1. 1. OCULAR STEROID Suraj Chhetri B.Optometry 16th batch
2. 2. PRESENTATION LAYOUT Introduction to steroids Introduction to adrenal gland Inflammatory response Pharmacologic principle of steroids Common ophthalmic steroids Indications, contraindications and side effects of steroids
3. 3. 3 Steroid" is a chemical name for any substance that has a characteristic chemical structure consisting of multiple chemical rings of connected atoms. Contains four cycloalkane rings 3 rings : cyclohexane 1 ring : cyclopentane INTRODUCTION TO STEROID
4. 4. cortisol dexamethasone Some examples of natural steroids Vitamin D Cholesterol Estrogen Progesterone Cortisol Some examples of synthetic steroids Prednisolone Dexamethasone Betamethasone trimcinolone
5. 5. ADRENAL GLAND Two in number, superior and slight medial to kidneys Two parts: adrenal cortex (80%) adrenal medulla (20%) Each weight about 4 grams
6. 6. ADRENAL CORTEX Comprises 3 zones: Zona glomerulosa(15%) Zona fasciculata(75%) Zona reticularis(10%)
7. 7. ZONA GLOMERULOSA : Produce mineralocorticoids i.e Aldosterone ZONA FASCICULATA : Produce glucocorticoids e.g Cortisol , corticosterone , small amount of adrenal androgens and estrogens ZONA RETICULARIS : Produce androgens e.g Dehydroepiandrosterone ,small amount of estrogen and some glucocorticoids
8. 8. HYPOTHALAMO-PITUITARY- ADRENAL AXIS
9. 9. Secretion of mineralocorticoids depend upon extracellular fluid concentrations of angiotensin II and potassium Secretion of glucocorticoids controlled by hypothalmic pituitary axis via ACTH(adrenocorticotropic hormone) Thus secretion pathway of mineralocorticoids and glucocorticoids does not depend upon each other
10. 10. FUNCTION OF MINERALOCORTICOIDS Aldosterone increases renal tubular reabsorption of sodium and secretion of potassium Excess Aldosterone increases extracellular fluid volume and arterial pressure but has only small effect on plasma sodium concentration Excess aldosterone causes hypokalemia and muscles weakness
11. 11. FUNCTION OF GLUCOCORTICOIDS 1.Effect on carbohydrate metabolism i.e stimulation of gluconeogenesis Decrease glucose utilization by the cells Elevate the blood glucose concentration and cause Adrenal diabetes Cortisol increases the enzyme required to convert the amino acid into the glucose in liver cells Cortisol causes mobilization of amino acids from the extrahepatic tissue mainly from muscles
12. 12. 2.Effect on protein metabolism Reduction of cellular protein Cortisol increases the liver and plasma protein Excess of cortisol may cause muscle so weak that person can not rise from the squatting position Reduction of protein stored in essentially all body cells except those of liver cells Decreases protein synthesis and increases catabolism of protein already present
13. 13. 3.Effect on fat metabolism Mobilization of fatty acids Excess cortisol causes obesity It promotes mobilization of free fatty acids from adipose tissue Increases the concentration of free fatty acids in plasma , which increases there utilization for energy Excess deposition of fat in chest and head regions of body giving a buffalo like torso and rounded moon face
14. 14. 4.Effect in resisting stress Almost all type of stress ( trauma , infections , intense heat and cold , surgery ) cause immediate and marked increase adrenocotical secretion of cortisol Glucocorticoids cause rapid mobilization of amino acids and fat from there cellular store , making them immediately available both for energy and synthesis of other compounds
15. 15. 5. Effect on immunity and blood Decreases activation and migration of leukocytes Lyse and destroy lymphocytes Administration of large doses of the cortisol causes significant atrophy of all lymphoid tissue through out the body Cortisol increase the count of red blood cells , the cause of which is unknown Inhibit migration of neutrophils to extracellular space and adherence to vascular endothelium
16. 16. 6.Effect as strong anti-inflammatory agent To know about anti-inflammatory action , first inflammation should be discussed Inflammation is the entire complex tissue changes due to noxious agents Five different stages of the inflammation Inflammation
17. 17. 1.Chemicals such as histamine , bradykinin , proteolytic enzymes , prostaglandins and leukotrienes from damage tissue cells activates the inflammation 2. Increases blood flow due to vasodilation called erythema 3. Leakage of plasma out of capillaries into damaged area because increase capillary permiability 4. Infiltration of area by leukocytes 5. After few days ingrowth of fibrous tissue that often helps in the healing process
