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Therapeutics Pulmonary Sandoval
Exam 3 Asthma
75
Chemistry
Graduate
04/15/2010

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Cards

Term
Important Immunologica Pathway in Asthma
Definition

Th2 Pathway

 

Dendritic phagocytosis of allergen

Allergen presented on MHC II

CD4+ cells becomes activated

Th0 cells release IL-4 and become Th2 cells

Th2 cells release IL-4 and IL-13

B-cell transformation into IgE-producing Plasma cells

Term
Immunology of Acute Inflammation in Asthma
Definition

Following the Th2 pathway, B-cells transform into IgE-producing Plasma cells

IgE is released

IgE binds to FcεRI on mast cells (and basophils)

Allergen cross-links IgE and FcεRI

Mast cell is activated

Degranulation occurs

Release of histamine as well as prostaglandins D4, PGF2α, TXA2, and leukotrienes

Bronchoconstriction

Term
Role of IL-4 in Initial Acute Phase of Asthma
Definition
  • Stimulates Th2 development from undifferentiated T-cells
  • Inhibitory effects on Th1 pathway
  • Stimulates B cells to switch from producing IgG to producing IgE
Term
Role of IL-13 in Initial Acute Phase of Asthma
Definition
Stimulates B cells to switch from producing IgG to producing IgE
Term
Role of IL-5 in Initial Acute Phase of Asthma
Definition
  • Produced by Th2 cells and mast cells
  • Stimulates development of eosinophils from bone marrow precursor cells
  • Prolongs the survival eosinophils
Term
IL-13 Signaling
Definition

IL-13 binds to heterodimer receptor, composed of IL4Rα and IL13Rα1

Activation and release of STAT6 from receptor

Dimerization of STAT6

Nuclear transcription

 

Binding of IL13 to its receptor also results in increased expression of Acid Mammalian Chitinase (AMC)

 

Term
Important Prostanoids involved in Bronchoconstriction
Definition
  • PGF2α -- also enhances histamine action
  • PGD2
  • TXA2
Term
LTB4's Role in Asthma
Definition
Potent bronchoconstrictor
Term
LTC4's Role in Asthma
Definition
  • Can form LTD4
  • Airway edema, bronchospasm, mucus secretion, microvascular permeability

 

Term
LTD4's Role in Asthma
Definition
  • Can form LTE4
  • Airway edema, bronchospasm, mucus secretion, microvascular permeability
Term
LTE4's Role in Asthma
Definition
Airway edema, bronchospasm, mucus secretion, microvascular permeability
Term
Pathway and Effects of Leukotrienes
Definition

Mast cell degranulation results in activation of phospholipase A2

PA2 cleaves arachidonoyl group of phospholipids

Arachidonic acid is converted to Leukotriene A4 by 5-lipoxygenase

LTA4 can become LTB4 or LTC4

Generation of LTC4 results in formation of LTD4 or LTE4

Leukotrienes bind to CysLT1 receptor

Airway edema, bronchospasms, mucus secretion, microvascular permeability

Term
Central Effector Cells in Late Acute Phase of Asthma
Definition
Eosinophils
Term
Late Acute Phase
Definition
  • Occurs hours after initial provocation
  • Involves recruitment and activation of eosinophils, basophils, neutrophils, and macrophages
  • Leads to airway hyperresponsiveness
Term
Chronic Phase
Definition

Airway Remodeling

  • Nonspecific hyperresponsiveness and worsening of asthma
  • Epithelial cell damage and fibrosis
  • Inflammatory mediators
  • Muscle thickening
  • Mucus hypersecretion -- goblet cell hyperplasia
  • IL5 appears to have a role in airway remodeling through TGFβ
Term
Beta2 Adrenergic Receptor Agonists: MOA
Definition

1.  Relax bronchial smooth muscle

  • Mediated by increase in cAMP --> MLCK phosphorylated (by PKA) and inactivated --> MLCP activated --> MLC dephosphorylated --> smooth muscle relaxation
  • Increases conductance of large Ca2+ sensitive K+ channels in airway smooth muscle (independent of adenylyl cyclase activity and cAMP production)

