Cholinergic receptors and its modulators(agonists, antagonists etc)

Autonomic nervous system , specially about parasympathetic system. its agonists and antagonists.

1. Dr. Asif Hussain JNMCH A.M.U, Aligarh Cholinergic receptors and modulators

2. Autonomic nervous system Afferent neurons Efferent neurons Preganglionic and post ganglionic neurons Involuntary in nature 1) Parasympathetic nervous system 2) Sympathetic nervous system Introduction

3. Somatic nervous system Sensory neurons Motor neurons Voluntary in nature Somatic motor neurons are myelinated Somatic motor neurons are cholinergic

4. Parasympathetic System

5. Ganglia close to or on target organs Parasympathetic Innervation of Visceral Targets Preganglionic neurons - long Post ganglionic neurons - short

6. Acetic acid ester of choline Synthesis, storage , release and degradation Acetylcholine

7. Types of Cholinergic Receptors Nicotine = agonist Directly opens a Na + Ca + K + channels Curare = antagonist N M : Skeletal muscle endplate N N : Ganglionic cells, adrenal medulla, CNS (1 ) Nicotinic cholinergic receptor

8. Ionotropic Receptors Work very fast; important role in fast neurotransmission Each is made of several subunits (together form the complete receptor) At center of receptors is channel or pore to allow flow of neurotransmitter At rest - receptor channels is closed When neurotransmitter bind -- channel immediately opens When ligand leaves binding site -- channel quickly closes

9. Nicotinic Receptor signal transduction pathway Ionotropic : ligand gated ion channel Composed of 5 subunits ACh binds to extracellular domains of α subunits Receptor opens a central transmembrane ion channel Changes in membrane potential or ionic concentration within cell

10. Selectively stimulated by muscarine and blocked by atropine. Located primarily on autonomic effector cells of heart, smooth muscles, respiratory tract etc and CNS. Subtypes are M 1 ,M 2 , M 3 , M 4 & M 5 (2) Muscarinic receptors

11. NH 3 COOH G q Phospho - lipase C (+) PIP 2 IP 3 Diacylglycerol Increase Ca 2+ Activate Protein Kinase C Response Muscarinic Receptor signal transduction pathways M 3 muscarinic receptor C O O C H 2 C H 2 N C H 3 C H 3 C H 3 C H 3 Acetylcholine

12. General Effects of Acetylcholine

13. Choline esters Acetylcholine Methacholine Carbachol Bethanechol Alkaloids Muscarine Pilocarpine Arecoline Cholinergic agonists

14. Blocks action of Ach on autonomic effectors and in CNS exerts through muscarinic rceptors . Atropine is prototype drug of this class is highly selective for muscarinic receptors. All anticholinergics are competitive antagonists. Cholinergic antagonists

15. Natural alkaloid Atropine Hyoscine Semisynthetic derivatives Homatropine Ipratropium bromide Tiotropium bromide Classification

16. Synthetic compounds Mydriatics : cyclopentolate , tropicamide Antisecretory -antispasmodics: Propantheline Oxyphenonium Glycopyrrolate Dicyclomine Pirenzepine Vesicoselective : oxybutynin , flavoxate , tolterodine Antiparkinsonian : trihexyphenidyl , biperiden

17. Therapeutic Uses : Cholinergic Antagonists CVS Affect heart’s conduction system Low Doses High Doses Slows heart rate ↓ ↓ Block inhibitory vagal effects on SA & AV Nodes Sinus Bradycardia Sympatomatic 2 nd degree heart block Atropine (0.05 – 1 mg/ml injection)

18. Therapeutic uses Continued… CNS 1.Parkinson’s Disease 3.Motion Sickness Parkinsonian tremor & rigidity results from Relative Excess of Cholinergic activity Deficiency in the Dopaminergic activity in Basal ganglia-Striatum system This vestibular disturbance involve muscarinic cholinergic transmission Centrally acting Antimuscarinic Agents 2.Drug induced extra-pyramidal symptoms Benzhexol , Benztropine Scopolamine

19. Respiratory system Both smooth muscle & secretory glands of Airway receive Vagal innervation & contain Muscarinic receptors Decreased secretions from pharynx ,bronchi & bronchioles Relaxes smooth muscles in bronchi & bronchioles Asthma COPD Exercise-induced bronchospasm Ipratropium , Tiotropium

20. Gastrointestinal System Blockade of muscarinic receptors affect motility & secretory functions of the gut 1.Decreased secretions 2. Relaxation of smooth muscle 3. Decreased tone & peristalsis 1.To facilitate endoscopy & GI radiology by relaxing smooth muscles ( Hyoscine ) 2. As an antispasmodic in IBS & colonic divericula ( Dicyclomine ) 3. Peptic ulcer disease ( Pirenzepine – selective M 1 antagonist) 4. Traveler's diarrhea (atropine + diphenoxylate , Lomotil )

21. Genitourinary system Relaxes smooth muscles of ureters & bladder wall 1.Bladder spasm after urologic surgery 2. Reduces involuntary voiding in neurological disorder Oxybutinin Derifenacin Solifenacin Toltrodine

22. Eye Constrictor papillae muscle is blocked by Atropine Pupillary constrictor mucle depends on muscarinic cholinoceptor activation Results in unopposed sympathetic dilator activity 1 2 Weaken the contraction of ciliary muscle ( Cycloplegia) 1.Referactive error measurement 2. Fundoscopic examination 3. To prevent synechia (adhesion) formation in uveitis & iritis Atropine,homatropine, tropicamide,cyclopentolate

23. Cholinergic poisoning Cholinesterase inhibitors insecticide in rural communities Consumption of wild mushrooms 1.Antimuscarinic therapy 1-2 mg Atropine sulphate i /v every 5-15 minutes until signs (dry mouth, reversal of miosis) appears 2.Cholinisterase regenerator compounds Pralidoxime (PAM) & Diacetylmonoxime (DAM) (1-2 gm i /v infusion over 15-30 mins )

24. Body System Side/Adverse Effects Cardiovascular Increased heart rate, dysrhythmias CNS CNS excitation, restlessness, irritability, disorientation, hallucinations, delirium Cholinergic Blocking Agents: Side Effects

25. Body System Side/Adverse Effects Eye Decreased visual accommodation, increased intraocular pressure Gastrointestinal Decreased salivation, decreased gastric secretions, decreased motility Genitourinary Urinary retention Cholinergic Blocking Agents: Side Effects

26. Antihistamines, phenothiazines , tricyclic antidepressants, MAOIs When given with cholinergic blocking agents, cause ADDITIVE anticholinergic effects, resulting in increased effects Cholinergic Blocking Agents: Interactions

27. Ganglion blocking drugs Competitively block action of Acetylcholine & similar agonist at nicotinic receptors of both parasympathetic & sympathetic ganglia Effects are numerous & complex as both divisions of ANS are blocked indiscriminately Hexamethonium –historically 1 st effective antihypertensive agent Mecamylamine ---reducing nicotine craving in patients quitting smoking Trimethaphan ---occasionally used in hypertensive emergency & dissecting aortic aneurysm---to produce controlled hypotension

28. Thank You