Dugs used in Myasthenia gravis and Glaucoma.pptx

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1. Drugs used in Myasthenia gravis and Glaucoma

2. Myasthenia Gravis

3. I N T R O D UC T I ON Myasthenia gravis (MG) is a complex, autoimmune disorder in which antibodies destroy neuromuscular connections. Causes problems with the nerves that communicate with muscles. Affects the voluntary muscles of the body, especially the eyes, mouth, throat, and limbs.

4. Characterized by weakness and rapid fatigue of any of the muscles under the voluntary control. The cause of myasthenia gravis is a breakdown in the normal communication between nerves and muscles. No cure for myasthenia gravis, but treatment can help relieve signs and symptoms – such as weakness of arm or leg muscles, double vision, drooping eyelids, and difficulties with speech, chewing, swallowing and breathing.

5. TYPES OF MYASTHENIA GRAVIS Three types of MG in children: Congenital MG - Very rare non-immune form of MG that is inherited as an autosomal recessive disease. Symptoms of congenital MG usually begin in the baby's first year and are life-long. Transient neonatal MG - Between 10 and 20 percent of babies born to mothers with MG may have a temporary form of MG. Neonatal MG usually lasts only a few weeks, and babies are not at greater risk for developing MG later in life. Juvenile MG - This auto-immune disorder develops typically in female adolescents. It is a life-long condition that may go in and out of remission. About 10 percent of MG cases are juvenile-onset.

6. SYMPTOMS Congenital MG symptoms may begin in the first year, with generalized weakness in the arms and legs, and delays in motor skills such as crawling, sitting, and walking Babies with neonatal MG may be weak, with a poor suck, and may have respiratory difficulty. A few babies may need the help of a mechanical breathing machine if their respiratory muscles are too weak to breathe on their own. Juvenile MG symptoms may begin gradually over weeks or months. The child may become excessively tired after very little activity, and begin to have problems chewing and swallowing. Drooping eyelids may be so severe that the child cannot see.

7. Eye muscles In more than half the people who develop MG, their first signs and symptoms involve eye problems: Drooping of one or both eyelids (ptosis) Double vision (diplopia), which may be horizontal or vertical Blurred vision, which may come and go

8. Face and throat muscles In about 15 percent of people with myasthenia gravis, the first symptoms involve face and throat muscles, which can cause difficulties with: Speaking . The speech may be very soft or sound nasal, depending upon which muscles have been affected. Swallowing . May choke very easily, which makes it difficult to eat, drink or take pills. In some cases, liquids may come out of the nose. Chewing . The muscles used for chewing may wear out halfway through a meal, particularly if eating something hard to chew, such as sugarcane. Facial expressions . Family members may note "lost smile" if the muscles that control facial expressions are affected.

9. Arm and leg muscles Myasthenia gravis can cause weakness in arms and legs, but this usually happens in conjunction with muscle weakness in other parts of the body – such as eyes, face or throat. The disorder usually affects arms more often than legs. If it affects legs, may waddle when walking. Normal dumbbell Weakness dumbbell

10. W h e n t o se e a d o c tor If having trouble with: Breathing Seeing Swallowing Chewing Walking

11. C A U S E S Myasthenia gravis may be inherited, genetic disease, acquired by babies born to mothers with MG Nerves communicate with the muscles by releasing chemicals, called neurotransmitters, which fit precisely into receptor sites on the muscle cells. In myasthenia gravis, immune system produces antibodies that block or destroy many of the muscles receptor sites for a neurotransmitter called acetylcholine. With fewer receptor sites available, muscles receive fewer nerve signals, resulting in weakness.

12. Chemicals messengers, called neurotransmitters, fit precisely into receptor sites on your muscle cells. In myasthenia gravis, certain receptor sites are blocked or destroyed, causing muscle weakness.

