CORTICOSTEROIDS

Side effects, their prevention and management

 Adverse effect systemic corticosteroid can be divided into two types:
1.Dose dependent
2.Duration dependent(continued use
a)short term
b)long term
3. Due to withdrawal

(NOTE- most of s/e due to cont use of cs are directly related to dose, duration and
frequency of dosing, except for osteoporosis, avascular necrosis & cataract which
can develop even on alt day dosing and short course of cs)
Dose Dependent A/E
 Hyperglycemia
 Hyperlipidemia
 Peptic ulcer diease
 Psychosis

Withdrawal effect
1.Patient on CS for >2wks are likely to have some degree of HPA axis suppression, if
such pt are not tapered OFF they may develop:
-Glucocorticoid withdrawal synd(lethargy,nausea,headache, fever, myalgia, wt loss,
arthalgia)
2. Acute Adrenal Insuffciency and Adrenal shock may develop in severe HPA axis
supression
3.Flare up of existing disease
SHORT TERM GLUCOCORTICOSTEROID
THERAPY
 Gastrointestinal intolerance
 Increased predispostion to infections
 Delayed wound healing
 Increased apetite, Hyperglycemia
 Fluid and sodium retention
 Mood changes
 Weakness
 Insomnia
 Amenorrhea
 Acne
 LONG TERM GLUCOCORTICOID THERAPY

Musculoskeletal Metabolic
Grown retardation Нуреrglyсепіа
Osteoporosis Truncal obesity
Myopathy Hyperipidemia
Avascular necrosis of bone Hypokalemia
HPA axis Hypocalcemia
Suppression Cutaneous
Withdrawal syndrome hirsutism
Adrenal crisis Atrophy
Ophthalmologic Hyperpigmentation
Cataracts Acne
Glaucoma Nervous system
Gastrointestinal Mood and personality changes
Gastritis Psychosis
Peptic ulcer disease Pseudotumor cerebri
Pancreatitis
Intestinal perforation
 Risk of side effects depends on
1)Dose-
- Low dose(<10mg/day of prednisone)

- Medium dose(10-20mg/day)

- High dose(>20mg/day)

2)Type of steroid
-Long acting
-Short acting
3)Duration of Rx
4)Other medical problems/ co morbidities of patient
METABOLISM, ELECTROLYTES
EFFECTS(when CS taken for atleast 2-3 months)
 Weight gain with truncal obesity, buffalo hump, and moon face (Cushingoid appearance)
 proteolysis and lipolysis: proteolysis contributes to hyperglycemia whereas lipolysis leads to
hyperlipidemia and eventually to redistribution of fat tissue towards the trunk.
 Increased gluconeogenesis
 Hyperglycemia and ↑ insulin resistance → glucocorticoid-induced diabetes
 Hypocalcemia → PTH activation → secondary osteoporosis

RISK FACTORS- family or personal h/o DM, obesity, subclinical diabetes or imapaired
glucose tolerance,hyperlipidemia
other Hyperlipidemia RF-excess calorie, saturated fat
Diagnosed by a)Fasting Glucose levels b) Triglyceride levels
Prevention-1. Dietary measures
2.Regular monitoring of blood glucose level and HbA1C
Management-1.Proper diet and exercise
2. Insulin and OHA
3.Reduction in GC dose
4.Statins in hyperlipidemia
(If steroid stopped Hyperglycemia may fully reverse over many months)
CUSHING SYNDROME
MUSCULOSKELETOL
 Risk-Systemic therapy at any dose ≥ 3 months
A/E –
1. Avascular necrosis of bone
2.Glucocorticoid-induced osteoporosis, osteopenia: chronic glucocorticoid use → RANK ligand -
mediated activationof osteoclasts and apoptosis osteoblast → decreased bone formation and
increased bone resorption
3.
Growth inhibition in children (As a result of ↓ growth hormone and IGF-1 production; net result
delayed skeletal maturation )
4.Corticosteroid-induced myopathy (↓ Glucose and amino acid uptake by muscles, leading to
muscle atrophy/ wasting)
 Acute: generalized muscle weakness
 Chronic
 Classic form of steroid myopathy

