Asthma, COPD, and Allergic Rhinitis

Asthma, COPD, and Allergic Rhinitis
Jennifer Toy, PharmD UW Medicine Harborview Family Medicine Clinic January 2015

ASTHMA CASE 1 GD is a 56 yo male who comes to clinic c/o dyspnea and coughing that have progressively worsened over the past 2 days. Recently diagnosed with asthma ~ 1 mo ago. Reports inhaler is “not working.” Physical exam reveals audible wheezes, occasional coughing. Medications: Albuterol HFA inhaler 1-2 puffs q4-6h prn shortness of breath or cough  Your evaluation should consist of … ?

3 Point Evaluation – “3 T’s”
Appropriate Therapy? Change – increase or decrease dose Initiate new therapy Stop/discontinue therapy Appropriate Technique? Tolerability?

Proper Inhaler Technique
10-25% of expelled medication will reach pulmonary system Remainder is deposited on the mouth, pharynx, esophagus, and stomach 40% of persons are NOT able to demonstrate proper inhaler technique

Proper Inhaler Technique
Majority of medication accumulates on the throat and contributes to systemic side effects Use of proper technique or Aerochamber improves lung deposition and reduces systemic side effects Aerochamber improves lung deposition by 25%

Spacer vs Suspending Chamber

CASE 1 (continued) So how do we know the patient is using appropriate technique?

Proper Metered Dose Inhaler (MDI) Technique
When using MDI for first time: Shake the inhaler for 5 seconds Prime the inhaler by pressing down the canister with the index finger to release the medication Press canister down again 3 times After an inhaler is used for the first time, no need to prime again UNLESS patient has not used for 2 weeks or more

Proper MDI Technique Shake canister vigorously for 5 seconds
Uncap mouthpiece and check for loose objects in the device Breathe out normally Hold MDI upright Close lips around spacer OR if no spacer is available, close lips around mouthpiece or position it about 4 cm from the mouth Keep tongue away from the spacer opening or mouthpiece Exhale completely before MDI actuation Press down the top of the medication canister with the index finger to release the medication Slow deep inhalation (3-5 sec) until the lungs are completely filled

MDI Inhaler Technique Pearls
One puff per inhalation Wait 60 seconds between puffs, or long enough to perform the next inhalation properly Shake canister again before use Recap mouthpiece Rinse mouth after using an ICS, and spit the water out rather than swallow it

MDI vs. Dry Powder Inhaler (DPI)
DPI in response to CFC ban Powder requires different technique: Requires sufficient inspiratory effort for powder to reach lungs Does not require coordination Contains smaller particles Possibly improved lung deposition of medications Persons are unable to determine if they received the medication (no taste, no tactile sensation)

Dry Powder Inhaler (DPI) Technique
For single-use devices, load a capsule into the device as directed Breath out slowly and completely (not into the mouthpiece) Place mouthpiece between the front teeth and seal lips around it Breathe in through the mouth quickly and deeply over 2-3 seconds Remove inhaler from mouth Hold breath for as long as possible ~10 seconds Breathe out slowly

Short-Acting Beta Agonists (SABAs or Rescue Inhalers)
Bronchodilator Increases cAMP, decreases intracellular calcium Produces smooth muscle relaxation Stabilizes mast-cells (minimal effect)

Inhaled SABAs Short-Acting Beta Agonist Duration Onset Albuterol
Metaproterenol (no longer available) Terbutaline 3-6 hrs 4 hrs 1.5-4 hrs 5 mins 5-30 mins Nonselective B-agonist: Isoproterenol Epinephrine 1-3 hrs 2-5 mins 1-5 mins

Inhaled Beta-Agonists
PRN vs scheduled Asthma management vs exercise induced bronchospasm Monitor utilization of beta-agonist Improper technique Proper technique – relief indicates severity of asthma Use of SABA helps determine when to initiate inhaled steroids

CASE 2 – Asthma SM is 40 yo female with asthma presents to clinic with increasing SOB over the past few days. She is unable to complete sentences. What is your treatment of choice? What formulation?

MDI vs Nebulizer Outcomes Nebulizer Group Spacer Group P value
Severity score improvement % 80.9 79.4 0.79 Final PEFR, % Predicted 79 76 0.61 Final Oxygen Saturation % 97 0.67 Mean # of Treatments 2.5 2.3 0.55 Steroid Administration % 44 54 0.26 Admission Rate % 6.2 5.6 0.89 Mean Treatment Time (mins) 103 66 <0.001 Vomiting % 20 8 <0.05 Mean increase in Heart Rate 15 5

MDI vs Nebulizer Albuterol Dose MDI 90 mcg/dose Neb 2.5mg/ampule
MDI 2-4 puffs = 2.5mg Neb MDI + Spacer/Aerochamber is a MORE efficient delivery system than Nebulizer

Albuterol vs Levalbuterol
Racemic Albuterol (S and R) and Levalbuterol (R-albuterol) Pediatric exacerbations randomized to nebulized Albuterol vs Levalbuterol 83% African American children Significantly lower hospitalization rate with levalbuterol LOS not significantly different Similar rates of side effects: HR, RR, and nausea Carl. J Ped 2003; 143:731-6.

