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Asthma 1 Asthma Definition o Obstructive disease of the airways that is caused by hyperreactivity of airway smooth muscle, increased mucus secretion, or inflammation, and is completely reversible either spontaneously or with treatment. Epidemiology o Asthma affects ~ 14-15 million Americans (roughly 5% of the population) o Most common pulmonary disease o Children > adults, boys > girls o African Americans have 19% higher incidence than whites and are twice as likely to be hospitalized Morbidity / Mortality o >5000 deaths occur yearly in the U.S. due to asthma o Estimated that 80-90% of the deaths could have been prevented o Mortality increasing (may be due to pollutants, non-compliance with medications, or inadequate access to health care) Risk factors for early recurrent wheezing o Low Birth Weight o Male Gender Etiology Atopy o Parental Smoking Genetic Predisposition Genetically determined state of hypersensitivity to environmental Occupational Major risk factors for asthma allergens (production of IGE in response Atopy o Parental History to normal household allergens or things found in the environment) Minor risk factors for asthma Presence can indicate a poor prognosis o Eosinophilia o Wheezing without colds o Allergic rhinitis Indicator of poor prognosis: _Atopy_(can cause asthma, allergic rhinitis, eczema) Asthma triggers If have acid in stomach, lay down at night, aspirate that and cause damage to lungs and trigger asthma exacerbations Respiratory Infections Other diseases Allergens Environment Emotions Exercise Drugs/preservatives Occupational Stimuli RSV, rhinovirus, flu, parainfluenza, Mycoplasma pneumonia Sinusitis/rhinitis, premenstrual/pregnancy, nocturnal asthma, GERD, smoking Airborne pollen, house-dust mites, animal danders, cockroaches, fungal spores, foods Cold air, fog, ozone, sulfur dioxide, nitrogen dioxide, tobacco smoke, wood smoke Anxiety, stress, laughter Cold, dry climate ASA, NSAIDS, sulfites, benzalkonium chloride, beta blockers, iodinated radiocontrast media, ACEI Bakers, farmers, chemical workers, plastics, rubber, wood workers Bronchial Constriction, SOB Asthma 2 Mucus in airways, inflammatory cascade is kicking in Pathophysiology o Early asthmatic reaction o Late asthmatic reaction o BHR – bronchial hyperresponsiveness Clinical Relevance of Phases: Not all pts will develop LAR or BHR, however seen in most patients with moderate & severe persistent asthma Identifies ways to interfere with disease process Determines how meds are used Significance of repeated trigger exposure End result (late asthmatic response/BHR) Increases lung vascular permeability Leads to edema Prolong exposure Increased mucus production/secretion to triggers Eosinophils/inflammatory mediators continue to flood to the lung tissue Inflammatory cascade potentiated Clinical Presentation o Symptoms caused by Inflammation, Mucus plug, Bronchoconstriction Signs/Symptoms of Asthma Cough Wheeze Dyspnea and chest tightness Tachypnea and tachycardia Hypoxemia Hypercapnia and respiratory acidosis Pulsus paradoxus Diagnosis Spirometry -FEV1 – volume of air exhaled in 1st sec < 80 abnormal -FEV1/FVC – flow in 1st sec over total volume of air expired < 80% = obstruction to airflow in the airways Peak flow rates Predicted vs. personal best Predicted values -Based on ht, wt, sex -Reported as % predicted -Normal > 80% Peak expiratory flow rate (PEFR) -Air exhaled in 1st 10 msec -Personal best is preferred -Green zone: > 80% “go” -Yellow zone: 50-80% “caution” -Red zone: <50% “stop” Asthma Histopathy Edema Mast cell activation Infiltration of inflammatory cells: Neutrophils Eosinophils Lymphocytes To diagnose asthma, abnormal PFTs should improve 15% or more, following bronchodilator administration Want people to use their peak flow meter in the morning when they get up and in the afternoon (when get home from school), # should be close to each other Staging Asthma •Severe Persistent •Allergic asthma •Moderate Persistent •Exercise-induced asthma •Mild Persistent •Nocturnal asthma •Mild Intermittent Asthma 3 Staging asthma SYMPTOMS STEP 4 SEVERE PERSISTENT STEP 3 MODERATE PERSISTANT STEP 2 MILD PERSISTENT STEP 1 MILD INTERMITTENT Continual symptoms Limited physical activity Frequent exacerbations Daily symptoms Daily use of inhaled short acting beta 2 agoninsts Exacerbations affect activity Exacerbations > 2 times a week; may last days Symptoms > 2 times a week but < once a day