Drugs for Respiratory System Disorders

• Drugs for disorders of the respiratory system
• Includes asthma, chronic obstructive pulmonary disease (COPD), and allergic rhinitis.
• Symptoms include a troublesome cough.
• Asthma affects over 235 million people worldwide.
• COPD is the fourth leading cause of death worldwide and is predicted to be the third leading cause by 2030.
• Allergic rhinitis is characterized by itchy, watery eyes, runny nose, and a nonproductive cough.
• Respiratory conditions can be managed with lifestyle changes and medications.
• Medications can be delivered topically, inhaled, or systemically.
• Local delivery is preferred to minimize systemic adverse effects.

Preferred Drugs Used to Treat Asthma

• Asthma is a chronic inflammatory disease of the airways causing bronchoconstriction.
• Symptoms include shortness of breath, cough, chest tightness, wheezing, and rapid respiration.

Pathophysiology of Asthma

• Airflow obstruction is due to bronchoconstriction, inflammation of the bronchial wall, and increased mucus secretion.
• Inflammation contributes to airway hyper-responsiveness, airflow limitation, respiratory symptoms, and disease chronicity.
• Asthma attacks can be triggered by allergens, exercise, stress, and respiratory infections.
• Asthma can be episodic or chronic.
• Mast cell degranulation releases mediators such as histamine and inflammatory cytokines.
• The inflammatory phase leads to bronchoconstriction, edema, mucus secretion, vasodilation, and activation of sensory nerves.
• Chronic inflammation can cause structural modifications in the airway epithelium.
• Asthma is usually not progressive like COPD but can cause airway remodeling if untreated, leading to increased severity and exacerbations.

Goals of Therapy

• Asthma can present as mild, moderate-to-severe, or life-threatening exacerbations.
• Treatment depends on the severity of asthma.
• Trigger factors should be identified and avoided.
• Smoking should be stopped, and regular breathing exercises should be started.
• Physical activity and weight loss can help prevent acute episodes.
• Drug therapy aims to reverse and prevent airway inflammation, decrease symptom intensity and frequency, prevent exacerbations, and minimize activity limitations.

β2-Adrenergic Agonists

• Inhaled β2-adrenergic agonists relax airway smooth muscle.
• Used for quick relief of asthma symptoms and as adjunctive therapy for long-term control.

Quick Relief

• Short-acting β2 agonists (SABAs) have a rapid onset of action (5 to 30 minutes) and provide relief for 4 to 6 hours.
• Used for symptomatic treatment of bronchospasm and acute bronchoconstriction.
• All asthma patients should have a SABA inhaler.
• β2 agonists have no anti-inflammatory effects and should not be used as monotherapy for persistent asthma.
• Monotherapy with SABAs may be appropriate for mild, intermittent asthma or exercise-induced bronchospasm.
• Direct-acting β2-selective agonists include salbutamol and terbutaline.
• Adverse effects, such as tachycardia, hyperglycemia, hypokalemia, hypomagnesemia, and B2-mediated skeletal muscle tremors, are minimized with inhaled delivery.

Long-Term Control

• Salmeterol and formoterol are long-acting β2 agonists (LABAs) and chemical analogs of salbutamol.
• Salmeterol and formoterol have a long duration of action, providing bronchodilation for at least 12 hours.
• LABA monotherapy is contraindicated.
• LABAs should be used only in combination with an asthma controller medication, such as an inhaled corticosteroid (ICS).
• ICS remains the long-term controller of choice in asthma.
• LABAs are considered useful adjunctive therapy for moderate-to-severe asthma.
• Some LABAs are available as a combination product with an ICS.
• Adults and adolescents with moderate persistent asthma can use the ICS/formoterol combination for relief of acute symptoms.
• Adverse effects of LABAs are similar to quick-acting β2 agonists.
• Bambuterol is a prodrug of terbutaline slowly released over 24 hours by pseudocholinesterase.

Corticosteroids

• ICS are the drugs of choice for long-term control in patients with persistent asthma.
• Corticosteroids inhibit the release of arachidonic acid through inhibition of phospholipase A2, producing direct anti-inflammatory properties.
• Must be used regularly to be effective in controlling inflammation.
• Exacerbations may require a short course of oral or intravenous corticosteroids.

