Treatment Techniques II

Inflammation

the core component of the cycle of dry eye disease triggered by hyperosmolar desiccating stress which upregulates pro-inflammatory cytokines, chemokines, MMP 9 activity, and T cell activation.

Corticosteroids

drugs that inhibit the formation of phospholipase A2 thereby blocking the cyclooxygenase and lipoxygenase inflammatory pathways.

Cyclooxygenase

pathway involving the conversion of arachidonic acid to prostaglandins which mediate pain and vascular permeability in inflammation. Blocking of this pathway by corticosteroids decreases pain, redness, and edema.

Lipoxygenase

pathway involving the conversion of arachidonic acid to leukotrienes which recruit PMNs and eosinophils to the site of inflammation. Blocking of this pathway by corticosteroids reduces damaged caused by excess healing mechanisms of these cells.

cytokine and chemokine

Corticosteroids decrease inflammation by Inhibiting _____ (2) production

MMPs and prostaglandins

Corticosteroids decrease inflammation by Decreasing synthesis of _____ (2)

cell adhesion molecules

Corticosteroids decrease inflammation by Decreasing expression of _____

lymphocyte

Corticosteroids decrease inflammation by Stimulating _____ apoptosis

cell membranes

Corticosteroids decrease inflammation by Stabilizing _____

lipophilic, hydrophilic

In order for corticosteroid to reach intraocular targets by penetrating the cornea, they must be ____ AND _____

ketone

corticosteroids having a biphasic structure enabling them to penetrate intraocularly.

phosphate

Ketone corticosteroids having a ______ base have the lowest levels of penetrance and can be used in the treatment of ocular surface disease

ester

corticosteroids that do not penetrate intraocularly being useful in the treatment of ocular surface disease as they are broken down and effective at the level of the ocular surface.

2 weeks, drug potency

Steroid response is more common with steroid use longer than _____ but can also depend on _____

increased resistance to aqueous outflow

The proposed mechanism of steroid response is...

Fluorometholone 0.1% suspension (FML)

soft ketone corticosteroid used off label in the management of dry eye. Has a very low risk of IOP spike.

Lotemax (loteprednol 0.5%)

soft ester corticosteroid used off label in the management of dry eye. Is available in suspension, gel, and ointment forms.

0.38, 2

____% Loteprednol is claimed to be made up of submicron particles that increase penetrance into the anterior chamber ____x

Eysuvis (loteprednol 0.25%)

low concentration loteprednol suspension that is FDA approved for up to 2 weeks in the treatment of dry eye disease flare ups. Nanoparticle technology increases delivery of the drug to the ocular surface and coating reduces adhesion to tear film mucins.

mildest

In the treatment of ocular surface disease the (mildest or strongest) steroid should be prescribed. Steroids are useful in the initiation of treatment to break the inflammatory cycle, or during ongoing therapy to address recurrences. They do not cure the underlying disease process.

1 gtt QID for 2 weeks

dosage of soft corticosteroids in the treatment of ocular surface disease

no refills

Corticosteroids should be prescribed with (how many refills)

15-20%

the overall efficacy of topical immunomodulators in the treatment of dry eye disease

Schirmer score

Clinical trials showing statistically significant results of topical immunomodulators are questionable as their method of evaluating efficacy was...

Cyclosporine A

immunomodulator that works by binding to and inhibiting cytoplasmic proteins cyclophilin A and B. Inhibition of these proteins results in an overall decrease in goblet cell squamous metaplasia and an increase in goblet cell density. Is available as a generic or as trade name formulations (Restasis, Cequa).

Cyclophilin A

protein that stimulates T cell activation and inflammatory cascade via increased cytokine levels. The primary protein blocked by cyclosporine A that mediates the therapeutic anti-inflammatory effects in dry eye treatment.

