Lesson 32 - Glucocorticoids PDF

Lesson 32 Glucocorticoids 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25  ADRENAL GLANDS Adrenal glands are small, triangular-shaped glands located on top of both kidneys. The adrenal glands are made up of two parts: the medulla (inner part) , w...

Lesson 32 Glucocorticoids 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25  ADRENAL GLANDS Adrenal glands are small, triangular-shaped glands located on top of both kidneys. The adrenal glands are made up of two parts: the medulla (inner part) , which releases catecholamines (adrenaline, noradrenaline and dopamine) the outer cortex that secretes steroids  CORTICAL STEROIDS Medulla Cortex Mineralcorticoides: Zona glomerulosa Aldosterone and desoxicorticosterone Glucocorticoids: Zona fasciculata cortisol and corticosterone Gonadal hormones: Zona reticularis Dehydrostiandrostery, androstenodis, and testosterone MINERALCORTICOIDS regulate water and electrolyte balance GLUCOCORTICOIDS they influence the metabolism of carbohydrates and proteins (glycemia), regulate defense mechanisms  Cholesterol esters Colesterol Steroid Formula Pregnenolone 17-OH-pregnenolone Deshidroepiandrosterone 3β-HED 3β-HED 3β-HED Progesterone 17-OH-progesterone Androstenedione 21β-hidroxilase 21β-hidroxilase 11-desoxicorticosterone 11-desoxicortisol 11β-hidroxilase 11β-hidroxilase Corticosterone Cortisol 11β-hidroxilase 18-OH-corticosterone Aldosterone sintetase Aldosterone  Hypothalamic-pituitary regulation The biosynthesis of glucocorticoids and mineralocorticoids is regulated by independent mechanisms: 1. Mineralocorticoids are synthesized under the influence of angiotensin II. 2. Glucocorticoids are synthesized and released under the influence of peptide hormones secreted by the hypothalamus and adenohypophysis (ACTH) to stimulate the adrenal cortex. Cortisol secretion depends on the circadian rhythm (with maximum release in the early hours of the morning) Hypothalamo–pituitary–adrenal (HPA) axis  Physiological Effects of Adrenal Steroids In the renal tubules, activation of the mineralocorticoid receptor presents salt-retaining effects: The glucocorticoid receptor has a high affinity for cortisol but a much lower affinity for aldosterone, whereas the mineralocorticoid receptor has a high affinity for both aldosterone and cortisol. This enables cortisol to exert both glucocorticoid and mineralocorticoid actions. Glucocorticoids mainly mediate metabolic and anti-inflammatory effects Glucocorticoids induce: Enzymes involved in gluconeogenesis and have an antiinsulin effect. Enzymes involved in protein catabolism Lipolysis and inhibit the uptake of glucose by adipose tissue; excessive glucocorticoid levels can lead to abnormal fat distribution and muscle wasting  Glucocorticoids Mechanism of action and physiological effects Glucocorticoids interact with intercellular receptors: the resulting steroid- receptor complex migrates to the nucleus where it binds to DNA and modifies gene transcription. This induces the synthesis of some proteins and inhibits the synthesis of others. This gives rise to different actions: 1. Metabolic Actions 2. Regulatory actions CORTISOL  1. Glucocorticoids more anti infla only anti infla  1. Glucocorticoids 1. METABOLIC ACTIONS: CARBOHYDRATES Decreased uptake and utilisation of glucose accompanied by increased gluconeogenesis Hyperglycaemia There is a concomitant increase in glycogen storage, which may be a result of insulin secretion in response to the increase in blood sugar. PROTEINS Increased catabolism, reduced anabolism: tissue wasting. LIPIDS Lipolytic effects  1. Glucocorticoids 2. Regulatory actions Inflammation and immunity Decrease inflammation: acute and chronic Action on lymphoid tissues: decreased clonal expansion of T and B cells, and decreased cytokine secretion 1. Glucocorticoids 2. Regulatory actions Muscoskeletal actions: Decreased osteoblast and increased osteoclast activity OSTEOPOROSIS  1. Glucocorticoids 2. Regulatory actions Hypothalamus and anterior pituitary gland Negative feedback action resulting in reduced release of endogenous glucocorticoids. Cardiovascular system Vasopressor effect Mineralcorticoid action (increased reabsorption of Na+ and K+ excretion) SNC: Euphoria and mood alterations Skin: Increased