1. Adrenocorticosteroids & Adrenocortical antagonists

2. Introduction
The adrenal cortex synthesizes three classes of steroids: the glucocorticoids, mineralocorticoids and the androgens
Glucocorticoids, those having important effects on intermediary metabolism and immune function, mineralocorticoids, those having principally salt-retaining activity and those steroids having androgenic or estrogenic activity

3. Introduction
In humans, cortisol (hydrocortisone) is the main glucocorticoid and aldosterone is the main mineralocorticoid
Quantitatively, dehydroepiandrosterone (DHEA) is the major adrenal androgen (20 mg) secreted daily
Adrenal androgens constitute the major endogenous precursors of estrogen in women after menopause and in younger patients in whom ovarian function is deficient or absent

4. Introduction
The adrenal gland synthesizes steroids from cholesterol, which is derived from plasma lipoproteins
Some of the reactions in the biosynthetic pathway can be inhibited by drug
Ex: Metyrapone prevents the β-hydroxylation at C11, and thus the formation of hydrocortisone and corticosterone

5. 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.

6. Introduction
Both natural and synthetic corticosteroids are used for the diagnosis and treatment of a variety of inflammatory and immunological disorders
Secretion of the adrenocortical steroids is controlled by the pituitary release of corticotropin (ACTH)
Secretion of the salt retaining hormone aldosterone is primarily under the influence of angiotensin
Inhibitors of the synthesis or antagonists of the action of adrenocortical steroids are important in the treatment of several conditions

7. - - 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

8. 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

9. 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

10. Copyright © 2015 McGraw-Hill Education. All rights reserved.
From: Adrenocorticosteroids & Adrenocortical Antagonists
Basic & Clinical Pharmacology, 13e, 2015
Legend:
Circadian variation in plasma cortisol throughout the 24-hour day (upper panel). The sensitivity of tissues to glucocorticoids is also circadian but inverse to that of cortisol, with low sensitivity in the late morning and high sensitivity in the evening and early night (lower panel). The sensitivity of tissues to glucocorticoids is inversely related to that of glucocorticoid receptor (GR) acetylation by the transcription factor CLOCK; the acetylated receptor has decreased transcriptional activity. (Adapted, with permission, from Nader N, Chrousos GP, Kino T: Interactions of the circadian CLOCK system and the HPA axis. Trends Endocrinol Metab 2010;21:277. Copyright Elsevier.)
Date of download: 2/15/2015
Copyright © 2015 McGraw-Hill Education. All rights reserved.

11. 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

12. Synthetic glucocorticoids
Alterations in the glucocorticoid molecule influence its protein-binding affinity, side chain stability, rate of elimination, and metabolic products
Chemical modifications to the cortisol molecule have generated derivatives with greater separations of glucocorticoid and mineralocorticoid activity
The relative anti-inflammatory potency of each of the synthetic analogues is compared with cortisol and is roughly correlated with its biological half-life

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

14. 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

15. Metabolic effects
GCs have important dose-related effects on CHO, protein, and fat metabolism
Glucocorticoids stimulate and are required for gluconeogenesis and glycogen synthesis in the fasting state
Stimulate the release of amino acids in the course of muscle catabolism
Glucocorticoids increase serum glucose levels and inhibit the uptake of glucose by muscle cells resulting in increased blood glucose levels

16. Metabolic effects
They stimulate hormone sensitive lipase and thus lipolysis
The increased insulin secretion stimulates stimulates lipogenesis and to a lesser degree inhibits lipolysis
Net effect is to increase in fat deposition combined with increased release of FA and glycerol into the circulation
These results are most apparent in the fasting state where maintains adequate glucose supply to the brain
Direct effect while there are also other effects—called permissive effects—without which many normal functions become deficient. For example, the response of vascular and bronchial smooth muscle to catecholamines is diminished in the absence of cortisol and restored by physiologic amounts of this glucocorticoid. Similarly, the lipolytic responses of fat cells to catecholamines

