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
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
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
synapsis
Butyrylcholinesterase – plasma, tissues
(atypic form of BCh esterase = ↓ activity !!!)
 Ach esterase –

Cholinergic Transmission
cholinomimetics
direct
muscarinic
inderect
iAchE
nicotinic
reversible
irreversible
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. irreversible = 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)
Cholinergic Transmission
parasympatholytics
3´nitrogen
atropine
homatropine
skopolamine
4´nitrogen
oxybutine
butylskopolamine
solifenacine
ipratropium
Parasympatholytics
= block muskarinic receptors
With 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
non-depolarising
b. depolarising
a.
 Centrally acting
plate
kurare - tubokurarine
Muscle Relaxants
= relaxation of skeletal muscles
structure similar to Ach, peripheral + central
1. Peripheral:
a. nondepolarising
• competitive blockade of nicotinic (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 – peripheral, non-depolarising
 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 – peripheral, non-depolarising
 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 – peripheral, depolarising
b. depolarising
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 – peripheral, depolarising
 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 – centrally acting
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 – centrally acting
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
neuromuscular
junction
↑ Ach
↑ Ach
therapy of
Alzheimer´s disease
↓ Ach
therapy of
Parkinson´s disease
parasympathomimetics:
glaucoma
atony of the bladder, GIT
↑ Ach
↓ Ach
↓ Ach
parasympatholytics:
Spasmolytics of GIT,
bronchi, urogenital tract
periferal muscle relaxants,
intoxication with
organophosphates
myastenia gravis