13. How antibodies against acetylcholine receptor block impulse conduction in synapse

14. It's believed that the thymus gland, a part of the immune system located in the upper chest beneath the breastbone, may trigger or maintain the production of these antibodies. Large in infancy, the thymus is small in healthy adults. But, in some adults with myasthenia gravis, the thymus is abnormally large. Some people also have tumors of the thymus. Usually, thymus gland tumors are noncancerous.

15. COMPLICATIONS Myasthenic crisis : A life-threatening condition, which occurs when the muscles that control breathing become too weak to do their jobs. Emergency treatment is needed to provide mechanical assistance with breathing. Thymus tumors : About 15 percent of the people who have myasthenia gravis have a tumor in their thymus, a gland under the breastbone that is involved with the immune system. Most of these tumors are noncancerous.

16. Other disorders Underactive or overactive thyroid . The thyroid gland, located in the neck, secretes hormones that regulate metabolism. If thyroid is underactive, body uses energy more slowly. An overactive thyroid makes body use energy too quickly. Lupus . Disease of immune system. Common symptoms include painful or swollen joints, hair loss, extreme fatigue and a red rash on the face. Rheumatoid arthritis . Caused by problems with immune system. It is most conspicuous in the wrists and fingers, and can result in joint deformities that make it difficult to use hands.

17. Diagnostic tests Blood tests Genetic tests - diagnostic tests that evaluate for conditions that have a tendency to run in families. Electromyogram (EMG) - a test that measures the electrical activity of a muscle or a group of muscles. An EMG can detect abnormal electrical muscle activity due to diseases and neuromuscular conditions. Muscle biopsy - a small sample of the muscle is removed and examined to determine and confirm a diagnosis or condition.

18. TREATMENTS & DRUGS Specific treatment to age, overall health, and medical history and extent of the condition No cure for MG, but the symptoms can be controlled. MG is a life-long medical condition and the key to medically managing MG is early detection. The goal of treatment is to prevent respiratory problems and provide adequate nutritional care to the child since the swallowing and breathing muscles are affected by this condition.

19. Medications Cholinesterase inhibitors . Drugs like pyridostigmine (Mestinon) enhance communication between nerves and muscles. These drugs don't cure, but improves muscle contraction and strength. Corticosteroids . These types of drugs inhibit the immune system, limiting antibody production. Prolonged use of corticosteroids, can lead to serious side effects, like bone thinning, weight gain, diabetes, increased risk of some infections, and increase and redistribution of body fat. Immunosuppressants . Doctor may also prescribe other medications that alter immune system, like azathioprine (Imuran), cyclosporine (Sandimmune, Neoral) or mycophenolate (CellCept).

20. T h e r a p y Plasmapheresis . This procedure uses a filtering process similar to dialysis. Blood is routed through a machine that removes the antibodies that are blocking transmission of signals from nerve endings to muscles receptor sites. However, the beneficial effects usually last only a few weeks. Intravenous immune globulin . This therapy provides body with normal antibodies, which alters immune system response. It has a lower risk of side effects than do plasmapheresis and immune- suppressing therapy, but it can take a week or two to start working and the benefits usually last less than a month or two.

21. Thymectomy - surgical removal of the thymus gland. The role of the thymus gland in MG is not fully understood, and the thymectomy may or may not improve a child's symptoms. About 15 percent of the people who have MG have a tumor in their thymus For people with MG who don't have a tumor in the thymus, it's unclear whether the potential benefit of removing the thymus outweighs the risks of surgery. This is an individualized decision between patient and the doctor, but most doctors don't recommend surgery if: Symptoms are mild Symptoms involve only the eyes Patients over 60 years old Surgery

22. Plasmapheresis - a procedure that removes abnormal antibodies from the blood and replaces the child's blood with normal antibodies through donated blood. Extent of the problems is dependent on the severity of the condition and the presence of other problems that could affect the child. In severe case s , a b r e a t h in g m a c hin e m a y b e required to help the child breathe easier. It is important to allow the child as machine dependent function and self care, especially with juvenile MG, as possible and to promote age- appropriate activities to ensure a sense of normalcy.

