VII.

STEROIDAL ANTI-INFLAMMATORY COMPOUNDS

Classification of adrenocorticosteroids: 1. Natural and synthetic. 2. Glucocorticoids and mineralocorticoids. Glucocorticoids: concerned with CH metabolism and may include natural glucocorticoid as Hydrocortisone (cortisol) and Cortisone and synthetic ones including Prednisone, Prednisolone, Methylprednisolone,Triamcinolone, Betamethasone and Dexamethasone. Mineralocorticoids: concerned with salt and water metabolism and may include natural mineralocorticoid as Aldosterone and Desoxycorticosterone (DOC) and synthetic ones including Fludrocortisone. Mechanism of Action of Glucocorticoids: 1) Diffusion of glucocorticoid across the membrane of the target cell to bind to a glucocorticoid receptor-heat-shock protein complex in the cytoplasm. 2) Release of the heat-shock protein and transport of the hormonereceptor complex into the nucleus. 3) Binding of the hormone-receptor complex to specific nucleotide sequence along the DNA called glucocorticoid response elements (GREs). 4) Decreased or increased accumulation of mRNA within the target cell (alteration of transcription). 5) Changes in the rate of synthesis of specific proteins that carry the biological actions of the hormones.

Mechanism of action (some details) 1. Enter cells where they combine with steroid receptors in cytoplasm. 2. Combination enters nucleus where it controls synthesis of protein, including enzymes that regulate vital cell activities over a wide range of metabolic functions including all aspects of inflammation. 3. Formation of a protein that inhibits the enzyme phospholipase A2 which is needed to allow the supply of arachidonic acid. The latter is essential for the formation of inflammatory mediators. 4. Also act on cell membranes to alter ion permeability 5. Also modify the production of neurohormones

Effects of glucocorticoids may be: A) Direct effects: Direct actions in the cell. B) Indirect effects: the results of the homeostatic responses (e.g. by insulin, glucagon, PTH). A) Physiologic (or pharmacologic) effect: dose-dependent effect. B) Permissive effect: dose-independent effect Important to distinguish between physiological effects (replacement therapy) and pharmacological effects (occur at higher doses).

1. Metabolic Effects:
A) Carbohydrate Metabolism 1. Increased gluconeogenesis in liver and kidney. 2. Increased glycogen synthesis and storage. 3. Inhibition of glucose uptake and utilization by both adipose tissue and skeletal muscle. 4. The hyperglycemia stimulates insulin secretion B) Lipid Metabolism: 1. Increased lipolysis which leads to an increased in plasma levels of free fatty acids. 2. Insulin secretion stimulates lipogenesis leading to a net increase in fat deposition. 3. Increased fat absorption from the intestine. 4. Redistribution of body fat (increased in the back of the neck and face, decreased in the extremities). C) Protein Metabolism 1. Increased protein synthesis in the liver. 2. Decreased synthesis (anabolism is decreased). 3. Increased breakdown of proteins in lymphoid and connective tissue, muscle, fat and skin. Catabolism continues unabated or is increased resulting in negative N balance and muscle wasting. Osteoporosis occurs, growth slows in children, skin atrophies (together with increased fragility leads to brusing and striae), healing and fibrosis delayed.

D) Salt and Water Metabolism: 1. Salt and water retention 2. Less than mineralocorticoids. 3. Negligible with some synthetic glucocorticoids. 4. Mineralocorticoids cause: A) Na retention by renal tubule B) Increased K excretion in urine 2. Cardiovascular Effects: A. Permissive Effects: maintenance of: 1. A normal capillary permeability. 2. A normal vasomotor response to CAs. 3. A normal heart contractility. 4. A normal cardiac output. B. Direct effect: 1. Direct vasoconstriction on small vessels. 2. Hypertension. 3. Renal Effects: A) Permissive Effects: maintenance of: 1. A normal glomerular filtration. 2. A normal water permeability in the distal collecting tubules due to inhibition of vasopressin secretion. B) Increased excretion of Ca++. C) Renal urate excretion increased 4. Gastrointestinal Effects: 1. Maintenance of normal function of visceral smooth muscle (permissive Effect). 2. Increased production of gastric acid and pepsin. 3. Decreased cytoprotection of gastric mucosa. 4. Decreaed Ca++ absorption from the intestine (also, due to blockade of vitamin D action). 5. Antiemetic effects. 6. General depressive effects on intestinal functions after high doses.

