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Steroid Use in Clinical Practice

Steroid Use in Clinical Practice

Steroid Use In Clinical Practice

DR. TIN WIN AUNG Consultant Endocrinologist Department of Diabetes & Endocrinology North Okkalapa General & Teaching Hospital Outlines

◼ Overview of → What are steroids? →Steroidogenesis, Regulation, Physiological & Adverse Effects

◼ Steroids use in Clinical practice

→ Classification

→ Topical Steroids

→ Inhaled

→ Systemic Corticosteroids

→ Prevention & Treatment of Complications of using CS What are steroids?

◼ Steroids (short for corticosteroids) are synthetic drugs that closely resemble , a hormone that your adrenal glands produce naturally.

◼ Corticosteroids are different from the male hormone-related compounds that some athletes use. Corticosteroids

◼ Corticosteroids divided into:

–

–Mineralocorticoids Endogenous Steroidogenesis Regulation of Cortisol Secretion ◼ Three major mechanisms control ACTH release and the Cortisol secretion

(1) Negative feedback mechanism →ACTH from anterior pituitary

(2) Diurnal variation →Levels are the highest in the morning on waking and the lowest in the middle of evening.

(3) Stress- physical (trauma, surgery, exercise) - psychological (pain, anxiety, apprehension) - physiological (nausea, fever and hypoglycemia) The Role of Cortisol in Regulation of HPA Axis

20 mg/day

Plasma Cortisol -140- 700 nmol/l (Ref: range) Glucocorticoids Physiological Effects Carbohydrate metabolism ↑gluconeogenesis and conserve glucose for use during stress or starvation.

Protein metabolism catabolic effect → negative nitrogen balance with muscle wasting, osteoporosis, growth slowing, skin atrophy, increased capillary fragility, bruising and striae. → Delayed wound healing

Fat deposition → ↑on shoulders, face and abdomen.

Anti-inflammatory and immunosuppressive effects → ↓ recruitment and function of inflammatory cells and vascular permeability at the site of inflammation. → Inhibit prostaglandin and leucotriene synthesis by inhibiting the release of arachidonic acid from the phospholipids. Use as anti-inflammatory and immunosuppressive agents Maintainance of blood pressure → enhances the vascular reactivity to other vasoactive substances such as nor- epinephrine and angiotensin-II

Anti-vitamin D action → ↓ calcium absorption from the gut and ↑ urinary calcium excretion, → useful in treatment of hypercalcemia in sarcoidosis and vitamin D intoxication.

Fluid and electrolyte balance

Renal excretion of urate is increased

Systems Adverse Effects Cautions/Comments

Fluid/Electrolyte Sodium Retension Caution in CHF/hypertension disturbances Edema ↓ Salt intake ↑ Potassium exerction Potassium supplements ↑ Calcium excretion ↑ risk of osteoporosis, Ca supplements Gastrointestinal Gastric Irritation Risk ↑ with ↑doses & prolonged use. N, V, Wt loss/ Wt gain Use PPI only in long term high dose Abd distension, Peptic ulcer steroid therapy Endocrine Hypercortisolism (Cushingoid state) Associated with long term use even at Secondary adrenal insufficiency lower dosages

Menstrual difficulties: Amenorrhea, post-menopausal bleeding

Precipitation of diabetes mellitus

Glucose Intolerance: hyperglycemia

Others Insomnia Psychiatric disturbances Immunosuppression Cataracts / Glaucoma Hirsutism/ Acne Classification of Corticosteroids Classification of Synthetic Corticosteroids by Chemical Structure

Progesterone-type - -type Acetonides & type related Beclomethasone Prebediolone Progestrin→ acetate acetate Halocinonide Triamcinolone acetonide

