Anti – Cholinergic Drugs

1. Anti – Cholinergic Drugs

2. Contents • Introduction • Classification • Pharmacological actions of Atropine • ADRs of anti cholinergic drugs • Uses of anti cholinergic drugs • Atropine Substitutes • Summary

3. 63-year-old architect, complains of urinary symptoms to his family physician. H/O HTN 8yrs on ACEIs, BPH requiring prostatectomy. He now complains that he has an increased urge to urinate as well as urinary frequency, and this has disrupted the pattern of his daily life. • What do you suspect is the cause of his problem? • What information would you gather to confirm your diagnosis? • What treatment steps would you initiate?

5. Anti-Cholinergic Drugs • Muscarinic Receptor Antagonists • Parasympatholytics • Atropinic Drugs • Definition: agents that antagonise actions of Ach mediated through M receptors • All these agents exhibit Competitive Antagonism

6. Classification • Natural Alkaloids: • Atropine • Hyoscine (Scopolamine) • Semi-synthetic agents: • Homatropine • Atropine methonitrate • Hyoscine butyl bromide • Ipratropium bromide • Tiotropium bromide

7. Synthetic agents: • Mydriatics: • Cyclopentolate, Tropicamide • Antisecretory-antispasmodics: • QuarternaryCompounds: Propantheline, Oxyphenonium, Clidinium, Pipenzolate, Isopropamide, Glycopyrrolate • Tertiary amines : Dicyclomine, Oxybutynin, Flavoxate, Pirenzepine, Telenzepine • Antiparkisonian: Benzhexol, Benzotropine, Procyclidine, Biperiden

8. Pharmacological actionsAtropine • CNS: • Overall stimulant action (appreciable at higher doses) • Depresses vestibular excitation • Suppresses cholinergic overactivity in basal ganglia • CVS: • Most prominent action is Tachycardia (M2 receptor block) • Initial transient bradycardia on iv use (M1 auto receptor block) • Cardiac centre stimulation and tachycardia increases BP

9. Eye: • Topical instillation causes Mydriasis • Abolition of light reflex and cycloplegia for 7 days • Blurring of vision and photophobia • Due to mydriasis, IOT increases • Smooth muscles: • Relaxation of all smooth muscles (M3 blockade) • Does not stop peristalsis, but constipation can occur • Produces bronchodilation and reduces airway resistance • Relaxant effect on uterus and urinary bladder

10. Glands • Decreased secretion by salivary, lacrimal, sweat and tracheobronchial glands • Decreases the volume of gastric secretions • Body temperature: • Increase in body temperature • Due to inhibition of sweat secretion • Due to stimulation of temperature center in hypothalamus • Local anesthetic action: • Mild anesthetic action on the cornea

11. Pharmacokinetics • Rapidly absorbed from GIT • Freely penetrates cornea on topical use • Restricted entry into CSF • 50% metabolized • Metabolites and free drug excreted in urine • t1/2 = 3 – 4 hours

12. Actions/Uses • Anti-secretory: • Preanesthetic medication (glycopyrrolate 0.3mg im) • Peptic ulcer (pirenzepine, telenzepine – M1 blockade) • Pulmonary embolism – reduce reflux secretion • Parkinsonism - reduces excessive salivation and sweating (benzhexol, biperiden, benzatropine)

13. Antispasmodic: • Intestinal and renal colic, abdominal cramps. (Hyoscine butyl bromide, Dicyclomine) • Nervous and drug induced diarrhoea • Gastric hypermotility • To relieve urinary frequency and urgency (Oxybutynin, Flavoxate)

14. Bronchial asthma, asthmatic bronchitis, COPD • COPD: given by aerosol • Atropine methonitrate • Ipratropium bromide • Tiotropium bromide • Asthma: given by nebulization • Ipratropium bromide with β2 agonist

15. As Cycloplegic and Mydriatic • Diagnostic: fundoscopy, testing errors of refraction • Homatropine – cycloplegia and mydriasis for 3 days • Cyclopentolate – shorter duration of action (1 day) • Tropicamide – unreliable cycloplegia. short duration (6 hours) • Treatment:iritis, iridocyclitis, keratitis, corneal ulcers, adhesion between iris and lens, and iris and cornea - Above mentioned drugs - Atropine

