1. Adrenal Hormons
Dr. Hashem Mansour

2. OVERVIEW The adrenal gland consists of the cortex and the medulla.
The medulla secretes catecholamines, whereas the cortex secretes two types of corticosteroids (glucocorticoids, mineralocorticoids and the adrenal androgens).

3. OVERVIEW
The secretion is controlled by pituitary adrenocorticotropic hormone (ACTH; also called corticotropin), which is released in response to hypothalamic corticotropin-releasing hormone (CRH).
Glucocorticoids serve as feedback inhibitors of ACTH and CRH secretion.

5. CORTICOSTEROIDS
The corticosteroids bind to specific intracellular cytoplasmic receptors in target tissues.
Glucocorticoid receptors are distributed throughout the body, whereas mineralocorticoid receptors are confined mainly to excretory organs, such as the kidney, colon, salivary glands and sweat glands.
Both types of receptors found in the brain.

6. CORTICOSTEROIDS
The receptor present the nucleus, where it attaches to gene promoter elements.
There it acts as a transcription factor to turn genes on or off depending on the tissue.
This mechanism requires time to produce an effect.
However, other glucocorticoid effects are immediate, such as the interaction with catecholamines to mediate relaxation of bronchial musculature.

7. Glucocorticoids Cortisol is the principal human glucocorticoid.
Normally, its production is diurnal, with a peak early in the morning followed by a decline and then a secondary, smaller peak in the late afternoon.
Factors such as stress and levels of the circulating steroid influence secretion.

8. Glucocorticoids function
1. Promote normal intermediary metabolism:
Glucocorticoids favor gluconeogenesis through increasing amino acid uptake by the liver and kidney.
Glucocorticoid insufficiency may result in hypoglycemia.

9. Glucocorticoids function
2. Fat metabolism lipolysis.
Redistribution of body fat over face, neck and shoulder ‘moon face’, ‘fish mouth’, ‘buffalo hump’.
3. Calcium metabolism
They inhibit intestinal absorption and enhance renal excretion of Ca2+ results in spongy bone.

10. Glucocorticoids function
4. Water excretion Glucocorticoids maintain G.F.R and help excreting excess water load.
5. CVS Glucocorticoids restrict capillary permeability, maintain tone of arterioles and myocardial contractility.
They play a permissive role in the development of hypertension.
6. Skeletal muscles Optimum level of corticosteroids is needed for normal muscular activity.
Weakness occurs in both hypo-and hypercorticism

11. Glucocorticoids function
Hypocorticism: diminished work capacity and weakness are primarily due to hypodynamic circulation.
Hypercorticism: Excess glucocorticoid action → muscle wasting and myopathy → weakness.
7. CNS Mild euphoria is quite common with supraphysiological doses of glucocorticoids. This sometimes progresses to cause insomnia, anxiety or depression.
8. Stomach Secretion of gastric acid and pepsin is increased—may aggravate peptic ulcer.
9. Lymphoid tissue Glucocorticoids enhance the rate of destruction of lymphoid cells (T cells are more sensitive than B cells).

12. Glucocorticoids function
10. Anti-inflammatory action: The most important therapeutic properties of the glucocorticoids are their potent anti-inflammatory and immunosuppressive activities.
These agents inhibit the ability of leukocytes and macrophages to respond to and antigens.
Lastly, these agents influence the inflammatory response by stabilizing mast cell and basophil membranes, resulting in decreased histamine release.

13. Mechanism of action at cellular level
Corticosteroids penetrate cells and bind to a high affinity cytoplasmic receptor protein → a structural change occurs in the steroid-receptor complex that allows its migration into the nucleus and binding to glucocorticoid response elements (GRE)→ transcription of specific m-RNA → regulation of protein synthesis.

14. Mineralocorticoids
Mineralocorticoids help to control fluid status and concentration of electrolytes, especially sodium and potassium.
Aldosterone acts on distal tubules and collecting ducts in the kidney, causing reabsorption of sodium, bicarbonate, and water.
Conversely, aldosterone decreases reabsorption of potassium, which is then lost in the urine.
Hyperaldosteronism is treated with spironolactone.

15. Pharmacokinetics
Absorption and fate: Orally readily absorbed. Selected compounds can also be administered I.V, I.M, intra-articular, topically, or via inhalation or intranasal delivery.
All topical and inhaled glucocorticoids cause hypothalamic–pituitary–adrenal (HPA) axis suppression.
Corticosteroids are metabolized by the liver.
Excreted by the kidney.
Prednisone is preferred in pregnancy because it minimizes steroid effects on the fetus.
It is a pro-drug that is not converted to the active compound, prednisolone in the fetal liver.

