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