L58 – Drugs Used in the Treatment of Airway Diseases Flashcards by Max Kam

What test distinguishes Asthma from COPD?

Spirometry test: pre- and post- bronchodilator

Airflow limitation in asthma is completely reversible by
bronchodilator

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Compare the inflammatory cells in airway between Asthma and COPD?

Asthma =

CD4+ T-lymphocytes
Eosinophils

COPD =

CD8+ T-lymphocytes
Macrophages
Neutrophils

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Compare the inflammatory consequences in airway between Asthma and COPD?

Asthma = Airway remodeling

COPD = Parenchymal destruction
Loss of alveolar wall and capillaries

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Compare the thickness of basal membrane in airway between asthma and COPD?

Asthma = Thickened reticular basal membrane

COPD = normal BM

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Compare the change in airway epithelia in airway between asthma and COPD?

Asthma = Epithelial loss

COPD = Epithelial metaplasia

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What is atopy?

genetic tendency to develop allergic diseases

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What are some risk factors that that are unique to Asthma but not COPD?

Parasitic infections
Obesity
Gender
Genetic predisposition

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What are the inflammatory cells involved in Asthma- COPD overlap syndrome? (ACOS)

Neutrophil
+
eosinophil

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What can be used to present a bronchial challenge to trigger asthma?

Whole allergen extract (e.g. methacholine)

Used as non-specific bronchoconstrictor stimuli

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After an allergen provocation test, what are the differences between an early response and late response?

Drop in FEV1:

Early response: due to rapid bronchoconstriction

Late response: due to inflammation and hyperreactivity

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What is used as a control in an allergen provocation test?

Negative control = normal saline

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What changes in FEV1 after bronchodilator distinguish asthma from COPD?

Post-bronchodilator FEV1/FVC <70% confirms airflow limitation:

1) Positive response = Increase FEV1 from baseline of >200mL and >=15% of prebronchodilator value = asthma
2) Not fully reversible = COPD

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What assessments are included in the Combined assessment of COPD ?

Assessment of :
Symptoms 
Exacerbation history 
Lung function test
Airflow limitation

> > give 4 groups: A,B,C,D

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Which group in the combined assessment of COPD is the most severe?

Group B

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What are the 2 therapy goals of asthma treatment?

Induce bronchodilation (relieves bronchoconstriction)

2. Decrease inflammatory response (targets chronic airway inflammation)

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4 classes of drugs for treatment of asthma? BLAC

1) bronchodilators
2) Leukotirene pathway modifiers
3) Anti-inflammatory drugs
4) Cytokine targeted asthma therapies (monoclonal antibodies)

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What is the first line drug in asthma therapy and what are the 2 kinds?

B2-agonists

Short acting and Long acting (LABA)

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Name some short and long term B2 agonists?

Short-acting agents: e.g. Salbutamol (Albuterol), Terbutaline

Long-acting agents (LABA): e.g. Salmeterol, Formoterol

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What is the second line of drug in asthma therapy? Give 2 examples

Methylxanthines

e.g. theophylline, aminophylline

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Apart from B2 agonists and Methylxanthines, what is the 3rd bronchodilator drug for asthma?

Muscarinic receptor antagonists (anticholinergics)

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When are Muscarinic receptor antagonists (anticholinergics used?

Not for 1st/2nd line for asthma, but useful for COPD

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What are the 2 types of Muscarinic receptor antagonists? Give 1 example of each?

a) Short-acting agent: e.g. ipratropium (Atrovent®)

b) Long-acting agent (LAMA) e.g. tiotropium bromide

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Why is Methyxanthines used as second line and not first line asthma drug?

Drug action takes longer time than B2 agonist

Oral admin

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What are some pharmacological effects of B2 agonists in asthma patients?
(think cilia, smooth muscle, vascular)

1) relax smooth muscle = relief bronchoconstriction
2) Decrease vascular permeability and oedema
3) Increase ciliary beat frequency > Increase mucus clearance
4) Marked protection against non-specific bronchoconstrictor stimuli

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Compare the duration of action between short acting and long acting B2 agonists in asthma drugs?

