Drugs acting on Cholinergic System

1. Drugs acting on Cholinergic System By Ms. SindhuPriya E S Assistant Professor Dept. of Pharmacology YPCRC

3. Sites of cholinergic transmission

4. Cholinergic transmission • Acetyl Choline (Ach) is a major neurohumoral transmitter at autonomic, somatic as well as central sites

5. Synthesis, storage and destruction of Ach

7. AChE and BChE

8. Cholinoceptors • Two classes of receptors for Ach • Muscarinic (M) -GPCR • Nicotinic (N) – Ligand gated cation channels

9. Muscarinic receptors • They are selectively stimulated by muscarine and blocked by atropine. • They are located primarily on autonomic effector cells in heart, blood vessels, eye, smooth muscles and glands of gastrointestinal, respiratory and urinary tracts, sweat glands, etc. and in the CNS. • Subsidiary muscarinic receptors are also present in autonomic ganglia where they appear to play a modulatory role by inducing a long-lasting late EPSP.

10. Subtypes of M receptors • M1, M2, M3, M4 and M5 receptors • M1 receptors • Location: autonomic ganglia, CNS, gastric glands • Functions: Depolarization (late EPSP), learning, memory and motor function, Hist release, acid secretion

11. M2 receptors Location • SA node • A V node • Atrium • Ventricle • Cholinergic nerve endings • CNS • Visceral smooth muscle Function • Hyperpolarization & rate of impulse generation • velocity of conduction • Shortening of APD, contractility • contractility (slight)(receptors sparse) • ACh release • tremor, analgesia • contraction

12. M3 receptors Location • Visceral smooth muscles • Exocrine glands • Vascular endothelium Functions • Contraction • Secretion • Release of NO leading to vasodilation

14. Nicotinic receptors • They are selectively activated by nicotine and blocked by tubocurarine or hexamethonium. • They are rosette-like pentameric structures which enclose a ligand gated cation channel: their activation causes opening of the channel and rapid flow of cations resulting in depolarization and an action potential. • On the basis of location and selective agonists and antagonists two subtypes NM and NN are recognized

15. NM receptors • These are present at skeletal muscle end plate are selectively stimulated by phenyl trimethyl ammonium (PTMA) and blocked by tubocurarine. • They mediate skeletal muscle contraction.

16. NN receptors • These are present on ganglionic cells (sympathetic as well as parasympathetic), adrenal medullary cells and in spinal cord and certain areas of brain. • They are selectively stimulated by dimethyl phenyl piperazinium (DMPP), blocked by hexamethonium, and constitute the primary pathway of transmission in ganglia.

18. Cholinergic drugs • Cholinomimetics or Parasympathomimetics • Drugs which produce actions similar to that of ACh either by directly interacting with cholinergic receptors or by increasing the availability of ACh at these sites • Eg: 1. Cholinergic agonists 2. Anticholinesterases

19. 1. Cholinergic agonists A. Choline esters • Acetyl choline • Methacholine • Carbachol • Bethanechol B. Alkaloids • Muscarine • Pilocarpine • Arecoline

20. Pharmacological actions of Choline esters • Muscarinic actions • Nicotinic actions • CNS actions

21. a. Muscarinic actions • Heart (M2)

23. b. Nicotinic actions c. CNS actions Direct injection into brain causes arousal and later depression

24. 2. Cholinomimetic alkaloids Pilocarpine • Obtained from leaves of Pilocarpusmicrophyllus • Has muscarinic and ganglionic actions Actions • Sweating, salivation • Cardiovascular effects: low dose causes fall in BP, high dose causes rise in BP • Eye: Miosis and fall in intraocular tension Uses • Eye drops in Glaucoma

25. Therapeutic uses • Gastrointestinal disorders: Bethanechol 10-20 mg 3 or 4 times a day orally used in cases of postoperative abdominal distention and in gastric atony • Urinary bladder disorders: Bethanechol may be useful in treating urinary retention • Xerostomia: Pilocarpine is administered orally in 5–10 mg doses • Glaucoma: Pilocarpine is used in the treatment of glaucoma, where it is instilled into the eye usually as a 0.5–4% solution • Ach is available as an olphthalmic surgical aid used to produce rapid miosis

26. Contraindications • Muscarinic agonists are contraindicated in • Asthma • Hyperthyroidism • Coronary insufficiency or hypotensive patients • Acid-peptic disease

27. Mushroom poisoning (Mycetism) • Muscarine intoxication (salivation, lacrimation, nausea, vomiting, headache, visual disturbances, abdominal colic, diarrhea, bronchospasm, bradycardia, hypotension, shock) develop within 30–60 minutes of ingestion • Treatment with atropine (1–2 mg intramuscularly every 30 minutes) effectively blocks these effects

28. Anticholinesterases • Anticholinesterases (anti-ChEs) are agents which inhibit ChE, protect ACh from hydrolysis-produce cholinergic effects in vivo and potentiate Ach both in vivo and in vitro. Some anti ChEs have additional direct action on cholinergic receptors

29. Classification • Reversible • Carbamates: Physostigmine (Eserine), Neostigmine, Pyridostigmine, Edrophonium, Rivastigmine, Donepezil, Galantamine • Acridine: Tacrine • Irreversible • Organophosphates: Dyflos (DFP), Echothiophate, Parathion*, Malathion*, Diazinon*, Tabun£, Sarin£, Soman£ • Carbamates: Carbaryl*, Propoxur* (BAYGON), Insecticides and Nerve gas

31. Chemistry • Anti-ChEs are either esters of carbamic acid or derivatives of phosphoric acid. • In carbamates, R1 may be tertiary amino N which is non-polar or quaternary ammonium N+ which is lipid insoluble (edrophonium) • All organophosphates are highly lipid soluble except echothiophate