5. Central Nervous System Effects: 1. Decreased cortical threshold for convulsions. 2. Behavioural disturbances after high doses. 3. Increased intracranial pressure after high doses. Euophoria or psychotic states may occur probably due to CNS electrolyte changes 6. Endocrine Effects: 1. Decreaed release of CRH, ACTH and beta-lipotropin, TSH, FSH, and ADH. 2. Increased release of GH. 7. Hematopoietic Effects: 1. Decreased concentration of lymphocytes, monocytes, basophils and eosinophils in blood due to increased efflux of these cells from blood to the lymphoid tissue. 2. Increaed concentration of neutrophils in blood due both to 1) increased efflux from bone marrow and to decreased migration from the blood vessels. 3. Increased concentration of red blood cells and platelets.

8. Locomotor System Effects: 1. Permissive effect: Maintenance of normal function of striatal muscle (Permissive effect). 2. Decreased muscle mass after high doses. 3. Decreased bone formation (direct effect due to iinhibition of osteoblasts. 4. Increased bone resorption (indirect effect due to increased secretion of PTH and decreased secretion of calcitonin. 5. Negative total body Ca++ balance. 9. Antineoplastic action due to: 1. Dissolution of pathologic lymphocytes and lymphoid tissue (lympholythic action). 2. Inhibition of growth of mesenchymal cancer tissue.

3. In many tumors, the effect is the consequence of their antiinflammatory action. 10. Anti-Inflammatory action: Have two important characters: 1. All types of inflammatory reactions are affected. 2. Both early and late phases of inflammation are inhibited. Inlammatory response depressed Main mechanisms of anti-inflammatory actions are: 1) Alteration of number, distribution and function of peripheral leukocytes and tissue macrophages. 2. Inhibition of PG and leukotriene synthesis. 3) Additional mechanisms.

Alteration of number, distribution and function of peripheral leukocytes and tissue macrophages includes: For leukocytes: 1. Decreased migration of neutrophils from the blood vessels. 2. Increased movements of lymphocytes, monocytes, basphils and eosinophils from vascular bed to the lymphoid tissue. 3. Decreased production of Interleukins (mainly I 2). TNF, and interferon gamma. 4. Inhibition of histamine release from basophils and mast cells. 5. Inhibition of fibroblast proliferation both due to the decrease in growth factor production and the decreae in interleukin 1. For macrophages: 1. Decreased accumulation of macrophages at the site of inflammation. 2. Decreased macrophage ability to phagocytose and kill microorganisms. 3. Decreased production of interleukins (mainly I 1), TNF, interferon gamma and pyrogens. 4. Decreased activation of T cells.

Inhibition of PG and leukotriene synthesis. 1. Inhibition of phospholipase A2 production. 2. Inhibition of COX-II production. Additional mechanisms of anti-inflammatory action include Decrease in postcapillary permeability due to 1. Inhibition of histamine release and kinin activity. 2. Inhibition of the effects of complement system. 11. Immunosuppressive action: Have two important characters: 1. Humoral immunity is slightly affected as the antibody production is reduced only after high doses. 2. Cellular immunity is strongly inhibited as the distribution and function of immune cells are deeply modified. Mechanisms of immunosuppressive action are: A) Most of the effects on leukocytes and macrophages mentioned above can impair immunity. Especially in this regard are: 1. Inhibition of interlekin 1 production which in turn decreases the proliferation of T cells and impairs the responses of both T and B cell to antigen. 2. The direct lympholythic effect on certain subset of T cells (cytotoxic T cells and inflammatory T cells). B) Additional mechanisms include: 1. Inhibition of antigen release from grafted tissue. 2. Stimulation of the catabolism of IgG antibodies thus lowering the effective concentration of specificantibodies.

