Adreno-cortico-steroids, Inhibitors, and Antagonists

Kaukab Azim, MBBS, PhD

Drug ListGlucocorticoids 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

Learning OutcomesBy 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.

Hypothalamic-Pituitary-Adrenal Axis

Aldosterone

Androgens

Adrenal MedullaAdrenal Cortex➨ Zona Glomerulosa➨ Zona Fasciculata➨ Zona Reticularis

-Stress

+

Adrenal Gland Histology

Adrenal Cortex Hormones1. Mineralocorticoid: Aldosterone

2. Glucocorticoid: cortisol

3. 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.

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

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

Release of the heat-shock protein and transport of the hormone receptor complex into the nucleus

Binding of the hormone-receptor complex to specific nucleotide sequences along the DNA, called Glucocorticoid response elements (GREs)

Decreased or increased transcription of genes coding for specific proteins

Decreased or increased accumulation of mRNA within the target cell

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

Pharmacodynamics of GlucocorticoidsThe effects of glucocorticoids can be subdivided into:

1. Direct: the effects are due to direct actions of these hormone in the cells.

2. Indirect: the effects are the result of homeostatic responses (e.g. by insulin, glucagon, PTH, etc.).

They can also be subdivided into:

3. Physiologic (or pharmacologic): the effects are dose-dependent.

4. "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.

Pharmacodynamics of GlucocorticoidsMetabolic 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.

Pharmacodynamics of GlucocorticoidsMetabolic 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).

Pharmacodynamics of Glucocorticoids

Cardiovascular Effects➨ Hypertension (mechanisms are still uncertain: they may

include blockade of prostaglandin synthesis, Na+ retention, etc.).

Renal effectsMaintenance 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.

Pharmacodynamics of GlucocorticoidsGastrointestinal 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.

Pharmacodynamics of GlucocorticoidsCentral 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.

Pharmacodynamics of GlucocorticoidsLocomotor 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:

a. Dissolution of pathologic lymphocytes and lymphoid tissue (lympholythic action).

b. 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.

The Anti-Inflammatory Action of Glucocorticoids

Features

☛ All type of inflammatory reactions are affected

☛ Both early and late phases of inflammation are inhibited

The Anti-Inflammatory Action of Glucocorticoids

MechanismsMain mechanisms of anti-inflammatory action are:1. Alteration of number, distribution and function of peripheral

leukocytes and tissue macrophages.It includes:a. 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

The Anti-Inflammatory Action of Glucocorticoids

MechanismsMain mechanisms of anti-inflammatory action are:1. Alteration of number, distribution and function of

peripheral leukocytes and tissue macrophages.It includes:b. 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)

The Anti-Inflammatory Action of Glucocorticoids

MechanismsMain mechanisms of anti-inflammatory action are:2. 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

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)

The Immunosuppressive Action of Glucocorticoids

Mode of Action1. 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.

The Immunosuppressive Action of Glucocorticoids

Mode of Action2. 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).

3. 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.

Relative Potencies of Corticosteroids

DrugRelative Potency

Equivalent Oral Dose (mg)Anti-inflammatory

activitySalt-retaining

activity

Cortisol* 1 1 20

Prednisone 4 0.3 5

Triamcinolone 5 0 4

Betamethasone 25-40 0 0.6

Dexamethasone 30 0 0.7

Fludrocortisone 10 250 2

Desoxycorticosterone 0 20 -

* Potencies relative to cortisone (taken as 1)

Pharmacokinetics of GlucocorticoidsABSORPTION➨ 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

BIOLOGICAL HALF-LIVES (DURATION OF ACTION) OF CORTICOSTEROIDS

SHORT ACTING Plasma t½: 0.5 – 2 hoursBiological t½: 8 – 12 hours

CortisolCortisoneFludrocortisone

INTERMEDIATE ACTING Plasma t½: 2 – 5 hoursBiological t½: 18 – 36 hours

PrednisonePrednisolone

LONG ACTING Plasma t½: 3 – 6 hoursBiological t½: 36 – 54 hours

DexamethasoneBetamethasone

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.

