Adreno-cortico-steroids, Inhibitors, and Antagonists Kaukab Azim, MBBS, PhD
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.
Hypothalamic-Pituitary-Adrenal Axis - + Stress Adrenal Gland Histology Aldosterone • Adrenal Medulla • Adrenal Cortex • ZonaGlomerulosa • ZonaFasciculata • ZonaReticularis Androgens
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.
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 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
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.
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)Lipidmetabolism • 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 Glucocorticoids Metabolic effects c)Proteinmetabolism • 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 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.
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.
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.
Pharmacodynamics of Glucocorticoids Locomotorsystem 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.
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 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
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)
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
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 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 cytotoxicT cells.
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.
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
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, eyedrops) 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 Adrenalsuppression • 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 • 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 • Long-term effects (months, years) • Central obesity, cutaneous fragility • Osteoporosis • Opportunistic infections • Growth failure (in children) • Raised intracranial pressure • Diabetes mellitus (in riskpatients) • Increased intraocular pressure (common)
Diabetogenic Effect of Glucocorticoids Glucocorticoidsmaycause diabetes mellitus in riskpatientsby: • Stimulation of gluconeogenesisdue to; • increased transcription of enzymes that convert amino acids into glucose in liver and kidney cells. • increased mobilization of amino acids from extrahepatictissues (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
Most Common Infections Occurring in Patients Receiving Glucocorticoids
Glucocorticoid Contraindications and Precautions • Cushing’ssyndrome • Diabetes mellitus • Heartfailure • Renalfailure • Peptic ulcer • Hypertension • Osteoporosis • Glaucoma, cataracts • Herpes simplex infection • Varicella, measles, acuteviralhepatitis • Bacterial and fungal infections • Hypothyroidism (sensitivity to GC is increased) • Schizophrenic or depressive psychoses • Seizures • Children • Pregnancy
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 Glucocorticoids Therapeutic uses • Endocrinedisorders • 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 • Congenitaladrenalhyperplasia • Non-endocrinedisorders • Musculoskeletal and connective tissue diseases • Arthritis (rheumatoid arthritis, gouty arthritis, etc.) • Bursitis, tenosynovitis • Lupus erythematosus • Polyarteritis nodosa • Myasthenia gravis
Clinical Uses of Glucocorticoids Therapeutic uses • Non-endocrinedisorders (....contd.) • Neoplastic diseases • Leukemias, lymphomas, multiple myeloma • Complications of malignancy • Hematologic diseases • Autoimmunehemolytic anemia • Acute allergic purpura • Immunologic thrombocytopenic purpura • Transfusion reactions
Clinical Uses of Glucocorticoids Therapeutic uses • Gastrointestinal diseases • Inflammatoryboweldiseases (ulcerative colitis, Crohn's disease) • Nontropicalsprue • Pulmonary diseases • Bronchial asthma • Aspiration pneumonia • Prevention of infant respiratory distress syndrome (administered to the mother during pregnancy) • Idiopathic pulmonary fibrosis • Sarcoidosis • Eosinophilicpneumonia
Clinical Uses of Glucocorticoids Therapeutic uses • Cardiovascular diseases • Rheumaticcarditis • Renal diseases • Nephrotic Syndrome • Neurologic diseases • Acute cerebraledema • Multiple sclerosis • Mysathenia gravis • Spinal cordinjury
Clinical Uses of Glucocorticoids Therapeutic uses • Allergic and immune diseases • Subacute thyroiditis • Allergic rhinitis • Angioneuroticedema • Insect venom allergy • Drug reactions • Transplantation rejection (host-versus-graft disease and graft-versushostdisease) • Most immunologically mediated diseases
Clinical Uses of Glucocorticoids Therapeutic uses • Eye diseases • Scleritisandepiscleritis • Uveitis • Ophthalmicherper zoster • Malignantthyroidexophthalmos • Skin diseases • Urticaria • Various dermatitis (seborrheic, exfoliative, atopic) • Pruritisani • Psoriasis • Pemphigus
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.
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.
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)
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+.
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)