 Progressive weakness of proximal limb muscles, myalgia

Risk factors-1. Female gender, increased age, thin, inactive patients, previous fracture, smoking,
alcohol use, history of falls, vitamin D deficiency
2.Significant trauma, smoking, alcohol abuse, hypercoagulable conditions, hyperlipidemia
3.Lack of exercise(RF for myopathy)
Diagnosis- 1.Focal pain in hip, shoulder or knee; MRI scan is the definitive test
2. Plotting height and weight on growth chart in children
Contd….
PREVENTION:

Before starting CS –Assess fracture risk, bone mineral density testing, Promote patient education
on modifiable risk factors.
 During therapy-For all patients taking ≥ 2.5 mg/day prednisone(or equivalent) for ≥ 3 months
 Optimise bone health
 Calcium intake > 1,000–1,200 mg/day

 Vit D supplementation

 Encourage physical activity.

 Start pharmacotherapy for glucocorticoid-induced osteoporosis for patients with moderate

or high risk for osteoporosis
Management:
1. Gradual taper of CS dose; exercise especially if muscle atrophy/wasting
2. Strongly consider bisphosphonates; also nasal calcitonin, teriparatide
EFFECT ON IMMUNITY

 Immunosuppression
 Can result in the reactivation of latent
infectious diseases (e.g., CMV,
tuberculosis) and
opportunistic infections (e.g.,
candidiasis)
 Blood test may
show leukocytosis since
white blood cells get demarginalized.
 Risk factors-Systemic therapy for at least 2–
4 weeks at doses > 20 mg/day
contd,..
Before CS therapy
 Screening
 Screen for HIV, hepatitis B, and hepatitis C
 TB screening if risk factors for tuberculosis.

 Vaccinations: Give missing or indicated vaccinations to patients before initiating therapy planned to last >
14 days.
 Live vaccines: ≥ 4 weeks prior to starting therapy,
 Inactive vaccinations: > 2 weeks prior to starting therapy

 Alternate-morning therapy and doses of < 10 mg/d of prednisone equivalent may significantly reduce the
chance of opportunistic infection.
Baseline chest radiograph & Mantoux test should be done.
During therapy-
 Avoid live vaccines during treatment and for at least 1 month after completion.

Strategies for treatment of established immune suppression:

 There should be no abrupt stoppage of steroid - this will almost certainly lead to acute Al.
 Safe course is - lower dose of steroid to a level which should no longer suppress the host's defences and
vet which is adequate to prevent the development of acute glucocorticoids withdrawl.
CARDIOVASCULAR
1. Hypertension
Due to Mineralocorticoid effect i.e Na retention and also d/t GC induced vasocontriction(can be d/t
medium- to high-dose systemic steroid regimen)
Increased sensitivity to catecholamines due to the upregulation of alpha-1 receptors
Risk factors-1)elderly patient
2)Prior hypertension
Diagnosis- regular BP monitoring
Prevention- Na restriction diet, choose CS with minima MC effects
Management-
1.Na restriction
2. Antihypertensives
3.In some patient blocking MC receptors with spironolactone may be more effective than using other
agents
2.Sodium and fluid retention
3.Increased risk of atherosclerosis
4.hypokalemia
OCULAR COMPLICATIONS
 Conjunctival necrosis
 Corneal stromal calcification & Delayed corneal wound healing
 Glaucoma:POAG
-Ocular hypertension,Open angle, Optic nerve cupping,VF loss
- Glucocorticoid induced glaucoma is usually observed within a few weeks after initiation of
steroid therapy.
-May also be seen years after cessation of steroid therapy hence monitoring should continue even
after steroids are stopped
 Cataract(Posterior subcapsular cataract)
The risk of cataracts increases after > 1 year of high-dose systemic therapy.
 Retinal/choroidal emboli
 Central serous chorioretinopathy.
Mechanism-Glucocorticoid-induced morphological & functional changes in trabecular meshwork
(TM) are considered to be main mechanisms leading to increased intraocular pressure.
 Other-increased glucose levels due to an increased gluconeogenesis
 inhibition of Na + /K + -ATPase
 covalent binding of steroids to lens proteins.
 Children are at greatest risk since they can develop cataracts with lower doses &
shorter treatment durations than adults
 Cataracts may be seen as early as within 6 months of treatment & even in children on
alternate day therapy.

