GlucocorticoidsGlucocorticoids

Guochang Hu, MD, PhDDepartment of Pharmacology

University of IllinoisCollege of Medicine

gchu@uic.edu

Knowledge Objectives

1. Synthesis, regulation and mechanisms of action

2. Physiological effects

3. Pharmacological effects

4. Glucocorticoid drugs

5. Clinical uses

6. Side effects

Adrenal MedullaAdrenal Medulla Adrenal CortexAdrenal Cortex

Zona GlomerulosaZona Glomerulosa Zona FaciculataZona Faciculata Zona ReticularisZona ReticularisCortex

Medulla

Sites of Steroid Synthesis – Adrenal gland

Mineralocorticoid

Glucocorticoid

Sex steroids

Sites of corticosteroid Synthesis – Cortex of Adrenal gland

Diurnal Variation of GlucocorticoidsDiurnal Variation of Glucocorticoids

0

-100

+100

% Change

12 Midnight

12Noon

12 Midnight

8-10 am

2 am

Note: Related to sleep-Wake Cycle

LKS

Hypothalamic-Pituitary-Adrenal (HPA) Hypothalamic-Pituitary-Adrenal (HPA) Axis FeedbackAxis Feedback

CRH – CRH – Corticotropin releasing hormone Corticotropin releasing hormone

ACTH – ACTH – Adreno-corticotropic hormone Adreno-corticotropic hormone

ACTH binds receptors on surface ACTH binds receptors on surface of cells in zona fasciculata of of cells in zona fasciculata of adrenal cortex – cAMP second adrenal cortex – cAMP second messenger increases messenger increases production of glucocorticoid from production of glucocorticoid from cholesterolcholesterol

Cortico-centersCortico-centers-Amygdala – anterior brain Amygdala – anterior brain - circadian rhythm- circadian rhythm- Reticular Formation – Reticular Formation – -Stressful stimuliStressful stimuli

Glucocorticoid

The long negative feedback loop is more important than the short loop.

Exogenous glucocorticoid negatively regulates synthesis and secretion of endogenous glucocorticoid

CRH

ACTH

Regulation of synthesis and secretion of adrenal corticosteroids

Daily 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)

Metyrapone inhibits both glucocorticoid and mineralocorticoid synthesis. Aminoglutethimide and trilostane blocks synthesis of all three types of adrenal steroid.

Mineralocorticoid

Biosynthesis of corticosteroids and adrenal androgens

Cholesterol

Mechanism of ActionMechanism of Action

Enters target cells by simple diffusionEnters target cells by simple diffusion Binds to cytosolic receptorsBinds to cytosolic receptors The steroid receptor complex translocates The steroid receptor complex translocates

into the nucleusinto the nucleus Regulates the synthesis of specific Regulates the synthesis of specific

proteinsproteins

Steroid Receptor ActivationSteroid Receptor Activation

S: steroid

CBG: corticosteroid-binding globulin

HSP: heat shock protein

GRE: glucocorticoid response element

Glucocorticoid Receptor (GR)Glucocorticoid Receptor (GR)

Expressed in a Expressed in a almost every cell almost every cell (cytosol) in the (cytosol) in the body and regulates genes controlling the body and regulates genes controlling the development, metabolism, and immune development, metabolism, and immune response. response.

Associated with HSPs (e.g. HSP90)Associated with HSPs (e.g. HSP90)Upon activation by cortisol, GR translocates as a dimer Upon activation by cortisol, GR translocates as a dimer

(w/o HSPs) to nucleus(w/o HSPs) to nucleus

Can also activate rapid signaling events in cytosolCan also activate rapid signaling events in cytosol

(non-genomic)(non-genomic)

Target Tissues of GlucocorticoidsTarget Tissues of Glucocorticoids

LiverLiver Skeletal MuscleSkeletal Muscle Adipose TissueAdipose Tissue BoneBone BrainBrain SkinSkin RetinaRetina KidneysKidneys

HeartHeart LymphoidsLymphoids Smooth MuscleSmooth Muscle LungLung StomachStomach IntestinesIntestines FibroblastFibroblast TestesTestes

= Most Important

Physiological Effects

Direct receptor-mediated effectsDirect receptor-mediated effects

Indirect effects – homeostatic Indirect effects – homeostatic responses to other endogenous responses to other endogenous

signalssignalse.ge.g. . – increase blood glucose– increase blood glucose

– – increase in insulinincrease in insulin

Physiological Effects

1. Metabolic Effects: Catabolic, glucose 1. Metabolic Effects: Catabolic, glucose

2. Antiinflammatory and2. Antiinflammatory and

Immunosuppressive Effects Immunosuppressive Effects

3. Other Effects 3. Other Effects

Metabolic effectsMetabolic effects

Glucose Glucose Influence carbohydrate and fat metabolism to Influence carbohydrate and fat metabolism to

ensure adequate delivery of glucose to the brainensure adequate delivery of glucose to the brain Increase gluconeogenesis, decrease peripheral Increase gluconeogenesis, decrease peripheral

use of glucose use of glucose

FatFat Increase in free fatty acids (increased Increase in free fatty acids (increased lipolysislipolysis)) Redistribution of fat Redistribution of fat from the extremities to the from the extremities to the

trunk and face (buffalo hump)trunk and face (buffalo hump)

ProteinProtein Favors Favors protein breakdown protein breakdown and helps mobilize and helps mobilize

amino acids to the liver for gluconeogenesisamino acids to the liver for gluconeogenesis

Anti-inflammatory and immunosuppressant Anti-inflammatory and immunosuppressant activityactivity

Increase in circulating levels of Increase in circulating levels of neutrophilsneutrophils by by interfering with adhesioninterfering with adhesion

Decrease in Decrease in eosinophils, lymphocytes, and eosinophils, lymphocytes, and monocytesmonocytes

Decrease leukocyte migration, and phagocytic Decrease leukocyte migration, and phagocytic activity activity

Decrease production of phospholipase ADecrease production of phospholipase A2, , prostaglandins, thromboxanes and leukotrienesprostaglandins, thromboxanes and leukotrienes

Other Effects Other 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 EEG

Pharmacokinetic FeaturesPharmacokinetic Features

Well absorbed orallyWell absorbed orally Highly bound to plasma proteins (90%) - CBGHighly bound to plasma proteins (90%) - CBG Metabolized by Metabolized by liverliver (P450 3A4 enzymes); (P450 3A4 enzymes);

excreted by excreted by kidneykidney (75%) (75%) Plasma half-life shorter than biological half-Plasma half-life shorter than biological half-

lifelife Substantial lag time before onset of actionSubstantial lag time before onset of action Persistence of effect after disappearance Persistence of effect after disappearance

from plasmafrom plasma

Pharmacological Effects (1)Pharmacological Effects (1)

Osteoporosis of BoneOsteoporosis of Bone Skin Thinning and WastingSkin Thinning and Wasting Connective Tissue BreakdownConnective Tissue Breakdown Blood ChangesBlood Changes

Neutrophils & Thrombocytes & RBC’sNeutrophils & Thrombocytes & RBC’s Lymphocytes & Eosinophils & BasophilsLymphocytes & Eosinophils & Basophils

CNS Effects: Mood Stability, Psychoses,CNS Effects: Mood Stability, Psychoses, ExcitabilityExcitability

HH22O RetentionO Retention

Pharmacological Effects (2)Pharmacological Effects (2)

Suppressed Immune Response--Suppressed Immune Response--Antiinflammatory ReactionAntiinflammatory Reaction Destruction of EosinophilsDestruction of Eosinophils Stabilization of Lysosomal MembranesStabilization of Lysosomal Membranes Inhibition of Arachidonic MetabolismInhibition of Arachidonic Metabolism

Lipocortin (annexin) productionLipocortin (annexin) production

Phospholipase APhospholipase A22

Prostaglandins & Prostacyclins & Leucotrienes Prostaglandins & Prostacyclins & Leucotrienes Vasoconstriction and loss of EdemaVasoconstriction and loss of Edema

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

B. Transrepression mechanism: down-regulate the expression of

proinflammatory proteins (NF-кB, Fos, IL-1, TNF- α)

Molecular mechanism of Anti-inflammatory effect

Transcriptional machinery (TM) transcription factors (TF).

