Muscrinic Antagonist and nicotinic antagonist Drugs.pptx

Anti Muscrinic Drugs

1. Cholinergic Antagonists Muscarinic & NICOTINIC AGONISTS

2. Introduction These agents block cholinergic receptors thereby inhibit cholinergic transmission hence these agents are also called as parasympatholytic. These drugs can block specifically either muscarinic receptors or nicotinic receptors. These drugs binds with Ach receptors but have intrinsic activity equal to zero and do not activate the receptor.

3. History Roman empire and middle ages Deadly nightshade shrub: Atropa belladonna The plant contains atropine and scopolamine, potent antimuscarinic agents. Ancient Greeks and Romans used belladonna for its medicinal properties, including pain relief and as a muscle relaxant. Datura stramonium In ancient – Use of Jimson weed – roots and leaves – burnt – smoke was inhaled by asthmatics. Women used belladonna to dilate their pupils, a practice considered to enhance beauty. The name "belladonna" means "beautiful lady" in Italian.

4. BELLADONNA EYES MYDRIASIS

5. Classification • • • • • Natural: Atropine and Hyoscine (scopolamine) Semisynthetic derivatives: Homatropine, Atropine methonitrate, Hyoscine butylbromide, Ipratropium bromide, Tiotropium bromide Synthetic Compounds: Mydriatics: Cyclopentolate and Tropicamide Antisecretory-antispasmodics:   Quartenary ammonium compounds: Propantheline, Oxyphenonium, Clidinium, Pipenzolate methylbromide, Glycopyrrolate, Isopropamide Tertiary amines: Dicyclomine, Valethamate, Pirenzepine • • • Vasicoselective: Oxybutynin, Flvoxate, Tolterodine Antiprkinsonian: Trihexyphenidyl (Benzhexol), Procyclidine, Biperiden Additionally – TCAs, Phenothiazines and antihistaminics

6. Classification

7. Muscarinic Receptors Muscarinic receptors are G-protein coupled receptors involved in parasympathetic nervous system functions, with five subtypes designated M1 to M5. M1 Receptors : Located primarily in the CNS and gastric parietal cells. M2 Receptors : Found mainly in the heart and CNS. M3 Receptors : Present in smooth muscles, exocrine glands, and the eyes. M4 Receptors : Predominantly in the CNS. M5 Receptors : Located in the CNS and peripheral tissues. Nicotinic Receptors Nicotinic receptors are ligand-gated ion channels that mediate fast synaptic transmission. They are categorized into two main types based on their location and function. Nicotinic N (NN) Receptors: Found in autonomic ganglia, the adrenal medulla, and the CNS. Nicotinic M (NM) Receptors : Located at the neuromuscular junctions of skeletal muscles. Anticholinergic Receptors

8. Non-selective muscarinic antagonists Atropine Scopolamine Dicyclomine Cyclopentolate Tropicamide Ipratropium Tiotropium Solifenacin Oxybutynin Tolterodine Benztropine Trihexyphenidyl

9. Selective muscarinic antagonists Selective cholinergic antagonists are available on M1, M2 and M3 receptors. M1 antagonist Pirenzepine M2 antagonist Gallamine M3 antagonist Darifenacin

10. Mechanism of action Competitive antagonism Reversible (surmountable) blockade Competition of atropine and scopolamine with acetylcholine for the muscarinic receptor

11. Mechanism of action

12. Absorption Tertiary antimuscarinic drugs Absorbed rapidly from the GI tract and conjunctival membrane When applied in suitable vehicle, some are even absorbed across the skin Scopolamine: transdermal patch in the post-auricular region Quaternary antimuscarinic drugs only 10-30% is absorbed after oral administration Decreased solubility of the charged molecule Less readily penetrate the conjunctiva of the eye

13. Tertiary anti-muscarinic drugs Atropine and other tertiary agents widely distributed in the body Significant levels are achieved in CNS within 30 min to 1 hr Scopolamine is rapidly and fully distributed into the CNS where it has greater effects than most others Crosses placental barrier and secreted in milk and saliva Quaternary anti-muscarinic drugs Quaternary derivatives are poorly taken up by the brain and therefore free of CNS effects Distribution

14. Metabolism & Elimination Atropine has a t 1/2 of ≈4 hours Hepatic metabolism accounts for the elimination of about half of a dose Remainder is excreted unchanged in the urine.

