Anti-inflammatories, Steroids

What is inflammation?

A protective physiological response intended to eliminate the initial cause of cell injury as well as the necrotic cells and tissues resulting from the original insult.

What can cause a inflammatory stimulus?

• Infection

• Mechanical/Trauma

• Toxic (foreign substance)

• Immunologic/Hypersensitive

  • Exogenous substances: allergies

  • Endogenous substances: autoimmune conditions

What is the goal of the inflammatory response?

To get as many white blood cells and other immune system components from the bloodstream into the tissues at the site of the inflammatory stimulus.

What is the physiological sequence of the inflammatory response.

1. Vasodilation to increase blood flow to site of origin

2. Increase vascular permeability to allow WBC to enter tissue

3. Chemotaxis: signals WBC where to go

What are the signs and symptoms from inflammatory response.

• Rubor: redness form increased blood flow

• Tumor: Swelling from increase vascular permeability

• Calor: Heat from increased blood flow

• Dolar: pain from increased cellular and fluid swelling, causing increase in pressure → stimulates pain nerves

What are the side effects of an aggressive or chronic inflammatory response?

• Neovascularization

• Tissue necrosis

• Scar formation

What is the arachidonic acid cascade a response to?

Antigens

What does Phospholipase A2 do?

It converts phospholipids to arachidonic acid, initiating the arachidonic acid cascade.

What are the major products and effects of the arachidonic acid cascade?

COX pathway: transforms arachidonic acid into prostaglandins and thromboxanes (pain, fever, vasodilation, platelet effects). LOX pathway converts arachidonic acid into leukotrienes (bronchoconstriction, neutrophil recruitment, allergy/asthma).

What inhibits Phospholipase A2?

Corticosteriods

What is the MOA of steriods?

1. Bind to receptor and pass through cell membrane

2. Bind cytoplasmic receptor

3. Enter nuceus to alter protein synthesis: creating lipocortin-1

4. Lipocortin-1 inhibits Phospholipase A2, limiting the formation of arachidonic acid

What are the therapeutic effects of steroids on the arachidonic acid cycle?

• Decrease vasodilation → Decrease redness from PGD2

• Decrease vascular permeability to reduce swelling from decreased PGD2 and leukotrienes

• Decrease chemotaxis to reduce swelling from decreased leukotrienes

• Decrease pain from decreased PGE2

What are the therapeutic effects of steroids outside of the aracidonic acid cycle?

• Decrease circulating WBC and lymphocyte proliferation

• Inhibit lymphocyte cell mediated response and cytokine synthesis

• Inhibit migration of neutrophils

• Inhibit Fibroblast proliferation

• Inhibit Fibrin deposition

• Inhibit Collagen deposition

What are the ocular side effects of steroids?

• IOP spike: 8-10 mmHg or greater

• Posterior subcapsular cataracts

• Increase risk of infection

• Decrease healing/delayed wound healing

How many people are steriod responders?

7-8% o fgeneral population will have a IOP spike when given steroids.

What increases the risk of being a steroid responder?

If pt has primary open angle glaucoma.

How long does a patient have to be on steroids before there is a risk of an IOP spike?

At least 10 days/2 weeks

How does the risk of posterior subcapsular cataracts change with the route of administration?

• Highest risk via intra-ocular injections

• 2nd highest risk getting PSE via oral administration

What are contraindication for topical ocular steroid use?

• Presence or suspicion of infection, expecially of ocular dendritic keratitis

• Unsure of diagnosis

• Concurrent contact lens wear (must wear glasses when using topical steroids)

What are relative contraindications for topical ocular steroid use?

• Epithelial defects. Depends on cause and size. If inflammation is cause, the OK. May need antibiotic/steroid combo for prophylaxis if risk of infection

• Glaucoma. FHx of glaucoma increases risk of steroid responder. OK if short term (7-10 days). Can address IOP spike with glaucoma meds

Are there systemic side effects of topical ocular steroid use?

No systemic SE from topical ocular steroid use.

How is anti-inflammatory efficacy determined?

1. ocular absorption

2. Receptor affinity

3. Rate of metabolization

   1. Ketone-based steroids vs ester-based steroids

What are the “…ates” formulation steroid characteristics?

Acetates, prednates, propionates, and etabonates have lipophilic structure and has higher hydrophobicity that leads to greatest tissue absorption and corneal absorption and penetrance.

What are alcohol steroid characteristics?

Have intermediate corneal penetrance.

What are Sodium phosphates (NaPh) steroid characteristics?

Hydrophilic in nature; significantly decrease tissue absorption and corneal penetrance. Is in a solution.