Other Classification of Corticosteroids by Route of Administration

❑ Topical ❑ Oral →creams ❑ Parental →IV/ IM ❑ Inhalation- Aerosol →ointments ❑ Others →lotions, mousses, → Intrarticular →shampoos → ocular, nasal, rectal (enema), in ear or spinal →gels or tapes Steroid Use in Clinical Practice Common clinical uses of systemic corticosteroids Allergy and •Moderate to severe asthma exacerbations/ Acute exacerbations of COPD respirology • Allergic rhinitis • Atopic dermatitis • Urticaria/angioedema • Anaphylaxis/ Food and drug allergies • Hypersensitivity pneumonitis • Sarcoidosis • Acute and chronic eosinophilic pneumonia • Interstitial lung disease Dermatology •Pemphigus vulgaris • Acute, severe contact dermatitis Endocrinology • Adrenal insufficiency • Congenital adrenal hyperplasia Gastroenterology • Ulcerative colitis/ Crohn’s disease • Autoimmune hepatitis Hematology •Lymphoma/leukemia • Hemolytic anemia • Idiopathic thrombocytopenic purpura Rheumatology/ • Rheumatoid arthritis/ Systemic lupus erythematosus immunology • Polymyalgia rheumatica • Polymyositis/dermatomyositis • Polyarteritis/ Vasculitis Ophthalmology • Uveitis • Keratoconjunctivitis Other • Organ Transplant • Multiple sclerosis • Nephrotic syndrome • Chronic active hepatitis • Cerebral edema PRESCRIBING CORTICOSTEROIDS ◼ In non-endocrine disorders,

GCs are commonly given in pharmacologic (therapeutic) doses to suppress inflammation

◼ In endocrine disorders, doses are often given at or close to physiologic doses (rather than in therapeutic ranges) Topical Corticosteroids Potency Ratings of Topical Corticosteroids Ultra high Augmented betamethasone dipropionate 0.05% (I) 0.05%, diacetate 0.05% 0.1%, Flurandrenolide 4 mcg per m2 Halobetasol propionate 0.05% High Amcinonide 0.1% (II) Betamethasone dipropionate 0.05% , 0.05% Fluocinonide 0.05%, 0.1% Medium to Amcinonide 0.1% High Betamethasone dipropionate 0.05% (III) 0.005% 0.5% Medium , Desoximetasone 0.05% (IV and V) 0.025%, Fluticasone propionate 0.05% 0.1%/probutate 0.1%/valerate 0.2% Triamcinolone acetonide 0.025%/ acetonide 0.1%

Low Alclometasone dipropionate 0.05%, Desonide 0.05% (VI) Fluocinolone 0.01%, Hydrocortisone butyrate 0.1% Least potent Hydrocortisone 1%, 2.5% (VII) http://www.factsandcomparisons.com Indications of topical corticosteroids

Disorders very responsive to topical Disorders less responsive to topical corticosteroids corticosteroids (remission with low to medium topical CS) (high potency steroids at higher CS) •Atopic dermatitis •Dscoid lupus erythematosus •Seborrheic dermatitis •Psoriasis of palms and soles •Lichen simplex chronicus •Necrobiosis lipoidica diabeticorum •Pruritus ani •Sarcoidosis •Later phase of allergic contact dermatitis •Lichen striatus •Later phase of irritant contact dermatitis •Pemphigus •Nummular eczematous dermatitis •Familial benign pemphigus •Stasis dermatitis •Vitiligo •Psoriasis •Granuloma annularae Is Corticosteroid cream safe?

◼ In most cases, topical steroids are safe and well tolerated if used correctly.

◼ People who experience side effects usually are not using steroid creams properly.

◼ Applying the cream or ointment thinly and evenly to the affected areas on the skin is important.

◼ This minimizes the amount absorbed through the skin into the body Clobetasol propionate (0.05%)

◼ Use of 2g/day → ↓ morning cortisol level after a few days

◼ Use over 100 g/week or 100-300 g/week →features of Cushing’s $ and symptoms of adrenal insufficiency.

◼ Allenby et al (1987) Clobetasol propionate > 50 g/week→ Adrenal suppression

Recommended dose- Not more than 50 g/week for Not more than 2 weeks ◼ Cushing’s $ was also reported with the use of relatively low potent triamcinolone acetonide (0.1%) of 38 g daily under occlusion for ~ 4 years Tips for use of Topical steroids

◼ Once or twice-daily application is recommended for most preparations

◼ More frequent administration does not provide better results

◼ Chronic application of topical steroids →tolerance & tachyphylaxis.

◼ Ultra-high-potency steroids should not be used for > 3 weeks continuously.