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17. As Cardiac vagolytic: • Atropine is used in bradycardia and partial heart block occurring due to increased vagal tone, digitalis toxicity • To antagonise cholinergic action of drugs/poisons • OP poisoning: atropine is specific antidote (2mg iv/10 mins) • Used to block muscarinic effects of neostigmine

19. For Central action: • Parkinsonism: Benzhexol, Benzatropine, Procyclidine, Biperiden • Motion sickness: Hyoscine (0.2mg oral) • Labour: Hyoscine is used to produce amnesia and sedation • Diagnosis of Alzheimer’s disease

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22. ADRs • Dry mouth – difficulty in swallowing and speech • Dry, flushed and hot skin • Dilated pupils – photophobia, blurring of near vision • Excitement, psychotic behaviour • Hypotension, weak and rapid pulse – CVS collapse • Respiratory centre depression

23. Belladona poisoning • Diagnosis: Neostigmine (1mg sc) dose not produce muscarinic effects • Treatment: • Supportive measures • Gastric lavage • Dark, quiet room • Cold sponging • Physostigmine 3mg sc/4-6 hours

24. Contraindications • Individuals with narrow irido-corneal angle • Elderly males with Benign Prostatic Hypertrophy

25. Atropine Substitutes Qualities • Selective • Lesser side effects • Better applications

26. Quartenary compounds • Incomplete oral absorption • Poor penetration in brain, eye, central and ocular effects not seen after oral/parenteral administration • Slower elimination : longer acting • Higher ganglion blockade: postural hypotension, impotence • Neuromuscular blockade at high dose

27. Quarternary compounds • Hyoscine • Atropine methonitrate • Ipratropium bromide • Tiotropium bromide • Propantheline • Oxyphenonium • Isopropamide • Glycopyrrolate (pre-anesthetic medication)

28. Hyoscine butyl bromide • Less potent • Longer acting • Motion sickeness • Spastic conditions • Cutaneous patches • Also IM, SC injections

29. Ipratropium Bromide • Inhalational drug • Bronchodilation • No effect on secretions or bronchociliary clearance • Gradual onset and late peak in action • Prophylaxis of COPD > Asthma • Only transient local side effects

30. Tiotropium Bromide • High bronchial selectivity • Relative M1, M3 receptor selective • Similar to Ipratropium • Long lasting bronchodilation

31. Tertiary amines • Dicyclomine • Valethamate • Pirenzepine • Vesicoselective drugs: • Oxybutynin • Tolterodine • Flavoxate • Drotaverine

32. Dicyclomine • Anti spasmodic • Direct smooth muscle relaxant • Anti cholinergic acitivity • Avoid in <6m • Dysmenorrhea, irritable bowel • Anti emetic • Morning sickenss • Motion sickenss • Oral/IM route

33. Pirenzepine • Selective M1 blocker • No typical anti – cholinergic side effects • Reduces gastric secretion • Acts in intramural plexus and ganglia • Reduces ulcer pain • Promotes healing

34. Vasicoselective drugs • Oxybutynin: • Vasicoselective smooth muscle relaxant • M1, M3 > M2 • Urge incontinence, neurogenic bladder, nocturnal enuresis • Fewer anti cholinergic side effects • Tolterodine: • M3 selective

35. Mydriatics • Atropine: • Slow onset • 30-40min for dilation • 1-3hrs for cycloplegia • Prolonged action for about a week • Homatropine • Cyclopentolate • Tropicamide

37. Summary

38. Patient’s symptoms are often displayed by patients following prostatectomy to relieve significant obstruction of bladder outflow. • Urge incontinence can occur in patients whose pro- static hypertrophy caused instability of the detrusor muscle. • He should be advised that urinary incontinence and urinary frequency can diminish with time after prostatectomy as detrusor muscle instability subsides.

39. Patient can be helped by daily administration of a single tablet of extended-release tolterodine (4 mg/day) or oxybutynin (5–10 mg/day). A transdermal patch containing oxybutynin (3.9 mg/day) is

40. References • Tripathi K.D., Essentials of Medical Pharmacology 8th ed. Jaypee Brothers 2018-09-06 • Tara V Shanbhag, Smitha Shenoy, Veena Nayak, Pharmacology for Dentistry 3rd ed. Elsevier 2017 • Bertram G. Katzune et. Al., Basic and Clinical Pharmacology 12th ed. Mc. Graw Hill publications 2012 • Lippincott’s Illustrated Reviews 4th ed. Wolters Kulver 2009