Relative potencies of corticosteroids Drug AI Hydrocortisone 1 Prednisone 4 Prednisolone 5 Triamcinolone 5 Betamethasone 25-40 Dexamethasone 30 Fludrocortisone 10 Desoxycorticosterone 0 AI: Antiinflammatory activity SR: Salt-retaining activity. EOD: Equivalent oral dose (mg) SR 1 0.3 0.3 0 0 0 250 20 EOD (mg) 20 5 5 4 0.6 0.7 2 -

Duration of action of corticosteroids Group Short-Acting Intermediate Acting Long Acting Plasma t1/2 0.5-2 hrs 2-5 hrs 3-6 hrs Biological t1/2 Examples 8-12 hrs Hydrocortisone, cortisone, Fludrocortisone 12-36 hrs Prednisone, prednisolone, Triamcinolone 36-72 hrs Betamethasone, Dexamethasone

Routes of administration of corticosteroids Dosage form Oral Tablets, syrups, etc. Rectal Suppositories, enemas Intramuscular Solutions, suspensions Intra-articular Solutions, suspensions Intravenous Solutions Respiratory Oral aerosol Topical Cream, lotions, sprays, eye drops Note: Some absorption of topical preparations always occurs and may be high. Route

Toxicity of glucocorticoids 1. Adrenal suppression 2. Iatrogenic Cushings syndrome 3. Other toxic effects: subdivided into: A) Early toxic effects (days, weeks) B) Later toxic effects (months, years) Adrenal suppression: 1. The degree and duration of adrenal suppression depend on the dose and duration of glucocorticoid therapy 2. It takes at least 2-3 months for the pituitary and adrenals to become responsive, after chronic steroid therapy is discontinued 3. If therapy is to be stopped, corticosteroid dosage should be tapered slowly. 4. If the dose of glucocorticoid is reduced too rapidly, acute or chronic adrenal insufficiency could ensue. What are the symptoms of acute or chronic adrenal insufficiency? A) Nausea and vomiting B) Weight loss C) Lethargy D) Fever E) Muscle pain F) Circulatory collapse G) Renal failure N.B. Steroid suppressed adrenal continues to secrete aldosterone.

Iatrogenic Cushings syndrome: Treatment with high dose for more than 2-3 weeks Symptoms of Cushings syndrome include: 1. Moon face: rounding and puffiness of the face 2. Buffalo hump: Redistribution of fat to the face andtrunk 3. Thin limbs 4. Thin and atrophic skin 5. Acne 6. Hypertrichosis Early Toxic effects (days or weeks after administration) 1. Weight gain 2. Mood changes 3. Retarded wound healing 4. Glucose intolerance 5. Allergic contact dermatitis when given 6. Rare early toxic effects: - Hypertriglyceridemia - Peptic ulcer - Acute pancreatitis

Later toxic effects (months or years after administration) 1. Central obesity 2. Cutaneous fragility 3. Ecchymosis 4. Osteoporosis 5. Myopathy 6. Opportunistic infections 7. Growth failure in children (Growth reduction occurs where new cells are being added (as in children) but not where they are replacing cells as in adult tissues. 8. Raised intracranial pressure (pseudotumor cerebri)

9. Diabetes mellitus in risk patients 10. Hypertension (rare with synthetic glucocorticoids) 11. Rare late toxic effects: 12. Aseptic necrosis in bone 13. Posterior subcapsular cataracts, glaucoma

Infections occurring with increased frequency and severity in patients receiving glucocorticoids Bacterial infection caused by: Mycobacterium tuberculosis Proteus Vulgaris Pseudomonas aeruginosa Staphylococcus species Viral infection caused by: Herpes simplex virus Varicella-Zoster virus Fungal infection caused by: Aspergillus fumigatus Candida albicans Parasitic infection caused by; Entamoeba histolytica, Toxoplasma gondii Contraindications and Cautions of Glucocorticoids 1. Diabetes mellitus 2. Hypertension 3. Heart failure 4. Renal failure 5. Osteoporosis 6. Osteoarthritis 7. Glaucoma 8. Bacterial infections 9. Herpes simplex infection 10. Acute viral hepatitis 11. Schizophrenic or depressive psychosis 12. Pregnancy

