Muscarinic agonist and antagonist

The Muscarinic agonist and antagonist drugs from the ANS briefly described also structures of the drugs are mentioned. The important drug indications and their dosage are also mentioned. The receptor types with respect to cholinergic system explained how these receptors were discovered by which technique is also mentioned.

1. MUSCARINIC RECEPTOR AGONIST AND ANTAGONIST BY GAJENDRA CHOUDHARY 1

2. Ach and its Muscarinic Receptor Target Found primarily on autonomic effector cells innervated by postganglionic parasympathetic nerves. Also present in autonomic ganglia and on some cells (e.g., vascular endothelial cells ) Within the CNS , the hippocampus, cortex and thalamus have high densities of muscarinic receptors. 2 LOCATION

3. 3 Acetylcholine the naturally occurring neurotransmitter for these receptors. No systemic therapeutic applications Because its actions are diffuse , and its hydrolysis is catalyzed by both AChE and plasma butyrylcholinestrase, is rapid.

4. 4

5. Properties and subtypes of Muscarinic Receptors Initially was characterized by analysis of the responses of cells and organ systems in the periphery and the CNS. Bethanechol and McN-A-343 , on the tone of lower oesophageal sphincter led to initial designation of muscarinic receptors as M1 (ganglionic) and M2 (effector cell). Molecular cloning identified 5 distinct gene products now designated as M1-M5. All are GPCR. 5

6. 6 ACh Gq IC Loops EC Loops 1 2 5 3 4 6 α β γ GDP GTP Gq α GTP GEF PLC IP3 DAG PIP2 ER Ca+2 Ca+2 Ca+2 Ca+2 Ca+2 Ca+2 Ryanodin receptor Calcium mediated responses M1, M3, M5

7. Gi 7 7 ACh IC Loops EC Loops 1 2 5 3 4 6 α β γ GDP GTP Gi α GTP GEF AC cAMP M2, M4 Decrease in biological responses

8. X-Ray Crystallographic studies Demonstrated the classical (orthosteric) binding site for muscarinic agonist and antagonist , highly conserved among muscarinic receptor subtypes . Consists of cleft (deeply buried in the membrane), formed by conserved amino acid chains located on several of the receptors seven TM helices. A feature unique to muscarinic receptors is hydrogen bond interaction between the orthosteric ligand and a TM6 asparagine residue. Agonist binding to receptor leads to considerable contraction of the ligand-binding pocket, reflecting the relatively small size of muscarinic agonist, as compared to muscarinic antagonist . Residues that line the orthosteric binding site are highly conserved among all muscarinic receptors. So, DEVELOPING MUSCARINIC LIGANDS WITH A HIGH DEGREE OF RECEPTOR SUBTYPE HAS PROVEN DIFFICULT. 8

9. Pharmacological effects of ACh CARDIOVASCULAR SYSTEM Vasodilation Decrease in heart rate (negative chronotropic effect) Decrease in conduction velocity in AV node (negative dromotropic effect) Decrease in the force of cardiac contraction (negative ionotropic effect) 9

10. 10 RESPIRATORY TRACT M3, bronchial and tracheal smooth muscle Plays a major role in regulating branchiomotor tone. Bronchoconstriction Increased tracheobronchial secretion Stimulation of the chemoreceptors of carotid and aortic bodies. URINARY TRACT M3 –detrusor muscle contraction, increased voiding pressure, and ureteral peristalsis M2- inhibit adrenergic receptor- cAMP-mediated relaxation of the bladder

11. 11 GASTROINTESTINAL TRACT M3, M2 Increases tone Increases amplitude of contractions Increases secretory activity of the stomach and intestine Responses are inconsistently seen with administered ACh MISCELLANEOUS PERIPHERAL EFFECTS Stimulates secretion from glands (M3) Lacrimal, nasopharyngeal, salivary (M1) and sweat glands Eye (M3) Miosis by contracting the pupillary sphincter muscle Accommodation for near vision by contracting the ciliary muscle Other subtypes may contribute to the ocular effects of cholinergic stimulation

12. 12 CNS EFFECTS Systemically administered Ach has limited CNS penetration, muscarinic agonists that can cross BBB evoke a characteristic cortical arousal or activation response. Similar to that produced by injection of cholinesterase inhibitors or By electrical stimulation of the brainstem reticular formation M1-M5 Muscarinic receptor-regulated pathways may have an important role in cognitive function, motor control, appetite regulation, nociception and other processes.

