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CORTICOSTEROIDS

1Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior.Glucocorticoids such as cortisol control carbohydrate, fat and protein metabolism and are anti-inflammatory by preventing phospholipid release, decreasing eosinophil action and a number of other mechanisms.

Mineralocorticoids such as aldosterone control electrolyte and water levels, mainly by promoting sodium retention in the kidney. common natural hormonescorticosterone (C21H30O4),

cortisone (C21H28O5, 17-hydroxy-11-dehydrocorticosterone)

aldosteroneBiosynthesis The corticosteroids are synthesized from cholesterol within the adrenal cortex. Most steroidogenic reactions are catalysed by enzymes of the cytochrome P450 family. They are located within the mitochondria and require adrenodoxin as a cofactor Aldosterone and corticosterone share the first part of their biosynthetic pathway. The last part is either mediated by the aldosterone synthase (for aldosterone) or by the 11-hydroxylase (for corticosterone). These enzymes are nearly identical (they share 11-hydroxylation and 18-hydroxylation functions).

Moreover, aldosterone synthase is found within the zona glomerulosa at the outer edge of the adrenal cortex; 11-hydroxylase is found in the zona fasciculata and reticularis.Classes of corticosteroids Corticosteroids are generally grouped into four classes, based on chemical structure. Allergic reactions to one member of a class typically indicate an intolerance of all members of the class. "Coopman classification"

The highlighted steroids are often used in the screening of allergies to topical steroidsGroup A(short to medium acting glucocorticoids) Hydrocortisone, Hydrocortisone acetate, Cortisone acetate, Tixocortol pivalate, Prednisolone, Methylprednisolone, and Prednisone.Group BTriamcinolone acetonide, , Mometasone, Amcinonide, Budesonide, Desonide, Fluocinonide, Fluocinolone acetonide, and Halcinonide.Group CBetamethasone, Betamethasone sodium phosphate, Dexamethasone, Dexamethasone sodium phosphate, and Fluocortolone.Group DHydrocortisone-17-butyrate,Betamethasone valerate, Betamethasone dipropionate, Prednicarbate, , , , , and Fluprednidene acetateGlucocorticoidsKnowledge Objectives

1. Synthesis, regulation and mechanisms of action

2. Physiological effects

3. Pharmacological effects

4. Glucocorticoid drugs

5. Clinical uses

6. Side effects11Adrenal MedullaAdrenal CortexZona GlomerulosaZona FaciculataZona Reticularis

CortexMedullaSites of Steroid Synthesis Adrenal gland12

MineralocorticoidGlucocorticoidSex steroidsSites of corticosteroid Synthesis Cortex of Adrenal gland13Diurnal Variation of Glucocorticoids0-100+100% Change12 Midnight12Noon 12 Midnight8-10 am 2 amNote: Related to sleep-Wake CycleLKS14Hypothalamic-Pituitary-Adrenal (HPA) Axis Feedback

CRH Corticotropin releasing hormone ACTH Adreno-corticotropic hormone

ACTH binds receptors on surface of cells in zona fasciculata of adrenal cortex cAMP second messenger increases production of glucocorticoid from cholesterolCortico-centersAmygdala anterior brain - circadian rhythm Reticular Formation Stressful stimuliGlucocorticoid15The long negative feedback loop is more important than the short loop.

Exogenous glucocorticoid negatively regulates synthesis and secretion of endogenous glucocorticoid

CRHACTHRegulation of synthesis and secretion of adrenal corticosteroidsDaily administration of corticosteroidat physiological concentrations for atleast 2 weeks suppresses the HPA resulting in decreased production of endogenous hormones. Recovery may take up to 9-12 months.ACTH has only a minimal effect on mineralocorticoid production.

ADH, antidiuretic hormone (vasopressin)16

Metyrapone inhibits both glucocorticoid and mineralocorticoid synthesis. Aminoglutethimide and trilostane blocks synthesis of all three types of adrenal steroid.MineralocorticoidBiosynthesis of corticosteroids and adrenal androgensCholesterol17Mechanism of ActionEnters target cells by simple diffusionBinds to cytosolic receptorsThe steroid receptor complex translocates into the nucleusRegulates the synthesis of specific proteins

18Steroid Receptor Activation

S: steroid

CBG: corticosteroid-binding globulin

HSP: heat shock protein

GRE: glucocorticoid response element19Glucocorticoid Receptor (GR)Expressed in a almost every cell (cytosol) in the body and regulates genes controlling the development, metabolism, and immune response. Associated with HSPs (e.g. HSP90)Upon activation by cortisol, GR translocates as a dimer (w/o HSPs) to nucleusCan also activate rapid signaling events in cytosol(non-genomic)20Target Tissues of GlucocorticoidsLiverSkeletal MuscleAdipose Tissue BoneBrainSkinRetinaKidneysHeartLymphoidsSmooth MuscleLungStomachIntestinesFibroblastTestes= Most Important21Physiological Effects Direct receptor - mediated effects

Indirect effects homeostatic responses to other endogenous signalse.g. increase blood glucose increase in insulin22Physiological Effects 1. Metabolic Effects: Catabolic, glucose 2. Antiinflammatory and Immunosuppressive Effects 3. Other Effects 23Metabolic effects

