1. Adrenocorticosteroids & Adrenocortical Antagonists
Dr. Shereen Ayoub
Faculty of Medicine
2009

3. Adrenal Gland
Adrenal cortex – mineralocorticoids, glucocorticoids, adrenal androgens (androstenedione & dehydroepiadrosterone)
Adrenal medulla – catecholamines (Epinephrine and Norepinephrine)

4. Adrenal Cortex
Outer zone (zona glomerulosa) – secretes mineralocorticoids
- Aldosterone: under control of Renin-angiotensin system
Inner zone (zona fasciculata and reticularis) – secrete glucocorticoids and adrenal androgens

7. Anterior pituitary
Anterior pituitary: connected to the hypothalamus by hypothalmoanterior pituitary portal vessels.
The anterior pituitary produces six peptide hormones:
prolactin, growth hormone (GH),
thyroid stimulating hormone (TSH),
adrenocorticotropic hormone (ACTH),
follicle-stimulating hormone (FSH),
luteinizing hormone (LH).

9. Adrenocorticosteroids
Bind to specific intracellular cytoplasmic receptors target tissue
Production is diurnal
Peak early in the morning
Smaller peak in the late afternoon

10. Adrenocorticosteroids
Glucocorticoids
Natural – e.g. cortisone and hydrocortisone
Semi-synthetic and synthetic – e.g. prednisolone, fludrocortisone, triamcinolone, dexamethasone, fluocinonide
Preparations available: systemic, topical, inhalation, ophthalmic, otic, nasal
Discontinuation/withdrawal of therapy should be gradual after long-term use

11. Classification of Adrenocorticosteroids
I. Short to medium-acting glucocorticoids:
a. Hydrocortisone (cortisol)
b. Cortisone
c. Prednisone
d. Prednisolone
e. Methylprednisolone
f. Meprednisone

12. II. Intermediate-acting glucocorticoids
a. Triamcinolone
b. Paramethasone
c. Fluprednisolone
III. Long-acting glucocorticoids
a. Betamethasone
b. Dexamathasone
IV. Mineralocorticoids
a. Fludrocortisone
b. desoxycorticosterone acetate

13. Physiologic effects
Carbohydrate and protein metabolism: protect glucose-dependent tissues from starvation
( gluconeogenesis, glycogen synthesis)
periphery: ↓glucose utilization, ↑protein breakdown (amino acids), activate lipolysis (glycerol)
catabolic effects: decrease muscle mass, atrophy of lymphoid tissue, negative nitrogen balance, thinning of the skin

14. Physiologic effects (cont.):
Lipid metabolism: redistribution of body fat (buffalo hump, moon facies, supraclavicular area with loss of fat in the extremities)
induce lipolysis in adipocytes ( FFA)
Electrolyte and water balance: enhances the reabsorption of Na (aldosterone)
renal excretion of free water and interferes with
Ca uptake, while there is ↑Ca excretion by the kidneys (glucocorticoids)

15. Physiologic effects (cont.)
Cardiovascular system:
- mineralocorticoid-induced changes – hpn
- enhance vascular reactivity to other vasoactive substances
Skeletal muscle: normal function (steroid myopathy)
CNS: neurosteroids (regulate neuronal excitability)

16. Physiologic effects:
Formed elements of blood: minor effects on hgb and
erythrocyte production; affect circulating WBC
(Addison’s: lymphocytosis, ↑ mass of lymphoid tissue)
Anti-inflammatory and Immunosuppressive action
alter immune response of lymphocytes
- ↓release of vasoactive and chemoattractive
factors,
- diminished secretion of lipolytic and proteolytic
enzymes
- decreased extravasation of leukocytes to injury
- decreased fibrosis
- effect on cytokine production

17. Other effects:
↑amounts – insomnia, euphoria, depression, pseudomotor cerebri
↓amounts – psychiatric depression
large doses – peptic ulcer, promote fat distribution; vit D antagonist on Ca absorption; ↑ # of platelets and RBCs
absence – impaired renal function
fetal lung effects

18. Pharmacokinetics: Absorption: Plasma Protein binding:
Well absorbed from all sites of administration.
Plasma Protein binding:
90% to globulin.
Half life (t1/2):
hr.
Metabolism and Excretion:
Excreted in urine after glycosylation with glucuronic acid.

19. B. Mineralocorticoids 1. Aldosterone – zona glomerulosa
- promotes reabsorption of Na+ from the distal convoluted tubules and proximal collecting tubules; loosely coupled with K+ and H+ ions,t ½ 15-20mins , excreted in the urine as tetrahydroaldosterone and 3-oxo-glucoronide
2. Deoxycortisone: as precursor of aldosterone
3. Fludrocortisone – most widely used;
both mineralocorticoid and glucocorticoid activity

20. Therapeutic uses of adrenal corticosteroids
Replacement for primary adrenocortical insufficiency (Addison’s disease9
Hydrocortisone , 2/3 in am, 1/3 in pm
Fludrocortisone- synthetic mineralocorticoid
Replacement for secondary or tertiary adrenocortical insufficiency
Lacking ACTH or CRH, but you still treat with hydrocortisone
Synthesis of mineralocorticoids is less impaired

21. Addison’s Disease
Disease in which patients lack cortisol from zona fasiculata, and thus lacks negative feedback that suppresses ACTH production
Result: overproduction of ACTH
Skin color will darken
JFK had Addison’s disease and was treated with cortisol injections

23. Therapeutic uses of adrenal corticosteroids
Diagnosis of Cushing’s syndrome
Hypersecretion of glucocorticoids that results either from excessive release of ACTH or adrenal tumor
Dexamethasone suppression test is used to diagnose the cause
Suppresses cortisol release in pituitary dependent Cushings, but not when it is released from adrenal tumors

