glucocorticoids guochang hu, md, phd department of pharmacology university of illinois college of...
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GlucocorticoidsGlucocorticoids
Guochang Hu, MD, PhDDepartment of Pharmacology
University of IllinoisCollege of Medicine
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