Advanced Pharmacology Respiratory Pharmacology

Transcription

1 Advanced Pharmacology Respiratory Pharmacology Thomas W. Barkley, Jr., PhD, ACNP BC, FAANP President, Barkley & Associates and Professor of Nursing Director of Nurse Practitioner Programs California State University, Los Angeles Robert Fellin, PharmD, BCPS Faculty, Barkley & Associates Pharmacist, Cedars Sinai Medical Center Los Angeles, CA Allergic Rhinitis Allergic rhinitis (hay fever) resembles the common cold: Tearing Sneezing Nasal congestion Postnasal drip Itchy throat Due to antigen (allergen) exposure Pollen, mold spores, dust mites, certain foods, animal dander Genetic predisposition 1

2 Allergic Rhinitis Seasonal vs. perennial allergic rhinitis Pathophysiology: Inflammation of the mucous membranes in the nose, throat and airways Normal nasal mucosa has many mast cells and basophils (try to recognize environmental agents as the enter the body) Allergic rhinitis patients have more mast cells Histamine (chemical mediator of inflammation): responsible for many of the symptoms of allergic rhinitis H 1 -receptors: Responsible for allergic symptoms H 1 -receptor Antagonists/Antihistamines FIRST Generation Adverse brompheniramine (Dimetapp), chlorpheniramine (Chlor-Trimeton), clemastine (Tavist), cyproheptadine (Periactin), dexchlorpheniramine (Polaramine), dimenhydrinate (Dramamine), diphenhydramine (Benadryl), hydroxyzine (Atarax, Vistaril), promethazine (Phenergan) sedation, dry mouth, headache, dizziness, urinary retention, thickening of bronchial secretions, nausea, vomiting, hypotension, tachycardia, QT prolongation All equally effective Often combined with decongestant/antitussive Most effective when taken prophylactically to prevent allergic symptoms Ability to reverse acute allergic symptoms is limited Caution with alcohol and other CNS depressants Some patients experience paradoxical excitation 2

3 H 1 -receptor Antagonists/Antihistamines SECOND Generation Adverse azelastine (Astelin), cetirizine (Zyrtec), desloratadine (Clarinex), fexofenadine (Allegra), levocetirizine (Xyzal), loratadine (Claritin), olopatadine (Patanase, Patanol) dry mouth, headache, dizziness, drowsiness, bitter taste (olopatadine), nausea, hypotension, sedation (less than 1 st generation) Azelastine: intranasal formulation Most effective when taken prophylactically to prevent allergic symptoms Ability to reverse acute allergic symptoms is limited All equally effective Caution with alcohol and other CNS depressants Some patients experience CNS stimulation (nervousness, insomnia, tremor, etc.) Considered less effective than 1 st generation agents Nasal Decongestants Adverse naphazoline (Privine), oxymetazoline (Afrin), phenylephrine (Neo- Synephrine), pseudoephedrine (Sudafed) sympathomimetic, alpha-adrenergic activity Intranasal: transient nasal irritation, burning, sneezing, nasal dryness, rebound congestion All: headache, nervousness, insomnia, headache, dry mouth, CNS excitation, tremors, dysrhythmias, tachycardia, difficulty in voiding Provide immediate relief for acute allergy symptoms Intranasal: duration should not exceed 3 to 5 days as tolerance develops Tolerance: gradually switch to intranasal corticosteroids Oral products do not produce rebound congestion Prolonged use: hypersecretion of mucus, worsening nasal congestion Onset of action: intranasal much faster than oral agents Do not relive sneezing, tearing 3

