Glucocorticoids Alena Máchalová, MD Endogenous cortisol secretion: • Basal: 20 - 30 mg /24 h • In stress: up to 10 fold • Maximal: 4. (6.) - 8. a.m. Pharmacokinetics • Bound to CBH and albumin • Intensively metabolised • Reduction of double bond between C4 and C5 • Metabolites excreted in 72 h • Synthetic slower • (prednison – prednisolon) Mechanism of glucocorticoid action on cellular level After entering the cell they bind to specific receptors in cytoplasma causing change of conformation = activation of receptors Complexes of corticoid + receptor are transported to cell nucleus and bind to DNA elements. The result is incerased transcription of genes eitzher inducing or inhibiting synthesis of other proteins • GLC receptors are present in all tissues!!! • Proteins called lipocortins are able to suppress phospholipase A Glucocorticoids Phospholipase A2 Membrane phospholipids Arachidonic acid lipooxygenase cyclooxygenase LEUCOTRIENS PROSTAGLANDINES PROSTACYKLINES TROMBOXANES inflammation Mobilization of fagocytosis Changes in vessels permeability Inflammation A-A NSAID Inh. 5-LOX Antiinflammatory and immunosuppressant effect • Impaired migration and function of leukocytes • Inhibition of AA cascade, ↓production of Pg, IgG, influx and activity of neutrophils and macrophages • Inhibition of adhesive factors synthesis (gene transcription level) Antiinflammatory and immunosuppressant effect • ↓ release of HIS from basophiles • ↓ blood vessels proliferation… • ↓ function of fibroblasts • ↓ activity of osteoblasts • ↑ osteoclasts (= osteoporosis) Inhibit all types of inflammation regardless of localisation or ethiology ! Antiallergic effect • decreased release of His from basophiles • inhibition of leucotriens and PG synthesis • Increase of β2 receptors density • antiedematic eff. Metabolic effects • glucose: • decreased glucose uptake and utilistion in cell • increase of gluconeogenesis (glucose synthesis from non-sugar sources – aminoacids, fatty acid) • increase of glycemia ... Insulin...lipogeneze • proteins: increased catabolizms, atrophy Metabolic effects • fat: • permissive effect on lipolytic hormones • fat redistribution (Cushing sy) • connective tissues • ↓ function of fibroblasts, osteoblasts • ↑ osteoclasts (= osteoporosis) • impair in colagen metabolism, decreased growth of fibrose tissues BUT!! generally: body fat deposition, redistribution, ↑glycerole, FA in blood Ontogenetic effects Permissive effect on - organogenesis - development and maturation of intestinal enzymes - increased synthesis of surfactant in fetal lungs - suppressed bone growth Effects of „pharmacological doses“: powerful antiinflammatory effect – decrease of early: erythema, edema, pain, flush late: healing of the wound, fibrose proliferation powerful immunosuppressant effect – decrease of rejection reactions (in organ transplantation) autoimunne reactions Ions • decrease of calcemia • increased loss of • retention of natrium and chlorides "Permissive effects" catecholamines activity calorigenic effect, smooth muscle in airways and vessels reactivity lipolytic effect of catecholamines, ACTH,GH heart catecholamines, AT II, inotropic effect, ↑ vessel tonus kidney normal excretion of water maintenance of GF and tubular clearance "Permissive effects" • Low levels of cortisol abnormal vasodilatation decreased preload decreased of BP • High levels of cortisol increase of BP (blood volume + suppressed synthesis of NO) Regulatory effects negative feed-back in hypothalamus and adenohypophysis decreased release of endogenous glucocorticoids vazotropic suppression of vasodilatation, edema and NO synthesis on cellular level on site of acute inflammation – immunosuppressant eff. on site of chronic inflammation – suppressed proliferation in connective tissues and angiogenesis in lymphoid tissue – suppressed B and T lymphocytes expansion immunology mediators suppressed synthesis of cytokines and PG Adverse effects (after pharmacological doses!) 1) suppressed response to infectious agents or tissue damage even after inhalations !!! risk of infections, ulcerous disease or mycosis 2) suppression of endogenous glucocorticoids synthesis (axis supression) acute adrenal insufficiency in sudden stop of therapy by pharmacological doses prevention: slow withdrawal (at first the evening dose) long supervision after the end of treatment (> 2 months) 3) osteoporosis (after chronic treatment) 4) mineralocorticoid effects water and electrolytes retention ↑ BP, loss of K+ ↓ endogenous NO synthesis Adverse effects (after pharmacological doses!) 5) steroid diabetes 6) muscle weakness, atrophy children: retarded growth (therapy > 6 months) 7) psychotropic effects: euphoria/ depression/psychoses 8) increase of gastric HCl secretion 9) damage of cartilage, impaired wound helaing, development of striae 10) others: increased hemocoagulation and aggregation ↑ trombocytes, erythrocytes (necessary thrombosis prevention) glaucoma increased intracranial pressure Adverse effects of local application • Mouth – mycosis, – hoarse voice (rinsing mouth after application!!) • Skin: – atrophy – teleangiectasia – acne • Eye – glaucoma – cataracta Indications Physiological doses = substitution therapy adrenocortical insufficiency congenital adrenal hyperplazia Addison disease (hydrocortison, fludrocortison) Pharmacological doses • antiinflammatory and immunosuppressant therapy asthma (inhalations) locally on skin, mucouse affections, allergic conjunctivitis, rhinitis hypersenzitive reactions, anaphylaxis autoimmune and inflammatory diseases (eg. arthritis rheumatica, morbus Crohn, morbus Bechterev = spondylartritis ankylosa) prevention of rejection reaction Indications Pharmacological doses • oncology specific tumors - ALL, Hodgkin disease brain tumors (antiedematous effect - dexametazon) antiemetic effects • others mountain sickness nephrotic syndrome sclerosis multiplex malign exophtalmus subacute thyreoitis Dexamethason suppression test • Cushing. sy. diagnosis • depression diff. dg. • 1 mg of dexamethason in 23 h • In the morning evaluation of cortisol plasma levels - normally under 3 ug/l - in Cushing more than 5 ug/l Potency of glucocorticoids antiflogistic effect retention of natrium cortisol 1 1 cortison 0,8 0,8 prednison 4 0,8 prednisolon 5 0,8 triamcinolon 5-10 0 betamethazon 30 0 dexamethazon 30 0 Overwiev of the most important drugs Drug GC MC Uses (antiinflam) Hydrocortison 1 1 substitution therapy, 8 - 12 h (cortisol) Cortison 0,8 0,8 prodrug Prednisolon 4 0,8 antiinflammatory,immunosuppressant therapy, 12 - 26 h Prednison 4 0,8 prodrug Methylprednisolon 5 minimal antiinflammatory, immunosuppressant therapy, 12 - 26 h Triamcinolon 5 0 more AE, 12 - 26 h Dexamethason 30 minimal antiinflammatory, immunosuppressant therapy, especially when water retention is unwanted Betamethazon 30 minimal - „ Beklomethazon + - Local antiinflammatory, immunosuppressant therapy Budesonid + - - „ - Systemically administered glucocorticoids • 1-5x more potent than cortisol – methylprednisolon, prednisolon – prednison, hydrokortison • 5-15x more potent than cortisol – triamcinolon – paramethason – fluprednisolon • cca 30x more potent than cortisol – betametason – dexamethason short acting intermediate acting long acting (stronger axis supression) Topically administered glucocorticoids – hydrocortison – dexamethason – prednisolon – triamcinolon – flumethason – prednicarbate – bethametason valerate – fluocinolon – betamethason adipate – budesonid – halcinomid – clobetasol Weak Very strong Intensive corticotherapy • megadoses (2 - 4 g of metylprednisolon) polyutraumas, septic or toxic shock 30 mg / kg methylprednisolon in short infusion anaphylactic shock, status asthmaticus, hypoglycemic coma, acute hypercalcemia, brain edema of different etiology, thyreotoxic crisis, snakebite, dangerous stinging of insects, acute spinal cord injuries… more than 500 mg i.v. / 24 h • pulse therapy 1 g methylprednisolon (infusion) 3 - 5x – alternating intervals (during a day, on different days…) Only on hospitalisation • prolonged treatment most of cases using antiinflammatory, antiallergic and immunosupressant effects Intensive corticotherapy CAVE ! Axis suppression - prevention • Application cca in 10 days • Application in mornings 6 - 8 h a.m. • Preparations with lower suppressant effect (non-fluorinated derivates) • Pulse therapy Substitution therapy • hydrocortison – minerals • Individual sufficient dose – basal + situations with incerased demand!! • Usual basal dose 20 – 30 mg • If it is not possible to administer perorally, hospitalisation and im or iv application • In