SABAs Short-Acting -Agonist Dosage Forms Strengths Cost Albuterol
(Proventil, Ventolin, AccuNeb) Neb MDI Tabs Syrup 0.63 mg/3 ml 1.25 mg/3 ml 2.5 mg/3 ml 5 mg/ml 90 mcg/puff 2 mg, 4 mg 2 mg/ 5 ml Neb #25 = $17-40 MDI = $30-$78 Tab #30 = $5 (cash $ ) #120 ml = $14 Levalbuterol (Xopenex) 0.31 mg/neb 0.63 mg/neb 1.25 mg/neb 45 mcg/puff Neb #24 = $ MDI = $71-81

Short-Acting -Agonist
Brands Dosing* Adults & Children  12 years Dosing* Children 5-11 years Children 0-4 years Pearls Albuterol HFA Proventil Ventolin ProAir AccuNeb 2 puffs every 4-6 hours 2 puffs 5 min prior to exercise mg neb every 4-6 hours 1.2-5 mg neb every 4-6 hours 1-2 puffs 5 min prior to exercise mg neb every 4-6 hours Contains EtOH and Oleic Acid No Excipients Levalbuterol HFA* Xopenex mg neb 3 times a day (Dose for 4-11 years) mg neb 3 times a day MDI safety and efficacy not established mg neb every 4-6 hours *Prime 4 times before use *Usually used in COPD Pirbuterol Maxair 2 puff every 4-6 hours Safety and efficacy not established No longer available – phased out d/t CFC ban

Acute Asthma Exacerbations
Albuterol vs Albuterol + Ipratropium Efficacy: Pediatric and Adult studies demonstrate variable results and do not consistently show benefit Combination of Albuterol + Ipratropium may benefit patients with severe obstruction or FEV1 <50%

Albuterol and Ipratropium
MDI or Nebulizer Strength Cost Albuterol HFA Ipratropium HFA (Atrovent) Albuterol/Ipratropium (Combivent) 90 mcg/puff 18 mcg/puff 103 mcg – 18 mcg/puff MDI = $30-78 MDI = $40-51 MDI = $ Albuterol Neb Ipratropium Neb Albuterol/Ipratropium Neb (DuoNeb) 2.5 mg/3 ml 0.2 mg/ml 0.5mg-2.5mg/3 ml Neb #24 = $16-40 Neb #25 = $13-38 Neb #30 = $49-76

Albuterol and Ipratropium
MDI or Nebulizer Dosing*Adults and Children  12 years Dosing*Children 5-11 years Dosing* Children 0-4 years Albuterol HFA Ipratropium HFA (Atrovent) Albuterol/Ipratropium (Combivent) 2 puffs every 4-6 hours 2-4 puffs every 6 hours 2 puffs every 6 hours Safety and efficacy not established Albuterol Neb Ipratropium Neb Albuterol/Ipratropium Neb (Duoneb) mg neb every 4 hours 500 mcg every 20 minutes, then as needed 3 ml every 4-6 hours mg neb every 4 hours mg neb every 4-6 hours

Home Acute Asthma Exacerbation
Peak Flow (PF) < 50% Predicted Albuterol MDI 2-4 puffs every 20 mins OR Single nebulizer treatment PEF > 80% -Continue Albuterol every 3-4 hrs x 2-4 days -Double inhaled steroid x 7-10 days PEF 50-80% -Continue Albuterol every mins -Oral steroid burst PEF < 50 % -Continue Albuterol every 20 mins -Oral steroid burst, call provider, or go to ED

ER Acute Asthma Exacerbation
FEV1 or PEF > 50% -Albuterol MDI or Neb x 2 in the 1st hr -O2 to achieve O2 sat ≥ 90% -Oral steroids if no immediate response FEV1 or PEF < 50% -Albuterol MDI or Neb every 20 mins or continuously for 1 hr -O2 to achieve O2 sat ≥ 90% -Then Levalbuterol OR Albuterol AND Anticholinergic every 20 mins for 1 hr -Oral steroids Impending or actual respiratory arrest -Intubation or medical ventilation with 100% O2 -Nebulized Albuterol AND anticholinergic -IV steroid

CASE 3 – Acute Asthma Exacerbation
You are about to prescribe prednisone for an acute exacerbation. How would you prescribe prednisone? Dose? Taper or no taper?

Steroid Bursts (Taper vs Non-Taper)
Taper prednisone 10mg Take 4 tabs daily x 3 days Take 3 tabs daily x 3 days Take 2 tabs daily x 3 days Take 1 tab daily x 3 days then stop Non-Taper prednisone 20mg Take 2 tabs daily for 5-7 days or Take 3 tabs daily x 3 days then take 2 tabs daily x 3days then stop

CASE 4-Step Up Therapy JZ 25 yo male returns to the clinic after being prescribed albuterol He states the albuterol helps relieve his shortness of breath but it does not last long State requiring the albuterol at night about 3 times in the last month

Inhaled Corticosteroids (ICS)

Inhaled Corticosteroids (ICS)
Brand Strengths Cost Budesonide DPI Pulmicort 90 mcg/puff 180 mcg/puff $ $ Beclomethasone MDI QVAR 40 mcg/puff 80 mcg/puff $ $ Flunisolide MDI Aerospan AeroBid (d/c-ed) $ Fluticasone Flovent HFA Flovent DPI 44 mcg/puff 110 mcg/puff 220 mcg/puff 50 mcg, 100mcg, 250mcg/blister $ $ $ $ Mometasone DPI Asmanex $ $ Ciclesonide MDI Alvesco 160 mcg/puff $ $

Inhaled Corticosteroids Dosing* Adults and Children  12 years
Dosing* Children 5-11 years Dosing* Children 0-4 years Budesonide (Pulmicort) Low Dose ( mcg)/day Medium Dose (> mcg)/day High Dose (>1200 mcg)/day Low Dose ( mcg)/day Medium Dose (> mcg)/day High Dose (>800 mcg) *Can use Pulmicort Respules NA Beclomethasone MDI (QVAR) Low Dose ( mcg)/day Medium Dose (> mcg)/day High Dose (>480 mcg)/day Low Dose ( mcg)/day Medium Dose (> mcg)/day High Dose (>320 mcg)/day Flunisolide MDI (AeroBid) Low Dose ( mcg)/day Medium Dose (> mcg)/day High Dose (>2000 mcg)/day Low Dose ( mcg)/day Medium Dose (> mcg)/day High Dose (>1250 mcg)/day Fluticasone MDI (Flovent) Low Dose ( mcg)/day Medium Dose (> mcg)/day High Dose (>440 mcg)/day Low Dose ( mcg)/day Medium Dose (> mcg)/day High Dose (>352 mcg)/day Approved for 4 years and older Mometasone DPI (Asmanex) Low Dose (220 mcg)/day Medium Dose (440 mcg)/day Dose (110 mcg)/day Ciclesonide MDI (Alvesco) Low Dose (160 mcg) Medium Dose (320 mcg) High Dose (640 mcg)