4 Intranasal Glucocorticoids Adverse beclomethasone (Beconase AQ), budesonide (Rhinocort Aqua), ciclesonide (Omnaris), flunisolide (Nasalide), fluticasone (Flonase), mometasone (Nasonex), triamcinolone acetonide (Nasacort AQ) reduce inflammation, edema; cause vasoconstriction transient nasal irritation, burning, sneezing, nasal dryness, epistaxis DOC for allergic rhinitis Minimal adverse effects All administered by metered-spray device All equally effective May take 3-4 weeks to achieve peak response Most effective when taken in advance of expected allergen exposure Miscellaneous Agents Adverse cromolyn (NasalCrom), ipratropium (Atrovent), montelukast (Singulair) mast cell stabilizer, anti-inflammatory (cromolyn) anticholinergic agent (ipratropium) leukotriene receptor antagonist (montelukast) nasal burning, irritation (cromolyn) nasal irritation, burning, sneezing, nasal dryness, cough, HA (ipratropium) HA, nausea, diarrhea (montelukast) Reserved for patients unresponsive to other therapies May take 4 weeks to achieve peak response Most effective when taken in advance of expected allergen exposure Limited effectiveness/less effective than other agents Role of montelukast remains to be defined 4

5 Antitussives: Opioids Adverse codeine, (Robitussin-AC), dextromethorphan (Benylin, Delsym), hydrocodone (Hycodan) suppress the cough reflex via CNS lightheadedness, sedation, nausea, headache and dizziness Most effective agents available for cough suppression Suppression of cough obtained at doses lower than those needed for analgesia Dextromethorphan max dose: 120 mg/day Dextromethorphan: most frequently used antitussive (OTC cough & cold products) Use of codeine/hydrocodone has diminished Codeine/hydrocodone: controlled substances Antitussives: Non-Opioids Adverse benzonatate (Tessalon Perles) anesthetizes the stretch receptors in the lungs, thus suppressing cough nausea, dizziness, headache, sedated, somnolence Benzonatate requires prescription Well tolerated with minimal adverse effects Do not crush/chew benzonatate = numbing of the mouth and pharynx Chemically related to local anesthetics 5

6 Expectorants guaifenesin (Robitussin) increases the volume and reduces the viscosity of secretions in the trachea and bronchi Adverse nausea, vomiting Most effective OTC expectorant (?) Common ingredient in many OTC cough and cold preparations Maximum dose: 2400 mg/24 hours FDA Statements: OTC Cold Products Not appropriate to take data from adults and apply it to children under 12 years of age Products containing decongestants, antihistamines and antitussives are NOT effective in children < 6 years of age and may cause serious side effects FDA: strongly recommend NOT using such OTC products in children < 2 years of age More studies about how these medicines affect children are needed 6

7 Mucolytics N-Acetylcysteine (Mucomyst) Dose: Adverse Adjuvant therapy in patients with abnormal or viscid mucous secretions in acute and chronic bronchopulmonary disease exerts mucolytic action through its free sulfhydryl group which opens up the disulfide bonds in the mucoproteins thus lowering mucous viscosity 1 ml of 20% solution or 2 ml of 10% solution via nebulizer 4 times/day Nausea, vomiting, bronchospasm Patients should receive a bronchodilator prior to administration 7

8 Dornase Alfa (Pulmozyme) Dose: Adverse Adjunct management of CF to reduce the frequency of respiratory infections, and to improve pulmonary function recombinant Human Deoxyribonuclease (rhdnase); selectively cleaves DNA of neutrophils thereby decreasing mucous viscosity 2.5mg nebulized inhalation daily chest pain, pharyngitis, cough dyspnea, hemoptysis, wheezing, rash, conjunctivitis Should not be used routinely as a mucolytic outside cystic fibrosis patients Drugs for Lower Pulmonary Disorders 8

9 Pulmonary Drugs via Inhalation Aerosol suspension of minute liquid droplets or fine sold particles suspended in gas Major Advantage: Delivers drugs to the immediate site of action (reducing systemic effects) An oral drug would have to be given in a higher dose to have an equivalent therapeutic dose All inhalation agents have the potential to produce systemic effects (e.g., anesthetics, paint thinners, etc.) Devices for Inhalation Metered Dose Inhalers (MDIs) use a propellant to deliver a measured dose of drug to the lungs during each breath of drug emitted from the MDI Dry Powder Inhalers (DPIs) small device that is activated by inhalation to deliver a fine powder directly to the bronchial tree Nebulizers small machines that vaporize a liquid medication into a fine mist that can be inhaled, using a face mask of handheld device 9