13. 13 MUSCARINIC RECEPTOR AGONIST

14. 14 Carbamoyl ester related to acetylcholine Resistant to hydrolysis by AChE: long duration of action Choline is methylated: No nicotinic action Half life is longer Non obstructive urinary retention/stimulate atonic bladder in postoperative conditions. Oral: 10-50 mg TDS/QID BETHANECHOL Uses

15. 15 Thursday, January 14, 2021 15 Carbamoyl ester related to acetylcholine Resistant to hydrolysis by AChE: long duration of action Lacks methyl group of bethanechol: both muscarinic and nicotinic action Half life is longer Mitotic agent to treat glaucoma Ophthalmic surgery: instilled into anterior chamber for miosis. CARBACHOL Uses

16. 16 Thursday, January 14, 2021 16 16 Beta methyl analog of Ach Largely resistant to hydrolysis by AChE: Long duration of action . Shows muscarinic action with minor nicotinic action. Do not cross BBB and poor absorption from GIT Diagnosis of bronchial hyperactivity. Bronchial challenge test: subjects are exposed to methacholine aerosols which leads to bronchoconstriction. Rarely performed. METHACHOLINE Uses

17. 17 Thursday, January 14, 2021 17 17 17 Quinuclidine derivative of acetylcholine. Muscarinic agonist with high affinity to M3 receptors on lacrimal and salivary glands. Xerostomia: Sjogren’s syndrome CEVIMELINE Uses Oral:30 mg TDS

18. 18 Thursday, January 14, 2021 18 18 18 18 Chief alkaloid obtained from shrubs of genus Pilocarpus Shows only muscarinic action, no nicotinic action Tertiary amine: can cross BBB Narrow angle glaucoma: used to lower IOP and removing pupillary block Open angled glaucoma: used as last resort Reversing mydriasis due to atropine Xerostomia: Radiation induced and Sjogren’s syndrome PILOCARPINE Uses 1-4% ophthalimic solution applied every 6 hours or as directed. Oral for Xerostomia: 5-10 mg TDS/QID

19. 19 Thursday, January 14, 2021 Obtained from poisonous mushroom Amanita muscaria. Shows only muscarinic action. No therapeutic use; only toxicological significance. MUSCARINE Uses

20. 20 Thursday, January 14, 2021 20 Thursday, January 14, 2021 Chief alkaloid of Areca catechu and betel nuts. Has muscarinic as well as nicotinic action. Tertiary amine: can cross BBB. Acts on Nm type of receptors also Used for recreation; no therapeutic use. ARECOLINE

21. 21 21 Thursday, January 14, 2021 21 Thursday, January 14, 2021 Synthetic quaternary amine : does not enter CNS. Intermediate duration of action: 30 min-2 hours Poor oral bioavailability (1-2%) NEOSTIGMINE Uses Myasthenia gravis: symptomatic treatment and diagnosis. Reversal of non depolarising neuromuscular blockers. Myasthenia treatment- Acute 0.5-2.5 mg IM/SC Maintenance 15-375 mg/day Oral in divided doses. Myasthenia diagnosis – 0.022 mg/kg along with atropine Reversal of nondepolarizing neuromuscular blockers – 0.03-0.07 mg/kg IV

22. 22 22 22 Thursday, January 14, 2021 22 Thursday, January 14, 2021 Natural tertiary amine : enters CNS Intermediate duration of action: 2-4 hours Instilled in eyes: penetrates cornea and causes miosis and decrease in IOP. PHYSOSTIGMINE Uses Glaucoma Antidote for drugs having anticholinergic activity: atropine, phenothiazine, tricyclic antidepressants 0.1-1% eye drops. 0.5-2 mg slow IV as antidote.

