HO35_Ocular Allergies_Ocular vs Systemic Steroids

There are multiple medication classes used for ocular allergies/DED:

Ocular Steroids vs Systemic Steroids

Endocrine System: Hypothalamic-Pituitary Axis

The Hypothalamic-Pituitary-Adrenal Axis (HPA) the main stress response system involving the hypothalamus, pituitary gland, and adrenal gland.

The primary function of the HPA is to release glucocorticoids (cortisol) in response to stress.

Hypothalamus: sending signals to the pituitary gland to release hormones.

Pituitary:produces hormones, adrenal glands,

Endocrine System: Hypothalamic-Pituitary Axis

Hormones of the Anterior Pituitary

The anterior lobe of the pituitary produces and releases (secretes)

• Adrenocorticotropic hormone (ACTH/Corticotropin): Stimulates the adrenal glands to produce cortisol (adrenal hormones).

• Growth Hormone (GH): muscle formation

• Thyroid-stimulating hormone (TSH): thyroid hormones.

• Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (the gonadotropins):

• Prolactin:

Hormones of the Anterior Pituitary

The Adrenal Gland: Consists of the Cortex and the Medulla

The adrenal cortex or cortex secretes:

• Adrenal androgens: testosterone

• Two types of corticosteroids:

  • Glucocorticoids: Involved with metabolism and response to stress (e.g., cortisol)

  • Mineralocorticoids: Regulate salt and water metabolism (e.g., aldosterone).

The adrenal medulla or medulla secretes:.

• Catecholamines (epinephrine and norepinephrine).

The Adrenal Gland: Glucocorticoids (Steroids)

Cortisol is the principal human glucocorticoid.

Cortisol production is diurnal,

Stress and level of circulating steroid influence secretion.

• Exogenous steroid replacement resulting in a reduction of endogenous steroid production,

• This is the rationale behind “tapered steroid dosing” which is when large doses of steroids are tapered downward

Exogenous: originating from outside the body; Endogenous: originating from within the body.

Increase resistance to stress

Anti-Inflammatory Actions

Immunosuppressive Actions

Corticosteroids: Comparative Potency – Systemic Steroids

Ocular Allergies: Ocular Steroids vs Systemic Steroids

Corticosteroids (Steroids)

Adverse drug effects of steroids are dose and duration related (e.g., suppression of the hypothalamic-pituitary-adrenal axis).

Always evaluate the risk vs benefit

In general, systemic steroids disrupt the inflammatory cascade and suppress normal immune response by impacting every aspect of the immune system.

Corticosteroids

Mechanism of Action: Steroids suppress normal immune response by impacting every aspect of the immune system.

• Inhibit phospholipase A2 synthesis

• Inhibit both production and release of inflammatory mediators

• Suppress of T-cell lymphocyte proliferation

Summary of Effects:

Corticosteroids: Warnings/Significant ADEs Endocrine Effects: Adrenal Suppression

• Reversible HPA (hypothalamic-pituitary-adrenal) axis suppression with the possibility of glucocorticoid insufficiency.

• HPA suppression may be minimized by gradual reduction of dosage (e.g., tapered dose schedule or tapering).

• Tapered Dose Schedule or Steroid Tapering

  • Gradual daily dosage reduction to allow the HPA to recover from the HPA-suppressant effects of large steroid doses.

  • Medrol Dose-Pack (Methylprednisolone)

Steroid adverse effects are dose and duration related.

Corticosteroids: Warnings/Significant ADEs Cardiovascular Effects

• Elevation of blood pressure due to salt and water retention,

• Caution

Corticosteroids: Warnings/Significant ADEs

Gastrointestinal (GI)

• Increased risk of GI perforation

Corticosteroids: Warnings/Significant ADEs General: Hyperglycemia,

Hyperglycemia,

Corticosteroids: Warnings/Significant ADEs

CNS and Psychiatric/Behavioral Effects

Euphoria, mood swings, insomnia, personality changes

(steroid psychosis)

Corticosteroids: Warnings/Significant ADEs

Decrease in Bone Density

Increased potential for osteoporosis and fractures decrease bone formation and increase bone resorption

May lead to growth retardation and inhibition of bone growth in

children and adolescents.

Corticosteroids: Warnings/Significant ADEs Ocular Effects

Increased intraocular pressure (IOP), glaucoma (open-angle)

Posterior subcapsular cataract.

Ocular Steroids

Ocular corticosteroids relative anti-inflammatory efficacy.

The effectiveness of ocular steroids in suppressing inflammation is also due to differences in penetrating the cornea,

The ideal steroid should be biphasic in its polarity,

Modification of a steroid base impacts the following:

– Formulation of the steroid product.

– Ocular penetration and metabolism.

– Anti-inflammatory potency/efficacy.

Ocular steroids are produced in three main formulations:

• Alcohol and Acetate formulations (sparingly soluble in water, lipid soluble suspensions/ointment)

• Phosphate formulations (water soluble solutions)

The more lipid-soluble derivatives (alcohol and acetates) are available as suspensions/ointments

The water-soluble salts (phosphates) generally are formulated as solutions.

Injectable Ocular Administration

Ocular Steroids: Impact of Formulation on Potency and Efficacy

Systemic steroids are categorized

Ocular steroids

• Potency/Drug Concentration

• Ocular penetration

  • Formulation/Vehicle

    • Alcohol and Acetate (lipid soluble suspensions/ointment)

    • Phosphate (water soluble solutions)

Alcohol and acetate formulations are sparingly soluble in water (e.g., more lipophilic) and are formulated as suspensions.

