Skeletal Muscle Relaxants Relax skeletal muscle tone Two types: Spasmolytics Reduce abnormally elevated tone caused by neurological or muscle endplate disease Without paralysis Neuromuscular blockers Induce paralysis Blockade at the motor end plate

Spasmolytics Relax painful contractions/spasm of skeletal muscles During radicular syndrome, cerebral palsy, stroke, multiple sclerosis etc. Most act in CNS Benzodiazepines – tetrazepam, diazepam GABAB agonists – baclofen a2-agonists - tizanidine Antiepileptics – gabapentin – relax in multiple sclerosis ??? - mephenoxalone, tolperison, carisoprodol dantrolene Exception – blockade of ryanodine receptor in muscles reduces Ca release from sarcoplasmic reticulum Emergeny – i.v. - malignant hyperthermia Thiokolchikosid Malignant hyperthermia – general anesthesia, succinylcholine or tubocurarine

a2 Glu a2 Action potentials Postulated site of spasmolytic action of tizanidine (a2), benzodiazepines (GABAA), and baclofen (GABAB) in the spinal cord. Inhibitory interneuron Tizanidine Corticospinal pathway Baclofen a2 GABAB Glu GABA Motor neuron GABAB AMPA a2 Muscle GABAA Dantrolene Benzodiazepines Action potentials (according to Katzung BG et al: Basic and clinical pharmacology, 11th ed., 2009)

Inhibition of tonic output at spinal motoneurons Baclofen GABAB agonist Presynaptically Reduce Ca2+ influx – inhibition of glutamate release reduce motor impulse transmission Postsnaptically Inhibition of AP generation??

Spasmolytics - AE Benzodiazepines Baclofen Tizanidine Sedation Less sedative, dependence – withdrawal syndrome !! Reduce dose slowly after long term usage Tizanidine Dry mouth, hypotension, sedations Cyklobenzaprin pro akutní podání - neregistrován

Neuromuscular blockers Induce paralysis for surgical procedures etc. Skeletal muscle physiology Cholinergic tranmission at the end plate ACH released from presynaptic part NM – Na+ channels – depolarization NM blockade postsynaptic Nondepolarizing type – curare Depolarizing – succinylcholine Presynaptic Reduce ACH release Botulinum toxin, aminoglycosides some snake poisons - bungarotoxin

Nondepolarizing neuromuscular blocking drugs Competitive (surmountable) antagonists of Ach at NM receptors 70-80% receptor blocked - effect Cumulating ACH – reverses the blockade ACHE inhibitors – antagonize effect of relaxants Neostigmine, pyridostigmine Larger muscles more resistant Abdominal, diaphragm Recover more rapidly than small (facial, hand etc) kompetitivní antagonizmus vůči ACH na N receptorech - nedepolarizující, pachykurarové antagonista obsadí receptor (má k receptoru afinitu), ale není schopen navodit depolarizaci (chybí mu vnitřní aktivita). depolarizující, acetylcholine-like, leptokurarové. suxamethonium

Nondepolarizing - Pharmacokinetics, classification Large hydrophilic molecules i.v. administration necessary quarternary amonium bases – positive charged Poor permeation (BBB, placenta, GIT) Benzylisochinolines d-tubokurarin, gallamin mivacurium atracurium, cisatracurium Steroid molecule pancuronium, piperuconium rocuronium, vecuronium Cumulation in muscles during prolonged administration strukturou podobné Ach –

Nondepolarizing - Pharmacokinetics Elimination Unchanged by the kidneys (GF) tubokurarine Biotransformation in the liver  bile vecuronium, rocuronium Metabolized by pseudoChE in plasma Mivacurium Spontaneous decomposition in plasma atracurium, cisatracurium (used more now) !!! Elimination does not depend on function of liver or kidneys!!!

Nondepolarizing classification according duration of effect Long acting (1-2 h) tubokurarine, pancuronium a pipecuronium Medium (10 - 30 min) rocuronium, vecuronium, (cis-)atracurium, Short acting (< 15 min) mivacuronium Ultra-rapid onset of effect rocuronium Can replace succinylcholine Nevýhodou tubokurarinu je jeho schopnost nesensibilisovanou cestou uvolňovat histamin s následnou bronchokonstrikcí a hypotenzí.

