Anticholinergic drugs, Atropinic drugs - AJ

Anticholinergic drugs - Muscarinic antagonists/atropinic drugs/ parasympatholytic drugs.
Includes pharmacological actions, comparative features of atropine and hyoscine, Uses, adverse effects of anticholinergic drugs. Quaternary compounds, tertiary amines, vasicoselective anticholinergics. Atropine toxicity

1. Anticholinergic drugs Presenter: Dr. Anie Jacob 2 nd Year Junior Resident Moderator – Dr. Shoebul Haque (SR) Peer support – Dr. Vishal Tiwari (JR2) Department of Pharmacology and Therapeutics King George’s Medical University, Lucknow, U.P, India e-mail : [email protected]

2. Contents Introduction Classification Pharmacological action Therapeutic uses Adverse effects Contraindications Summary References

3. Learning objective To classify anticholinergic drugs To describe the mechanism of action, classification, adverse effects, indications and contraindications of anticholinergic drugs. To describe the treatment of Atropine toxicity

4. Anticholinergic Drugs Mechanism of action: B lock actions of Acetyl Choline (Ach) on autonomic effectors and in the CNS exerted through muscarinic receptors Parasympatholytic drugs/Muscarinic Receptor Antagonists/ Cholinergic Antagonists Competitive antagonists Atropine as prototype drug / Atropinic drugs

5. Classification

6. Natural alkaloids Atropinic natural alkaloids , plants of Solanaceae family Belladonna alkaloids Atropa Belladonna ‘Atropos’- Greek God who cuts the thread of life ‘Belladona’ means Beautiful Lady (Italian)

7. Pharmacological actions Atropine: Prototype Prominent effect: organs which receive strong parasympathetic tone Non-selective muscarinic receptor blockers

8. CNS Atropine – CNS stimulant action, Hyoscine – depressant Atropine stimulates medullary centers - vagal, respiratory, vasomotor. Depresses vestibular excitation: anti-motion sickness property Block cholinergic overactivity in basal ganglia: suppresses tremor and rigidity of parkinsonism High doses: cortical excitation, restlessness, disorientation, hallucinations and delirium followed by respiratory depression

9. CVS Heart Most prominent effect – Tachycardia Abbreviates refractory period of A-V node and facilitates A-V conduction BP Does not have any consistent or marked effect High doses: flushing of the face and hypotension due to cutaneous vasodilatation – Atropine flush

10. Eye Topical instillation: mydriasis, abolition of light reflex and cycloplegia, lasting 7-10 day Photophobia and blurring of near vision Intraocular tension rises

11. Smooth muscles All visceral smooth muscles that receive parasympathetic motor innervation are relaxed by atropine : M3 blockade Stomach and intestine: Constipation, Antispasmodic Ureter and Urinary Bladder: Urinary retention Bronchodilatation and reduces airway resistance Effect on biliary tract and uterus: minimal

12. Glands Decreases sweat, salivary, tracheobronchial and lacrimal secretion: M3 Blockade Dry eyes Xerostomia, talking and swallowing difficulty Decreases secretion of acid, pepsin and mucus in the stomach

13. Body temperature Rises , Skin becomes hot and dry Atropine Fever Children are highly susceptible Local anaesthetic Mild anaesthetic action on the cornea

14. Sensitivity to Atropine An important consideration in the therapeutic use : physiological functions in different organs vary in their sensitivity to muscarinic receptor blockade Saliva, sweat, bronchial secretion > eye, bronchial muscle, heart > smooth muscle of intestine, bladder > gastric glands and smooth muscle.

15. Dose (mg) Effects of atropine 0.5 Slight cardiac slowing, some dryness of mouth, inhibition of sweating 1 Definite dryness of mouth, thirst, acceleration of heart 2 Rapid heart rate, marked dryness of mouth, dilated pupils, blurring of near vision 5 Previous symptoms marked, difficulty in speaking and swallowing, restlessness and fatigue, headache, dry hot skin, difficulty in micturition, reduced intestinal peristalsis ≥ 10 Previous symptoms more marked, pulse rapid and weak, vision very blurred, skin flushed, hot, dry, and scarlet; ataxia, restlessness, and excitement; hallucinations and delirium; coma

16. ATROPINE HYOSCINE Chief source Atropa belladonna, Datura Stramonium Hyoscyamys niger Alkaloidal ester of tropic acid with Tropine (base) Scopine (base) CNS effect Excitatory Depressant Anticholinergic property More potent on heart, bronchial muscle and intestines More potent on eye and secretory glands Pharmacokinetics 50% metabolized in liver and rest is excreted unchanged in urine Completely metabolized Duration of action Longer Shorter Anti-motion sickness ++ +++

17. Atropine substitutes Semisynthetic derivatives and Synthetic compounds Selective action M1 selective – Pirenzepine M3 selective – Darifenacin, Solifenacin

18. Quaternary compounds Hyoscine butyl bromide Less potent and longer acting than atropine Esophageal and Gastrointestinal spastic conditions Atropine methonitrate Abdominal colics and hyperacidity

19. Ipatropium bromide Selective - bronchial muscle, without altering the volume or consistency of secretions - Does not depress mucociliary clearance Gradual onset and late peak of bronchodilator effect - regular prophylactic use Action: 4-6 hours Acts on receptors located mainly in the larger central airways Parasympathetic tone is the major reversible factor – more effective in COPD Transient local side effects