• acetate 0.1%, ((Flarex®, gen.) is more potent than Fluorometholone alcohol 0.1% ophth. suspension (FML Liquifilm®).

Phosphate derivatives are very soluble in aqueous media (e.g., more hydrophilic) and are formulated as solutions.

• acetate 1% ophthalmic suspension (Pred Forte®, gen.) is more potent than Prednisolone sodium phosphate 1% ophthalmic solution (generic).

Ocular Steroids: Steroid-Related IOP Elevation

prolonged ocular steroids can result in steroid-related IOP elevation

Changes in the trabecular meshwork and its extracellular matrix causes resistance to aqueous outflow which increases IOP.

• Steroid responders can experience IOP increases within a few hours of therapy.

Ocular Steroids: Indications

Indications: Treatment of steroid-responsive inflammatory conditions

• Allergic Conjunctivitis and Infective Conjunctivitis

Ocular Steroids: Mechanism of Action

Mechanism of Action: Steroids suppress normal immune response by impacting every aspect of the immune system.

• Inhibit phospholipase A2 synthesis

• Inhibit both production and release of inflammatory mediators

• Suppress of T-cell lymphocyte proliferation.

• Reduce/Reverse capillary permeability and cellular exudation.

Ocular Steroids: Relative Contraindications/ADEs/Cautions

Relative Contraindications: Infections in general

In general, ocular steroids with greater anti-inflammatory potency have potential for increased risks of elevated IOP, cataracts, etc.

General Ocular ADEs/Cautions: elevated IOP, glaucoma, cataracts, optic nerve damage, keratitis, secondary ocular infections (viral, fungal, bacterial), exacerbation of current infection, corneal thining erosion/ulceration/edema, globe perforation,

General Non-Ocular ADEs/Cautions:

Ocular Steroids: Steroid Related IOP Elevation – “Soft” vs “Hard”

“Soft” corticosteroids have been strategically designed to reduce the risk of IOP elevation

• Loteprednol etabonate 0.2% and 0.5%

• Fluorometholone alcohol

“Hard” corticosteroids are more potent or stronger and have a greater risk of side effects.

• Difluprednate 0.05% (Durezol® emulsion), Prednisolone acetate 1% suspension (Pred Forte®), and Dexamethasone Acetate 0.1% suspension (Maxidex®).

Ocular Steroids: Ketone vs Ester Classification

Ketone Steroids:

Ester Steroids: Loteprednol

• Loteprednol is formulated with an ester instead of a ketone group at the C-20 position which makes loteprednol less cataractogenic

• “soft” steroid

Ocular Allergies: Ocular Steroids

Ocular Steroids: Comparative Potency Highlighted by suspension, solution, or emulsion.

Ocular Steroids: Comparative Potency Highlighted by active ingredient and formulation.

Ocular Steroids: Comparative Potency Highlighted by “soft” vs “hard” steroid classes.

Fluorometholone

Products

• Fluorometholone alcohol 0.1% ophth. suspension (FML Liquifilm®)

• Fluorometholone acetate 0.1% ophth. suspension (Flarex®, gen.)

• Fluorometholone alcohol 0.25% ophth. suspension (FML Forte®)

Note: The 0.1% acetate formulation (Flarex®) is more potent than the 0.1% alcohol formulation (FML®).

In general Acetate > Alcohol.

FML® = Alcohol; Flarex® = Acetate

Dexamethasone

Dosage

• Solution

• Suspension

Pharmacology:hard or strong corticosteroid, 3rd

most potent steroid

ADEs:

Products

• Dexamethasone sodium phosphate 0.1% ophthalmic solution generic)

• Dexamethasone 0.1% ophthalmic suspension = acetate (Maxidex®)

Acetate is more potent than phosphate.

Generic solution = Phosphate; Maxidex® suspension = Acetate

Ocular Steroids: Comparative Potency

Loteprednol etabonate 0.2% ophthalmic suspension (Alrex®) indicated for seasonal allergic conjunctivitis.

Loteprednol

Pharmacology

• Considered a soft corticosteroid

• “soft” steroid

• formulated with an ester instead of a ketone

• ADEs:

Products

• Loteprednol etabonate 0.2% ophthalmic suspension (Alrex®)

• Loteprednol etabonate 0.5% ophthalmic suspension, ointment and gel (Lotemax®)

Indicated for SAC Lowest % suspension.

4 times daily.

Prednisolone

Pharmacology: The acetate suspension (Pred Forte®) is considered a hard or strong corticosteroid, 2nd in potency after difluprednate

Indications: Ophthalmic inflammatory conditions/corneal injury.

ADEs:

Products

• Prednisolone acetate 0.12% ophthalmic suspension (Pred Mild®)

• Prednisolone acetate 1% ophthalmic suspension (Various generic, Omnipred®, Pred Forte®)

• Prednisolone sodium phosphate 1% ophthalmic solution (generic)

Note:acetate more potent than the

phosphate

Acetate is more potent than phosphate.

Generic solution = Phosphate; Pred Mild® and Pred Forte® = Acetate

Difluprednate(Durezol® – emulsion)

History

• A difluorinated derivative of prednisolone

Pharmacology: The most potent ophthalmic steroid.

ADEs:

Dosage

• Endogenous anterior uveitis:

• Inflammation/pain associated with ocular surgery: