NU 607: Advanced Pharmacology - Drugs Affecting Respiratory System PDF

1 COPD as the slide reads is an obstructive alteration which if you remember from patho is associated with normal or above TLC and prolonged expiratory phase (basically – air gets in but has difficulty getting out  There are four disorders associated with COPD – three we talked about in patho (em...

1 COPD as the slide reads is an obstructive alteration which if you remember from patho is associated with normal or above TLC and prolonged expiratory phase (basically – air gets in but has difficulty getting out  There are four disorders associated with COPD – three we talked about in patho (emphysema, chronic bronchitis and asthma). Bronchiectasis is a disorder that is characterized by dilation of bronchi and bronchioles as a result of infection (bacterial and/or viral) and inflammation. 2 Medications frequently prescribed for COPD include the following: Bronchodilators  used to assist in opening narrowed airways. Three categories commonly used include: 1. Adrenergics 2. Anticholinergics 3. Methylxanthines Glucocorticoids  used to decrease inflammation; used in chronic treatment of COPD Leukotriene modifiers & Mast cell stabilizers reduce inflammation in the lung tissue by suppressing the release of histamine and other mediators from the mast cells. These are basically used as prophylactic agents Expectorants  used to assist in loosening the mucus from the airways Antibiotics  prescribed when bacterial infections complicate the respiratory status 3 Treatment principles for COPD are based on GOLD standards Short summary of GOLD: Stage I requires a short acting beta agonist to manage acute episodes of difficulty breathing. Stage II includes a short acting beta agonist bronchodilator as needed in addition to a long acting anticholinergic bronchodilator for symptom management. Consideration is given to combination therapy with theophylline for those with breakthrough symptoms. Stage III includes the addition of inhaled steroids along with the scheduled long acting bronchodilator and short acting as needed bronchodilator. Stage IV employs the use of oxygen therapy in conjunction with treatment provided during Stages I to III. FYI: Inhaled steroids do not affect the rate of decline of lung function in COPD but do reduce the frequency of exacerbations. For that reason, inhaled steroids are recommended in stage III and IV COPD with frequent exacerbations 4 5 6 There are a number of factors that contribute to bronchoconstriction. Cyclic adenosine monophosphate (cyclic AMP, or cAMP), a cellular signaling molecule, is involved in many cellular activities and is responsible for maintaining bronchodilation. When histamine, eosinophil chemotactic factor of anaphylaxis (ECF-a), and leukotrienes inhibit the action of cAMP bronchoconstriction results. Adrenergics and methylxanthines increase the amount of cAMP in bronchial tissue cells In acute asthmatic attack, the short-acting sympathomimetics (beta-2- adrenergic agonists) are the 1st line of defense  they promote cAMP production and enhance bronchodilation. The long acting sympathomimetics are used for maintenance therapy, their onset of action is too long to make them appropriate for acute episodes 7 Sympathomimetics increase cAMP  causing dilation of the bronchioles. In acute bronchospasm caused by anaphylaxis from an allergic reaction: Epinephrine (Adrenalin)  nonselective sympathomimetic is given It is an alpha1, and beta1 and beta 2 agonists For bronchospasm associated with chronic asthma or COPD: Selective beta2-adrenergic agonists are given by aerosol or orally. Inhaled routes are preferred as the drug gets to the site of action quickly and inhaled route should limit systemic side effects. Adverse effects are more often seen with SAB vs. LAB Adrenergics Albuterol (Proventil) prototype Selective beta-2 agonist Drug of choice for first-line therapy – also referred to as a short acting bronchodilator (SAB). Commonly used on an as needed basis for SOB associated with COPD Use of a SAB more than 2-3X wk means asthma is not well controlled and adjustments to baseline therapy need to be made Metaproterenol (Alupent); Formoeterol; Salmeterol (Serevent Diskus) Long-acting inhaled bronchodilator s (LAB) used in chronic maintenance of asthma & COPD and also used in the prevention of exercise induced asthma. Half-life is 12 hours Typically a LAB and inhaled corticosteroid is used in combination to control asthma symptoms. LAB should not be used more than 2X QD and NOT as an on needed basis In 2005, FDA issued a black box warning that the LAB are not indicated for abortive therapy for bronchospasm. If taken they could result in unrelieved bronchospasm. As LAB are associated with increased risk of asthma related death, intubation or hospitalization it is no longer recommended as monotherapy for asthma. They are frequently used in combination with corticosteroids and in the treatment of COPD. 8 9 High doses or overuse may cause some degree of beta-1 responses. Adverse effects occur more frequently when the drug is administered orally than when it is inhaled. The most common adverse effects include: CNS  nervousness, tremors, insomnia CVS  tachycardia, heart palpitations (high doses); increased blood pressure GI  n, v **Overuse of albuterol may induce rebound bronchoconstriction, regardless of the method of administration. Side effects of beta2-agonists may diminish after a week