOA: ***Structurally related to tricyclic antidepressants (TCA) ***CAUSES DEPRESSANT effect on SEROTONERGIC neurons ***STRONG ANTICHOLINERGIC and ANTIHISTAMINE properties Clinical Use: - Acute local MUSCLE SPASMS; use as adjunctive treatment with physical therapy ***- INEFFECTIVE in treating muscle spasm DUE to CEREBRAL PALSY OR SPINAL CORD INJURY ***- LOWER doses (5mg) have show SAME efficacy as 10mg dose Precaution: - CAN LOWER SEIZURE THRESHOLD, especially in combination with TRAMADOL (Ultram)

Adverse Effects: ***- Drowsiness (39% of patients), - ANTI-MUSCARINIC effects; dry mouth, urinary retention, transient visual hallucination, increased intraocular pressure, etc. ***- SEROTONIN SYNDROME - CAUTION combining with ALCOHOL and OTHER CNS depressants - High risk for CONFUSION IN ELDERLY Contraindications: ***- Myocardial Infarction - Cardiac conduction defects ***- Patients receiving MAO-INHIBITORS Pregnancy: Adverse events HAVE NOT been observed in animal reproduction studies

CNS DEPRESSANTS- CARISOPRODOL (Soma) C-IV (CONTROLLED) MOA: ***- BLOCKS INTERNEURONAL activity ***- DEPRESSES POLYSYNAPTIC NEURON TRANSMISSION ***- METABOLIZED TO MEPROBAMATE, which has ANXIOLYTIC and SEDATIVE EFFECTS Clinical Use: - Relief of discomfort associated with acute, PAINFUL MUSCULOSKELETAL conditions in adults ***- USED SHORT TERM (2-3 weeks) •No evidence for prolonged use has been established

Adverse Effects: ***- MEPROBAMATE (active metabolite) CAUSES physical and psychological DEPENDENCE ***- WITHDRAWL symptoms may occur - Sedation, dizziness, headache, seizures (reported in overdose setting) ***- CAUTION combining with ALCOHOL and other CNS depressants - High risk for CONFUSION IN ELDERLY Pregnancy: - adverse events HAVE been observed in animal reproduction studies

OTHER ANTISPASTIC AGENT- DANTROLENE SODIUM (Dantrium, Rynodex) MOA: ***- REDUCES SKELETAL MUSCLE STRENGTH by INTERFERING with EXCITATION-CONTRACTION COUPLING in MUSCLE FIBERS Clinical Use: - IV: DOC in the treatment of MALIGNANT HYPERTHERMIA(MH) - ORAL: CHRONIC SPASTICITY resulting from UPPER MOTOR NEURON disorders (eg. Spinal cord injury, stroke, cerebral palsy, or MS) - NOT indicated for skeletal muscle spasm resulting from RHEUMATIC DISORDERS (i.e., Chorea, Rheumatic Fever) (does not cross CNS)

Adverse Effects: ***- MUSCLE WEAKNESS - Sedation - Slight risk of hepatotoxicity • Monitor LFTs • AVOID in symptomatic HEPATITIS GOOD INFO TO KNOW Rynodex Vs. Dantrium - *MH dose is 2.5mg/kg • Repeat PRN up to cumulative 10mg/kg - *Typical adult patient: 64kg (160mg dose) - Dantrium vial is 60mL - Rynodex vial is 5mL - Fastest time to admin: • Dantrium 15-20min • Rynodex 1min

CNS DEPRESSANTS- METAXALONE (Skelaxin) MOA: - unknown ***- GENERAL DEPRESSION of the NERVOUS SYSTEM Clinical Use: - RELIEF of discomforts associated with acute, PAINFUL MUSCULOSKELETAL conditions ***- CAUSES LESS DROWSINESS than others

Adverse Effects: ***- SEROTONIN SYNDROME - Nausea, gastrointestinal upset, sedation, dizziness, headache, anxiety, or irritability - CAUTION combining with ALCOHOL and other CNS depressants - High risk for CONFUSION IN ELDERLY

CNS DEPRESSANTS- METHOCARBAMOL (Robaxin) MOA: - unknown ***- SUPPRESSES SPINAL POLYSYNAPTIC REFLEXES Clinical Use: - Adjunctive treatment of MUSCLE SPASM associated with acute painful musculoskeletal conditions ***- TX MUSCLE SPASTICITY OF TETANUS (toxin) POISONING

