autonomic nervous system ii
DESCRIPTION
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. Parasympatomimetics Parasympatolytics - PowerPoint PPT PresentationTRANSCRIPT
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
• 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 Localisation G protein Effector M1 Nerve fibres + IP3, DAG M2 Heart, nerve fibres,
smooth muscles + cAMP
M3 Glands, smooth muscles + IP3, DAG M4 CNS? + cAMP M5 CNS? + IP3, DAG NM Neuromuscular junction - Opening of Na+/K+ ion
channel NN Ganglial receptors - Opening of Na+/K+ ion
channel and depolarisation
Stimulation of muscarinic receptorOrgan Effect
Eye m. sphincter pupillae Contraction –miosis
m.ciliaris Contraction- accommodation
Heart SA nodus frequency (neg. chronotropic)
Atriums contractility (neg. inotropnic)
AV nodus conduction speed (neg. dromotropic)
Ventricules contractility (neg. inotropic)
Vessels Dilatation (EDRF) – NO
Airways Bronchoconstriction
Glands Stimulation
GIT motility increases
Sfincters relaxation
Glands secretion increases
Vesica urinaria
Detrusor Contraction
Trigonum and sfinkter Relaxation
Glands sweat, salivary, lacrimal, nasopharyngeal
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. directM receptor agonistsN receptor agonists
(most of them are nonspecific)
2. indirect (AChE inhibitors) short acting-edrofoniumintermediate acting - carbamateslong 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 Effect PharmacokineticsEdrofonium M, N Quartery amine, parenteral
administration, effect 5-15 minCarbamates
Physostigmine M, N Tercialy amine, per os admin., effect0.5-2 h.
Neostigmine M, N Quartery amine, effect 0.5-3 h.Pyridostigmine M, N 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)
effect
0,5bradycardia, xerostomia, sweating decrease
1,0tachycardia, mydiasis
2,0tachycardia, mydriasis, accommodationdisorders
5,0worsening of previous effect, fatigue,headache, obstipation, hot and dry skin,swallowing problems
>10,0tachycaria, 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