or longer. The bronchodilating effects may decrease with continued use. It is believed that tolerance to these drugs can develop  it this occurs, the dose may need to be increased. Failure to respond to a previously effective dose may indicate worsening asthma that requires reevaluation before increasing the dose. 10 Methylxanthines (Xanthines) were once used as the first-line drug for treating clients with chronic asthma (now beta-agonists and corticosteroids are the primary drugs used in asthma). Xanthines are now used more as a treatment option in COPD. However, use has declined sharply d/t the serious adverse effects associated with them and efficacy has not been found to be greater than the beta agonists or glucocorticoids. Mechanism of action  increases cAMP leading to bronchial smooth muscle & pulmonary vessel relaxation Have impact on most body systems including: Powerful CNS stimulants CVS effects – dilate coronary vessels Diuretic effect Also, increases the force of contraction of diaphragmatic muscles to draw more air into the lungs. 11 While not as frequently used in asthma or COPD as other drugs, you will see them used in the treatment of apnea of prematurity (AOP) d/t effect on CNS stimulation and effect on diaphragmatic contraction. 12 The average onset of action for theophylline is 30 minutes; for sustained-release capsules, it is 1 to 2 hours. The duration of action for the sustained-release form is 8 to 24 hours and approximately 6 hours for the other IV or oral theophylline preparations. Large volumes of fluid and high-protein meals may increase the rate of absorption. Tobacco smoking increases metabolism of theophylline drugs, thereby decreasing the half-life of the drug  important, hint, hint 13 Important information  Theophylline has a narrow therapeutic drug window. Clients who receive theophylline need to be closely monitored for serious side effects and drug interactions Precautions & Contraindications clients with cardiac d/t its stimulatory effects, renal or hepatic dysfunction Adverse drug reactions  n, v, gastric pain (due to increased gastric acid secretion), tachycardia, irritability, seizures, cardiorespiratory collapse **there is no antidote for theophylline toxicity Monitoring Serum theophylline levels Toxicity likely to occur when level exceeds 20 mcg/ml When levels exceed 30 mcg/ml  hyperglycemia; hypotension, seizures, brain damage and death can occur. ***if serum levels of theophylline have not been stabilized, screen the client’s diet, other drugs being taken (including OTC drugs, smoking habits and adherence to prescribed regimen. hint, hint 14 Important slide Theophylline has a substantial interaction with a number of drugs. Beta-blockers & erythromycin  decrease liver metabolism of theophylline-thereby increasing the half-life and adverse effects of theophylline Barbiturates  induce CP450, stimulating theophylline metabolism which can result in subtherapeutic levels of theophylline Macrolide antibiotics inhibits metabolism of theophylline & increase renal clearance of e-mycin Digoxin  increased risk of digoxin toxicity Lithium  theophylline decreases the effects of lithium *****Smoking  decreases theophylline levels. Some patients who smoke may require an increase in theophylline dosage of up to 50%****  hint, hint! for quiz Caffeine the effects of theophylline can be increased by foods containing caffeine (also remember that many OTC preparations frequently contain caffeine. Remember that theophylline in a prodrug and is converted to caffeine. 15 Inhaled anticholinergic drugs are considered first-line treatment for clients with COPD whose symptoms have become persistent. They are less effective against asthma Ipratropium antagonizes the action of acetylcholine by blocking receptors. The blocking of these receptors results in decreased contractility of smooth muscle thereby reducing bronchospaam. It can be administered by oral inhalation or intranasal spray Unlike other anticholinergics, ipratropium (Atrovent) has fewer systemic effects. However, paradoxic bronchospasm has been reported (especially in those using newly opened MDI). The combination of ipratopium with albuterol (Combivent) is used to treat chronic bronchitis: The combination is more effective & has longer duration of action than if either agent is used alone The combination is more effective in increasing FEV1 (which is the parameter used to evaluate asthmatics and obstructive lung disease & response to the bronchodilators) 16 Clients who use a beta-agonist inhalant should administer it 5 minutes before using ipratropium. When using the anticholinergic agent in conjunction with an inhaled glucocorticoid or cromolyn, the ipratropium should be used 5 minutes before the steroid or cromolyn This causes the bronchioles to dilate so the steroid or cromolyn can be deposited in the bronchioles **ipratropium aerosols can produce a paradoxic acute bronchospam that can be life-threatening in some clients. It usually is seen with the first inhalation from a newly opened MDI The new MDI should be primed with 2 sprays before use 17 18 Monitor & report serum theophylline levels greater than 20 mcg/ml  therapeutic level is considered between 5 and 15 **** No antidote for theophylline toxicity Charcoal, emesis, gastric lavage decrease absorption of the oral medication Lidocaine  to treat dysrhythmias Diazepam  to control seizures 19 Suppress inflammation in the airways  which helps decrease