Cholinergic Transmission, Muscle Relaxants

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

kurare - tubokurarine

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

Botulotoxine

cervical dystonia

strabismus

blepharospasmus

hyperhidrosis

spastic bladder

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