23. 23 23 23 23 Thursday, January 14, 2021 23 Thursday, January 14, 2021 Attaches reversibly to choline substitute and inhibits AChE. Does not react with AChE enzyme. Rapid renal elimination: due to quaternary amine Short duration of action 10-20 mins EDROPHONIUM Uses Diagnosis of Myasthenia gravis Differentiating cholinergic crisis from myasthenia crisis: Cholinergic crisis improves risky and infrequently indicated Reversal of non depolarizing neuromuscular blockers Paroxysmal atrial tachycardia. Myasthenia gravis diagnosis: 2 mg IV Antidote: 10 mg IV

24. 24 24 24 24 24 Thursday, January 14, 2021 24 Thursday, January 14, 2021 Synthetic quaternary amine: does not enter CNS Intermediate duration of action: 3-6 hours PYRIDOSTIGMINE Uses Myasthenia treatment Reversal of non depolarising neuromuscular blockers Myasthenia gravis treatment: 600 mg/day Oral in 3 divided doses Antidote: 0.1-0.25 mg/kg/dose IV

25. 25 25 25 25 25 25 Thursday, January 14, 2021 25 Thursday, January 14, 2021 Synthetic quaternary amine: does not enter CNS Intermediate duration of action: 4-8 hours AMBENONIUM Uses Myasthenia treatment Oral:5-50 mg TDS-QID

26. 26 26 26 26 26 26 Thursday, January 14, 2021 26 Thursday, January 14, 2021 Centrally acting cholinesterase inhibitor Poorly absorbed from oral route Bioavailability – 36% RIVASTIGMINE Uses Mild to moderate Alzheimer’s Disease Oral 1.5 -6 mg BD Transdermal patch: 4.6- 13.3 mg/24 hrs

27. 27 27 27 27 27 27 27 Thursday, January 14, 2021 27 Thursday, January 14, 2021 DONEPEZIL Uses Mild to moderate and moderate to severe Alzheimer’s Disease Oral initial 5 mg HS Maximum 23 mg/day Centrally acting cholinesterase inhibitor Reversibly binds to active site of AChE with high affinity Does not react with AChE enzyme Well absorbed from oral route Bioavailability- 100%

28. 28 28 28 28 28 28 28 28 Thursday, January 14, 2021 28 Thursday, January 14, 2021 GALANTAMINE Uses Mild to moderate Alzheimer’s Disease Oral 4mg BD or 8 mg OD Centrally acting cholinesterase inhibitor Reversibly binds to active site of AChE with high affinity Does not react with AChE enzyme Well absorbed from oral route Bioavailability- 90%

29. 29 29 29 29 29 29 29 29 29 Thursday, January 14, 2021 29 Thursday, January 14, 2021 TACRINE Centrally acting cholinesterase inhibitor. Attaches reversibly to choline substitute and inhibits AChE Was used for the treatment of Alzheimer’s disease Hepatotoxic is a major adverse effects. Discontinued due to safety concerns in most of the countries.

30. 30 30 30 30 30 30 30 30 30 30 Thursday, January 14, 2021 30 Thursday, January 14, 2021 PROPOXUR Non systemic insecticide used for pest control. Toxic to children Toxicological importance: Accidental and suicidal consumption

31. 31 31 31 31 31 31 31 31 31 31 Thursday, January 14, 2021 31 Thursday, January 14, 2021 ECHOTHIOPHATE Possess long duration of action Can cause lens opacites Uses Open angled glaucoma 0.03% eye drops instilled BD

32. 32 32 32 32 32 32 32 32 32 32 32 Thursday, January 14, 2021 32 Thursday, January 14, 2021 MALATHION Organophosphate insecticide: low toxicity to humans Uses Pediculosis capitis (head lice) treatment 0.5% lotion applied to dry hair

33. 33 DYFLOS SARIN TABUN DIAZINON Organophosphorus insecticide Rarely used for chronic glaucoma treatment Organophosphorus insecticide Fat soluble: more careful handling required Extremely toxic Used in chemical warfare. Extremely toxic Used in chemical warfare. SOMAN Extremely toxic Used in chemical warfare

34. 34 Anticholinesterase overdose Available as insecticides Accidental or suicidal consumption is common Symptoms: Salivation, Lacrimation, urination, involuntary defecation, miosis, increased respiratory secretions, hypotension, cardiac arrythmias, muscle fasciculations, weakness and paralysis Death mainly due to respiratory paralysis. Treatment Preventing further exposure: Gastric lavage, washing skin and mucous membrane Maintaining patient airway Supportive measures like maintaining BP, hydration and ventilation Antidotes Atropine Reverses muscarinic effects 2 mg IV every 10 minutes is required Pralidoxime Started as early as possible preferably within 24 hours before aging sets in Useful only in organophosphate poisoning and C/I in carbamate insecticide poisoning