2.  Inhibits release of inflammatory mediators and cytokines

  • Not sufficient enough to be used alone as anti-inflammatory therapy
Term
Metaproterenol
Definition

Beta2 Receptor Agonist

  • More selective for Beta2 receptors than isoproterenol
  • Binding to beta receptors results in relaxation of bronchial smooth muscle, which relieves bronchospasm, reduces airway resistance, facilitates mucous drainage, and increases vital capacity
  • Can inhibit degranulation and release of inflammatory autocoids from mast cells
  • Actions on peripheral vascular smooth muscle causes vasodilation and a modest decrease in diastolic blood pressure
  • Weaker Beta2 agonist than other drugs -- not used that much anymore
  • Has Beta1 receptor agonism = increased chronotropy/inotropy

 

Term
Differences between short-acting vs long-acting Beta2 agonists
Definition
  • Short-acting provides immediate relief
  • LABA's have longer duration of action
  • Long acting cannot be administered alone -- combo with corticosteroids -- due to asthma related deaths
  • With LABA's, tolerance might develop to the bronchodilatory effect

 

Term
Advantages of Topical Beta2 Agonist vs Inhalation
Definition
  • Inhalation is preferred route
  • Topical provides more rapid response, greater protection against provocation, and fewer side effects

 

Term
Albuterol
Definition

Short Acting Beta2 Agonist

  • Combination of R and S isomer
  • R is responsible for bronchodilation as well as producing side effects
  • S is responsible for pro-inflammatory and induces bronchial hyperreactivity?
  • S-albuterol is metabolized 12x slower than R-albuterol
Term
Levalbuterol
Definition

Short Acting Beta2 Agonist

  • R isomer of albuterol
  • R is responsible for bronchodilation as well as producing side effects
  • Has not shown any advantage over racemic albuterol
Term
Salmeterol
Definition

Partial Beta2 Agonist

  • Compared to full agonists, partial has fewer side effects
  • Cannot protect against bronchoconstrictors as well as full agonist
Term
Formoterol
Definition

Long Acting Beta2 Agonist

  • Compared to partial agonists, full agonists have greater side effects
  • Greater protection against bronchoconstrictors than partial agonist
Term
Side Effects of Beta2 Agonists
Definition
  • Tremor
  • Tachycardia
  • Increased QTc interval -- ventricular arrhythmias and death
  • Hyperglycemia
  • Hypokalemia
Term
Pirbuterol
Definition

Short Acting Beta2 Agonist

  • Quick onset/short duration of action
Term
Terbutaline
Definition

Short Acting Beta2 Agonist

  • Quick onset/short duration of action
Term
What drugs first choice for relief of asthmatic symptoms?
Definition

Inhaled Short acting Beta2 agonist!

 

Albuterol, Pirbuterol, Terbutaline

Term
Chronic administration of short acting Beta2 agonists can lead to:
Definition

TOLERANCE

  • Downregulation of Beta2 receptors
  • Decrease affinity for Beta2 agonist
  • Cross-tolerance may occur as well
Term
What can be used to prevent tolerance of Beta2 agonists?
Definition
Systemic corticosteroids
Term
Systemic Corticosteroids are indicated for asthma when:
Definition
patients are not responding well to short-acting Beta2 agonists or in severe asthmatics whose asthma cannot be controlled well without its use
Term
Actions of Corticosteroids in the Lungs
Definition
  • Increase the number of Beta2 adrenergic receptors and receptor responsiveness
  • Reduce mucus production and hypersecretion
  • Reduce bronchial airway hyperreactivity
  • Decrease pro-inflammatory cytokine release
  • Prevent and reverse airway remodeling
Term
Actions of Pro-Inflammatory Stimuli on Gene Transcription
Definition

IL-1β, TNFα bind to receptor

Activates IKKβ

IKKβ phosphorylates inhibitory protein IκBα that is normally complexed with NF-κB

