*Steroids Flashcards
Steroid use/misuse
STEROID HORMONES
- Cholesterol backbone
- Sex hormones are a special class of steroids
that control growth, sexual development and
behavior - Steroids passively cross cell membranes and
bind to intracellular receptors - Glucocorticoids, released during stress,
suppress the immune response, increase blood
glucose, and regulate energy metabolism
Adrenal hormones
What are glucocorticoids responsible for
Homeostasis regulation
What are mineralocorticoids reponsible for
- Fluid and electrolyte balance
- Wound healing
What are androgens responsible for
Male sexual characteristics
What are progestinsa nd estrogens responsible for
Progestins
- progesterone-like Pregnancy hormone
Estrogens
- Female sexual charateristics
- Pregnancy hormone
GLUCOCORTICOID MECHANISM OF ACTION
- Glucocorticoids are endogenous and synthetic anti-
inflammatory mediators - As lipids, they can passively diffuse across a cell membrane and bind to/active the cytosolic glucocorticoid receptor
- Once bound, the complex enters the nucleus where it promotes transcription of genes whose products suppress inflammatory pathways
- Steroids also interfere with the activity of pro-inflammatory transcription factors such as NF-kB and activator protein-1 (AP-1)
- Steroids are routinely used in overactive immune responses associated with allergy, asthma, AI disease and sepsis
GLUCOCORTICOID-MEDIATED HOMEOSTASIS
- Physiologic and pharmacologic mechanisms of GC action are
inherently linked since they are mediated by the same receptor - Accordingly, supraphysiologic exposure to corticoids is
potentially detrimental to several metabolic, hormonal, and
immunologic functions (importance of taperig)
HYPOTHALAMUS-PITUITARY-ADRENAL AXIS
(Regulation of Corticosteroid Secretion)
- The HPA axis serves the primary role of managing the body’s response to STRESS
- The end-products of this axis are cortisol, and to some degree, epinephrine, the body’s stress hormones
- In response to stressful stimuli, cortisol is released for several
hours - Inflammatory and immune diseases are associated with
cytokine-mediated activation of the HPA-axis, leading to
cortisol release as an autoregulatory endo product of the
cascade, thereby linking immune and neuroendocrine pathways
Glucocorticoid physiology
ENDOGENOUS ANTIINFLAMMATORY MEDIATION
- Lipocortin (Annexin A-1) is a member of the annexin group of cellular and bloodborne proteins which acts as an endogenous protein inhibitor of the phospholipase A2 (PLA2) enzyme, COX-2 and leukocyte inflammatory
pathways at multiple levels - PLA2 is a primary activation enzyme of the arachidonic acid inflammation pathway
- During the inflammatory response, annexin A-1 is mobilized to the cell surface where it conversely assumes a dual role: inhibiting the innate immune response and promoting the adaptive T-cell response
- Induction of expression of the annexin-A1 gene is the main anti-inflammatory, immunosuppressive mechanism of glucocorticoids
GLUCOCORTICOID EFFECTS
MMP Role in Biological Processes
STEROID TAPERING
- Adrenal cortical atrophy (adrenal crisis) due to HPA axis suppression can result within weeks of steroid therapy initiation
- Abrupt discontinuation of oral steroid use can result in a
dramatic HPA axis upregulation due to the suddenly low
circulating levels - Symptoms of abrupt withdrawal include
headache, lethargy, fainting, weight loss, hypoglycemia, N&V\ - Tapering the dose down to physiologic levels (equivalent to 5-7.5 mg prednisone) allows the body to gradually ramp up endogenous production
- Depending on the dose and duration of therapy, tapering may proceed by 2.5-10 mg every 2-7 days
- Rebound inflammation requires a return to the last dose used prior to the final reduction (examquestion)
- Relapse is avoided by continuing therapy slightly beyond
resolution of inflammation - Topical ophthalmic steroids should also be tapered,consider ester-based steroids due to their safety profile
- Some chronic condtions require lifelong low-dose steroid use - corneal transplant, stromal immune corneal disease, chronic uveitis, recalcitrant dry eye disease
STEROID ADMINISTRATION
- Topical
- Most common route of administration in eye care
- Oral
- Renal function is a key concern
- Inhalation
- Local injection
- Intravenous
Prednisone indications
- Corticosteroid-responsive conditions
- Adrenal insufficiency
- MS; acute exacerbation
- Asthma; acute
- Asthma; severe persistent
- Gout; acute
- COPD exacerbation
- Alcoholic hepatitis; acute
STEROIDS: GENERAL ADVERSE EFFECTS
Dose & Duration Dependent
- Increased hunger
- Depression
- Muscle fatigue
- Cataracts
- Elevated IOP
- Hair pattern changes
- Easy bruising
- Acne
- Osteoporosis
- Swelling
- Hirsutism
- glaucoma
- cataracts
- hypokalemia
- Xanthomas
- Diabetic complications
- Peptic ulceration
- Hypertension
- Mood changes
- Delayed wound healing
- Adrenal insufficiency
- Growth inhibition in kids
- Immunosuppression
- Cushing’s syndrome
- Hypokalemia
Topical opthalmic drug interactions and cautions of prednisone
Topical Ophthalmic Drug Interactions
• Naphazoline, tetrahydrozyline, phenylephrine: additive
hypertensive effects
Cautions
• Diabetes
• Active infection
• Hypertension
• Myasthenia gravis
• Optic neuritis
• Ocular HSV
Relative glucocorticoid potency vs mineralocorticoid influence
Which cortisones have the longes half lives?
