Muscle relaxants Spasticity characteristics: - Flexor muscle spasms - Elevated tonic stretch - Muscle weakness - Various CNS causes

GABA/Glycine agonists and analogues - Diazepam (valium) - BZ active at GABA A receptor, causes unwanted sedation - Baclofen (LIoreseal) - GABA - B agonist, closes Ca channels and opens NA ones presynaptic ally - Pregabide: not approved in US, GABA a and B agonist - Gabapentin: GABA analogue but doesn't affect GABA receptors, blocks Ca channels, anti epileptic, effective in MS spasticity - Glycine: not FDA approved, but many OTC supplements Other CNS acting muscle relaxants - Tizanidine: alpha 2 agonist action. Causes pre/postsynaptic inhibition with analgesic effects. Causes drowsiness, hypotension, dry mouth - Riluzole: glutamate release blocker for ALS Tx Dantrolene: peripherally active muscle relaxant - Blocks calcium release from SR, inhibits muscle contraction, almost no effect on cardiac/SM - Adverse effects: muscle weakness, sedation - Good for malignant hyperthermia which as massive Ca release esp during anesthesia Acute local muscle spasm - Botox: blocks vesicular release of Ach., flaccid paralsys good for cerebral palsy - Cyclobenzaprine: 5HT2 receptor block, relieves local spasm from tissue trauma,/muscle straine. Not useful for spinal injury or CP Conclusions - only FDA approved: diazepam, baclofen, tizantidine, Dantrolene - Riluzole good for ALSO - All are centrally cating ectp for Dantrolene Idirect muscle action) andBotox -

Spasmolytic: drug that reduces abnormally elevated muscle tone (spasm) without paralysis Subclass Mechanism of Action Receptor Interactions Pharmacokinetics Adverse Effects

Subclass Depolarizing Succinylcholine

Mechanism of Action Agonist at AChN receptors causing initial twitch then persistent depolarization
Competitive antagonists at skeletal muscle ACh-N receptors

Receptor Interactions Stimulates ANS ganglia and M receptors

Pharmacokinetics

Adverse Effects

Parenteral: short Muscle pain, action, inactivated hyperkalemia, by plasma esterases increased intragastric and intraocular pressure
Parenteral use, variable disposition Spontaneous inactivation (atracurium, cisatracurium) Plasma ChE (mivacurium) Muscle relaxation is potentiated by Hepatic metabolism (rocuronium, vecuronium) inhaled anesthetics, aminoglycosides and possibly Renal elimination quinidine (doxacurium, pancuronium, tubocurarine) Histamine release (mivacurium, tubocurarine) Laudanosine formation (atracurium)

Nondepolarizing
D-Tubocurarine Atracurium Cisatracurium Mivacurium Rocuronium Vecuronium ANS ganglion block (tubocurarine) Cardiac M block (pancuronium)

Centrally acting Baclofen Facilitates spinal inhibition of motor neurons GABAB receptor activation: preand postsynaptic Mechanism unknown Oral and intrathecal Sedation, for severe spasticity muscle weakness

Cyclobenzaprine Inhibition of (many others; see spinal stretch text) reflex Diazepam

Oral for acute muscle spasm due to injury or inflammation Oral and parenteral for acute and chronic spasms

M block, sedation, confusion, and ocular effects Sedation, additive with other CNS depressants abuse potential

Facilitates GABAA receptor GABA-ergic activation transmission in postsynaptic CNS

Tizanidine

Pre- and postsynaptic inhibition

Oral for acute and Agonist in 2 chronic spasms spinal cord

Muscle weakness, sedation,

Subclass

Mechanism of Action

Receptor Interactions

Pharmacokinetics

Adverse Effects hypotension

Direct-acting Dantrolene Weakens muscle contraction by reducing myosin-actin interaction

Blocks RyR1

Oral for acute and chronic spasms IV for malignant hyperthermia

Blocks RyR1 Ca2+ channels in skeletal muscle

Muscle weakness

Skeletal muscle relaxants

Neuromusclar blockers

Spasmolytics

Nondepolarzing

Depolarizing (succinylcholine)