mucus secretions and decreases edema; also helps repair epithelial cell damage Increase number of adrenergic receptors improves the patient’s response to adrenergic bronchodilators Drug combinations used to treat asthma include: Inhaled corticosteroid  helps decrease frequency and severity of acute episodes of asthma; helps prevent lung damage with chronic asthma and COPD Leukotriene receptor antagonists Mast cell stabilizer 20 Glucocorticoid steroids are the most effective anti-inflammatory drugs available for managing respiratory disorders. They can be given orally, parenterally, or by inhalation. Oral and parenteral agents are the most potent and are reserved for an exacerbation of COPD or asthma that occurs despite the use of inhaled steroids. Inhaled steroids have become the first-line treatment for persistent asthma. Although there may be health care provider preferences. The prototype is flunisolide. Inhaled steroids have several actions: They inhibit the production of leukotrienes and prostaglandins through interference with arachidonic acid metabolism Reduce the migration & activity of the inflammatory cells Increase the number & responsiveness of beta receptors in airway smooth muscles Decrease the production of mucus 21 Despite being an inhaled drug, some systemic absorption does occur. During inhalation especially when a spacer is not used, flunisolide is deposited in the mouth and pharynx where some of the drug is swallowed. But, adverse effects are limited – sore throat, hoarseness, coughing, dry mouth and oral fungal infections are the most common. Suppression of the hypothalamic-pituitary-adrenal (HPA) axis is possible with long term daily use, but this effect is very rare. *** However, be aware that clients making the transition from oral to inhaled steroids have an increased risk of adrenal insufficiency if they experience trauma, surgery, or infections (especially gastroenteritis). Because of the route of administration, no important drug-drug interactions occur with flunisolide. 22 23 Vasoactive substances such as histamine, serotonin, bradykinin, and leukotrienes are located with the mast cell. When the mast cell undergoes degranulation, these substances are released and cause an inflammatory response, such as bronchial constriction, which accounts for the symptoms of an acute asthma attack. The prototype mast cell stabilizer is cromolyn sodium (Intal). It is an anti- inflammatory agent that works at the surface of the mast cell to inhibit its rupture and degranulation after contact with an antigen. This action, in turn, prevents the release of histamine and mediators of Type-I allergic reactions. These medications also decrease inflammatory cells such as eosinophils and macrophages ***While these medications are used infrequently, it is important to remember that it is not a bronchodilator. It is contraindicated for treating acute bronchospam Omalizumab  monoclonal antibody binds to IgE and lowers the concentration of free IgE and prevents binding of IgE to mast cells (thus preventing the activation and degranulation of mast cells). It will also reduce the late phase of allergic response by preventing the IgE binding to other cells in the body. It’s given SQ every 2-4 weeks (has a very long half-life of 26 days) and dose is based on IgE levels per body weight. 24 In general, cromolyn is well tolerated. No clinically important drug interactions are known with cromolyn 25 26 Leukotrienes are inflammatory mediators that are powerful bronchoconstrictors and vasodilators. Leukotriene receptor antagonists are used as prophylaxis or for treating chronic asthma; they are not indicated for symtpoms of an acute attack. They block the binding of LTD4 to its receptor (LTD4 is the predominant leukotriene in the airways and lung). Basically this drug class inhibits leukotriene synthesis by preventing the conversion of arachidonic acid into leukotrienes. Can be used as an alternative to inhaled corticosteroids but are less effective Zafirlukast is administered orally. In treating asthma, the peak action is noted as early as day one of therapy – but more commonly takes up to 2 weeks. Use in adults and children over 12 years of age. The most common adverse effects are headache, gastritis, pharyngitis, and rhinitis. They are known to be hepatotoxic and baseline LFTs need to be obtained prior to use and monitor your patient for clinical manifestations of liver toxicity (nausea, anorexia, and abdominal pain). This drug does interact with theophylline, warfarin, aspirin and drugs metabolized through the P450 enzyme system. Theophylline levels may increase while on Zafirlukast so need to monitor serum theophylline levels Aspirin increases the plasma concentration of Zafirlukast by 45% There is increased warfarin elimination and anticoagulant dosages should be adjusted 27 The remainder of the slides will look at agents used to treat upper respiratory disease. Antihistamines are used to relieve symptoms of allergies. These drugs, which block the action of histamine as it is released during the inflammatory response to an antigen, are very effective for allergic rhinitis. Their action restores normal airflow throw the upper respiratory system. Because of their OTC availability, these drugs are often misused to treat colds and influenza. 