Autonomic nervous system II.

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Autonomic nervous system II.

• MUDr. Martin Votava

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Main functions

• contraction and relaxation of smooth muscles
• function of all exocrine and some endocrine
  glands
• heart beat
• some metabolic pathways

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Homotropic and heterotropic inhibition
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AUTONOMIC NERVOUS SYSTEM II.

• Parasympatomimetics
• Parasympatolytics

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• Parasympatomimetics
• Parasympatolytics
• Drugs affecting autonomic ganglia

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Cholinomimetics

• Effect similar to stimulation of cholinergic
  nervous system
• Act on muscarinic (M) a nicotinic (N) receptors

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M1, M3, M5 receptors
muscarinic receptor
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M2, M4 receptors
muscarinic receptor
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Muscarinic and nicotinic (cholinergic) receptors
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Stimulation of muscarinic receptor
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Nicotinic effects

• Ganglial receptors
• Depends on autonomic stimulation. When
  sympathetic nervous system outweighs (vessels),
  then their stimulation stimulates sympathetic
  neurons.
• When parasympathetic system outweighs (heart,
  GIT), then their stimulation stimulates
  parasympathetic neurons.
• Adrenal medula - adrenalin and noradrenalin
  release
• Neuromuscular junction - spasms and convulsions
  of skeletal muscles

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Cholinomimetics

• 1. direct
• M receptor agonists
• N receptor agonists
• (most of them are nonspecific)
• 2. indirect (AChE inhibitors)
• short acting-edrofonium
• intermediate acting - carbamates
• long acting (irreversible blockers) -
  organophosphates

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Direct cholinomimetics

• Acetylcholine - direct endogenous
  cholinomimetics, which is released in
• sympathetic and parasympathetic ganglias
  (N-effects)
• postganglial parasympathetic neurons (M-effects)
• neuromuscular junction (N-effects)
• adrenal medula (N-effect, adrenaline secretion)
• CNS (N-effect)
• Very fast hydrolysis by acetylcholinesterase.

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Acetylcholine

• poor absorption p.o. and s.c., does not cross HEB
• rapid hydrolysis by AChE
• BP decrease, bradycardia, heart arrest
• sweating, salivation, lacrimation, glands
  secretion
• nauzea, cough, dyspnoe
• vessels dilatation EDRF (NO) release
• effect

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Pilocarpine

• tercial N atom - increased lipofility, cross HE
  barrier and enters cornea
• M and N effect
• miosis and decreases intraocular pressure

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Carbachol

• quartery N atom, does not cross HEB, resistance
  to AChE
• secretion GIT glands
• GIT muscles atonia
• miosis and decreases intraocular pressure
• CI - obstruction GIT

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Metacholine, betanechol

• quartery N atom, does not cross HEB, resistance
  to AChE
• GIT motility increasing, urinary retention after
  anesthesia or vagotomia
• examination of exocrine pancreas secretion
• CI - obstruction GIT

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Intoxication

• M receptors CNS stimulation, miosis,
  accommodation, dyspnoe, (bronchoconstriction,
  hypersecretion of bronchial glands), diarrhoea
  (hypermotility and hypersecretion), hypotension
  (vazodilatation), bradycardia.
• N receptors convulsions, BP increase (adrenal
  and ganglia N receptor stimulation).

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Indication

• postoperative and neurogenic ileus, urinary
  retention.
• glaucoma (carbachol, pilokarpine).

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Reversible (competitive) AChE inhibitors
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Indications

• Postoperative and neurogenic ileus, urinary
  retention neostigmine
• Glaucoma- physostigmine
• Myastenia gravis neostigmine, pyridostigmine,
  edrophonium
• Treatment of neuromuscular blocks
• Alzheimer disease
• rivastigmine, donezepil

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Ireversible AChE inhibitors - organphosphates

• M and N effect
• AChE activity 70 - mild intoxication
• AChE activity ? 30 - severe intoxication

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Toxicology importance

• agriculture - herbicids and pesticids
• chemical weapons tabun, sarin, soman (cross skin
  and mucos membranes)
• Intoxication - nausea, vomitus, cephalea,
  weakness, sweating, salivation, bradycardia,
  dyspnoe, breathing arrest
• Pharmacotherapy
• Very rare glaucoma echothiophtate
• scabies malathione