17. Anti-inflammatory & Immunosuppressive Effects
Glucocorticoids dramatically reduce the manifestations of inflammation
They inhibit both the early and the late manifestations of inflammation
They reverse virtually all types of inflammatory reaction, whether caused by invading pathogens, by chemical or physical stimuli, or by inappropriate deployed immune responses (hypersensitivity or autoimmune disease)

18. Catabolic and Antianabolic Effects
Glucocorticoids have catabolic and antianabolic effects in lymphoid and connective tissue, muscle, peripheral fat, and skin
Supraphysiologic amounts of glucocorticoids lead to decreased muscle mass and weakness and thinning of the skin
Catabolic and antianabolic effects on bone are the cause of osteoporosis in Cushing's syndrome
In children, glucocorticoids reduce growth

19. Other physiologic effect
CNS effects: Indirect and direct effects on mood, behaviour, and brain excitability (adrenal insufficiency is associated with depression). Large doses of glucocorticoids may increase intracranial pressure (pseudotumor cerebri).
GIT: Large doses of glucocorticoids have been associated with the development of peptic ulcer
GC tend to produce a negative calcium balance: decrease Ca2+ absorption in the GIT and increase its excretion by the kidney
Chronically suppress the pituitary release of ACTH, GH, TSH, and LH

20. Other physiologic effect
Development of the fetal lungs: stimulates the production of surfactant required for air breathing during development of fetal lungs

21. Clinical Pharmacology
Replacement therapy in adrenocortical insufficiency
Adrenal insufficiency can result from:
Structural or functional lesions of the adrenal cortex (primary adrenal insufficiency or Addison's disease)
Structural or functional lesions of the anterior pituitary or hypothalamus OR exogenous corticosteroid use (secondary adrenal insufficiency)

22. Clinical Pharmacology
Chronic adrenocortical insufficiency (Addison's disease):
Characterized by weakness, fatigue, weight loss, hypotension, hyperpigmentation, and inability to maintain blood glucose during fasting
About 20–30 mg of hydrocortisone must be given daily, with increased amounts during periods of stress
Synthetic glucocorticoids that are long-acting and devoid of salt-retaining activity should not be administered to these patients

23. Clinical Pharmacology
Chronic adrenocortical insufficiency (Addison's disease):
Although hydrocortisone has some mineralocorticoid activity, this must be supplemented by an appropriate amount of a salt-retaining hormone such as fludrocortisone
In an effort to mimic the normal diurnal rhythm of cortisol secretion, glucocorticoids are generally in two divided doses; two-thirds in the morning and one-third in the afternoon

24. Clinical Pharmacology
Acute adrenocortical insufficiency (adrenal crisis)
Life-threatening disease characterized by GI symptoms (nausea, vomiting, and abdominal pain), dehydration, hyponatremia, hyperkalemia, weakness, lethargy, and hypotension
The most common cause is abrupt withdrawal of exogenous glucocorticoids in patients receiving chronic treatment
When acute adrenocortical insufficiency is suspected, treatment must be instituted immediately with parenteral hydrocortisone

25. Clinical Pharmacology
Congenital Adrenal Hyperplasia (CAH)
In 90% of patients results from mutations in CYP21 (21β-hydroxylase) leading to virilization
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)

26. P450scc

27. 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

28. 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

29. 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

30. 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

31. Route of administration of glucocorticoids
Agent
Oral
All can be administered orally IM
Cortisone, desoxycorticosterone, triamicnolone
IV, IM
Dexamethasone, hydrocortisone, methylprednisolone, prednisolone
Aerosol
Beclomethasone, flunisolide, triamcinolone
Intra-nasal
Beclomethasone dipropionate, triamcinolone acetonide, budesonide, flunisolide
Topical
Beclomethasone, dexamethasone, hydrocortisone, triamcinolone

32. ADEs
Two categories of toxic effects result from the therapeutic use of corticosteroids:
Those resulting from continued use at supra-physiological doses
Those resulting from withdrawal of steroid therapy

33. ADE Iatrogenic Cushing’s syndrome
Rounding, puffiness, fat deposition, and plethora (moon facies)
Fat redistribution from the extremities to the trunk, the back of the neck, and the supraclavicular fossae
Increase growth of fine hair over thigh, trunk & face
Acne
Insomnia & increase appetite
Wound healing impairement
Myopathy and muscle wasting
Thinning of the skin, with striae and bruising
Hyperglycemia; and eventually diabetes
Osteoprosis
Aseptic necrosis of the hip

