1. Adreno-cortico-steroids, Inhibitors, and Antagonists
Kaukab Azim, MBBS, PhD

2. Inhibitors / Antagonists
Drug List
Glucocorticoids
Mineralocorticoids
Inhibitors / Antagonists
Short-acting
Hydrocortisone (cortisol)
Cortisone
Aldosterone
Fludrocortisone
Desoxycorticosterone
(DOC)
Inhibitors of Corticosteroids
Ketoconazole
Metyrapone
Aminoglutethimide
Mitotane
Intermediate-acting
Prednisolone
Prednisone
Methyprednisolone
Triamcinolone
Glucocorticoid receptor antagonist
Mifepristone (RU 486)
Mineralocorticoid receptor antagonists
Spironolactone
Eplerenone
Long-acting
Betamethasone
Dexamethasone

3. Learning Outcomes
By the end of the course the students should be able to
Explain the molecular mechanism of action of corticosteroids
Describe the pharmacological and permissive effects of glucocorticoids upon different organ systems
Explain the mechanism of the anti-inflammatory, immunosuppressive and antineoplastic action of glucocorticoids
Describe the factors that regulate aldosterone secretion.
Describe the main features of the pharmacokinetics of corticosteroids.
List the routes of administration of corticosteroids.
Describe the adverse effects of glucocorticoids after acute or long-term administration.
List the main microorganisms that can cause an infection in patients receiving glucocorticoids.
Describe the clinically relevant interactions between glucocorticoids and other drugs
List the main contraindications to the use of glucocorticoids.
Outline the therapeutic uses of corticosteroids in adrenal and in non-adrenal disorders.
Describe the mechanism of action and therapeutic uses of the antagonists of glucocorticoids.

4. Hypothalamic-Pituitary-Adrenal Axis
Aldosterone
Androgens - +
Stress
Adrenal Gland Histology
Adrenal Medulla
Adrenal Cortex
Zona Glomerulosa
Zona Fasciculata
Zona Reticularis

5. Adrenal Cortex Hormones
Mineralocorticoid: Aldosterone
Glucocorticoid: cortisol
Adrenal androgens: Dehydroepiandrosterone (DHEA), Androstenidione: these are converted into testosterone and estrogen. Adrenal androgens constitute the major endogenous precursors of estrogens in women after menopause.
Regulation:
The secretion of adrenal steroids is regulated by corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH). The secretion of CRH and ACTH is affected by physical and mental stress. Cortisol regulates CRH and ACTH secretion by a feedback mechanism. The secretion of aldosterone is chiefly regulated by renin-angiotensin system.
Mechanism of action:
All are steroidal hormones. They enter the cell and bind to cytosolic receptors. The hormone-receptor complex translocates into the nucleus, and alter the gene expression by binding to the glucocorticoid-response element (GRE) or mineralocorticoid response element.

6. What would be the consequence of genetic deficiency of 21β/11β hydroxylase?

7. Mechanism of Action of Glucocorticoids
Diffusion of glucocorticoid across the membrane of the target cell to bind to a glucocorticoid receptor-heat-shock protein complex in the cytoplasm
Decreased or increased accumulation of mRNA within the target cell
Release of the heat-shock protein and transport of the hormone receptor complex into the nucleus
Decreased or increased transcription of genes coding for specific proteins
Binding of the hormone-receptor complex to specific nucleotide sequences along the DNA, called Glucocorticoid response elements (GREs)
Changes in the rate of synthesis of specific proteins that carry out the biologic actions of the hormones
Glucocorticoid receptor is a member of the nuclear hormone receptor superfamily that include the receptors for steroid hormones, thyroid hormone, Vit D and retinoic acid

8. Pharmacodynamics of Glucocorticoids
The effects of glucocorticoids can be subdivided into:
Direct: the effects are due to direct actions of these hormone in the cells.
Indirect: the effects are the result of homeostatic responses (e.g. by insulin, glucagon, PTH, etc.).
They can also be subdivided into:
Physiologic (or pharmacologic): the effects are dose-dependent.
"Permissive": the effects take place at a significant rate only in the presence of glucocorticoids, but they are not further stimulated when larger doses are given.

