Therapeutics Pulmonary Sandoval Flashcard

Important Immunologica Pathway in Asthma

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

Immunology of Acute Inflammation in Asthma

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

Role of IL-4 in Initial Acute Phase of Asthma

  • Stimulates Th2 development from undifferentiated T-cells
  • Inhibitory effects on Th1 pathway
  • Stimulates B cells to switch from producing IgG to producing IgE

Role of IL-13 in Initial Acute Phase of Asthma
Stimulates B cells to switch from producing IgG to producing IgE
Role of IL-5 in Initial Acute Phase of Asthma

  • Produced by Th2 cells and mast cells
  • Stimulates development of eosinophils from bone marrow precursor cells
  • Prolongs the survival eosinophils

IL-13 Signaling

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)

 

Important Prostanoids involved in Bronchoconstriction

  • PGF2α — also enhances histamine action
  • PGD2
  • TXA2

LTB4’s Role in Asthma
Potent bronchoconstrictor
LTC4’s Role in Asthma

  • Can form LTD4
  • Airway edema, bronchospasm, mucus secretion, microvascular permeability

 

LTD4’s Role in Asthma

  • Can form LTE4
  • Airway edema, bronchospasm, mucus secretion, microvascular permeability

LTE4’s Role in Asthma
Airway edema, bronchospasm, mucus secretion, microvascular permeability
Pathway and Effects of Leukotrienes

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

Central Effector Cells in Late Acute Phase of Asthma
Eosinophils
Late Acute Phase

  • Occurs hours after initial provocation
  • Involves recruitment and activation of eosinophils, basophils, neutrophils, and macrophages
  • Leads to airway hyperresponsiveness

Chronic Phase

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

Beta2 Adrenergic Receptor Agonists: MOA

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

Metaproterenol

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

 

Differences between short-acting vs long-acting Beta2 agonists

  • 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

 

Advantages of Topical Beta2 Agonist vs Inhalation

  • Inhalation is preferred route
  • Topical provides more rapid response, greater protection against provocation, and fewer side effects

 

Albuterol

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

Levalbuterol

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

Salmeterol

Partial Beta2 Agonist

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

Formoterol

Long Acting Beta2 Agonist

  • Compared to partial agonists, full agonists have greater side effects
  • Greater protection against bronchoconstrictors than partial agonist

Side Effects of Beta2 Agonists

  • Tremor
  • Tachycardia
  • Increased QTc interval — ventricular arrhythmias and death
  • Hyperglycemia
  • Hypokalemia

Pirbuterol

Short Acting Beta2 Agonist

  • Quick onset/short duration of action

Terbutaline

Short Acting Beta2 Agonist

  • Quick onset/short duration of action

What drugs first choice for relief of asthmatic symptoms?

Inhaled Short acting Beta2 agonist!

 

Albuterol, Pirbuterol, Terbutaline

Chronic administration of short acting Beta2 agonists can lead to:

TOLERANCE

  • Downregulation of Beta2 receptors
  • Decrease affinity for Beta2 agonist
  • Cross-tolerance may occur as well

What can be used to prevent tolerance of Beta2 agonists?
Systemic corticosteroids
Systemic Corticosteroids are indicated for asthma when:
patients are not responding well to short-acting Beta2 agonists or in severe asthmatics whose asthma cannot be controlled well without its use
Actions of Corticosteroids in the Lungs

  • 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

Actions of Pro-Inflammatory Stimuli on Gene Transcription

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

Actions of Low-Dose Corticosteroids on Gene Transcription

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

 

Actions of High-Dose Corticosteroids on Gene Transcription

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

 

 

Adverse Effects of Systemic Corticosteroids

  • 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

Beclomethasone Dipropionate

Inhaled Corticosteroid

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

Fluticasone

Inhaled Corticosteroid

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

Budesonide

Inhaled Corticosteroid

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

Typical Adverse Effects of Inhaled Corticosteroids

  • Thrush
  • Dry Mouth
  • Growth Retardation in Kids

High Doses of Inhaled Corticosteroids May Cause:

  • Osteoporosis
  • Cataracts
  • Adrenal Insufficiency

Theophylline: Possible MOA

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

 

Theophylline: ADRs

At lower concentrations:

  • nausea
  • vomiting
  • insomnia

At high concentrations:

  • seizures
  • cardiac arrhythmias
  • death

 

Theophylline: Drug-Drug Interactions

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

Cromolyn Sodium: MOA

  • 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

Nedocromil Sodium: MOA

  • 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

Zileutin: MOA

5-Lipoxygenase Inhibitor

  • Prevents the formation of leukotrienes
  • Anti-inflammatory properties
  • Does not replace the use of inhaled short-acting Beta2 agonists

Zileutin: ADRs

  • Liver toxicity
  • Headache
  • Irritations of gastric mucosa

Zileutin: CI
Hepatic disease
Zileutin: Drug-Drug Interactions
Inhibits CYP1A2 — important for metabolizing theophylline and caffeine
Montelukast: MOA

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

Zafirlukast: MOA

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

Cysteinyl Leukotriene 1 Receptors: Physiological Actions in the body

In response to Leukotrienes:

  • sustained bronchoconstriction
  • mucus secretion
  • edema in airways

Cysteinyl Leukotriene 2 Receptors: Physiological Actions in the body

In response to Leukotrienes:

  • Contributes to inflammation
  • vascular permeability
  • tissue fibrosis

B Leukotriene 1 Receptors: Physiological Actions in the body

  • High affinity receptor for LTB4
  • Mediates the chemoattraction and proinflammatory actions of LTB4

B Leukotriene 2 Receptors: Physiological Actions in the body

  • Low affinity receptor for LTB4
  • Airway hyperreactivity and inflammation

Zafirlukast: ADR

  • Hepatitis
  • Drug-Drug Interactions

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

 

 

Montelukast: ADR

  • Well tolerated
  • Does not inhibit CYP450 enzymes

Omalizumab: MOA

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

Omalizumab: ADRs and Precautions

  • 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

Erythromycin: MOA

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

Clarithromycin: MOA

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

Azithromycin: MOA

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

COPD vs Asthma: Important Cells Involved

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

COPD vs Asthma: Important Chemical Mediators Involved

COPD

  • LTB4
  • IL-8
  • TNFα

Asthma

  • LTD4
  • IL-4, IL-5
  • TNFα

COPD vs Asthma: Important Cellular and Tissue Consequences

COPD

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

Asthma

  • Fragile epithelium
  • Thickening of basement membrane
  • Mucus metaplasia
  • Glandular enlargement

Inherited Emphysema involves deficiency of:

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

COPD Development

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

Pharmacological Strategies for Treating COPD

  • Antimuscarinics and Muscarinic Receptor Antagonists
  • Alpha1-Antitrypsin Replacement Therapy
  • Beta2 Agonists
  • Corticosteroids (variable effects)
  • Combo therapy

Ipratropium Bromide: MOA

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

Tiotropium Bromide: MOA

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

Antimuscarinics: ADRs

  • Dry mouth
  • Constipation
  • Urinary retention
  • Tachycardia
  • Blurred vision
  • Precipitation of narrow-angle glaucoma have been reported

Roflumilast: MOA

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

Rolipram: MOA

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

CDP840: MOA

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

Cilomilast: MOA

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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