Myasthenia gravis

1. Myasthenia gravis • A condition where voluntary muscles become easily fatigued (tired) and weak • Due to a problem with the immune system (acquired immunological disorder and genetic abnormalities).

3. Myasthenia gravis • Autoimmune disorder • Antibodies against nicotinic (NM) receptor • Weakness, fatigueability on repeated activity • Drugs used are:- i) {Neostigmine/ Pyridostigmine}+ Atropine ii) Prednisolone iii) Azathioprine/ Cyclosporine

4. Rationale of using Neostigmine/ Pyridostigmine • They improve muscle contraction by allowing Ach released from prejunctional endings to accumulate & act on receptors over a larger area & by directly depolarizing the endplate. • Neostigmine 15mg orally 6 hourly • Atropine is combined with neostigmine to prevent intolerable muscarinic side effects caused by neostigmine

5. Anticholinesterase Poisoning Manifestations :- • DUMBELS Diarrhea Urination Miosis , muscular weakness Bronchospasm Excitation Lacrimation Sweating , salivation, seizures

6. Treatment of Anticholinesterase Poisoning • Prevent further exposure • Maintain patent airway • Maintain BP • Control convulsions using Diazepam • SPECIFIC ANTIDOTES i) atropine ii) oximes

7. Rationale of using Atropine • Highly effective in counteracting muscarinic symptoms • Dose 2 mg IV repeated every 10 min till pupil dilates • Upto 200 mg can be administred per day • Maintenance dose may require for 1-2 weeks • First choice drug

8. Rationale of using OXIMES • They are cholinesterase reactivators • Used to restore neuromuscular transmission • Pralidoxime  Slow IV injection in a dose of 1-2g • Treatment should be started as early as possible • Second choice drugs

10. ANTIMUSCARINICS

11. INTRODUCTION • Anticholinergic drugs are also referred as muscarinic receptor antagonists, atropinics parasympatholytics. • These drugs are those which blocks the actions of Ach on autonomic effectors and in the CNS, exerted through muscarinic receptor.

12. Anti Cholinergics • Nicotinic antagonists also block certain actions of Ach and are generally referred to as “GANGLIONIC BLOCKERS” and “NEUROMUSCULAR BLOCKERS”

13. CLASSIFICATION OF DRUGS Synthetic derivatives

14. ATROPINE • Atropine, the prototype drug of this class is highly selective for muscarinic receptors but some of its synthetic substitutes do possess significant nicotinic blocking property. • SOURCE: • It is an alkaloid obtained from the plant “Atropa belladonna" and in “Datura stramonium”

15. CHEMISTRY: • Atropine is a tertiary amine alkaloid esters of tropic acid.

16. ABSORPTION: • Atropine, the natural alkaloid is well absorbed from the gut and conjunctival membranes. DISTRIBUTION: • Atropine and other tertiary agents are widely distributed in the body. Significant levels are achieved in the CNS within 30min to 1hr.

17. METABOLISM & EXCRETION: • Atropine disappears rapidly from the blood after administration, with a half life of 2hr. About 60% of the dose is excreted unchanged in the urine.

18. MECHANISM OF ACTION: • Atropine causes reversible blockade of cholinomimetic actions at muscarinic receptors i.e. blockade by small dose of atropine can be overcome by a larger conc. of Ach.

19. PHARMACOLOGICAL ACTIONS • Atropine is highly selective for muscarinic receptors and the prominent effects are seen in organs which normally receive strong parasympathetic tone.

20. CNS :Atropine has overall stimulant action. • It stimulates many medullary centers –vagal,respiratory,vasomotor. • It depresses vestibular excitation and has anti-motion sickness property

21. It supresses tremor & rigidity of parkinsonism. • High doses causes Cortical excitation, disorientation,hallucination, & delirium followed by respiratory depression & Coma.

22. CVS : • Heart : most prominent effect of atropine is to cause “TACHYCARDIA” • BP: It doesn't have any marked or consistent effect on BP.

23. EYE : Topical instillation of atropine causes mydriasis, abolition of light reflex and cycloplegia lasting 7-10 days. This results in photophobia and blurring of near vision

24. SMOOTH MUSCLES : • All visceral smooth muscles that receive parasympathetic motor innervations are relaxed by atropine(M3 blockade). • Constipation may occur, Spasm may be relieved. • Effect on the uterus is minimal.

