2 CORTICOSTEROIDS ILOs By the end of this lecture you will be able to: Revise synthesis, regulations & dysregulations of corticosteroidsClassify available natural vs synthetic glucocorticoides; whether systemic or topical; expanding on their properties & indicationsContrast their different ADRs & methods of prevention or treatmentFocus on therapeutic roles of mineralocorticoids & relevant mechanism of actionHint on drugs antagonizing corticosteroid action
3 Are a class of steroid hormones that are produced in the adrenal cortex CORTICOSTEROIDSGlucocorticoids [GC]Released from Zona Fasciculata as Cortisol , Cortisone & Corticosterone Regulated by ACTH + cytokines (IL-1, IL-6, TNF), neuropeptides & catecholamines (stressors)Control carbohydrate, fat & protein metabolism. They are also anti-inflammatory & immunosuppressantsMineralocorticoids [MC] Released from Zona Glomeruloza as Aldosterone Regulated by angiotensin II, potassium, and ACTH. In addition, dopamine, atrial natriuretic peptide (ANP) and other neuropeptidesControl water & electrolyte homeostasis
4 CIRCADIAN pattern of CORTISOL CRHcorticotropinACTHCORTISOL-REGULATIONGlucocorticoidsCIRCADIAN pattern of CORTISOLsecretion
5 Mineralocorticoids REGULATION FLUID LOSSHow Fluid & Electrolyte changes converge to activate MINERALOCORTICOIDS secretionACTH specifically stimulates GC & has little control over secretion of aldosterone
6 Hyperaldosteronism Hypernatremia Hypervolemia Hypertension Hypokalemia DYSREGULATIONDeficiency in corticosteroids [Addison’s disease]Hyponatremia, hyperkalemia, hypoglycemia, progressive weakness & fatigue, low blood pressure, depression, anorexia & loss of weight, skin hyperpigmentationIf subjected to stresses [Addisonian Crisis ] symptoms fever, confusion sever vomiting, diarrhea, abdominal pain & shockDeficiency of mineralocorticoids, seldom alone Hyponatremia, hyper kalemia, acidosis & wasting + ECF volume, hypotension & shock .Increased production of glucocorticoids Cushing's syndromeIncreased production of mineralocorticoids Conn’s syndromeHyperaldosteronismHypernatremiaHypervolemiaHypertensionHypokalemia
7 PHARMACOLOGY OF EXOGENOUS GLUCOCORTICOIDS Cortisol, Cortisone, Hydrocortisone, Prednisone, Prednisolone, Methylprednisolone, Triamcinolone, Dexamethasone, Betamethasone, Beclomethasone, Fluticasone, Budesonide, Mometasone, …etc.GC binds to GRsIn the cytosolOn cell membraneMECHANISMCytosolic GC R mediates GENOMIC Action slow process needs hrs-daysExpression of proteins Anti-inflammatory EffectsRepression of proteins Pro-inflammatory EffectsBinding & ActivationNuclear translocationDimerization on GREGene TranscriptionmRNA TranslationNew Protein Formatione.g. Lipocortin –ve PLA2-ve COX-2Prevent other transcription factors (AP-1) from binding to their REe.g. No proinflamm. cytokines (IL-2,6..) & chemokines
8 ANTINFLAMMATORY ACTION OF GC Inflammation occurs due to expression of proinflammatory mediators, cytokines & chemokines….etc.Activated GRs prevent AP-1 from binding to RE & expressing pro-inflammatory mediators, cytokines,….etcActivated GRs dimerize & bind to GRE allowing expression of anti-inflammatory mediators; as Lipocortin, cytokines,….etcINFLAMMATIONANTINFLAMMATORY ACTION OF GC
9 2. Membranous GC R mediates NON-GENOMIC Action ProteinCacAMPPKAPKCGCREmRNA2. Membranous GC R mediates NON-GENOMIC Action cross talks with GP coupled receptors alter Ca, cAMP, their downstream kinases (PKA & PKC) rapidly exert anti-inflammatory effects & shut down proinflammatory effects rapid process needs minutes-hrs
10 PHARMACOLOGICAL ACTIONS = PHYSIOLOGICAL ACTION 1. On METABOLISMCHO:glucose utilization.gluconeogenesis hyperglycaemiaFats: fat deposition on shoulders, face and abdomen.Proteins: anabolism & catabolism leading to:Negative nitrogen balance with muscle wasting + uric a. productionOsteoporosis.Retardation of growth in children.Skin atrophy + capillary fragility bruising and stria.