Comparative ICS Potency

Summary: Comparative ICS Potency
Potency is not related to efficacy Potency equates to # of puffs required Differences between inhaled steroids # of puffs required per day Bioavailability (1st pass effect) Receptor affinity and half-life

Side Effects of ICS Effects of local deposition: dysphonia, topical candidiasis, contact hypersensitivity Systemic ADRs: Adrenal suppression Lung infection Ocular effects Skeletal effects Other Concerns

ICS: Adrenal Suppression?
Mixed results Dependent on dose, duration, frequency, and timing glucocorticoid administration Effects of ICS on HPA axis appear infrequent and clinically insignificant

ICS: Lung Infection? Mixed results
Some studies found small increase in risk for bacterial lung infection No increased mortality

ICS: Ocular Effects? Intraocular pressure Cataracts
Limited data demonstrate no relationship between glaucoma or increased intraocular pressure and inhaled steroids Lifetime doses of >2000mg may increase prevalence of cataracts

ICS: Growth Deceleration?
Childhood Asthma Management Program (CAMP) N=1041, age 5-12, randomized to inhaled budesonide or nedocromil Results: Year 1: reduction of growth velocity in budesonide group End of study: no difference in growth results CAMP Follow-Up Study N=943, age 24.9± 2.7 yrs Mean adult height was 1.2 cm lower in budesonide group vs placebo compared to growth difference of 1.1 cm at time of trial

ICS: Osteoporosis? Mixed results – clinical significance is unclear
No strong evidence that low-med dose inhaled steroids reduce bone mineral density May affect bone health in certain populations eg post- menopausal women, pts taking higher doses, men with COPD

ICS: Drug-Drug Interactions
Ritonavir and Fluticasone propionate Ritonavir – strong CYP3A4 inhibitor  increased serum concentration of fluticasone propionate  increased serum concentrations and increased systemic effects Ketoconazole and Fluticasone furoate/vilanterol Ketoconazole – strong CYP3A4 inhibitor  serum concentration fluticasone furoate  increased serum concentrations and increased systemic effects

Long-Acting Beta Agonists (LABAs)

Stepping Up Therapy

LABAs LABAs Onset Peak Duration Binding Affinity Formoterol Salmetorol
Indacaterol *COPD Arformoterol 2-3 mins 10-20 mins 5 mins 7-20 mins 1-3 hours 2-3 hours 15 min 8-12 hours 10-12 hours 40-56 hours 26 hours +++ ++

LABAs Long-Acting -Agonist Dosage Forms Strengths Cost
Formoterol (Foradil) *Must be used with ICS in asthma Formoterol Neb (Perforomist) *COPD Powder Caps Neb 12 mcg/cap 20 mcg/2 ml #60 caps = $ #30 vials = $368 Arformoterol Neb (Brovana) 15 mcg/2 ml #30 vials = $ Salmeterol (Serevent) Diskus 50 mcg/dose DPI = $

LABAs Long-Acting -Agonist Brands Dosing*Adults & Children  12 yeas
Children 5-11 years Children 0-4 years Formoterol Foradil 1 cap BID Safety and efficacy not established Salmeterol Serevent 1 blister BID (Dose for 4-11 years)

LABA Controversies Differences between salmeterol and formoterol
Salmeterol may attenuate response to SABAs Slight benefit of formoterol but probably clinically equivalent Safety of LABAs used alone in asthma patients

Should LABAs be used as controller medications in Asthma?
Salmeterol Multi-center Asthma Research Trial (SMART) Salmeterol BID vs Placebo Interim results demonstrated no significant differences in primary endpoints Non-significant higher asthma related events in patients receiving Salmeterol Study discontinued 2002

SMART Trial 47% of patients received inhaled steroids 50% Caucasian
38% African-American No differences in endpts in pts receiving inhaled steroids Patients without inhaled steroids experienced higher rates of asthma-related deaths compared to placebo Long acting B-agonists are NOT controller medications for asthma Long acting B-agonists are not substitutes for inhaled steroids and should NOT be used as monotherapy Inhaled steroid should not be discontinued

Black Box Warning Data from a large placebo controlled study compared Salmeterol or placebo + usual care Results showed a small but significant increase in asthma related death in patients receiving Salmeterol 13 deaths /13,174 ~ 0.098% treated versus 4 deaths/13,179 ~ 0.03% placebo for 28 wks Subgroup analysis suggest the risk may be greater in African-American patients compared to Caucasians

Fluticasone + Salmeterol
Inhaled Steroid + Long acting -agonist Brands Strengths Dosing Cost Fluticasone + Salmeterol Advair (DPI) Advair (HFA) Fluticasone 100 mcg Salmeterol 50 mcg Fluticasone 250 mcg Salmeterol 50 mcg Fluticasone 500 mcg Salmeterol 50 mcg Fluticasone 45 mcg Salmeterol 21 mcg Fluticasone 115 mcg Salmeterol 21 mcg Fluticasone 230 mcg Salmeterol 21 mcg Adult and Child  12 years: 1 puffs BID Children 4-11 years: 1 puff of (100/50) BID $ $ $ $ $ $