23. Glaucoma

24. What is glaucoma ? Glaucoma – ancient meaning (Greek) clouded or blue- green hue Glaucoma – blindness coming from advancing years (!) Second leading cause of blindness Glaucoma is a group of disorders characterized by a progressive optic neuropathy resulting in a characteristic appearance of optic disc & specific pattern of irreversible visual field defects that are associated frequently but not invariably with ↑IOP (>21 mm Hg) All types of glaucoma – progressive optic neuropathy due to the death of retinal ganglion cells (RGCs)

25. Aqueous humor dynamics Aqueous is continuously produced by the ciliary body (2-3 µl/minute) Aqueous flows from the posterior chamber through the pupil into the anterior chamber Aqueous filters largely through the trabecular meshwork (90%) and canal of Schlemm→ episcleral venous plexus and into systemic circulation. Aqueous also exits to a smaller extent through the ocular venous system (10%) – Uveoscleral outflow (ciliary body, choroid, scleral vessels)

26. Types of glaucoma Congenital glaucoma Primary glaucoma Open angle Closed angle Secondary glaucoma – lens induced, traumatic or steroid induced Absolute glaucoma

27. Therapeutic goal Lower IOT by Reduction of aqueous humor secretion Promoting aqueous drainage Lowering of IOT retards the progression of optic nerve damage even in normal/low i.o.t

28. Open angle/wide angle/chronic simple glaucoma Genetically predisposed degenerative disease affecting patency of trabecular meshwork Meshwork becomes less efficient at draining IOP builds up progressively Damage of the optic nerve Has no symptoms in its early stages after middle age Ocular hypotensive drugs - reduce formation of AH, increase drainage or protect optic nerve

29. Open-angle Glaucoma (OAG)

30. D rugs for Glaucoma β- adrenergic blockers: Timolol, Betaxolol and Levobunolol α- adrenergic agonists: Dipivefrine, Apraclonidine and Brimonidine PG analogues: Latanoprost, Travoprost and Bimatoprost Carbonic anhydrase inhibitors: Acetazolamide and dorzolamide Miotics: Pilocarpine and Physostigmine

31. Location of targets of drugs

32. β- adrenergic blocker in glaucoma - MOA Topical β- adrenergic blockers have been the first line of drugs - PG F 2α are preferred now Contrast to miotics – no effects on pupil size, tone of cilliary muscle and outflow facility Lower IOP by reducing aqueous formation Down regulation of adenylylcyclase due to β 2 receptor blockade in cilliary epithelium Reduction of blood flow Advantages over miotics – produce less ocular side effects, lipophillic and weak anaesthetic (corneal hyposthesia and damage)

33. β- adrenergic blockers – contd. Ocular side effects: mild and infrequent Stinging, redness, dryness Corneal hypoesthesia Blurred vision Systemic adverse effects: Major limitation of use Nasolacrima duct Life threatening bronchospasm – COPD and asthma Bradycardia, heart block and CHF – ADRs

34. Individual drugs – beta blockers Timolol (0.25-0.5% eye drops): Non-Selective- β1 + β2 sympathomimetic action ↓ IOT by 20-35% - 1 hour to 12 hours Smooth and well sustained action after chronic dosing→ high level of clinical safety – advantage 30% patients response Betaxolol (0.5 %) Selective β1 blocker - Less bronchopulmonary, probably less cardiac, central and metabolic effects Exert protective effect on retinal neurones Less efficacious in ↓ IOT than timolol (β2) Levobunolol: Once daily dosing alt. to timolol Ocular and systemic side effects similar to timolol

35. α – adrenergic agonists MOA α1 constrict ciliary body - reduced aqueous secretion α2 in ciliary epithelium reduce aqueous secretion Secondary role in enhancing drainage of aqueous mainly through uveoscleral outflow and also trabecular outflow Dipivefrine (0.1 %) Adrenaline – ocular smarting, reactive hyperemia Prodrug of adrenaline→ Adr. ↓ IOT by ↑ uveoscleral outflow,↑ trabecular outflow (β2), ↓ aqueous production (α1 + α2 ) Not used now due to systemic effects & ocular intolerance Maybe used as an add-on therapy

