Lecture-Molecular Pharmacology of Cholinergic Agents.pptx

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1. Drugs acting on cholinergic system NON-COMMERCIAL JOIN-STOCK COMPANY «KARAGNDA MEDICAL UNIVERSITY» Department of Clinical Pharmacology and Evidence-Based Medicine Lecturer : Assistant Professor Dr. М anoj Kumar Sharma

2. The purpose of the lecture By the end of the discipline, students should be able to analyze the features of the pharmacokinetics and pharmacodynamics of drugs acting on Cholinergic systemthat includes: Parasympathomimetic Drugs Parasympatholytic Drugs

3. General overlay of efferent neurons of Somatic and Autonomic Nervous System Important point to be remembered is that all the neurons that are originating from CNS (Brain or spinal cord) releases Ach. The major sites of cholinergic action: Neuromuscular junction: Synaptic site between somatic neuron and skeletal muscles Parasympathetic ganglion: Synaptic sites between Pre ganglionic neuron and Postganglionic neuron Parasympathetic Neuroeffector site: Synaptic site between Postganglionic Neuron and autonomic effector site Sympathetic Ganglion: Synaptic sites between Preganglionic neuron and Postganglionic Neuron Sympathetic Neuroeffector site: Synaptic site between sympathetic Postganglionic neuron and sweat glands

4. Drugs acting on Cholinergic System Parasympathomimetics Parasympatholytics Muscarinic receptor agonists Reversible Inhibitors Indirect Acting Anti- cholinesterases Irreversible Inhibitors Direct Acting Drugs Nicotinic receptor agonists Muscarinic receptor antagonists Ganglionic blocking drugs ( Nn ) Neuromuscular blocking drugs (Nm) Nicotinic receptor antagonists

5. Cholinergics Parasympathomimetics Muscarinic receptor agonists Acetylcholine Methacholine Bethanichol Carbachol Pilocarpine Areocholine Muscarine Reversible Inhibitors Indirect Acting Cholinergics Anti- cholinesterases Irreversible Inhibitors Direct Acting Cholinergics Cholinergic Receptor Agonists Nicotinic receptor agonists: Nicotine Succinylcholine Water Soluble Neostigmine Pyridostigmine Edrophonium Lipid Soluble Physostigmine Tachrine Donepezil Rivastigmine Galantamine Organophosphates Dyflos (DFP) Malathion Diazinon (Tik-20) Nerve Gases for chemical warfare: Tabun Sarin Soman Carbamates Carbary ( Sevin ) Propoxur ( Baygon )

6. Direct Acting Cholinergics Muscarinic Cholinergic Receptor Agonists Acetylcholine: (M+N): Not used Therapeutically because of very short duration of action and non specific action Methacholine: (M): Methacholine challenge test to diagnose asthma Bethanichol : (M): Indications: Post-operative Ileus. Non-obstructive Urinary retention after surgery or Postpartum Carbachol: (M+N): Not used systemically. As miotic Agent for Glaucoma Pilocarpine: As miotic agent for Glaucoma As spray for Xerostomia Areocholine and Muscarine: Both are not used therapeutically and are responsible for poison

7. Direct Acting Cholinergics Nicotinic Cholinergic Receptor Agonists Nicotine MOA**- Low doses – ganglionic stimulation causing euphoria and arousal. CNS effects cause relaxation and improves attention (Acute) Indications – None Adverse effects – Vomiting, convulsions, hypertension, cardiac arrhythmias, Respiratory arrest – (depolarizing blockade), Muscarinic effects - PNS ganglia stimulation. Succinylcholine: MOA - Overstimulation results in depolarizing blockade Indications – muscle relaxation/paralysis associated with intubation, other procedures Adverse effects – Fasciculations, respiratory arrest, malignant hyperthermia