9. Pharmacodynamics of Glucocorticoids
Metabolic effects
a) Carbohydrate metabolism
Increased gluconeogenesis (in liver and kidney).
Increased glycogen synthesis and storage (in liver).
Inhibition of glucose uptake and utilization by both adipose tissue and skeletal muscle. (the hyperglycemia stimulates insulin secretion)
b) Lipid metabolism
Increased lipolysis, which leads to an increased plasma levels of free fatty acids (but insulin secretion stimulates lipogenesis leading to a net increase in fat deposition)
Increased fat absorption from intestine.

10. Pharmacodynamics of Glucocorticoids
Metabolic effects
c) Protein metabolism
Increased protein synthesis in the liver.
Decreased synthesis and increased breakdown of proteins in lymphoid and connective tissue, muscle, fat and skin.
d) Salt and water metabolism
The effect is less pronounced than those of mineralocorticoids (for some synthetic compounds these effects are negligible).
Decreased synthesis and increased breakdown of proteins in lymphoid and connective tissue, muscle, fat and skin (nitrogen balance becomes negative).

11. Pharmacodynamics of Glucocorticoids
Cardiovascular Effects
Hypertension (mechanisms are still uncertain: they may include blockade of prostaglandin synthesis, Na+ retention, etc.).
Renal effects
Maintenance of:
a normal water permeability in the distal collecting tubules (due to inhibition of vasopressin secretion) (the above mentioned effects are "permissive")
Increased excretion of calcium.

12. Pharmacodynamics of Glucocorticoids
Gastrointestinal effects
Increased production of gastric acid and pepsin.
Decreased cytoprotection of gastric mucosa.
Decreased calcium absorption from the intestine (also due to blockade of Vit D action).
Antiemetic effects (mechanism is unknown).
Endocrine effects
Decreased release of CRH, ACTH, GH, TSH, FSH and ADH.
Increases release of PTH and glucagon.

13. Pharmacodynamics of Glucocorticoids
Central nervous system effects
Decreased cortical threshold for convulsions.
Behavioral disturbances (after high doses).
Increased intracranial pressure (after high doses).
Hematopoietic effects
Decreased concentration of lymphocytes, monocytes, eosinophils, and basophils (due to increased efflux from blood to the lymphoid tissue)
Increased concentration of neutrophils (due both to increase efflux from bone marrow and to decreased migration from the blood vessels).
Increased concentration of red blood cells and platelets.

14. Pharmacodynamics of Glucocorticoids
Locomotor system effects
Decreased muscle mass (after high doses).
Decreased bone formation (direct effect due to inhibition of osteoblasts).
Increased bone reabsorption (indirect effect due to increased secretion of PTH and decreased secretion of calcitonin).
Antineoplastic action
It is mainly due to:
Dissolution of pathologic lymphocytes and lymphoid tissue (lympholythic action).
Inhibition of growth of mesenchymal cancer tissue.
In many tumors glucocorticoids exert a non-specific effect which is mainly the consequence of their anti-inflammatory action.
Maintenance of normal function of striatal muscle ("permissive effect")
Negative total body calcium balance.

15. The Anti-Inflammatory Action of Glucocorticoids
Features
All type of inflammatory reactions are affected
Both early and late phases of inflammation are inhibited

16. The Anti-Inflammatory Action of Glucocorticoids
Mechanisms
Main mechanisms of anti-inflammatory action are:
Alteration of number, distribution and function of peripheral leukocytes and tissue macrophages.
It includes:
For leukocytes:
Decreased migration of neutrophils from the blood vessels (but phagocytic activity of neutrophils is not affected)
Decreased production of interleukins (mainly IL-2).
Inhibition of histamine release from basophils and mast cells.
Inhibition of fibroblast proliferation (due to the decrease in growth factors and IL-2).
Increased movement of lymphocytes, monocytes, eosinophils and basophils from the vascular bed to the lymphoid tissue
Increased movement of lymphocytes, monocytes, eosinophils and basophils from the vascular bed to the lymphoid tissue

17. The Anti-Inflammatory Action of Glucocorticoids
Mechanisms
Main mechanisms of anti-inflammatory action are:
Alteration of number, distribution and function of peripheral leukocytes and tissue macrophages.
It includes:
For macrophages:
Decreased accumulation of macrophages at the site of inflammation
Decreased macrophage ability to phagocytize and kill microorganisms
Decreased production of interleukins (mainly IL-1), TNF , interferon gamma and pyrogens .
Decreased activation of T cells (due to decreased production of IL-1)
Decreased production of interleukins (mainly IL-1), TNF, interferon gamma and pyrogens.

18. The Anti-Inflammatory Action of Glucocorticoids
Mechanisms
Main mechanisms of anti-inflammatory action are:
Inhibition of PG and leukotriene synthesis
Inhibition of phospholipase A2 production (through induction of lipocortin the synthesis of lipocortin, an enzyme the acts as an inhibitor of phospholipase A2)
Decreased Transcription of genes coding for cyclooxygenase 2
Additional Mechanisms:
Decrease in capillary permeability (due to inhibition of histamine release and kinin activity) and inhibition of the effects of complement system

19. The Immuno-suppressive Action of Glucocorticoids
Features
Humoral immunity is slightly affected (antibody production is reduced only after high doses)
Cellular immunity is strongly inhibited (distribution and function of immune cells are deeply modified)

20. The Immunosuppressive Action of Glucocorticoids
Mode of Action
Most actions of glucocorticoids on leukocytes and macrophages can impair immunity. Especially important in this regard are:
The inhibition of macrophage-mediated production of interleukin-1 and interleukin-6 (which in turn decreases T cells activation and B cells proliferation) and of TNF
The inhibition of T cell-mediated production of interleukin-2 (which in turn decreases T cells proliferation and impairs the activation of NK cells
The direct lympholythic effect on certain subset of T cells, including cytotoxic T cells.
Most actions of glucocorticoids on leukocytes and macrophages can impair immunity. Especially important in this regard are:
The inhibition of macrophage-mediated production of interleukin-1 and interleukin-6 (which in turn decreases T cells activation and B cells proliferation) and of TNF
The inhibition of T cell-mediated production of interleukin-2 (which in turn decreases T cells proliferation and impairs the activation of NK cells) and of interleukin 3 and 4.
The direct lympholythic effect on certain subset of T cells, including cytotoxic T cells.

21. The Immunosuppressive Action of Glucocorticoids
Mode of Action
Additional mechanisms are:
Inhibition of other cytokines (glucocorticoids inhibit the synthesis of almost all known cytokines).
Inhibition of antigen release from grafted tissue.
Stimulation of the catabolism of IgG (thus lowering the effective concentration of specific antibodies).
The antiinflammatory effect of glucocorticoids
Is due to decreased synthesis of prostaglandins, leukotrienes, PAF, TNF, histamine and kinins, and increased transcription of genes coding from anti-inflammatory proteins such as IL-10, IL-12.
In fact the anti-inflammatory and immunosuppressive effects of glucocorticoids are inextricably linked, perhaps because both involve inhibition of leukocyte functions.

22. Relative Potencies of Corticosteroids
Drug
Relative Potency
Equivalent Oral Dose (mg)
Anti-inflammatory activity
Salt-retaining
activity
Cortisol* 1 20
Prednisone 4
0.3 5
Triamcinolone
Betamethasone
25-40
0.6
Dexamethasone 30
0.7
Fludrocortisone 10
250 2
Desoxycorticosterone -
* Potencies relative to cortisone (taken as 1)

23. Pharmacokinetics of Glucocorticoids
ABSORPTION
Oral bioavailability: 60-90%
Rectal bioavailability: generally quite good.
Absorption also occurs easily through the skin.
DISTRIBUTION
Vd (70 Kg): cortisone 20 L; betamethasone 90 L
Distributed in all tissues, including brain.
BIOTRANSFORMATION
> 95% by the liver and other organs.
EXCRETION
< 5% by the kidney.
Half-lives: 1-6 hours

24. BIOLOGICAL HALF-LIVES (DURATION OF ACTION) OF CORTICOSTEROIDS
SHORT ACTING
Plasma t½: – 2 hours
Biological t½: 8 – 12 hours
Cortisol
Cortisone
Fludrocortisone
INTERMEDIATE ACTING
Plasma t½: – 5 hours
Biological t½: 18 – 36 hours
Prednisone
Prednisolone
LONG ACTING
Plasma t½: – 6 hours
Biological t½: 36 – 54 hours
Dexamethasone
Betamethasone

25. Routes of Administration for Corticosteroids
Oral (tablets, syrups, etc.)
Rectal (suppositories, enemas)
Intramuscular (solutions, suspensions)
Intra-articular, intralesional (solutions, suspensions)
Intravenous (solutions)
Respiratory (oral aerosol)
Topical (cream, lotions, sprays, eye drops)
Absorption rate of various preparations depends on drug formulation (salts, esters, excipients)
Some absorption of topical preparations always occurs and may be high.

26. Toxicity of Glucocorticoids
Adrenal suppression
The degree and duration of suppression depends on the dose and duration of therapy.
It takes at least 2-3 months for the pituitary and adrenals to become responsive, after chronic steroid therapy is discontinued.
If therapy is to be stopped corticoid dosage should be tapered slowly (ACTH administration is not useful)
If the dose is reduced too rapidly acute or chronic adrenal insufficiency could ensue (nausea and vomiting, weight loss, lethargy, fever, muscle pain, circulatory collapse, renal failure).
Iatrogenic Cushing's syndrome
(treatment with high dose for more than 2-3 weeks)
Rounding and puffiness of the face ("moon face"), redistribution of fat to the face and trunk ("buffalo hump"), thin limbs, thin and atrophic skin, acne, hypertrichosis, purple striae.
(additional effects may be present)

27. Toxicity of Glucocorticoids
Other effects
Early effects (days, weeks)
Weight gain
Mood changes (hypomania or depression)
Glucose intolerance
Retarded wound healing
Allergic contact dermatitis (when given topically)

28. Toxicity of Glucocorticoids
Other effects
Long-term effects (months, years)
Central obesity, cutaneous fragility
Osteoporosis
Opportunistic infections
Growth failure (in children)
Raised intracranial pressure
Diabetes mellitus (in risk patients)
Increased intraocular pressure (common)
Ecchymoses
Myopathy
Hypertension (rare with synthetic glucocorticoids)
Aseptic necrosis of bone (rare)
Posterior subcapsular cataracts, glaucoma (rare)

29. Diabetogenic Effect of Glucocorticoids
Glucocorticoids may cause diabetes mellitus in risk patients by:
Stimulation of gluconeogenesis due to;
increased transcription of enzymes that convert amino acids into glucose in liver and kidney cells.
increased mobilization of amino acids from extrahepatic tissues (thereby providing amino acids for gluconeogenesis).
increased lipolysis (thereby providing glycerol for gluconeogenesis).
Decreased glucose utilization by the cells.
Mechanism is uncertain
Increased glucagon secretion
Decreased glucose utilization by the cells.
Mechanism is uncertain but may involve
direct inhibition of glucose transporters which in turn decreases glucose uptake by many tissues.
decreased sensitivity of many tissues to the effects of insulin on glucose uptake and utilization.

30. Most Common Infections Occurring in Patients Receiving Glucocorticoids
Causative Agent
Bacterial
Mycobacterium tuberculosis
Staphylococcus Species
Viral
Herpes simplex virus
Varicella-zoster virus
Fungal
Candida albicans
Cryptococcus neoformans
Parasitic
Toxoplasma gondii
Entemoeba histolytica

31. Glucocorticoid Contraindications and Precautions
Cushing’s syndrome
Diabetes mellitus
Heart failure
Renal failure
Peptic ulcer
Hypertension
Osteoporosis
Glaucoma, cataracts
Herpes simplex infection
Varicella, measles, acute viral hepatitis
Bacterial and fungal infections
Hypothyroidism (sensitivity to GC is increased)
Schizophrenic or depressive psychoses
Seizures
Children
Pregnancy

32. Drugs Interacting with Corticosteroids
Interaction
Clinical Relevance
Ethacrynic acid
Increased K+ loss and risk for gastric hemorrhage
High
Cyclosporine
Decreased cyclosporine metobolism
Estrogens
Decreased metabolism of corticosteroids
Barbiturates
Phenytoin
Rifampin
Carbamazepine
Increased metabolism of corticosteroids
Salicylates
Increased salicylate excretion (mechanism not established).
Enhancement of gastric effects

33. Clinical Uses of Glucocorticoids
Diagnostic uses
The dexamethasone suppression test is used for:
The differential diagnosis in patients with Cushing's syndrome (cortisol levels are reduced in the presence of Cushing’s disease).
The differential diagnosis of depressive psychiatric states (the test is abnormal in the presence of a severe mental disorder).

34. Clinical Uses of Glucocorticoids
Therapeutic uses
Endocrine disorders
Replacement or supplementation therapy
Acute and chronic adrenocortical insufficiency
During and after surgical removal of a pituitary or adrenal adenoma.
Feed-back inhibition of ACTH
Congenital adrenal hyperplasia
Non-endocrine disorders
Musculoskeletal and connective tissue diseases
Arthritis (rheumatoid arthritis, gouty arthritis, etc.)
Bursitis, tenosynovitis
Lupus erythematosus
Polyarteritis nodosa
Myasthenia gravis
Congenital adrenal hyperplasia (kun-JEN-i-tul)is a collection of genetic conditions that limit your adrenal glands' ability to make certain vital hormones. In most cases of congenital adrenal hyperplasia, the adrenal glands don't produce enough cortisol. The production of two other classes of hormones also may be affected, including mineralocorticoids (for example, aldosterone) and androgens (for example, testosterone).

35. Clinical Uses of Glucocorticoids
Therapeutic uses
Non-endocrine disorders (....contd.)
Neoplastic diseases
Leukemias, lymphomas, multiple myeloma
Complications of malignancy
Hematologic diseases
Autoimmune hemolytic anemia
Acute allergic purpura
Immunologic thrombocytopenic purpura
Transfusion reactions

36. Clinical Uses of Glucocorticoids
Therapeutic uses
Gastrointestinal diseases
Inflammatory bowel diseases (ulcerative colitis, Crohn's disease)
Nontropical sprue
Pulmonary diseases
Bronchial asthma
Aspiration pneumonia
Prevention of infant respiratory distress syndrome (administered to the mother during pregnancy)
Idiopathic pulmonary fibrosis
Sarcoidosis
Eosinophilic pneumonia

37. Clinical Uses of Glucocorticoids
Therapeutic uses
Cardiovascular diseases
Rheumatic carditis
Renal diseases
Nephrotic Syndrome
Neurologic diseases
Acute cerebral edema
Multiple sclerosis
Mysathenia gravis
Spinal cord injury

38. Clinical Uses of Glucocorticoids
Therapeutic uses
Allergic and immune diseases
Subacute thyroiditis
Allergic rhinitis
Angioneurotic edema
Insect venom allergy
Drug reactions
Transplantation rejection (host-versus-graft disease and graft-versushost disease)
Most immunologically mediated diseases

39. Clinical Uses of Glucocorticoids
Therapeutic uses
Eye diseases
Scleritis and episcleritis
Uveitis
Ophthalmic herper zoster
Malignant thyroid exophthalmos
Skin diseases
Urticaria
Various dermatitis (seborrheic, exfoliative, atopic)
Pruritis ani
Psoriasis
Pemphigus
Psoriasis is an autoimmune disease that affects the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of stroke, and treating high blood lipid levels may lead to improvement.
Pemphigus is a rare group of blistering autoimmune diseases that affect the skin and mucous membranes.
In pemphigus, autoantibodies form against desmoglein. Desmoglein forms the "glue" that attaches adjacent epidermal cells via attachment points called desmosomes. When autoantibodies attack desmogleins, the cells become separated from each other and the epidermis becomes "unglued", a phenomenon called acantholysis. This causes blisters that slough off and turn into sores. In some cases, these blisters can cover a significant area of the skin.