Actions on Lung

• ICS therapy directly targets underlying airway inflammation.
• Decreases the inflammatory cascade, reversing mucosal edema, decreasing capillary permeability, and inhibiting leukotriene release.
• After regular use, ICS reduces airway smooth muscle hyper-responsiveness to various stimuli.

Routes of Administration

• Inhalation: ICS has reduced the need for systemic corticosteroid treatment.
• Appropriate inhalation technique is critical.
• Oral/systemic: Severe exacerbations may require intravenous methylprednisolone or oral prednisone to reduce airway inflammation.
• A dose taper is unnecessary.
• Adverse effects: Oral or parenteral corticosteroids have potentially serious adverse effects.
• ICS have few systemic effects, especially if used with a spacer.
• ICS deposition on the oral and laryngeal mucosa can cause oropharyngeal candidiasis and hoarseness.
• Patients should rinse the mouth in a "swish-and-spit" method after use.

Alternative Drugs Used to Treat Asthma

• Useful in patients poorly controlled by conventional therapy or experiencing adverse effects secondary to corticosteroid treatment.
• Should be used in conjunction with ICS therapy for most patients.

Leukotriene Modifiers

• Leukotrienes (LT) are products of the 5-lipoxygenase pathway of arachidonic acid metabolism.
• Zileuton is a selective inhibitor of 5-lipoxygenase, preventing the formation of both LTB4 and the cysteinyl leukotrienes.
• Zafirlukast and montelukast are selective antagonists of the cysteinyl leukotriene-1 receptor, blocking the effects of cysteinyl leukotrienes.
• These agents are approved for the prevention of asthma symptoms and have also shown efficacy in preventing exercise-induced bronchospasm.
• Pharmacokinetics: These agents are orally active and highly protein-bound.
• Food impairs the absorption of zafirlukast.
• The drugs undergo extensive hepatic metabolism.
• Zileuton and its metabolites are excreted in urine, whereas zafirlukast, montelukast, and their metabolites undergo biliary excretion.
• Adverse effects: Elevations in serum hepatic enzymes may occur, requiring periodic monitoring.
• Other effects include headache and dyspepsia.
• Zafirlukast is an inhibitor of cytochrome P450 (CYP) isoenzymes, and zileuton inhibits CYP1A2.

Mast Cell Stabilizers

• Cromolyn is a prophylactic anti-inflammatory agent that inhibits mast cell degranulation and histamine release.
• It is an alternative therapy for mild persistent asthma and is available as a nebulized solution.
• Cromolyn is not a bronchodilator and is not useful in managing an acute asthma attack.
• Requires dosing three or four times daily.
• Adverse effects are minor and include cough, irritation, and unpleasant taste.
• Ketotifen is an antihistaminic reported to have mast cell stabilization activity.
• It shows moderate antiasthmatic activity on prolonged use and is useful in patients with allergy.
• Unlike cromolyn, it induces sedation and dry mouth.

Cholinergic Antagonists

• Block vagally mediated contraction of airway smooth muscle and mucus secretion.
• Ipratropium, a short-acting quaternary derivative of atropine, is not recommended for routine treatment of acute bronchospasm in asthma.
• May be useful in patients unable to tolerate a SABA or patients with asthma-COPD overlap syndrome.
• Tiotropium, a long-acting anticholinergic agent, can be used as an add-on treatment in adult patients with severe asthma and a history of exacerbations.
• Adverse effects such as xerostomia and bitter taste are related to local anticholinergic effects.

Methylxanthines

• Theophylline is a bronchodilator that relieves airflow obstruction in chronic asthma and decreases its symptoms.
• It may also possess anti-inflammatory activity.
• Mechanism of action is unclear.
• Has been largely replaced with β2 agonists and corticosteroids due to its narrow therapeutic window, adverse effect profile, and potential for drug interactions.
• Overdose may cause seizures or potentially fatal arrhythmias.

Monoclonal Antibodies

• Omalizumab is a monoclonal antibody that selectively binds to human immunoglobulin E (IgE).
• Reduces the release of mediators of the allergic response.
• Mepolizumab, benralizumab, and reslizumab are interleukin-5 (IL-5) antagonists.
• Indicated for the treatment of severe persistent asthma in patients who are poorly controlled with conventional therapy.
• Use is limited by the high cost, route of administration, and adverse effect profile.

