Drugs for Asthma and COPD

Pathophysiology of Asthma

Characterized by chronic airway inflammation and acute episodes of hypersensitivity to certain triggers (allergic reaction)

Normal Airway

Relaxed smooth muscle

Asthmatic Airway

Wall inflamed and thickened

Asthmatic airway during attack

Air trapped in alveoli

Tightened smooth muscles

Common Allergens in Allergic Reactions

Poison plants, animal scratches, pollen, latex, bee sting, medications, nuts and shellfish, dust, mold and mildew, and animal dander

Antihistamine Drugs

Treat allergic rhinitis (hay fever), allergic conjunctivitis, hives, eczema, erythema

Angioedema

Soft tissue allergic reaction

Immediate Allergic Reaction

Type I hypersensitivity to an antigen

Involves IgE antibodies against the soluble antigen (allergen)

Type II Hypersensitivity

AKA Cytotoxic reactions

Engages IgG and IgM antibodies

Type III Hypersensitivity

AKA immune complex reactions

Involves IgG, IgM, and sometimes IgA antibodies

Type IV hypersensitivity

AKA delayed type and involves T-cell-mediated reactions

5 Steps of Type I Hypersensitivity

1. Initial contact with allergen

2. Released IgE antibodies

3. IgE binds to receptor on mast cell

4. Subsequent contact with allergen releases granule

5. Histamine and other inflammatory mediators cause allergic reaction

Mast cells

hematopoietic defense cells located in connective tissue at the boundaries between tissues and the external environment, for example, at mucosal surfaces of the gut and lungs, in the skin and around blood vessels.

Asthma - Type I Hypersensitivity Reaction

Bronchoconstriction and inflammation are due to the release of leukotrienes from IgE sensitized mast cells

Leukotriene modifiers are used for Asthma only

LTC4 & LTD4

Cause immediate bronchoconstriction

LTB4

Attracts inflammatory cells to airways and cause chronic inflammation

Asthma exacerbations

AKA asthma attacks

induced by triggers cause shortness of breath, cough, chest tightness and rapid respiration, mainly due to reversible bronchoconstriction of the airways.

Treatments are available for acute asthma attacks and for long-term control of the disease.

Chronic Obstructive Pulmonary Disease (COPD)

characterized by chronic, progressive and irreversible airflow limitation due to airway remodeling with acute episodes of exacerbations often triggered by respiratory infections (inflammation).

Some bronchodilators and anti-inflammatory drugs can be used for both asthma and COPD

Airway Remodeling in COPD

The airways and alveoli (air sacs) lose their elastic quality.

The walls between many of the alveoli air sacs are destroyed.

The walls of the airways become thick and inflamed.

The airways lose their shape and make more mucus than usual, which can clog them.

COPD symptoms

coughing with large amounts of mucus, wheezing, tightness of chest and shortness of breath.

COPD Risk Factors

prolonged exposure to noxious (cigarette smoking, others), age and sex (females more at risk).

COPD Treatment Goals

No cure yet, airway remodeling damage is irreversible, treatment is symptomatic

Changes in lifestyle help patients feel better, be more active, and slow down the progression of disease

Bronchodilators (smooth muscle relaxants)

β adrenoceptor agonists

Muscarinic antagonists (Anticholinergics)

Leukotriene modifiers

Methylxanthines

(Theophylline)

Anti-inflammatory drugs

Corticosteroids

Leukotriene modifiers

Mast cells stabilizer

Anti-IgE antibody

Autonomic Nervous System Effects on Lungs

Sympathetic Bronchodilation

releases NE, NE activates β2 receptors in lungs and induces bronchodilation

Selective β2 adrenoreceptor agonists MOA

cAMP inhibits myosin light chain kinase (MLCK) inducing smooth muscle relaxation = bronchodilation

Selective β2 adrenoreceptor agonists Administration

Inhalers and Nebulizers

Both devices used to deliver drugs into the lungs by inhalation

Selective β2 adrenoreceptor agonists: SABA

Rapid onset (5-30 min) & short-acting (4-6 h)

