• Steroids are molecules having GONANE nucleus• Produced in body from cholesterol • Adrenal Cortex – Glucocorticoids ( Cortisol ), Mineralocorticoids ( Aldosterone ), weak Androgens • Testes – testosterone • Ovary & Placenta – Oestrogens and progesterone• Glucocorticoids ( Cortisol ) have a wide range of Physiologic roles involving metabolism and hemostasis. • A major component of response to STRESS Stimulus • Apart from replacement therapy in Adrenocortical deficiency, Supra Physiologic doses have been used extensively in medicine for treatment of spectrum of disorders (natural & synthetic)
• 1930 – Swingle, Pfiffner, Hartman – prepared adrenocortical extracts• 1935 – Kendall isolated cortisone in lab• 1942 – Reichstein and Shoppee – chemical structure of steroids• 1949 – Hench – first clinical use of steroids – Rheumatoid arthritis• 1950 – Cordon and Mclean – introduced steroids into ocular therapy
MECHANISM OF ACTION• ..DownloadsVideoAnimation explaining mechanism of action of glucocorticoids.flv
• GLUCOCORTICOID RECEPTOR - Member of nuclear receptor superfamily carboxyl end binds ligand ( steroid) middle region Zn fingers (9 cysteine residues) bind to pallindromic sequence in GRE (promotor DNA) amino terminal activation of Transcription by RNA polymerase II
• COREGULATORS bridge with other nuclear factors like NF- kB and AP1 – affect transcription of other genes – TRANSREPRESSION enzymes for acetylation / deacetylation of Histones – altering structure of nucleosomes• ONSET OF ACTION – 90 to 120 mins• DURATION - long
• Constriction of blood vessels & reduction in permeability• Inhibition of macrophage recruitment and migration• Reduction in circulating monocytes, basophils, eosinophils and lymphocytes. However neutrophilic leukocytosis occur• Decrease in expression of adhesion molecules (ICAM) over endothelium• Decrease in Diapedesis• Stability of basophil, mast cell, neutrophil intracellular granules
• Decrease in Antigen Presentation• T lymphocyte function and proliferation affected more than B lymphocytes (cell mediated immunity)• Suppression of Fibroplasia
ROUTES OF DELIVERY• Topical – skin ointments eye drops eye ointments• Peri Ocular Injections – sub conjunctival sub tenon – anterior and posterior retrobulbar• Intra Vitreal – injections implants• Systemic – Oral Parenteral – iv, im
SYSTEMIC PHARMACOKINETICS• Well absorbed orally• i v route – water soluble compounds like Hydocortisone hemisuccinate, dexamethasone sod phosphate• i m route – both water soluble or insoluble compounds like hydrocortisone acetate, triamcinolone acetonide etc given depending upon duration of effect desired• Hydrocortisone is 90 % bound to plasma proteins – CBG and albumin• Metabolized by hepatic microsomal enzymes – reduction/hydroxylation/oxidation followed by conjugation.• Metabolites excreted in urine – major form is 17 keto compound• Biologic t ½ is much longer than Plasma t ½
• Systemic corticosteroids are the initial drug of choice for most patients with bilateral endogenous sight threatening uveitis.• Prednisone/prednisolone is the most commonly used oral corticosteroid• Initial dose 1-2 mg/kg/day• Maximum adult oral dose 60 – 80 mg/day• Maintenance dose (adult) = 10mg/day• Single morning dose after breakfast, if possible on alternate days• Combined with proton pump inhibitors or anti H 2 anti histaminics
SYSTEMIC SIDE EFFECTS• Sodium and water retention, hypokalaemic hypochloremic alkalosis• Rise in BP• Edema occurs in cases of hypoproteinemia, renal disease, liver disease• Heart failure in compromised myocardial function• Cushing‟s Habitus – rounded face (moon face), narrow mouth, supraclavicular hump, obesity of trunk with relatively thin limbs –iatrogenic cushing‟s syndrome occurs >100 mg hydrocort / day• Fragile skin, striae, telangiectasias, hirsutism , acne• Growth retardation in children• Diabetes MellitusHyperlipidemia• Secondary amenorrhoea