11 Calcium metabolism: urinary excretion & absorption from intestine (antivitamin D action). 2. On INFLAMMATORY & IMMUNE RESPONSEvascular permeability; so edema & redundancy of soft tissues release & synthesis of inflammatory mediators; so -ve PLA2 -ve AA & LTs pathways….antigen antibody reaction mast cell degranulation & transmitter releaseinfiltration & activity of inflammatory cells (eosinophilic, lymphocytic, …etc ) by cytokines & chemokine production Complement formation3. ON HYPOTHALAMIC-PITUITARY-ADRENAL AXISOccurs with high doses & long periods of treatment.Sudden withdrawal of corticosteroidsproduce a state of adrenocortical insufficiency4. OthersEuphoria or psychotic states: may occur (probably due to CNS electrolyte changes).
12 Absorption; Most preparations are effective orally. PHARMACOKINETICSAbsorption; Most preparations are effective orally.Parentral forms are also available.Can get absorbed systemically when given at local sites (e.g. skin, respiratory tract, conjunctival sac, synovial spaces etc.)Distribution; 90% or more of cortisol in plasma is transported by reversible binding to Corticosteroids Binding Globulin (CBG) & to albumin* Corticosteroids compete with each other on CBG;Glucocorticoids bind with high affinityMineralocorticoids bind with low affinity* Only the unbound free form is active & can enter cells by diffusionMetabolism; are metabolized by the liver* Some preparations transform to active form in liver Cortisone Hydrocortisone Prednisone Prednisolonet ½ is variable [ short, intermediate & long acting ]Excretion; as soluble sulphates in the urine.
14 CLASSIFICATION ACCORDING TO t 1/2 & METHOD OF ADMINISTRATION INHALANT DRUGSAdministration FormsBeclomethasone50,100,200 mcg/md inhalerFluticasone25, 50 mcg/md inhalerBudesonide100,200 mcg/md inhalerTOPICAL DRUGSPreparationPotencyBeclomethasone0.025 % creamPotentBetamethasone0.025 & 0.12 % cream, ointmentTriamcinolone actonide0.1 % ointmentFluocinolone actonide0.025% ointmentModerateMometasone0.1 % cream, ointmentFluticasone0.05 % creamHydrocortisone acetate2.5 % ointment0.1 – 1.0% ointmentMildN.B. Mild-moderate topical steroids are applied on the face as creams only
15 Dosage ScheduleTime of administration of GCs specially on prolonged use follows natural circadian rhythm i.e. early morning to minimize hypothalamo-pituitary-adrenal axis impairment. Better if administered on alternate days
16 1. ADRENAL INSUFFECIENCY INDICATIONSHORMONE REPLACEMENT THERAPY1. ADRENAL INSUFFECIENCYACUTE & ChronicAddisonian CrisisAddison’s DiseaseEmergency situationParental Cortisol (hydrocortisone) 100 mg IV / every hrs until patient is stable. Dose gradually reduced reach maintenance dosage in 5 dysFluids and electrolytes should be corrected.Treatment of precipitating factors.Cortisol (20-30 mg/day orally) + (fludrocortisone (0.1 mg orally)Dexamethasone could be given on prolonged useDoses must be increased in stress to prevent development of Addisonian crisisDoses should follow circadian rhythm2. CUSHING’S SYNDROMEIn Diagnoses Dexamethasone suppression testIn Treatment Cortisol; Temporally administred AFTER surgical removal of pituitary / adrenal / corticosteroid secreting tumors
17 I. ANTI-INFLAMMATORY & IMMUNOSUPPRESSANT INDICATIONSI. ANTI-INFLAMMATORY & IMMUNOSUPPRESSANTPrednisoloneDexamethasoneBetamethasoneSevere allergic reactions e.g. serum sickness, angioneurotic edema... etc.Diseases of allergic origin; bronchial asthma, rhinitis, conjunctivitis, eczema & many other atopic & proliferative skin diseasesAutoimmune disorders; rheumatoid arthritis, inflammatory bowel disease systemic lupus erythrematosus, nephrotic syndrome,…Organ transplantation; kidney, cardiac, bone marrow (rejection)Blood dyscrasias; hemolytic anemia, thrombocytopenic purpura, agranulocytosis ... etc.Acute gout (resistant) to other drugs> Anti-inflammatory& Immuno-suppression
18 If water retention is undesirable DexamethasoneBetamethasoneINDICATIONSII. OTHERSRaised intracranial pressureIn neoplastic diseasesWith cytotoxic drugs as in Hodgkin's disease, acute lymphocytic leukaemiaPry or 2ndry neoplasms in the brain & postoperative to brain surgery edemaIn antiemetic regimens prevent / cure emesis of chemotherapySuppress excess ACTH productionIf water retention is undesirableADRsdose &timerelated1. HYPOTHALAMIC PITUITARY ADRNAL AXIS3. Others2. IATROGENIC CUSHING’sSYNDOME
19 SUPPRESSION OF HYPOTHALAMIC PITUITARY ADRNAL AXIS 1. ADRsHOW TO AVOIDWithdrawal of Corticosteroids RegimensIf < than 1 w. & not used in big doses no fear.If big dose you may mg prednisolone at an interval of 2-3 daysIf longer periods & high dose halve dose weekly until 25 mg prednisolone or equivalent is reachedThen by about 1mg every 3-7 days.