Adverse Effects: ***- URINE DISCOLORATION (BLK/BRN/GREEN) ***- DROWSINESS - CAUTION combining with ALCOHOL and other CNS depressants - High risk for CONFUSION IN ELDERLY Contraindications: - IV formulation in patients with RENAL IMPAIRMENT - CAUTION in HEPATIC IMPAIRMENT

GABA AGONIST- BACLOFEN (Lioresal) MOA: ***- ORALLY ACTIVE GABA-MIMETIC agent at the level of the SPINAL CORD ***- PRESYNAPTIC INHIBITION by REDUCING Ca2+ influx and REDUCES the release EXCITATORY TRANSMITTERS in both the BRAIN and SPINAL CORD ***- May also reduce pain in patients with SPASTICITY by INHIBITING the RELEASE of SUBSTANCE P in the SPINAL CORD Clinical Use: - ANTI-SPASTIC agent ***- DOC for Multiple Sclerosis (MS) - At least as effective as DIAZEPAM in reducing SPASTICITY and causes LESS SEDATION - Does NOT REDUCE overall muscle strength

Adverse Effects: - Drowsiness (patients become tolerant to the sedative effect with chronic administration), nausea, confusion ***- INCREASED SEIZURE ACTIVITY reported in EPILEPTIC patients, therefore WITHDRAWAL SLOWLY

Botulinum Toxin Injection Products Clinical Use Non-cosmetic: ***- Chronic migraines (headache ≥15 d/mo x 3 mo; ≥8 headaches/mo are migraines w/o aura) •Only evidence for onabotulinumtoxinA as a second-line agent - Cervical dystonia and blepharospasm: no recommendation for which product to use - Multiple other off-label uses

Adverse Reactions: - Long-acting agents: 12-16 weeks - Hypersensitivity, localize pain at injection site, tenderness, and swelling - Can be used as a biological weapon, botulinum causes respiratory paralysis Antidote: ***- EQUINE BOTULINUM ANTITOXIN

ANTISPASTIC/ ANTISPASMODIC/ NEUROMUSCULAR AGENTS Antispastic Agents: - reduce muscle cramping and tightness in NEUROLOGICAL disorders and SPINAL CORD injury and disease *2 TYPES - CENTRAL AND PERIPHERAL ACTING Centrally acting: - ALL EXCEPT Dantrolene & Botulinum Toxin A are • DO NOT alter the function of the NICOTINIC-muscle receptors OR the SKELETAL MUCLE FIBERS Peripherally acting: - ONLY Dantrolene and Botulinum Toxin A act

Antispasmodic Agents: - used in treatment of SMOOTH MUSCLE DISORDERS, such as irritable bowel syndrome ***- ALL Centrally and Peripherally acting Neuromuscular Blocking Agents: - used in ANETHESIA to STOP all movements of SKELETAL MUSCLES ***- ONLY Peripherally Acting

Botulinum Toxin Injection Products - OnabotulinumtoxinA (Botox, Botox Cosmetic) MOA: - INHIBITS the release of ACETYLCHOLINE from CHOLINERGIC nerve fibers at NEUROMUSCULAR JUNCTIONS - Produced by the bacteria clostridium botulinum » Botulism is a rare but serious paralytic illness » Poisoned victim becomes gradually weaker as nerves lose their ability to stimulate muscle contraction - Symmetric descending FLACCID PARALYSIS of MOTOR and AUTONOMIC NERVES, ALWAYS beginning with CRANIAL NERVES » Double vision, blurred vision, eyelids droop, slurred speech, the head sags, the legs lose their ability to support one's body, breathing stops (cause of death)...but the wrinkles disappear!