• Muscle weakness• Osteoporosis• Avascular necrosis• Nausea• Peptic ulceration• Pancreatitis• Intestinal perforation• Hypomania, insomnia, acute psychosis, later depression• Raised intracranial tension – pseudotumor cerebri• Delayed healing• Flaring up of latent infections especially TB/ acquisition of secondary infections – fungal (opportunistic)• Thrombosis
• Steroids in pregnancy – category C Fetal abnormalities• Nursing mothers – secretion into breast milk Adrenocortical suppression and growth retardation in child
OCCULAR SIDE EFFECTS• cataract• occular hypertension and glaucoma• secondary infections• retardation of wound healing – post operative• inhibition of corneal epithelial & stromal healing – corneal melting• central serous retinopathy• exophthalmos• pseudotumor cerebri
HPA AXIS SUPPRESSION• If systemic steroid given for more than 2-3 weeks• HPA suppression due to feedback mechanisms• sudden stoppage precipitates acute adrenocortical deficiency. Tapering of dose has to be done to avoid this During tapering, glucocorticoid dependence may manifest nausea, vomiting, weight loss, lethargy, headache, fever, muscle pain , postural hypotension
• During acute stress, dose has to be increased even if stressful event occurs months after tapering has been done• Many patients achieve normal serum cortisol levels in less than one year of stopping steroids but in majority of cases, the ability to respond to stress by increase in steroid levels remains hampered for upto 2 yearsMinor – 2 fold maintenance dose for 24-48 hrsMajor – 10 fold maintenancedose for 48-72 hrs• If patients on steroids develop systemic infection, steroids should not be discontinued. Dose needs to be increased along with addition of specific antimicrobial.
GENERAL GUIDELINES• Use local therapy wherever possible.• A single dose ( even excessive ) is not harmful – can tide over mortal crisis even when benefit is not certain• Short courses ( even high doses ) are not likely to be harmful in the absence of contradictions• Long term use is potentially hazardous – duration and dose to be kept at minimum, which is found by trial and error.• High doses to begin with, in severe diseases, titrating downwards acc to response whereas low doses to begin with, in mild diseases, titrating upwards.• If chronic use beyond 1 month, addition of immuno - suppresants to be considered• No abrupt stoppage after use for 2-3 weeks
• TAPERING SCHEDULE for oral prednisolone > 40mg/day, decrease by 10mg/day every 1-2 weeks 40–20mg/day, decrease by 5mg/day every 1-2 weeks 20–10mg/day, decrease by 2.5mg/day every 1-2 weeks 10-1 mg/day, decrease by 1-2.5mg/day every 1-4 weeks
• EVALUATION Chest X Ray Tuberculin test Assessment of DM, osteoporosis, peptic ulcer, psychological disturbances, cardiovascular status, renal and hepatic status• MONITOR-Blood Pressure, Weight, Blood Glucose level every 3 months and annually. Measure bone density within first 3 months and annually thereafter. Supplementary treatment - Calcium 1500 mg daily andVitamin D 400 IU daily. Bisphosphonates and Estrogens as needed. Increased potassium and protein intake
I V METHYL PREDNISOLONE PULSEselected cases where immediate effect is needed1 g/day or 250 mg q 6 hrly, slow I v infusion X 3 days Followed by oral prednisoloneTemporarily “switches off ” the IMMUNE SYSTEM Optic neuritis Severe corneal graft rejection Severe sight threatening posterior uveitis Sympathetic ophthalmitis VKH
PRECAUTIONS• Should be given under ICU settings• Monitoring of BP and pulse every 15 – 20 mins• Electrolyte imbalances and ECG changes likely to occur