 Prevention
Ophthalmologic examinations are recommended every 6 months for pts on long-term
systemic glucocorticoid therapy.
 Strategies for treatment of established ocular complications:
1.cataracts often are small but can affect visual acuity significantly requiring surgical
intervention.
2.Stopping treatment will halt the progress of cataract but will usually not reverse the
changes already present.
GASTROINTESTINAL
 Adv Effects seen are
1.Gastritis
2.Peptic ulcers disease, intestinal perforation(if existing pud)
3.Upper gastrointestinal bleeding
4.Oral candidiasis
5.Acute pancreatitis - is another major complication especially in children
Pathophysiology:
1. ↓ Mucus production, ↑ acid production;
2.gastrin and parietal cell hyperplasia
3.delay the healing of ulcers
RF-Concomitant ASA, NSAID therapy, age >65 years, smoking, alcohol, history of PUD,
Helicobacter pylori or autoimmune connective tissue disease
-Recent bowel anastomosis, active diverticulitis
Diagnosis- History; upper GI endoscopy
Prevention-
1.by administration of oral steroid with food
2. use of antacids - including H2 receptor antagonists or PPI
Management-
Any symptoms suggestive of PUD should be promptly investigated with gastroduodenoscopy &
appropriate treatment started in consultation with gastroenterologist
NEUROLOGICAL MANIFESTATIONS

 Steroid-induced psychosis spectrum & can occur at any time during treatment. S/E are related to dosage
1. Mild-to-moderate symptoms include –
- Agitation
-Anxiety
-Insomnia
-Irritability
-Restlessness
2. Severe symptoms include –
-delirium & dementia
-Mania
-Depression(long term therapy
-Psychosis(in short term therapy also)

Mechanism-Possibly because of electrolyte shifts, altered nerve excitability, possibly mild cerebral edema
-Depression via a reduction in serotonin levels.

prevention- Careful patient selection if prior psychiatric disorder

No prophylactic therapy given
Management-
 First-line treatment- to taper /discontinue steroid
 If this is not possible because of comorbid disease or severe psychosis consider adding low-dose atypical
antipsychotics in pts with manic / hypomanic symptoms.
 Second-line treatment Consider mood stabilizers such as lithium or valproic acid or ssri in pts with normal
RFT
DERMATOLOGICAL SIDE EFFECTS
CATEGORY MECHANISM ADVERSE EFFECT
1. Wound healing & related • Decrease collagen, Non-healing wounds ,ulcer,
changes ground sub,dec re- striae
epithelization & atrophy,telangiectasis
angiogenesis

2.pilosebaceous unit Androgenicity,P.ovale steroid acne & rosacea

purpura
3.Vascular Catabolic effect on
vascular smooth muscle
Staphylococcal, herpes
4.Cutaneous inf. •

Telogen effluvium,
5.Hair effects hypertrichosis

6. Others ↓ CS immunosuppression Acanthosis nigricans

Insulin resistance Pustular psoriasis flare
ACUTE ADRENAL INSUFFICIENCY
 predominantly when glucocorticoids are discontinued suddenly after chronic intake
 Occurs more often in patients older than > 60 years
 Any systemic, high-dose topical, or high-dose inhaled CS therapy
Prevention
Educate patients on sick days leave.
 Provide patient with a CS card
 Provide an emergency hydrocortisone kit for injection
 Patients should add 5-10 mg hydrocortisone to their normal regimen shortly before strenuous
activities
 More severe physical stress such as fever requires doubling of daily doses until recovery.
 For major surgery, trauma and diseases that require monitoring in intensive care pt should
receive iv infusions of 100-150 mg hydrocortisone in 5% glucose per 24 h.
Management
Immediate iv administration of 100 mg hydrocortisone followed by 100-200 mg in 24 h and
continuous infusion of larger volumes of physiological saline solution (initially1 L/h) under
continuous cardiac monitoring.
 In case of newly diagnosed (or suspected) adrenal crises treatment must not be delayed by
diagnostic work-up.
 Baseline blood samples for ascertainment of cortisol and
ACTH should be drawn immediately before hydrocortisone administration
HPA AXIS SUPRESSION
 Pathophysiology: Reduced GC & MC reserves
- Corticosteroid administration results in a negative feedback effect via glucocorticoid receptors in
anterior hypothalamus which in turn suppresses production of CH & ACTH
- Prolonged suppression of ACTH levels leads to atrophy of adrenal cortex & secondary adrenal
insufficiency.
Chronic administration of exogenous glucocorticoids induces atrophy of pituitary corticotroph
cells.
C/F: anorexia, nausea, emesis, weight loss, fatigue, myalgias, arthralgias, headache, abdominal pain,
lethargy, postural hypotension, fever & skin desquamation
A/D Effects: 1.Steroid withdrawl syndrome
2. Addisonian crisis
Therapy Effects: Steroid taken>3weeks,evening dose, long half life followed by abrupt cessation
Additional risk factors: Major surgery, trauma, liness,severe gastroenteritis with fluid & electrolyte
loss