8. Indirect Acting Cholinergics Reversible Ach. esterase inhibitors (Water soluble) Neostigmine, Pyridostigmine, Edrophonium As these drugs are water soluble so they do not cross BBB and actions are restricted in peripheral tissues and practically no actions in CNS MOA - Prolongs duration of acetylcholine by binding with and blocking acetylcholinesterase. Therefore both Nicotinic(N) and Muscarinic(M) effects! Indications: Myasthenia Gravis, Glaucoma, Atropine Poisoning Neostigmine: Also stimulate Nicotinic receptors so is more effective in myasthenia gravis Pyridostigmine: Long acting so offer dose convenience Atropine can be used with these drugs to prevent muscarinic side effects Edrophonium: Duration of action 15-20 minutes only so only used for diagnosis of myasthenia gravis To diagnosis of cholinergic crisis and myasthenic crisis

9. Indirect Acting Cholinergics Reversible Ach. esterase inhibitors (Lipid soluble) Physostigmine, Tacrine, Donepezil, Rivastigmine, Galantamine As these drugs are lipid soluble so crosses BBB therefore has more CNS effects. MOA - Prolongs duration of acetylcholine by binding with and blocking acetylcholinesterase, therefore both Nicotinic(N) and Muscarinic(M) effects! Indications: Physostigmine: DOC for Atropine (Anticholinergic drugs) poisoning Tacrine, Donepezil, Rivastigmine, Galantamine: DOC in Dementia due to Alzheimer’s Disease: Tacrine was the DOC but due to frequent dosing, hepato-toxicity, now Donepezil, Rivastigmine, Galantamine are preferred

10. Indirect Acting Cholinergics Irreversible Ach. esterase inhibitors Drugs of this group are not used clinically except Ecothiophate which due to long duration of action is used for profylaxis of Glaucoma These drugs due to potent and irreversible binding and inhibition of Ach-Esterase results in highly toxic cholinergic effects so are not used clinically except Ecothiophate . Other drugs in this group are used as insecticides and pesticides and some are nerve gases which are chemical warfares . These are either organophosphates or Carbamates Organophosphates Dyflos (DFP) Malathion Diazinon (Tik-20) Nerve Gases for chemical warfare: Tabun Sarin Soman Carbamates Carbary l ( Sevin ) Propoxur ( Baygon )

11. Indirect Acting Cholinergics Irreversible Ach. esterase inhibitors Atropine is the DOC for both organophosphate and carbamate poisoning. Atropine administration in case of Anticholinergic Drug Poisoning. Enzyme reactivators like Pralidoxime (PAM), Obidoxime and Diacetylmonoxime in organophosphate poisoning but not for carbamate poisoning. The esteratic site to which Enzyme re-activators bind to and re-activate Ach-E, are occupied by carbamate and is not free for the binding of Enzyme re-activators, so these are not effective in Carbamate poisoning. O rganophosphate binds only to anionic site of the Ach and esteratic site remains free to which Enzyme reactivators can bind and can remove the drug and re-activates the Ach- Esrerases . DAM can not cross the BBB whereas PAM and Obidoxime are lipid soluble so can cross BBB

12. Parasympatholytics Anti- Cholinergics in CNS Atropine is a CNS stimulant whereas scopolamine causes CNS depression. S copolamine (Hyoscine): Indications: Due to CNS depressant action Hyoscine is used as a Lie-Detector Test or or Truth serum in suspects DOC for Motion sickness: For Drug induced Parkinsonism: T rihexiphenidyl (benzhexol), benztropine and biperidin are drugs of choice for the treatment and prevention of drug induced Parkinsonism. Oxybotulinum -A: Recommended to prevent headaches with chronic migrane

13. Parasympatholytics Anti- Cholinergics in Eyes Due to their cycloplegic action by blocking M3 receptors on Ciliary smooth muscles, these drugs are used as cycloplegic agent for the correct assessment of refractive error of the Eye lens Due to their mydriatic action by blocking M3 receptors in constrictor pupili , they are used as mydriatic agents for fundoscopy (Fundus examination) Atropine: Strong cycloplegic action but very long mydriatic action these are not preferred in adults. But can be use for children because ciliary tone is very strong in children so strong cycloplegic agent is required in children. Homatropine: Less potent and shorter duration of action Cyclopentolate: Duration of action 24 hours. Produces mydriasis for shorter duration then Atropine so is preferred T ropicamide: Duration of action 6 hours: Shortest duration action. Preferred over Atropine as mydriatic but has weak cycloplegic action as compared to Atropine.