What is Pred Forte?

• 1.0% prednisolone acetate suspension

• Considered the gold standard due to highest efficacy

  • Due to great absorption, high receptor affinity, ketone based steroid

• FDA indications to treat ocular inflammation

• Has highest risk for IOP spike d/t super efficacious nature

What are the common uses for Pred Forte?

• Uveitis

• Keratitis

• Post-op inflammation

• Moderate-severe ocular surface inflammation

What is Pred Mild?

• 0.12% prednisolone acetate suspension

• No generic available at this conc

• FDA indications: open indication to treat ocular inflammation

• Rarely used

What is 1.0% prednisolone NaPh?

• A solution

• Only available as generic

• FDA indications: open indication to treat ocular inflammation

What are the common uses of 1.0% prednisolone NaPh?

• External diseases of the ocular surface:

  • Pingueculitis

  • Allergic conjunctivitis

  • Episcleritis

What is Durezol?

• 0.05% difluprednate

• Is an emulsion (no shaking required)

• Generic version is a suspension

• Is equally efficacious as Pred Forte with 50% less dosing

• FDA indicated for: uveitis & post-op inflammation and pain

• Induces IOP spike like Pred Forte, but not as often and higher in younger patients

What is the dosing of Durezol for post-op?

QID x14 days, then taper accordingly

What is Byqlovi?

• 0.05% clobestasol propionate suspension

• FDA indicated for: post-op inflammation and pain following ocular surgery

• Uses Acitve pharmaceutical nanoparticle technology to enhance ocular absorption

• Dosage: BID x2wks following surgery

What is Loteprednol etabonate?

• The only ester-based steroid

• Rapidly metabolized

• Nearly equal efficacy to Pred Forte while less likely to induce IOP spike

• Good for pt with known steroid response

• Good for protracted case of anti-inflammation

Why is Loteprednol etabonate less likely to induce IOP spike?

Natural tissue contains esterases in ocular tissue, therefore can break down drug → increase safety profile as excess drug is metabolized

What are the various formulations of loteprednol etabonate?

• Lotemax suspension

• Lotemax gel

• Lotemax SM gel

• Lotemax ointment

• Alrex

• Inveltys

• Eysuvis

What is Lotemax suspension?

• 0.5% loteprednol etabonate

• Open indications for ocular inflammation

• Dosage: QID x2weeks, then taper accordingly

• Preserved with BAK 0.01%

What is Lotemax gel?

• 0.5% loteprednol etabonate

• Only indicated for use following ocular surgery

• Dosage: QID x2weeks, then taper accordingly

• Preserved with BAK 0.003%

What is Lotemax SM gel?

• 0.38% loteprednol etabonate GEL

• Only indicated for use following ocular surgery

• Dosage: TID x2weeks, then taper accordingly

• Preserved with BAK 0.003%

What is Lotemax ointment?

• 0.5% loteprednol etabone

• Only indated for use following ocular surgery

• Dosage: QID x2weeks, then taper accordingly

• Non-preserved

What is Alrex?

• 0.2% loteprednol etabonate

• Suspension

• Only FDA indicated for allergic conjunctivitis

What is Inveltys?

• 1.0% loteprednol etabonate

• Suspension

• AMPPLIFY

• FDA indicated for post-op inflammation

• Dosage: 1gt BID x2weeks

What is Eysuvis?

• 0.25% loteprednol etabonate

• Suspension

• AMPPLIFY

• FDA indicated for short-term treatment of signs and symptoms of inflammatory dry eye

• Dosage: 1gt QID x up to 2wks

What is AMPPLIFY?

nanotech drug delivery with mucus-penetrating particles (MPP) to increase corneal and intraocular absorption

What are the common uses for loteprednol?

• Dry eye (short-term use as diagnostic agent or management of flare-ups)

• Inflammatory keratitis (DOC for Thygeson’s SPK)

• Post-op inflammation (particularly refractive surgery)

• Episcleritis (particularly nodular)

• Allergic conjunctivitis

• DOC for Giant Papillary Conjunctivitis (GPC)

  and Vernal Keratoconjunctivitis (VKC)

• Any inflammatory condition requiring long, protracted steriod therapy due to its safety profile

What is Maxidex?

• 0.1% dexsamethasone alcohol

• Targets cells in Anterior chamber more than target tissues in cornea

• Suspension

• Also available in generic

• FDA indicated for ocular inflammation

• Has highest chance to induce IOP spike

• Not as efficacious as Loteprednol etabonate

What is FML?

