Pharm chapter 37 respiratory
Leukotriene Receptor Antagonists
A chain reaction starts when a trigger allergen, such as cat hair or dust, initiates a series of chemical reactions in the body. Several substances are produced, including a family of molecules known as leukotrienes. In people with asthma, leukotrienes cause inflammation, bronchoconstriction, and mucus production. This in turn leads to coughing, wheezing, and shortness of breath.
Corticosteroids Action
Although the exact mechanism of action of the corticosteroids has not been determined, it is thought that they have the dual effect of both reducing inflammation and enhancing the activity of beta agonists. The corticosteroids produce their antiinflammatory effects through a complex sequence of actions. The overall effect is to prevent various nonspecific inflammatory processes. Corticosteroids essentially work by stabilizing the membranes of cells that normally release bronchoconstricting substances. These cells include leukocytes, which is another name for white blood cells (WBCs). There are five different types of WBC, each with its own specific characteristics. The five types of WBC, their role in the inflammatory process, and the way in which corticosteroids inhibit their normal action, combat inflammation, and produce bronchodilation are summarized in Table 37-5. Inflammatory mediators are primarily released by lymphocytes in the circulation as well as by mast cells and alveolar macrophages. These latter two cell types are stationary (noncirculating) inflammatory cells that remain localized in the various tissues and organs of the respiratory tract.
Anticholinergics Indications
Because their actions are slow and prolonged, anticholinergics are used for the prevention of bronchospasm associated with chronic bronchitis or emphysema and not for the management of acute symptoms.
Nonbronchodilating Respiratory Drugs
Bronchodilators (beta-adrenergic agonists, anticholinergics, and xanthines) are just one type of drug used to treat asthma, chronic bronchitis, and emphysema. There are also other drugs that are effective in suppressing the various underlying causes of some of these respiratory illnesses. These include leukotriene receptor antagonists (montelukast, zafirlukast, and zileuton) and corticosteroids (beclomethasone, budesonide, dexamethasone, flunisolide, fluticasone, ciclesonide, and triamcinolone). Another drug class known as mast cell stabilizers is now rarely used. However, these drugs are still listed in the national guidelines as alternative therapy and include cromolyn and nedocromil; they are sometimes used for exercise-induced asthma. As their class name implies, they work by stabilizing the cell membranes of mast cells to prevent the release of inflammatory mediators such as histamine.
Beta agonists Contraindications
Contraindications include known drug allergy, uncontrolled hypertension or cardiac dysrhythmias, and high risk for stroke (because of the vasoconstrictive drug action).
Xanthine Derivatives Contraindications
Contraindications to therapy with xanthine derivatives include known drug allergy, uncontrolled cardiac dysrhythmias, seizure disorders, hyperthyroidism, and peptic ulcers.
Corticosteroids
Corticosteroids, also known as glucocorticoids, are either naturally occurring or synthetic drugs used in the treatment of pulmonary diseases for their antiinflammatory effects. All have actions similar to those of the natural steroid hormone cortisol, which is chemically the same as the drug hydrocortisone. Synthetic steroids are more commonly used in drug therapy. They can be given by inhalation, orally, or even intravenously in severe cases of asthma. Corticosteroids administered by inhalation have an advantage over those administered orally in that their action is relatively limited to the topical site in the lungs. This generally limits, although does not totally prevent, systemic effects. The chemical structures of the corticosteroids given by inhalation have also been slightly altered to limit their systemic absorption from the respiratory tract. The corticosteroids administered by inhalation include the following: • beclomethasone dipropionate (Beclovent) • budesonide (Pulmicort Turbuhaler) • dexamethasone sodium phosphate (Decadron Phosphate Respihaler) • flunisolide (AeroBid) • fluticasone (Flovent) • triamcinolone acetonide (Azmacort) • ciclesonide (Omnaris)
Anticholinergics
Currently there are four anticholinergic drugs used in the treatment of COPD: ipratropium (Atrovent), tiotropium (Spiriva), 584aclidinium (Tudorza), and the combination product umeclidinium and vilanterol (Anoro Ellipta).