◼ If a longer duration is needed, the steroid should be gradually tapered to avoid rebound symptoms, and treatment should be resumed after a steroid-free period of at least one week. Inhaled Corticosteroids Major ICS

◼ beclomethasone dipropionate (Half life- 15 hrs)

◼ fluticasone propionate (Half life- 14 hrs)

◼ Budesonide (Half life- 2 to 3 hrs)

◼ furoate (Half life- 5 to 8 hrs) Newer generations of ICS

◼ ciclesonide (Half life 0.71 hrs)

◼ Flunisolide (Half life 1-2 hrs)

Relative ICS potencies

◼ mometasone > fluticasone propionate > ciclesonide > beclomethasone monoproprionate > budesonide EVIDENCE FOR SYSTEMIC ABSORPTION OF ICS

◼ ~ 10% to 20% of a dose of ICS → respiratory tract

◼ 80% to 90% →swallowed and absorbed through the GI tract.

◼ Most of the drug that is swallowed will undergo first-pass metabolism and does not enter the systemic circulation.

◼ The ICSs in current use have a high first pass metabolism, exceeding 99% in the case of fluticasone propionate. Extent of absorption is determined by

◼ inhaler device

◼ particle size

◼ deposition site, pharmacokinetic and physicochemical properties of the drug (lipophilicity)

◼ The rate of dissolution of different ICSs in human bronchial fluid

→ 6 min for budesonide

→ 5 hours for beclomethasone

→ 8 hours for fluticasone ICS & HPA Axis Suppression

◼ prevalence of adrenal insufficiency in asthmatics using ICS ranged from 2.4% (low dose) to 21.5% (high dose),

◼ according to treatment duration from 1.4% (<28 days) to 27.4% (>1 year).

◼ In addition, adrenal suppression can persist for prolonged periods after corticosteroid discontinuation, including ICS (around 6 to 9 months).

◼ Budesonide has the least systemic effects with fluticasone having a higher risk especially at doses above 400 mcg/day.

◼ Other ICS→ ciclesonide and flunisolide still lack sufficient evidence

◼ Clinicians should use the lowest effective dose (ideally less than 400 mcg/day) when commencing patients on ICS, and be aware of the dose-dependant nature of the systemic effects ◼ Among ICS molecules, fluticasone has greater systemic side effects than other steroids, with budesonide having a better systemic adverse effect profile.

◼ Newer ICS such as ciclesonide might be of better beneficial effects in reducing the risk of systemic effects Systemic Corticosteroids Classification & Comparison of Systemic Steroids

Glucocorticoid Anti- Na- Duration of Equivalent inflammato retaining Action Dose ry Potency Potency Cortisol* 1 1 S 20

Cortisone 0.8 0.8 S 25

Prednisone 4 0.8 I 5

Prednisolone* 4 0.8 I 5

Methylprednisolone* 5 0.5 I 4

Triamcinolone 5 0 L 4

Betamethasone 25 0 L 0.75

Dexamethasone* 25 0 L 0.75

S=Short (8-12 hr), I=Intermediate(12-36 hr), L=Long( 36-72 hr)

How long and how much can you take prednisone safely? ◼ physiological secretory rate of cortisol ~ 6 mg/m2/day

◼ the bioavailability of cortisol is reduced by gastric acids and first pass metabolism in liver

◼ Reasonable initial starting dose-8-10 mg/m2 /day of oral hydrocortisone (HC) ◼ Low dose ≤7.5 mg

◼ Medium dose >7.5 mg but ≤30 mg

◼ High dose >30 mg but ≤100 mg

◼ Very high dose >100 mg

◼ Pulse therapy ≥250 mg prednisone equivalent a day for one or a few days. (Prednisolone equivalence a day) Usual dose

◼ between 5 mg and 60 mg daily Chronic Steroid Dosing And HPA Suppression

◼ Likelihood of suppression increases with:

→ Dose

→ Duration NHS-UK

◼ Do not stop taking prednisolone if you've been on it

→for more than 3 weeks or

→have taken high doses (> 40mg) for > 1 week

WWW.NHS.UK/Medicine/Prednisolone Safety Dose

DOSE

◼ 5 mg or 7.5 mg or 10 mg ???

DURATION

◼ 3 Weeks or 1 month or 3 months ??? Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study (Akbar K Waljee et.al)

Participants Adults (aged 18-64 years) who were continuously enrolled from 2012 to 2014

Main outcome measures Short term use of oral corticosteroids =< 30 days duration. Incidence Rates of adverse events in corticosteroid users and non-users. Incidence rate ratios for adverse events within 30 day and 31-90 day risk periods after drug initiation.

