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Chol i nerg ic Transmission, Muscle Relaxants

Chol i nerg ic Transmission, Muscle Relaxants. Chol i nerg ic Transmission. CNS neuromuscular junction ganglia of the autonomic nervous system (sympathetic and parasympathetic) postganglionic parasympathetic neurons. Parasympathetic Nervous System (= Craniosacral System).

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Chol i nerg ic Transmission, Muscle Relaxants

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  1. Cholinergic Transmission, Muscle Relaxants

  2. Cholinergic Transmission • CNS • neuromuscular junction • ganglia of the autonomic nervous system (sympathetic and parasympathetic) • postganglionic parasympathetic neurons

  3. Parasympathetic Nervous System (= Craniosacral System) • mediator of parasympathicus = acetylcholine • learning, memory (cognitive f.), motoric f. • Deficiency in CNS: Alzheimer´s disease, Parkinson´s disease

  4. 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

  5. Degradation of Ach = acetate + choline • Ach esterase – synapsis • Butyrylcholinesterase – plasma, tissues (atypic form of BCh esterase = ↓ activity !!!)

  6. Cholinergic Transmission cholinomimetics direct inderect iAchE muscarinic nicotinic reversible ireversible

  7. 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

  8. Parasympathomimetics • organophosphates:  ireversible covalent bond to Ach esterase, cummulation of Ach insecticides, chemicalweapons (Sarin, Tabun)  ↑ resorption through mucosa + skin  ↑ lipophilia = ↑ penetration to CNS

  9. 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)

  10. 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

  11. Cholinergic Transmission parasympatholytics 3´nitrogen 4´nitrogen oxybutine butylskopolamine solifenacine ipratropium atropine homatropine skopolamine

  12. 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 !!!

  13. 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)

  14. 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)

  15. Muscle Relaxants • Peripheral - acting on the neuromuscular plate a. non-depolarizingb. depolarizing • Central

  16. kurare - tubokurarine

  17. Muscle Relaxants = relaxation of skeletal muscles structure similar to Ach, peripheral + central • 1. Peripheral: 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 !!!

  18. 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

  19. 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.

  20. 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 !!!

  21. 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

  22. Botulotoxine cervical dystoniastrabismusblepharospasmushyperhidrosisspastic bladder

  23. 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

  24. 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)

  25. 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

  26. acetylcholine autonomous nervous system neuromuscular junction CNS ↑ Ach parasympathomimetics: glaucoma atony of the bladder, GIT ↑ Ach therapy of Alzheimer´s disease ↑ Ach myastenia gravis ↓ Ach parasympatholytics: Spasmolytics of GIT, bronchi, urogenital tract ↓ Ach periferal muscle relaxants, intoxication with organophosphates ↓ Ach therapy of Parkinson´s disease

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