catabolism, and decreased proliferation of keratinocytes and fibroblasts Decreased synthesis of collagen type II 1. Glucocorticoids  2. Clinical uses of glucocorticoids Replacement therapy ADDISON’S DISEASE (also called adrenal failure) It is an uncommon illness that occurs when the body doesn't make enough of certain hormones. The adrenal glands make too little cortisol and aldosterone. Acute adrenal insufficiency (adrenal crisis, addisonian crisis) is a medical emergency IV hydrocortisone for up to 48 hours. In the treatment of chronic adrenal insufficiency, hydrocortisone is administered orally mimicking the circadian secretion of cortisol 2. Clinical uses of glucocorticoids ANTI-INFLAMMATORY/IMMUNOSUPPRESSIVE THERAPY Asthma (mometasone, inhaled) Inflammatory conditions (topically) of: Skin (contact) and seborrheic dermatitis, pruritus (itching) from various causes, psoriasis, sunburn, and a number of other condition Eye (corneal inflammation or keratitis), ear, nose, eczema, allergic conjunctivitis Allergic rhinitis (beclomethasone, nasal) Hypersensitivity states (e.g. severe allergic reactions) Topical corticosteroids are grouped according to their relative anti-inflammatory potency: Low-potency drugs are preferred for treating areas with thinner skin Low- to medium-potency steroids can be used on the ears, trunk, arms, legs, and scalp. Medium- to very-high-potency drugs may be needed to treat disorders in areas of thicker skin (e.g., the palms and soles). 2. Clinical uses of glucocorticoids Diseases with autoimmune and inflammatory components Rheumatoid arthritis Lupus erythematosus Inflammatory bowel disease, ulcerative colitis Haemolytic anaemia Idiopathic thrombocytopenic purpura (ITP)  2. Clinical uses of glucocorticoids CANCER Lymphotoxic effects (decrease the activation of T cells) : treatment of lymphocytic leukemias and lymphomas DEXAMETHASONE is a long-acting glucocorticoid used in combination with other drugs to prevent emesis during cancer chemotherapy. RESPIRATORY DISTRESS SYNDROME This condition may happens when a baby's lungs are not fully developed and cannot provide enough oxygen, causing breathing difficulties. BETAMETHASONE is used to prevent respiratory distress syndrome in premature newborn. Promotes fetal lung maturation  2. Clinical uses of glucocorticoids HYPERCALCEMIA Glucocorticoids are commonly used in the treatment of hypercalcemia associated with sarcoidosis due to their anti-inflammatory and immunosuppressive effects. In sarcoidosis, granulomas can increase calcium levels in the blood by producing excess vitamin D. Glucocorticoids help reduce granuloma formation, lower the production of active vitamin D, and thus help normalize calcium levels. PREVENT ORGAN GRAFT REJECTION They decrease the production of pro- inflammatory cytokines and inhibit the activity of immune cells like T lymphocytes, which play a major role in graft rejection. Glucocorticoids can also suppress the activation of other immune components that would attack the graft.  3. Unwanted effects of glucocorticoids ADRs: Supraphysiologic doses of glucocorticoids for more than 2 weeks produces a series of tissue and metabolic changes that result in a form of Cushing syndrome Clinical signs “Moon face”, buffalo hump, hirsutism, weight gain, and muscle wasting and weakness are often observed. Dermatologic changes can include acne (steroid acne), bruising, and thinning of the skin. 17  3. Unwanted effects of glucocorticoids ADRs: ATROPHY OF THE ADRENAL CORTEX. Glucocorticoids can cause atrophy of the adrenal cortex due to the negative feedback effect on the anterior pituitary gland and hypothalamus, leading to suppressed endogenous cortisol production. It may take many months to return to normal function once the drugs are stopped.  3. Unwanted effects of glucocorticoids ADRs: Hyperglycemia, glucose intolerance, and hypertension. Osteoporosis Alterations in the mood in some persons and can cause euphoria or psychosis. Large doses of glucocorticoids stimulate gastric acid and pepsin production and may thereby exacerbate peptic ulcers. Cataracts and glaucoma In children, long-term use can cause growth retardation. Contraindications Patients with psychosis, peptic ulcers, heart diseases, hypertension, diabetes, osteoporosis, and certain infections.