Autonomic nervous system II.

1. Autonomic nervous system II. MUDr. Martin Votava

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

5. Homotropic and heterotropic inhibition

6. Parasympatomimetics Parasympatolytics Drugs affecting autonomic ganglia

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

8. M1, M3, M5 receptors muscarinic receptor

9. M2, M4 receptors muscarinic receptor

10. Muscarinic and nicotinic (cholinergic) receptors

11. Organ Effect Eye m. sphincter pupillae Contraction –miosis m.ciliaris Contraction- accommodation HeartSA 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 Stimulation of muscarinic receptor

12. 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

13. 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

14. 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.

16. 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

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

19. 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

20. 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

21. 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).

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

23. Reversible (competitive) AChE inhibitors

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

25. Ireversible AChE inhibitors - organphosphates • M and N effect • AChE activity 70% - mild intoxication • AChE activity  30% - severe intoxication

26. 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

27. 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

28. 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)

29. 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

30. Atropine - competitive reversible inhibitor

31. 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

32. 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

33. 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

34. 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

35. 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)

36. 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

37. 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)

38. 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)

39. Contraindications glaucoma, (closed angle) prosthatic hypertrophy

41. 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

42. Ganglion-blocking drugs • Interference with acetylcholine release • Botulinum toxin, hemicholinium • Prolonged depolarization • Nicotine • Competitive antagonist • Hexamethonium, tetraethylamonium