 prevent steroid induced HPA axis suppression
Clinical evaluation remains key element in its diagnosis.
 During stress situation, steroid administration is then recommended depending on
the severity of the stress.
 Long-term steroids should be tapered gradually to allow the adrenal glands to
resume cortisol production.
 The first step is reduction from pharmacological to physiological doses.
 The next step is to taper from physiological dose to complete withdrawal and this
depends on the degree of HPA suppression.
MANAGEMENT OF ESTABLISHED HPA AXIS SUPPRESSION

 In the end of the protocol for dose reduction HPA axis testing can be performed with morning
dosage of serum cortisol.
 Levels greater than 10 mcg/dL indicate adequate recovery of the axis and allow glucocorticoid
withdrawal.
 Levels less than 5 mcg/dL indicate suppressed axis and need of dose reduction with an
additional waiting period of 2-4 weeks before cessation.
 Cortisol concentration kept between 5 and 10 mcg/dL requires ACTH stimulation test to ensure
adrenal recovery& adequate endogenous cortisol production in the face of stressful situations.
Primary Tests Used to Evaluate Adrenal Insufficiency
1. AM cortisol
2. Twenty-four hour urine free cortisol
3. ACTH stimulation
4. Insulin hypoglycemiab
5. Corticotropin-releasing factor (CRF
RENAL SYSTEM -FLUID AND ELECTROLYTE BALANCE

 Associated with sodium & water retention

 Potassium loss occurs & hypokalaemic alkalosis may develop.
PREVENTION
 The blood pressure should be checked at each outpatient visit & antihypertensive treatment may
be necessary.
 Corticosteroids should be used with extreme caution in patients with limited cardiac reserve as
cardiac failure can develop.
MANAGEMENT
 Recommend a low salt diet
 Diet rich in K (most fruits, vegetables, especially broccoli and carrots, fish & poultry)
 Occasionally K supplements are required.
 If a thiazide diuretic is chosen as the antihypertensive agent the serum potassium should be
carefully monitored.
 Thiazides also have a beneficial effect on osteoporosis by reducing calcium loss in the urine
ENDOCRINE SYSTEM
 Secondary amenorrhea
 Growth retardation in children d/t premature fusion of epiphysis
 Supression of HPA axis
HAEMATOLOGICAL EFFECTS
 Promotes blood coagulation and alters the patient's response to anticoagulants
 Hence frequent checks on the extent of anticoagulation are necessary especially if the steroid dose is
varying.
 ↑ LDL, ↓ HDL, ↑ hematocrit

REPRODUCTIVE SYSTEM
 Men
-can experience longer erections / higher frequency of erections yet a decrease in sperm production-
resulting in sterility.
-Men might also find that they are impotent
-prostate cancer rare instances.
 In females-
-interruption of their menstrual cycle
-Can develop infertility issues
 Both sexes might experience changes in sex drive, either an increase in desire or a loss of
desire.
STEROIDS AND PREGNANCY
CATEGORY - C DRUG
 Cataracts, cyclopia, interventricular septal defect, gastroschisis, cleft lip, hydrocephalus,
coarctation of aorta,clubfoot ,LBW,IUGR stillbirth has been reported
 For maternal disease, derivatives of cortisone and prednisone are suggested since they are more
readily inactivated by placenta as opposed to dexamethasone & betamethasone which are more
likely to reach the fetus in the active state.
 As with any medication use of steroid must be weighed against severity of maternal disease.
SUMMARY OF PREVENTING COMPLICATIONS
OF GLUCOCORTICOID THERAPY
 Complications are most common with long-term use.The risk of complications can be reduced by
keeping treatment durations short or doses low.
 Choose short-term higher-dose pulse therapy if possible.
 If continuous treatment is necessary, aim for the lowest possible daily dose. [26]

