Drug Therapy of Asthma Glucocorticoids & Anti-Inflammatory Agents

DRUG THERAPY OF ASTHMA
Glucocorticoids & Anti-Inflammatory Agents
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LEARNING 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
GLUCOCORTICOIDS
• Reduce inflammation and immune responses

• In clinical practice since 1948
• $10,000,000,000./year market size in US
Steroid Hormones: Derived from Cholesterol
Lipid Soluble: Able
to cross plasma
membrane by
passive diffusion
PHYSIOLOGICAL EFFECTS OF
GLUCOCORTICOIDS
• Regulation of carbohydrate, protein
and lipid metabolism
• Maintenance of fluid and electrolyte
balance
•Preservation of normal function of the
cardiovascular system, the immune
system, the kidney, skeletal muscle, the
endocrine system and the nervous system
•Preservation of organismal homeostasis
GR
GR
Effects of Glucocorticoids on Components
of Inflammatory/Immune Responses
CELL TYPE FACTOR COMMENTS
Macrophages Prostaglandins, Inhibition of COX-2,

Monocytes Leukotrienes Phospholipase A2
IL-1, IL-6. TNFα Inhib. Transcript., Release
Endothelial Cells ICAM-1. ELAM-1 Inhib. Transcript., Release

IL-1, Prostagl., Leuko. As above
Basophils Histamine, Leukotriene Inhib. IgE Release
Lymphocytes IL-1, IL-2, IL-3, etc As above
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 Effects
IMPORTANT CONCEPT 3: The beneficial
effects of systemic glucocorticoids to limit
inflammation is counter-balanced by its
many adverse side effects
NUCLEAR RECEPTOR SUPERFAMILY
Glucocorticoid Receptor Regulation of Transcription
Glucocorticoid Response Unit of the PEPCK Gene
HNF4 HNF3 GR GR COUP +1

CEBP/ß TBP
-445 -410 -380 -325 -90 -27
Accessory DNA-binding Factors

Required!!
(Can impart tissue-specificity)
NOTE: Phosphoenolpyruvate carboxykinase (PEPCK) gene
is glucocorticoid regulated in liver only
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
Basic Mechanisms of Transcriptional Activation/Repression
by the Glucocorticoid Receptor
H H
GR GR +1
GRE Transcriptional Activation
H
GR +1
Transcriptional Repression I
nGRE
(Direct DNA-binding)
H
GR AP1 +1
Transcriptional Repression II
cGRE (Co-occupancy)
H
GR
NFκ B +1
Transcriptional Repression III
(Tethering)
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 Rosenfeld
IMPORTANT CONCEPT 6: The
glucocorticoid receptor regulates gene
transcription (either positively or negatively)
through the gene-selective recruitment of
histone modifying enzymes
Glucocorticoid Analogs
Relative 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
Schematic representation of the disposition of inhaled drugs
Mouth
Deposition
~90% swallowed
Lung Lung
Pulmonary Topical effect
absorption ~2-10%
Liver
First pass
Metabolism
GI Tract
(inactivation)
BLOOD STREAM
Drug systemic effect + inactive metabolite
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)
cytochrome P450 3A4

(Liver)
FP-17ß-carboxylic acid derivative

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
Transactivation from Transrepression Activity
of 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 Asthma
Increased GRß Expression in Airway T cells of
QuickTime™ and a
TIFF (Uncompressed) decompressor
Patients with Glucocorticoid-Insensitive Asthma

are needed to see this picture.
QuickTime™ and a
Bronchoalveolar
lavage (BAL)
cells and
peripheral blood
QuickTime™ and a
mononuclear cells
(PBMC)
From: Hamid QA et al., (1999) Am J Respir Crit Care Med 159, pp. 1600-1604
Effects of Stress on GR mRNA Expression in
Normal Versus Asthmatic Children
GR mRNA
analyzed in
total RNA
samples from
lymphocytes
Acute stress in midst of ongoing chronic stress associated with

reduced GR mRNA expression
2. Efficiency of GR transcriptional regulation related to GR expression
3. Stressful experiences may exacerbate asthma symptoms in children
From: Miller GE & Chen E (2006) Proc Natl Acad Sci USA 103, 5496-5501.
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 Pathway
Leukotriene Synthesis Pathway
Role of Leukotrienes in the Pathogenesis of Asthma
Leukotriene-Modifying Drugs for the
Treatment of Asthma
ZYFLO: 5-Lox Inhibitor

SINGULAIR: Leukotriene-receptor antagonist
Cromolyn 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

cells and sensory neurons
Mechanism of Action of Omalizumab (XOLAIR)
Omalizumab
Novel Therapy: Nasal Delivery of an Anti-
inflammatory 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
• 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
DOMAIN OF CTLA-4 TO AIRWAY CELLS IN
VIVO www.freelivedoctor.com
STRATEGY: USE PROTEIN TRANSDUCTION

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
PTD-linked peptide
Ovalbumin-induced asthma in mice
Goblet cell staining
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

Drug Therapy of Asthma Glucocorticoids & Anti-Inflammatory Agents

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DRUG THERAPY OF ASTHMA

Glucocorticoids & Anti-Inflammatory Agents

• Reduce inflammation and immune responses

CELL TYPE FACTOR COMMENTS

Macrophages Prostaglandins, Inhibition of COX-2,

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

Endothelial Cells ICAM-1. ELAM-1 Inhib. Transcript., Release

Basophils Histamine, Leukotriene Inhib. IgE Release

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

HNF4 HNF3 GR GR COUP +1

-445 -410 -380 -325 -90 -27

Accessory DNA-binding Factors

Compound Anti-Inflammatory Na+ -Retaining Duration

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

fluticasone propionate (FP)

cytochrome P450 3A4

FP-17ß-carboxylic acid derivative

Patients with Glucocorticoid-Insensitive Asthma

Acute stress in midst of ongoing chronic stress associated with

ZYFLO: 5-Lox Inhibitor

•Reduce airway reactivity resulting from exposure to a range

MECHANISM: Inhibit specific chloride channels in mast

Intranasal delivery of the cytoplasmic domain

Je-Min Choi et al. (2006) Nature Medicine Vol.

• The cytoplasmic domain of CTLA-4 is known

STRATEGY: USE PROTEIN TRANSDUCTION

•Initially identified in Drosophila

Ovalbumin-induced asthma in mice

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