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)

Toxicity of Glucocorticoids

Other effects

a. Early effects (days, weeks)

➨ Weight gain➨ Mood changes (hypomania or depression)➨ Glucose intolerance➨ Retarded wound healing➨ Allergic contact dermatitis (when given topically)

Toxicity of Glucocorticoids

Other effects

b. 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)

Diabetogenic Effect of GlucocorticoidsGlucocorticoids may cause diabetes mellitus in risk patients by:

1. 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).

2. Decreased glucose utilization by the cells.

Mechanism is uncertain

3. Increased glucagon secretion

Most Common Infections Occurring in Patients Receiving Glucocorticoids

Infection Causative Agent

Bacterial ➨ Mycobacterium tuberculosis➨ Staphylococcus Species

Viral ➨ Herpes simplex virus➨ Varicella-zoster virus

Fungal ➨ Candida albicans➨ Cryptococcus neoformans

Parasitic ➨ Toxoplasma gondii➨ Entemoeba histolytica

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

Drugs Interacting with Corticosteroids

Drug Interaction Clinical Relevance

Ethacrynic acid Increased K+ loss and risk for gastric hemorrhage High

Cyclosporine Decreased cyclosporine metobolism High

Estrogens Decreased metabolism of corticosteroids High

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).

Clinical Uses of GlucocorticoidsTherapeutic usesa. Endocrine disorders

1. Replacement or supplementation therapy➨ Acute and chronic adrenocortical insufficiency➨ During and after surgical removal of a pituitary or adrenal adenoma.

2. Feed-back inhibition of ACTH➨ Congenital adrenal hyperplasia

b. Non-endocrine disorders☛ Musculoskeletal and connective tissue diseases

➨Arthritis (rheumatoid arthritis, gouty arthritis, etc.)➨Bursitis, tenosynovitis➨ Lupus erythematosus➨Polyarteritis nodosa➨Myasthenia gravis

Clinical Uses of GlucocorticoidsTherapeutic usesb. 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

Clinical Uses of GlucocorticoidsTherapeutic 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

Clinical Uses of GlucocorticoidsTherapeutic uses☛ Cardiovascular diseases

➨ Rheumatic carditis

☛ Renal diseases➨ Nephrotic Syndrome

☛ Neurologic diseases➨ Acute cerebral edema➨ Multiple sclerosis➨ Mysathenia gravis➨ Spinal cord injury

Clinical Uses of GlucocorticoidsTherapeutic 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

☛ Eye diseases➨ Scleritis and

episcleritis➨ Uveitis➨ Ophthalmic herper

zoster➨ Malignant thyroid

exophthalmos

☛ Skin diseases➨ Urticaria➨ Various dermatitis

(seborrheic, exfoliative, atopic)

➨ Pruritis ani➨ Psoriasis➨ Pemphigus

Clinical Uses of GlucocorticoidsTherapeutic uses

Guidelines for Glucocorticoid Therapy

1. For any disease, in any patient, the appropriate dose to achieve a given therapeutic effect must be determined by trial and error.

2. The dosage should be kept flexible, being raised or lowered according to the status of the disease or the appearance of unwanted effects.

3. The synthetic analogs are generally preferable to natural steroids because of their negligible sodium-retaining effects.

4. A single dose of corticosteroids, even if very large, is virtually without harmful effects.

Guidelines for Glucocorticoid Therapy

5. A few days of glucocorticoid therapy, in the absence of specific contraindications, are unlike to produce harmful results.

6. 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.

7. A long-term corticosteroid therapy should be considered only when there is either an undisputed therapeutic indication or after other therapeutic measures have failed.

8. 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.

Regulation of Aldosterone Secretion

Aldosterone secretion can be stimulated by 4 main factors:

1. The increased concentration of K+ in the extracellular fluid. (small changes in K+ concentration can increase aldosterone secretion several folds).

2. 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)

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:a. Distal renal tubules (the main effect).

b. Salivary glands

c. Gastrointestinal mucosa

d. Across cell membranes in general.

➨ Increased renal secretion of K+.➨ Increased renal secretion of H+.

Pharmacology of Mineralocorticoids

Pharmacokinetics and administration➨ Plasma t½: aldosterone: . 20 min; DOC and fludrocortisone: . 1.5 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)

CORTICOSTEROID INHIBITORS AND ANTAGONISTDrug 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

Cushing’s syndrome

Receptor antagonists

Mifepristone(high doses)

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