15. Pharmacological actions

16. Effects of Atropine in Relation to Dose DOSE (mg) EFFECTS 0.5 Slight cardiac slowing; some dryness of mouth; inhibition of sweating 1 Definite dryness of mouth; thirst; acceleration of heart, sometimes preceded by slowing; mild dilation of pupils 2 Rapid heart rate; palpitation; marked dryness of mouth; dilated pupils; some blurring of near vision 5 Above symptoms marked; difficulty in speaking and swallowing; restlessness and fatigue; headache; dry, hot skin; difficulty in micturition ; reduced intestinal peristalsis 10 Above symptoms more marked; pulse rapid and weak; iris practically obliterated; vision very blurred; skin flushed, hot, dry, and scarlet; ataxia, restlessness, and excitement; hallucinations and delirium; coma

17. EYE Just like muscarinic agonists, these drugs act on two muscles in the eye. M3 Receptors Constrictor muscle ( Ciliary muscle Relaxation of this muscle by muscarinic antagonists produce pupillary dilatation. ciliary muscle is required for adjustment of the lens with respect to the distance of the object Ciliary muscle paralysis Loss of accommodation – cycloplegia (Blurred Vision) Both atropine and scopolamine produced this effect. Long duration of action Pupillary and accommodation reflex recover 7-12 days after.

18. Therapeutic uses Mydriasis Examination of retina and optic disc and for refractive errors (Short acting agents used) Cyclopentolate, Tropicamide_ Therapy of iridocyclitis and keratitis (Cornea inflammation) Cycloplegia In Rx of iridocyclitis and choroiditis Measurement of refractive errors Young – long acting mdriatics + cycloplegia preferred Adults- short acting drugs preferred Above 40 no need of complete cycloplegia because lens already have adjusted it curvature and can’t adjust any more

19. In therapy of iridocyclitis Adminstered alternately with miotics Long lasting preparations like Homatropine To break/prevent adhesions between iris and lens Complete cycloplegia is necessary in treatment of iridocyclitis & choroiditis If complete cycloplegia is required atropine or scopolamine preferred >> cyclopentolate or tropicamide. CONTRAINDICATED IN NAROW ANGLE GLUCOMA BECAUSE DIALATION CLOSE THE ANGLE FURTHER.

20. Anti-muscarinic Drugs Used in Ophthalmology Drug Duration of Effect (days) Usual Concentration (%) Ocular side effects Atropine 7–10 0.5–1 Scopolamine 3–7 0.25 Homatropine 1–3 2–5 Photosensitivity, blurred vision Cyclopentolate 1 0.5–2 Tropicamide 0.25 0.5–1

21. Glands All the glandular secretions are inhibited. Salivary secretions (Xerostomia) Lacrimal secretions (Xeropthalmia) Sweat secretion (Anhidrosis) Bronchial secretions ( Gastric secretions Reduction of salivary secretion leads to dry mouth and reduction of lacrimal secretions leads to blurred vision therapeutic uses Drug induced salivation Heavy metal poisoning Parkinson disease

22. Clinical Relevance – Sialorrhoea Sialorrhoea is drooling or excess saliva that cannot be controlled. There are two mechanisms by which this can occur: Lack of swallowing – resulting in saliva pooling in the mouth. This is typically due to neuromuscular dysfunction such as cerebral palsy, Parkinson’s disease or Motor Neuron Disease. Increased secretion of saliva – which is typically due to medication. It is often noted within the treatment of Alzheimer’s disease or myasthenia gravis, as treatment of both conditions involves the use of anti-cholinesterases.

23. MANAGEMENT depends on the cause involves treatment of any reversible factors. For example, drug regimes may need to be changed or even stopped depending on the severity. Behaviour modification may be necessary in terms of learning methods to help clear the pooled saliva. In severe cases anticholinergic medication can be used. Belladona alkaloids Synthetic tertiary amine derivatives like DICYCLOMINE are very effective Side effects If nothing else is successful radiation injection of botulinum toxin or surgery may be considered.

24. Heart

25. The decrease in the heart rate leads to tachycardia. Since they produce tachycardia, they can be indicated in sinus bradycardia. Atropine is particularly used for this condition. Usual clinical dose (0.4 to 0.6 mg) Larger dose Receptor action M1 M2 mechanism Inhibition of pre synaptic receptor M1  inc. Ach release SA and AV node Effect Bradycardia Tachycardia

26. Pharmacological Actions Effect on rhythmicity Prevents or abolishes Sinus bradycardia Effect on conduction Facilitate AV node conduction  removal of vagal influence on the heart and increase ventricular rate E.g in Atrial fibrillation II degree heart block In complete heart block

27. Antimuscarinic agent Preparations Atropine Oral: 0.4, 0.6 mg tablets Parenteral : 0.05, 0.1, 0.3, 0.4, 0.5, 0.8, 1 mg/ mL for injection

28. Bronchioles These drugs block M3 receptors on bronchioles and produce bronchodilatation . Bronchial secretions are also inhibited which is useful in asthma.