35. 35 Cholinesterase reactivators PRALIDOXIME Approaches anionic site on AChE; displaces the phosphate group of organophosphates; reactivation of AChE enzyme Contraindicated in carbamate poisoning: anionic site is occupied by carbamates, pralidoxime has weak anti AChE activity that worsens the condition. Cannot penetrate into CNS: no reversal of central effects No effect if given after the enzyme goes aging Usually used combination with atropine for organophosphate poisoning 1-2 g IV over 15-30 mins repeat after 8-12 hours as required or 30 mg/kg over 20 minutes followed by 8 mg/kg/hour 600 mg 3 doses IM 15 minutes apart

36. 36 OBIDOXIME Cholinesterase reactivator similar to pralidoxime 0.25 g slow IV infusion followed by 0.75 g/24 hour infusion

37. 37 MUSCARINIC RECEPTOR ANTAGONIST

38. 38 ANTICHOLINERGICS Also referred as: cholinergic blockers, parasympatholytic, cholinergic antagonist Muscarinic receptor antagonist/antimuscarinic agents Bind to muscarinic receptor but do not elicit any response Some muscarinic receptor antagonists can have minimal blocking action on nicotinic receptors Nicotinic receptor antagonists of Nn type in sympathetic and parasympathetic ganglia is classified as ganglionic blockers Nicotinic receptor antagonists of the Nm type is classified as neuromuscular blocking agents

39. 39 ATROPINE Belladonna alkaloid: tertiary amine Blocks all type of muscarinic receptors Has both central and peripheral action Pharmacokinetics Rapidly absorbed 50% metabolised and 50% excreted unchanged Duration of action: 3-4 hours Ophthalmic Onset of action: dilation – 30 minutes; cycloplegia 1-2 hours Duration of action: more than one day; blurred vision for up to a week.

40. 40 Gastrointestinal Visceral smooth muscles are relaxed Reduces acid secretion Cardiovascular system Initial bradycardia: inhibition of M1 receptors on prejunctional neurons. Followed by tachycardia: blockade of M2 receptors on Sinu atrial node. CNS Stimulant action: vagal, respiratory, vasomotor Depressant action: vestibular pathway (useful in motion sickness) Secretions Atropine blocks glandular secretions Reduces sweat, salivary secretions, tracheobronchial and lacrimal secretions. Eye – Mydriasis Abolition of light reflex Cycloplegia: paralysis of accommodation Narrow angle glaucoma: IOP can raise significantly

41. 41 ADVERSE EFFECTS Dry Mouth Blurred vision Dry, flushed and hot skin Excitement, delirium, psychotic behaviour Urinary retention, constipation Increase body temperature: Atropine fever in infants and children USES Pylorospasm and other spastic condition of GIT Anticholinesterase poisoning Sinus bradycardia Pre-anaesthetic medication: to decrease secretions Ophthalmic uses: Refraction testing: mydriasis and fundoscopic examination: cycloplegia Preferred for children (<5 years) as they have high ciliary tone Iritis, Uveitis, iridocyclitis: decrease the spasms

42. 42 DOSAGE Ophthalmic 1% Solution 30 minutes before testing 1% solution applied QID for therapeutic effect Spastic conditions 0.4 mg oral every 4-6 hours Antidote 2 mg IV repeated as needed Sinus bradycardia 0.5-1 mg IV Preanesthetic medication 0.4-0.6 mg IV 30-60 minutes before procedure

43. 43 HYOSCINE/SCOPOLAMINE Plant alkaloid and a tertiary amine CNS effects are more marked than atropine. Therapeutic doses: causes sedation rather than excitation Route of administration: transdermal patches, oral route, ophthalmic route USES Prophylaxis of motion sickness and postoperative nausea and vomiting Nausea and vomiting treatment GI tract spasm, irritable bowel syndrome treatment Ophthalmic: Refraction testing Dosage: IV/IM/SC: 0.3-0.65 mg every 6-8 hours or as required Oral: 10 mg TDS-20 mg QID Motion sickness Transdermal patch delivering 1 mg/72 hours Apply 1 hour before travel; change every 3 days Apply night before surgery; remove after 1 day Refractory testing 0.25% solution 1 hour before procedure

44. 44 HOMATROPINE Semisynthetic derivative of atropine Onset of action:45-60 mins Duration of action: 24-48 hours Less potent and having shorter duration of action than atropine Dosage: 1-2% 1 hour before procedure Refraction testing USES

45. 45 ATROPINE METHONITRATE Quaternary ammonium salt of atropine Less lipid soluble compared to atropine: do not cross BBB Used for abdominal spastic conditions Initially used for inhalational form for asthma Decreases ciliary clearance and reduces respiratory secretion: formation of mucus plugs Also resulted in higher incidence of anticholinergic side effects.