Betamethasone and dexamethasone ( 36-72hours)
Fludrocortisone
Is a potent mineralocorticoid (fluid/electrolyte balance)
Which fatty acid has the highest bioavailablity and the greatest anti-inflam potential?
- Alpha linoleic acid
- Evening primrose oil
- Linoleic acid
- Eicosapentaenoic acid
EPA
Alpha linoleic- plant based, low bioavailability
Evening primrose oil- omega 6
Which of the following is a prodrug?
- Bromfenac
- Keotrolac
- Nepafenac
- Flubiprofen
Nepafenac
Which NSAID structural subclass do the majority of topical opthalmic NSAIDs belong?
- Salicylates
- Acetic acids
- Carboxamides
- Propionic acids
Acetic acids
Oral steroid indications
Inflammatory eye diseases
- Scleritis
- Temporal arteritis
- Endophthalmitis
- Ocular Myasthenia Gravis
- Graves opthalmopathy
- Idiopathic cranial hypertension
- Steven’s Johnsons syndrome
- Posteior segment disease - vitritis, retinitis, choroiditis, papillitus
Drug interactions with steroids
- Barbiturates
- Phenylbutazone
- Phenytoin
Anticoagulants
- Reduced anticoagulant effects
- Steroids may promote coagulation by reducing prostacyclin levels
Steroid contraindications
- Active Viral infection
- TB positive
- Fungal infection
- Immunosupressed
- Peptic ulcer history
- Osteoporosis
- Psychosis
- Pregnancy
Success of topical steroid treatment depends on
Type and location of inflammation
most effective ACUTE > SUBACTE >> CHRONIC least effective
Anterior segment inflammation is much more responsive totopical steroids than posterior
Ester-based steroids vs classic ketones
Ester based steroids have much less potential to causec cataracts or elevated IOP since ketone based steroids are not broken down by anterior chamber esterses
Ketone based- eg prednisolone
Ester based- loteprendol
Which steroid is the only ester based steroid?
Loteprednol
Which opthalmic drug is the only one preserved with sorbic acid instead of BAK?