18. 18. Membrane phospholipid Arachidonic acid Chemical and mechanical stimuli Phospholipase A cyclooxygenase lipooxygenase endoperoxidases leukotrienes Prostacycli n PGI2 PGE2 , PGD2 , PGF2a Thromboxane A2 glucocorticoids NSAIDs Basis of inflammation
19. 19. Basic steroidal activities towards inflammation Reduce histamine release from basophils induced by IgE dependent stimulus Inhibit phospholipase A2 which prevents biosynthesis of arachidonic acid and subsequent formation of prostacyclin, prostaglandins and leukotrienes Decrease capillary permeability and fibroblast proliferation and the quantity of collagen deposition thus influencing tissue regeneration and repair The anti-inflammatory effects are nonspecific, occurring whether the etiology is allergic, traumatic or infectious
20. 20. Mode of action Every tissue has receptor for steroids Binds to glucocoticoid receptor in nucleus Because cortisol is lipid soluble it can easily diffuse through the cell membrane
21. 21. Transactivation : upregulates the expression of anti-inflammatory proteins in nucleus Transrepression : downregulates the expression of proinflammatory proteins in cytosol
22. 22. It is better to understand Increased concentration of drug better than increased dozes
23. 23. Common Ophthalmic steroids Corticosteroid Derivative Formulation Concentration Prednisolone Acetate suspension 0.125% or 1% Prednisolone Sodium phosphate solution 0.125% or 1% Dexamethasone Alcohol Suspension 0.1 Dexamethasone Sodium phosphate Solution Ointment 0.1 0.05 Flourometholo ne Alcohol Ointment Suspension 0.1 0.1 Flourometholo ne Acetate Suspension Suspension 0.25 0.1
24. 24. Prednisolone A synthetic analogue of the major glucocorticoid i.e cortisol or hydrocortisone Effective for external as well as intraocular inflammation Commercially formulated as acetate and phosphate ; acetate derivative being more effective anti-inflammatory agent Not available as an ophthalmic ointment.
25. 25. Available in concentration of 0.5% and 1% W/V Prednisolone acetate 1% is considered the standard, by which all other topical ocular corticosteroids are compared As compared with other topical ocular steroids , 1% prednisolone acetate is generally considered the most effective anti-inflammatory agent for anterior segment ocular inflammation
26. 26. Has the greatest efficacy when compared to all other available ophthalmic agents So,is more likely to elevate IOP and have greater side effects than its weaker counterparts Systemic prednisolone recommendation Tab. Prednisolone acetate 1 mg/kg of body weight *OD Tab. Ranitidine 150 mg *OD * AC Tab. Calcium * 500 mg * OD
27. 27. Dexamethasone Structurally resemble cortisol Available as an alcohol or phosphate derivative 0.1% ophthalmic suspension or solution Alcohol derivative more active than phosphate Resistant to metabolism after penetration into the aqueous humor.
28. 28. Very effective in reducing ocular inflammation But has the propensity to increase IOP more than any other topical ophthalmic corticosteroid Usually limited to shortcourse therapy Dexamethasone ointment is very useful for nighttime coverage in cases of uveitis
29. 29. Fluorometholone (FML) Structurally resemble progesterone Formulated both as an alcohol and acetate derivative Relatively weaker corticosteroid Decreased risk of unwanted complications, such as IOP rise
30. 30. Treatment of choice in those patients with a history of pressure rise due to corticosteroid therapy or previously diagnosed glaucoma An effective agent in external ocular inflammations , like conjunctivitis, piguiculitis , scleritis and episleritis Available as 0.1% drop
31. 31. Medrysone Like fluorometholone , a synthetic derivative of progesterone Weakest of the available ophthalmic steroids Useful for superficial ocular inflammations , including allergic and atopic conjunctivitis Generally do not respond to intraocular inflammatory conditions Elevates IOP minimally or not at all
32. 32. Betamethasone Available as 0.1% eyedrop or ointment Marked anti-inflammatory action Low dose is enough So, reduces the risk of side effects
33. 33. Hydrocortisone 1st corticosteroid used in medicine Available as 1% eyedrop and 0.5%, 1% or 3% ointment
34. 34. Rimexolone Available as a 1% ophthalmic suspension (Vexol) Effective in suppressing cells, flare, keratin precipitates and photophobia Main advantage - more of site-specific action than other corticosteroids Less tendency to increase the IOP.
