Usage of glucocorticoids in bronchial asthma

DRUG THERAPY OF ASTHMADRUG THERAPY OF ASTHMA

Glucocorticoids & Anti-Inflammatory AgentsGlucocorticoids & Anti-Inflammatory Agents

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LEARNING OBJECTIVESLEARNING OBJECTIVES

To understand the mechanism of action of the anti-inflammatory agents used in treating asthma.

To understand the basic physiology of glucocorticoids and the mechanism of action of the glucocorticoid receptor.

To understand the basis for the anti-inflammatory actions of glucocorticoids

To understand the basic mechanisms and pharmacology of glucocorticoid therapy for asthma



IMPORTANT CONCEPT 1: Asthma is an inflammatory disease and thus effective treatments for the chronic management of asthma should be directed to reduce the inflammatory response


• Reduce inflammation and immune responsesReduce inflammation and immune responses

• In clinical practice since 1948In clinical practice since 1948

• $10,000,000,000./year market size in US$10,000,000,000./year market size in US

GLUCOCORTICOIDSGLUCOCORTICOIDS


Steroid Hormones: Derived from CholesterolSteroid Hormones: Derived from CholesterolLipid Soluble: Able Lipid Soluble: Able to cross plasma to cross plasma membrane by membrane by passive diffusionpassive diffusion


PHYSIOLOGICAL EFFECTS OF GLUCOCORTICOIDS

Regulation of carbohydrate, protein and lipid metabolism Maintenance of fluid and electrolyte balancePreservation of normal function of the cardiovascular system, the immune system, the kidney, skeletal muscle, the endocrine system and the nervous systemPreservation of organismal homeostasis


GRGR

GRGR


CELL TYPE FACTOR COMMENTS

Macrophages Prostaglandins, Inhibition of COX-2,Monocytes Leukotrienes Phospholipase A2

IL-1, IL-6. TNF Inhib. Transcript., Release

Endothelial Cells ICAM-1. ELAM-1 Inhib. Transcript., ReleaseIL-1, Prostagl., Leuko. As above

Basophils Histamine, Leukotriene Inhib. IgE Release

Lymphocytes IL-1, IL-2, IL-3, etc As above

Effects of Glucocorticoids on Components of Inflammatory/Immune Responses


IMPORTANT CONCEPT 2: The anti-inflammatory and immunosuppressive actions of glucocorticoids play an important role in preventing potential damaging effects of an unopposed inflammatory response and can be exploited therapeutically


Glucocorticoids: Side EffectsGlucocorticoids: Side Effects


IMPORTANT CONCEPT 3: The beneficial effects of systemic glucocorticoids to limit inflammation is counter-balanced by its many adverse side effects


NUCLEAR RECEPTOR SUPERFAMILYNUCLEAR RECEPTOR SUPERFAMILY



Glucocorticoid Receptor Regulation of TranscriptionGlucocorticoid Receptor Regulation of Transcription


Glucocorticoid Response Unit of the PEPCK GeneGlucocorticoid Response Unit of the PEPCK Gene

CEBP/ß TBP

-27-90-325

COUPGR GR

-380

HNF3HNF4

-410-445

+1

Accessory DNA-binding Factors Accessory DNA-binding Factors Required!!Required!!

((Can impart tissue-specificity)Can impart tissue-specificity)

NOTE: Phosphoenolpyruvate carboxykinase (PEPCK) gene NOTE: Phosphoenolpyruvate carboxykinase (PEPCK) gene is glucocorticoid regulated in liver onlyis glucocorticoid regulated in liver onlywww.freelivedoctor.comwww.freelivedoctor.com

IMPORTANT CONCEPT 4: Tissue- and cell type-specific effects of glucocorticoids are likely to be driven by many factors that influence the gene regulatory activity of the glucocorticoid receptor