32. Mechanism of action

34. Pharmacological actions • Ganglia : High doses cause persistent depolarization of the ganglionic nicotinic receptors and blockade of transmission • CVS: CVS effects are complex. muscarinic action would produce bradycardia and hypotension, ganglionic stimulation would tend to increase heart rate and BP. • Skeletal muscles: Twitching and fasciculations. Higher doses cause persistent depolarization of endplates resulting in blockade of neuromuscular transmission weakness and paralysis. • Others : stimulation of smooth muscles and glands of the gastrointestinal, respiratory, urinary tracts and in the eye

35. Pharmacokinetics • Physostigmine: Readily absorbed from GIT and parenteral sites. It penetrates cornea freely. Crosses BBB and hydrolysed by ChE • Neostigmine and congeners: These are poorly absorbed orally; oral dose is 20-30 times higher than parenteral dose. They do not effectively penetrate cornea or cross blood-brain barrier • Organophosphates: These are absorbed from all sites including intact skin and lungs. They are hydrolyzed as well as oxidized in the body and little is excreted unchanged

36. Contraindications • Pepticulcer • Hypotension • Asthma • COPD • Seizure patients

37. Therapeutic Uses • Miotic • Glaucoma • Reverse mydriatic effect • Myasthenia gravis • Postoperative paralytic ileus/urinary retention • Postoperative decurarization • Cobra bite • Belladonna poisoning • Alzheimer's disease

38. Myasthenia gravis • Myasthenia gravis is an autoimmune disorder caused due to development of antibodies directed to nicotinic receptor at the motor endplate (NM) • NM receptors are reduced to 1/3 or less and structural damage to NMJ

39. Affected organs: eyelids, external ocular, facial and pharyngeal muscles are affected first. Later muscles of limbs and respiratory system are affected. • Symptoms: fatigue and weakness • Diagnosis: • Ameliorative test: Edrophonium 2 mg i.v. injection/neostigmine with atropine pretreatment • Provocative test: 0.5 mg D-tubocurarinei.v. • Treatment: • Neostigmine 15 mg orally 6 hourly / pyridostigmine • Thymectomy • Corticosteroids : prednisolone 30-60 mg/day • Immunosuppresants : azathioprine and cyclosporine

40. ANTICHOLINESTERASE POISONING • Anticholinesterases are easily available & extensively used as agricultural and household insecticides; accidental homicidal poisoning is common. • Symptoms are: • Irritation of eye, lacrimation, salivation, sweating, copious tracheo-bronchial secretions, miosis, blurring of vision, breathlessness, colic, bronchospasm, involuntary defecation and urination. • Fall in BP, bradycardia or tachycardia, cardiac arrythmias, vascular collapse. • Muscular fasciculations, weakness, respiratory paralysis (central as well as peripheral). • Excitement, tremor, ataxia, convulsions, coma and death. • Death is generally due to respiratory failure

41. Treatment • Termination of further exposure to poison • Maintain patent airway • Supportive measures-maintain BP, hydration, control of convulsions with judicious use of diazepam • Specific antidotes- ( a) Atropine (b) Cholinesterase reactivators: Oximes

43. Anticholinergic drugs • Also called as Muscarinic receptor antagonists, Atropinic, Parasympatholytic drugs • Anticholinergic drugs are those which block actions of ACh on autonomic effectors and in the CNS exerted through muscarinic receptors • Nicotinic antagonists also block certain actions of ACh, they are generally referred to as 'ganglion blockers (NN)' and 'neuromuscular blockers (NM)

44. Classification 1. Natural alkaloids: Atropine, Hyoscine (Scopolamine). 2. Semisynthetic derivatives: Homatropine, Atropine methonitrate, Hyoscine butyl bromide, Ipratropium bromide, Tiotropiumbromide. 3. Synthetic compounds (a) Mydriatics: Cyclopentolate, Tropicamide (b) Antisecretory-antispasmodics: (i) Quaternary compounds: Propanthelin, Oxyphenonium, Clidinium, Pipenzolate, methylbromide, Isopropamide, Glycopyrrolate. (ii) Tertiary amines: Dicyclomine, Valethamate, Pirenzepine. (c) Vasicoselective: Oxybutynin, Flavoxate, Tolterodine. (d) Antiparkinsonian:Trihexyphenidyl (Benzhexol), Procyclidine, Biperiden.

45. Pharmacological actions • 1. CNS actions • High doses cause cortical excitation, restlessness, disorientation, hallucinations and delirium followed by respiratory depression and coma.

47. Pharmacokinetics

48. Therapeutic uses • Antisecretory • Preanaesthetic medication • Peptic ulcer • Pulmonary embolism • Antispasmodic • Bronchial asthma, asthmatic bronchitis COPD • As mydriatic and cycloplegic • Central actions • Parkinsons disease • Motion sickness • Used in the treatment of muscarinic poisoning

49. Side effects and toxicity • Belladonna poisoning may occur due to drug overdose or consumption of seeds and berries of belladonna/ datura plant. • Dry mouth, difficulty in swallowing, fever, difficulty in micturition, decreased bowel sounds, Dilated pupil, photophobia, blurring of near vision, Excitement, psychotic behaviour, dreadful visual hallucinations. weak and rapid pulse, cardiovascular collapse with respiratory depression. Convulsions and coma occur only in severe poisoning. • Treatment: gastric lavage and Physostigmine 1-3 mg s.c. or i.v.

50. Contraindications • In narrow iridocorneal angle-may precipitate acute congestive glaucoma • Elderly males with prostatic hypertrophy Interactions • slower absorption and peripheral degradation of levodopa • Antacids interfere with absorption of anticholinergics • Antihistaminics, tricyclic antidepressants, phenothiazines, disopyramide, pethidine have anticholinergic property