34. ADEs
Immune Responses: glucocorticoid use is associated with an 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
CNS:
Hypomania or acute psychosis may occur, particularly in patients receiving very large doses of corticosteroids
Long-term therapy with intermediate- and long-acting steroids is associated with depression and the development

35. ADEs
Ocular: Increased intraocular pressure is common, and glaucoma may be induced.
Growth retardation: particularly medium-, intermediate-, and long-acting glucocorticoids

36. 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

37. Contraindications & Cautions
Peptic ulcer
Hypertension
Infections
Psychoses
Diabetes
Heart failure
Osteoporosis
Glaucoma
CAUTIONS:
Monitor for developing hyperglycemia, hypokalemia, hypernatremia
In case of withdrawal supply with adequate fluids and maintain electrolyte balance

38. Mineralocorticoids
The most important mineralocorticoid in humans is aldosterone
Fludrocortisone, a synthetic corticosteroid, is the most common prescribed salt-retaining hormone
The quantities of aldosterone produced by the adrenal cortex and its plasma concentrations are insufficient to participate in any significant feedback control of ACTH secretion
ACTH produces a moderate stimulation of its release

39. 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

40. Physiologic & Pharmacologic Effects
Aldosterone and other steroids with mineralocorticoid properties 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+
Excessive levels of aldosterone (tumors or overdosage with synthetic mineralocorticoids) lead to hypokalemia, metabolic alkalosis, increased plasma volume, and hypertension .

41. Mineralocorticoid Deficiency
Leads to hypotension and vascular collapse, Na+ wasting and contraction of the extracellular fluid volume, hyperkalemia, and acidosis
Oral fludrocortisone is used in the treatment of adrenocortical insufficiency associated with mineralocorticoid deficiency
Has both mineralo- & glucocorticoid and activity but the doses used are to small to exert anti-inflammatory and antigrowth effects

42. Antagonists of Adrenocortical agents

43. Synthesis Inhibitors Aminoglutethimide
Blocks the conversion of cholesterol to pregnenolone and causes a reduction in the synthesis of all hormonally active steroids
Aminoglutethimide can be used in conjunction with metyrapone or ketoconazole to reduce steroid secretion in patients with Cushing’s syndrome due to adrenocortical cancer who do not respond to mitotane

44. Synthesis Inhibitors 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
It can be used in diagnostic tests of adrenal function and can be used to treat pregnant women with Cushing’s syndrome
ADEs: water retention, hirsutism, transient dizziness, & GIT disturbances

45. Synthesis Inhibitors Abiraterone
It blocks 17α-hydroxylase (P450c17) and 17,20-lyase, and predictably reduces synthesis of cortisol in the adrenal and gonadal steroids in the gonads
A compensatory increase occurs in ACTH and aldosterone synthesis, but this can be prevented by concomitant administration of dexamethasone
Abiraterone is approved for the treatment of refractory prostate cancer

46. Recptor antagonists Mifepristone (RU 486)
At high doses, it is a potent glucocorticoid antagonist as well as an antiprogestin
Its use can only be recommended for inoperable patients with ectopic ACTH secretion or adrenal carcinoma who have failed to respond to other options tone

47. Recptor antagonists Spironolactone
Competes aldosterone for the MR and thus inhibits sodium reabsorption in the kidney
It also compete with DHT for the androgen receptor and inhibits 17α-hydroxylase activity
It is effective against hyperaldosteronism. It is also useful in the treatment of hirsutism in women, probably due to interference at the androgen receptor of the hair follicle
ADEs: hyperkalemia, gynecomastia, menstrual irregularities, and skin rask

48. Recptor antagonists
Eplerenone is a aldosterone antagonist approved for the treatment of HTN. It specifically avoids the gynecomastia associated with spironolactone
Drospirenone is a progestin in an oral contraceptive (Yasmin®), also antagonizes the effects of aldosterone