GRGR +1GRGR

GREGRE Transcriptional ActivationTranscriptional Activation

Transcriptional Repression ITranscriptional Repression I((Direct DNA-bindingDirect DNA-binding))

HH HH

+1

nGREnGRE

GRGRHH

+1

cGREcGRE

GRGRHH

Transcriptional Repression IITranscriptional Repression II((Co-occupancyCo-occupancy))

+1

GRGRHH

NFNFBB

Transcriptional Repression IIITranscriptional Repression III((TetheringTethering))

AP1AP1

Basic Mechanisms of Transcriptional Activation/RepressionBasic Mechanisms of Transcriptional Activation/Repressionby the Glucocorticoid Receptorby the Glucocorticoid Receptor


Glucocorticoid Side Effects: Molecular Mechanisms


IMPORTANT CONCEPT 5: The broad anti-inflammatory actions of glucocorticoids are due primarily to transcriptional repression of many pro-inflammatory genes in multiple cell types by the glucocorticoid receptor.


From Glass and RosenfeldFrom Glass and Rosenfeldwww.freelivedoctor.comwww.freelivedoctor.com



IMPORTANT CONCEPT 6: The glucocorticoid receptor regulates gene transcription (either positively or negatively) through the gene-selective recruitment of histone modifying enzymes


Glucocorticoid AnalogsGlucocorticoid Analogs


Relative Potencies of GlucocorticoidsRelative Potencies of Glucocorticoids

Compound Anti-Inflammatory Na+ -Retaining Duration

Potency Potency of Action

Cortisol 1 1 S

Cortisone 0.8 0.8 S

Prednisolone 4 0.8 I

Triamcinolone 5 0 I

Betamethasone 25 0 L

Dexamethasone 25 0 L

S, short (i.e., 8–12 hour biological half-life); I, intermediate (i.e., 12–36 hour biological half-life); L, long (i.e., 36–72 hour biological half-life)


IMPORTANT CONCEPT 7: Structural modifications of the natural glucocorticoid cortisol generate hormones with enhanced half-life and more potent and efficacious glucocorticoid activity


LungTopical effect~2-10%

LiverFirst passMetabolism(inactivation)

GI Tract

MouthDeposition~90% swallowed

LungPulmonary absorption

BLOOD STREAMDrug systemic effect + inactive metabolite

Schematic representation of the disposition of inhaled drugsSchematic representation of the disposition of inhaled drugs


IMPORTANT CONCEPT 8: The aerosol delivery of glucocorticoids to the lungs limits systemic exposure to the hormone and greatly reduces side effects


New Approaches for Glucocorticoid Treatment of Asthma

• Fluticasone propionate (FLONASE)


New Approaches for Glucocorticoid Treatment of Asthma

fluticasone propionate (FP)

FP-17ß-carboxylic acid derivative

cytochrome P450 3A4(Liver)

1/2000 affinity for GR than FP!!


IMPORTANT CONCEPT 9: New generation synthetic glucocorticoids with more rapid metabolism in the liver overcome potential side effects due to ingested hormone upon aerosol delivery


Dissociated Glucocorticoids: Dissociating Dissociated Glucocorticoids: Dissociating Transactivation from Transrepression Activity Transactivation from Transrepression Activity of the Glucocorticoid Receptorof the Glucocorticoid Receptor


IMPORTANT CONCEPT 10: New generation synthetic glucocorticoids that maintain gene repression but limit gene activation by the glucocorticoid receptor (i.e. dissociated glucocorticoids) may hold promise as anti-inflammatory drugs with reduced side effects


Mechanisms of Glucocorticoid Resistance in AsthmaMechanisms of Glucocorticoid Resistance in Asthma


Increased GRß Expression in Airway T cells of Increased GRß Expression in Airway T cells of Patients with Glucocorticoid-Insensitive AsthmaPatients with Glucocorticoid-Insensitive Asthma

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From: Hamid QA et al., (1999) Am J Respir Crit Care Med 159, pp. 1600-1604