Budesonide + Formoterol
Inhaled Steroid + Long-Acting -agonist Brands Strengths Dosing Cost Budesonide + Formoterol Symbicort Budesonide 80 mcg + Formoterol 4.5 mcg Budesonide 160 mcg + Fomoterol 4.5 mcg Adults and Children  12 years: 1-2 puffs BID Children 5-11 years: 2 puffs (80/4.5) BID $272- $300 $318- $335

Leukotriene Receptor Antagonists & Mast Cell Stabilizers
Leukotriene Receptor Antagonists (LTRAs) Brand Strengths Dosing Cost Montelukast Singulair 4 mg 5 mg 10 mg Adults and Children  15 years: 10 mg daily $30-170/mo Children 6-23 months: 4 mg daily Children 2-5 years: 4 mg daily Children 6-14 years: 5 mg daily Mast Cell Stabilizers Cromolyn Sodium NA Neb 20 mg/amp Adults and Children  12 years: 1 amp 4 times daily $60-170/mo Children 5-11 years: Children 2-4 years: 1 amp 4 times daily

Theophylline MOA: Phosphodiesterase inhibitor, results in increased cAMP and decreases cGMP to produce bronchodilation, also increases muscle contraction of diaphragm Drug Brand Strengths Dosing Cost Theophylline Theo-24 Hr Theochron-ER-12 Hr Theophylline ER-24 Hr 100 mg, 200 mg, 300 mg, 400 mg 100 mg, 200 mg, 300 mg 400 mg, 600 mg Doses should be individualized, based on peak serum concentrations, and should be based on ideal body weight. The elimination half-life is highly variable based on age, liver function, lung disease, and smoking history. Monitor Serum Peak Levels: Asthma: 5-12 mcg/ml $30-$44 $44-$50 $30-$60

Theophylline Side effects: tachycardia, nausea, GI upset, hyperkalemia, hyperglycemia, SEIZURES Maintain concentration 5-12 mcg/ml The following INCREASE theophylline levels: Erythromycin, ciprofloxacin, carbamazepine, CHF, cimetidine, disulfiram, hepatic disease, isoniazid, mexiletine, thiazolidinedione

Omalizumab Pts with Serum Ig-E level of 30-700IU/ml
Pts uncontrolled on High dose inhaled steroids and Long acting beta-agonist and Oral steroids (max 20mg/day) Omalizumab Placebo p-value ER visit 24% 44% 0.038 Hospitalization 6.2% 11% 0.117

Management of Asthma in Pregnancy
Albuterol preferred SABA Budesonide preferred ICS Salmeterol is preferred LABA Leukotriene receptor antagonists alternative but NOT preferred Treatment for acute exacerbations including systemic glucocorticoids – key is to monitor mother and fetus

Monitoring Symptoms (use of rescue inhaler, exacerbations, nocturnal symptoms) Side effects Inhaler technique Barriers or difficulties with therapy Review home care plan with patient/caregivers Review proper use of medications with patient/caregivers

Chronic Obstructive Pulmonary Disease (COPD)

Pharmacotherapy Bronchodilator therapy Beta-agonists Anticholinergics
Methylxanthines Provides symptomatic relief No benefit in mortality Goal: Reduction of symptoms

Recommended Therapy for Stable COPD
Stage I: Mild [FEV1: FVC < 70%, FEV1  80% ± symptoms] Smoking cessation Influenza vaccine + pneumococcal vaccine Short-acting bronchodilator

Stage II: Moderate [FEV1: FVC < 70%, 50% < FEV1 < 80% ± symptoms] Smoking cessation Influenza vaccine + pneumococcal vaccine Short-acting bronchodilator + long-acting bronchodilator + rehabilitation

Stage III: Severe [FEV1: FVC < 70%, 30% < FEV1 < 50% ± symptoms] Smoking cessation Influenza vaccine + pneumococcal vaccine Short-acting bronchodilator + long-acting bronchodilator + rehabilitation Add inhaled corticosteroids if repeat exacerbations

Stage IV: Severe [FEV1: FVC<70%, FEV1<30% ± symptoms] Smoking cessation Influenza vaccine + pneumococcal vaccine Short-acting bronchodilator + long-acting bronchodilator + rehabilitation Add inhaled corticosteroids if repeat exacerbations Add long-term oxygen if chronic respiratory failure

Short-Acting Bronchodilators: Albuterol vs Ipratropium
Onset Peak Onset Albuterol 5 mins 15-30 mins Ipratropium 15 mins 30-60 mins

Short-Acting Anticholinergic Ipratropium
Ipratropium MOA Ipratropium decreases ↓ cGMP cGMP causes contraction of airway smooth muscles, bronchoconstriction and enhances inflammation by indirectly stimulating release of mast cell contents May reduce mucus gland secretion Side effects: Dry mouth, anxiety, palpitations, nausea, blurred vision, headaches

Ipratropium Ipratropium reduces the volume of sputum without altering its viscosity Ipratropium can block Vagal mediated reflex preventing bronchoconstriction triggered by dusts, fumes and cigarette smoke

Albuterol or Ipratropium?
Approximately 70% of patients who were initially unresponsive to albuterol demonstrated responsiveness after subsequent administration Albuterol and Ipratropium are equally efficacious in the treatment of acute exacerbations of COPD Neither medication potentiates the action of the other

COPD Short-Acting Bronchodilators
Drug Brand Strength *Adult Dosing Cost Albuterol Levalbuterol ProAir HFA Proventil HFA Ventolin HFA Xopenex 90 mcg/puff 45 mcg/puff 1-2 puffs every 4-6 hours 2 puffs every 4-6 hours $30-78 $71-81 Ipratropium Atrovent HFA 18 mcg/puff 2-4 puff 3 to 4 times daily $ Albuterol + Ipratropium Combivent Respimat Ipratropium bromide 20 mcg/albuterol base 100 mcg 1 puffs every 6 hours $

