Lecture #37
PHARMACOLOGY: ASTHMA & CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)
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Relate the mechanism of action of each drug class to drugs that modify the disease process verses drugs that relieve symptoms
Formulate a plan on using combinations of agents to manage chronic asthma and chronic obstructive pulmonary disease (COPD)
Distinguish between the agents used to treat acute episodes of asthma and those used in the treatment of exercised/-induced asthma
Compare the agents used in the treatment of asthma versus the treatment of COPD
Choose agents to reduce asthma and COPD exacerbations and improve clinical outcomes
Asthma
● Reversible
○ SABA​ treatment will return back to patient’s normal baseline ​FEV1
● Usually diagnosed in childhood (​younger person’s disease​)
● Symptoms
○ Dyspnea
○ Wheezing
○ Chest tightness
○ Cough (worse at night)
○ Worsen with exercise
● Diagnostics
○ Spirometry
○ CBC (​eosinophilia​)
○ IgE levels
COPD
● Irreversible
○ SABA treatment will relieve symptoms​ but w
​ ill NOT return to patient’s normal baseline FEV1
● Usually diagnosed in adulthood (​Usually 40+ years old and a tobacco smoker)
● Symptoms
○ Dyspnea
○ Wheezing
○ chest tightness
○ persistent cough
● Diagnostics
○ Spirometry
○ CBC
Asthma Drug Treatments
● “Relievers” Bronchodilators
○ SABAs
■ Albuterol
■ Terbutaline
■ Pirbuterol
■ Bitolterol
○ Anticholinergics (Muscarinic receptor antagonists)
■ Ipratropium Bromide
■ LAMA
● Tiotropium Bromide (COPD Only)
● “Controllers” Anti-inflammatory Agents
○ Corticosteroids
○ LABA (Long-acting Beta2 -receptor Agonists)
■ Salmeterol
■ Formoterol
■ COPD ONLY
● Arformoterol
● Vilanterol
● Indacaterol
● Olodaterol
○ Methylxanthines
■ Theophylline
■ Aminophylline
○ Cromolyn
○ Leukotriene Inhibitors
○ Anti-IgE monoclonal antibodies
ANS Lung Control
Beta2 selective receptor agonists
● Mechanism of actions: Bronchodilation & Mucus Clearance
○ Beta2 receptor stimulation
■ Increases cAMP
■ Relaxation of bronchial smooth muscle
○ Mucus clearance by increasing lung ciliary beat frequency
○ Binds 200-400 times more strongly to beta2 receptor and causes milder cardiac effects (Beta1 receptor found in
heart)
● SABAs
○ Drugs
■ Albuterol
■ Terbutaline
■ Pirbuterol
■ Bitolterol
○ Effects
■ Rapid Onset of Action (15 to 30 minutes)
● Maximum effect in 30 to 60 minutes
■ Duration of action 4 to 6 hours
○ Used as a rescue inhaler for acute attacks
● LABAs
○ Drugs
■ Salmeterol
■ Formoterol
○ Effects
■ Duration of action 12 to 24 hours
○ Used regularly for maintenance therapy
○ Should not be used for asthma flare
● ASEs
○ Throat Irritation
○ Muscle tremors
○ Palpitation, restlessness
○ Ankle edema
● Patient can develop tolerance with overuse of albuterol rescue inhaler
● Use of SABA >2 days a week for symptom relief generally indicates inadequate asthma control and the need for initiating
or intensifying anti-inflammatory therapy
Anticholinergics/Muscarinic Antagonists
● Drugs
○ LAMA
■ Tiotropium Bromide
○ Ipratropium bromide
● Mechanism of Action
○ Prevents acetylcholine (ACh) from producing smooth muscle contractions and excess mucus in bronchi
○ M3 receptors mediate smooth muscle contraction and mucus gland secretion in the airway
● Anticholinergics are less effective than beta2 receptor agonists
● Anticholinergics enhance bronchodilator induced by beta2 receptor agonist so patients often take both drug classes
together
● ASEs
○ Dry Mouth
○ Gastrointestinal Upset
■ Inadvertent oral absorption from deposits left in mouth (decrease by using spacer)
○ Mydriasis (Pupillary dilation)
■ If nebulizer and delivered to eye
○ Anti-SLUD
■ Inhibits Salivation, Lacrimation, Urination, Defecation
Methylxanthines
● Drugs
○ Theophylline
○ Aminophylline
○ Roflumilast
■ phosphodiesterase
inhibitor approved for
treatment of severe COPD
● Mechanism of Actions
○ Inhibit phosphodiesterase
■ Increases cAMP
● Bronchodilation
○ Inhibit phosphodiesterase in T
lymphocytes and eosinophils
■ Anti-inflammatory effect
○ Adenosine receptor antagonist
■ increased ventilation during hypoxia
■ decreased adenosine-stimulated mediator release from mast cells
● ASEs
○ Plasma levels must be monitored to prevent toxic levels of these agents
○ Gastrointestinal upset
○ Insomnia, restlessness, irritability
○ Tremor
○ Cardiac arrhythmias
○ Drug-drug interactions
■ CYP3A inhibitors such as cimetidine and azole antifungals
○ Adverse side effects has limited the role of methyxanthines in the treatment of asthma BUT is used when beta2
receptor agonists and corticosteroids are ineffective or contraindicated
Inflammation in Asthma
● Normal response ​to an environmental allergen is mediated through a​ TH1 response a​nd the antigen is taken care of
discretely
● Asthma (Hyperresponsiveness) response to an environmental allergen i​s exaggerated and TH2 response ​predominates
and generate​s airway inflammation
○ Hypersensitivity response
■ low levels of stimuli result in a constriction response