35. 35. LOTEPREDNOL Available as 0.2% and 0.5% concentration Less potent steroid Indicated for temporary relief of the signs and symptoms of seasonal allergic conjunctivitis
36. 36. Dexamethasone Prednisolone Fluorometholon Medrysone A N T I N F L A M M A T O R Y A C T I N C R E A S E I N I O P
37. 37. BIOAVAILABILITY OF TOPICAL STEROIDS Fraction of unchanged drug reaching the systemic circulation Depends upon the ability to penetrate cornea The ideal steroid should be biphasic i.e solubility in both the lipid (hydrophobic) layers of the epithelium and endothelium and the aqueous (hydrophilic) media of the stroma
38. 38. Acetate and alcohol derivatives more lipophilic i.e fat soluble Sodium phosphate and hydrochloride more hydrophilic i.e water soluble So, in intact epithelium , penetration of acetate greater while in absence of epithelium penetration of phosphate greater Acetate and alcohol derivatives are more effective then the phosphate derivatives in suppressing corneal inflammation both in the presence and absence of corneal epithelium
39. 39. Preparations LOCAL : Eyedrops-suspension or solution Ointments Injection - subconjuctival , sub-tenons capsule or retrobulbar SYSTEMIC : Tablets Injections(intra venous) -
40. 40. Routes of administration TOPICAL SYSTEMIC Effective in anterior segment diseases Effective in posterior segment diseases Ease of application, relative low cost Difficult application, relatively high cost Dosage vary with severity of disease Generally single dose daily Absence of systemic complications Systemic complications present
41. 41. Ocular indications Topical Systemic Blepharitis Uveitis Allergic conjunctivitis Allergic keratitis Viral keratitis Pingueculitis Inflammation of pterygim Cystoid macular edema After ocular surgery posterior uveitis Systemic ophthalmia Papillitis Retrobulbar neuritis Scleritis Anterior ischemic optic neuropathy Malignent exopthalmus Orbital pseudotumor
42. 42. Alternate day therapy Single dose on alternate day systemic administration of corticosteroids is as effective as divided daily dose Permits metabolic recovery and prevents toxic side effects from accumulating Patients receives the entire total dose that would be given over a 2-day period as a sing dose , every other morning Alternate-day systemic therapy applies only to shorter acting systemic steroids like prednisone, in case like chronic uveitis
43. 43. Double edged sword It only inhibit the inflammatory response not the cause of inflammation Magical drug
44. 44. Why steroids dozes tapered ?? Synthetic cortisone medication mimic cortisol,i.e naturally occuring hormone produced by adrenal gland Excess production of cortisol negative feedback mechanism (HPA axis) Using large dose for few days or smaller dose for more than two weeksprolonged decrease in HPA axis function
45. 45. So tapering is required i.e continuing the therapy for several days in reduced dose Gives time for adrenal glands to return their normal patterns of secretion Also reduces the chance of recurrence of the disease
46. 46. Locally (in case of topical) ?? Corticosteroids reduce the leukocyte cells locally White cells proliferate when therapy stops Immature cells can produce large quantities of antibodies to residual antigen in the ocular tissue Massive polymorphonuclear leukocytic reaction follows the resultant antigen- antibody reaction
47. 47. This sequence of events , unless interrupted immediately , can lead to a recurring , serious necrotizing inflammation Thus depending upon response and dozes used , topical therapy should generally be tapered over several days to weeks Removal of corneal epithelium caused appearance of leukocytes in tear fluid within 2-5 hrs which was greatly reduced by 1% prednisolone and 0.01% flurbiprofen
48. 48. Eyelids Allergic blepharitis Contact dermatitis Herpes zoster dermatoblepharitis Chemical burns Neonatal hemangioma
49. 49. Conjunctiva Allergic conjunctivitis Vernal conjunctivitis Herpes zoster conjunctivitis Chemical burns Mucocutaneous conjunctival lesions
50. 50. Cornea Immune reaction after keratoplasty Herpes zoster keratitis Disciform keratitis Marginal corneal infiltrates Superficial punctate keratitis Chemical burns Acne rosacea keratitis Interstitial keratitis
51. 51. Uvea Anterior uveitis Posterior uveitis Sympathetic ophthalmia
52. 52. Sclera Scleritis Episcleritis
53. 53. Retina Retinal vasculitis Optic nerve Optic neuritis Temporal arteritis (arteretic anterior ischaemic optic neuropathy)
54. 54. Globe Endophthalmitis (except fungal endopthalmitis) Hemorrhagic glaucoma Orbit Pseudotumor Graves ophthalmopathy Extraocular muscles Ocular myasthenia gravis
55. 55. Generally contraindicated in: Peptic ulcer Osteoporosis (an increased risk of fracture ) psychoses
56. 56. Should be used with caution in Diabetes mellitus Chronic renal failure Congestive heart failure worsen the condition Systemic hypertension Infectious diseases glaucoma
57. 57. Patients with prolonged systemic therapy, lack sufficient adrenal reserve to respond to stress like trauma and surgery , so require additional corticosteroids to cover the stress.
58. 58. Adrenal insufficiency Cushings syndrome Peptic ulceration Osteoporosis Hypertension Muscle weakness or atrophy Inhibition of growth Diabetes Activation of infection Mood changes Delay in wound healing SYSTEMIC SIDE EFFECTS
59. 59. OCULAR SIDE EFFECTS Adverse event can occur with all routes of administration & all preparations currently available. Side effects more with long term high doses therapy.