40. Guidelines for Glucocorticoid Therapy
For any disease, in any patient, the appropriate dose to achieve a given therapeutic effect must be determined by trial and error.
The dosage should be kept flexible, being raised or lowered according to the status of the disease or the appearance of unwanted effects.
The synthetic analogs are generally preferable to natural steroids because of their negligible sodium-retaining effects.
A single dose of corticosteroids, even if very large, is virtually without harmful effects.

41. Guidelines for Glucocorticoid Therapy
A few days of glucocorticoid therapy, in the absence of specific contraindications, are unlike to produce harmful results.
When glucocorticoid therapy is prolonged over periods of weeks or months, with doses exceeding the equivalent of substitution therapy, the incidence of adverse effects is greatly increased.
A long-term corticosteroid therapy should be considered only when there is either an undisputed therapeutic indication or after other therapeutic measures have failed.
The lowest effective dose should be prescribed for the shortest possible time. Moderation of symptoms with minimal untoward effects is preferable to complete palliation with major complications.

42. Regulation of Aldosterone Secretion
Aldosterone secretion can be stimulated by 4 main factors:
The increased concentration of K+ in the extracellular fluid. (small changes in K+ concentration can increase aldosterone secretion several folds).
The activation of the renin-angiotensin system. (the system can be activated by a decrease of mean arterial pressure, renal blood flow, or plasma Na+ concentration)
Aldosterone secretion can be stimulated by 4 main factors:
The increased concentration of K+ in the extracellular fluid. (small changes in K+ concentration can increase aldosterone secretion several folds).
The activation of the renin-angiotensin system. (the system can be activated by a decrease of mean arterial pressure, renal blood flow, or plasma Na+ concentration)
The decreased concentration of Na+ in the extracellular fluid. (this stimulation is not dependent on activation of renin-angiotensin system)
ACTH (stimulation is modest and not sustained for more than a few days in normal subject)
The first two factors are by far the most important

43. Pharmacology of Mineralocorticoids
Mechanism of action
A mineralocorticoid receptor (quite similar to the glucocorticoid receptor) is present in the cytoplasm of target cells.
Regulation of gene expression is the same as described for glucocorticoids.
Pharmacological effects
Stimulation of absorption of Na+ in:
Distal renal tubules (the main effect).
Salivary glands
Gastrointestinal mucosa
Across cell membranes in general.
Increased renal secretion of K+.
Increased renal secretion of H+.

44. Pharmacology of Mineralocorticoids
Pharmacokinetics and administration
Plasma t½: aldosterone: . 20 min; DOC and fludrocortisone: hrs.
Administration: fludrocortisone, by oral route.
Adverse effects
Hypernatremia
Hypervolemia
Hypokalemic alkalosis (weakness, paralytic ileus and tetany)
Hypertension
Therapeutic uses
Acute adrenal insufficiency
Chronic adrenal insufficiency (Addison's disease)
(in both cases cortisol must always be given concomitantly)

45. CORTICOSTEROID INHIBITORS AND ANTAGONIST
Drug
Mechanism of Action
Clinical Use
Corticosteroid synthesis inhibitors
Aminoglutethimide
Reversible blockade of the conversion of cholesterol to pregnenolone (production of all adrenal steroids is inhibited)
Cushing’s syndrome
Ovariectomized women with metastatic breast cancer (to eliminate adrenal estrogen production)
Ketoconazole
(high doses)
Reversible blockade of several steps of steroidogenesis requiring cytochrome P450 enzymes
Receptor antagonists
Mifepristone
Blockade cytoplasmic glucocorticoid receptor
Inoperable patients with ectopic ACTH secretions or adrenal carcinoma (it is also an antiprogestin)
Spironolactone
Blockade of cytoplasmic mineralocorticoid receptor
Hyperaldostronism
Hirsutism in women