Short acting = 4-6 hours Long = > 12 hours

Compare the administration of B2 agonist in acute vs chronic asthma attacks?

``` Acute = IV Chronic = inhalation ```

Name some benefits of long term B2 agonists asthma drug?

 Improved lung function  Less symptoms  Less nocturnal asthma  Improved quality of life

What are some common adverse effects of B2 agonist in treating asthma?

Tremor Tachycardia Hypokalemia

What are some Long term adverse effects of B2 Agonist usage in asthmatic patients?

Desensitization (tachyphylaxis): Due to decoupling of G protein to B2AR surface receptor > low receptor responsiveness Down-regulation: Low receptor number due o internalization and degradation

What drug is used with long term B2 agonists to combat long term desensitization and down-regulation?

Glucocorticoids

How does Methylxanthines relieve asthma? (think PDE- Phosphodiesterase- and adenosine)

1. PDE inhibitors (less degradation) > increase intracellular cAMP > smooth muscle relaxation * PDE usually degrades cAMP to AMP* 2. Block adenosine receptors: a) On airway smooth muscle to decrease contraction b) On mast cells to decrease histamine release

What are some adverse effects of Methylxanthines?

Nervousness chronotropic and inotropic Diuresis Nausea and vomiting

Why are side effects of Methyxanthines common?

narrow therapeutic range >> | difficult to adjust dose

What is the action of Muscarinic receptor antagonists to relive asthma?

Bind to all parasympathetic muscarinic (M1, M3)receptors >> decrease vagal cholinergic tone 1) decrease mucus secretion 2) Decrease airway SM contraction

Side effects of Muscarinic receptor antagonists?

Inhalation: few adverse effects

What are the specific targets of the 2 types of muscarinic receptor antagonists?

Short acting: ipratropium (Atrovent®) targets parasympathetic nerves Long- acting (LAMA): tiotropium bromide targets M1 and M3 receptors

What chemicals can counteract the effects of Muscarinic receptor antagonist and Methylxanthines?

Muscarinic - countered by Ach (Ach- mediated bronchospasm) Methylxanthines - countered by Adenosine (methyxanthine is an adenosine receptor blocker)

What is the role of Leukotrienes in body normally?

Potent bronchoconstrictor

What are the 2 classes of Leukotriene pathway modifiers?

Cysteinyl leukotriene (LT) receptor antagonists 5-lipoxygenase inhibitor

Name some Leukotriene pathway modifiers?

``` Cysteinyl leukotriene (LT) receptor antagonists (e.g. Montelukast (Singulair), Zafirlukast ``` 5-lipoxygenase inhibitor (e.g. Zileuton)

What is the action of Cysteinyl leukotriene receptor antagonists?

Bind to LTC4 and LTD4 receptors >> inhibit LTC4 | and LTD4-mediated bronchospasm

What is the action of 5-lipoxygenase inhibitor ?

arachidonic acid (AA) turns to cyclooxygenase pathway instead > make lipid inflammatory mediators >> inhibit production of Leukotrienes from arachidonic acid

Route of admin for leukotriene pathway modifiers? Is it first line?

Oral | Use as an add on therapy, not first line

What are the ways that Glucocorticoids can suppress inflammation?

 Decrease synthesis and release of inflammatory mediators  Decrease infiltration and activity of inflammatory cells  Decrease oedema Decrease airway mucus production

How does glucocorticoid counteract the downregulation effect of Long term B2 agonists?

Increase the number of bronchial B2-receptors and their responsiveness to B2-agonists (prevent down-regulation)

Explain the action of glucocorticoids on modifying gene expression of a cell? (remember it has to enter a cell)

Glucocorticoids enter cell > Bind to cytoplasmic glucocorticoid receptors (GR) > enter nucleolus > bind to glucocorticoid response element (GRE) > regulate gene expression

Name some inhaled glucocorticoids for chronic asthma?