TOPICAL PHARMACOKINETICS• Topical – eye drops – solutions and suspensions – hydrochloride, phosphates, alcohol, acetates - eye ointments - drug depots on ocular surface – cotton pledgets and collagen shields – steady sustained and slow release
EXTENT OF ABSORPTION INTO CORNEA AND ANTERIOR CHAMBERtime for which drug remains in cul de sac and tear filmflow to lacrimal passagebinding to taer proteinsMetabolism by tear and external tissuesstatus of corneal epithelium and stromatype of steroid and its solubilityconcentrationosmolarity, pH, viscosity, vehicle, size of particlesdosing frequency
• CORNEA TRILAMINAR STRUCTURE• Corneal and aqueous humor concentrations - Studies in animal models – • Keratitis with intact epithelium – Pred acetate > pred sod phosphate > dexamethasone alcohol. No dexamethasone sod phosphate was absorbed • Keratitis with denuded epithelium – Pred sod phosphate > dexamethasone sod pshpate > pred acetate • Intraocular inflammation with intact corneal epithelium – Pred acetate = pred sod phosphate = dexamethasone sod phosphate
• CONCENTRATION : Prednisolone e/d 1% vs 0.125 %• DOSING FREQUENCY
• PREDNISOLONE SOLUTION VS PREDNISOLONE SUSPENSION equivalent for intra ocular inflammation models (anterior uveitis) rabbit keratitis model shows superiority of prednisolone acetate over prednisolone sod phosphate But sophisticated mathematical models show equivalence in practice efficacy of suspension(pred acetate) is assumed to be lower due to lack of patient compliance in shaking well before instillation
• OINTMENT VERSUS DROPS Dexamethasone phosphate ointment had lower penetration into cornea and aqueous humor than solution because of slow release of drug molecule Whereas FML ointment produced similar concentrations as suspension• VEHICLE – cyclodextrin (Gate-Dx, Apdrops-Dx) improves corneal penetration of dexamethasone
• TYPE OF STEROID -FML 0.1 % and 0.25 % has much less corneal penetration but is comparable to Prednisolone 1% in alleviating corneal inflammation gets concentrated in corneal epithelium -Loteprednol ( modification of prednisolone ) – undergoes rapid hydrolysis by esterase in anterior chamber. Effective for corneal and conjunctival inflammations -Medrysone 1% – very low penetration of cornea – discontinued by FDA – used earlier for mild conjunctival inflammations
• SYSTEMIC ABSORPTION after topical treatment is considerable – through conjunctiva, nasal mucosa and aqueous humor By passes hepatic metabolism suppression of adrenal cortex after 6 weeks of topical 0.1 % dexamethasone phosphate elevation of blood glucose levels in controlled diabetics
OCCULAR SIDE EFFECTS• occular hypertension and glaucoma• secondary infections – viral keratitis, fungal keratitis, toxoplasmosis• retardation of post operative wound healing• inhibition of corneal epithelial & stromal healing – corneal melting• cataract• uveitis• mydriasis• ptosis• Toxic to cornea, conjunctiva, skin e g punctate keratopathy• hypersensitivity
PRECAUTIONS AND CONSIDERATIONS-for initial prescription and renewal beyond 14 days - to rule out infective pathology especially viral, fungal, mycobacterial- Slit Lamp biomicroscopy and fluorescein staining if necessary-Re evaluate if no improvement in 2 days of start of therapy-Any drug used beyond 10 days – monitoring of IOP-Suspicion of fungal infection in long term therapy – cultures may have to be taken-To remove contact lens before instillation and re insertion after 15 mins – absorption of BAK by CL-Separate bottle for other eye in case of post op treatment-to be SHAKEN WELL- Storage b/w 8 – 25 deg celsius- No abrupt withdrawl – to prevent rebound flaring up
