•Centrally active •Spasmolytics • •Baclofen •Benzodiazepines: •Tetrazepam •Diazepam •Clonazepam •Thiocolchicoside •Mephenoxalone •Tizanidine •Guaifenesin •Orphenadrine • • • • •Peripherally active •Neuromuscular blockers • •Presynaptically active: botulinum toxin • •Postsynaptically active: •Depolarizing blocking agents (suxamethonium) • •Non-depolarizing blocking agents (atracurium, vecuronium, pancuronium etc.) Mechanism of action •Attenuate transmission of motoric impulses in spinal cord and CNS •Decrease muscle tone, do not influence intentional contractions → weaker muscle relaxant activity •AE: depression of CNS → sedation, somnolence, confusion… •Acute and chronic painful spasms – p.o., parenterally •Spastic rheumatism •Damage of n. ischiadicus (spasms of deep paravertebral muscles, compressions in intervertebral space etc.) •Spastic disorders associated with cerebral palsy, multiple sclerosis, injuries of brain or spine… •Mechanism of action: •Increase effects of inhibitory neurotransmitter γ-aminobutyric acid (GABA) in CNS and spine cord •Baclofen •Attenuates the activation of motor neurons in the spine cord •GABAB receptor agonist •Activation of GABAB receptors → opening of K+ channels → change in ion homeostasis → hyperpolarization, decrease of Ca2+ influx → inhibition of neurotransmitter release presynaptically •Multiple sclerosis, cerebral palsy, injuries of brain and spinal cord… • •Baclofen •Benzodiazepines: •Tetrazepam •Diazepam •Clonazepam •Thiocolchicoside •Mephenoxalone •Tizanidine •Guaifenesin •Orphenadrine • Psychiatric medication with 5 effects: Anxiolytic Hypnotic Muscle relaxant Anticonvulsant Amnestic Low doses have expectorant effect, Higher doses have muscle relaxant and anxiolytic effect MoA: Enhance of GABAergic transmission – GABAA receptors Influx Cl- = depolarizace = snížená schopnost excitace neuronu •Centrally active •Spasmolytics • •Baclofen •Benzodiazepines: •Tetrazepam •Diazepam •Clonazepam •Thiocolchicoside •Mephenoxalone •Tizanidine •Guaifenesin •Orphenadrine • • • • •Peripherally active •Neuromuscular blockers • •Presynaptically active: botulinum toxin • •Postsynaptically active: •Depolarizing blocking agents (suxamethonium) • •Non-depolarizing blocking agents (atracurium, vecuronium, pancuronium etc.) Mechanism of action •Influence neuromuscular junction •Inhibits impulse transmission to myofibrils: • •1.) Presynaptically active agents –Decrease ACh release –Botulinum toxin • •2.) Postsynaptically active agents –Act on nicotinic receptors (NM) •Non-depolarizing •Depolarizing •Firstly described in 15th century by european explorers in S. America •Used by natives as arrow poisons •Tubocurarine – natural alkaloid • •Competitive NM receptors antagonists •AE: release of histamine (bronchoconstriction, hypotension, syncope – fainting) •Progressive relaxation: eye muscles → muscles of mastication → neck and limbs → trunk → diaphragm •Administered parenterally •Effect weakens and is reversible – competition of receptors Účinek lze antagonizovat zvýšením hladiny ACh v ploténce – kompetice, účinek postupce slábne, je krátký Parenterální podání – mají N+ •With long effect (1-2 h): tubocurarine, pancuronium, pipecuronium, vecuronium •With short efect (10-30 min): alcuronium, atracurium • •Surgery – muscle relaxation in the operating field, or before mechanical ventilation (tracheal intubation) • •Ovedosing: antidote = acetylcholinesterase inhibitors (neostigmine, pyridostigmine…) •NM receptor agonists •Open Na+ channels → cause long-term depolarization → resistancy to activation by ACh = depolarization blockade •Remain on the receptor for a longer time, resistant to AChE •Fasciculation (muscle twitches) • → muscle relaxation (paralysis) •AE: cardiac arrhythmias, hyperkalemia, increase of intraocular pressure (IOP) + malignant hyperthermia ! •Decamethonium •Suxamethonium (succinylcholine) • •Short-term muscle relaxation (3-5 min) •Mechanical ventilation (tracheal intubation) •Orthopedic manipulations – repositiong of dislocated joint, fractures •Rare AE of depolarizing MR and/or volatile general anesthetics •Mechanisms: •Defect of RYR receptor – controls release of Ca2+ from sarcoplasmic reticulum •Increase of Ca2+ in myocyte → uncontrolled increase of contractions, aerobic/anaerobic metabolism •Symptoms: hyperthermia, cramps and rigidity, ↑ heart rate and breathing, cyanosis, lactate acidosis, rhabdomyolysis... •60 % of untreated cases are lethal (5 % of treated) •Therapy: dantrolene, intensive cooling Volatile GA triggering MH: halothan, sevoflurane, desflurane, isoflurane, enflurane •Peripherally active muscle relaxant •Blocks the release of Ca2+ from sarcoplasmic reticulum by interaction with RYR •Do not affect smooth muscle and myocardium • •Malignant hyperthermia •Spastic disorders associated with spinal cord injury, stroke, cerebral palsy and multiple sclerosis ‒Advantage: no CNS depression