36. α – adrenergic agonists – contd. Apraclonidine (0.5- 1%): Clonidine congener No CNS penetration - acts on both α 1 & α 2 receptors of ciliary body→ ↓ aqueous production . ↓ IOT by ~25% ADRs: itching, lid dermatitis, follicular conjunctivitis, mydriasis, eyelid retraction, dryness of mouth and nose etc. Use is restricted to short term control of IOT spikes (trabeculoplasty or iridotomy). Brimonidine (0.2%): Newer clonidine congener , more selective to α 2 More lipophilic than apraclonidine ↓ IOT by 20-27% by ↓ aq. production and ↑ uveoscleral flow. Uses both in short term (post surgery) and long term therapy in glaucoma. – add on therapy

37. Prostaglandin analogues Low concentration of PGF2α analogues ↓ IOT by: Increase uveoscleral outflow (↑ciliary tissue permeability and vascular permeability) Trabecular outflow less marked Latanoprost (0.005% eye drop) Topically IOT ↓ 25-35%, well sustained ↓ IOT in normal pressure glaucoma also Ocular irritation and pain Good efficacy, once daily application and absence of systemic complications – first choice in open angle glaucoma Other ADRs: Blurring of vision, iris pigmentation, thickening and darkening of eye lashes etc. Travoprost and Bimatoprost: similar efficacy with Latanoprost

38. Carbonic anhydrase inhibitors Carbonic anhydrase present within ciliary epithelial cells generates HCŌ3 ion secreted into aq. humour. Inhibition of carbonic anhydrase - Limits generation of bicarbonate ion → reduction of aqueous humour Acetazolamide: Orally – 0.25 gm 6-12 hourly Used to supplement ocular hypotensive drugs for short term indication like angle closure, before & after surgery/laser therapy Long term use when IOP not controlled by topical drugs Side effects: Systemic s/e – paresthesia, anorexia, hypokalemia , acidosis, malaise, depression (on long term use) Dorzolamide: 2% eyedrop topical – 20% efficacy

39. Miotics In 1970s – were standard antiglaucoma drugs Last option because of several drawbacks – myopia, diminution of vision, headache Pilocarpine: Causes miosis by contraction of iris sphincter muscle → removes pupillary block and reverses obliteration of iridocorneal angle Contraction of ciliary muscle → pulls on scleral spur and improves trabecular patency. Max of 10-20% IOP reduction - 0.5% to 4% solution

40. OAG – current approach Monotherapy with Latanoprost or a topical β - blocker If not target attained – change to alternative drug or both together Brimonidine/dorzolamide (or dipivefrine) used when above two contraindicated Acetazolamide and Miotics – last option

41. Angle closure (narrow angle, acute congestive) Glaucoma Emergency situation occurring in person with narrow iridocorneal angle and shallow anterior chamber IOT raised after it is being precipitated by mydriasis IOT rises rapidly to very high levels (40 - 60 mmHg) Marked congestion of eyes and severe headache Failure to lower IOT → loss of sight Definite treatment – surgery (iridotomy/laser therapy)

42. Closed angle glaucoma

43. Therapy of closed angle glaucoma Hypertonic mannitol (20%) 1.5-2 g/kg or Glycerol (10%): IV infusion – decongest eye by osmotic action Glycerine 50% - retention enema Acetazolamide (0.5g) IV followed by oral BD started concurrently Miotic: If above reduced the IOP -topical Pilocarpine 1-4 % every 10 mins initially & then at longer intervals. Topical β blocker: Timolol 0.5% 12 hourly in addition. Latanaprost (0.005%) / Apraclonidine (1%) may also be added. Chronic narrow angle: miotic/other drugs for longer period

44. Must know Different categories of drugs used in open angle glaucoma Their sites and mechanism of action Management of closed angle glaucoma

45. Thank you