Guidelines from the Association of Anaesthetists, the Royal College of Physicians and the Society for Endocrinology (UK)

Prednisolone ≥ 5 mg per day in adults or

(hydrocortisone-equivalent dose of 10–15 mg/m2/day in children) if administered for 1 months or more across all routes of administration (oral, inhaled, topical, intranasal, intra-articular), can cause suppression of the HPA axis, and is the most common cause of adrenal insufficiency Prevention and treatment of systemic side effects Side effects -pecific pretreatment screening, ongoing monitoring, and counseling recommendations

1. Counseling -Choose the lowest dose and duration of therapy -Explain side effects of glucocorticoids -Document patient understanding of side effects in the health record; consider asking patient to sign consent to treatment with steroids -Consider prescribing glucocorticoid identification bracelet

2. Laboratory assessments and screening before initiating therapy/ongoing monitoring (A) Bone health American College of Rheumatology Recommendation - GC (prednisone equivalent of 5 mg/day or higher) with plans for treatment for > 3 months - taking long-term glucocorticoids (prednisone equivalent of 5 mg/ day or higher)

Take 1200 mg calcium and 800 IU vitamin D daily - Baseline height and bone mineral density assessment (using DEXA) - Pharmacologic therapy as indicated (see chart) - Annual DEXA scan to monitor bone mineral density - Replete vitamin D and calcium before prescribing bisphosphonate if indicated (B) Gastrointestinal -Assess history of PUD risk factors, including NSAID use, smoking, history of H. pylori infection, alcohol use, age > 65 years, current or previous PUD, bisphosphonates, and other medications that the increase risk of PUD Prescribe proton pump inhibitor, if indicated

(C)Endocrine -Screen for diabetes with baseline Hb A1C level, finger stick, or basic metabolic panel -Establish baseline electrolytes and renal function with basic metabolic panel - In conjunction with primary care provider, repeat with regular laboratory monitoring -Consider prescribing a glucometer for home glucose monitoring to those taking moderate- or high-dose steroids chronically

(D) Ocular -Ask about history of cataracts and glaucoma - Consider baseline ophthalmology examination - Repeat examinations as indicated (E) Cardiovascular health - Check blood pressure at every visit -Check fasting lipids as part of regular laboratory monitoring

(F) Vaccinations (see section on vaccinations) - Take immunization history before initiating therapy - If possible, give missing or indicated vaccines before therapy; give live vaccines at least 2-4 weeks before therapy

(G) Infectious -Hepatitis B virus, hepatitis C virus screening - HIV screening - Tuberculosis skin test or interferon-gamma release assay (eg, QuantiFERON-TB Gold) - Strongyloides testing as appropriate

(H) Mood and cognitive - Assess for past or current neuropsychiatric disorders - Ask all youth for history of depression and suicidality - Refer any positive findings to primary care provider or psychiatry - If concern for suicidality, urgent referral to emergency services “stress-dose steroids” Historical Context 1949 →glucocorticoid was developed → chronic rheumatoid arthritis by Hench and colleagues

1952→ Fraser et al described a 34-yearold man with RA undergoing hip arthroplasty who developed hemodynamic collapse immediately following his operation. Tx with cortisone for 8 months with dosing at 25 mg twice daily for the 2 months prior to surgery; this had been discontinued 2 days before the operation. Autopsy showed bilateral adrenal atrophy

1953→ Lewis et al described -a 20-year-old woman with RA undergoing knee surgery, who had developed hemodynamic instability and then to death just 5 hours after surgery. -on cortisone for 5 months preoperatively→ discontinued the day prior to surgery. Autopsy showed bilateral adrenal atrophy and hemorrhage “stress-dose steroids”

◼ supplemental steroid dosing for patients with tertiary (iatrogenic) adrenal insufficiency as a result of glucocorticoid (GC) use.

◼ Recommended stress doses depend on severity of stress the patient may experience (medical or surgical) ◼ All glucocorticoid-dependent patients are at risk of adrenal crisis as a consequence of surgical stress or illness,

◼ It is essential to be able to recognise and diagnose this medical emergency.