60. 60. Posterior subcapsular cataracts Ocular hypertension or glaucoma Secondary ocular infection Retardation of corneal epithelial healing Keratitis Corneal thinning or melting Scleral thinning Uveitis Mydriasis Ptosis Transient ocular discomfort OCULAR SIDE EFFECT
61. 61. Cataract Occurrence of PSCC with all routes High incidence found in long term systemic therapy then the topical therapy Opacity associated with steroid administration resemble with those produce by ionizing radiation and ocular disease such as uveitis , retinitis pigmentosa and retinal detachment
62. 62. Glucocorticoids enter lens fibres reacts with lens crystallins conformational change within cells release of sulfhydryl groups Form disulfide bonds protein aggregation CATARACT Mechanism
63. 63. Mechanism High blood glucose level High level of sorbitol Indrawing of water Swelling of fibers and disruption of cytoskeletal structures cataract
64. 64. mechanism Corticosteroid induces the production of the new lens fibers through equatorial region Which goes and accumulate in posterior sub capsular region Finally causes cataract
65. 65. Ocular hypertension or glaucoma Reversible elevation of pressure with repeated use of topical steroids. Steroid induced glaucoma ; a form of secondary open-angel glaucoma Recently developments in corticosteroids are aimed at developing agents with less IOP effect and agents that can be used intraocularly and periocularly
66. 66. How steroids increase IOP..? GAGs present in the trabecular meshwork can not depolimerized (stabilizing lysosomal membrane)and they retain water in extracellular space lead to narrowing of trabecular meshwork Suppress the phagocytic activity of endothelial cells of trabecular meshwork leading to collection of deberies in trabecular meshwork Inhibit the formation of PGE and PGF leading to decrease in aqueous outflow facility Obstruction of aqueous outflow
67. 67. IOP elevation in different steroid Dexamethasone 0.1% 22.0 +/- 2.9 Prednisolone 1% 10.0 +/-1.7 Fluoromethalone 0.1% 6.1 +/-1.4 Hydrocortisone 0.5% 3.2 +/-1.0 Tetrahydrotriamcenalone 0.25% 1.8 +/-1.3 Medrysone 1% 1.0 +/-1.3 Preparation Avreage IOP rise in MM/Hg Dexamethasone 0.005% 8.2+/-1.7
68. 68. Individuals differ in their responsiveness: approximately 4% develop pressures higher than 31 mm Hg after 6 weeks of therapy with topical dexamethasone Steroid- induce IOP elevation almost never occurs in less than 5 days and rarely in less than 2 weeks Steroid-induce IOP rises are usually reversible by discontinuance of therapy if the drug has not been used for more than 1 year , but permanent elevations of pressure are common if the therapy has continued for 18 months or more 1 1 (armaly MF and becker b . Mills DW ARCH OPHTHALMOL 2003)
69. 69. If IOP rises when we use the steroid ? 1) First stop steroid therapy and may use other anti- infalmmatory agents like NSAIDs and cyclosporine 2) If IOP persist at higher level then IOP lowering agent can be used like beta-blocker , carbonic acid inhibitor but prostaglandin analogue are contraindicated 3) If IOP remains at higher level then we can move to other surgical procedure
70. 70. Retardation of corneal epithelial healing Effect on collagen synthesis and fibroblastic activity Persistent epithelial staining can be noted
71. 71. Corticosteroid induce uveitis Pain, photophobia, blurred vision, and perilimbal (ciliary) hyperemia; anterior chamber cells and flare
72. 72. Mydriasis Increase in pupillary diameter approximately 1 mm Belharoptosis Due to inhibition of sympathetic innervation on mular muscle
73. 73. Other ocular side effects Transient ocular discomfort Calcium deposits on cornea ; (Dry eye develop a calcific band keratopathy)
74. 74. SOME IMPORTANT FACTS s Is not s i.e cotricosteroids are not stored in adrenal gland, they synthesized from cholesterol in the presence of stimulus They promote growth of skeletal muscle (anabolic effect) and the development of male sexual characteristics (androgenic effects) Drugs used by athletes to boost strength and enhance physical performance Anabolic steroid ??
75. 75. PYRIMON BETNOR FML FML-NEO OCUPOL-D PRED-FORTE OXOP D Some topical steroid : Trade name and combination (Dexamethasone 0.1% + Chloramphenicol 0.1% ) ( Betamethasone 0.1% + Neomycin 0.5% ) (Fluromethalone 0.1%) ( Fluromethalone 0.1% + Neomycin 0.5%) ( Each gram contains : Dexamethasone 1 mg + chloramphenicol 10 mg + polymyxin B sulphate 10000 IU) (Prednisone acetate 1%) (Ofloxacin 0.3% + Dexamithasone 0.1% )
76. 76. REFRENCES