Functional divisions within the nervous system

1. Autonomic nervous systemCholinergic agonists (CHOLINOMIMETICS) Cholinergic antagonists (CHOLINOBLOCKERS)

2. Functional divisions within the nervous system

3. Efferent neurons of the autonomic nervous system

4. Sympathetic and parasympathetic actions

5. Sympathetic ANS • The 1st neuron of sympathetic division is located in the thoracolumbar region of the spinal cord (T1-L3) and the 2nd is disposed either in the paravertebral, or in the prevertebral ganglia. Postganglionic non-myelinated nerve fibres arising from neurones in the ganglia, innervate most organs of the body • The neurotransmitter released by sympathetic nerve endings is noradrenaline.

6. Parasympathetic system • The 1st neuron of parasympathetic system is located in the brain stem and in the sacral region of the spinal cord. The preganglionic fibres leave the central nervous system in the III, VII, IX and X pairs of cranial nerves and the third and fourth sacral spinal roots. • Ganglia are located either in the tissue of effector organ or near it. The nerve endings of the postganglionic parasympathetic fibres release neurotransmitter acetylcholine. All the preganglionic nerve fibres (sympathetic and parasympathetic;) are myelinated and release acetylcholine from the nerve terminals which depolarizes the ganglionic neurones by activating nicotinic receptors.

7. Cholinergic transmission Main NT is Acetylcholine (Ach). A large number of peripheral ANS fibers which synthesize & release Acetylcholine are called CHOLINERGIC fibers. They include: • All pre-ganglionic efferent autonomic fibers. • Somatic motor fibers to skeletal muscles. • Most parasympathetic post ganglionic fibers. • A few sympathetic post ganglionic fibers– to sweat glands. Some parasympathetic post ganglionic fibers utilize nitric oxide or peptides for transmission.

8. Cholinergic synapse • Nerve terminal of cholinergic fibre contains numerous vesicles with neurotransmitter acetylcholine (ACh) that is released from presynaptic membrane. • Release of acetylcholine depends on sufficient influx of Ca 2+, which occurs under the influence of action potential. ATP negative feedback ATP

9. Fate of acetylcholine released by cholinergic fiber • ACh is released from the nerve into the synaptic cleft and binds to ACh receptors on the post-synaptic membrane, relaying the signal from the nerve. • Ach-esterase, located on the post-synaptic membrane, terminates the signal transmission by hydrolyzing ACh. • The liberated choline is reuptaken by the pre-synaptic membrane and used for resynthesis of ACh.

10. Cholinergic receptor types • Two cholinergic receptor subtypes have been identified by selective agonists: muscarinic (M-cholinoceptors) and nicotinic (N-cholinoceptors). At least 5 subtypes of muscarinic receptors (M1 – M5) have been distinguished. • There are 3 main classes of N- cholinoceptors: the muscle, ganglionic, and CNS classes. MUSCARINIC NICOTINIC M1 NM M5 NN M2 M4 M3 • Ganglions • Carotid sinus • Skeletal muscles • Adrenal glands • CNS • Eye • Heart • Smooth muscles • Exocrine glands • CNS

11. Muscarinic receptors • High affinity to muscarine • M1 – gastric parietal cells, saliva, CNS • M2 - cardiac cells, smooth muscle, CNS • M3 - bladder, exocrine glands, smooth muscle, eye, CNS • M1&M3 – Gq • M2 - Gi Amanita muscaria

12. Nicotinic receptors • High affinity to nicotine • NM- neuro-muscular junction • NN – ganglion, adrenal gland CNS, carotid sinus

13. Mechanisms of impulse transmission • Muscarinic receptors belong to G-protein coupled receptors. Transmission of impulses throughM1, M3, M5 cholinoceptors is realized by phospholipase C, inositol triphosphate and diacylglycerol • Stimulation of M2 and M4 cholinoceptors results in inhibition of adenylate cyclase and decrease in intracellular cAMP. • N- cholinoceptors are ion channel coupled. Their stimulation results in opening of Na+ channels that causes depolarization.

14. Muscarinic receptors M1 M3

15. M-cholinoceptors

16. N-cholinoceptors

17. I. Direct acting 1. Muscarinic agonists (M-cholinomimetics) Pilocarpine Oxothermorine Aceclidine 2. Nicotinic agonists Lobeline Dimethylphenylpiperazinum (DMPP) 3. Muscarinic and nicotinic agonists Acethylcholine Carbachol II. Indirect acting (muscarinic and nicotinic agonists – anticholinesterase agents) 1. Reversible Neostigmine (Proserinum) Physostigmine Pyridostigmine Edrophonium Ambenonium chloride (Oxazylum) Galanthamine 2. Irreversible (Organophosphates) Echotiophate Isoflurophate Arminum Drugs used in poisoning with organophosphates 1. Reactivators of acetylcholine esterase Pralidoxime Dipiridoxinum Izonitrozinum Obidoxime 2. M-cholinoblockers Atropine Cholinomimetics

18. Pharmacological effects • Bradycardia, decrease in blood pressure • Raising the tone of smooth muscles of internal organs • Stimulation of intestinal motility • Reducing sphincter of alimentary canal and bladder • Increased secretory activity of the exocrine glands • Constriction of the pupil of the eye (miosis) • spasm of accommodation • Reducing intra ocular pressure • Relief of pulses in mionevralnomu skeletal muscle synapse, strengthening their contractility (anticholinergic drugs) • Stimulation of the central nervous system (means of penetrating the blood-brain barrier)

