CORTICOSTEROIDS

The adrenal cortex secretes a number of steroid hormones into circulation:Glucocorticoids: cortisol (hydrocortisone).Mineralocorticoids: aldosterone.Sex hormones

I. Cortisol The major glucocorticoid in humans.controlled by ACTH secreted from the anterior pituitary.circadian rhythm peaks in early morning & troughs at midnight.95% of Cortisol circulates in blood bound to globulin; Corticosteroid binding globulin (CBG).

II. AldosteroneMost important mineralocorticoid (inhibits Na+ excretion & stimulates K+ & H+ excretion) with minimal glucocorticoid activity.Very important in regulating blood volume & pressure.Control of Aldosterone Secretion

1. Renin-angiotensin system activation by hypovolemia & hyponatremia (most important).

2. Hyperkalemia.

Pharmacokinetics : cortisol is bound to corticosteroid binding globulin [CBG]. CBG is increased by oestrogen, decreased in cases of liver cirrhosis and nephrosis of kidney, t 1/2 is 90-110 min, Metabolised in the liver, Excreted by kidneys as water soluable reduced conjuagates, about 10% is excreted as 17 - ketosteroids.

Mechanism of Action of CorticosteroidsThey enter cells where they combine with steroid receptors in the cytoplasm forming a macro molecular complex which enters the nucleus where it interacts with chromosomal constituents and alters gene expression effects on organs and tissues.

Pharmacological Actions Adverse Effects & PrecautionsI. Metabolic EffectsCarbohydrates: ↑ blood glucose: Gluconeogenesis, ↓ glucose utilization.

 - Hyperglycemia → diabetes.CI: diabetes.

Fat Metabolism: - redistributes fat from extremities to

face, abdomen & shoulders.( increase lipolysis, hyperglycemia → ↑insulin secretion →fat dep.

- Moon face.

- ↑ abdominal fat.

- Buffalo hump - obesity.

Proteins Metabolism

Catabolic (↑protein breakdown) in lymphoid ,

connective tissues, muscle and bone

(except in liver).

- Muscle wasting: thin arms & legs.

- Thinning of skin.

- Retardation of growth (children).

- Osteoporosis (↓ protein & Ca2+). Salt and Water Metabolism

-↓ Ca2+ absorption from GIT.

-Weak mineralocorticoid action:

- ↑ Na+ reabsorption.

- ↑ K+ excretion. 

 - Osteoporosis (CI).- Edema - ↑ weight.- Hypertension - heart failure (CI).- Hypokalemic alkalosis.

II. Anti-inflammatory & immunosupressive

↓ VD & edema & redness of acute

inflammation. *↓ Healing - ↓ fibrosis.

Mechanism: ↓ Ab-Ag reaction

↓ Eosinophils, macrophages, monocytes &

lymphocytes conc., migration & function.

Inhibit cytokine release.

Inhibit phospholipase A2 → ↓ PGs, LTs, PAF.

↓ COX 2 expression

- Mask manifestations of

inflammation.

-Delay healing of wounds.

- Spread of infection.

CI: severe infection, e.g. TB.

III. Adrenal suppression Prolonged use of high

doses → ↓ ACTH Sudden withdrawal

→ acute adrenal

insufficiencyIV. GIT: ↑ HCl & pepsin - ↓ mucus. Peptic ulcer (CI).

V. CNS: euphoria- behavioral changes. Psychosis - depression (CI).

VI. Other effects: Glucoma, cataract, hirsutism, acne

Preparations of Corticosteroids

A. Preparations with Primarily Glucocorticoid Activity

I. Cortisol (hydrocortisone)Disadvantages of Cortisol

1. Mineralocorticoid activity.

2. Short duration: (t½ dramatically  in liver insufficiency).

3. Poorly absorbed through normal skin (but readily absorbed through inflamed skin & mucus membrane).

II. Synthetic Preparations

Prednisone - prednisolone – dexamethazone.