20 IATROGENIC CUSHING’s SYNDOME 2. ADRsIATROGENIC CUSHING’s SYNDOMEHOW TO TREATIf possible slow withdraw to allow body to slowly resume its normal balance of ACTH & cortisolIf not possible to stop because of underlying disease treat concurrent symptom separately* Antidiabetic for hyperglycaemia* Bisphosphonates for osteoporosis* H2 blocker or proton pump inhibitors for peptic ulcer
21 Growth retardation short stature ADRsSystemicHyperglycemia , diabetes mellitus > use better fluorinated preparationsGrowth retardation short statureMuscle wasting > use better fluorinated preparationsFat redistribution & abnormal depositionHypertension, Edema, Na retention. HypokalaemiaOsteoporosisAvascular necrosis of head of femurMenstrual irregularitiesPsychiatric disordersLow immunity serious infections, activate T.B hepatitis,Delayed wound healingPeptic ulcer specially if with NSAIDsSkin, acne, striae, hirsutismOcular toxicity glaucoma & cataract
22 Skin infection, atrophy, bruising. Local ToxicitySkin infection, atrophy, bruising.Eye viral infection, cataract, glaucoma.Inhalation fungal infection, hoarsenessIntrarticular infection, necrosis3. ADRsCONTRAINDICATIONSDiabetes mellitus.Hypertension or heart failureHistory of mental disorders or Epilepsy.OsteoporosisPeptic ulcerPresence of infection or Tuberculosis requires chemotherapy before administrationPrecautionsPatients receiving GCs and is subjected to stress double the doseIn children receiving take care of live attenuated vaccinesIn pregnant women; better avoid fluorinated GCs teratogenicityNeo-born to mothers taking high dose GCs -ve HPA axis
23 PHARMACOLOGY OF MINERALOCORTICOIDS Aldosterone, Deoxycorticosterone, FludrocortisoneeMECHANISMBinds GC > MCBind to mineralocorticoid receptors [MC R] in MC responsive cells i.e. distal nephronGC is destroyed, enzymatically in MC responsive cells so MC will bind to its receptor alone without any competition from GC.Cytosolic MC R mediates GENOMIC Action Expression of proteinsNa pumps Na retentionNa channels Na reuptake from lumenK simporters excretion of K & HIn distal & collecting tubulesN.B. Actions also on (colon, sweat & salivary glands)2. Membranous GC R mediates NON-GENOMIC ActionInteract with GP coupled receptors & channels to mediate rapid adaptive changes to fluid depletion
24 EFFECTS / USES/ PREPARATIONS MINERALOCORTICOIDSEFFECTS / USES/ PREPARATIONSNet effect is to conserve body sodium osmotic effect water follows expansion of extracellular fluidrenal excretion of potassium & intracellular potassiumIn excess hypertension, atherosclerosis , fibrosis vascular & cardiac remodeling cerebral hemorrhage / stroke & or cardiomyopathySYSTEMIC DrugsAnti-inflam.Na retentionPreparations & dosesAldosterone0.33000Natural / Not used clinicalDeoxycortone sterone[DOCA]1002.5 mg sublinual, ineffective orally ? Inactive in liverFludrocortisone10150100mcg oral tablets / duration of 36-72hrs / Drug of Choice in Replacement Therapy
25 PHARMACOLOGY OF CORTICOSTEROID ANTAGONIST Medications that inhibit adrenal steroid synthesis to GC-ve 11 b-hydroxylaseCorticosteroid production its peripheral metabolism & plasma & urine levelsUsed in Cushing syndrome; whether iatrogenic, or to alleviate severe symptoms till removal by surgerySafe in pregnancyMITOTANEMedications that compete with steroids on receptors to block MC actionsSPIRONOLACTONEIs a competitive aldosterone antagonist Is a K+ sparing diuretic (weak, slow onset & prolonged effect)Used in hypertension (alternation with others), in heart failureIn Hyperaldosteronism (Conn’s)