29. Respiratory System Pharmacological Actions Broncho-dilation and decrease in tracheobronchial secretion Reduction of mucous secretion and mucociliary clearance Belladona alkaloids  decreases secretions caused by irritant anaesthetics like diethyl ether Side effects: decrease mucus secretion and clearance  mucus plugs obstruction Quarternary ammonium derevatives have minimal inhibitory effect on mucociliary clearance

30. Therapeutic uses Advantages of ipratropium No effect on mucociliary clearance Inhalational – decreased systemic side effects Longer acting – can be given once daily Can be used as adjunct to pulm . Rehab. In increasing exercise intolerance Therapeutic uses COPD & Asthma Used along with adrenergic receptor agonists Decrease the rhinorrhea associated with the common cold or with allergic and nonallergic rhinitis

31. Antimuscarinic agent Duration of action Preaparations Ipratropium 4-6hrs Aerosol: 200 dose metered-dose inhaler(18mcg/puff). Solution for nebulizer: 0.02%(500mcg/vial). Nasal spray: 0.03, 0.06%(21, 42mcg/spray). Tiotropium 24hrs Aerosol: 18 mcg tablet for inhaler

32. Smooth muscle ( GIT)

33. GI Tract Therapeutic uses To facilitate endoscopy and gastrointestinal radiology by relaxing gastrointestinal smooth muscle Once used in management of peptic ulcer disease Pirenzepine and telenzepine were used Hyoscine N Butyl Bromide Anti Spasmodic

34. Once most widely used for management of peptic ulcer disease. Anti secretory doses produced – S/E- dry mouth, loss of visual accomodation , photophobia, and difficulty urination This reduced patient compliance Pirenzepine Similar in structure to imipramine It is tricyclic antidepressant Selective for M1 receptors (also M4) Inhibition of gastric acid secretion by Neural stimuli > muscarinic agoinsts Telenzepine Analogue of pirenzepine Higher potency Selective for M1 receptors

35. Antimuscarinic agent Preparations Pirenzepine Oral: 50mg tablets Telenzepine Oral: 3mg tablets Dicyclomine Oral: 10, 20 mg capsules; 20 mg tablets; 10 mg/5 mL syrup Parenteral : 10 mg/ mL for intramuscular injection     Glycopyrrolate Oral: 1, 2 mg tablets Parenteral: 0.2 mg/mL for injection

36. Genito -Urinary Tract Pharmacological Actions Relaxes smooth muscles of ureter and bladder wall and slows voiding lower intra-vesicular pressure increase capacity reduce the frequency of contractions alter bladder sensation during filling This effect is achieved only after the inhibition of salivation, lacrimation & blurring of vision Mediated by multiple receptor subtypes M2 < M3

37. Genito -Urinary Tract Therapeutic uses Motor Urge (Hypertonic) Incontinence: This is the most common incontinence in elderly Etiology. Involuntary rises in bladder pressure occur from idiopathic detrusor contractions that cannot be voluntarily suppressed Urge incontinence can be linked to stroke, Parkinson's disease, multiple sclerosis and other health conditions which interfere with the brain's ability to send messages to the bladder via the spinal cord. These conditions can affect a person's ability to hold and store urine.

38. Motor Urge (Hypertonic) Incontinence: Management. Anticholinergic medications Oxybutynin [Ditropan] 5mg BD oral Dicyclomine 10-20 mg BD Solifenacin 5-10 mg BD oral Tolterodine 2 mg BD oral Fesoterodine Flavoxate 200 mg TDS oral Non-steroidal anti-inflammatory drugs (NSAIDs) to inhibit detrusor contractions; Tricyclic antidepressants; Calcium -channel blockers Newer addition for the t/t of urge incontinence Mnemonic SOFT bladder Therapeutic uses

39. Stress incontinence • Involuntary loss of urine • With coughing and sneezing • No urine lost at night Treatment: Medical therapy some success with duloxetine ( yentreve ) (SNRI) Surgical therapy Therapeutic uses

40. Drugs - Inhibit/Promote Voiding

41. 3.R x of enuresis in children by lowering intra-vesicular pressure, increasing capacity and reducing frequency of contractions 4.Used to reduce urinary frequency in spastic paraplegia and to increase capacity of bladder 5. To relieve spasm after urological surgery Prostatectomy

42. 6. Used to reduce involuntary voiding in patients with neurological disease Children with menigomyelocele – Oxybutynin orally or can be instilled via catheter 7. Propiverine is a newer anticholinergic drug used for the treatment of urinary urgency, frequency and urge incontinence, all symptoms of overactive bladder syndrome. It is a muscarinic antagonist. A modified release preparation is also available, taken once daily.