Combivent Respimat Drug Brand Strength *Adult Dosing Cost
Ipratropium/Albuterol Combivent Respimat 18 mcg/103 mcg 1 puff every 4 hours $320-$375

Long-Acting Anticholinergic Tiotropium
Drug Brand Strength *Adult Dosing Cost Tiotropium DPI Spiriva 18 mcg/puff 1 cap inhaled daily $340-$385

Long-Acting Anticholinergic Aclindinium bromide
Drug Brand Strength *Adult Dosing Cost Aclindinium bromide Tudorza Pressair 400mcg/puff 1 puff BID $

Long-Acting Beta-Agonists Salmeterol and Formoterol
Long-Acting -agonist Brand Strengths * Adult Dosing Cost Formoterol Foradil 12 mcg/cap 1 cap BID #60 caps = $ Salmeterol Serevent 50 mcg/dose 1 puff BID #1 inh =$

Long-Acting Beta-Agonist Indacterol and Olodaterol
Long-Acting -agonist Brand Strengths * Adult Dosing Cost Indacaterol FDA Approval Date: July 1, 2011 Arcapta Neohaler *COPD Powder Caps 75mcg/dose 1 cap inhaled daily #30 caps = $ Olodaterol FDA Approval Date: August 1, 2014 Striverdi Respimat 2.5 mcg/actuation 2 oral inhalations (5 mcg) once daily at same time every day #1 inhaler per month $$$ (?)

LABA + ICS Combination Inhaler
Long-Acting -agonist + ICS Brand Strengths Adult Dosing Cost Fluticasone + salmeterol Advair Diskus 250mcg/salmeterol 50 mcg 1 inhalation twice daily $ Fluticasone furoate + vilanterol FDA Approval Date: 2013 Breo Ellipta 100mcg/25mcg per inhalation 1 inhalation once daily $

Tiotropium vs Salmeterol
Included persons with COPD and FEV1 39% of predicted Randomized to tiotropium daily or salmeterol BID x6 mos Brausasco. Thorax 2003;58:399–404

Tiotropium vs Salmeterol
Brausasco. Thorax 2003;58:399–404

Tiotropium vs Salmeterol (POET-COPD)
7376 patients with moderate-to-severe COPD 1 year randomized, double-blind, parallel-group trial Tiotropium 18mcg/day vs. Salmeterol 50mcg BID Tiotropium increased the time to first exacerbation compared with Salmeterol 187 days vs. 145 days; HR 0.83 (95% CI 0.77 to 0.90; P< 0.001) Tiotropium also reduced the annual number of moderate or severe COPD exacerbations compared to Salmeterol 0.64 vs. 0.72; RR 0.89 (95% CI 0.83 to 0.96; P = 0.002); NNT=25 Vogelmeier V, Hederer B, Glaab T, et al. NEJM 2011; 364:1093.

Salmeterol/Fluticasone vs Tiotropium (INSPIRE)
1323 patients with severe COPD High-dose Salmeterol/Fluticasone (Advair) 50/500mcg vs. Tiotropium (Spiriva) 18mcg/day Exacerbation rate did not differ between treatment groups (P=0.656) In exacerbations… Salmeterol/Fluticasone patients needed an antibiotic Tiotropium patients needed an oral corticosteroid Mortality was lower in the Salmeterol/Fluticasone group than in the Tiotropium group (3% vs 6%, p=0.032) Pneumonia was more frequent in the Salmeterol/Fluticasone group (HR 1.94, 95% CI 1.19 to 3.17; p=0.008) Wedzicha JA, Calverley PMA, Seemungal TA, et al. Am J RespirCrit Care Med 2008; 177:19-26.

Towards A Revolution in COPD Health (TORCH)
6112 patients, mostly severe COPD, randomized to treatment for 3 years - Salmeterol 50mcg BID - Fluticasone 500mcg BID - Salmeterol + Fluticasone combination - Placebo There was no significant mortality difference between combination therapy and Salmeterol Patients treated with combination therapy were less likely to die than those treated with Fluticasone alone (HR 0.774, 95% CI to 0.934; P=0.007) Fewer exacerbations in those receiving Salmeterol + Fluticasone compared to either agent alone or placebo; NNT = 4 (Combination vs. Placebo) However, any group that received treatment with an ICS had increased reports of pneumonia – 19.6% combination therapy , 18.3% fluticasone group vs. placebo 12.3% (p<0.001) Calverley et al. NEJM 2007;356:75-89.

Evidence to Support Triple Inhaler Therapy
In patients with severe COPD, triple therapy with a LABA, ICS, and LAAC is often used UPLIFT TRIAL 6000 patients 2/3 LABA + ICS + LAAC (Tiotropium) 1/3 LABA + ICS Addition of Tiotropium to LABA + ICS significantly improved airflow, reduced exacerbations, and improved health related quality of life Several retrospective cohorts have also found that the combination of LABA + ICS + Tiotropium is associated with ↓ mortality, ↓ exacerbations, and ↓ hospitalizations

Theophylline MOA: directly relax bronchial and pulmonary blood vessel smooth muscle, central respiratory stimulant, and more Therapeutic levels: 8-12 mcg/ml Side effects: Common: Nausea, vomiting, insomnia, restlessness, anxiety, anorexia, palpitations Serious: Seizures, arrhythmias Place in therapy?