NF-κB is activated and dimerizes (p50 and p65)

p50 and p65 dimer mobilizes to nucleus

Activates Histone Acetyltransferase (HAT)

HAT acetylates histone H4

Increased transcription of inflammatory genes

Term
Actions of Low-Dose Corticosteroids on Gene Transcription
Definition

Corticosteroids bind to GR

GR monomer translocates to nucleus

Inhibits Histone Acetyltransferase (HAT) activity

Recruits Histone Deacetylase-2 (HDAC2)

Histone H4 is deacetylated

Repression of inflammatory gene transcription

 

Term
Actions of High-Dose Corticosteroids on Gene Transcription
Definition

Corticosteroids bind to GR

GR dimerizes and translocates to nucleus

GR dimer binds to Glucocorticoid Response Elements (GRE) in the promoter region of steroid-sensitive genes and to coactivators that have intrinsic HAT activity

Acetylation of lysines on histone H4

Transcription of genes encoding anti-inflammatory proteins and Beta2 receptors

 

 

Term
Adverse Effects of Systemic Corticosteroids
Definition
  • Retention of Na+ and fluid
  • Weight gain
  • High blood pressure
  • Facial puffiness
  • Adrenal suppression, hyperadrenocorticism
  • Mood disturbances
  • Psychotic behavior
  • Increased frequency and/or severity of infections
  • Osteoporosis (long-term)
  • Impaired healing
Term
Beclomethasone Dipropionate
Definition

Inhaled Corticosteroid

  • Provides potent topical anti-inflammatory effects with fewer systemic side effects
  • Reduces bronchial airway hyperreactivity
Term
Fluticasone
Definition

Inhaled Corticosteroid

  • Provides potent topical anti-inflammatory effects with fewer systemic side effects
  • Reduces bronchial airway hyperreactivity
Term
Budesonide
Definition

Inhaled Corticosteroid

  • Provides potent topical anti-inflammatory effects with fewer systemic side effects
  • Reduces bronchial airway hyperreactivity
Term
Typical Adverse Effects of Inhaled Corticosteroids
Definition
  • Thrush
  • Dry Mouth
  • Growth Retardation in Kids
Term
High Doses of Inhaled Corticosteroids May Cause:
Definition
  • Osteoporosis
  • Cataracts
  • Adrenal Insufficiency
Term
Theophylline: Possible MOA
Definition

1.  Inhibitor of PDE 3 and 4

  • Allows for build up of cAMP and subsequent bronchodilation

 

2.  Adenosine antagonism

  • Theophylline is structurally similar to adenosine
  • Adenosine can provoke bronchoconstriction in asthmatic patients and antagonize theophylline-induced bronchodilation

3.  Restores HDAC2 Activity

  • Restores senstivity to glucocorticoids
  • Reduces inflammatory gene expression

 

Term
Theophylline: ADRs
Definition

At lower concentrations:

  • nausea
  • vomiting
  • insomnia

At high concentrations:

  • seizures
  • cardiac arrhythmias
  • death

 

Term
Theophylline: Drug-Drug Interactions
Definition

1.  Sympathomimetics

  • Caffeine -- theophylline is a dimethylxanthine
  • Results in excessive sympathetic stimulation
  • Tremors, insomnia, seizures, cardiac arrhythmias

2.  Beta2 Agonist

  • May amplify hypokalemic effects

3.  Theophylline Metabolism Inhibitors

  • Zileutin (CYP1A2 inhibitor)
  • Erythromycin
  • Clarithromycin
  • Beta Blockers

4.  Theophylline Metabolism Inducers

  • Barbiturates
  • Carbamezepine
  • Rifampin
Term
Cromolyn Sodium: MOA
Definition
  • Blocks Cl- and Ca2+ Entry Channels?
  • Inhibits release of inflammatory mediators from mast cells and other inflammatory cells
  • Inhibits IgE production
  • Inhibits neutrophil superoxide generation
  • Inhibits mast cell degranulation
  • Inhibits immediate allergic response to allergen challenge or exercise challenge
Term
Nedocromil Sodium: MOA
Definition
  • Blocks Cl- and Ca2+ Entry Channels?
  • Inhibits release of inflammatory mediators from mast cells and other inflammatory cells
  • Inhibits IgE production
  • Inhibits neutrophil superoxide generation
  • Inhibits mast cell degranulation
  • Inhibits immediate allergic response to allergen challenge or exercise challenge
Term
Zileutin: MOA
Definition