 Low dose: equivalent to < 2.5 mg prednisolone/day

 Moderate dose: equivalent to 2.5–7.5 mg prednisolone/day
 High dose: equivalent to > 7.5 mg–29 mg prednisolone/day
 Very high dose: equivalent to ≥ 30 mg prednisolone/day

 Assess risk factors for complications of glucocorticoid therapy.

 Initiate measures to prevent complications of glucocorticoid therapy.
 When discontinuing long-term steroid regimens:
 Advise patients not to stop the medication suddenly because of the risk of
adrenal suppression.
 Taper under medical supervision in courses lasting > 3 weeks.
 Contd…

Systemic administration
 Tapering to avoid toxicity
 Short-term administration (≤ 3 weeks): usually no tapering necessary

 Long-term administration (> 3 weeks): tapering regimen based on patient age and

condition and on duration/dose of prior glucocorticoid administration → e.g., tapering

over 2 months
 Sudden discontinuation after chronic use should be avoided because of the risk of
adrenal insufficiency (adrenal crisis) secondary to long-term
hypothalamic-pituitary-adrenal axis suppression.
BASELINE (WHEN ANTICIPATING LONG-TERM
CORTICOSTEROID THERAPY)
 Baseline (When Anticipating Long-term Corticosteroid Therapy)
 History • Obtain vaccination history [hemophilus influenza B, hepatitis A, hepatitis B, human
papillomavirus, influenza, neisseria meningitides, rubella (for women of childbearing age),
streptococcus pneumoniae, tetanus toxoid, varicella zoster]
 Examination • Blood pressure, weight
• Height and weight plotted on a growth curve (in children)
• Ophthalmoscopic examination for cataracts
 Laboratory
• Tuberculosis screening—interferon-γ-releasing assay > tuberculin skin test, chest x-ray
• Strongly consider screening for hepatitis B, hepatitis C, human immunodeficiency virus
• Consider screening for Strongyloides in endemic areas (rural Appalachia, immigrants)
• Fasting glucose or hemoglobin A1c and triglycerides; potassium level
• Baseline bone densitometr
• Consider pneumocystis pneumonia prophylaxis if appropriat
FOLLOW-UP (WITH LONG-TERM CS THERAPY ABOVE
PHYSIOLOGIC DOSE LEVELS)
 Examination At 1 month, then at least every 2–3 months:
• Blood pressure, weight
• Height and weight plotted on a growth curve (in children)
• Thorough history each visit for adverse effectsa At least every 6 months initially; at
least every 12 months long term:
• Ophthalmologic examination for cataracts and glaucoma Laboratory At 1 month, then
at least every 3–4 months while on pharmacologic dose CS: • Potassium levels
• Glucose levels (fasting)
• Triglycerides (fasting)
)
• AM cortisol level (or another suitable test of adrenal function or the entire HPA axis)
Pulse Intravenous Methylprednisolone Therapy
• electrolyte and glucose levels
 DRUG INTERACTION
Drug Category
1.Antidiabetic therapies
2. Anti-inflammatory
3.Anticoagulants
4.Immunosuppressants
5.Diuretics—potassium losing
6. Inotropic agents
7. Vaccines
8. Macrolide, azalide antibacterials
Drug Examples
Insulin, OHGA, many others
Aspirin, NSAID
Warfarin
Widevariety—relatively uncommon to
have these SAE in dermatology
Thiazides, loop diuretics
Digoxin
Live attenuated (Zostavax, etc.)
Erythromycin >> clarithromycin >
azithromycin
Comments
Inc Insulin resistance with resultant potential for
severe hyperglycemia
In combination may ↑ PUD risk and subsequent
GI hemorrhage
CS may potentiate anticoagulant effects of
warfarin
Biologics, JAK inhibitors, traditional
(azathioprine, cyclosporine, mycophenolates,
etc.), chemotherapy with risk of severe infections
and/or myelosuppression
Potassium depleting effects of CS may ↑ risk of
hypokalemia and resultant toxicities
Same
Small risk of prednisone dose <20mg <2 weeks
CYP3A4 inhibitors can ↑ CS drug levels and
resultant toxicity—DM, high blood pressure, ↑
lipids, etc. (likely a more significant risk with
dexamethasone, methylprednisolone
 Drug category example comments
9.Antifungals (azoles, triazoles) Ketoconazole >> CYP3A4 inhibitors can ↑ CS drug
itraconazole > fluconazole (only levels and resultant toxicity
≥300mg daily