46. 46 HYOSCINE BUTYL BROMIDE Semisynthetic derivative of scopolamine Do not pass BBB hence no CNS effect USES Gastrointestinal spastic conditions Renal colic

47. 47 MYDRIATICS CYCLOPENTOLATE TROPICAMIDE Synthetic antimuscarinic Onset of action: 30-60 mins Duration of action: 24 hours USES USES Refraction testing and fundoscopic examination Dosage : 0.5-1% solution 60 minutes before examination Synthetic antimuscarinic Short and rapid acting mydriatic Onset of action: 20-40 mins Duration of action : 6-8 hours Refraction testing and fundoscopic examination Dosage: 0.5-1% 15-20 mins before examination

48. 48 BRONCHODILATORS: QUATERNARY AMINES IPRATROPIUM Short acting muscarinic antagonist Duration of action 4-6 hours Minimal effect of mucocilliary clearance, volume or consistency of respiratory secretions Blocks all subtypes of muscarinic receptors Blockade of presynaptic M2 receptors may increase Ach release and counteract M3 receptor antagonism mediated inhibition of bronchoconstriction USES AND DOSAGE COPD MDI: 2 puffs (34 mcg) every 6 hours Nebulisation: 500 mg every 6-8 hours Severe bronchospasm treatment: Nebulisation: 500 mg repeated as needed Perennial and seasonal allergic rhinitis/ non-allergic rhinitis: reduces rhinorrhoea Nasal spray (0.03%): 2 sprays per nostril every 6-12 hours

49. 49 TIOTROPIUM BROMIDE Long acting muscarinic antagonist Minimal effect on mucocilliary clearance, volume or consistency of respiratory secretions Duration of action: up to 24 hours Once daily dosing is sufficient More selective to M1 and M3 receptors Presynaptic effect on M2 receptors is nil/minimal USES AND DOSAGE COPD, acute bronchospasm prophylaxis MDI: 2 puffs (10 mcg) OD

50. 50 UMECLIDINIUM Long acting muscarinic antagonist Dissociates slowly from M3 receptors Long duration of action: once daily dosing is sufficient USES AND DOSAGE COPD maintenance therapy Powder: single actuation (52.5 mcg) OD ACLIDINIUM Long acting muscarinic antagonist Has more selectivity to M3 receptors USES AND DOSAGE COPD maintenance therapy MDI: 1 puff (400 mg) BD

51. 51 DICYCLOMIE Synthetic tertiary amine antimuscarinic Additive direct smooth muscle relaxation USES Spasmodic conditions Antimotion sickness, antiemetic Dysmenorrhoea Irritable bowel syndrome DOSAGE ORAL 20 mg QID OXYBUTYNIN Synthetic tertiary amine antimuscarinic Relatively selective for M1/M3 receptors CYP3A4 substrate USES and DOSAGE Overactive bladder: reduces intravesicular pressure, increases bladder capacity, reduced bladder contractions Oral 5 mg TDS/QID Transdermal patch 3.9 mg/day Apply twice weekly Gel sachet 10%: Apply 1 sachet (100mg/1 g) OD

52. 52 ANTISECRETORY ANTISPASMODICS : QUATERNARY AMINES PROPANTHELINE GLYCOPYRROLATE Synthetic quaternary amine antimuscarinic Used for reducing gastric secretion in peptic ulcer Also used as an antispasmodic DOSAGE 15 mg TDS administered 30-60 mins before food Synthetic quaternary amine anti muscarinic Potent and rapidly acting USES and DOSAGE Preoperative medication : to reduce secretions Intraoperative: reduce cholinergic side effects Preoperative: 4 mcg/kg IV/IM 30-60 mins before surgery Intraoperative: 0.1 mg IV Reversal: 0.2 mg IV for 1 mg of neostigmine

53. 53 ANTIPARKINSONIAN DRUGS BENZHEXOL/ TRIHEXYPHENIDYL BIPERIDEN BENZTROPINE Central anticholinergic Central anticholinergic Central anticholinergic USES Parkinsonism and Drug induced EPS

54. 54 REFERRENCES Goodman & Gilman, The Pharmacological basis of Therapeutics, 13 th edition Classify Rx

55. 55 THANK YOU