Glucose Influence carbohydrate and fat metabolism to ensure adequate delivery of glucose to the brainIncrease gluconeogenesis, decrease peripheral use of glucose FatIncrease in free fatty acids (increased lipolysis)Redistribution of fat from the extremities to the trunk and face (buffalo hump) ProteinFavors protein breakdown and helps mobilize amino acids to the liver for gluconeogenesis24 Anti-inflammatory and immunosuppressant activity

Increase in circulating levels of neutrophils by interfering with adhesionDecrease in eosinophils, lymphocytes, and monocytesDecrease leukocyte migration, and phagocytic activity Decrease production of phospholipase A2, prostaglandins, thromboxanes and leukotrienes

25Other Effects 1. Electolytes: Decrease absorption of Ca2+ from the intestine and increase renal excretion of Ca2+Increased Na+ and H2O reabsorption, increased K+ excretion.2. Cardiovascular effects: Facilitates the effects of catecholamine, Maintenance of BP3. Respiratory: Facilitates action of catecholamines (relax airway smooth muscle) Fetal lung maturation, increased surfactant secretion4. Muscle: Maintain normal skeletal muscle5. CNS Effects: mood, sleep patterns, and EEG26Pharmacokinetic FeaturesWell absorbed orallyHighly bound to plasma proteins (90%) - CBGMetabolized by liver (P450 3A4 enzymes); excreted by kidney (75%)Plasma half-life shorter than biological half-lifeSubstantial lag time before onset of actionPersistence of effect after disappearance from plasma27Pharmacological Effects (1)Osteoporosis of BoneSkin Thinning and WastingConnective Tissue BreakdownBlood Changes Neutrophils & Thrombocytes & RBCs Lymphocytes & Eosinophils & BasophilsCNS Effects: Mood Stability, Psychoses, ExcitabilityH2O Retention28Pharmacological Effects (2)Suppressed Immune Response--Antiinflammatory ReactionDestruction of EosinophilsStabilization of Lysosomal MembranesInhibition of Arachidonic Metabolism Lipocortin (annexin) production

Phospholipase A2

Prostaglandins & Prostacyclins & Leucotrienes Vasoconstriction and loss of Edema29

A. Transactivation mechanism: up-regulate the expression of anti-inflammatory proteins (lipocortin I).

B. Transrepression mechanism: down-regulate the expression of proinflammatory proteins (NF-B, Fos, IL-1, TNF- )

Molecular mechanism of Anti-inflammatory effectTranscriptional machinery (TM)transcription factors (TF).30Mechanism of Anti-Inflammatory EffectSuppress T-cell activation and cytokine production

Suppress mast cell degranulation

Decrease capillary permeability indirectly by inhibiting mast cells and basophils

Reduce the expression of cyclooxygenase II and prostaglandin synthesis

Reduce prostaglandin, leukotriene and platelet activating factor levels by altering phospholipase A2 activity31Mechanism of Action of Anti-Inflammatory Steroids

32Effects on cytokines and Inflammatory Mediators

of33Glucocorticoid Drugs34Endogenous Glucocorticoids

35Synthetic Glucocorticoids

36Comparison of CorticosteroidsStronger potencyLower doseLonger duration

Differences between glucocorticoid drugs are potency, duration of action of the base, and pharmacokinetic behavior of the salts. Synthetic Drugs37Clinical Uses of Glucocorticoids Replacement Therapy

Anti-Inflammatory

Immuno-suppression

Treatment of Allergic Disorders

38Low adrenal activity

Hypoglycemia, hypotension, weakness, anorexia, irritability

Hyperpigmentation, hyperkalemia, hyponatremia

Glucocorticoid Insufficiency(Addisons Disease)39

Anti-inflammatory and anti-allergic effects

40

Immuno-suppression41Glucocorticoids Uses for diseasesArthritisAllergic reactionsAsthmaAutoimmune diseasesCollagen disease Collagen vascular diseases polymyalgia rheumatica, temporal arteritisNephrotic syndromePrevention of graft rejection (transplant)Dermatological disordersRespiratory distress syndrome42Side EffectsAdrenocortical insufficiency: Suppression of HPA

Adrenocortical excess (Cushings disease): Moon face, buffalo humpDiabetes Mellitus

CNS effects: psychological and behavioral changes; aggravation of pre-existing psychiatric disorders

Impaired wound healing

Musculoskeletal effects: osteoporosis (brittle bones), muscle weakness and atrophy

Cardiovascular effects: fluid retention, edema, hypertension

43Cushings Syndrome

44Hyper-AdrenalismPrimarily the Glucocorticoids

CushingsSyndrome45Side effects

impaired release of GH and decreased activity of insulin-like growth factor-1 (IGF-1) in growing bone46

Side effects47Cold turkey if glucocorticoid therapy of less than 2 weeks duration Taper off if Glucocorticoid therapy of greater than 2 weeks duration. Rate of taper should be proportional to duration of prior therapy. The longer the original therapy, the slower the rate of dose reduction.

Withdrawal syndrome: hypotension, hypoglycemia, myalgia and fatigue, joint pain, muscle stiffness, muscle tenderness, or fever.Withdrawal48