10. Hormonal Various CYP3A4 substrates; can ↑ CS half-life,

contraceptives ↓ clearance with resultant ↑ CS level

Lower risk drug interaction

1. CYP3A4 induction with resultant ↓ CS drug levels and loss efficacy
-Rifampin, rifabutin, rifapentine
-Phenytoin, carbamazepine, oxcarbazepine, phenobarbital
-griesofulvin

2.other
-calcitrol
-isoniazid
-Cholestyramine
CONTRAINDICATIONS
 General: hypersensitivity
 Systemic
 Systemic fungal infections
 Intrathecal administration
 Cerebral malaria (dexamethasone)
 Concomitant live or live attenuated virus vaccination (if glucocorticoids are used in immunosuppressive doses)
 Use in premature infants (formulations containing benzyl alcohol)
 Topical
 Dermatological: bacterial, viral or fungal infection of the mouth or throat (triamcinolone)
 Ophthalmic
 Systemic fungal infection (triamcinolone)
 Acute untreated purulent ocular infections (prednisolone)
 Fungal or mycobacterial ocular infections, viral conjunctivitis, or keratitis (prednisolone, dexamethasone)
 Inhalation: status asthmaticus or acute asthma episode requiring intensive measures (beclomethasone
, budesonide)
 Relative contraindications: Glucocorticoids should be avoided in certain conditions due to increased
risk of toxicity.
 Adrenocortical atrophy
 Cushing syndrome
 Diabetes mellitus (steroid diabetes), hyperglycemia
 Amenorrhea
 Osteoporosis
 Avascular necrosis (e.g., of the femoral head)
 Peptic ulcers
 Cataracts
 Psychosis
SUMMARY OF PREVENTIVE MEASURES
Side effects Preventive measures

1.Hypertension Blood pressure (baseline; repeat with each visit

Weight (baseline; repeat With each visit.

2.Welght gain 1.Purified protein derivative,
2.Hepatitis screen.
3.Re-activation of infection 3.Consider Pneumocystis carinni pneumonia prophylaxis
(Bactrim 1 DS three tires a week).

1.Electrolytes. lipids, glucose baseline; repeat early after

starting therapy: repeat annually; more frequent
monitoring with known factors (e.g., da-betes,
4. Metabolic abnormalities hyperlipidemnias

1.Bone density (baseline: repeat annually is early bone

prophylaxis done).
2.Instruct about diet, exercise, other measures.
5. Osteoporosis 3.Calcium and vitamin D supplementation.
4.Start bisphosphonate for men, post-menopausal women.
5.Evaluate post- menopausal women for hormone
replacement therapy.
 Contd…
Side effects Preventive measures

6.Eyes
a)Cataract Slit-lamp examination (every 6-12 mo).
b)Glaucoma Intraocular pressure examination (at 1 mo and every 6 mo

In patients with two or more risk factors, consider

7. Peptic ulceration prophylaxis with and H,-antagonist or proton dump inhibitor.

1.Single, early maring doses, preferably every other day.

2.Check 8 A.M. serum cortisol before tapering prednisone <
8. Suppression of 3 mg/day
hypothalamic-pituitary-adrenal axis If < 10 mg/dL, repeat every 1-2 mo and maintain low
prednisone dose until baseline cortisol adequate
CONCLUSION

 The appropriate anticipation of these side-effects with timely implementation of evidence-based

guidelines has the potential significantly to prevent, minimize and treat common and disabling
complications of glucocorticoid therapy.
When steroids are prescribed measures should be taken to minimise their side effects.
 Clearly chance of significant side effects increases with dose & duration of treatment and so
minimum dose necessary to control disease should be given