○ Hyperreactivity response
■ exaggerated response to normal levels of stimuli
● Anti-inflammatory Agents
○ Corticosteroids
■ Inhaled
● Beclomethasone
● Triamcinoline
● Fluticasone
● Budesonide
● Flunisolide
● Mometasone
● Ciclesonide
■ Oral
● Prednisone
● Methylprednisolone
● Dexamethasone
○ Cromolyns
■ Cromolyn sodium
○ Leukotriene Pathway Modifying Agents
■ Zileuton
■ Montelukast
■ Zafirlukast
○ Anti-IgE Antibodies
■ Omalizumab
Corticosteroids
● Anti Inflammatory drugs similar to natural corticosteroid hormones produced by the adrenal cortex
● Chief preventative treatment for asthma
● Drugs
○ Inhaled (decrease systemic side effects and allows for 100-fold decrease in dose)
■ Beclomethasone
■ Triamcinoline
■ Fluticasone
■ Budesonide
■ Flunisolide
■ Mometasone
■ Ciclesonide
○ Oral (used either for a short-term therapy for acute exacerbation or long-term therapy for cases that cannot be
controlled with other medications)
■ Prednisone
■ Methylprednisolone
■ Dexamethasone
● Mechanism of Action
○ Inhibit last phase allergic reactions by various mechanisms
■ Decrease cytokine production by eosinophils, monocytes, mast cells and lymphocytes
■ Indirectly inhibit mast cells
■ Reduce vascular permeability resulting in decreased airway edema
○ Overall a decrease in airway hyperresponsiveness due to inhibition of inflammatory cascade
● ASEs
○ Inhaled
■ Oropharyngeal candidiasis (Spacer decreases ASE)
■ Hoarseness (Spacer decreases ASE)
■ Lower doses & first-pass metabolism in liver limits systemic adverse side effects of inhaled
corticosteroids
○ Oral
■ Increase appetite, Weight gain
■ Diarrhea
■ Hyperglycemia
■ Long term use will suppress the immune system, promote osteoporosis, delayed growth in children
● Long term used will need to be tapered to allow the adrenal glands to return to normal function
Cromolyns MOA
● Drug
○ Cromolyn sodium
■ only available as nebulizer solution, inhalers used CFCs (chlorofluorocarbons) as propellant and were
banned in US
● Mechanism of Action
○ mast cell stabilizing agents
■ Decrease activity of mast cells and inhibit release of inflammatory mediators
■ Inhibits inflammatory mediators from eosinophils, neutrophils, monocytes, macrophages, and
lymphocytes
● Used as prophylactic therapy in patients with allergic asthma associated with specific triggers
● Better safety profile than other asthma drugs, ​but must be taken four times a day
● ASEs
○ Abnormal taste
○ Cough
○ Throat irritation
○ Gastrointestinal upset
○ Dizziness
Leukotriene antagonists
● arachidonic acid derivatives involved in the inflammatory processes
○ enzyme 5-lipoxygenase catalyzes synthesis of arachidonic acid to leukotrienes
○ A number of airway cells (including mast cells, macrophages, eosinophils, and basophils) synthesize, store, and
secrete several subtypes of proinflammatory leukotrienes
○ Leukotriene B4 (LTB4) attracts additional leukocytes
○ Leukotriene C4 (LTC4), Leukotriene D4 (LTD4) and Leukotriene E4 (LTE4) increase bronchial reactivity,
bronchoconstriction, and secretion of mucus
● Drugs
○ Zileuton
■ MOA
● inhibits 5-lipoxygenase causing decreased synthesis of leukotrienes
■ ASE
● Headache
● hepatotoxicity (4% incidence)
○ periodic liver function testing is required
○ Montelukast AND Zafirlukast
■ MOA
● cysteinyl leukotriene (CysLT1) receptor antagonists and cause inhibition of binding of LTC4,
LTD4, and LTE4 to the CysLT1 receptor
■ ASE
● Headache
● Churg-Strauss syndrome (RARE)
○ A serious granulomatous vasculitis affecting small arteries and veins of lungs, heart,
kidneys, pancreas, spleen and skin.
○ Churg Strauss syndrome is independently associated with asthma and eosinophilia
● useful in treating the effects of ​aspirin-exacerbated respiratory disease
○ Patients with aspirin-sensitive asthma have exaggerated leukotriene response to aspirin & inhibition of
leukotriene pathway is an effective treatment
● Are available in oral tablets rather than inhaled formulations
○ Easier for children to use
● All three agents are well tolerated and safe when taken orally, an advantage when compared with inhaled corticosteroids
(more ASE)
● Leukotreiene pathway modifiers are less effective than inhaled corticosteroids
○ Corticosteroids have broader anti-inflammatory effects.
Anti-IgE Antibody
● Drug
○ Omalizumab
■ Humanized mouse monoclonal antibody
● Mechanism of Action
○ Monoclonal antibody that binds to the high-affinity IgE receptor binding domain on human IgE
○ Prevents IgE from binding to receptor on mast cells and antigen-presenting cells
○ Decreases the quantity of circulating IgE
○ Overall decreases the allergic response in asthma
● ASEs
○ Injection site reaction
○ Nausea
○ Arthraligia
○ Headache
○ Cough
○ Respiratory infection
COPD Treatments
● Chronic obstruction of lung airflow
● Drug treatment involves
○ Bronchodilators
○ Corticosteroids
● Less options because it involves the destruction of lung tissue.
○ Treatment of Asthma has more options because it is an inflammatory disease with bronchocontriction