AE – Nondepolarizing Respiratory paralysis Mechanical ventilation always required Histamine release from mast cells Especially benzylisochinoline congeners – mivacurium, atracurium Also succinylcholine bronchospasm, ↓ BP Autonomic ganglion blockade ↓ BP, tachycardia, prolong GIT atonia – tubocurarine – ex now Prolongation of myorelaxation during liver or renal impairment Better start with short acting drug Antidote: AChE inhibitor (neostigmin, i.v.) + atropin M- receptor antagonits to block neoastigmin AE

Depolarizing suxamethonium (succinylcholine) Partial agonist at NM receptors Effect – two phases 1st phase – depolarization NM receptor stimulation  depolarization of end plate contraction/fasciculations immediately after adm AChE inhibitors may potentiate Also decrease degradation of the drug 2nd phase – desenzitization - Depolarizing blockade loss of electric excitability of membrane Na+ channels blocked despite partial repolarization Mucsle relaxation Blockade may by alleviated (možné zmírnění inhibitory AChesterasy)...pachy

repolarizace nervosvalové ploténky depolarizace kontrakce repolarizace nervosvalové ploténky trvalá depolarizace nervosvalové ploténky rychlé štěpení Ach acetylcholinesterasou sukcinylcholin se acetylcholinesterasou nerozkládá může vzniknout nový AP a kontrakce vznik AP a kontrakce nejsou možné Sukcinylcholin buňka koster. svalu šíření akčního potenciálu

Suxamethonium Duration of effect - 5-10 min idiosyncrasy mtb pseudocholinesterase idiosyncrasy Even 3-6 h paralysis Genetically reduced activity – 1:2500 Therapy – fresh frosen plasma 10 donors – contain pseudocholinesterase ventilation O depolarisaci svědčí počáteční svalové fascikulace – dlouhodobě depolarizovaná postsynaptická membrána přestane reagovat (důvod nejasný) na přítomnost molekul ACH, což má za následek myorelaxaci. lze také vyčkat na spontánní odeznění myorelaxace za podpory umělé plicní ventilace

Suxamethonium - AE Acute Asphyxia/apnea - respiratory muscle paralysis Ventilation required ? Genetic cause? Prolonged paralysis Idiosyncrasy, newborns, liver diseases Prolonged postoperative muscle pain Sceletal muscle impairment – myoglobin release – due to fasciculation during 1st phase hyperkalemia  arrhythmias or even cardiac arrest Risk patients – with burns, injuries, sepsis, kidney failure, hypercalemia drugs Leak of K+ through ion channels from depolarized muscles bradycardia: Direct effect on M receptors ↑ intracranial, intraoccular pressure (KI: glaucoma), or intraabdominal ↑ risk of vomiting Malignant hyperpyrrexia caution: combination with halothane th: cooling, dantrolene K jejich prevenci je možno zvolit metodu prekurarisace, jež spočívá v podání malé dávky nedepolarisujícího myorelaxancia 3-5 min před aplikací suxamethonia.

Muscle relaxants - interactions AChE inhibitors slows degradation of suxamethonium  prolongation of effect Local anesthetics and antiarrhythmics of I. class In large doses they inhibit neuromuscular conduction Ca2+ channel blockers ↑ skeletal muscle blockade Amidoglykosides, magnesium salts Inhibition of Ach release Block Ca2+ entrance to presynaptic part th: administration of Ca2+ General anesthetic Potentiation by stabilization of membranes th: dosage correction prokain (kompetice o AChE)

Myorelaxants - clinics Nondepolarizing surgery After general anesthesia induction, ventilation required ↓ consuption of general anesthetics – reduced AE Depolarizing Rapid and short myorelaxation (3-5 min) Intubation, endoscopy, orthopedic manipulation, cesarean section Introduction to general anesthesia with consequent nondepolarizing myorelaxation Seizures/Jerks, th of intoxication with increased muscle tone etc. myastenia gravis diagnosis - nondepolarizing

Botulotoxine A Contains neurotoxin A Inhibits release of ACH Protein complex from Cl. botulinum Contains neurotoxin A Penetrate by endocytosis to nerv endings Increases proteasome degradation of SNAP25 – syntaxin complex botulotoxin B inhibits synaptobrevin (vesicular protein) Inhibits release of ACH Impairs attachement of vesicles to membrane Duration – weeks or even 3 M Function is restored by synthesis of new membrane proteins PK – slow absorption to circulation excretion by kidneys – without systemic effect I: blepharospasm, hemifacial spasm, tortikolis, reactive bladder, cosmetics i.m. or s.c. administration to site of action/spasms

Suxametonium - SPC výkony vyžadující krátkodobou relaxaci Tracheální intubace, zejména k tzv. bleskové intubaci, nekrvavé repozice, divulze análního svěrače, usnadnění sutury peritonea, laryngospazmus, relaxace při císařském řezu do vybavení plodu, kardioverze