10 Methods of Aerosol Delivery Population Optimal technique Therapeutic issues MDI Spacer and Valve holding chamber Nebulizer Age > 5 years old Age > 4 years old For patient who cannot use MDI or a face mask Actuation during slow deep inhalation followed by 10 second breath holding Open mouth technique Close mouth technique Actuation during slow deep inhalation followed by 10 second breath holding Slow tidal breathing with occasional deep breaths Using a blow-by technique is not appropriate Deposition of 50~80% of actuated dose in oralpharynx Bulky to carry Decrease oral-pharyngeal deposition & decrease risk of thrush Output is dependent on device and operating parameters Use of face mask decreases delivery to lungs by 50% Expert Panel Report: NHLBI Guidelines for the Diagnosis and Management of Asthma - Summary Report Disadvantages of Aerosols Precise dose received by the patient is difficult to measure Optimally, only 10-50% actually reaches the lower respiratory tract Swallowing medication may cause systemic SE Rinse mouth thoroughly after use

11 Which Method of Drug Delivery is Superior? Metered-Dose Inhaler Nebulizer Dry Powder Inhaler Pharmacology for Nurses: A Pathophysiologic Approach (4th Edition) Asthma Chronic inflammatory disorder of the airways causing recurrent episodes of wheezing, breathlessness, chest tightness and coughing that is reversible either spontaneously or with treatment million people in the US have asthma One of the most common chronic diseases of childhood Variability in response to medications requires individualization of therapy 11

12 Asthma Increased responsiveness of the trachea and bronchi to stimuli Narrowing of airways Asthma: Pathophysiological Characteristics Hypertrophy of smooth muscle Mucosal edema and hyperemia Thickening of epithelial basement membrane Hypertrophy of mucus gland Acute inflammation Plugging of airways by thick, viscous mucus 12

13 Asthma Most important allergens are encountered indoors! Dust, pets, roaches, molds, cigarette smoke, exercise, etc. Labs/Diagnostics Signs and symptoms (intermittent dyspnea, cough & wheezing) Physical exam & Patient history PFT values (spirometry) Chest x-ray findings: hyperinflation 2007 Asthma Guidelines: National Heart, Lung and Blood Institute Classification of Asthma Severity Components of Severity Intermittent Asthma Severity Persistent Mild Moderate Severe Symptoms < 2 days/week >2 days/week Daily Throughout the day Nighttime awakening < 2 x/month 3-4 x/month > 1 x/week, not nightly Often 7 x/week Short acting β agonist for symptom control < 2 day/week > 2 days/week Daily Several times a day Interference with normal activities none Minor Some Extreme Lung function FEV1 > 80% > 80 % % < 60% FEV1/ FVC normal normal Reduced < 5% Reduced > 5% Risk Exacerbation requiring oral systemic corticosteroids 0-1 / year > 2 / year Recommended Step for Initiating therapy Step 1 Step 2 Step 3 Step 4 or 5 Consider short course of oral systemic corticosteroids Expert Panel Report: NHLBI Guidelines for the Diagnosis and Management of Asthma - Summary Report

14 Management of Asthma Expert Panel Report: NHLBI Guidelines for the Diagnosis and Management of Asthma - Summary Report Beta-Agonists/Sympathomimetics Adverse DOC for acute bronchoconstriction; Intermittent symptoms; Exercise-Induced Bronchospasm (EIB) Short acting agents (SABA s): albuterol (Proventil), levalbuterol (Xopenex), metaproterenol (Alupent), pirbuterol (Maxair), terbutaline (oral; Brethine) cause bronchial smooth muscle relaxation dose-related tachycardia, tremor, palpitations, nausea, headache, hypokalemia Scheduled daily use not recommended Quick onset of action Duration of action: 5-6 hours Levalbuterol is NOT superior to other agents DPI s not indicated for acute severe exacerbations 14