Cyclophilin B

protein that initiates mitochondrial stimulated apoptosis of conjunctival epithelial cells

>3 months, BID, 70-90 days

The effect of cyclosporine A can take up to _____ of ____ dosage to occur due to a T cell half-life of ____

72, 57

Data shows that after 3 months of BID dosage of cyclosporin A, about ____% of patients were satisfied with their results and ____% reported a reduction to mild or no symptoms

6 months

It may take cyclosporin A up to _____ to see significant reduction in corneal staining and improved visual performance

stinging, emulsion

Many patients complain of ____ upon instillation of cyclosporin A due to _____ formulation of the drug vehicle

loteprednol

A two week treatment with _____ has been shown to improve comfort and enhance therapeutic effect of cyclosporin A

emulsion, single use vials

Generic cyclosporin is available in ____ formulation as _____

Restasis

FDA approved formulation of cyclosporin A in an emulsion (STINGS!) of glycerin, castor oil, polysorbate 80, and carbomer copolymer type A to be used in patients not taking topical anti-inflammatory medications or using punctal plugs. It was marketed to increase tear production by reducing inflammation of the lacrimal gland. Is available in single use vials or a non-preserved bottle.

Cequa (0.08% cyclosporin A)

FDA approved formulation of cyclosporin A in an aqueous vehicle (does not sting as much as emulsion formulations such as Restasis). Is available in single use vials.

4 weeks

The nanomicellar technology found in the Cequa formulation of cyclosporin A is proposed to increase delivery to the ocular surface showing effects as early as...

Xiidra (5% Lifitegrast)

FDA approved drug that is a small molecule integrin antagonist blocking the recruitment and activation of CD4+ T lymphocytes to the ocular surface.

Integrins

cell surface receptors that mediate cellular adhesion to the extracellular matrix and T cell activation. Are inhibited by drugs such as Xiidra (5% Lifitegrast) to reduce inflammation associated with ocular surface disease

LFA 1, ICAM 1

Integrin ____ binds to adhesions protein ____ to activate T cells and promote inflammation. This specific process is blocked by Xiidra (5% Lifitegrast) in the treatment of dry eye

2 weeks, BID

Xiidra (5% Lifitegrast) begins to show symptomatic relief after ____ of ____ dosing

3 months

Xiidra (5% Lifitegrast) can take up to ____ to show a reduction in clinical signs of corneal and conjunctival staining

Discomfort upon instillation (24%)

Dysgeusia (24%)

Blurred vision (11%)

3 Adverse Effects of Xiidra (5% Lifitegrast)

the patient's insurance

The decision of whether to prescribe cyclosporine A versus Xiidra (5% lifitegrast) will often be determine by...

AzaSite

a topical 1% azithromycin solution that can be used off label in the treatment of dry eye.

BID for 2 days, QHS for 1-2 months

dosage of Azasite in the treatment of dry eye

1 month, 3 months

Azasite shows significant improvement of symptoms and clinical signs in ____, but this fails to persist any longer than ____ as individual treatment

very little

There is (very little or substantial) evidence that the use of oral antibiotics are useful in the treatment of dry eye

Tetracyclines

class of drugs that when given at adequate concentrations has a broad spectrum bacteriostatic effect via binding to ribosomal 30s subunits and thereby blocking protein synthesis.

Minocycline

tetracycline that is rarely used as it has worse adverse effects

better absorbed

Doxycycline is more commonly used than tetracycline as it is ____, reaching peak serum concentrations more quickly

bacterial lipase

Doxycycline reduces the production of pro-inflammatory free fatty acids by decreasing the production of...

cytokines, MMP 9

Doxycycline has anti-inflammatory action by decreasing the production of _____ and decreasing _____ activity

neutrophil and lymphocyte, MMPs and cytokines

Doxycycline has antioxidative effects by modulating ____ (2) function via decreased production of _____ (2)

antiapoptotic and antiangiogenic

In addition to anti-inflammatory effects, doxycycline may have ____ (2) effects at the ocular surface

recurrent corneal erosion, collagenase and MMPs

In addition to the treatment of dry eye, doxycycline is effective in the treatment of _____ as it promotes corneal healing via activity against _____ (2)

50, BID, 4-6 weeks, QD, 3-6 months

The dosage of doxycyline monohydrate in the treatment of dry eye is initially ____ mg ____ for _____, then ____ for _____ depending on therapeutic response