Chronic use

Acute use (cyclobenzaprine)

Long action (tubocurarine)

Short action (mivacurium)

CNS action (baclofen, diazepam, tizanidine)

Muscle action (dantrolene)

I. Subclass

Skeletal Muscle Relaxants Mechanism of Action Effects Clinical Applications Pharmacokinetics, Toxicities, Interactions

DEPOLARIZING NEUROMUSCULAR BLOCKING AGENT Succinylcholine Agonist at nicotinic (ACh) receptors, Initial depolarizatio n causes transient Placement of Rapid metabolism by endotracheal tube plasma cholinesterase at start of normal duration, anesthetic

especially at contractions, neuromuscula followed by r junctions prolonged flaccid depolarizes may stimulate ganglionic nicotinic ACh and cardiac muscarinic ACh receptors dTubocurarine Competitive antagonist at nACh receptors, especially at neuromuscula r junctions paralysis depolarizatio n is then followed by repolarization that is also accompanied by paralysis

procedure ~5 min Toxicities: rarely, control of Arrhythmias muscle hyperkalemia contractions in status epilepticus transient increased intraabdominal, intraocular pressure postoperative muscle pain

NONDEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS Prevents Prolonged depolarizatio relaxation for n by ACh, surgical causes flaccid procedures paralysis superseded by can cause newer histamine nondepolarizing release with agents hypotension weak block of cardiac muscarinic ACh receptors Cisatracurium Similar to tubocurarine Like tubocurarine but lacks histamine release and antimuscarini c effects Prolonged relaxation for surgical procedures relaxation of respiratory muscles to facilitate mechanical ventilation in intensive care unit Not dependent on renal or hepatic function duration, Renal excretion duration, ~4060 min Toxicities: Histamine release hypotension prolonged apnea

~2545 min Toxicities: Prolonged apnea but less toxic than atracurium

Rocuronium

Similar to Like Like cisatracurium cisatracurium cisatracurium but slight

Hepatic metabolism duration, ~2035

antimuscarini c effect

useful in min Toxicities: patients with Like cisatracurium renal impairment

Mivacurium: Rapid onset, short duration (1020 min); metabolized by plasma cholinesterase Vecuronium: Intermediate duration; metabolized in liver CENTRALLY ACTING SPASMOLYTIC DRUGS Baclofen GABAB agonist, facilitates spinal inhibition of motor neurons Pre- and postsynaptic inhibition of motor output Severe spasticity due to cerebral palsy, multiple sclerosis, stroke Oral, intrathecal Toxicities: Sedation, weakness

Cyclobenzaprin Poorly e understood inhibition of muscle stretch reflex in spinal cord

Reduction in hyperactive muscle reflexes antimuscarini c effects

Acute spasm due to muscle injury inflammation

Hepatic metabolism duration, ~46 h Toxicities: Strong antimuscarinic effects

Chlorphenesin, methocarbamol, orphenadrine, others: Like cyclobenzaprine with varying degrees of antimuscarinic effect Diazepam Facilitates GABAergic transmission in central nervous system Increases interneuron inhibition of primary motor afferents in spinal cord central sedation Tizanidine Presynaptic 2and Adrenoceptor postsynaptic agonist in the inhibition of spinal cord reflex motor output Chronic spasm Hepatic metabolism due to cerebral duration, ~1224 palsy, stroke, spinal cord injury h Toxicities: See acute spasm Chapter 22 due to muscle injury

Spasm due to Renal and hepatic multiple sclerosis, elimination stroke, amyotrophic duration, 36 h lateral sclerosis Toxicities: Weakness, sedation hypotension

DIRECT-ACTING MUSCLE RELAXANT

Dantrolene

Blocks RyR1 Ca2+-release channels in the sarcoplasmic reticulum of skeletal muscle

Reduces actin-myosin interaction

IV: Malignant hyperthermia

IV, oral

duration,

Toxicities: Oral: Spasm 46 h Muscle weakness weakens due to cerebral skeletal palsy, spinal cord muscle injury, multiple contraction sclerosis