Cholinergic drugs 2017

lecture presentation

1. Cholinergic drugs For BSN 1 st Year Dr. Pravin Prasad 2 nd Year Resident, MD Clinical Pharmacology Maharajgunj Medical Campus 17 th February, 2017 (Falgun 6, 2073), Friday

2. Nervous System: Overview

3. Autonomic Nervous System: Organization

4. Sympathetic vs Parasympathetic NS NE ACh ACh

5. Cholinoceptors Muscarinic (GPCRs) Selective Agonist: Muscarine Antagonist: Atropine Five Subtypes: M 1 -M 5 M 1 , M 3 , M 5 : excitatory ( G q ) Nicotinic (ligand gated ion channel) Selective Agonist: Nicotine Antagonist: d-tubocurarine Two subtypes: N N & N M Usually excitatory

6. Muscarinic Cholinoceptors : Locations & Functions M1 M2 M3 Autonomic ganglia: depolarization Gastric glands: increased secretion CNS: learning, memory, motor function Heart: Decrease rate, force CNS: tremor, analgesia Visceral smooth muscle: contraction Visceral smooth muscle: contraction Iris: constriction of pupil Ciliary muscle: contraction Exocrine glands: secretion Vascular endothelium: vasodilatation

7. Nicotinic Cholinoceptors N M N N Neuromuscular junction: contraction of skeletal muscle Autonomic ganglia: depolarization Adrenal medulla: catecholamine release CNS: site specific action

8. Cholinergic Transmission

9. Cholinergic/ Parasympathomimetic Drugs Cholinergic Agonists Anti- cholinesterases Choline esters Alkaloids Reversible Irreversible Acetylcholine Pilocarpine Carbamates : Physostigmine, Neostigmine, Pyridostigmine , Edrophonium, Rivastigmine , Donepezil, Galantamine Carbamates : Carbaryl , Propoxur Methacholine Arecoline Organophosphates : Dyflos , Echothiophate , Malathion, Diazinon , Tabun , Sarin, Soman Carbachol Muscarine Bethanechol Acridine : Tacrine

10. Muscarinic Actions of Cholinergic Agonists (ACh) Organ Receptor Involved Mechanism Effect Heart M 2 Hyperpolarization of SA Node Increased Refractory Period at AV node and His-Purkinje Fibres Bradycardia, cardiac arrest, Delayed conduction, Prolonged P-R interval, Heart Block Blood Vessels Nitric Oxide(NO) release: Vasodilation Fall in BP, flushing M 3 Vasoconstriction NO – dilatation of cavernous sinus Erection of penis

11. Muscarinic Actions of Cholinergic Agonists (ACh) Organ Receptor Involved Mechanism Effects Smooth Muscle M 3 + M 2 Increased tone and peristalsis of GIT, sphincters relaxed Abdominal cramps, evacuation of bowels M 3 Increased peristalsis in ureters, detrusor contracts, trigone & sphincter relaxes Voiding of bladder M 3 Constriction of bronchial muscles Bronchospams , dyspnoea, asthamatic attack

12. Muscarinic Actions of Cholinergic Agonists (ACh) Organ Receptor Involved Mechanism Effects Glands M 3 + M 2 Increased secretion Salivation, sweating, lacrimation, increased tracheobronchial and gastric secretions Eyes M 3 Contraction of circular muscle of iris Miosis Contraction of ciliary muscle Blurring of near vision, increased aqueous outflow, decreased intra ocular pressure in glaucomatous eye

13. Nicotinic Actions of Cholinergic Drugs (ACh) Organ Receptor Involved Mechanism & Effects Autonomic Ganglia N N Stimulation at higher doses Skeletal Muscles N M Contraction of muscle fibres Intra-arterial injection: twitching and fasciculations

14. Choline esters: Uses and Side Effects Uses: Rarely used (evanescent and non selective action) Bethanechol : non-obstructive urinary retention, neurogenic bladder Side effects: Belching, colic Involuntary urination/defecation Flushing, sweating Fall in BP Bronchospasm

15. Cholinomimetic Alkaloids:Pilocarpine Prominent muscarinic actions; ganglionic action via M 1 receptors Dose dependent CVS Effects Eyes: Local application – penetrates cornea, miosis, ciliary muscle contraction, fall in intraocular tension (M3) Use: as miotics S/E: marked sweating, salivation, increased secretions

16. Cholinomimetic Alkaloids Arecholine Source: betel nut Areca catechu Muscarinic as well as Nicotinic actions No therapeutic use Muscarine Source: mushrooms Amanita muscaria , Inocybe sps . Only muscarinic actions Not used therapeutically, has toxicological importance

17. Anti- cholinesterases ( AChE ) Inhibits Cholinesterase ( ChE )  protects ACh from hydrolysis (A mplification of endogenous ACh)  Cholinergic effects Additional direct action on Nicotinic receptors

18. AChE : Pharmacological Actions Characteristics (Example) Muscarinic Nicotinic CNS Ganglia Skeletal Muscle Lipid soluble (Physostigmine, organophosphates) +++ + Less prominent +++ Lipid insoluble (Neostigmine) Less prominent + +++ none

19. AChE: Pharmacological Actions Skeletal Muscles: twitching and fasciculations at low dose, weakness and paralysis at high dose Prolonged action of ACh on motor end plates and prejunctional fibres twitching and fasciculations High dose: persistent depolarization  neuromuscular transmission blockade  weakness and paralysis Ganglia: stimulation at low dose, blockade at high dose CVS: complex, unpredictable effects CNS: general arousal at low dose, excitement, confusion at high dose

20. AChE: Pharmacokinetics Physostigmine: Rapid absorption (oral, parenteral, topical in eye) Crosses BBB, central effects Metabolism by hydrolysis Organophosphates: Absorbed from all sites Hydrolysed and oxidised and then excreted Neostigmine: Poor oral absorption (20-30 times parenteral dose) Does not cross BBB, cornea Partially hydrolysed and partially excreted unchanged in urine

21. AChE : Uses As Miotic Glaucoma: Pilocarpine - rapid and short lasting (4-6hrs) S/E: diminution of vision especially in dim light, spasm of accommodation, brow pain; nausea, diarrhoea, sweating, bronchospasm with higher concentration Physostigmine 0.1% - supplement pilocarpine Reversal of mydriasis after refraction Prevent/break adhesions: In conjunction with mydriatics

22. AChE:Uses Myasthenia gravis(MG) Treatment Neostigmine 15 mg orally 6 hourly Adjusted according to response Dose requirement fluctuates Pyridostigmine Diagnostic Tests Ameliorative Test : Inj Edrophonium 2mg i.v. (test dose) followed by 8 mg i.v. after 30-60 sec. reversal of weakness and short lasting improvement of strength: + ve for MG Provocative Test

23. AChE : Uses Post-operative paralytic ileus/urinary retention: Inj. Neostigmine 0.5-1 mg s.c. Post-operative decurarization : Neostigmine 0.5-2 mg i.v. preceeded by atropine to block muscarinic effects  rapidly reversal of muscle paralysis induced by competitive neuromuscular blockers Cobra bite: Neostigmine + Atropine to prevent respiratory paralysis Belladona poisoning/ Dhatura poisoning: Physostigmine 0.5-2 mg i.v. repeat as required (S/E – hypotension, arrhythmia, undesireable central effects: last resort), Neostigmine safer Drug Overdose: TCA, phenothiazines , antihistaminics – Physostigmine (rare) Alzheimer’s Disease: cerebroselective AChE ( rivastigmine , donepezil, galantamine )

24. Thank you That will be all for today Please revise the topic…. Next class: Anticholinergics Drugs