1. Adrenocorticosteroids & Adrenocortical antagonists

2. Introduction
The adrenal cortex synthesizes three classes of steroids: the glucocorticoids, mineralocorticoids and the androgens
The adrenal gland synthesizes steroids from cholesterol, which is derived from plasma lipoproteins

3. Copyright © 2015 McGraw-Hill Education. All rights reserved.
From: Adrenocorticosteroids & Adrenocortical Antagonists
Basic & Clinical Pharmacology, 13e, 2015
Legend:
Outline of major pathways in adrenocortical hormone biosynthesis. The major secretory products are underlined. Pregnenolone is the major precursor of corticosterone and aldosterone, and 17-hydroxypregnenolone is the major precursor of cortisol. The enzymes and cofactors for the reactions progressing down each column are shown on the left and across columns at the top of the figure. When a particular enzyme is deficient, hormone production is blocked at the points indicated by the shaded bars. (Reproduced, with permission, from Ganong WF: Review of Medical Physiology, 22nd ed. McGraw-Hill, Copyright © The McGraw-Hill Companies, Inc.)
Date of download: 2/15/2015
Copyright © 2015 McGraw-Hill Education. All rights reserved.

4. Regulation of adrenocortical hormone Secretion
Three characteristic modes of regulation of the HPA axis:
Diurnal rhythm in basal steroidogenesis
Marked increases in steroidogenesis in response to stress (e.g injury, hemorrhage, severe infection, major surgery, hypoglycemia, cold, pain, and fear)
Negative feedback regulation by adrenal corticosteroids

5. - - The role of the HPA in the regulation
of glucorticoid hormone synthesis and release
Stress + +
Circardian & pulsatile rhythms
Hypothalamus +
CRH -
Anterior pituitary
gland - +
ACTH
Adrenal cortex
Cortisol

6. Glucocorticoids Principal human glucocorticoid is cortisol
In the normal adult, in the absence of stress, 10–20 mg of cortisol is secreted daily
It exerts a wide range of physiologic effects, including regulation of intermediary metabolism, CV function, growth, and immunity
Rate of secretion follows circadian rhythm governed by irregular pulses of ACTH that peak in the early morning hours and after meals

7. Pharmacokinetic In plasma, 90% of cortisol is bound to CBG
~5–10% is free or loosely bound to albumin (large capacity but low affinity)
CBG is increased in pregnancy and with estrogen administration and in hyperthyroidism
Synthetic corticosteroids (dexamethasone) largely bound to albumin rather than CBG
T1/2 of cortisol in the circulation ~60–90 minutes
Only 1% of free cortisol is excreted unchanged in the urine; most is metabolized in the liver
CBG increases during pregnancy, estrogen administration or hyperthyroidism; while decreases by hypothyroidism, genetic defects in synthesis, and protein deficiency states

8. Synthetic glucocorticoids
Available in a wide range of preparations: orally, IV, IM, intra-articularly, topically, or as an aerosol for inhalation
All of the other undesirable side effects of supraphysiological concentrations of hydrocortisone have been observed with the synthetic analogues

9. Agent
Activity1
Equivalent Oral Dose (mg)
Forms Available
Anti-Inflammatory
Topical
Salt-Retaining
Short- to medium-acting glucocorticoids
 Hydrocortisone (cortisol) 1 20
Oral, injectable, topical
 Cortisone
0.8 25
Oral
 Prednisone 4
0.3 5
 Prednisolone
Oral, injectable
 Methylprednisolone
0.25
 Meprednisone2
Intermediate-acting glucocorticoids
 Triamcinolone 53
 Paramethasone2 10 2
 Fluprednisolone2 15 7
1.5
Long-acting glucocorticoids
 Betamethasone
25–40
0.6
 Dexamethasone 30
0.75
Mineralocorticoids
 Fludrocortisone
250
 Desoxycorticosterone acetate2
Injectable, pellets

10. Metabolic effects
Stimulate gluconeogenesis and glycogen synthesis in the fasting state
Stimulate the release of a.a s in the course of muscle catabolism
Inhibit the uptake of glucose by muscle
Increase insulin secretion
Stimulates stimulates lipogenesis
Stimulate hormone sensitive lipase and thus lipolysis
Anti-inflammatory & Immunosuppressive Effects

11. Other physiologic effect
CNS effects: effects on mood
GIT: development of peptic ulcer
GC tend to produce a negative calcium balance: decrease Ca2+ absorption and increase its excretion
Chronically suppress the pituitary release of ACTH, GH, TSH, and LH
Development of the fetal lungs: stimulates the production of surfactant required for air breathing during development of fetal lungs

12. Clinical Pharmacology
Replacement therapy in adrenocortical insufficiency
Adrenal insufficiency (primary & Secondary)
About 20–30 mg of hydrocortisone must be given daily, with increased amounts during periods of stress
Appropriate amount of a salt-retaining hormone such as fludrocortisone is required in some
Generally administered in two divided doses; two-thirds in the morning and one-third in the afternoon

13. Clinical Pharmacology
Acute adrenocortical insufficiency (adrenal crisis)
Life-threatening disease caused by abrupt withdrawal of exogenous glucocorticoids in patients receiving chronic treatment
Treatment must be instituted immediately with parenteral hydrocortisone

14. Clinical Pharmacology
Congenital Adrenal Hyperplasia (CAH)
The goals of therapy are to normalize the patient hormone level by suppressing the release of CRH and ACTH (decrease production of adrenal androgens)
Patients require replacement therapy with hydrocortisone, and those with salt wasting also require mineralocorticoid replacement (fludrocortisone acetate)