15 Inhaled Corticosteroids (ICS) Preferred therapy for long-term control of persistent asthma in all patients beclomethasone (Beclovent), budesonide (Pulmicort), ciclesonide (Alvesco), flunisolide (Aerospan), fluticasone (Flovent), mometasone (Asmanex) anti-inflammatory; inhibits inflammatory cells and release of inflammatory mediators Adverse headache, pharyngitis, dysphonia, oral candidiasis Administer on scheduled basis, not prn NOT used to treat an acute asthma attack Rinse mouth thoroughly after inhalation Budesonide is preferred in pregnancy Systemic adverse effects can occur with any ICS Beta-Agonists/Sympathomimetics Adverse Treatment and prevention of bronchospasm only as concomitant therapy inhaled corticosteroid; Exercise-Induced Bronchospasm (EIB) Long acting (LABA s): arformoterol (Brovana)*, formoterol (Foradil), indacaterol (Arcapta)*, salmeterol (Serevent) cause bronchial smooth muscle relaxation tachycardia, tremor, palpitations, nausea, headache, hypokalemia DO NOT act quickly NOT for acute symptom management Duration of action: 12 hours Should not be used as monotherapy *FDA labeled only for COPD 15

16 Methylxanthines Adverse Alternative, not preferred, therapy for mild persistent asthma or as adjunct therapy with ICS aminophylline (IV), theophylline (oral; Theo-Dur) bronchodilation through smooth muscle relaxation nausea, vomiting, headache, insomnia, tremor, irritability, restlessness, tachycardia, seizures Clinical utility limited by low therapeutic index Many drug-drug interactions Metabolism/clearance is age dependent Monitor dug levels Mast Cell Stabilizers Adverse Alternative, but not preferred for mild persistent asthma; Exercise induced bronchospasm (EIB) cromolyn (Intal) anti-inflammatory; prevents bronchoconstriction; blocks the release of histamine Relatively non-toxic; taste disturbances, cough Not a substitute for ICS Not as effective as beta-agonist for EIB As effective as theophylline or leukotriene antagonists May take up to 4 weeks to achieve benefit 16

17 Leukotriene Modifiers Adverse Alternative, but not preferred for mild persistent asthma; Exercise induced bronchospasm (EIB) montelukast (Singulair), zafirlukast (Accolate), zileuton (Zyflo) inhibit bronchoconstriction; may prevent airway edema and smooth muscle contraction abdominal pain, dizziness, rash, dyspepsia, hepatotoxicity Not all patients report a benefit with treatment Difficult to predict who will respond Several drug interactions Zileuton: hepatotoxicity; monitor LFT s Less effective than low dose ICS Not as effective as LABA s when added to ICS Anticholinergics Adjunct therapy in acute asthma exacerbation not completely responsive to beta agonist ipratropium bromide (Atrovent) blocks acetylcholine at parasympathetic sites in bronchial smooth muscle causing bronchodilation Adverse Rare: mydriasis, dry mouth, taste disturbances ipratropium + beta agonists = greater and prolonged bronchodilation than using either agent separately Additional long-term studies are needed to determine its role in asthma *Not FDA labeled for asthma 17

18 Systemic Corticosteroids Adverse Acute severe exacerbations not responding completely to initial inhaled beta-agonist therapy prednisone (Deltasone), methylprednisolone (Solu- Medrol), prednisolone (Millipred) anti-inflammatory; inhibits inflammatory cells and release of inflammatory mediators nausea, hyperglycemia, psychosis, weight gain, osteoporosis IV therapy offers no therapeutic advantage over oral administration Duration of therapy: 5-10 days High-dose regimens do not enhance outcomes and are associated with higher rate of side effects Should not be used as chronic maintenance therapy Recombinant Anti-IgE Antibody Agent: Dose: Adverse Treatment of allergic asthma not well controlled on oral corticosteroids or ICS omalizumab (Xolair) binds to the mast cells limiting the of release of mediators in response to allergen exposure Based on baseline total serum IgE level & weight injection site reaction, headache, pharyngitis, sinusitis, thrombocytopenia, anaphylaxis Do not abruptly stop systemic or ICS upon initiation of therapy Subcutaneous injection Cost of therapy is significant Due to the potential for anaphylaxis, patients should be observed for 2 hours after injection 18