High concentrations at site of inflammation without systemic toxicityTo be given close to site of inflammationEliminates daily complianceBlood – ocular barrier limits diffusionINDICATIONS – resistent anterior uveitis, intermediate uveitis, posterior uveitis, CME (mainly unilateral) especially in patients contraindicated to systemic steroidsCONTRAINDICATIONS – conditions associated with scleral thinning like scleritis – scleral perforation may occurPRECAUTIONS – to rule out steroid responders - and infections
SUBCONJUNCTIVAL Inj– absorption directly across the sclera as compared to sub conjunctival antibiotics soluble drugs for sub conjunctival inj – insoluble drug will give unsightly appearance and will lead to irritation SUB TENON(ANTERIOR and POSTERIOR) – suspensions are used for better absorption depot steroids : Inj Depo Medrone(methyl pred acetate) (0.5ml of 80mg/ml) Inj Kenalog (triamcinolone acetonide) effect lasts for 1-2 weeks
COMPLICATIONS RELATED TO TECHNIQUE perforation of globe and intraocular injection sub conjunctival hemorrhage retrobulbar hemorrhage Extraocular muscle fibrosis scarring between conjunctiva and globe
• More targeted delivery• Controlled and consistent• Immediate achievement of therapeutic concentration• By passes BLOOD OCULAR barrier• Reduced systemic toxicity• Compliance eliminated
Dexamethasone – very short half life – 3-4 hoursTriamcinolone acetonide– longer half life. 4 mg inj : detectable after 3 months effect upto 6 months earlier TRICORT and KENACORT Inj – Benzyl alcohal newer preservative free FDA approved preparations TRIVARIS (80mg/ml) – 0.05 ml : Uveitis TRIESCENCE (40mg/ml) – 0.025 to 0.1 ml : visualization of tissues ILM, ERM in VR surgery
• Off label uses of IVTA ARMD Diabetic Retinopathy Venous Occlusions Pseudophakic Macular Edema Proliferative vitreoretinopathy
• IVTA Injection Tranconjunctivally, 3.5 – 4 mm from limbus, inferotemporally 26 / 27 / 30 guage needle over tuberculin syringe Under direct visualization : dilated pupils required Immediately afterwards – CRA pulsations are checked by IDO IOP measured after 30 mins Biomicroscopy after 3 and 7 days
• IMPLANTS RETISERT – 0.59 mg Fluocinolone acetonide Sustained Release implant for chronic non infectious posterior uveitis implanted through pars plana incision, after vitrectomy lasts for 30 months : has to be removed ILUVIEN – half of retisert : FAME study for DR : not approved yet OZURDEX – 0.7 mg dexamethasone in injectable, biodegradable implant for macular edema after CRVO & BRVO and non infectious chronic posterior uveitis. lasts upto 6 weeks
COMPLICATIONS DUE TO TECHNIQUESub conjunctival hemorrhagevitreous hemorrhagetraumatic cataractVitreous detachmentretinal detachment pseudo endophthalmitis / pseudo hypopyon (more likely in aphakia and pseudophakia)sterile endophthalmitis ( benzyl alcohol related )infective endophthalmitisdislocation of implant
• As Post-operative treatment- In most intraocular & ocular surface surgeries, topical CSd are usually given according to the severity of inflammation for few days to weeks. Refractive surgery, corneal surgery, intraocular surgery, glaucoma surgery ( prevents scarring) Delayed wound healing in cataract surgery may lead to bleb formation
• Periorbital Dermatitis (Atopic, Contact, Irritant, Seborrheic). Most patients benefit from short course of CSd ointment application for 1-2 weeks.
• Allergic conjunctivitis (Hay fever, AKC, VKC, GPC, Phlyctenular)- Topical CSd are used only as 2nd or 3rd line drugs CSd bring dramatic improvement with potential side effects.. Use diluted CSd (e.g. 0.01% Dexamethasone or 0.12%Prednisolone) or „milder‟ CSd (e.g. Flurometholone, Loteprednol) as pulse therapy (4-8x/day for 1 week followed by fast tapering). Tear substitutes, Antihistamine vasoconstrictor combination, Mast cell stabilizers are the first line drugs generally.