Drug interactions with corticosteroids: 1. with ethacrynic acid (high clinical relevance) Increased K+ loss Increased risk of gastric hemorrhage 2. with cyclosporine (high clinical relevance) Decreased metabolism of cyclosporine 3. with estrogens (high clinical relevance): Decreased metabolism of corticosteroids 4. with enzyme inducers as barbiturates, phenytoin. Rifampin and carbamazepine (medium clinical relevance): Increased metabolism of corticosteroids 5. with salicylates (medium clinical relevance): Increased salicylate excretion Enhancement of gastric effects 6. Among the drugs that interact with corticosteroids are: * Insulin and diabetes medicines * Heart medicines such as digitalis * Diuretics * Medicines containing potassium or sodium * Immunization (vaccination) * Blood thinners such as warfarin Clinical uses of glucocorticoids: 1. Diagnostic uses 2. Therapeutic uses A. Endocrine disorders B. Non-endocrine disorders

Diagnostic uses: Dexamethazone suppression test is used for: A) Differential diagnosis in patients with Cushings syndrome B) Differential diagnosis of psychiatric states (the test is abnormal in the presence of severe mental disorder) Uses of glucocorticoids in endocrine disorders: 1. Replacement or supplementation therapy in: A. Acute and chronic adrenal insufficiency B. During and after surgical removal of a pituitary or adrenal adenoma C. Feed-back inhibition of ACTH as in congenital adrenal hyperplasia Uses of glucocorticoids in non-endocrine disorders: 1. Musculoskeletal and connective tissue diseases * Rheumatoid arthritis * Gout arthritis * Bursitis * Polymyalgia rheumatica * Polymyositis * Polyarteritis nodosa * Lupus erythematosus Neoplastic diseases *n Leukemias *n Lymphomas * Multiple myeloma * Complications of malignancy Hematologic diseases: * Acquired hemolytic anemia * Autoimmune hemolytic anemia * Some forms of aplastic anemias

* Idiopathic thrombocytopenic purpura * Acute allergic purpura * Transfusion reactions Gastrointestinal diseases * Ulcerative colitis * Crohns disease * Chronic active hepatitis * Subacute hepatic necrosis Pulmonary diseases * Bronchial asthma * Aspiration pneumonia * Prevention of infant respiratory distress syndrome (administered to the mother during pregnancy) * Idiopathic pulmonary fibrosis Cardiovascular diseases * Myocarditis and pericarditis * Rheumatic carditis * Temporal arteritis Renal disease * Nephrotic syndrome Neurologic diseases * Acute cerebral edema * Meningitis * Multiple sclerosis * Myasthenia gravis * Spinal cord injury Eye diseases * Anterior uveitis * Posterior uveitis * Optic neuritis

* Malignant thyroid exophthalmos Allergic and immune diseases * Subacute thyroiditis * Allergic conjunctivitis * Allergic rhinitis * Angioneurotic edema * Serum sickness * Insect venom allergy * Drug reactions * Anaphylaxis * Transplantation rejection (host-versus-graft disease and graft-versus-host disease) Skin diseases * Urticaria * Various types of dermatitis * Erythema multiforme * Psoriasis **Normal daily secretion of hydrocortisone is 10-30 mg. exogenous daily dose that completely suppresses cortex is 4080 mg (or prednisolone 10-20 mg). **Prednisolone is standard choice for anti-inflammatory therapy and can be given orally or IM **Methylprednisolone used for IV pulsed therapy **Dexamethazone longer acting **Fludrocortisone used to replace aldosterone where the adrenal cortex has been destroyed **Beclomethazone and budesonide used by inhalation for asthma.

Principles for using glucocorticoids

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 raises or lowered according to the activity of the disease or the development 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 5. in the absence of specific contraindications, a few days of corticosteroid therapy are unlike to produce harmful effects, except at the most extreme dosage 6. as corticosteroid 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. Committing a patient to long-term corticosteroid therapy should be considered only when there is 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 9. in stable treatment programs, use of the alternate day dosage schedule should be considered. With this regimen, unwanted effects are fewer and less severe

10. Abrupt cessation of prolonged, high dosage corticosteroid therapy is associated with significant risk of adrenal insufficiency that can be threatening to life 11. Patients who have received cortisone 50 mg or more per day (or equivalent amount of other corticosteroids) for more than one month should be considered to have some degree of pituitary adrenal suppression for at least one year after corticosteroid withdrawal 12. except in adrenal insufficiency, the administration of corticosteroids is neither an etiological nor a curative therapy but only a symptomatic one

END OF THE LECTURE