ENDOCRINE PHARMACOLOGY DR A.

Adrenocortical hormones (Corticosteroids)

Steroid hormones secreted from adrenal (suprarenal) cortex. they include

A-The corticosteroids which are essential for life:

1 -Mineralocorticoids: e.g. Aldosterone

2 -Glucocorticoids: e.g. Cortisol (Hydrocortisone) .

B- The sex hormones: e.g. estrogen & androgen

1- Mineralocorticoids

Aldosterone
• Steroid hormone synthesized and secreted from Zona glomerulosa.

• Very powerful mineralocorticoid & very weak glucocorticoid activity.

*Control Of Release of Aldosterone:
A) Renin-Angiotensin-Aldosterone System (RAAS):activation by hypovolemia and hyponatremia
B) ↑ K in blood

*Escape Phenomenon: Prolonged hypervolemia → ↓Sensitivity of D.C.T. to the effect

of Aldosterone → NO Na & Water retention BUT still K excretion.

*Causes of Hyper-Aldosteronism:

1- Primary → Adenoma in Zona glomerulosa → Conn’s disease.

2- Secondary to Heart failure, Nephrotic syndrome & Liver disease e.g. Cirrhosis.

*Therapeutic Uses of Aldosterone:

Aldosterone is rarely used clinically.

its antagonist (Spironolactone) is useful as Retaining diuretic especially in cases of Hyper-

aldosteronism.

2- Des-Oxy-Corticosterone (D.O.C.)
1- Pure mineralocorticoid with NO glucocorticoids activity.

2- 1/100 activity of aldosterone.

3- Used to replace mineralocorticoid activity in Addison’s disease.

4- NOT effective orally due to extensive hepatic first pass metabolism.

1
 ENDOCRINE PHARMACOLOGY DR A.E

5- Preparations:

a- Desoxycorticosterone Acetate (D. 0. C .A.):

- Sublingual: 2 —6 mg / day.

- I.M: 1—3mg/day.
- Subcutaneous Pellet Implantation: 75 mg / 6 months.

b- Desoxycorticosterone Trimethyl Acetate: 25 — 100 mg I.M. / month

3- Fludrocortisone Acetate (9-Fluoro Hydrocortisone)

1- Synthetic mineralocorticoid.

2- Mineralocorticoid (125 X Cortisol) & Glucocorticoid (10 X Cortisol) activities.

3- Useful orally (0.1 — 0.3 mg) to replace Glucocorticoids:

2 -Glucocorticoids:

Hydrocortisone (Cortisol)

*pharmacokinetics of Cortisol:

1- Well absorbed orally & Distributed all over the body.

2- Bound to plasma proteins mainly to Corticosteroids-Binding-Globulin (CBG = Transcortin) & albumin.
3- In liver: Inactive Cortisone Active Hydrocortisone (Cortisol).
Conjugation with glucuronic acid & sulfuric acid →Excreted in urine.
4- t 1/2 of endogenous cortisol = 90 minutes.

2
 ENDOCRINE PHARMACOLOGY DR A.E

*Mechanism Of Action Of Cortisol:

1- Genomic Mechanism: Cortisol → Steroid → Lipid soluble →Gain access intracellularly by

passive diffusion → Bind to cytoplasmic glucocorticoids receptor (GR-α & GR-β)→Activation →
Nuclear receptors:
a- Gene expression →DNA transcription → mRNA → Protein synthesis e.g. Lipocortin-I (Annexin-l)
& catabolic enzymes.
b- Gene repression →↓Protein synthesis (Catabolic) →↓COX-Il, Nitric oxide Synthase,
Inflammatory mediators & Immunoglobulins (Antibodies).

2- Non-genomic Mechanism: Cortisol ↑membrane receptors e.g. in Hippocampus.

Actions, adverse effects, contraindications and precautions : see table

Uses : see later

Preparations Of Commonly Used Corticosteroids

A) Preparations with primarily glucocorticoid activity:

1) Short acting Hydrocortisone (cortisol) & cortisone:

Equal glucocorticoid (anti-inflammatory) & mineralocorticoid (salt-retaining) activities
cortisone is a prodrug .

2) Intermediate & long acting : synthetic preparation :

Prednisone
dexamethasone
Mineralocorticoid activity is less with Prednisone (prodrug) and absent with dexamethasone
with longer duration of action.

3) In pregnancy:
The only glucocorticoid that has no effect on the fetus in pregnancy is Prednisone. It is a
prodrug that is not converted to the active compound, prednisolone, in the fetal liver.

B) Preparations with primarily mineralocorticoid activity:Fludrocortisone

3
 ENDOCRINE PHARMACOLOGY DR A.E

Adrenostatics
Drugs that inhibit Adrenocortical activity → Useful in treatment Of Cushing’s disease.

A.C.T.H. Dependent Cushing’s:

Pasireotide: A somatostatin analogue inhibits ACTH and growth hormone secretion

Reduces the circulating levels of cortisol in patients with ACTH-producing pituitary tumors
Used in the treatment of acromegaly.

Cabergoline: - long-acting dopamine D2 receptor agonist

used primarily to treat hyperprolactinemia.
also inhibits ACTH secretion from corticotrophin tumors (off-label use). Bromocriptine can also be used

Cyproheptadine: Antihistamine (H1-blocker) + Anti-serotonin. Suppresses release of A.C.T.H.

A.C.T.H. Independent Cushing’s:

Ketoconazole: Anti-fungal. Inhibits adrenal steroid hormone synthesis when used in larger doses
Useful in Cushing’s disease.

Metyrapone (Mitopirone): Inhibits 11--Hydroxylase enzyme selectively → Synthesis of

BOTH Aldosterone & Cortisol →  ACTH .

Uses: Cushing’s disease + Aminoglutethimide.

Test the function of anterior pituitary to secrete A.C.T.H

3-Mitotane: Destruction of adrenocortical cells.

Useful in Cushing’s disease & Inoperable adrenocortical carcinoma.

4- Aminoglutethimide: It causes a reduction in the synthesis of all hormonally active steroids.

Because it inhibits conversion of Cholesterol → Pregnenolone (First step in steroidogenesis).

It can be used with metyrapone or ketoconazole to reduce steroid secretion in patients with Cushing’s
syndrome due to adrenocortical cancer who do not respond to mitotane.