Leukotriene Receptor Antagonists action
Currently two subclasses of LTRAs are available. These subclasses differ in the mechanism by which they block the inflammatory process in asthma. The first subclass of LTRAs acts by an indirect mechanism and inhibits the enzyme 5-lipoxygenase, which is necessary for leukotriene synthesis. Zileuton (Zyflo) is the only drug of this type currently available. Drugs in the second subclass of LTRAs act more directly by binding to the D4 leukotriene receptor subtype in respiratory tract tissues and organs. These drugs include montelukast (Singulair) and zafirlukast (Accolate). The drug effects of LTRAs are primarily limited to the lungs. As their name implies, LTRAs prevent leukotrienes from attaching to receptors located on circulating immune cells (e.g., lymphocytes in the blood) as well as local immune cells within the lungs (e.g., alveolar macrophages). This alleviates asthma symptoms in the lungs by reducing inflammation. They prevent smooth muscle contraction of the bronchial airways, decrease mucus secretion, and reduce vascular permeability (which reduces edema) through their reduction of leukotriene synthesis. Other antileukotriene effects of these drugs include prevention of the mobilization and migration of such cells as neutrophils and lymphocytes into the lungs. This also serves to reduce airway inflammation.
Corticosteroids Contraindications
Drug allergy is the primary contraindication and is usually due to other ingredients in the drug formulation. These drugs 588are not intended as sole therapy for acute asthma attacks. Inhaled corticosteroids are contraindicated in patients who are hypersensitive to glucocorticoids, in patients whose sputum tests positive for Candida organisms, and in patients with systemic fungal infection, as the corticosteroids can suppress the immune system.
Corticosteroids Interactions
Drug interactions are more likely to occur with systemic (versus inhaled) corticosteroids. These drugs may increase serum glucose levels, possibly requiring adjustments in dosages of antidiabetic drugs. Because of interactions related to metabolizing enzymes, they may also raise blood levels of the immunosuppressants cyclosporine and tacrolimus. Likewise, the antifungal drug itraconazole may reduce clearance of the steroids, whereas phenytoin, phenobarbital, and rifampin may enhance clearance. There is also greater risk for hypokalemia with concurrent use of potassium-depleting diuretics such as hydrochlorothiazide and furosemide.
Corticosteroids Indications
Inhaled corticosteroids are used for the primary treatment of bronchospastic disorders to control the inflammatory responses that are believed to be the cause of these disorders; they are indicated for persistent asthma. They are often used concurrently with the beta-adrenergic agonists. In respiratory illnesses, systemic corticosteroids are generally used only to treat acute exacerbations, or severe asthma. Their long-term use is associated with adverse effects (see later). When a rapid, pronounced antiinflammatory effect is needed, as in an acute exacerbation of asthma or other COPD, intravenous corticosteroids (e.g., methylprednisolone) are often used.
Leukotriene Receptor Antagonists Contraindications
Known drug allergy or other previous adverse drug reaction is the primary contraindication to the use of these drugs. Allergy to povidone, lactose, titanium dioxide, or cellulose derivatives is also important to note, because these are inactive ingredients in these drugs
Beta agonists Adverse Effects
Mixed alpha/beta agonists produce the most adverse effects because they are nonselective. These include insomnia, restlessness, anorexia, cardiac stimulation, hyperglycemia, tremor, and vascular headache. The adverse effects of the nonselective beta agonists are limited to beta-adrenergic effects, including cardiac stimulation, tremor, anginal pain, and vascular headache. The beta2 drugs can cause both hypertension and hypotension, vascular headaches, and tremor. Overdose management may include careful administration of a beta blocker while the patient is under close observation due to the risk for bronchospasm. Because the half-life of most adrenergic agonists is relatively short, the patient may just be observed while the body eliminates the medication.
