Asthma Medications - Josh Corwin



Asthma Medications

Overview of Asthma

In asthma, there is hyper responsiveness to stimuli that produce bronchoconstriction. Stimuli include cold air, exercise, allergens, and emotional stress. It is characterized by airway inflammation and edema resulting from the release of various mediators from mast cells, eosinophils, macrophages, etc. Mediators include histamine, adenosine, bradykinin, leukotrienes, and prostaglandins.

Airway obstruction results from bronchial inflammation, smooth muscle constriction and obstruction of the lumen with mucus, inflammatory cells and epithelial debris. Symptoms of obstruction include dyspnea, coughing, wheezing, headache, tachycardia, syncope, diaphoresis, pallor, and cyanosis.

Bronchodilators

Bronchodilators relax the bronchial smooth muscle and prevent or relieve bronchospasm. Beta-2 agonists are the only agents that can counteract an acute asthmatic attack. Anticholinergics are less useful in asthma and better for COPD and emphysema. Theophylline is used on long term basis to prevent bronchoconstriction in asthma and emphysema.

Mixed non-selective bronchodilators are sympathetic agonists. Include Epinephrine, which is available in an inhaled or subcutaneous form. When it binds to beta-2 receptors, it bronchodilates. Also available in an injectable form.

Beta agonists have some effects on beta-1 receptors also, which can produce some cardiac effects. Includes Isoproterenol (Isuprel) and Pirbuterol (Maxair).

Beta-2 selective agonists are the preferred treatment. They are specific for beta-2 receptors; therefore they have less cardiac stimulation. Selectivity is limited as doses become high, resulting in increased heart rate and contractility. Albuterol (Proventil) is short acting and is used prn. It is available as an MDI, nebulizer, or oral tablet/solution. Nebulizers are not more effective than MDI. Nebulizers are just given in higher doses. Longer acting beta-2 selective agonists are not used for acute attacks. They include Salmeterol (Serevent) and Formoterol (Foradil). All beta agonists SE include dry irritated throat, cough, bad taste, CNS effects, and cardiac effects.

Anticholinergics include Ipratropium (Atrovent), which is not as effective as a beta agonist. It is not a prn drug, so it should be used in combo with Albuterol for asthma. It is mainly used for COPD, emphysema, and rhinitis. SEs include CNS, palps, bitter taste, and cough. Can be used alone for COPD. Combivent is a combination of Albuterol and Atrovent. Tiotropium (Spiriva) is a new long acting anticholinergic drug. It has a longer duration than Atrovent, so fewer dosing is needed. May also have a more sustained response over time than the long acting beta-2 agonists. Pediatric dosing is not recommended.

Xanthine derivatives include Theophylline (Theodur, SloBid). It is a phosphodiesterase inhibitor causing bronchodilation and some anti-inflammatory effects. Produces high amounts of CNS stimulation and diuresis. It is metabolized by CYP1A2 and has many DDI. Narrow TI, so you must monitor levels. ADRs include N, V, epigastric pain, tachycardia, and seizures. Caffeine is the main chemical in xanthine derivatives. Enzyme inhibitors of CYP450 will increase toxicity of Theophylline.

Glucocorticosteroids

Glucocorticoids are effective for a wide variety of diseases. They are available PO, INJ, topical, and inhalational. Inhaled forms are the focus for asthma, although PO and INJ are also used for management of asthma exacerbations. They work in bronchioles to reduce inflammation. They are the cornerstone of treatment in patients with moderate to severe asthma and can also play a role in mild asthma.

Glucocorticoids are used on a long term basis for asthma treatment. The inhaled form is not for acute attacks but will minimize the rise of ADRs. Maximal response requires 8 weeks to develop. They can reduce the number and severity of symptoms and decrease the need for beta-2 agonists and other bronchodilators. Injectable forms can be used for acute attacks. Patients are then usually followed up with a high-dose oral.

