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Autonomic nervous system II.
MUDr. Martin Votava
Main functions
• contraction and relaxation of smooth
muscles
• function of all exocrine and some
endocrine glands
• heart beat
• some metabolic pathways
Homotropic and heterotropic inhibition
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•
•
Parasympatomimetics
Parasympatolytics
Drugs affecting autonomic ganglia
Cholinomimetics
• Effect similar to stimulation of
cholinergic nervous system
• Act on muscarinic (M) a nicotinic (N)
receptors
M1, M3, M5 receptors
muscarinic
receptor
M2, M4 receptors
muscarinic
receptor
Muscarinic and nicotinic (cholinergic)
receptors
Receptor
M1
M2
M3
M4
M5
NM
Localisation
Nerve fibres
Heart, nerve fibres,
smooth muscles
Glands, smooth muscles
CNS?
CNS?
Neuromuscular junction
NN
Ganglial receptors
G protein Effector
+
IP3, DAG
+
 cAMP
+
+
+
-
IP3, DAG
 cAMP
IP3, DAG
Opening of Na+/K+ ion
channel
Opening of Na+/K+ ion
channel and depolarisation
Stimulation of muscarinic receptor
Eye
Effect
Organ
m. sphincter pupillae
Contraction –miosis
m.ciliaris
Contraction- accommodation
Heart SA nodus
Atriums
AV nodus
Ventricules
Vessels
 frequency (neg. chronotropic)
 contractility (neg. inotropnic)
 conduction speed (neg. dromotropic)
 contractility (neg. inotropic)
Dilatation (EDRF) – NO
Airways
Bronchoconstriction
Glands
Stimulation
GIT
motility
Sfincters
increases
Glands secretion
increases
Vesica urinaria
Detrusor
Trigonum and sfinkter
Glands sweat, salivary, lacrimal,
nasopharyngeal
relaxation
Contraction
Relaxation
Secretion
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
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
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.
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
Acetylcholine effect
Pilocarpine
• tercial N atom - increased lipofility, cross HE
barrier and enters cornea
• M and N effect
• miosis and decreases intraocular pressure
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
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
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).
Indication
• postoperative and neurogenic ileus,
urinary retention.
• glaucoma (carbachol, pilokarpine).
Reversible (competitive) AChE inhibitors
Drug
Edrofonium
Effect
M, N
Physostigmine
M, N
Neostigmine
Pyridostigmine
M, N
M, N
Pharmacokinetics
Quartery amine, parenteral
administration, effect 5-15 min
Carbamates
Tercialy amine, per os admin., effect
0.5-2 h.
Quartery amine, effect 0.5-3 h.
Quartery amine, effect 4-8 h.
Indications
• Postoperative and neurogenic ileus, urinary
retention – neostigmine
• Glaucoma- physostigmine
• Myastenia gravis – neostigmine,
pyridostigmine, edrophonium
• Treatment of neuromuscular blocks
• Alzheimer disease
– rivastigmine, donezepil
Ireversible AChE inhibitors organphosphates
• M and N effect
– AChE activity 70% - mild intoxication
– AChE activity  30% - severe intoxication
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
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
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)
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
Atropine - competitive reversible inhibitor
dose
(mg)
0,5
1,0
2,0
5,0
>10,0
effect
bradycardia, xerostomia, sweating decrease
tachycardia, mydiasis
tachycardia, mydriasis, accommodation
disorders
worsening of previous effect, fatigue,
headache, obstipation, hot and dry skin,
swallowing problems
tachycaria, hot and red skin, ataxia,
excitation, hallucinations, delirium, coma
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
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
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
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
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)
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
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)
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)
Contraindications
glaucoma, (closed angle)
prosthatic hypertrophy
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
Ganglion-blocking drugs
• Interference with acetylcholine release
– Botulinum toxin, hemicholinium
• Prolonged depolarization
– Nicotine
• Competitive antagonist
– Hexamethonium, tetraethylamonium