20 mg

dosage of doxyxyline hyclate in the treatment of dry eye. While this dosage is less than that of doxycycline monohydrate because hyclate is more water soluble, this may be cost prohibitive

Nausea

Gastritis

Diarrhea

Photosenstivity

Hives

Tooth discoloration

6 Common Side Effects of Doxycyline

Stevens-Johnson syndrome

Idiopathic intracranial hypertension

Anemia

Pancreatitis

Esophagitis

5 Severe Side Effects of Doxycyline

Pregnancy/nursing

3 Contraindications of Doxycyline

Azithromycin

macrolide antibiotic that has gram positive coverage, but also reduced inflammation by inhibiting the release or proinflammatory molecules and increasing TGF beta1 expression.

cardiac QT prolongation, anti-arrhythmic medication

Azithromycin should not be used in patient with _____ due to use of _____

Omega 3 fatty acids

essential polyunsaturated fatty acids that cannot be synthesized by the body and must be obtained from dietary sources. Have anti-inflammatory properties via competitive enzyme inhibition of arachidonic acid (omega 6) as a subtrate for inflammatory cascades. This results in the productionof anti-inflammatory resolvins and protectins that decrease ocular surface inflammation, increase tear volume, and maintain corneal epithelial integrity.

Alpha linolenic acid (ALA)

a short chain fatty acid that can be consumed through walnuts, soy beans, flaxseed oil

Eicosapentaenoic acid (EPA), Docosahexaenoic acid (DHA)

two long chain fatty acids that can be consumed through oily fish

desaturation, omega 6

The body can produce long chain fatty acids from short chain via _____. High levels of ____ rich oils may inhibit this elongation thereby promoting inflammation

Triglyceride

form of fatty acids that is found in nature having fewer GI side effects, better absorption, and is more shelf stable

Ethyl ester

form of fatty acids that is an alcohol based conversion in order to remove mercury and carcinogens found in commercially available fish. This form has higher GI side effects

re-esterfied

The ethyl ester form of fatty acids must be ____ in order to remove artificially induced alcohol and to increase concentrations of EPA and DHA compared to the natural triglyceride form

decrease, unsaturated fatty acid

While the primary mechanism of omega 3 supplementation in dry is anti-inflammatory, they may also ____ the phase transition of meibum by increasing _____ levels

Bleeding disorders, immunosuppression

two cases in which omega 3 supplementation should be used in caution. Consult with the patient's PCP.

DREAM Study

Study that compared the effectiveness of fish-derived EPA/DHA triglyceride form to refined olive oil in improving the signs and symptoms of dry eye. Both groups had improvements in dry eye signs and symptoms with no statistically significant difference between the two groups.

No change in patients going from taking the omega 3 supplement to the olive oil

VITAL Study

Study that found no evidence that omega 3 supplementation prevented the onset of dry eye or dry eye symptoms

Tyrvaya (Varenicline)

FDA approved nasal spray that is a highly selective nicotinic acetycholine agonist approved for the treatment of dry eye. It stimulates acetylcholine receptors in the anterior ethmoid branch of the trigemintal nerve in order to stimulate the production of basal tears, mucin, and meibomian gland secretions.

BID

dosage of tyrvaya

Sneezing

Coughing

Throat irritation

Nose irritation

4 Side Effects of tyrvaya

miebo

a 100% perfluorohexyloctane water free solution not requiring preservatives. It has a low surface and interface tension resulting in spreading optimal spreading across the ocular surface. Its amphiphilic nature allows for dissolving of lipids and inhibition of aqueous evaportation. Penetrates into meibomian glands and dissolves meibum.

8 weeks QID, 2 weeks

Studies show improvements in corneal staining after _____ (dosage and duration) use of Miebo with dry eye scores reducing as early as _____

Vevye

cyclosporine A 0.1% water free solution avoiding oils, surfactants, and preservatives allowing for increased contact time, improved tolerability, and reduced visual disturbances.

4 weeks BID

Studies show improvements in corneal staining after ____ (duration and dosage) use of Vevye