Advantages over Cortisol

1. Mineralocorticoid activity is less with prednisolone & absent with dexamethazone.

2. Longer duration of action.

3. More absorption through skin.

B. Preparations for Bronchial Asthma Beclomethazone, budesonide, fluticasone inhalationAdvantages in Asthma

1. Readily penetrate airway.

2. Very short half lives after entering the blood (if swallowed while being inhaled) due to extensive 1st pass metabolism so that systemic effects and toxicity are greatly reduced.

Agent Anti-inflammatory Salt-RetainingPrimarily Glucocorticoid

Cortisol

(short-acting → 12 h)1 1

Prednisolone

(intermediate → 24 h)4 0.8

Dexamethazone

(long-acting > 36 h)30 0

Primarily Mineralocorticoid

Fluodrocortisone 10 125-250

Aldosterone (not used) - 3000

Therapeutic Uses I. Adrenal Disorders

A. Acute Adrenal Insufficiency (Addisonian Crisis)1. Saline & 5% glucose  maintain fluid & salt balance & blood sugar.

2. IV hydrocortisone hemisuccinate.

3. Fluodrocortisone is started when total cortisol dose is  to 50 mg/d.

4. Treat precipitating factors, e.g. antibiotics for infection.

B. Chronic Adrenal Insufficiency (Addison’s disease)1. Oral hydrocortisone: dose is  during stress or surgery.

2. Fluodrocortisone (orally): maintains Na+ balance & BP.

II. Nonadrenal Disorders

A. Anti-allergic1. Bronchial asthma. 2. Allergic conditions: skin, eye, GIT.

B. Immunosuppressants in:1. Autoimmune diseases: systemic lupus - rheumatoid arthritis.

2. Organ transplantation, skin grafts.

III. Other Uses

1. Cerebral edema:  VD -  exudation of fluids.

2. leukemia - lymphomas:  lymphocytes.

3. Antistress in: bleeding - trauma - septic & anaphylactic shock ( VC effect of CA -  glucose level, providing energy to counteract stress).

4. Hypercalcemia: vit. D activation in liver  Ca2+ absorption).

5- Respiratory distress lung syndrome (stimulatin of lung maturation in the fetus by

stimulation of surfactant production

Precautions of use of glucocorticoids: I-Avoid adrenocortical suppression by using smallest doses, alternate day

schedule and gradual withdrawal.

2- The dose should increased during periods of stress in chronic therapy.

3- Diet should contain low Na+, high K+, high Ca++ and high proteins.

4- regular examination of blood pressure, blood glucose and body weight.

5-X ray spine every 6 months to detect osteoporosis.

6- anabolic steroid may be given to counteract catabolic effects.

7 - Never stop therapy suddenly to avoid acute adrenocortical insufficiency

Mineralocorticoids 1- Aldosterone:

2- Deoxycorticosterone (DOC(

it is potent mineralocorticoid with no glucocorticoid action used in hypoadrenal states by IM injection or as DOCA pellet sc.

3-Fluodrocortisone Synthetic prep. with potent mineralocorticoid & glucocorticoid activity. used for replacement therapy in hypoadrenal states, e.g. after adrenalectomy.

Agent Mechanism Uses & SE

1-Aminoglutethimide

blocks the conversion of cholesterol to pregnenolone It inhibits syn. of all ster. H.

with metyrapone or ketoconazole in Cushing's syndrome due to adrenocortical cancer

3-Metyrapone:inhibitor of steroid 11-hydroxylation, interfering with cortisol and corticosterone synthesis

diagnostic test.Cushing disease *adverse effects are salt and water retention and hirsutism.

4-Trilostane:dehydrogenase inhibitor that interferes with the synthesis of adrenal and gonadal hormones

GIT upset

5-Abiraterone: blocks 17 -hydroxylase and 17,20-lyase and reduces synthesis of cortisol and gonadal steroids

refractory prostate cancer

6-Mifepristone: antiprogestin activity. High doses of

mifepristone blocking the gluc.

receptor

inoperable patients with ectopic ACTH

secretion or adrenal carcinoma

7-Mitotane: cytotoxic on adrenal cortex

in patients with adrenal cancer.Side effects diarrhea, nausea, vomiting, depression, somnolence,skin rashes.