20. Tiotropium bromide Newer Congener, High bronchial selectivity M1 and M3 selectivity: Long lasting Bronchodilatation, 24 hours Once daily dosing Propantheline Peptic ulcer and Gastritis Oxyphenonium Peptic Ulcer and GI Hypermotility

21. Cimetropium bromide, Clidinium Irritable bowel Syndrome Isopropamide Hyperacidity, nervous dyspepsia, IBS Glycopyrrolate Potent, rapidly acting , lack central effects Preanaesthetic medication and during anaesthesia

22. Tertiary amines

23. Dicyclomine Anti-spasmodic action: dysmenorrhoea and irritable bowel syndrome Antiemetic property: morning sickness and motion sickness Valethamate Delayed Labour: hasten dilatation of cervix Visceral antispasmodic: urinary, biliary, intestinal colic Pirenzepine M1 selective blocker, Peptic Ulcer

24. Vasicoselective anticholinergics

25. Oxybutinin Selective – M3 and M1, Detrusor instability Tolterodine M3 selective antagonist, Overactive bladder Flavoxate Urinary frequency, urgency and dysuria associated with lower urinary tract infections Darifenacin, Solifenacin M3 selective

26. Mydriatics Tropicamide Quickest (20-40min) and briefest action (3-6 hours) Shortest acting mydriatic – Refraction testing in adults

27. Antiparkinsonian

28. Antiparkinsonian Central anticholinergics, higher central: peripheral anticholinergic action ratio Act by reducing the unbalanced cholinergic activity in the striatum Used alone in mild cases Drug induced parkinsonism Trihexyphenidyl (Benzhexol) most commonly used drug

29. Uses As antisecretory Preanaesthetic medication: Atropine, Glycopyrrolate - to decrease salivary and tracheobronchial secretions - to prevent Laryngospasm Pulmonary Embolism Parkinsonism 2. Bronchial Asthma, asthmatic bronchitis, COPD – Ipatropium Bromide, Tiotropium Bromide

30. 3. As Antispasmodic Intestinal and Renal Colic, Abdominal cramps Nervous, functional and drug induced diarrhoea Irritable bowel syndrome Pylorospasm , gastric hypermobility, gastritis, nervous dyspepsia Relieve urinary frequency and urgency, enuresis in children Dysmenorrhoea

31. 4. As Mydriatic and Cycloplegic Diagnostic Refractory testing: Tropicamide Children below 5 years: Atropine 1% ointment , 24 hours and 2 hours before Fundoscopy Therapeutic Iritis , Iridocyclitis, Choroiditis, Keratitis and Corneal Ulcer: reduce spasm, prevent adhesions - Atropine

32. 5. As Cardiac Vagolytic MI and Digitalis toxicity: Counteracting sinus bradycardia and partial heart block due to increased vagal tone 6. For Central Action Parkinsonism : Early stages, tremor predominant and drug induced Motion sickness: Hyoscine Prophylactically , 0.2 mg oral , action 4-6 hours Transdermal Patch, behind the pinna 4 hours before journey, 3 days Scopolamine: amnestic and depressant action ‘Lie detector’

33. 7. To antagonise muscarinic effects of drugs and poisons Specific antidote : Anti-ChE and Early mushroom poisoning Block muscarinic actions of Neostigmine: Myasthenia Gravis, Decurarization , Cobra envenomation 8. Others Primary axillary hyperhidrosis Rhinorrhoea Sialorrhoea

34. Adverse effects and Contraindications Predictable consequences of muscarinic receptor blockade Adverse effects : dry mouth, constipation, blurred vision, gastrointestinal discomfort, and cognitive impairment. Contraindications : urinary tract obstruction, GI obstruction, and uncontrolled (or susceptibility to attacks of) angle-closure glaucoma, benign prostatic hyperplasia

35. Toxicity Belladona Poisoning Drug Overdose/ Consumption of seeds and berries of belladonna/datura plant Children are highly susceptible Manifestations : exaggerated pharmacological actions.

36. C linical picture: high (toxic) dose of atropine may be remembered by an old mnemonic device that summarizes the symptoms: Red as a beet, Dry as a bone, Blind as a bat, Hot as firestone, and Mad as a hatter

37. Treatment Gastric Lavage: Tannic acid Dark quiet room Cold sponging or ice bags Physostigmine 0.5 -2 mg i.v. Other general measures – maintenance of blood volume, assisted respiration, control of convulsions

38. Summary Mechanism of action : B lock actions of ACh at muscarinic receptors Classification : Natural alkaloids, Semisynthetic derivatives, Synthetic compounds Therapeutic uses : Antisecretory, antispasmodic , mydriatic, COPD Adverse effects : Dry mouth, constipation, blurred vision, GI discomfort and cognitive impairment Contraindications : Urinary tract and GI obstruction, angle-closure glaucoma, benign prostatic hyperplasia

39. References Sharkey K, MacNaughton W. Muscarinic Receptor Agonists and Antagonists. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw Hill; 2023. p. 213-219 Tripathi KD. Anticholinergic Drugs and Drugs acting on Autonomic Ganglia. 9th ed. New Delhi: Jaypee Medical Publishers; 2023. p.124-133 .

40. THANK YOU!

41. Questions 1.What is the mechanism of action of anticholinergic drugs? 2.Describe the effects of anticholinergic drugs on the eye. 3.Name the atropine substitute that has M3 selective action. 4.Name the anticholinergic used in motion sickness and explain its administration. 5.What are the contraindications of anticholinergic drugs?