PLC 401 Pharmacology III - Steroids PDF

 Learning Outcomes (LOs)  By the end of this lecture students will be able to: 1. Identify the adrenal glands hormones and their regulation. 2. Differentiate between mineralocorticoids and glucocorticoids. 3. Explain the pharmacological actions of mineralocorticoids and glucocorti...

 Learning Outcomes (LOs)  By the end of this lecture students will be able to: 1. Identify the adrenal glands hormones and their regulation. 2. Differentiate between mineralocorticoids and glucocorticoids. 3. Explain the pharmacological actions of mineralocorticoids and glucocorticoids. 4. Understand major diseases associated with adrenal glands disorders. 5. Assess the side effects and contraindications of glucocorticoids.  Adrenal glands  The adrenal glands, also known as suprarenal glands, are the triangular-shaped endocrine glands that sit on top of the kidneys. Suprarenal glands are responsible for releasing hormones in conjunction with acute and chronic stress through the synthesis of many hormones.  Adrenal glands Each adrenal gland is separated into two distinct structures:  The adrenal cortex mainly produces: 1. Glucocorticoids (cortisol) 2. Mineralocorticoids (aldosterone) 3. Sex Hormones (androgens mainly) The adrenal medulla (for fight, flight & fright reactions) mainly produces epinephrine and norepinephrine.  The adrenal gland is essential for life. It is rich in cholesterol and ascorbic acid, which is involved in oxidation-reduction reactions.  The adrenal cortex It is formed of 3 zones: 1. zona glomerulosa mineralocorticoids 2. zona fasciculata glucocorticoids 3. zona reticularis sex hormones Classification of adrenocortical steroids: 1. Mineralocorticoids: They cause sodium retention and potassium wasting When their level is increased, they produce edema and hypertension. e.g. Deoxycorticosterone (DOC), Aldosterone 2. Glucocorticoids: They have a catabolic effect on carbohydrates, fats and proteins. They have anti-inflammatory actions and are immunosuppressants. e.g. Cortisone, Hydrocortisone 3. Sex hormones: Dehydroepiandrosterone(DHEA) Androstenedione Testosterone Synthesis of adrenocorticoids Synthesis: The biosynthetic precursor is cholesterol which is converted to pregnenolone which by turn is transformed to adrenocortical steroids. Transport: They are bound to corticosteroid-binding globulin (CBG) and to albumin. Metabolism & Excretion:  They are metabolized in the liver into 17-ketosteroids which is excreted in the urine.  Determination of the level of 17-ketosteroids in a 24-hour collective urine sample has a diagnostic value for any condition associated with increased adrenal cortex hormones secretion. e.g. in hirsutism (caused by increased testosterone secretion from the adrenal cortex).  Regulation of Mineralocorticoids Aldosterone is regulated by the renin-angiotensin aldosterone system (RAAS) and not by adrenocorticotrophic hormone (ACTH)  Regulation of Glucocorticoids The release of cortisone is regulated through the hypothalamus-pituitary axis (HPA) : the hypothalamus produces a corticotropin releasing hormone (CRH) which stimulates the anterior pituitary gland to release ACTH (adrenocorticotrophic hormone) which by turn stimulates the adrenal cortex to release cortisone. Cortisone causes a feedback inhibition of ACTH & CRH release. This negative feedback may lead to atrophy of the adrenal gland upon long term treatment with cortisone; therefore cortisone must not be stopped suddenly.  Diurnal cycle of cortisone  Cortisone release undergoes a diurnal rhythm: i.e. the level in blood is not constant all over the day. o Maximum level is at 8-10 AM o Minimum level is at midnight. This is very important in cortisone therapy because it is better to simulate natural release of cortisone, therefore, cortisone is given in the morning, also, if a blood analysis for cortisone is requested, it should be in the morning.  Pharmacological actions I. Mineralocorticoids  Stimulate sodium and water reabsorption from renal tubules. They also stimulate potassium excretion. II. Glucocorticoids 1. Effect on metabolism: i) Increased glucose release from liver and inhibit glucose utilization by peripheral tissues resulting in hyperglycemia, insulin resistance and a diabetes-like state. ii) Increased lipolysis leading to increase in free fatty acids (FFA). In addition, they are responsible for fat mobilization. iii) Increased protein catabolism (The muscular mass is reduced).  Pharmacological actions II. Glucocorticoids 2. Anti-inflammatory, immunosuppressive effects and antiallergic effect. 3. Anti-stress action (coping with stress and noxious stimuli). 4. They keep the integrity of the cardiovascular system, skeletal muscles and CNS. 5. Maintain normal water excretion independent of their weak mineralocorticoids actions.  Pharmacological actions II. Glucocorticoids 6. Others:  Reduction in the count of eosinophils and monocytes increasing the susceptibility for infection. Increase in uric acid excretion.  