• Chronic Adenoviral Keratoconjunctivitis- Topical CSd only temporarily resolve the subepithelial infiltrates without affecting the clinical course.• Herpetic (H. simplex) stromal keratitis- CSd contraindicated in any form of active epithelial keratitis while topical diluted CSd (1:10 dexamethasone) bd/tds is useful for stromal disease (immunological basically) given along with prophylactic antiviral treatment.
• Scleritis- Topical steroids are not effective unlike in episcleritis. Periocular steroids are contraindicated (chances of scleral thinning & perforation). oral Prednisolone is given for 2-3 weeks followed by slow tapering.
• Corneal chemical injury- topical steroids, qid to 2 hourly depending upon the severity) for the first week only followed by shifting to topical NSAIDs. Risk of corneal melting/ulceration is very minimal in the first week of chemical injury. After which corneal stromal repair is inhibted
• Herpes Zoster Keratitis- Topical CSd are used for stromal keratitis & uveitis. Sometimes also used for epithelial keratitis, cautiously topical CSd don‟t increase viral replication in Zoster epithelial keratitis. Pseudodendrites are present (elevated mucous plaques) that are fluorescein stain negative.
• Corneal graft rejection- Topical CSd every hourly for endothelial rejection. Topical CSd 4x/day for epithelial rejection (relatively benign). Systemic CSd, if topical CSd fail or recurrence occurs. For severe rejection (generalised corneal edema), IV methyl Pred (pulse steroid therapy) is given along with intensive topical CSd (1 hourly).• Also as prophylaxis
• Anterior uveitis- In acute non-granulomatous uveitis, topical pred acetate drops every 1-6 hourly depending on the severity. Periocular steroids are used for noncompliant patients.
• Intermediate uveitis i) Topical CSd are not much effective. Might be given along with periocular CSd. ii) Periocular CSd (posterior subtenon‟s injection of combination of steroid depot iii) Systemic CSd is required in bilateral cases or those with severe inflammation. Generally no treatment is required if visual acuity is >/= 6/12..
• Posterior uveitis- Non-specific posterior uveitis needs oral prednisolone Very severe cases may need IV Methylpred pulse. posterior subtenon depot inj, IVTA(TRIVARIS), Depot CSd implants (RETISERT & OZURDEX)• VKH, sarcoidosis, sympathetic ophthalmitis – systemic (oral) therapy. I v methyl prednisolone pulse may haveto be given
• Postoperative endophthalmitis) i)In early endophthalmitis, along with antibiotics, give topical prednisolone 1-2 hrly or I-Vit Dexamethasone (0.4 mg) with antibiotic.(role controversial) ii) Late endoph (starting after a week) - Avoid all CSd until fungus infection is ruled out & patient is definitely responding to antibiotics.
• Thyroid eye disease- oral Prednisolone 1-2mg/kg/ D for significant proptosis causing exposure keratopathy, significant diplopia or vision loss because of optic neuropathy..
• Orbital pseudotumour- Early & aggressive systemic therapy is the mainstay of treatment. For recurrent & non-responding cases, retrobulbar or intralesional CSd injection may be tried. Low dose orbital irradiation & immunosuppressives are the alternatives
• Optic neuritis- If patient seen early, IV methyl prednisolone pulse therapy followed by oral prednisolone 1 mg/kg/D X11days with tapering over a week. Oral CSd not recommended, recurrences become commoner (ONTT study). IV CSd offers- Reduced recurrence rate, Shortened visual recovery time, But no long term visual benefit Only observe, in cases of recurrent ON or known case of multiple sclerosis.