◼ If in doubt about the need for glucocorticoids, they should be given as there are no long-term adverse consequences of short- term glucocorticoid administration Hydrocortisone Stress Dose

◼ Siginificant Illness or Emergency = 50-100 mg/m2/day

◼ Mild to moderate illness = 20-30 mg,m2/day

◼ Maintenance/ Daily requirement = 10 mg/m2/day Screening recommendations for Adrenal Suppression When to Screen?

◼ Patient has received systemic corticosteroids for: > 2 consecutive weeks or >3 cumulative weeks in the last 6 months

◼ Patient has persistent symptoms of AS: Weakness/fatigue, malaise, nausea, vomiting, diarrhea, abdominal pain, headache (usually in the morning), poor weight gain and/or growth in children, myalgia, arthralgia, psychiatric symptoms, hypotension*, hypoglycemia How to Screen?

◼ Measure early morning cortisol

◼ GC dose tapered to physiologic dose prior to test

◼ No oral GCs the evening and morning prior to the test†

◼ Must be completed by 8:00 am or earlier

◼ Fasting not required

◼ If morning cortisol is normal but patient has symptoms of AS, perform low-dose ACTH stimulation test‡ to confirm diagnosis:

◼ 1 μg of cosyntropin; cortisol levels taken at 0, 15–20 and 30 minutes

◼ Peak cortisol < 500 nmol/L = AS

◼ Peak cortisol>500 nmol/L = normal) HPA AXIS SUPPRESSION BASED ON GLUCOCORTICOID EXPOSURE HISTORY HPA axis Glucocorticoid (GC) exposure Management status NOT <3 weeks Take usual AM dose of GC suppressed ■ Every-other-day therapy ■ AM dose of <5 mg prednisone or equivalent

MAY be Intermediate-dose GC use Check 8 AM serum cortisol suppressed (5–20 mg prednisone or equivalent/day) (24 h off usual GC dose) vs. ■ Inhaled GC use empiric supplemental GC ■ >3 GC intra-articular or spinal injections in without testing the past 3 months ■ If <3 mcg/dL, supplemental GC ■ Significant GC use in the past year ■ If >20 mcg/dL, take usual ■ Class I topical GC use AM dose of GC (betamethasone dipropionate0.05 %, ■ If 3–20mcg/dL, do ACTH clobetasol propionate 0.05 %, diflorasone stimulation test & diacetate 0.05 %, fluocinonide 0.1 %, and empiric supplemental GC halobetasol propionate 0.05 % Is ■ >20 mg/day of prednisone or Supplemental GC suppressed equivalent for >3 weeks ■ Clinically Cushingoid appearance Steroid Coverage for Illness & Procedures

Minimal illness usual replacement dose -non febrile cough or upper respiratory tract infection Minor illness double or triple the usual dose -viral illness, bronchitis, and uncomplicated urinary tract infection Moderate illness hydrocortisone 50 mg bd orally or iv. Taper -gastroenteritis, pneumonia, pyelonephritis rapidly to maintenance dose as patient recovers Severe illness hydrocortisone 100 mg iv every 8th hrly. -pancreatitis, myocardial infarction, labour Taper dose to maintinence level by decreasing by half every day Minor procedures no extra supplementation -under LA and most radiological studies Moderately stressful procedures a single 100 mg iv dose of hydrocortisone -barium enema, endoscopy, or just before the procedure arteriography

William Textbook of Endocrinology, Wilson & Foster, 8th Edition ◼ Hydrocortisone 100 mg by intravenous (IV) injection should be given at induction of anaesthesia in adult patients with adrenal insufficiency from any cause followed by a continuous infusion of hydrocortisone at 200 mg-24 hr

◼ Dexamethasone is not adequate as glucocorticoid treatment in patients with primary adrenal insufficiency as it has no mineralocorticoid activity Take Home Message

◼ Always clearly document reasons for prescribing steroids

◼ Give lowest effective dose for short duration

◼ Always outweigh Risks Vs Benefits

◼ Do not stop the steroid abruptly

◼ Give steroids before midday to minimize risk of sleep disturbance

◼ Give prophylactic gastric protection if also taking NSAIDS or previous GI bleed

◼ Consider prophylaxis against osteoporosis if patient is on steroids for > 3 months

◼ Weekly urinalysis or monitoring of blood sugars, particularly if symptomatic

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