Although they are the most efficacious anti-inflammatory drugs, they have the greatest potential for ADRs. The inhalation forms minimizes systemic ADRs, but they can still occur. ADRs that can occur with the inhaled form include excessive deposition of drug in mouth and upper airway leading to thrush. Patients must rinse their mouth after using steroid inhalers. Other ADRs include local irritation, cough, headache, URTI, nasal congestion, and pharyngitis. There is also a concern of suppression of growth in children.

Inhaled glucocorticoids include Beclomethasone (Vanceril) and Fluticasone (Flovent). For treatment, and beta-2 inhaler should be given first, followed by Ipratropium, and then a steroid inhaler last. Patients should rinse after use.

Systemic glucocorticoids include Prednisone (Deltasone), Methylprednisolone (Medrol, Solumedrol), and Prednisolone (Pediapred suspension). They are used for short course burst therapy and for asthma exacerbations.

Mast cell Stabilizers

Mast cell stabilizers stabilize the plasma membrane of mast cells and eosinophils. This prevents the degranulation and release of histamine, leukotrienes and other mediators. As a result, inflammation is reduced. Not used for acute attacks, mainly for prophylaxis. ADRs include local irritation, bad taste, cough, and bronchospasm (give beta-2 inhaler to relieve).

Include Cromolyn (Intal) and Nedcromil (Tilade).

Leukotriene Inhibitors

Leukotriene inhibitors are a relatively new class of drugs to treat asthma. Leukotriene is an arachidonic acid metabolite and an inflammatory mediator. Leukotriene receptors mediate airway inflammation, edema, bronchoconstriction, and secretion of thick, viscous mucus. Leukotriene inhibitors inhibit both early and late stage bronchoconstriction induced by antigens.

Include Zafirlukast (Accolate) and Montelukast (Singulair). Both are leukotriene receptor blockers. They are used for mild to moderate long term treatment. Effects are cumulative and may take weeks to see the benefit, which is improved pulmonary function, control of symptoms, reduction in attacks, and reduction in airway inflammation. They are not for acute treatment but used in conjunction with beta-2 agonists. Both drugs are highly protein bound (99%) so there are many DDI with other highly protein bound drugs. They have excessive CYP450 metabolism as well.

ADRs are minimal. Zafirlukast can cause fever, malaise, peripheral neuropathy (28%), rash, and GI disturbances. Montelukast causes headache (18%).

DDIs are also minimal. Zafirlukast – ASA, warfarin, and Theophylline. No dose adjustments are needed for Montelukast.

Montelukast is more common because of once per day dose, less peripheral neuropathy, and low DDI.

Zileuton (Zyflo) inhibits 5-lipooxygenase, decreasing the production of leukotriene. It is administered ACHS (4x per day with meals at bedtime), resulting in poor compliance. Has a very short half-life (2 hours) because of extensive 1st pass metabolism via glucoronidation. Used in the treatment of mild to moderate asthma. SEs include flu like symptoms, headache, drowsiness, dyspepsia, and increased hepatic enzymes. Caution should be taken in patients who consume substantial alcohol. DDI include increased beta blocker, Theophylline, and warfarin levels.

Zafirlukast can be used in kids over 5. Montelukast can be used in kids over 12 months old. Zileuton can be used in kids over 12 years old. As a class, they are not effective in everyone, but generally have better ADRs than steroids.

Asthma Management

Goals of asthma treatment:

1) Minimal or no chronic symptoms days or night

2) Minimal or no exacerbations

3) No limitations on activity – no school/work missed

4) Minimal use of inhaled short acting beta-2 agonists

5) Minimal or no ADRs

All patients over 5 years old must use inhaled short acting beta-2 agonists prn. The intensity of treatment depends on the severity of exacerbation. The use of beta-2 agonists prn or increased use indicated need to initiate or titrate long term therapy.

Patients should be taught self management and about controlling environmental factors. Administration techniques and compliance should also be reviews as well as the use of written plans.

A stepwise approach for asthma management is used:

1) Step 1 – mild intermittent

2) Step 2 – mild persistent

3) Step 3 – moderate persistent

4) Step 4 – severe persistent

These steps provide general guidelines and not specific prescription. A rescue course of systemic corticosteroids may be needed at any time and at any step.

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