Inhibit intestinal absorption and enhance renal excretion of Ca2+ and indirectly results in loss of calcium from bones producing osteoporosis. Increase in gastric acid secretion so they may induce ulcer. They reduce ACTH release by a negative feed-back mechanism.  Diseases Related to Adrenal Glands Dysfunctions 1. Addison’s disease  It is a hypofunction of the adrenal gland, which may be:  Primary i.e. due to a defect in the adrenal gland itself.  Secondary due to ↓↓ACTH secondary to defects in the pituitary gland or the hypothalamus.  1. Addison’s disease Symptoms: 1. Sodium loss and reduced water retention leading to hypotension. 2. Increase in potassium level. 3. Hypoglycemia. 4. Muscle weakness as cortisone is important for skeletal muscle integrity. 5. Hyperpigmentation of the skin (bronze pigmentation of skin) because of reduced cortisone caused by adrenal hypofunction leads to a feedback stimulation of ACTH release. ACTH has a very similar structure and action to MSH (melanocyte stimulating hormone) causing pigmentation of the skin. 6. Weight loss. Treatment: Replacement therapy with corticosteroids and NaCl. The most commonly used drug is fludrocortisone, which can be taken orally to supplement the necessary glucocorticoid replacement.  2.Cushing syndrome  It is a hyperfunction of the adrenal gland, which may be:  Primary i.e. due to a defect in the adrenal gland itself. Secondary due to increase in ACTH as secondary to defects in the pituitary gland or the hypothalamus, e.g. an adrenocorticotrophic hormone-secreting tumor. N.B: Symptoms similar to Cushing syndrome could be drug-induced by the administration of large amounts of cortisone.  2. Cushing syndrome Symptoms: 1. Sodium and water retention leading to edema & hypertension. 2. Mobilization of fat stores leading to moon face like & buffalo hump. 3. Muscle weakness and cutaneous stria (skin folds or marks of a fatty person). 4. Hyperglycemia 5. Menstrual disturbances & hirsutism due to increased release of sex hormones.  2.Cushing syndrome Treatment: 1. Surgical removal of adrenal tumor or irradiation. 2. Medications: A. Steroidogenesis inhibitors (steroid biosynthesis inhibitors): inhibit one or more enzymes in steroids pathway such as hydroxylase. e.g. Metyrapone, Aminoglutethimide and ketoconazole. B. Adrenolytic agents: mitotane (direct inhibition of adrenal functions). It is chiefly used to treat adrenocortical carcinomas. C. Receptor antagonists: mifepristone at high doses (glucocorticoid receptor competitive antagonist). At low doses, mifepristone works by being a selective antagonist of progesterone. 3. Adrenogenital syndrome ; Congenital adrenal hyperplasia (CAH) It is an inborn error of metabolism involving the deficiency of a specific enzyme responsible for adrenal steroid biosynthesis (mostly 21-hydroxylase). 3. Adrenogenital syndrome ; Congenital adrenal hyperplasia (CAH) The deficiency of this enzyme reduces aldosterone & corticosteroid biosynthesis resulting in a feedback stimulation of ACTH secretion leading to adrenal hyperplasia. 3. Adrenogenital syndrome ; Congenital adrenal hyperplasia (CAH)  In addition, the other pathway involving androgen production will lead to an excessive production of androgens leading to:  In females: Masculinization & Pseudohermaphroditism.  In males: Precocious puberty.  Treatment: cortisone to block the feedback mechanism.  4. Conn’s syndrome or hyperaldosteronism  This condition is characterized by an excessive release of aldosterone which may be:  Primary (idiopathic).  Secondary due to increased activity of the renin-angiotensin aldosterone system (RAAS) in nephrosis, cirrhosis or congestive heart failure.  It is characterized by potassium loss with paraesthesia and even paralysis and hypertension. Treatment: Spironolactone (aldosterone antagonist). Mechanisms of anti-inflammatory action of corticosteroids  Corticosteroids are used in rheumatic diseases and in prevention of tissue rejection (together with the immunosuppressant cyclosporin).  Mechanisms of anti-inflammatory action of corticosteroids: Corticosteroids produce the following: 1. They stimulate the synthesis of “lipocortin” or “macrocortin” which inhibit Phospholipase A2 (PLA2) and hence the synthesis of eicosanoids. 2. They inhibit (interleukin 1) IL1 to stop further proliferation of T-cells. 3. They inhibit (interleukin 2) IL2 to prevent the activation of B-lymphocytes. 4. They inhibit the (tumor necrosis factor)TNF. 5. They inhibit interferon and other interleukines. 6. They stimulate the macrophage migration inhibitory factors (MIF). Members of corticosteroids with anti-inflammatory activity  The ideal selective anti-inflammatory corticosteroid should have no sodium & water retention side effect (relative mineralocorticosteroid activity).  