Mechanism of Anti-Inflammatory EffectMechanism of Anti-Inflammatory Effect

Suppress T-cell activation and cytokine productionSuppress T-cell activation and cytokine production

Suppress mast cell degranulationSuppress mast cell degranulation

Decrease capillary permeability indirectly by Decrease capillary permeability indirectly by inhibiting mast cells and basophilsinhibiting mast cells and basophils

Reduce the expression of cyclooxygenase II and Reduce the expression of cyclooxygenase II and prostaglandin synthesisprostaglandin synthesis

Reduce prostaglandin, leukotriene and platelet Reduce prostaglandin, leukotriene and platelet activating factor levels by altering phospholipase Aactivating factor levels by altering phospholipase A22 activityactivity

Mechanism of Action of Mechanism of Action of Anti-Inflammatory SteroidsAnti-Inflammatory Steroids

Effects on cytokines and Effects on cytokines and Inflammatory MediatorsInflammatory Mediators

of

Glucocorticoid Drugs

Endogenous GlucocorticoidsEndogenous Glucocorticoids

Synthetic GlucocorticoidsSynthetic Glucocorticoids

Comparison of CorticosteroidsComparison of Corticosteroids

1. Stronger potency2. Lower dose3. Longer duration

Differences between glucocorticoid drugs are potency, duration of action of the base, and pharmacokinetic behavior of the salts.

Synthetic Drugs

Clinical Uses of GlucocorticoidsClinical Uses of Glucocorticoids

• Replacement Therapy

• Anti-Inflammatory

• Immuno-suppression

• Treatment of Allergic Disorders

Low adrenal activityLow adrenal activity

Hypoglycemia, hypotension, Hypoglycemia, hypotension, weakness, anorexia, irritabilityweakness, anorexia, irritability

Hyperpigmentation, Hyperpigmentation, hyperkalemia, hyponatremiahyperkalemia, hyponatremia

Glucocorticoid Insufficiency

(Addison’s Disease)

Anti-inflammatory and anti-allergic effectsAnti-inflammatory and anti-allergic effects

Immuno-suppression

Glucocorticoids – Uses for diseasesGlucocorticoids – Uses for diseases

ArthritisArthritis Allergic reactionsAllergic reactions AsthmaAsthma Autoimmune diseasesAutoimmune diseases Collagen diseaseCollagen disease Collagen vascular Collagen vascular

diseases – polymyalgia diseases – polymyalgia rheumatica, temporal rheumatica, temporal arteritisarteritis

Nephrotic syndromeNephrotic syndrome

Prevention of graft Prevention of graft rejection (transplant)rejection (transplant)

Dermatological Dermatological disordersdisorders

Respiratory distress Respiratory distress syndromesyndrome

Side EffectsSide Effects

Adrenocortical insufficiency: Suppression of HPAAdrenocortical insufficiency: Suppression of HPA

Adrenocortical excess (Cushing’s disease): “Moon face”, Adrenocortical excess (Cushing’s disease): “Moon face”, “buffalo hump”“buffalo hump”

Diabetes MellitusDiabetes Mellitus

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

Impaired wound healingImpaired wound healing

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

Cardiovascular effects: fluid retention, edema, hypertensionCardiovascular effects: fluid retention, edema, hypertension

Cushing’s SyndromeCushing’s Syndrome

Hyper-Hyper-AdrenalismAdrenalism

Primarily the Primarily the GlucocorticoidsGlucocorticoids

Side effectsSide effects

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

Side effectsSide effects

1. “Cold turkey” if glucocorticoid therapy of less than 2 weeks duration

2. Taper off if Glucocorticoid therapy of greater than 2 weeks duration.

3. Rate of taper should be proportional to duration of prior therapy.

4. 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.

Withdrawal