19 Asthma Action Plan Individualize for each patient Allows for self-management Teaches patients to recognize triggers/ early signs of deterioration Allows early institution of therapy for acute exacerbations Improves outcomes COPD Chronic Bronchitis: Excessive secretion of bronchial mucus Present 3 months or more in each of 2 consecutive years Emphysema: Abnormal permanent enlargement of air spaces distal to the terminal bronchiole Destruction of the alveoli 19

20 COPD Diagnostics Symptoms (dyspnea at rest or on exertion, cough with or without sputum production, progressive limitation of activity) Spirometry showing airflow limitation that is incompletely reversible with inhaled bronchodilator FEV 1 and all other measurements of expiratory airflow reduced TLC, FRC and RV may be increased Absence of an alternative explanation for the symptoms and airflow limitation 2014 GOLD Guidelines for COPD: Global Strategy for Diagnosis, Management and Prevention of COPD Classification of COPD Classification of Severity of Airflow Limitation in COPD (Based on Post-Bronchodilator FEV1) In patients with FEV 1 /FVC < 0.70: GOLD 1: Mild FEV 1 80% predicted GOLD 2: Moderate 50% FEV 1 < 80% predicted GOLD 3: Severe 30% FEV 1 < 50% predicted GOLD 4: Very Severe FEV 1 < 30% predicted 20

21 Global Strategy for Diagnosis, Management and Prevention of COPD Combined Assessment of COPD Risk (GOLD Classification of Airflow Limitation) (C) (D) (A) (B) CAT < 10 CAT >10 Symptoms mmrc 0 1 mmrc >2 Breathlessness 2 or >1 leading to hospital admission 1 (not leading to hospital admission) 0 Risk (Exacerbation history) Management of COPD Smoking cessation Avoid irritants and allergens Pulmonary rehabilitation Immunizations Influenza vaccine Pneumococcal vaccine Pharmacotherapy Bronchodilators Theophylline Corticosteroids Antibiotics Oxygen 21

22 Beta-Agonists/Sympathomimetics Adverse DOC for intermittent symptoms of COPD Beta-agonist = anticholinergic Short acting agents (SABA s): albuterol (Proventil), levalbuterol (Xopenex), pirbuterol (Maxair) cause bronchial smooth muscle relaxation dose-related tachycardia, tremor, palpitations, nausea, headache, hypokalemia Improve symptoms; do not slow decline of COPD Scheduled daily use may be required Quick onset of action Levalbuterol is NOT superior to other agents Frequently used in combination with anticholinergic (Combivent) Anticholinergics Adverse DOC for COPD; use tiotropium for frequent and persistent symptoms NOT used as monotherapy for acute exacerbations Short acting: ipratropium bromide (Atrovent) Long acting: tiotropium (Spiriva), aclidinium (Tudorza) blocks acetylcholine at parasympathetic sites in bronchial smooth muscle causing bronchodilation Rare: mydriasis, dry mouth, taste disturbances Improve symptoms; do not slow decline of COPD Slower onset and more prolonged effect compared with beta-agonist Consider tiotropium when patients require short acting agents on a scheduled basis Frequently used in combination with beta-agonist 22

23 Beta-Agonists/Sympathomimetics Frequent and persistent symptoms of COPD; utilized when patients require short acting agents on a scheduled basis Long acting (LABA s): arformoterol (Brovana)*, formoterol (Foradil), indacaterol (Arcapta)*, salmeterol (Serevent) Cause bronchial smooth muscle relaxation Adverse Tachycardia, tremor, palpitations, nausea, headache, hypokalemia NOT for acute symptom management More convenient: 12 hour duration Useful for nocturnal symptoms No dose titration; standard dosage for all agents Improve symptoms and reduce exacerbations *FDA labeled for COPD Methylxanthines Adverse Adjunct therapy for patients who have not achieved optimal response to ipratropium/beta-agonist theophylline (oral; Theo-Dur) bronchodilation through smooth muscle relaxation; respiratory stimulant; reduces diaphragmatic fatigue nausea, vomiting, headache, insomnia, tremor, irritability, restlessness, tachycardia, seizures Clinical utility limited by low therapeutic index Many drug-drug interactions Monitor dug levels Considered only for those who are intolerant or unable to use an inhaled bronchodilator 23