Botulinum toxin type A: - MOST COMMON use is for COSMETIC APPLICATION - AbobotulinumtoxinA (Dysport) - IncobotulinumtoxinA (Xeomin) - OnabotulinumtoxinA (Botox, Botox Cosmetic) Botulinum toxin type B: - RimabotulinumtoxinB (Myobloc) MOA: - Derived from neurotoxins produced by Clostridium botulinum (bacterium responsible for botulism) - Inhibits release of acetylcholine from peripheral nerve cells into neuromuscular junctions

GABA AGONIST- DIAZEPAM (Valium) C-IV (CONTROLLED) MOA: ***- BIND TO SPECIFIC HIGH AFFINITY SITES on the CELL MEMBRANE separate but ADJACENT to the GABA RECEPTOR (allosteric binding) ***- ENHANCEMENT of the INHIBITORY effect of GABA on NEURONAL EXCITABILITY (increase chloride influx) ***• Diazepam is an ANZIOLYTIC that CAN also be used as a SPASMOLYTIC: exerts both antispasmodic and antispasticity actions • At HIGH doses, the benzodiazepines RELAX the SPASTICITY of SKELETAL MUSCLE, probably by INCREASING PRESYNAPTIC INHIBITION in the SPINAL CORD where the α2 GABA-A receptors are largely located

Clinical Use: ***- Oral formulation used in CEREBRAL PALSY, multiple sclerosis(MS), temporary muscle spasms (of any origin) ***- Management of ANXIETY DISORDERS - symptomatic relief of agitation, tremor, and acute delirium in ALCOHOL WITHDRAWAL Adverse Effects: - Drowsiness, fatigue, muscle weakness and ataxia (most common) - Combining with other CNS depressant agents will increase the risk of CNS effects - DEPENDENCE and TOLERANCE Pregnancy Category: D

ANALOG OF GABA- GABAPENTIN (Neurontin) MOA: ***- INHIBITION of voltage-dependent CALCIUM channels ***- An analog of GABA, but DOES NOT directly impact GABA RECEPTOR Clinical Use: ***- Generalized TONIC-CLONIC SEIZURES ***- NEUROPATHIC PX ***- POST HERPETIC NEURALGIA PX ***- DIABETIC NEUROPATHY (off-label)

Pharmacokinetics: - eliminated renally; adjustments may be necessary for renal dysfunction and hemodialysis Adverse Effects: - minimal side effects - Drowsiness, fatigue, dizziness, headache, - WEIGHT GAIN, and tremor during initiation Gabapentin Enacarbil (Horizant): - PRODRUG for gabapentin and is indicated for POST HERPETIC NEURALGIA and RESTLESS LEG SYNDROME ***- NOT FOR EPILEPSY

GABA DERIVATIVE- PREGABALIN (Lyrica) C-V (CONTROLLED) MOA: ***- INHIBITION of voltage-dependent CALCIUM channels. - GABA derivative SIMILAR to gabapentin Clinical Use: ***- Partial-onset seizure (adjunct) ***- Non-epileptic: neuropathic pain associated with DIABETIC NEUROPATHY ***- restless leg syndrome, post-herpetic neuralgia, fibromyalgia, pain due to spinal cord injury, social phobia

Pharmacokinetics: - eliminated renally; adjustments may be necessary for renal dysfunction and hemodialysis Adverse effects: - Drowsiness/fatigue greater than gabapentin - Sexual dysfunction, - DIZZINESS, WEIGHT GAIN, edema, angioedema, creatine kinase elevations - Insomnia, nausea, headache, diarrhea reported after abrupt discontinuation

- Onset of action of RIMABOTULINUMTOXIN B appears to be FASTER than that of onabotulinumtoxinA • OnabotulinumtoxinA provides LONGER duration of EFFICACY than rimabotulinumtoxinB • Injection pain is LESS with onabotulinumtoxinA than with rimabotulinumtoxinB

• RimabotulinumtoxinB is generally used in CERVICAL DYSTONIA ONLY • AbobotulinumtoxinA may DIFFUSE MORE EXTENSIVELY in the TISSUE than onabotulinumtoxinA • IncobotulinumtoxinA and onabotulinumtoxinA have similar properties and potency

CNS Depressants: - Cyclobenzaprine (Flexeril) - Orphenadrine (Norflex) - Carisoprodol (Soma) - Metaxalone (Skelaxin) - Methocarbamol (Robaxin) •Central α2 Agonist (pre-synaptic) - Tizanidine (Zanaflex)

•GABA Agonists - Baclofen (Lioresal) - Diazepam (Valium) Covered in GI section - Dicyclomine - Hyoscyamine