chronic hypotension, adynamia and hypocalemia, add fludrokortizon 0,1 mg/day • First signs of overdose is swelling of legs and hypertension One dose administration • One megadose in polytrauma, inhalation trauma and acidic aspiration • As soon as possible!!! • Short infusion of prednisolon 30 mg/kg (for an adult 3-4 ampules, each 1000 mg) Short term therapy Max 48 h, can be ended abruptly Indications hypocortical crisis anaphylaxis status astmaticus Quincke edema hypoglycemic coma acute hypercalcemia brain edema tyreotoxic crisis biting or stinging by dangerous snakes or insects spinal cord injury etc. Complications – dysrytmia (hypocalemia) hyperglycemia or ketoacidosis hemorrhagic stomach ulcerations latent infections including mycoses fluid retention or cardial insuff., thrombembolia myorelaxation or weakness corticoid psychosis acute pancreatitis bone infarction Short term therapy • Injection preparations • Hydrocortison – natriumretention • Prednison and prednisolon - weak natriumretention • Dexametason, betametason – no natriumretention, best for brain edema, psychotropic effects, the biggest axis suppression • Metylprednisolon has best penetration to alveolobronchial tree • Triamcinolon – smallest effect on BP and psychic, the highest incidence of myopathy Pulse therapy • rejection of transplantates • immunologically conditioned diseases woth no answer to standard therapy (resistant RA, lupus erythemoatodes, myasthenia gravis...) • some hematologic malignities (ultimum refigium) • always on hospitalisation Prolonged treatment • most of medical specialisations • All synthetic corticoids are suitable (not hydrocortison) • Tablets are manufactured in equipotent power • Long-acting more suppress axis • before starting the therapy check: • All infections • Rtg of chest to negate TBC (elderly people, foreigners) • Fasting glycema, ev compensate diabetics • Ophtalmology check (elderly - glaucoma, catarakta, infections) • Preventively substitute vit D, postmenopauzal women can get hormonal substitution, men - androgens, others – bisphosphonates • People with risk of osteoporosis can be send to densitometry • Watch out for gsatriculcers in people with anamnesis • Recommend corticoids with meals • Contraindication of vaccination!!! Prolonged treatment • in course of therapy watch for: • Glycemia • Depression, psychosis • In abdominal distress fibroscopy of stomach and duodenum, amylase • Osteoporosis, fractures • Recommend physical exercise • Lipidogram • Cardial insufficiency, potassium • Hypertension • Prevention of thrombembolic disease • In children somatotropin may be indicated Prolonged treatment • when stopping the therapy avoid: • Adrenal insuff. • Exacerbation of the original condition • Detraction syndrome – can be caused by sudden drop of corticoid levels (eve if you just decrease substitution doses) – musce pain and joint, nausea, anorexia, loss of body weight, hypotension • Syndrome of benign intracranial hypertension • Psychic addiction to corticoid therapy Prolonged treatment Stopping the therapy- rules • what does not suppress the axis yet? – 7,5 mg of prednison • still on therapy check endogenous secretion by taking plasma levels before the morning dose • patients with long-acting corticoids (triamcinolon, dexametason, betametason) should be switched to short-acting (prednison) • Dose of prednison should be decrased by 2,5 to 5 mg each 7 days, when we reach dose of 5 mg, check endogenous production • At this point wait until endogenous production is restored AE prevention • administer the lowest dose possible • whenever possible, administer locally (inh., rect., intraarticular, s.c.) with low absorption • the total dose can be sometimes decreased by coadministration with immunosuppressants • respect circadian rhythm whenever possible (increased risk of exacerbation) • avoid depot preparations • decrease the dose slowly cca 2,5 mg ekv. of prednisolon /3 days Glucocorticoid antagonists metyrapon – inh. hydroxylation on C11 trilostan – inh. 3 beta dehydrogenase aminoglutethimid – inh. aromatase ketokonazol – i-CYP mitotan similar MoA as metyrapon Contraindications • hypertension • cardial insuff. • developed Cushing. sy • peptic ulcers • diabetes • glaucoma • psychoses • bacterial infections • after vaccination with living vaccine