5-Lipoxygenase Inhibitor

  • Prevents the formation of leukotrienes
  • Anti-inflammatory properties
  • Does not replace the use of inhaled short-acting Beta2 agonists
Term
Zileutin: ADRs
Definition
  • Liver toxicity
  • Headache
  • Irritations of gastric mucosa
Term
Zileutin: CI
Definition
Hepatic disease
Term
Zileutin: Drug-Drug Interactions
Definition
Inhibits CYP1A2 -- important for metabolizing theophylline and caffeine
Term
Montelukast: MOA
Definition

Cysteinyl Leukotriene 1 Receptor Antagonist

  • Inhibits pro-inflammatory actions of leukotrienes
  • Decreases edema, mucus secretion, and eosinophil chemotaxis
  • Decreases bronchial hyperresponsiveness
  • Can produce bronchial relaxation -- still need a short acting Beta2 agonist
Term
Zafirlukast: MOA
Definition

Cysteinyl Leukotriene 1 Receptor Antagonist

  • Inhibits pro-inflammatory actions of leukotrienes
  • Decreases edema, mucus secretion, and eosinophil chemotaxis
  • Decreases bronchial hyperresponsiveness
  • Can produce bronchial relaxation -- still need a short acting Beta2 agonist
Term
Cysteinyl Leukotriene 1 Receptors: Physiological Actions in the body
Definition

In response to Leukotrienes:

  • sustained bronchoconstriction
  • mucus secretion
  • edema in airways
Term
Cysteinyl Leukotriene 2 Receptors: Physiological Actions in the body
Definition

In response to Leukotrienes:

  • Contributes to inflammation
  • vascular permeability
  • tissue fibrosis
Term
B Leukotriene 1 Receptors: Physiological Actions in the body
Definition
  • High affinity receptor for LTB4
  • Mediates the chemoattraction and proinflammatory actions of LTB4
Term
B Leukotriene 2 Receptors: Physiological Actions in the body
Definition
  • Low affinity receptor for LTB4
  • Airway hyperreactivity and inflammation
Term
Zafirlukast: ADR
Definition
  • Hepatitis
  • Drug-Drug Interactions

-Can inhibit CYP2C9 (major) and CYP3A4 (minor)

 

 

Term
Montelukast: ADR
Definition
  • Well tolerated
  • Does not inhibit CYP450 enzymes
Term
Omalizumab: MOA
Definition

Monoclonal Antibody Against IgE

  • Prevents crosslinking of IgE on cells associated with allergic response (Mast cells) -- Mast cell degranulation does not occur
  • FcεR1 receptor no longer recognizes IgE -- FcεR1 expression is downregulated
  • Early phase and late phase of allergic response is prevented
Term
Omalizumab: ADRs and Precautions
Definition
  • Generally well tolerated
  • Anaphylaxis may occur in patients allergic to hamsters since the antibody is derived from the chinese hamster
  • May cause rash, GI symptoms, and decreased platelets counts
Term
Erythromycin: MOA
Definition

Macrolide

  • Increases transepithelial resistance through increase tight junction protein expression
  • Increases the phagocytosis of apoptotic epithelial cells and neutrophils by macrophages
  • Reduces cytokine and chemokine expression
  • Modulates mucin gene expression and protein production --> decreased mucus hypersecretion
  • Increases expression of defensins
Term
Clarithromycin: MOA
Definition

Macrolide

  • Increases transepithelial resistance through increase tight junction protein expression
  • Increases the phagocytosis of apoptotic epithelial cells and neutrophils by macrophages
  • Reduces cytokine and chemokine expression
  • Modulates mucin gene expression and protein production --> decreased mucus hypersecretion
  • Increases expression of defensins
Term
Azithromycin: MOA
Definition