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Therapy of intoxication

• avoid absorption
• atropine - blocks muscarinic effects
• ventilation
• AChE reactivators- pralidoxime
• short acting AChE inhibitors - save AChE, which
  is not affected by poison

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Parasympatolytics

• tercial amonium basis (tercial amonium atom)
• natural alkaloids. Atropin (Atropa belladonna) or
  (Datura stramonium) and scopolamine (Hyosciamus
  niger).
• synthetic analogs - esterification of natural
  basis with organic acids
• Quartery amonium basis (quartery amonium atom)

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Pharmacokinetics

• absorption
• tercial basis - good GIT and corneal absorption
• Quartery basis - GIT absorption only 10-30
• distribution
• tercial basis - very wide distribution (HEB)
  after 1 hour - many CNS side effects
• Quartery basis - dont cross HEB

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Atropine - competitive reversible inhibitor
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CNS effects

• Antiemetic properties (scopolamine) - kinetosis,
  vestibular apparatus disorders
• tremor attenuation in Parkinson disease
  (Acetylcholine increased release)
• n. vagus center stimulation - bradycardia (after
  low doses of atropine), after high doses direct
  antimuscarinic effect - tachycardia

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Eye effect

• m. sphincter pupillae - inhibition of m.
  sfincter pupillae, m. dilatator pupillae indirect
  activation - mydriasis
• m. ciliaris paralysis - cycloplegia.
  accommodation attenuation
• cave - acute glaucoma attack
• lacrimation decrease

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GIT effect

• Attenuation of GIT motility (M receptors), then
  gland secretion
• Relaxation of GIT smooth muscles
• Contraction of sphincters, GIT paralyis
• Stomach secretion is attenuated after relatively
  high doses of parasympatolytics

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Termoregulation

• atropine attenuated sweating, one of the most
  important termoregulatory mechanism. It causes
  body temperature increase, but only after high
  doses. Children can have atropine fewer after
  lower doses of artropine

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Indications I.

• Parkinson disease, symptomatic therapy, (first
  line therapy are dopaminergic drugs)
• Kinetosis - scopolamine, transcutal form, (24-48
  h.), side effects
• Bradycardia
• Eyes
• mydriasis for diagnostic examination
• synechia prevention when inflammation is present
  (uveitis, iritis)

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Indications II.

• Gastrointestinal disorders (Quartery bases)
• peptic ulcer disease. (Antimuscarinic effect to
  the parietal cells - pirenzepine, poldine)
• spasmolytics - GIT - urolithiasis, cholelythiasis
• diarrhoea with cramps (combination with opiates)
  (e.g. atropine with diphenoxylate REASEC)
• bronchodilatation and inhibition of secretion
• asthma bronchiale therapy ipratropium
  (ATROVENT), or combination with fenoterole
  (BERODUAL)
• sweating

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Indications III.

• therapy of AChE irreversible inhibitors poisoning
  (organophaosphates). Atropinsulphate in high
  doses(1-2 mg) i.v. after 5-15 min. until atropine
  side effect are present (dry mouth, miosis)
• Mushroom poisoning
• Amanita muscarina - after 30 - 60 minutes -
  nausea, vomitus, diarrhoea, tachycardia,
  sweating, salivation, bronchoconstriction -
  atropine (1-2 mg parenteral)

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Side effects

• peripheral - dry skin, tachycardia, mydriasis,
  cycloplegia
• Stimulation, CNS excitation (hallucinations,
  delirium, convulsions, coma)
• Warm and red, dry skin, increased body
  temperature
• Quartery bases - mostly antimuscarinic affects,
  minimal central effects
• Antinicotinic effects - hypotension
• Therapy - neostigmine, sympatomimetics
  (fenylefrine)

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Contraindications

• glaucoma, (closed angle)
• prosthatic hypertrophy

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Drugs affecting autonomic ganglia

• Ganglion stimulants
• (acetylcholine)
• Nicotine (drug of abuse)
• Lobeline (found in tabacco leaves as well)
• Dimethylphenylpiperazinium (DMPP)
• Tetramethylamonium
• Used as experimental tools

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Ganglion-blocking drugs

• Interference with acetylcholine release
• Botulinum toxin, hemicholinium
• Prolonged depolarization
• Nicotine
• Competitive antagonist
• Hexamethonium, tetraethylamonium