24. Therapeutic uses of adrenal corticosteroids
Replacement therapy for congenital adrenal hyperplasia
Group of diseases resulting from an enzyme defect in the synthesis of one or more of the adrenal steroid hormones
Leads to virilization in females due to overproduction of adrenal androgens
Treatment: give enough steroids to normalize the patient’s hormone levels of CRH and ACTH
Relief of inflammatory symptoms
Arthritis, asthma, skin conditions, allergies, etc
Acceleration of lung maturation in premature infants
Beclomethasone IM given to mother 48 hours prior to birth , followed by a second dose 24 hours before delivery

25. Infectious Disease – P. carinii pneumonia – increases oxygenation and decreases the incidence of respiratory failure and mortality
H. influenzae type b meningitis – decrease the long-term neurological impairment
Ocular disease – 0.1% dexamethasone
Contraindication: herpes simplex keratitis (clouding of the cornea) , glaucoma

26. 7. Skin diseases – inflammatory dermatoses
8. GIT diseases – inflammatory bowel disease
9. Hepatic diseases – prednisolone – 80%
histologic remission in pts. with chronic, active
hepatitis
10. Malignancies – ALL, lymphomas
11. Cerebral edema
12. Miscellaneous dis – Sarcoidosis (induce
remission), thrombocytopenia (decrease bleeding
tendency), organ transplantation, spinal cod injury

27. Side effects of long term usage
1. Hyperglycemia-can be managed with diet and/or insulin
2. Fluid and electrolyte disturbances- hypertension, edema
3. Increased susceptibility to infection
4. Myopathy — can be severe, recovery may be slow or incomplete
5. Osteoporosis — Ca2+ uptake, all ages, related to dosage and duration, ribs/vertebrae, Ca2+, vitamin D therapy % of chronic
6. Osteonecrosis – mainly femoral head, joint pain/stiffness, progressive
7. Cataracts – especially children, may not resolve with cessation
8. Behavioral disturbances — nervousness, insomnia
9. Iatrogenic adrenal insufficiency — prolonged suppression of the hypothalamic-pituitary axis
Side effects can be explained by reference to physiology already covered.

28. Therapeutic considerations
1. Contraindications — peptic ulcer, osteoporosis, hypertension, infection, psychosis
2. Alternate day therapy- decreases the prolonged suppression
3. Relief of symptoms — glucocorticoids do not cure
4. Especially useful for:
a. Diseases that occur in episodes (e.g. rheumatoid arthritis)
b. Topical applications

29. Supplemental measures:
Diet rich in potassium and low in sodium
Caloric mgt to prevent obesity
High protein intake
Appropriate antacid therapy
Calcium and vit D, physical therapy
Alendronate biphosphonate

30. Corticosteroid Withdrawal Should Be Gradual
Most frequent side effect- flare-up or the underlying disease
Sudden cessation leads to acute adrenal insufficiency, due to the prolonged suppression of the HPA axis
Need weeks/months/year to have full recovery of the HPA axis
Normal withdrawal symptoms- fever, muscle and joint pain, and malaise

31. Antagonists of Adrenocortical Agents
Synthetic inhibitors and glucocorticoid antagonists
1. Metyrapone – inhibits 11-hydroxylation, interfering with cortisol and corticosterone synthesis
- used in tests of adrenal function
- treat hypercorticotism (cushing syndrome in pregnancy)

32. 2. Aminoglutethimide
blocks the conversion of cholesterol to pregnanelolone and causes a reduction in the synthesis of all hormonally active steroids
Used in treatment of breast Cancer and Cushing’s syndrome due to adrenocortical Cancer (malignancese of adrenal cortex)
enhances metabolism of dexamethasone

33. 3. Ketoconazole
an antifungal imidazole derivative; potent, non-selective inhibitor of adrenal and gonadal steroid synthesis; used in Cushing’s syndrome
4. Mifepristone (RU 486)
11β-aminophenyl-substituted 19-norsteroid;
has strong anti-progestin activity; blocks
glucocorticoid receptor
5. Trilostane
3β-17 hydroxysteroid dehydrogenase inhibitor that interferes with the synthesis of adrenal and gonadal hormones, comparable to aminogluthemide

34. B. Mineralocorticoid Antagonists
1. Spirinolactone – diagnosis of aldosteronism; preparing for surgery to reduce the incidence of arrhythmias; hirsutism in women; K-sparing diuretic
2. Eplerenone: aldosterone antagonist in clinical trials to treat hypertension
3. Drospirenone – progestin in a new oral contraceptive, antagonizes the effect of aldosterone

35. In practice (Goodman and Gilman):
1. For any disease, in any patient, the appropriate dose to achieve a given therapeutic effect must be determined by trial and error and be reevaluated from time to time as the stage and the activity of the disease change.
2. A single dose of corticosteroid, even a large one is virtually without harmful effects.
3. A few days of corticorticosteroid therapy, in the absence of specific contraindications, is unlikely to produce harmful results except at the most extreme dosages.
4. As corticosteroid therapy is prolonged over periods of weeks or months, and to the extent that the dose exceeds the equivalent of substitution therapy, the incidence of disabling and potentially lethal effects increases.
5. Except in adrenal insufficiency, the administration of corticosteroids is neither specific nor curative therapy, but only palliative by virtue of their antiinflammatory and immunosuppressive effects.
6. sudden stop of prolonged, high-dose corticosteroid therapy is associated with a significant risk of adrenal insufficiency of sufficient severity to be threatening to life.
I had pdfs posted at the public site of my homeroom, accessible only with their MNA password.