15. P450scc

16. Clinical Pharmacology
Acceleration of Lung Maturation
Reduces the incidence of respiratory distress syndrome in premature infants
When delivery is anticipated before 34 weeks of gestation, intramuscular betamethasone, 12 mg, followed by an additional dose of 12 mg 18–24 hours later

17. Clinical Pharmacology
Non-endocrine Diseases
The synthetic analogues of cortisol are useful in the treatment of a diverse group of diseases unrelated to any known disturbance of adrenal function
The usefulness of corticosteroids in these disorders is a function of their ability to suppress inflammatory and immune responses and to alter leukocyte function

18. Therapeutic Indications for the Use of Glucocorticoids in Nonadrenal Disorders
Examples
Allergic reactions
Angioneurotic edema, asthma, bee stings, contact dermatitis, drug reactions, allergic rhinitis, serum sickness, urticaria
Collagen-vascular disorders
Giant cell arteritis, lupus erythematosus, mixed connective tissue syndromes, polymyositis, polymyalgia rheumatica, rheumatoid arthritis, temporal arteritis
Eye diseases
Acute uveitis, allergic conjunctivitis, choroiditis, optic neuritis
Gastrointestinal diseases
Inflammatory bowel disease, nontropical sprue, subacute hepatic necrosis
Hematologic disorders
Acquired hemolytic anemia, acute allergic purpura, leukemia, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, multiple myeloma
Systemic inflammation
Acute respiratory distress syndrome (sustained therapy with moderate dosage accelerates recovery and decreases mortality)
Infections
Acute respiratory distress syndrome, sepsis
Inflammatory conditions of bones and joints
Arthritis, bursitis, tenosynovitis
Neurologic disorders
Cerebral edema (large doses of dexamethasone are given to patients following brain surgery to minimize cerebral edema in the postoperative period), multiple sclerosis
Organ transplants
Prevention and treatment of rejection (immunosuppression)
Pulmonary diseases
Aspiration pneumonia, bronchial asthma, prevention of infant respiratory distress syndrome, sarcoidosis
Renal disorders
Nephrotic syndrome
Skin diseases
Atopic dermatitis, dermatoses, lichen simplex chronicus (localized neurodermatitis), mycosis fungoides, pemphigus, seborrheic dermatitis, xerosis
Thyroid diseases
Malignant exophthalmos, subacute thyroiditis
Miscellaneous
Hypercalcemia, mountain sickness

19. Dosage
In determining the dosage of adrenocortical steroids many factors need to be considered:
Glucocorticoid: mineralocorticoid activity
Duration of therapy
Seriousness of the disease
Amount of drug likely to be required to obtain the desired effect
Type of preparation
Time of day when the steroid is administered

20. ADE Iatrogenic Cushing’s syndrome
Immune Responses: increased susceptibility to infection and a risk for reactivation of latent TB
Fluid and Electrolyte Handling: hypokalemic alkalosis and hypertension .Use synthetic non-salt-retaining steroids, Na+ restriction, & potassium supplements
Ocular: Increased intraocular pressure is common, and glaucoma may be induced.
Growth retardation: particularly medium-, intermediate-, and long-acting glucocorticoids

21. ADEs Withdrawal of Therapy
Characterized by flare-up of the underlying disease for which steroids were prescribed and acute adrenal insufficiency
Results from overly rapid withdrawal of corticosteroids after prolonged therapy has suppressed the HPA axis
A characteristic glucocorticoid withdrawal syndrome consists of fever, myalgia, arthralgia, malaise, and N, V, which may be difficult to differentiate from some of the underlying diseases for which steroid therapy was instituted

22. Mineralocorticoids
The most important mineralocorticoid in humans is aldosterone
They promote the reabsorption of Na+ from the distal part of the distal convoluted tubule and from the cortical collecting renal tubules, loosely coupled to the excretion of K+ and H+
Fludrocortisone, a synthetic corticosteroid, is used in the treatment of adrenocortical insufficiency associated with mineralocorticoid deficiency
Excessive levels of aldosterone lead to hypokalemia, metabolic alkalosis, increased plasma volume, and hypertension

23. Renin-Angiotensin System
 renal blood flow &/or  Na+
++ Juxtaglomerular apparatus of kidneys
Renin
Angiotensinogen
Angiotensin I
ACE
Angiotensin III
(powerful vasoconstrictor)
Angiotensin II
(powerful vasoconstrictor)
Adrenal
cortex
Aldosterone
Corticosterone

24. Antagonists of Adrenocortical agents

25. 1. Synthesis Inhibitors
Aminoglutethimide: Blocks the conversion of cholesterol to pregnenolone. Used to reduce steroid secretion in patients with Cushing’s syndrome due to adrenocortical cancer
Metyrapone: Interferes with corticosteroid synthesis by blocking the final step (11-hydroxylation) in glucocorticoid synthesis, leading to an increase in 11-deoxycortisol and the potent mineralocorticoid 11-deoxycorticosterone. Usedused in diagnostic tests of adrenal function. Main SE: water retention

26. Recptor antagonists
Mifepristone (RU 486)
At high doses, it is a potent glucocorticoid antagonist as well as an antiprogestin. Used for inoperable patients with ectopic ACTH secretion or adrenal carcinoma who have failed to respond to other options tone
Spironolactone
Competes aldosterone for the MR and thus inhibits sodium reabsorption in the kidney. It is effective against hyperaldosteronism. Major SEs: hyperkalemia, gynecomastia, menstrual irregularities, and skin rash
Eplerenone similar to spironolactone but without gynecomastia