Cholinergic Transmission, Muscle Relaxants
Parasympathetic Nervous System (= Craniosacral System) • mediator of parasympathicus = acetylcholine • learning, memory (cognitive f.), motoric f. • Deficiency in CNS: Alzheimer´s disease, Parkinson´s disease
Receptors for Ach • muskarinic:M1 = CNS, ganglions, stomach M2 = heart M3 = glands, smooth muscles M4,5 = CNS • nicotinic:NM (muscular) = neuromuscular junction NN (neuronal) = veg. ganglions
Degradation of Ach = acetate + choline • Ach esterase – synapsis • Butyrylcholinesterase – plasma, tissues (atypic form of BCh esterase = ↓ activity !!!)
Parasympathomimetics = stimulation of muscarinic recept. • 1. Direct:metacholine, carbachol, pilocarpine (locally: therapy of glaucoma) • 2. Indirect: inhibitors of Ach esterase a. reversible = neostigmine, pyridostigmine (myasthenia gravis, postoperational atonia of GIT and urinary bladder) b. ireversible = organophosphates
Parasympathomimetics • organophosphates: ireversible covalent bond to Ach esterase, cummulation of Ach insecticides, chemicalweapons (Sarin, Tabun) ↑ resorption through mucosa + skin ↑ lipophilia = ↑ penetration to CNS
Intoxication with Organophosphates = cholinergic syndrome:lacriamation, salivation, sweatting, diarrhoea, relaxation of sfincters, bradycardia, miosis, rhonchus, cyanosis, spasms, paralysis of breathing • therapy:rinse affected with water (gloves!!!), ensure vital functions, atropine + obidoxime i.v. as antidote as soon as possible !!! (reactivator of Ach esterase)
Indirect Parasympathomimetics in Alzheimer´s Demention Therapy • Deficiency of Ach in CNS • ↑ availability of Ach – reversible inhibitors of Ach esterase selectively in CNS (cognitives) • donepezil, rivastigmine, galantamine • only slowing progression of disease • ↓↓ efectivity atadvanced stage of disease
Parasympatholytics = block muskarinic receptors • 1. S tertial nitrogene:penetrate through HEB atropine:alkaloid (Atropa belladona, Durman), Ind.: premedication as antiemetic drug antidysrytmic drug – bradyarhyttmias mydriaticum – not suitable for ↑ effect on eye organophosphate poisoning KI : glaucoma !!!
Parasympatholytics • atropine poisoning:atropa belladona (black plants similar to bilberries) – dry red skin, dry mucosas, mydriasis, blurred vision, tachycardia, at children risk of spasms • therapy: symptomatic, prognosis usually good, in case of spasms at children diazepam 5 mg i.v. scopolamine: more sedative, patch homatropine: diagnostic mydriasis (advantage = short lasting effect)
Parasympatholytics • 2. With quarter nitrogen:don´t penetrate through HEB butylscopolamine: spasmolysis of smooth muscles of GIT and urogenit. tract (Ind.: colic pain, dysmenorea) oxybutynine: spasmolysis of smooth muscles of urinary bladder (Ind.: incontinence, hyperreflexion of detrussor, enuresis nocturna) ipratropium, tiotropium: select. bronchodilat. (Ind.: asthma, CHOPD, administration through inhalation)
Muscle Relaxants = relaxation of skeletal muscles structure similar to Ach, periférne + centrálne • 1. Periferally acting: a. nondepolarizing – competitive blockade of nikotinic (N) receptor on neuromuscular junction fast elimination (kidneys, ↓ liver) effect starts quickly, lasts about 1 hour after administration (i.v. injection, contin. infusion) always OT intubation !!!
Muscle Relaxants • muscle relaxation:mimic, chewing, oculomotory muscles, than head, neck, limbs, belly, at last diaphragma and intercostal muscles • Ind.: anestesiology (abdominal operations) • ADR:hypotension, tachycardia, release of histamine • interactions: potentiation of myorelaxation after inhalatory anesthetics and aminoglycosides • antidote: inhibitors of Ach esterase (neostigmine) + atropine
Muscle Relaxants • examples: atracurium, pancuronium, vecuronium, pipecuronium = less ADR as original d-tubocurarine (release of histamine, blockade of N recept. of veget. ganglions) • atracurium, cis-atracurium: spontaneous nonenzymat. cleavage through Hoffmann´s elimination (independently from kidney and liver function) • pancuronium: action till 60 min.
Muscle Relaxants • b. depolarizing – sukccinylcholine (suxamethonium) = depolarisation of neuromuscular junction, i.v. administration effect: fast and short (cca 5 min.) on the beginning fasciculations and spasms – always general anesthesia before administration !!! degradation =butyrylcholinesterase genet. defect of Bch esterase =long lasting paralysis of muscles and breathing no antidote – assisted breathing !!!
Muscle Relaxants • Ind.:short lasting manipulations (OT intubation, reposition of fractures and luxations, electroconvulsive therapy in psychiatry) • ADR: fasciculations, spasms, hypotension, bradycardia, ↑ intraocular pressure, hyperkalemia
Muscle Relaxants • 2. Centrally acting: act on the level of CNS + inhibition of polysynapt. spinal reflexes, through GABA (baclofen) Ind.: neurology, rheumatology (painful spasms of skeletal muscles), only symptomatic therapy !!! ADR:dose-dependent = sedation, fatigue, dizziness – be careful at older pac.!!! interactions: alcohol, benzodiazepines= ↑↑ ADR
Muscle Relaxants • examples: mefenoxalon, karisoprodol, tolperizon(the smallest suppressing effect) baclofen(acts through GABA neurotransmission, at abrupt discontinuation of treatment risk of spasms as rebound phenomenon) guaifenezin (also anxiolytic and expectorans) tetrazepam (benzodiazepine)
Dantrolen • inhibits Ca2+ ion release from sarkoplasmatic reticulum = suppression of muscle contraction, ↓ heat production • Ind.: malignant hyperthermia(rareserious complic. of general anesthesia, more after halothane and suxamethonium) malignant neurolept. syndrome(adjuvant treatment) • repeated i.v. injection