Theophylline Drug-Drug Interactions
Increase Metabolism Decrease Metabolism Cigarette smoking High protein diet Hyperthyroidism Marijuana smoking Carbamazepine Barbiturates Rifampin Phenytoin Age >60 years Severe hypoxemia (arterial Po2 <45 mmHg) CHF Viral infections Allopurinol Cimetidine Erythromycin Quinolone Verapamil

Acute COPD Exacerbations: Cortiscosteroids
Leuppi et al (2013) Treatment for 5 vs 14 days prednisone 40mg daily N=314 pts No sig diff in primary outcome treatment relapse No sig diff in lung function or in any subjective outcomes

Acute Exacerbations: Antibiotics
Coverage: Haemophilus, Streptococcus, and Moraxella Indicated for treating infectious exacerbations of COPD and other bacterial infections Tx options: trimethoprim-sulfamethoxazole Doxycycline beta-lactamase stable PCNs 2nd or 3rd gene cephalosporins extended spectrum macrolides antipneumococcal FQs

Azithromycin Daily? 8 studies have evaluated whether macrolide antibiotics DECREASE the risk of acute exacerbations of COPD Mixed results Albert et al (2011) Azithromcyin 250mg po qday vs placebo for one year No significant difference though fewer hospitalizations for any cause, fewer hospitalizations related to COPD, fewer emergency dept or urgent care visits

Vitamin D in COPD? No definitive evidence demonstrating benefit in patients with pulmonary disease Slight improvements may be observed in patients who are already vitamin D deficient – supplementation gets them back to normal levels

Summary of Step-Wise Therapy
Bronchodilator Therapy Beta-agonist (short-acting) or Ipratropium Ipratropium + Beta agonist (Combined) Tiotropium Inhaled steroid (may reduce exacerbations, but increase RISK of pneumonia) Consider addition of Theophylline

ALLERGIC RHINITIS

Allergic Response Allergic response: IgE Production of IgE antibodies
IgE bound mast cells interacts with allergen Release of inflammatory mediators Response Immediate: Histamines, leukotrienes, prostaglandin, bradykininis Late: eosinophils, monocytes, macrophage, basophil, lymphocyte

Allergies Immunologic IgE mediated reaction
Degranulation of mast cells and immediate release of histamine, leukotriene, prostaglandin, and kinins Vasodilation, Increased vascular permeability Rhinorrhea, Sneezing, Itchy eyes

Rhinitis Infectious Viral Bacterial Non-Infectious
Allergy (immune mediated) Non-allergic (vasomotor)

Non-Pharmacologic Treatment
Allergen avoidance Exposure reduction HEPA vacuums (poor evidence) Encase bedding (poor evidence) Dehumidifier supposed to limit mold (poor evidence)

Pharmacologic Treatment
Antihistamines: oral or nasal or ophthalmic Inhaled steroids Antihistamines + inhaled steroids Other: Mast cell stabilizers Leukotriene modifiers Ipratropium (anti-cholinergic) Decongestants

Antihistamines

Antihistamines: H1 Receptor Blockers
MOA: blocks H1 receptors, no effect on leukotrienes, prostaglandins, bradykinins Reduces nasal itching, sneezing, rhinorrhea (NOT as effective at reducing nasal congestion) Limited effectiveness When should patients administer?

Antihistamines Class 1st Generation 2nd Generation Alkylamines
Brompheniramine Chlorpheniramine Pheniramine Triprolidine Acrivastine Ethanolamines Clemastine (Tavist) Diphenhydramine (Benadryl) Doxylamine Piperazines Hydroxyzine (Vistaril) Meclizine (Bonine, Antivert) Cetirizine (Zyrtec) Levocetirizine (Xyzal) Piperidine Azatadine Cyproheptadine Astemizole Loratadine (Claritin) Desloratadine (Clarinex) Phenothiazines Promethazine Fexofenadine (Allegra) Olopatadine Terfenadine Other Doxepin Azelastine Emedastine

Antihistamines Active metabolite of Hydroxyzine Cetirizine (Zyrtec)
Levocetirizine (Xyzal)* Active metabolite of Terfenadine Fexofenadine (Allegra)* Loratadine (Claritin) Desloratadine (Clarinex)*

How long do Antihistamines take to work?
1st Generation Onset of effect: minutes Duration of effect: 4-8 hours Half-life: 3-8 hours 2nd Generation Onset of effect: 1-3 hours Duration of effect: hours Half-life: hours

1st Generation Antihistamines
Crosses blood brain barrier, lipophilic Anti-cholinergic Anti-serotonergic Anti-alpha-adrenergic Sedative effects minimized if initiated at bedtime

Adverse Effects Anti-cholinergic (muscarinic)
Dry mouth, urinary retention, constipation, tachycardia Anti-serotonergic Increased appetite Anti-alpha-adrenergic Hypotension, dizziness, tachycardia Cardiac-ion channels Prolong QT interval

Considerations in Kids & Elderly
Impaired school performance Paradoxical agitation Elderly more susceptible to anti-cholinergic effects Dyskinesia Urinary hesitancy Confusion

2nd Generation Antihistamines
MOA: bind more specifically to peripheral H- receptors Do NOT cross blood-brain barrier, less lipophilic This means LESS sedation, dizziness, fatigue, insomnia, irritability, nervousness, urinary retention

2nd Generation: Comparisons
Sedation: Cetirizine, Levocetirizine Onset of action: Levocetirizine < Cetirizine, fexofenadine < Loratadine Lack of evidence of superiority between 2nd generation antihistamines No evidence one antihistamine will be effective after failing a previous antihistamine

Comparative Efficacy 2nd generation are LESS effective in relieving nasal congestion compared to 1st generation antihistamines Both 1st and 2nd generation antihistamines are LESS effective vs intranasal steroids

2nd Generation Antihistamines: Sedation-Free?
Cetirizine Fexofenadine Loratadine Dizziness 2% - Drowsiness 13.7% 1.3% 8% Fatigue 5.9% 4%

2nd Generation Antihistamines: Safety Concerns
Prolongation of QTc interval Astemizole and Terfendadine removed from market No reports with current 2nd generation anti-histamines