24 Inhaled Corticosteroids (ICS) Adverse Symptomatic patients with a FEV 1 < 50% & repeated exacerbations (Stage III and IV) beclomethasone (Beclovent), budesonide (Pulmicort), ciclesonide (Alvesco), flunisolide (Aerospan), fluticasone (Flovent), mometasone (Asmanex) anti-inflammatory; inhibits inflammatory cells and release of inflammatory mediators headache, pharyngitis, dysphonia, oral candidiasis Does not modify long-term decline of FEV 1 in COPD Reduces frequency of exacerbations Combination therapy with LABA > either agent alone Not all patients will benefit from ICS Rinse mouth thoroughly after inhalation Systemic adverse effects can occur with any ICS Systemic Corticosteroids Adverse Acute exacerbation; Chronic therapy should be avoided if possible prednisone (Deltasone), methylprednisolone (Solu- Medrol), prednisolone (Millipred) anti-inflammatory; inhibits inflammatory cells and release of inflammatory mediators nausea, hyperglycemia, psychosis, weight gain, osteoporosis Clinical benefit in chronic management not evident and risk of toxicity is extensive NOT considered as routine maintenance therapy If required, use lowest effective dose 24

25 Phosphodiesterase 4 Inhibitors Adverse severe COPD associated with chronic bronchitis roflumilast (Daliresp) not well defined; increased levels of intracellular cyclic AMP in lung cells, and reduced neutrophil and eosinophil cell counts in the lungs weight loss, decrease in appetite, diarrhea, nausea, dizziness, headache, insomnia, anxiety, depression, suicidal ideation, completed suicide NOT for acute symptom management Contraindicated in liver impairment More studies are required to further define roflumilast s role in therapy Patient Group Recommended First Choice Alternative Choice Other Possible Treatments** A B C D Short-acting anticholinergic prn or Short-acting beta 2 -agonist prn Long-acting anticholinergic or Long-acting beta 2 -agonist Inhaled corticosteroid + long-acting beta 2 -agonist or Long-acting anticholinergic Inhaled corticosteroid + long-acting beta 2 -agonist and/or Long-acting anticholinergic Long-acting anticholinergic or Long-acting beta 2 -agonist or Short-acting beta 2 -agonist and short-acting anticholinergic Long-acting anticholinergic and long-acting beta 2 -agonist Long-acting anticholinergic and long-acting beta 2 -agonist or Long-acting anticholinergic and phosphodiesterase-4 inhibitor or Long-acting beta 2 -agonist and phosphodiesterase-4 Inhibitor Inhaled corticosteroid + long-acting beta 2 -agonist and long-acting anticholinergic or Inhaled corticosteroid + long-acting beta 2 -agonist and phosphodiesterase-4 inhibitor or Long-acting anticholinergic and long-acting beta 2 -agonist or Long-acting anticholinergic and phosphodiesterase-4 inhibitor Theophylline Short-acting beta 2 -agonist and/or Short-acting anticholinergic Theophylline Short-acting beta 2 -agonist and/or Short-acting anticholinergic Theophylline Carbocysteine Short-acting beta 2 -agonist and/or Short-acting anticholinergic Theophylline *Medications in each box are mentioned in alphabetical order, and therefore not necessarily in order of preference **Medications in this column can be used alone or in combination with other options in the Recommended First Choice and Alternative Choice columns 25

26 Pneumonia Pneumonia: Signs/Symptoms Fever Shaking chills Purulent sputum Lung consolidation on physical exam Malaise Increased fremitus 26

27 Management of Pneumonia Strep. pneumoniae: most common etiological agent for community acquired pneumonia (CAP) Outpatient Management of CAP: Healthy patients (< 60 years old with NO comorbidities) Macrolide (azithromycin, clarithromycin, erythromycin) Doxycycline Patients with other health problems (e.g., COPD, diabetes, heart failure, cancer or > 65 years old) Respiratory fluoroquinolone (moxifloxacin, gemifloxacin or levofloxacin Beta-lactam (amoxicillin-clavulanate, cefuroxime) plus a macrolide or doxycycline The End 27