Classification:  I- According to the duration of action: Short acting: Hydrocortisone (8-12 hours). Intermediate: Prednisolone & Triamcinolone (12-36 hours). Long acting: Dexamethasone & Betamethasone (24-72 hours). Members of corticosteroids with anti-inflammatory activity II- According to the potency (bioequivalence): Cortisone (least potent) (25 mg) Hydrocortisone (Hydrocortisyl T , Solucortef inj. 20 mg) Dexamethasone (Oradexon T , Decadron , Oradexon 0.75 mg) Betamethasone dipropionate & sodium phosphate (Diprofos) III- According to the relative mineralocorticosteroid activity: Fludrocortisone acetate (Florinef T): it has an aldosterone-like activity so it is used in Addison’s disease where both corticosteroids & mineralocorticoids are needed as replacement therapy. It is given orally.  Regimen of corticosteroids  Glucocorticoids are given in a large initial dose until the condition is stabilized, followed by a maintenance dose by reducing the dose gradually until reaching the minimum effective dose with least side effects.  Corticosteroids should not be stopped abruptly to avoid Addison’s like adrenal crisis. Addison’s like adrenal crisis  Corticosteroids produce a negative feedback inhibition of ACTH leading to atrophy of the adrenal gland or suppression of the patient’s adrenal capacity to synthesise corticosteroids.  Endogenous hormone synthesis takes time.  Therapeutic uses 1. Replacement therapy in adrenal insufficiency (Addison’s disease) and in congenital adrenal hyperplasia (CAH) to interrupt the feedback mechanism. 2. Inflammatory conditions: a) Ulcerative colitis: enema of cortisone and oral salazopyrine or other derivatives as olsasalazine, melsalazine, and balsalazide. b) Rheumatoid arthritis: it is a severe autoimmune disease treated by 4 lines of treatment: 1. NSAIDs (voltaren, ketoprofen, aspirin). 2. Disease modifying drugs: (gold compounds, penicillamine, chloroquine, sulfasalazine). 3. Immunosuppressants (cyclophosphamide, methotrexate) 4. Corticosteroids  Therapeutic uses 3. Organ transplantation: This acute tissue rejection is treated by both corticosteroids & immunosuppressants like cyclosporine (nephrotoxic) or immuno MonAb (non- nephrotoxic). 4. Allergic conditions: i) Bronchial asthma: it may be treated by corticosteroids locally i.e. by inhalation, or orally. ii) Status asthmaticus: emergency I.V. corticosteroids & theophylline. iii) Allergic rhinitis: treated by sodium chromoglycate & corticosteroids. iv) Allergic eye diseases. v) Allergic skin diseases.  Therapeutic uses 5. As a supportive treatment (together with 5HT3, Ondansetron) to prevent nausea & vomiting associated with chemotherapy of several malignancies. 6. Treatment of anaphylactic shocks as that result from penicillin injection (treated by Decadron injection). 7. Collagen diseases as systemic lupus erythematosus (SLE) and connective tissue diseases as arteritis nodosum. 8. Nephrotic syndrome (escape of proteins in urine). 9. Liver diseases and cerebral edema. 10.Minor uses in vitiligo, alopecia, acne and aphthous ulcer.  Corticosteroids side effects  During prolonged use of corticosteroids, we should take into consideration other diseased conditions together with the administration of the lowest possible dose by the proper route. The side effects are: 1. Iatrogenic (drug-induced) Cushing’s syndrome. 2. Infectious diseases due to inhibition of immune system leading to reactivation of bacteria & fungi. 3. They are ulcerogenic causing ulcer formation & reactivation especially if combined with NSAIDs. 4. Hyperglycemia therefore special care in diabetic patients. 5. Osteoporosis.  Corticosteroids side effects 6. Cataract & increased intraoccular pressure when used in ophthalmic preparations. 7. CNS disturbances producing psychosis (schizophrenia). 8. Fluid & electrolyte disturbances in the form of sodium and water retention and loss of potassium causing CNS problems. 9. Liver disease and cerebral edema. 10. Problems associated with WITHDRAWAL of steroid therapy: corticosteroids produce a negative feedback inhibition of ACTH leading to atrophy of the adrenal gland or adrenal suppression, this is why we should stop corticosteroids gradually otherwise, Addisonian-like syndrome (hypofunction) occur.  Drug interactions withcorticosteroids NSAIDs or other gastrointestinal irritants together with corticosteroids lead to peptic ulcers. Potassium depleting diuretics (thiazides) or chronic laxatives: producing severe hypokalemia, neurological and muscular problems. Cardiac glycosides: corticosteroids produce hypokalemia leading to increase digitalis toxicity. Hypoglycemics: corticosteroids increase the blood sugar level antagonizing the effect of hypoglycemics. Drugs which increase metabolism: rifampicin, phenobarbital and phenytoin.  Contraindications of corticosteroids Congestive heart failure and digitalis therapy. Diabetes mellitus. Glaucoma. Herpes, viral & fungal infection. Hypertension. Peptic ulcer disease (PUD). Osteoporosis.