Cholinergic Transmission, Muscle Relaxants

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Cholinergic Transmission, Muscle Relaxants
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Parasympathetic Nervous System ( Craniosacral
System)

• mediator of parasympathicus acetylcholine
• learning, memory (cognitive f.), motoric f.
• Deficiency in CNS
• Alzheimers disease,
• Parkinsons disease

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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

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Degradation of Ach

• acetate choline
• Ach esterase synapsis
• Butyrylcholinesterase plasma, tissues
• (atypic form of BCh esterase ? activity !!!)

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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

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Parasympathomimetics

• organophosphates
• ? ireversible covalent bond to Ach esterase,
  cummulation of Ach
• ? insecticides, chemical weapons (Sarin,
  Tabun)
• ? ? resorption through mucosa skin
• ? ? lipophilia ? penetration to CNS

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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)

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Indirect Parasympathomimetics in Alzheimers
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

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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 !!!

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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)

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Parasympatholytics

• 2. With quarter nitrogen dont 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)

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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 !!!

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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

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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 Hoffmanns
  elimination (independently from kidney and liver
  function)
• pancuronium action till 60 min.

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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 !!!

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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

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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

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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)

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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