• Arteritic Ischemic optic neuropathy- suspicion of Giant Cell Arteritis in a case of AION, immediately start pulse steroid therapy, followed by oral prednisolone for 2- 4 weeks if temporal artery biopsy is positive, thereafter maintaining for 6 months to a year (monitor ESR). Blindness from GCA is usually permanent & CSd basically help to prevent it in the other eye as the contralateral eye can get involved within 24 hours
• Optic nerve injury- Immediately institute „Mega‟ intravenous methyl-pred doses like that for spinal cord injuries. Loading dose of 30mg/kg by slow IV infusion followed by maintenance dose of 5.4mg/kg every hour for 48 hours. Followed by oral prednisolone Monitor the visual acuity & relative afferent pupillary defect (RAPD) closely.
OCULAR HYPERTENSION• Increase in IOP when applied locally or given systemically.• IOP elevation may lead to optic nerve damage & changes in visual field similar to POAG.• Incidence of ocular hypertension – 5 % in patients with no family history of POAG ; upto 90% in patients with positive history• Mostly reversible on stopping, but long term usage may lead to permanent elevations.• Mucopolysaccharide deposition in trabecular meshwork.• Gene involved – GLC1A / TIGR / MYOC on ch 1q21 – 1q31
• Development of softer topical steroids – FML (0.1 % and 0.25 %) Loteprednol (0.2 % and 0.5 %) Rimexolone Less percentage of patients developing ocular HTN and that too after longer duration compared to dexamethasone 0.1% or prednisolone 1% structure activity studies indicate close relationship between anti inflammatory potency and occular hypertensive effect
• PRECAUTIONS Regular IOP and Optic Disc monitoring, if steroids are used for than 10 days, INCLUDING „SOFTER‟ TOPICAL DRUGS Analysis of Risk Benefit ratio in cases already diagnosed with POAG Identification of steroid responders before PERIOCULAR and INTRAVITREAL injections – effect of 6 weeks of therapy with topical Dexamethasone 0.1 %• MANAGEMENT Require concurrent anti glaucoma medication Removal of implants/periocular depot, vitrectomy in case of IVTA, and trabeculectomy may have to be undertaken.
CATARACT• Development of posterior subcapsular cataract reported more commonly in literature with long term systemic therapy• Recent Advances - intravitreal implants(RETISERT and OZURDEX) and multiple intravitreal injections (IVTA) - upto 100 % incidence• Incidence correlates with the dose and duration of systemic therapy• 75 % patients >16mg/day prednisolone develop PSC• Dose of 10 mg/day for 1 year have minimal risk• Long term topical therapy also at risk e.g. vernal & atopic Keratoconjunctivitis, keratoplasty for keratoconus• Irreversible changes in lens due to binding of steroid molecules with lens fibres and biochemical alterations• Enhanced by concomitant Diabetes Mellitus
• Children are particularly at risk• Cataract progresses despite stopping treatment• Periodic slit lamp examination is recommended
CONCLUSION• 2 edged swords• Effect of Steroids are non specific, palliative and never curative• Concomitant specific treatment has to given• Appropriate Use relies on good clinical judgement and close watch on complications• Newer molecules having higher selectivity for anti inflammatory activity• Newer methods of drug delivery
REFERENCES• Goodman and Gilman : Pharmacological Basis of therapeutics – 12th ed (2011)• Katzung : Basic & Clinical Pharmacology – 11th ed (2011)• K D Tripathi : Pharmacology - 6th Ed (2010)• Albert Jakobiec : Principles & Practice of Ophthalmology in ch 23 Corticosteroids in practice – 3rd ed (2008)• Robbins : Pathologic Basis of Diseases – 8th ed (2012)• Corticosteroids in ophthalmology- overview : DOS Times- vol 12, no 8 ( 2007)• Steroids & immunosuppressives in Ophth : Kerela Journal of Ophthalmology – vol 18, no 3 (2006)
• Steroids for posterior segment : delivery systems & indications : DOS Times – Vol 10, No 4 (2004)• Intravitreal steroids in retinal disorders : DOS Times, vol 11, no 4 ( 2005)• Corticosteroid implant for vascular occlusions : DJO - vol 22, no 2 (2011)• www.fda.gov