Leukotriene Receptor Antagonists Interactions
Montelukast has fewer drug interactions than zafirlukast or zileuton. Phenobarbital and rifampin, both of which are enzyme inducers, decrease montelukast concentrations. For information on the drugs that interact with zafirlukast and zileuton
Anticholinergics action
On the surface of the bronchial tree are receptors for acetylcholine (ACh), the neurotransmitter for the parasympathetic nervous system (PSNS). When the PSNS releases ACh from its nerve endings, it binds to the ACh receptors on the surface of the bronchial tree, which results in bronchial constriction and narrowing of the airways. Anticholinergic drugs block these ACh receptors to prevent bronchoconstriction. This indirectly causes airway relaxation and dilation. Anticholinergic agents also help reduce secretions in COPD patients.
Anticholinergics Drug Interactions
Possible additive toxicity may occur when anticholinergic bronchodilators are taken with other anticholinergic drugs.
Leukotriene Receptor Antagonists Indications
The LTRAs montelukast, zafirlukast, and zileuton are used for the prophylaxis and long-term treatment and prevention of asthma in adults and children 12 years of age and older. Because it is dosed once daily, montelukast is the most widely used of these drugs and has also been approved for treatment of allergic rhinitis, a condition discussed in Chapter 36. These drugs are not meant for the management of acute asthmatic attacks. Improvement with their use is typically seen in about 1 week.
Leukotriene Receptor Antagonists Adverse Effects
The adverse effects of LTRAs differ depending on the specific drug. The most commonly reported adverse effects of zileuton include headache, nausea, dizziness, and insomnia. The most common adverse effects of montelukast and zafirlukast include headache, nausea, and diarrhea.
Beta-Adrenergic Agonists
The beta-adrenergic agonists are a group of drugs that are commonly used during the acute phase of an asthmatic attack to quickly reduce airway constriction and restore airflow to normal. They are agonists of the adrenergic receptors in the sympathetic nervous system
Xanthine Derivatives Adverse Effects
The common adverse effects of the xanthine derivatives include nausea, vomiting, and anorexia. Cardiac adverse effects include sinus tachycardia, extrasystole, palpitations, and ventricular dysrhythmias. Transient increased urination and hyperglycemia are other possible adverse effects. Overdose and other toxicity of xanthine derivatives are usually treated by the repeated administration of doses of activated charcoal.
Corticosteroids Adverse Effects
The main undesirable local effects of typical doses of inhaled corticosteroids in the respiratory system include pharyngeal irritation, coughing, dry mouth, and oral fungal infections. Instruct patients to rinse their mouths after use of an inhaled corticosteroid. Most of the drug effects of inhaled corticosteroids are limited to their topical site of action in the lungs. There is relatively little systemic absorption of the drugs when they are administered by inhalation at normal therapeutic dosages. However, the degree of systemic absorption is more likely to be increased in patients who require higher inhaled dosages. When there is significant systemic absorption, which is most likely with high-dose intravenous or oral administration, corticosteroids can affect any of the organ systems in the body. Some of these systemic drug effects include adrenocortical insufficiency, increased susceptibility to infection, fluid and electrolyte disturbances, endocrine effects, CNS effects (insomnia, nervousness, seizures), and dermatologic and connective tissue effects, including brittle skin, bone loss, osteoporosis, and Cushing's syndrome
Anticholinergics Adverse Effects
The most commonly reported adverse effects of inhaled anticholinergics are related to their pharmacology and include dry mouth or throat, nasal congestion, heart palpitations, gastrointestinal (GI) distress, urinary retention, increased intraocular pressure, headache, coughing, and anxiety. Ipratropium is classified as a pregnancy category B drug; all others in this class are pregnancy category C.
Xanthine Derivatives
The natural xanthines consist of the plant alkaloids caffeine, theobromine, and theophylline, but only theophylline and caffeine are currently used clinically. Synthetic xanthines include aminophylline and dyphylline. Caffeine, which is actually a metabolite of theophylline, has other uses described later in the chapter.