16. Adverse effects Adverse effects are often dose related. Osteoporosis
Decrease sex hormone synthesis.
Increased appetite is not necessarily an adverse effect. In fact, it is one of the reasons for the use of prednisone in cancer chemotherapy.
The classic Cushing-like syndrome (redistribution of body fat, puffy face, hirsutism, and increased appetite).
Cataracts may also occur with long-term.
Hyperglycemia.
Topical therapy can also cause skin atrophy, ecchymosis, and purple striae.

18. Relative activity

19. CONTRAINDICATIONS
Since steroids may have to be used as a life-saving measure, all of these are relative contraindications:
1. Peptic ulcer
2. Diabetes mellitus
3. Hypertension
4. Viral and fungal infections
5. Tuberculosis and other infections
6. Osteoporosis
7. Herpes simplex keratitis
8. Psychosis
9. Epilepsy
10. CHF
11. Renal failure.

20. Cautions Discontinuation
Abrupt removal of corticosteroids causes acute adrenal insufficiency that can be fatal.
Means that the dose must be tapered slowly according to individual tolerance.
Inhibitors of adrenocorticoid biosynthesis or function
Several substances have proven to be useful as inhibitors of the synthesis or function of adrenal steroids: ketoconazole, spironolactone, and eplerenone.

21. Drug interaction
1. Ketoconazole: strongly inhibits all gonadal and adrenal steroid hormone synthesis. It is used in the treatment of patients with Cushing syndrome.
2. Spironolactone: It can also antagonize aldosterone and testosterone synthesis. It is useful in the treatment of hirsutism in women
3. Eplerenone: specifically binds to the mineralocorticoid receptor, where it acts as an aldosterone antagonist. This specificity avoids the side effect of gynecomastia.

22. Dosage
Many factors should be considered in determining the dosage of corticosteroids, including glucocorticoid versus mineralocorticoid activity, duration of action, type of preparation, and time of day when the drug is administered.
When large doses of the hormone are required for more than 2 weeks, suppression of the HPA axis occurs.
Dose tapering prevent this adverse effect by allowing the HPA axis to recover function on.

23. USES
1. Collagen and autoimmune diseases: systemic lupus erythematosus, nephrotic syndrome, glomerulonephritis, rheumatoid arthritis, rheumatic fever, acute gouty arthritis, haemolytic anaemia, thrombocytopenia, myasthenia gravis, etc.
2. Severe allergic reactions: anaphylaxis, urticaria, serum sickness.
3. Bronchial asthma, aspiration pneumonia.
4. Eye diseases.

24. USES
5. Skin diseases: mostly topical use in dermatitis; systemic steroids are needed exfoliative dermatitis, Stevens-Johnson syndrome and other serious disorders.
6. Inflammatory bowel disease: ulcerative colitis, Crohn’s disease.
7. Infective diseases: only in serious life threatening infective diseases under effective antimicrobial cover, e.g. in bacterial tubercular meningitis, severe lepra reaction.
8. Neurological conditions: like cerebral edema due to tubercular meningitis cerebral t

25. USES
9. Malignancies: acute lymphatic leukaemia, Hodgkin’s disease, lymphomas, etc.
10. Renal and other organ transplantation, skin allograft.
11. Substitution therapy in acute and chronic adrenal insufficiency and congenital adrenal hyperplasia.

26. Therapeutic uses of the corticosteroids
12. Replacement therapy for primary adrenocortical insufficiency (Addison disease):
Hydrocortisone is given to correct the deficiency. Failure to do so results in death.
13. Replacement therapy for secondary or tertiary adrenocortical insufficiency: These disorders are caused by a defect in CRH production by the hypothalamus or in ACTH production by the pituitary.
14. Diagnosis of Cushing syndrome: Cushing syndrome is caused by hypersecretion of glucocorticoids (hypercortisolism)

27. Therapeutic uses of the corticosteroids
15. Replacement therapy for congenital adrenal hyperplasia (CAH): CAH is a group of diseases resulting from an enzyme defect in the synthesis of one or more of the adrenal steroid hormones.
16. Acceleration of lung maturation:
Respiratory distress syndrome is a problem in premature infants.
Fetal cortisol is a regulator of lung maturation.