Drugs Used to Treat Chronic Obstructive Pulmonary Disease (COPD)

• COPD is a chronic, irreversible obstruction of airflow characterized by symptoms like cough, excess mucus production, chest tightness, breathlessness, difficulty sleeping, and fatigue.
• Irreversible airflow obstruction distinguishes it from asthma.
• Smoking is the greatest risk factor.
• Drug therapy aims at symptom relief and preventing disease progression.

Bronchodilators

• Inhaled bronchodilators like B2-adrenergic agonists and anticholinergic agents are the foundation of therapy.
• Increase airflow, alleviate symptoms, and decrease exacerbations.
• Long-acting bronchodilators, LABAs and long-acting muscarinic antagonists (LAMAs), are preferred as first-line treatment for all patients except those at low risk with fewer symptoms.
• Combination therapy with an anticholinergic and a B2 agonist may be helpful in patients with inadequate response to a single inhaled bronchodilator.

Corticosteroids

• Adding an ICS to a long-acting bronchodilator may improve symptoms, lung function, and quality of life in COPD patients with FEV1 of less than 60% predicted or those with symptoms of both asthma and COPD.
• ICS treatment should be restricted due to the increased risk of pneumonia.
• Oral corticosteroids are not recommended for long-term treatment of COPD.

Other Agents

• Roflumilast is an oral phosphodiesterase-4 inhibitor used to reduce exacerbations in patients with severe chronic bronchitis.
• Not a bronchodilator and is not indicated for the relief of acute bronchospasm.

Inhaler Technique

• Technique differs between metered-dose inhalers (MDIs) and dry powder inhalers (DPIs).
• Proper technique is critical to the success of therapy.

Metered-Dose Inhalers and Dry Powder Inhalers

• MDIs have propellants that eject medication.
• Patients should exhale before actuating the inhaler and inhale slowly and deeply.
• DPIs require patients to inhale quickly and deeply to optimize drug delivery.
• Patients using inhaled corticosteroids should rinse their mouth after use.

Spacers

• A spacer is a large-volume chamber attached to an MDI.
• Patients should wash/rinse spacers to reduce the risk of bacterial or fungal growth.

Drugs Used to Treat Allergic Rhinitis

• Rhinitis is inflammation of the mucous membranes of the nose.
• Characterized by sneezing, itchy nose/eyes, watery rhinorrhea, nasal congestion, and sometimes a nonproductive cough.
• Precipitated by inhalation of an allergen.
• Antihistamines and/or intranasal corticosteroids are preferred therapies.

Antihistamines

• Oral antihistamines (H₁ receptor antagonists) have a fast-onset of action.
• Effective for preventing symptoms in mild or intermittent disease.
• Second-generation antihistamines are generally better tolerated.
• Ophthalmic and nasal antihistamine delivery devices are available for targeted, topical tissue delivery.

Corticosteroids

• Intranasal corticosteroids are the most effective medications for allergic rhinitis.
• Improve sneezing, itching, rhinorrhea, and nasal congestion.
• To minimize systemic absorption, patients should avoid deep inhalation during administration.
• Improvement may not be seen until 1 to 2 weeks after starting therapy.

α-Adrenergic Agonists

• Short-acting α-adrenergic agonists ("nasal decongestants") constrict dilated arterioles in the nasal mucosa.
• Intranasal formulations should be used for no longer than 3 days due to the risk of rebound nasal congestion.

Other Agents

• Intranasal cromolyn may be useful, particularly when administered before contact with an allergen.
• Some leukotriene receptor antagonists are effective for allergic rhinitis.
• An intranasal formulation of ipratropium is available to treat rhinorrhea associated with allergic rhinitis or the common cold.

Drugs Used to Treat Cough/Antitussive Agents

• Coughing is an important defense mechanism of the respiratory system.
• Treat the underlying cause of cough when possible.

Opioids

• Codeine decreases the sensitivity of cough centers and decreases mucosal secretion.
• Dextromethorphan is a synthetic derivative of morphine with no analgesic effects in antitussive doses.
• Guaifenesin, an expectorant, is available as a single-ingredient formulation and is commonly found in combination cough products with codeine or dextromethorphan.

Nonopioid Cough Suppressants

• Benzonatate suppresses the cough reflex through peripheral action.
• Noscapine acts as a cough suppressant through the nonopioid pathway.

Mucokinetics and Expectorants

• Mucokinetics are a class of drugs that aid in the clearance of mucus from the airways and lungs.
• Includes mucolytic agents, expectorants, and surfactants-wetting agents.