Durezol (difluprednate)
Opthalmic steroids
NB most potent on list is Durezol (difluprednate)
INVELTYS (loteprednol 1% suspension)
- Treatment for post-op pain and inflammation
- bd dose
- prior Inveltys- all post op steroids were only approved for qid dose
- Formulation uniquely employes AMPPLIFY drug delivery technology wich involes Mucus Penetratin Particles that transport loteprednol throug mucus barrier resulting in a 3x increase in corneal penetration andaccess to aqueous humor
Lotemax SM Gel 0.38%
- tid treatment of post-op inflammation
- Submicron particle size for faster drug dissolution in tears
- 2x greater penetration to aqeous humor vs Lotemax gel 0.5%
- Gels have lowest BAK concentration in Lotemax family
DEXTENZA 0.4mg Dexamethasone (pellet)
- Post-op pain and inflammation
- Allergic conjunctivitis
- Removable if necessary via saline irrigation or manual expression
- Designes to deliver tapered dose
- Contains fluorescine for visualization
- Preservative free
Topical steroid indications
Restasis (CYCLOSPORINE-A PF emulsion)
- 11 amino acid cyclic fungal peptide
- Historically used as an immunosuppressant for organ transplant rejection prophylaxis,rheumatoid arthritis and recalcitrant psoriasis
Mechanism of Action
- Inhibits the calcineurin-dependent activation of NFkB in inactive T-cells (NFkB normally stimulates IL-2 production and is upregulated by hyperosmolar tears)
- Inhibits mast cell degranulation
- Phagocytic function is unaffected
- Maximum effects after 110-day T-cell lifespan
- First immunosuppressant to come on the market for dry eye therapy in 16 yo+
- Refresh Endura (castor oil) vehicle enhances CsA absorption
- • FDA approved for keratoconjunctivitis sicca at 1gt bid
- Off-label use in AKC, VKC, meibomitis, MG, GPC, ocular rosacea
- Adverse reactions: burning >> redness, tearing, discharge, foreign body sensation, pruritus, blur
- Contraindicated in patients with active ocular infection or known hypersensitivity
XIIDRA® Lifitegrast 5% PF solution
- The only FDA-approved topical immunosuppressant indicated to treat both the signs and symptoms of Dry Eye Disease
- BID dosing in 17+ yo patients
- Lymphocyte function-associated antigen-1 (LFA-1) antagonist
- Inhibits T-cell activation by preventing binding of surface receptor to intercellular adhesion molecule commonly overexpressed on the dry ocular surface
- Common adverse reactions: irritation, dysgeusia, reduced VA
- Less common adverse reactions: conjunctival hyperemia, headache,tearing, discharge, pruritus, sinusitis
- Contraindicated in patients with known hypersensitivity (no reference to contraindication for eye infections exists)
Cequa (Cyclosporine 0.09%)
- 0.09% solution
- Due to CsA’s poor water solubility, NCELLTM technology was applied to improve drug delivery and increase tissue penetration
- NCELLTM technology uses nanomicelles composed of polymers that encapsulate CsA molecules
Eysuvis ((loteprednol suspension 0.25%)
- the first corticosteroid indicated for dry eye disease and the
first drug approved for short term (up to 2 wks) therapy of DED - AMPPLIFYTM drug delivery technology employs the
use of Mucus Penetration Particles that transport loteprednol etabonate through the mucus barrier esulting in a 3X increase in corneal penetration and access to aqueous humor - EYsuVIS® is approved for short term (2 wk) treatment of episodic dry eye flares
Truetear
- Bluetooth enabled intranasal neuro-stimulator indicated for dry eye disease bid
- Stimulates trigeminal nerve for 30-180 sec, enhancing basal lacrimation by 3X
- Studies show increase in meibum & mucin production
tyrvayaTM (Varenicline 0.03mg/50ul)
- Indicated for dry eye disease
- Varenicline 0.03mg/50ul spray volume bid each nostril
- Originally developed and marketed in a tablet formulation
under the tradename Chantix®, for smoking cessation - Acts as a highly selective cholinergic agonist
- Stimulates cholinergic receptors of the trigeminal nerve
leading to an increase in basal tear film production by
stimulating the lacrimal glands, meibomian glands and
goblet cells - Clinically significant improvement noted in 4 weeks
- Adverse effects include sneezing >> cough, throat irritation
Oxervate®
- Topical Cenegermin-bkbj 0.002% PF ophthalmic solution for use 1 drop 6x/d x 8 wks
- Supplied in weekly cartons containing 7 multi-dose vials
requiring refrigeration - First-in-class recombinant human nerve growth factor
(rhNGF) - FDA approved 8/2018 with orphan drug classification for 2yo and over for neurotrophic keratitis
- Adverse effects: eye pain following instillation, corneal
deposits, foreign body sensation, ocular hyperemia, ocular
inflammation and tearing - Contraindications: ocular infection
TEPEZZA
- First and only FDA-approved treatment for TED
- Teprotumumab-trbw administerd via IV infusion q3wks x 8
(t1/2=20d) - Antagonizes insulin-like growth factor-1 receptor (IGF-1R),
preventing orbital fibroblast stimulation - Adverse reactions include muscle spasm, nausea, alopecia,
diarrhea, fatigue, hyperglycemia, hearing impairment,
dysgeusia, headache, and dry skin