 Budesonide  Fluticasone  Mometasone

Name some oral/ systemic IV glucocorticoids for severe acute attacks / exacerbation

 Prednisolone |  Prednisone

Which route of administration of glucocorticoids can cause many adverse effect? Name some?

Oral steroids ``` Osteroporosis Cataracts Glucose intolerance Depressed immunity Cushingoid changes ```

Name one anti-allergic drug, its route of admin, when it is used and adverse effects?

Mast cell stabilisers e.g. cromolyn sodium - Inhalation - Prophylatic treatment Adverse effects: dry mouth, irritating cough

What is the action of cromolyn sodium?

 Inhibit mast cell degranulation (e.g. histamine) and activation  Depress the exaggerated neuronal reflexes triggered by irritant receptors in airways

Anti-IgE antibodies are used for which patients?

Prophylactic treatment for patients with severe uncontrolled asthma only (e.g. no response to steroids) or very high IgE in circulation

Name an Anti-IgE antibody drug for asthma treatment?

e.g. Omalizumab (Xolair)

What is the action of Anti-IgE antibodies?

Decrease circulating levels of IgE >> reduce IgE receptors (FceRI) expression on mast cells, basophils and dendritic cells >> Prevent release of inflammatory mediators

Route of administration of Anti-IgE antibodies?

Subcutaneous injection every 2-4 weeks

Side effects of Anti-IgE antibodies to treat asthma?

Anaphylaxis

What cytokine targeted therapies are there for asthma patients except for Anti-IgE antibodies?

IL-4 therapies | IL-5 specific Abs

monoclonal antibodies made against which interleukin has failed?

Anti-IL-13-mAb has failed

Name some Anti-IL-5 Abs?

Mepolizumab Reslizumab Benralizumab

Name a Anti-IL-4 mAb

Dupilumab fully human mAb against IL-4

Which of the drugs for treating asthma are RELIEVERS?

- Short acting B2 agonists - Muscarinic receptor antagonists (anticholinergics) - Methylxanthines

What drugs stop antigen on IgE and mast cells from inflammatory mediator release?

Cromolyn sodium (Anti-allergic drugs, Mast cell stabilizers) Glucocorticoids - Decrease synthesis and release of inflammatory mediators

What drugs block the action of inflammatory mediators from inflicting late response in asthma

Glucocorticoids

What drugs stop Inflammatory mediators from inflicting early response bronchoconstriction in asthma?

B2 agonist > SM relax Methyxanthines > block adenosine receptor > SM relax Antichollinergics > decrease vagal cholinergic tone > SM relax Leukotrienes antagonists > stop LTC4 and LTD4 mediated bronchospasm

Asthma ' controllers' are taken how frequently?

Daily on a long term basis

What are some goals of treating COPD?

 Relieve symptoms  Prevent disease progression (difficult to achieve)  Prevent and treat exacerbations, complications  Reduce mortality

What are the classes of drugs used to treat COPD?

Bronchodilators Anti-inflammatory drugs + many combo therapies

What are the combo therapies used to treat COPD?

1) B2 agonist/antichollinergics: SABA + SAMuscarinicA LABA + LAMA 2) Glucocorticoids/ B2 agonists (ICS + LABA) 3) Glucorticoids + B2 agonist + Antichollinergics (ICS + LABA + LAMA)

Combo therapies for COPD are all given in what form?

DPI | Dry powder inhaler

Are glucocorticoids usedful against all COPD patients?

What are some anti-inflammatory drugs used for COPD?

- Glucocorticoids | - Selective PDE4 inhibitors = Methylxanthines

What are the bronchodilators used for COPD?

B2 agonist | Anticholinergics

Name one B2 agonist that is used only for COPD?

Indacaterol

How is smoking associated with HDAC2 and inflammation? (think macrophage)

Normally, HDAC2 regulates cytokines (TNF-a, IL-8) released by alveolar macrophage by histone acetylation COPD patient: smoke contains Peroxynitrite > inhibits HDAC2 > cannot regulate cytokines made by macrophage > drastic inflammation

L58 – Drugs Used in the Treatment of Airway Diseases Flashcards

(74 cards)