25. Atropine causes bronchodilatation & reduces airway resistance, specially in COPD & asthmatics. • It has relaxant action on ureter & urinary bladder.

26. GLANDS : • Atropine markedly decreases sweat, salivary, tracheobronchial& lacrimal secretions(M3 blockade). • Skin and eyes become dry, talking & swallowing may be difficult. GENITOURINARY TRACT: • Smooth muscles of ureters & urinary bladder wall is relaxed →voiding is slowed→ urinary retention

27. BODY TEMPERATURE : • Hyperthermia occurs at higher doses. children are highly susceptible to “ATROPINE FEVER” LOCAL ANAESTHETIC: • Atropine has mild anesthetic action on the cornea

28. Sensitivity of different organs and tissues to atropine varies and can be graded as – saliva, sweat ,bronchial secretions > eye, bronchial muscle, heart > smooth muscles of intestine, bladder > gastric glands and smooth muscles.

30. PHARMACOKINETICS: • Atropine and hyoscine are rapidly absorbed from G.I.T. • Freely penetrate cornea. Passage across BBB is some what restricted. • About 50% of atropine is metabolized in liver and rest is excreted unchanged in urine. • t1/2 of 3-4 hrs.

31. Hyoscine is more completely metabolized and has better BBB penetration. PREPARATION: • Atropine sulfate: 0.6-2 mg i.m, i.v. (children 10mcg/kg ).1-2%topically in eye. • Hyoscine hydrobromide:0.3-0.5 mg oral i.m. ;also as transdermal patch.

32. Therapeutic Uses of Antimuscarinics • Motion sickness Scopolamine 0.6 -1.0 mg S.C Transdermal patches of Scopolamine applied on the skin behind the ear releases 0.5mg over a period of 3 days

33. Parkinson’s disease Benztropine 1-5mg/day orally Procyclidine 5-15mg/day orally Biperiden 2-10mg/day orally • As Mydriatic For the appropriate measurement of refractive errorneedsciliary paralysis Homatropine 1-2% Tropicamide 0.5-1% Cyclopentolate 0.5-1%

34. To prevent adhesions in inflammatory conditions of the eye To prevent adhesion between iris and lens as in iridocyclitis , iritis or uveitis Longer acting Homatropine is used

35. Bronchial Asthma & chronic obstructive pulmonary disease (COPD) ↓bronchial secretions Do not interfere mucociliary clearance & causes bronchodilatation Ipratropium can be given as nebulised bronchodilator along with Salbutamol in an acute attack of asthma

36. Preanaesthetic Medication To reduce bronchial secretions To prevent excessive vagal effect on heart Drugs used are Atropine, Scopolamine & Glycopyrrolate Glycopyrrolate cause less tachycardia & reduces bronchial & salivary secretions more effectively

37. Peptic ulcer Pirenzepine & Telenzepine Selective M1 blockers Pirenzepine 50mg TDS orally Telenzepine 3mg/day orally Acts by blocking the M1 receptors at paracrine cells in the gastric mucosa Equally effective in treatment & in preventing the recurrence of duodenal ulcer

38. As Antispasmodic Drugsused are Methyl atropine, Hyoscine methyl bromide, Dicyclomine, Oxyphenonium, Glycopyrrolate Used in hyper motility of the gut as in intestinal colic, traveller’s diarrhoea, irritable bowel syndrome, biliary colic For symptomatic relief drugs are often combined with opioids

39. To reduce excessive salivation In reducing excessive salivation due to heavy metal poisoning / parkinsonism • As Cardiac Vagolytic In counteracting bradycardia & partial heart block

40. Miscellaneous Uses • Treatment of mushroom poisoning • Treatment of muscarinic side effects of Neostigmine • Treatment of organophosphorous poisoning • In hyperhydrosis • Treatment of renal colic • To relieve ureteral smooth muscle spasm • Urinary incontinence in adults • To treat nocturnal enuresis in children

41. Adverse effects & Toxicities • Dryness of mouth, ↓ sweating • Blurred vision, Photophobia, precipitation of glaucoma • Constipation Symptoms of poisoning • Dry skin (as dry as bone) • Hyperpyrexia, Flushing of skin (as red as beet) • Photophobia (as blind as bat) • Dry mouth, Slurred speech, Difficulty in micturition, Confusion, Delirium, Restlessness , Hallucinations (as mad as hen)