Macrolide

  • Increases transepithelial resistance through increase tight junction protein expression
  • Increases the phagocytosis of apoptotic epithelial cells and neutrophils by macrophages
  • Reduces cytokine and chemokine expression
  • Modulates mucin gene expression and protein production --> decreased mucus hypersecretion
  • Increases expression of defensins
Term
COPD vs Asthma: Important Cells Involved
Definition

COPD

  • Neutrophils
  • Large increase in macrophages
  • Increase in CD8+ T lymphocytes

Asthma

  • Eosinophils
  • Small increase in macrophages
  • Increase in CD4+ Th2 lymphocytes
  • Activation of mast cells
Term
COPD vs Asthma: Important Chemical Mediators Involved
Definition

COPD

  • LTB4
  • IL-8
  • TNFα

Asthma

  • LTD4
  • IL-4, IL-5
  • TNFα
Term
COPD vs Asthma: Important Cellular and Tissue Consequences
Definition

COPD

  • Squamous metaplasia of epithelium
  • Parenchymal destruction
  • Mucus metaplasia
  • Glandular enlargement

Asthma

  • Fragile epithelium
  • Thickening of basement membrane
  • Mucus metaplasia
  • Glandular enlargement
Term
Inherited Emphysema involves deficiency of:
Definition

α1-Antitrypsin

  • this protein is produced by hepatic cells and protects the lungs by blocking the effects of elastases released by neutrophils
  • if this protein is not present, these elastases can degrade the alveolar wall elastin
Term
COPD Development
Definition

Noxious particles and/or gas

Reactive oxygen species are generated

Increased expression of IL-8, LTB4, TNFα

Recruitment of neutrophils into alveolar tissue

Increased expression of neutrohil elastase (inactivation of antiproteases through ROS and congenital α1-AT deficiency also result in this)

Tissue damage

Term
Pharmacological Strategies for Treating COPD
Definition
  • Antimuscarinics and Muscarinic Receptor Antagonists
  • Alpha1-Antitrypsin Replacement Therapy
  • Beta2 Agonists
  • Corticosteroids (variable effects)
  • Combo therapy
Term
Ipratropium Bromide: MOA
Definition

Short-Acting Muscarinic Antagonist

  • Quaternary amine -- does not penetrate cell membranes that well -- minimal systemic side effects
  • Blocks all 5 types of muscarinic receptors -- blockade of M3 is primarily how bronchodilation is produced
Term
Tiotropium Bromide: MOA
Definition

Long-Acting Muscarinic Antagonist

  • Quaternary amine -- does not penetrate cell membranes that well -- minimal systemic side effects
  • Blocks all 5 types of muscarinic receptors -- blockade of M3 is primarily how bronchodilation is produced
Term
Antimuscarinics: ADRs
Definition
  • Dry mouth
  • Constipation
  • Urinary retention
  • Tachycardia
  • Blurred vision
  • Precipitation of narrow-angle glaucoma have been reported
Term
Roflumilast: MOA
Definition

PDE4 Inhibitors

  • Increases cAMP -- increased bronchodilation
  • Reduced neutrophils by 36% in COPD patients
  • Improved lung function slightly, but did not reduce exacerbations or improve quality of life
Term
Rolipram: MOA
Definition

PDE4 Inhibitors

  • Increases cAMP -- increased bronchodilation
  • Reduced neutrophils by 36% in COPD patients
  • Improved lung function slightly, but did not reduce exacerbations or improve quality of life
Term
CDP840: MOA
Definition

PDE4 Inhibitors

  • Increases cAMP -- increased bronchodilation
  • Reduced neutrophils by 36% in COPD patients
  • Improved lung function slightly, but did not reduce exacerbations or improve quality of life
Term
Cilomilast: MOA
Definition

PDE4 Inhibitors

  • Increases cAMP -- increased bronchodilation
  • Reduced neutrophils by 36% in COPD patients
  • Improved lung function slightly, but did not reduce exacerbations or improve quality of life
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