• 0.1% fluorometholone alcohol

• Least to induce IOP spike

• Suspension

• Available in generic (preferred drug on insurance formularies)

• FDA indicated for ocular inflammation

• Commonly used for: episcleritis, superficial inflammation

What is FML Forte?

• 0.25% fluorometholone alcohol

• FDA indicated for ocular inflammation

• Rarely used, no generic available in 0.25%

What is Flarex?

• 0.1% fluorometholone acetate

• Suspension

• FDA indicated for ocular inflammation

• Rarely used, no generic available

• Possible benefit in treating protracted or recalcitrant Thygeson’s Keratits

• Does not have high receptor affinity → weak therapeutic effect

Rate the order of efficacy of the topical ophthalmic steroids. 1 being the most effective and 5 being the least.

1. a) Pred Forte
   b) Durezol

2. Lotemax/Inveltys

3. Maxidex

4. Alrex/Eysuvis

5. FML/Flarex

Rate the risk of the topical ophthalmic steroids inducing an IOP spike. 1 being the most likely and 5 being the least likely.

1. Maxidex (* increase frequency)

2. a) Durezol
   b) Pred Forte

3. Lotemax/Inveltys

4. Alrex/Eysuvis

5. FML/Flarex

What are the guidelines for dosing topical ophthalmic steroids?

• Dosage and length of course of Tx is determined by severity of presentation

• If condition warrants steroid Tx, initial dosage usually no less than QID

• For mild to moderate inflammation, common dosage is QID x7 days

• Initial dosage for significant cases of uveitis is commonly Q1h with Pred Forte or Q2h with Durezol

When is tapering topical ophthalmic steroids necessary?

• High dosage (> QID)

• Long duration of Tx (> 10-14 days)

When and how do you taper steroids?

• Taper only when improvement is seen on a follow up at current dose

• To taper: reduce dosage frequency by <50% of previous usage.

• Typically, do not teed to taper after BID (to QD)

What is the purpose of pulse dosing? When would one pulse dose?

• Purpose: rapidly reach peak drug conc in the target tissue to have an early impact on significant symptoms

• Pulsing is done when more severe symptoms warrant it

Do ophthalmic formulations cause systemic side effects?

Almost never

Do short-term ocular use of topical steroids cause any ocular side effects?

Rarely. But can affect IOP or PSC, so it is best to treat aggressively to limit length of Tx.

Are there refills for topical steroids?

No. Have pt discard after use.

What is Dextenza?

• 0.4 mg dexamethasone intracanalicular insert

• FDA approved for: inflammation and pain following ophthalmic surgery & allergic conjunctivitis

• Sustained release for 30 days

• Improved compliance vs. ~70 drops in 30 days

• No need for removal, disintegrates and flushed thru nasolacrimal system

What is 0.1% triamcinolone cream?

• Dermatological use

• For short term use for acute dermatitis of periocular adnexa

• Not for use on the ocular surface

• 10 times efficacy of OTC 1% hydrocortisone

• Rx: TID x 3d, then BID x 3d

• SE: high dose or chronic/excessive use on skin can lead to thinning and/or depigmentation of skin.

What are some systemic steroids?

Prednisone and Medrol (methylprednisolone)

What are the ocular indications for prescribing systemic steroids?

• Allergic inflammation of the conjunctiva, lids, and adnexa (Only indication allowed for ODs in OH)

• Graves Ophthalmopathy

• Orbital Pseudotumor

• Retinal Vasculitis

• Uveitis

• Myasthenia Gravis

• Giant Cell Arteritis

What can cause allergic inflammation of the conjunctiva, lids, and adnexa.

• Contact Dermatitis

• Severe Allergic conjunctivitis/blepharitis

• Poison Ivy

• Bee stings

What are the restrictions for prescribing oral steroids in ohio?

• Only for adults 18 years and older

• Methylprednisolone only

• Amount that does not exceed a single course of therapy (no refills)

  • single course of 6 day oral steroids per episode

• Prescribed on basis of an individual’s particular episode of illness

What are the SE of chronic, long-term use of systemic steroid use?

• Muscle wasting and altered fat distribution = Cushing’s syndrome

• Suppress adreno-pituitary axis → adrenal insufficiency → malaise, myalgia, muscle atrophy, hypotension, increased risk of infection, decreased wound healing

• Osteoporosis

• Steroid psychosis

• Thinning and depigmentation of the skin

What are the SE of short-term systemic steroid use?

• Peptic uclers (from protective prostaglandins inhibited)

  • Recommended OTC proton-pump inhibitor to counter act upset stomach and nausea

• Increased blood glucose (typically for out of control type 1 DM)

• Pregnancy (not contraindication, but most consult w/ OB-GYN)