CORTICOSTEROIDS

DR SEHRISH ZAFFAR
ASSISTANT PROFESSOR
PHARMACOLOGY
CMH LMC & IOD
Adrenal Steroids

Zona glomerulosa (outer): Mineralocorticoid

Zona fasciculata (middle): Glucocorticoid

Zona reticularis (inner): Adrenal Androgens

MINERALOCORTICOIDS – ALDOSTERONE
Regulates: salt & water metabolism.

GLUCOCORTICOIDS – CORTISOL
Regulates normal metabolism & resistance to stress.

ANDROGENS – DEHYDROEPIANDROSTERONE
Regulates anabolic functions
Cortisol Biosynthesis

Zona Fasiculata
Glucocorticoids
GLUCOCORTICOID
Synthesis and release
Circadian rhythm of cortisol secretion
Classification of Glucocorticoids
Short/medium Intermediate acting Long acting
acting

Hydrocortisone Triamcinolone Betamethasone

Cortisone Paramethasone Dexamethasone

Prednisolone Fluprednisolone

Methylprednisolone

Meprednisolone
 Pharmacokinetics
Daily secretion: 10-20 mg

CBG binds 90% of circulating hormone

Half life: 60-90 min

1% is excreted unchanged in the urine as free cortisol.

1/3rd metabolized to 17-hydroxysteroids and excreted in urine

Mechanism of Action
Bind to specific INTRACELLULAR cytoplasmic
receptors in target tissues.
Receptor-hormone complex translocate into the
nucleus.
 Alter gene expression by binding to glucocorticoid
response elements (GREs) or mineralocorticoid-
specific elements
Steroid hormones enter the cell and bind to receptors in the
cytoplasm. The hormone-receptor complex enters the nucleus
where it binds with chromatin and activates specific genes.
Genes (DNA) contain information to produce protein as
diagrammed below. When genes are active, protein is produced.
Organ & Tissue
Effects
 1. Metabolic effects

Increase in gluconeogenesis
Increase in glycogen synthesis
Decreased uptake and utilization of glucose by muscle
Increased blood glucose > Stimulate insulin secretion
Both lipolysis and lipogenesis are stimulated
Net increase of fat deposition in certain areas (eg, the face
and the shoulders and back).
2. Catabolic effects
Muscle protein catabolism

Anti anabolic effects on lymphoid, connective tissue,

fat and skin

Catabolic effect on bone > osteoporosis

Reduced growth in children

 3. Anti-inflammatory effects
Suppressive effects on inflammatory cytokines and
mediators of inflammation
Decreased mRNA for cyclooxygenase 2 (COX-2)
Decrease in interleukin-2 (IL-2) and IL-3
Decreases in platelet activating factor (PAF), an
inflammatory cytokine
Increased neutrophils in blood (due to decreased
chemotaxis)
Decreased lymphocytes, eosinophils, basophils
4. Immunosuppressive effects
Decreased generation of cytokines- IL-1,IL-2, IL-3,
IL-4, IL-5, IL-6, IL-8, TNF-
Inhibit peripheral lymphocytes & macrophages
Inhibition of T cell activity, and cellular immunity
Actively lymphotoxic > used in blood cancers
5. Other effects
Required for excretion of water loads
Fetal lung development
Effect on behavior and CNS
Stimulate gastric acid and pepsin production >
Exacerbate ulcers
Negative calcium balance- reduced Ca++ absorption
in GIT and increases its excretion in urine
Clinical Uses
Adrenal Disorders
1. Chronic adrenocortical insufficiency (Addison’s
disease)
2. Acute adrenal insufficiency
3. Congenital adrenal hyperplasia
4. Diagnosis of Cushing’s syndrome
(Dexamethasone suppression test)
Non Adrenal Disorders
1. Fetal lung maturation in preterm labour (Betamethasone)
2. Allergic reactions (rhinitis, dermatitis, urticaria)
3. Collagen-vascular disorders (rheumatoid arthritis, GCA)
4. Hematological disorders (leukemia, ITP)
5. Pulmonary disorders (Asthma, sarcoidosis, ARDS)
6. GIT disorders (chemotherapy induced vomiting, IBD)
7. CNS (multiple sclerosis, cerebral edema)
8. Organ transplants
9. Renal (nephrotic syndrome)
Adverse Effects
 Iatrogenic Cushing’s
Syndrome
Daily dose of 100mg of hydrocortisone or more (equivalent
amount of synthetic steroid) for longer than 2 weeks
Buffalo hump
Moon face with red plethoric cheeks
Increased abdominal fat
Thinning of skin
Thin arms and legs
Poor wound healing, easy bruising,
Insomnia, increased appetite
Adverse effects
Weight gain
Hyperglycemia > Diabetes
Osteoporosis
Cataracts and glaucoma
Psychosis and behavioral changes
Growth retardation
Delayed wound healing
Myopathy and muscle wasting
Fluid and sodium retention/loss of K+
Adrenal Suppression

When steroids are administered for > 2 weeks

Dosage to be tapered slowly

Stopping the therapy slowly

Contraindications
 Peptic ulcer disease
 Hypertension
 Congestive heart failure
 Psychosis
 Diabetes
 Osteoporosis
 Glaucoma
 Pregnancy
Infections e.g. Tuberculosis
Special precautions
Keep the dose as low as possible
Local application, where possible
Alternate therapy to be used, where possible
Therapy should not be decreased or stopped abruptly
Prolonged therapy > Take chest X-rays and TB test
Take into consideration diabetes, peptic ulcer,
osteoporosis etc
Mineralocorticoids
Mineralocorticoids
Aldosterone
Deoxycorticosterone - precursor of aldosterone
Fludrocortisone – significant glucocorticoid activity
MOA similar to glucocorticoids
Synthesis & Release depends upon
 Plasma electrolyte composition – (low plasma
Na, high plasma K)
 Renin-Angiotensin system
Effects and Use
Promote reabsorption of sodium from DCT and
proximal collecting renal tubules
Excretion of potassium and hydrogen ions
Used in the treatment of adrenocortical
insufficiency associated with mineralocorticoid
deficiency
Excess leads to Hypernatremia, Hypokalemia,
Metabolic alkalosis, Hypertension
Corticosteroid Antagonists
Corticosteroid Antagonists
1. Synthesis inhibitors
◦ Ketoconazole
◦ Aminoglutethemide
◦ Metyrapone
◦ Etomidate
2. Receptor antagonists
◦ Spironolactone
◦ Mifepristone
 Corticosteroid Antagonists
Ketoconazole (an antifungal drug) - inhibits the cytochrome P450
Used in a number of conditions in which reduced steroid levels are
desirable (adrenal carcinoma, hirsutism, breast and prostate cancer)
Aminoglutethimide blocks the conversion of cholesterol to
pregnenolone
Used in conjunction with other drugs for treatment of steroid-
producing adrenocortical cancer
Metyrapone inhibits the normal synthesis of cortisol but not that of
cortisol precursors
Can be used in diagnostic tests of adrenal function
Questions?