Pregnancy and Lactation
Category B Chlorpheniramine, Diphenhydramine Cetirizine, Loratadine Inhaled steroids Category C Hydroxyzine, Ketotifen Azelastine, Desloratadine, Fexofenadine, Olopatadine

Antihistamines: OTC vs Rx
Over the counter (OTC) 1st generation 2nd generation Loratadine (Claritin) Cetirizine (Zyrtec) Fexofenadine (Allegra) Prescription (Rx) Levocetirizine (Xyzal) Desloratadine (Clarinex)

Current Antihistamines
Drug *Adult Dosing *Child Dosing Generic OTC or Rx Chlorpheniramine (Chlor-Trimeton) 4 mg every 4-6 hours or SR 8-12 mg every hours ; NTE 24 mg/day 2-6 years: 1 mg every 4-6 hours NTE 6 mg in 24 hours Yes OTC $12.99 Clemastine fumurate (Tavist) 1.34 mg every 8 hours 6-12 years: 0.67 mg every 12 hours $18.00 Diphenhyramine HCl (Benadryl) 25-50 mg every 8 hours 5 mg/kg per day divided every 8 hours $4.00 Loratadine (Claritin) 10 mg daily 2-5 years: 5 mg once daily $21.99 Cetirizine (Zyrtec) 5-10 mg daily 6-12 mo: 2.5 mg daily 12 mo - < 2 years: 2.5 mg every 12 hours $29.99 Levocetirizine (Xyzal) 2.5-5 mg daily 6 mo-5 years: 1.25 mg daily 6-11 years: 2.5 mg daily No Rx $99.00 Desloratadine (Clarinex) 5 mg daily 6-11 mo: 1 mg daily 12 mo-5 years: 1.25 mg daily $147.00 Fexofenadine (Allegra) 60 mg every 12 hours or 180 mg daily 6 mo-< 2 years: 15 mg every 12 hours 2-11 years: 30 mg twice daily $15.00

Antihistamines: Intranasal
Drug *Adult Dosing *Child Dosing Generic Cost Azelastine (Astelin) (AH) 1 to 2 sprays in each nostril BID Ages 5 to 11 years: 1 spray in each nostril Yes $77-156 Olopatadine (Patanase) 2 sprays in each nostril Not approved for ages less than 12 years No $ Review cost

Antihistamines: Ophthalmic
Useful for allergic conjunctivitis Azelastine (Optivar) Emedastine (Emadine) Levocabastine (Livostin) Olopatadine (Patanol) Epinastine (Elestat) Ketotifen (Zaditor) (Zyrtec) OTC - antihistamine / mast cell stabilizer Study suggesting more effective compared to olopatadine Naphazoline/pheniramine (Naphcon-A, Opcon-A, Visine-A) OTC - can cause rebound symptoms – AVOID use >3 days

Nasal Corticosteroids

Blocks inflammatory response Reduces symptoms of Nasal congestion Rhinorrhea Sneezing, Nasal itching Conjunctivitis Generally MORE effective than antihistamines, decongestants, leukotriene antagonist and mast cell stabilizers

Drug *Adult Dosing *Child Dosing Generic Cost Beclomethasone (Beconase AQ) (S) 1 to 2 sprays in each nostril BID Ages 6 to 12 years: 1 to 2 sprays in each nostril BID No $149.99 Budesonide (Rhinocort Aqua) 1 to 4 sprays in each nostril daily Ages 6 to 11 years: 1 to 2 sprays in each nostril daily $111.96 Ciclesonide (Omnaris) 2 sprays in each nostril daily Ages 6 to 11 (seasonal allergic rhinitis indication only): 2 sprays in each nostril daily $105.99 Flunisolide (Nasarel) each nostril BID to TID (max 8 sprays in each nostril per day) Ages 6 to 14 years: 2 sprays in each nostril BID or 1 spray in each nostril TID (max 4 sprays in each nostril per day) Yes $45.99 Fluticasone furoate (Veramyst) Ages 2 to 11 years: $105.61 Fluticasone propionate (Flonase) Ages 4 to 17 years: $55.99 (generic) $85.98 (brand) Mometasone (Nasonex) 1 spray in each nostril daily $116.82 Triamcinolone (Nasacort AQ) $113.08 Prices from 2011

Evidence for Intranasal Corticosteroids vs Antihistamines
Percent % Eye Symptoms Symptom Free Rhinitis-Free Days Rinne. J All Clin Imm 2002;109(3):426

Combination Therapy: Antihistamines + Inhaled Steroids
Limited studies Little to minimal benefit Unfortunately minimal benefit at twice the cost

Decongestants

Decongestants Short-term benefit Efficacy: topical > oral
Oral decongestants; longer duration, increased systemic side effects

Decongestants Side Effects
Topical Rebound congestion (rhinitis medicamentosa) Do NOT use > 3-5 days Systemic HTN, urinary retention, mydriasis, tachycardia, restlessness, agitation, nervousness

Decongestants Phenylpropanolamine, Ephedrine were removed due to observational association with stroke Ephedrine (Ephedra, Ma Huang) Associated with stroke Avoid chronic use Pseudoephedrine, Phenylephrine Available

Efficacy: Pseudoephedrine vs Phenylephrine
“A placebo-controlled study of the nasal decongestant effect of phenylephrine and pseudoephedrine in the Vienna Challenge Chamber” Authors conclude that during 6 hr observation period, single dose of PSE but not PE resulted in significant improvement in measures of nasal congestion

Drug-Drug Interactions
MAO-Inhibitors Ergotamines (vasoconstrictors) SSRIs Diet pills, St. John’s Wort, Methamphetamines Linezolid

Decongestants: Precautions
Uncontrolled Hypertension History of cardiovascular disease History of stroke Glaucoma Arrhythmia Hyperthyroidism Prostatic hypertrophy Renal insufficiency