Albuterol (ProAir, Ventolin, Proventil)

Albuterol can be used in combination with another class of bronchodilator drug, an anticholinergic: Albuterol & Ipratropium (Combivent or DuoNeb)

Albuterol & Ipratropium

Combivent or DuoNeb

Selective β2 adrenoreceptor agonists: LABA

Slow onset & long-acting (12 – 24 h)

Salmeterol (Serevent), Formoterol (Foradil),

Vilanterol

Long-acting agents usually are not used alone; combined in an inhaler with a glucocorticoid

Fluticasone & Salmeterol (Advair)

Budesonide & Formoterol (Symbicort)

Fluticasone & Vilanterol (Breo)

Selective β2 adrenoceptor agonists: β1

Affects the heart, cardiac muscle contraction

Selective β2 adrenoceptor agonists: β2

Causes smooth muscle relaxation

Selective β2 adrenoceptor agonists Side Effects

Tachycardia (rapid heart rate) or palpitations (fluttering or pounding heartbeat) due to β-adrenoceptor activation in the heart

ANS Effects on Lungs: Parasympathetic Bronchoconstriction

Vagus nerve ACh in lungs.

ACh activates muscarinic receptors and induces bronchoconstriction and mucus secretion

Muscarinic receptor antagonists MOA

AKA anticholinergics

Blocks muscarinic receptors which blocks bronchoconstriction and mucus secretion

Muscarinic receptor antagonists Administration

Inhalation

SAMA Ipratropium (Atrovent)

Competitively block muscarinic receptors in airways

Short-acting → frequent daily administration

prevents bronchoconstriction and mucus secretion mediated by vagal discharge of ACh

Anticholinergic can be used in combination with β2 agonist:

Albuterol & Ipratropium (Combivent or DuoNeb)

Tiotropium (Spiriva)

Longer acting analogue of Ipratropium administered once daily

Combination with glucocorticoids is useful in asthmatic patients who have developed tolerance to β-agonists: Tiotropium (Respimat), add-on therapy to medium-dose inhaled corticosteroids (ICS)

Umeclidinium (Incruse)

Long-acting muscarinic agent administered once daily

FDA-Approved in 2017 for chronic COPD.

Used in combination with Vilanterol (LABA) or in combination with Vilanterol and Fluticasone (ICS)

Muscarinic receptor antagonists Side Effects

These compounds are locally delivered, so systemic anticholinergics side effects are minimal. However, dry mouth has been reported.

Methylxanthines

Caffeine (coffee), theophylline (tea) and theobromine (cocoa)

Theophylline (Uniphyl) is the only methylxanthine used for asthma and COPD

Methylxanthines Mechanisms of Action

Inhibit the phosphodiesterase (PDE) enzyme in airway smooth muscle cells which cause bronchodilation

Block adenosine receptors on mast cell which inhibits the release of LTC4 and inhibits bronchoconstriction

Primarily used as bronchodilator, but also has anti-inflammatory effect

Methylxanthines Administration, Formulation

Theophylline (Uniphyl) Oral formulation, slow-release, taken once or twice a day

Used for chronic treatment of asthma or COPD, when patients are not responding well to other therapies

Aminophylline (theophylline ethylenediamine)

A more soluble form of theophylline that may be given by i.v. in an emergency

Methylxanthines Pearls

Clearance varies, may decrease in patients with congestive heart failure, acute pulmonary edema, hepatic disease, cor pulmonale, acute hepatitis, ypothyroidism, cirrhosis, fever, or sepsis with multi-organ failure and shock.

Methylxanthines ADEs

Signs of toxicity: severe headache, tachycardia, nausea or vomiting

Measure serum levels and withhold subsequent doses if a patient develops signs and symptoms of toxicity

Corticosteroids Mechanism of action

Glucocorticoids bind to intracellular GC receptors

This induces or inhibits expression of target genes in the nucleus

anti-inflammatory proteins are up-regulated, decreasing inflammation and allergy

pro-inflammatory proteins are down-regulated, decreasing inflammation

In the cytosol, activated GR induce non-genomic effects. Inhibit PLA2 activity, ↓ synthesis of arachidonic acid, ↓ leukotrienes.

