cholinergic transmission, muscle relaxants. cholinergic transmission cns neuromuscular junction...
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Cholinergic Transmission
• CNS
• neuromuscular junction
• ganglia of the autonomic nervous system (sympathetic and parasympathetic)
• postganglionic parasympathetic neurons
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 !!!)
Cholinergic Transmission
cholinomimetics
inderectiAchE
direct
muscarinic nicotinic reversible
ireversible
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, chemical weapons (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 at advanced stage of disease
Cholinergic Transmission
parasympatholytics
4´nitrogen3´nitrogen
atropinehomatropineskopolamine
oxybutinebutylskopolaminesolifenacineipratropium
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
• Peripheral
- acting on the neuromuscular plate
a. non-depolarizingb. depolarizing
• Central
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 !!!
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 (rare serious complic. of general anesthesia, more after halothane and suxamethonium)
malignant neurolept. syndrome (adjuvant treatment)
• repeated i.v. injection
acetylcholine
CNS autonomous nervous system
↓ Ach
therapy of Parkinson´s disease
↑ Ach
therapy of Alzheimer´s disease
↑ Ach
parasympathomimetics:glaucomaatony of the bladder, GIT
↓ Ach
parasympatholytics:Spasmolytics of GIT, bronchi, urogenital tract
↑ Ach
myastenia gravis
↓ Ach
periferal muscle relaxants,intoxication with organophosphates
neuromuscular junction