14. Parasympatholytics Anti- Cholinergics in Cardio-vascular system Atropine causes bradycardia initially due to inhibition of presynaptic muscarinic receptors (M2) but further increase in dose causes tachycardia due to inhibition of post-synaptic M2 receptors. Atropine is useful in the treatment of arrhythmias like AV block and digitalis induced bradycardia. It has negligible effect on BP and cardiac contractility. Atropine is: DOC for mushroom poisoning due to Inocybe species. DOC for organophosphate and carbamate poisoning. I s used along with neostigmine (to decrease its muscarinic side effects) for the treatment of Myasthenia gravis and cobra bite.

15. Parasympatholytics Anti- Cholinergics in Respiratory System Anticholinergic drugs reverse the bronchoconstriction caused by stimulation of M3 receptors. Ipratropium and tiotropium are muscarinic receptor antagonists useful in the treatment of COPD and bronchial asthma. Ipratropium : H as non-selective action on all muscarinic receptors Tiotropium I s somewhat selective blocker of M1 and M3 receptors. Has longer duration of action as compared to Ipratropium Glycopyrolate is used as a pre- anaesthetic medication to decrease the secretions and reflex bronchospasm during general anaesthesia .

16. Parasympatholytics Anti- Cholinergics in GIT Selective M1 blocker: Pirenzapine and Telenzapine are used in peptic ulcer. DOC for peptic ulcer are PPIs. M3 Blockers: Hyoscine, dicyclomine, propantheline, oxyphenonium and clidinium are useful as anti-spasmodic agents for the treatment of intestinal colic. Darifenacin and solefenacin are selective M3 blockers useful for irritable bowel syndrome and overactive bladder.

17. Parasympatholytics Anti- Cholinergics in Genito-urinary Tract Anticholinergic drugs decrease the motility of urinary tract and thus may result in urinary retention (therefore contra-indicated in BPH). Dicyclomine, flavoxate and oxybutynin: Use ful for the treatment of urinary incontinence [detrusor instability] and renal colic. Tolterodine, Fesoterodine (a prodrug of tolterodine), arifenacin and solefenacin (selective M3 antagonist) are also useful for urinary incontinence.

18. Parasympatholytics Adverse Effects of Anti- Cholinergics Can cause Anticholinergic side effects: Confusion, Delirium, Restlessness Blurred vision Dry mouth Hyperthermia in children so should be avoided in children Brady cardia or Tachycardia Constipation Urinary retention Contra-indicated in patients of Glaucoma and Urinary retention.

19. Parasympatholytics Adverse Effects of Anti- Cholinergics Can cause Anticholinergic side effects: Confusion, Delirium, Restlessness Blurred vision Dry mouth Hyperthermia in children so should be avoided in children Brady cardia or Tachycardia Constipation Urinary retention Contra-indicated in patients of Glaucoma and Urinary retention.

20. Feedback Questions you must know What are important Parasympathetic actions? List different types of Cholinergic receptors and their signalling mechanism What are the major locations of different cholinergic receptors? Classify the Cholinomimetic Drugs with appropriate examples. Which group of Parasympathomimetic drugs are poison. What are the symptoms of poisoning? What is the management for this type of poisoning? Classify the Parasympatholytic drugs with suitable examples of each class. What are the symptoms and treatment of Atropa belladonna?

21. Literature Essentials of Medical Pharmacology – 8 th Edition, by KD Tripathi Review of Pharmacology – 14 th Edition, by Gobind Rai Garg and Sparsh Gupta Goodman & Gillman’s – The Pharmacological Basis of Therapeutics Lippincott Illustrated Reviews – Pharmacology – Seventh Edition

22. НАЗАРЛАРЫҢЫЗҒА РАХМЕТ! СПАСИБО ЗА ВНИМАНИЕ! THANK YOU FOR YOUR ATTENTION!