19. Main clinical usage • 1. Glaucoma (Pilocarpine, Physostigmine, Armine) • 2.Infants (Neostigmine) • 3.Postoperative atony of the intestines and bladder (Neostigmine) • 4. Paralysis, paresis, neuritis, polyneuritis (Neostigmine) • 5.Dusturbances of skeletal muscle contractile function after cranial trauma, polio and stroke (Galanthamine hydrobromide) • 6.Belladonna poisoning (Neostigmine, Physostigmine, Galanthamine) • 7. Overdose nondepolarizing muscle relaxants (Neostigmine) • 8. Xerostomia (Pilocarpine) • 9. Respiratory depression (Cititon, Lobeline)

20. Side effects of cholinomimetics • 1. Bradycardia • 2. Bronchospasm • 3. Intestinal cramps, colic, diarrhea • 4. Hypersalivation • 5. Blurred vision

21. Contraindications • 1. Bradycardia, A-V block • 2. Asthma • 3.Gastric ulcer and 12 duodenal ulcer • 4. Epilepsy (Neostigmine) • 5.Pregnancy (Neostigmine)

22. Direct acting cholinergic agonists ACETYLCHOLINE

23. Direct acting cholinergic agonists ACETYLCHOLINE • Decrease in heart rate and cardiac output 2. Decrease in blood pressure

24. Direct acting cholinergic agonists ACETYLCHOLINE 3. Other actions 4. Clinical use very rare: eye drops to obtain miosis

25. Direct acting cholinergic agonists • Stimulation of atonic bladder • Nonobstructive urinary retention • Neurogenic atony • Megacolon Ophthalmology

26. Direct acting cholinergic agonists PILOCARPINE • Tertiary nitrogen • Good adsorbtion • Penetrate BBB

27. Direct acting cholinergic agonists PILOCARPINE • Secretagoge (sweat, tears, saliva) • Jaborandi - what causes slobbering • Sjögren’s syndrome • Dry mouth, lack tears • Glaucoma Jaborandi (Pilocarpus pennatifolius)

28. Direct acting cholinergic agonists PILOCARPINE

29. Mushroom poisoning • Miosis • Hyper salivation • Excessive sweating, lacrimation • Cold, wet skin • Bradycardia • Polyuria • Diarrhea • Convulsions Atropine

30. Indirect acting cholinergic agonists Reversible Irreversible Edrophonium Neostigmine Physostigmine Rivastigmine Galantamine Echothiophate Organophosphates Arminum

31. Mechanism of action

32. Reversible Physostigmine • Tertiary nitrogen • Good adsorbtion • Penetrate BBB Calabar Bean

33. Reversible Physostigmine Indications 1. Atony of intestine 2. Atony of bladder 3. Glaucoma 4. Overdose of ATROPINE, ANTIPSYCOTICS, ANTIDEPRESSANTS Side effects • Convulsions • Bradycardia • Paralysis of skeletal muscle

34. Reversible Neostigmine • Quatenary nitrogen • Poor adsorbtion • Not penetrate BBB

35. Reversible Neostigmine Side effects Indications • Salivation • Flushing • Decreased BP • Abdominal pain • Diarrhea • Bronchospasm • Paralyzes • Myastenia gravis • Antidote of neuro-muscular blocker TUBOCURARINE

36. Reversible Neostigmine • Bronchial asthma • Intestinal inflammation, obstruction • Bladder obstruction • Peritonitis

37. Reversible Edrophonium • Quatenary nitrogen • Poor adsorbtion • Not penetrate BBB • Fast elimination • Duration 10-20 min

38. Reversible Edrophonium • Diagnosis of myasthenia gravis • Antidote of neuro-muscular blocker

39. Reversible Rivastigmine • Tertiary nitrogen • Good adsorbtion • Penetrate BBB

40. Reversible Rivastigmine Alzheimer disease

41. Irreversible Echothiophate Glaucoma

42. Toxicology Organophosphates

43. Toxicology Salivation Lacrimation Urination Defecation Gastrointestinal motility Emesis Miosis SLUDGEM

44. Toxicology • Reactivation of acetylcholinesterase • PRALIDOXIME • Not enter BBB • M-cholinoblocker • ATROPINE • Antimuscarinic only • Anticonvulsant • DIAZEPAM

45. CHOLINERGIC BLOCKERS

46. Classification of cholinoblockers • I. M-cholinoblockers (Muscarinic antagonists) • Natural agents • Atropine • Hyoscine /Scopolamine/ • Plathyphylline • Semisynthetic and synthetic • Homatropine • Propantheline • Methacinum • Ipratropium bromide /Atrovent/ • Cyclopentolate • Pirenzepine

47. Classification of N-cholinoblockers • 1. Ganglion blocking drugs • Hexamethonium /Benzohexonium/ • Hygronium • Mecamylamine • Pempidine tosilate • Trimethaphan • 2. Neuromuscular blockers • a) Nondepolarizing • Atracurium • Pancuronium • Tubocurarine • Vecuronium • b) Depolarizing • Succinylcholine • Dithylinum

48. Mechanism of action

49. Parasympatholythics • Eye • inability to focus for near vision, mydriasis, IOP ↑ • Saliva • xerostomia • Bronchi • bronchodilation, secretion ↓ • Heart • Rate ↑ • GIT • secretion, peristalsis ↓ sphincter tone ↑ • Bladder • detrusor ↓ sphincter tone ↑

50. Clinical uses of M-cholinoblockers • A-V block – Atropine • Colic, abdominal cramps – Atropine, Plathyphylline • Urinary frequency - Oxybutinin • Preanesthetic medication – Atropine, Hyoscine • Peptic ulcer – Pirenzepine (selective M1 cholinoblocker) • Bronchial asthma - Ipratropium bromide