28 Drugs within the antihistamine class can be separated into first-generation and second-generation agents. First generation – are also referred to as sedating antihistamines Diphenhydramine (Benadryl) prototype Second generation – are known as non-sedating antihistamines (although a better term might be less-sedating antihistamines) Fexofenadine (Allegra) prototype Loratadine (Claritin)  can be taken once a day. Most effective on empty stomach. Cetirizine (Zyrtec)  is most sedating of the 2nd generations; is approved for use in children as young as 6 months of age Azelastine (Asteline)  administered as a nasal spray. 29 Fexofenadine (prototype) – second generation antihistamine Blocks H1-receptor sites decreasing the allergic response. Has anticholinergic and antipruritic effects As a 2nd generation, it has less anticholinergic effect than the 1st generation antihistamines It binds to lung receptors substantially more than it binds to cerebellar receptors  so less CNS sedation produced (compared to 1st generation) Used to relieve symptoms associated with seasonal and perennial allergic rhinitis, allergic conjunctivitis, uncomplicated urticaria, and angioedema Most effective if used before onset of symptoms Taken orally & absorbed rapidly  peak drug effect is seen within 2 to 6 hours. Only slightly metabolized (~5%) in liver and is excreted in the feces (80%) and urine (11%). 30 Adverse Flu-like symptoms N,v Dysmenorrhea Dyspepsia ? QT-interval prolongation  fexofenadine is a metabolite of terfenadine, which has been associated with prolonged QT interval and ventricular tachycardias (and is no longer manufactured). While, fexofenadine had not induced QT-interval prolongation – patients should still be monitored for this adverse effect. Drug interactions Rifampin  reduces absorption Apple, grapefruit, orange  decrease the absorption 31 Diphenhydramine (Benadryl) Has anticholinergic activity  and all the contraindications & adverse effects seen with the anticholinergics apply to this drug. For example – should not be used in clients with glaucoma. Produces marked sedation in most patients  this is one of the most common side effects associated with the 1st generation antihistamines. Other side effects include: Dizziness, fatigue, disturbed coordination Anticholinergic symptoms  dry mouth, urinary retention, blurred vision, wheezing Unusual excitement or irritability can occur in children Has many uses in addition to treating allergy. These include: Antiemetic  relieves n, v Motion sickness  relieves vertigo associated Induce sleep 32 The following slides are FYI slides –you will not be tested on these drug classes Antitussives are drugs that suppress the cough reflex. Many disorders of the upper and lower respiratory tracts, including the common cold, sinusitis, pharyngitis, and pneumonia are accompanied by an uncomfortable, non-productive cough. Coughing normally is a protective mechanism that forces foreign irritants out of the respiratory system. Persistent coughing can be exhausting, cause muscle strain, irritate respiratory tract Cough that occurs without an active disease process should be investigated before any drug is given to alleviate it Antitussive drugs include: Dextromethorpan  prototype Codeine  controlled substance used in treating cough (more sedating than dextromethorphan & may induce respiratory depression Hydrocodone bitartrate (Hycodan) also a controlled substance; is a derivative of codeine 33 Dextromethorphan is used in treating non-productive cough. It is available in a wide variety of nonprescription forms such as: capsules. Lozenges. Syrups, extended- release oral suspension and chewable tablets. Suppress cough reflex in medulla Related chemically to the opiate agonists can suppress coughing as effectively as narcotics Therapeutic doses do not affect ciliary activity It is contraindicated in treating chronic coughs resulting from emphysema and asthma If coughing is suppressed in these patients, the retained secretions may exacerbate their disease. Rapidly absorbed from GI tract  antitussive activity occurs within 15 to 30 minutes Undergoes extensive hepatic metabolism Excretion mainly renal 34 Adverse effects are generally rare Drowsiness, dizziness, irritability and restlessness characterize toxicity Dextromethorphan abuse is a growing problem in high schools Drug Interactions Potentiate sedation when used with other CNS depressants May interact with monoamine oxidase inhibitors (MAOIs)  resulting in serotonin syndrome A dangerous condition that consists of nausea, hypotension, excitation, hyperpyrexia, and possible come Grapefruit and orange juice  inhibit metabolism resulting in increased risk of pharmacologic and adverse effects that can last for several days. 35 Expectorants are drugs that liquefy lower respiratory tract secretions. This effect decreases the viscosity of the secretions (which makes it easier for the patient to cough them up) and improves airflow. Found in many OTC cold remedies, antihistamines, decongestants and antitussives Guaifenesin (Robitussin)  prototype Well absorbed from the GI tract Onset of action is 30 minutes with duration of action 4 to 6 hours This drug enhances the output of respiratory tract fluids by reducing the adhesiveness and surface tension of the fluids  this allows for easier movement of the less viscous secretions Thinned secretion result in a more productive cough And, with a more productive cough  the frequency of coughing should decrease Adverse effects are mainly GI symptoms  n, v and anorexia There are no major drug-drug interactions, 36 37