Seem to ↑ responsiveness of airways to β-agonists (LABA/GC combination)

Corticosteroids Local Admin/formulation

Inhaled corticosteroids (ICS) for long-term Tx of Asthma and COPD

Nasal sprays: for allergic rhinitis

Budesonide (Pulmicort)

Fluticasone (Flovent)

Beclomethasone (QVAR)

Corticosteroids Systemic

Oral tablets (Prednisone) for long-term Tx of Asthma or COPD

Intravenous: Given in case of asthmatic attack, i.v. prednisolone (active metabolite of prednisone) and hydrocortisone are given.

toxic and used chronically ONLY when all other therapies are unsuccessful

Corticosteroids Adverse effects

Changes in oropharyngeal flora result in candidiasis (fungal infection), rinse mouth after administration.

Regular use of inhaled steroids in children causes mild growth retardation.

Leukotriene Modifiers Mechanism of action

Interfere with synthesis or action of leukotrienes

Zileuton (Zyflo)

Lipoxygenase inhibitor

Inhibits 5-lipoxygenase, a key enzyme in the conversion of arachidonic acid to leukotrienes

↓ leukotriene synthesis including LTB4, resulting in decreased inflammation and LTC4/LTD4 resulting in relaxation of smooth muscle.

Oral drug, used for maintenance treatment of asthma

NOT for acute episodes of asthma, used to prevent them

Montelukast (Singulair) and Zafirlukast (Accolate)

antagonists at the LTD4 receptor; resulting in relaxation of smooth muscle

Oral drug, used in the maintenance treatment of asthma, usually as a complementary therapy in adults in addition to inhaled corticosteroids, if needed

NOT for acute episodes of asthma

Leukotriene Modifiers Adverse effects

Headache

Hepatotoxicity, only with Zafirlukast (Accolate) and Zileuton (Zyflo)

Mast-cell stabilizers Mechanism of Action

Cromolyn (Intal)

Inhibits mast cell degranulation which inhibits release of histamine and other mediators from the mast cells.

Anti-inflammatory effects

Cromolyn (Intal)

Inhalation: Used for prevention of asthma attacks, not for ongoing acute asthma attack

Administered via a nebulizer

Inhalation four-times a day

Can also be used for rhinitis (intranasal) and conjunctivitis (eyedrops)

Mast-cell stabilizers Tolerability

Can irritate airways upon inhalation and induce coughing

Some people have shown allergies to cromolyn

Omalizumab (Xolair) MOA

Anti-IgE antibody (i.e. Mast-cell stabilizers)

a humanized murine monoclonal antibody (IgG1) to human IgE Ab.

Omalizumab (Xolair) Administration, Formulation

Injected: i.v. or s.c. Every 2 to 4 weeks

Rapid Onset and long duration of action (2-4 weeks)

Used for prevention of asthma attacks in individuals not responding to glucocorticoids and other agents.

Not all asthma patients respond to this therapy

IgE antibody

Omalizumab (Xolair) Tolerability

Allergic reactions (rare incidences of anaphylaxis) since it is a murine-derived antibody, i.e. foreign substance. Test for allergic reaction before use.

Very expensive therapy

Acute Treatments

Immediate relief usually with bronchodilators (smooth muscle relaxants):

Short-acting β2-adrenoceptor agonists (SABA)

Short-acting muscarinic receptor antagonists (SAMA)

Injected Theophylline

Injected Glucocorticoid

Long-term and preventative treatment

Inhaled Glucocorticoid

Long-acting β2-adrenoceptor agonists (LABA)

Long-acting muscarinic receptor antagonists (LAMA)

Leukotriene modifiers

Oral Theophylline

Mast Cell Stabilizers

Anti-IgE antibodies