adrenocorticoids and adrenocorticoids antagonist

description about adrenocorticoids

1. AdrenocorticosteroidsAdrenocorticosteroids
&&
Adrenocortical AntagonistsAdrenocortical Antagonists

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

4. AdrenocorticosteroidsAdrenocorticosteroids
•Bind to specific intracellular cytoplasmic
receptors target tissue
•Production is diurnal
–Peak early in the morning
–Smaller peak in the late afternoon

5. AdrenocorticosteroidsAdrenocorticosteroids
•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

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

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

8. 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

9. Physiologic effects (cont.):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)

10. Physiologic effects (cont.)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)

11. Physiologic effects: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

12. 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

13. Pharmacokinetics:Pharmacokinetics:
•Absorption:
–Well absorbed from all sites of administration.
•Plasma Protein binding:
–90% to globulin.
•Half life (t1/2):
–1- 1.5 hr.
•Metabolism and Excretion:
–Excreted in urine after glycosylation with glucuronic acid.

14. B. MineralocorticoidsB. 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

15. Therapeutic uses of adrenal Therapeutic uses of adrenal
corticosteroidscorticosteroids
•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

16. Addison’s DiseaseAddison’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

18. Therapeutic uses of adrenal Therapeutic uses of adrenal
corticosteroidscorticosteroids
•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

19. Therapeutic uses of adrenal Therapeutic uses of adrenal
corticosteroidscorticosteroids
•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

20. •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

21. 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

22. 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
30-50% 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

23. 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

24. 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

25. 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

26. Antagonists of Adrenocortical AgentsAntagonists of Adrenocortical Agents
A.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)

27. 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

28. 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

29. 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

30. 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.