Anticholinergics Contraindications
The only usual contraindication to the use of bronchial anticholinergic drugs is known drug allergy, including allergy to atropine. In the past, an allergy to peanuts or soy was listed as a contraindication to ipratropium inhalers. This was related to the propellant used, and the new HFA inhalers have eliminated the concern. Thus, there is no contraindication using ipratropium in patients with peanut or soy allergies. Caution is necessary in patients with acute narrow-angle glaucoma and prostate enlargement.
Beta agonists Indications
The primary therapeutic effect of the beta agonists is the prevention or relief of bronchospasm related to bronchial asthma, bronchitis, and other pulmonary diseases. However, they are also used for effects outside the respiratory system. Because some of these drugs have the ability to stimulate both beta1- and alpha-adrenergic receptors, they may be used to treat hypotension and shock
Xanthine Derivatives Interactions
The use of xanthine derivatives with any of the following drugs causes an increase in the serum level: allopurinol, cimetidine, macrolide antibiotics (e.g., erythromycin), quinolones (e.g., ciprofloxacin), influenza vaccine, and oral contraceptives. Their use with sympathomimetics, or even caffeine, can produce additive cardiac and CNS stimulation. Rifampin increases the metabolism of theophylline, which results in decreased theophylline levels. St. John's wort enhances the metabolism of xanthine drugs; thus, higher dosages of theophylline may be needed. Cigarette smoking has a similar effect because of the enzyme-inducing effect of nicotine. Interacting foods include charcoal-broiled, high-protein, and low-carbohydrate foods. These foods may reduce serum levels of xanthines through various metabolic mechanisms.
Bronchodilators
These drugs relax bronchial smooth muscle, which causes dilation of the bronchi and bronchioles that are narrowed as a result of the disease process. There are three classes of such drugs: beta adrenergic agonists, anticholinergics, and xanthine derivatives.
Beta agonists Interactions
When nonselective beta blockers are used with the beta agonist bronchodilators, the bronchodilation from the beta agonist is diminished. The use of beta agonists with monoamine oxidase inhibitors and other sympathomimetics is best avoided because of the enhanced risk for hypertension. Patients with diabetes may require an adjustment in the dosage of their hypoglycemic drugs, especially patients receiving epinephrine, because of the increase in blood glucose levels that can occur.
Xanthine Derivatives Indications
Xanthines are used to dilate the airways in patients with asthma, chronic bronchitis, or emphysema. They may be used in mild to moderate cases of acute asthma and as an adjunct drug in the management of COPD. Xanthines are now deemphasized because of their potential for drug interactions and the interpatient variability in therapeutic drug levels in the blood. Because of their relatively slow onset of action, xanthines are used for the prevention of asthmatic symptoms and COPD, not for the relief of acute asthma attacks. Caffeine is used without prescription as a CNS stimulant, or analeptic (see Chapter 13), to promote alertness (e.g., for long-duration driving or studying). It is also used as a cardiac stimulant in infants with bradycardia and for enhancement of respiratory drive in infants.
Xanthine Derivatives action
Xanthines cause bronchodilation by increasing the levels of the energy-producing substance cAMP. They do this by competitively inhibiting phosphodiesterase, the enzyme responsible for breaking down cAMP. In patients with COPD, cAMP plays an integral role in the maintenance of open airways. Higher intracellular levels of cAMP contribute to smooth muscle relaxation and also inhibit IgE-induced release of the chemical mediators that drive allergic reactions (histamine, slow-reacting substance of anaphylaxis, and others). Theophylline is metabolized to caffeine in the body, whereas aminophylline is metabolized to theophylline. Theophylline and other xanthines stimulate the CNS, but to a lesser degree than caffeine. This stimulation of the CNS has the beneficial effect of acting directly on the medullary respiratory center to enhance respiratory drive. In large doses, theophylline may stimulate the cardiovascular system, which results in both an increased force of contraction (positive inotropy) and an increased heart rate (positive chronotropy). The increased force of contraction raises cardiac output and hence blood flow to the kidneys. This, in combination with the ability of the xanthines to dilate blood vessels in and around the kidney, increases the glomerular filtration rate, which produces a diuretic effect.