Management of Allergic Rhinitis in Pregnancy
Intranasal corticosteroids most effective and when used at prescribed doses low risk Montelukast okay but minimal data Antihistamines loratadine and cetirizine okay Avoid oral decongestants; use nasal dilator, short- term topical oxymetazoline

Summary Inhaled steroids are more efficacious compared to:
Oral antihistamines (1st and 2nd generation) Inhaled antihistamines Montelukast Montelukast + oral antihistamines Cromolyn sodium Ipratropium Inhaled steroids are similar in efficacy compared to oral antihistamine + pseudoephedrine Antihistamine ophthalmic agents Combination Inhaled steroids + ophthalmic antihistamine is slightly more effective than Inhaled steroids + oral antihistamine EXPENSIVE

Step Wise Therapy Oral 1st generation Antihistamine
Inhaled Steroid (1st line therapy) OR 2nd generation antihistamines (not as effective as inhaled steroids) Inhaled nasal steroids + oral antihistamines (minimal benefit with increased cost) Montelukast (not as effective as inhaled steroids) Oral Prednisone Immunotherapy

References Kelly W, Sorkness CA. Asthma. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. McGraw Hill; 2010; Expert Panel Report 3 (EPR3): Guidelines for the Diagnosis and Management of Asthma. Report commissioned by the National Asthma Education and Prevention Program (NAEPP) Coordinating Committee (CC), coordinated by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health Available from: Williams DM, Bourdet SV. Chronic obstructive pulmonary disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L, eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York, NY: McGraw-Hill; 2008: Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) Available from:

References Carl J, et al. Comparison of racemic albuterol and levalbuterol for the treatment of acute asthma. J Pediatr 2003;143:731-6. Brambilla C, Le Gros V, Bourdeix I; Efficacy of Foradil in Asthma (EFORA) French Study Group. Formoterol 12 μg BID administered via single-dose dry powder inhaler in adults with asthma suboptimally controlled with salmeterol or on-demand salbutamol: A multicenter, randomized, open-label, parallel-group study. Clin Ther Jul;25 (7): Au DH, Lemaitre RN, Curtis JR, Smith NL, Psaty BM.The risk of myocardial infarction associated with inhaled beta-adrenoceptor agonists. Am J Respir Crit Care Med Mar;161(3 Pt 1): Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax May;58(5): Erratum in: Thorax Feb;60(2):105. Advair (salmeterol/fluticasone) vs Spiriva (tiotropium) for COPD. Pharmacist's Letter/Prescriber's Letter 2008;24(3): Albert RK, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011;365: LeuppiJD,SchuetzP,BingisserR,etal.Short-termvsconventionalglucocor- ticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial [published online May 21, 2013]. JAMA. 2013; 309(21):

References May JR, Smith PH. Allergic Rhinitis. In: Dipiro JT, Talbert RL, Yee GC, et al eds.Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York, NY: The McGraw-Hill Companies, Inc; 2008: Comparison of antihistamines. Pharmacist's Letter/Prescriber's Letter 2008;24(7): New drug: Xyzal (Levocetirizine). Pharmacist's Letter/Prescriber's Letter 2007;9: FDA approves Zyrtec / Zyrtec-D for over-the-counter (OTC) use. Pharmacist's Letter/Prescriber's Letter 2008;24(1): New formulation: Astepro (azelastine) nasal spray. Pharmacist's Letter/Prescriber's Letter 2009;25(3): Alvesco (ciclesonide inhalation aerosol). Pharmacist's Letter/Prescriber's Letter 2008;24(9): Patanase (olopatadine) and Omnaris (ciclesonide): new nasal sprays for allergic rhinitis. Pharmacist's Letter/Prescriber's Letter 2008;24(6): Nasal sprays for allergic rhinitis. Pharmacist's Letter/Prescriber's Letter 2008;24(6): Quillen DM, Feller DB. Diagnosing rhinitis: allergic vs. nonallergic.Am Fam Physician May 1;73(9): Wilken JA, Kane RL, Ellis AK, Rafeiro E, Briscoe MP, Sullivan CL, Day JH.A comparison of the effect of diphenhydramine and desloratadine on vigilance and cognitive function during treatment of ragweed-induced allergic rhinitis.Ann Allergy Asthma Immunol Oct;91(4): Crawford WW, Klaustermeyer WB, Lee PH, Placik IM. Comparative efficacy of terfenadine, loratadine, and astemizole in perennial allergic rhinitis. Otolaryngol Head Neck Surg May;118(5): Hampel F, Ratner P, Mansfield L, Meeves S, Liao Y, Georges G. Fexofenadine hydrochloride, 180 mg, exhibits equivalent efficacy to cetirizine, 10 mg, with less drowsiness in patients with moderate-to-severe seasonal allergic rhinitis. Ann Allergy Asthma Immunol Oct;91(4): Berger WE, White MV; Rhinitis Study Group.Efficacy of azelastine nasal spray in patients with an unsatisfactory response to loratadine. Ann Allergy Asthma Immunol Aug;91(2): Rinne J, Simola M, Malmberg H, Haahtela T.Early treatment of perennial rhinitis with budesonide or cetirizine and its effect on long-term outcome.J Allergy Clin Immunol Mar;109(3): Weiner JM, Abramson MJ, Puy RM. Intranasal corticosteroids versus oral H1 receptor antagonists in allergic rhinitis: systematic review of randomised controlled trials. BMJ 1998; 317:1624.

Asthma, COPD, and Allergic Rhinitis

Similar presentations

Presentation on theme: "Asthma, COPD, and Allergic Rhinitis"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Asthma, COPD, and Allergic Rhinitis

Similar presentations

Presentation on theme: "Asthma, COPD, and Allergic Rhinitis"— Presentation transcript:

Similar presentations

About project

Feedback