Bronchoalveolar lavage (BAL) cells and peripheral blood mononuclear cells (PBMC)


Effects of Stress on GR mRNA Expression in Effects of Stress on GR mRNA Expression in Normal Versus Asthmatic ChildrenNormal Versus Asthmatic Children



GR mRNA analyzed in total RNA samples from lymphocytes

Acute stress in midst of ongoing chronic stress associated with Acute stress in midst of ongoing chronic stress associated with reduced GR mRNA expressionreduced GR mRNA expression

1. Efficiency of GR transcriptional regulation related to GR expression2. Stressful experiences may exacerbate asthma symptoms in children

From: Miller GE & Chen E (2006) Proc Natl Acad Sci USA 103, 5496-5501.www.freelivedoctor.comwww.freelivedoctor.com

IMPORTANT CONCEPT 11: Disruptions in GR expression and signal transduction can contribute to corticosteroid-resistant asthma and underlie the worsening effects of stressful events on asthma symptoms.



Leukotriene Synthesis PathwayLeukotriene Synthesis Pathway


Leukotriene Synthesis PathwayLeukotriene Synthesis Pathway


Role of Leukotrienes in the Pathogenesis of AsthmaRole of Leukotrienes in the Pathogenesis of Asthma


Leukotriene-Modifying Drugs for the Leukotriene-Modifying Drugs for the Treatment of AsthmaTreatment of Asthma

ZYFLO: 5-Lox Inhibitor

SINGULAIR: Leukotriene-receptor antagonist


Cromolyn SodiumCromolyn Sodium

EFFECTS:• Prevent both early and late asthmatic responses to inhaled allergens such as pollen

•Reduce airway reactivity resulting from exposure to a range of inhaled irritants such as sulfur dioxide and cold air

MECHANISM: Inhibit specific chloride channels in mast MECHANISM: Inhibit specific chloride channels in mast cells and sensory neuronscells and sensory neurons


Mechanism of Action of Omalizumab (XOLAIR)Mechanism of Action of Omalizumab (XOLAIR)

Omalizumab


Novel Therapy: Nasal Delivery of an Anti-Novel Therapy: Nasal Delivery of an Anti-inflammatory Peptideinflammatory Peptide

Omalizumab

Intranasal delivery of the cytoplasmic domain of CTLA-4 using a novel protein transduction domain prevents allergic inflammation

Je-Min Choi et al. (2006) Nature Medicine Vol. 12, pp 574-579



Omalizumab

• CTLA-4 is an activation-induced surface molecule on T cells and is essential for the negative regulation of T-cell activation

• The cytoplasmic domain of CTLA-4 is known to interact with the phosphatases SHP-1 or SHP-2, resulting in dephosphorylation of CD3-TCR chains, ERK and JNK, thereby inhibiting T-cell activation

STRATEGY: DELIVER CYTOPLASMIC STRATEGY: DELIVER CYTOPLASMIC DOMAIN OF CTLA-4 TO AIRWAY CELLS IN DOMAIN OF CTLA-4 TO AIRWAY CELLS IN VIVOVIVO www.freelivedoctor.comwww.freelivedoctor.com


Omalizumab

STRATEGY: USE PROTEIN TRANSDUCTION STRATEGY: USE PROTEIN TRANSDUCTION DOMAIN!!DOMAIN!!

•Initially identified in Drosophila Antenaepedia protein and HIV Tat protein (1994)•Rich in basic residues•Efficiently enter cells even when linked to heterologous proteins, even when injected systemically



Omalizumab

Goblet cell staining

Ovalbumin-induced asthma in miceOvalbumin-induced asthma in mice

PTD-linked peptidePTD-linked peptide


IMPORTANT CONCEPT 12: Anti-inflammatory drugs that act on selective targets may be effective for the treatment of asthma and are likely to have fewer side effects than glucocorticoids


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Usage of glucocorticoids in bronchial asthma