43. NONPROPRIETARY NAME t 1/2 (HOURS)   METABOLISM & ELIMINATION PREPARATIONS   DAILY DOSE (ADULT) Oxybutynin 2-5 CYP3A4 Immediate Release 10-20 mg     Extended Release 5-30 mg     Transdermal patch 3.9 mg     Topical gel 100 mg Tolterodine 2-9.6 CYP2D6, CYP3A4 IR 2-4 mg   6.9-18 ER 4 mg Trospium chloride 20 KIDNEYS IR 20-40 mg   35 ER 60 mg Solifenacin 55 CYP3A4 IR 5-10 mg Darifenacin 13-19 CYP2D6, CYP3A4 ER 7.5-15 mg Fesoterodine 7 ER 4-8 mg

44. Other Smooth Muscle Biliary Tract Mild antispasmodic action Not effective to prevent the spasm induced by opioids Sweat Glands and Temperature Inhibits the activity of sweat glands Skin becomes hot and dry Sweating may be depressed enough to raise body temperature

45. Central Nervous System Pharmacological Actions Atropine : action on CNS is dose dependent Therapeutic doses Minimal effects, mild stimulation of the parasympathetic medullary centres With toxic doses Central excitation With still larger doses: Stimulation followed by depression Scopolamine Crosses BBB, has prominent central effects at low therapeutic doses; CNS depression, amnesia also causes euphoria In severe pain, same doses cause excitement

46. Parkinson disease Adjunct to levodopa Motion sickness Given prophylactically Therapeutic uses

47. Antimuscarinic agent Preparations Usual daily dose    Scopolamine Oral: 0.25 mg tablets Parenteral : 0.3, 0.4, 0.6, 1 mg/ mL for injection      Transdermal patch: delivers ≈0.5mg over 72hrs Benztropine Oral: 0.5, 1, 2 mg tablets Parenteral: 1mg/ml for injection 1–6mg Biperiden Oral: 2mg tablets Parenteral: 5mg/ml for injection 2–12mg Trihexyphenidyl Oral: 2, 5mg tablets Sustained release: 5mg capsules 6–20mg

48. Other uses Uses in Anesthesia Blocks vagal reflexes induced by surgical manipulation of viscera In anaesthetic premedication , atropine, and hyoscine block the vagus and reduce mucosal secretions; hyoscine also has useful sedative and amnestic effects

49. Organophosphorus Poisoning The use of atropine in large doses for the treatment of poisoning by anticholinesterase organophosphorus insecticides. 1-2 mg of atropine sulfate I.V every 5-15 min until signs of effect appear Acute effects of op poisioning last for 24-48 hrs

50. In mushroom poisoning : Rapid onset type: Characterized by early signs of muscarinic excess – nausea, vomiting, diarrhea, urinary urgency, vasodilation, reflex tachycardia, sweating, salivation and broncho -constriction Inocybe genus mushrooms causes rapid type poisioning Parenteral atropine 1-2 mg Delayed type Amanita phylloides A.virosa Atropine is of no value

51. Contraindications Include Urinary tract obstruction GI obstruction Uncontrolled (or susceptibility to attacks of) angle-closure glaucoma. Benign prostatic hyperplasia.

52. Atropine poisoning Atropine has wide margin of safety Lethal dose Children: 10-20mg Adults: 80-130mg Scopolamine is more toxic than atropine Poisoning may also occur following ingestion of natural sources.

53. Adverse effects

54. Signs and symptoms

55. Blind as Bat Dry as Bone Hot as Hare Red as Beat

56. diagnosis Intravenous injection of the anticholinesterase agent physostigmine may be used for confirmation. If physostigmine does not elicit the expected salivation, sweating, bradycardia , and intestinal hyperactivity, intoxication with atropine or a related agent is almost certain.

57. Contd … If Poison ingested Gastric lavage Universal antidote Muscarinic effects- counteracted by IV Physostigmine 1-4mg(adult), 0.5-1mg(children), repeated at intervals till satisfactory control Restlessness, delirium- Diazepam Dark room to alleviate photophobia Catherization for urinary retention Tepid sponging for pyrexia Good nursing care, oxygen, artificial ventilation (when necessary)

58. Summary Muscarinic receptor antagonists have a wide variety of therapeutic uses: Treatment of overactive bladder COPD Increased GI motility Ophthalmology OP poisioning

59. References HL Sharma & KK Sharma’s “Principles of Pharmacology” 3 nd edition Goodman & Gilman’s “The Pharmacological Basis of Therapeutics” Rang & Dale’s “Pharmacology” 8 th edition Katzung’s “Basic and Clinical Pharmacology” 14 th edition R.S. Satoskar’s “Pharmacology and Pharmacotherapeutics ” 23 rd edition KD Tripathi’s “Essentials of Medical Pharmacology” 7 th edition

60. Thank you