Exacerbations may affect activity Symptoms < 2 times a week Asymptomatic and normal PEF between exacerbations Exacerbations brief (from a few hours to a few days); intensity may vary MANAGING ASTHMA NON PHARMACOLOGIC THERAPY o o o o Dysphonia: problems with vocal cords Immunotherapy Flu shot yearly Avoid triggers Environmental control NIGHTTIME SYMPTOMS LUNG FUNCTION Frequent FEV1 or PEF < 60% predicted PEFR variability > 30% > 1 time a week FEV1 OR PEFR > 60% < 80% predicted PEFR variability > 30% > 2 times a month FEV1 OR PEFR >80% predicted PEFR variability 20-30% < 2 times a month FEV1 or PEF > 80% predicted PEFR variability < 20% Environmental Control: –Vacuuming carpets –Air conditioning –Dehumidifier –No smoking –Avoid exercise during pollution –Avoid fumes LONG TERM CONTROLLERS VS. QUICK ACTING AGENTS INHALED CORTICOSTEROIDS (ICS) BEST DRUG FOR CONTROLLING ASTHMA Indication o Long term prevention of symptoms o Suppression, control, and reversal of inflammation o Reduces need for oral corticosteroids MOA: blocks late reactions to allergen and reduces airway hyperresponsiveness o Inhibits cytokine production, adhesion protein activation, and inflammatory cell migration and activation o Reverses beta 2 receptor down regulation Potential Adverse effects Rinse mouth with water after use, use spacer to minimize o Cough, dysphonia, oral thrush o In high doses – systemic effects may occur (although studies are not conclusive – clin sig has not been established) Adrenal suppression, osteoporosis, skin thinning, easy bruising Place in therapy o Preferred long term controller if have asthma that you don’t treat long o Most evidence to support reducing airway remodeling term, the chronic inflammation of the lung can lead to COPD # of different products o Differ with regard to potency Asthma 4 o No one is “better than another,” just more potent Clinical pearls of ICS o High dose monotherapy not preferred; marginal benefit with increasing dose from medium range o Spacer / holding chamber decreases local side effects and systemic absorption o Risks of uncontrolled asthma usually outweigh the risks of ICS o Most effective long term controller – decreases airway remodeling o Growth controversy -Long term data say that inhaled steroids may delay growth but it doesn’t stunt growth o Titrate to minimum dose required o Education points: rinse mouth with water, impt of compliance, time to onset, proper technique Estimated Comparative Daily Dosages for Inhaled Corticosteroids Adults Drug Beclomethasone dipropionate 42mcg/puff 84mcg/puff Beclomethasone HFA (40 or 80 mcg/puff) Low Dose 168-504 mcg 4-12 puffs 2-6 puffs 80-240 mcg Medium Dose 504-840 mcg 12-20 puffs 6-10 puffs 240-480 puffs High Dose >840 mcg >20 puffs >10 puffs >480 mcg Budesonide Turbuhaler 200mcg/dose Flunisolide 250mcg/puff Fluticasone propionate MDI:44, 110, 220 mcg/puff 600-1200 mcg 3-6 inhalations 1000-2000 mcg 4-8 puffs 264-660mcg 2-6 puffs – 110 mcg DPI: 50, 100, 250mcg/dose 200-600 mcg 1-3 inhalations 500-1000mcg 2-4 puffs 88-264 mcg 2-6 puffs – 44 mcg 2 puffs – 110 mcg 2-6 inhalations – 50 mcg Triamcinolone acetonide 100mcg/puff 400-1000mcg 4-10 puffs 1000-2000 mcg 10-20 puffs >1200 mcg >6 inhalations >2000mcg >8 puffs >660 mcg >6 puffs – 110 mcg >3 puffs – 220 mcg >6 inhalations – 100 mcg >2 inhalations – 250 mcg >2000 mcg >20 puffs Beclomethasone dipropionate 42mcg/puff 84mcg/puff 84-336 mcg 2-8 puffs 1-4 puffs 336-672 mcg 8-16 puffs 4-8 puffs >672 mcg >16 puffs >8 puffs Beclomethasone HFA (40 or 80mcg / puff) Budesonide Turbuhaler (DPI) 200mcg/dose Flunisolide 250mcg/puff Fluticasone propionate MDI:44, 110, 220 mcg/puff 80-160mcg 160-320mcg. >320mcg 200-400 mcg DPI: 50, 100, 250mcg/dose 2-4 inhalations – 50mcg 400-800 mcg 2 –4 inhalations 1000-1250 mcg 4-5 puffs 176-440 mcg 4-10 puffs – 44mcg 2-4 puffs – 110mcg 2-4 inhalations – 100mcg Triamcinolone acetonide 100mcg/puff 400-800mcg 4-8 puffs 800-1200mcg 8-12 puffs >800 mcg >4 inhalations >1250 mcg >5 puffs >440 mcg >4 puffs – 110mcg >2 puffs – 220mcg >4 inhalations – 100mcg >2 inhalations – 250mcg >1200mcg >12 puffs 3-6 inhalations – 100 mcg Children 500-750 mcg 2-3 puffs 88-176 mcg 2-4 puffs – 44mcg Product Budesonide (Pulmicort Respules) 0.25,0.5/2ml inhalation solution Dosage Low dose: 0.5 mg Medium: 1 mg High: 2.0 mg Comments Don’t mix with other neb solns Rinse mouth after use Asthma 5 LONG ACTING BETA AGONISTS Indications o Long term prevention of symptoms (especially nocturnal) o Added to anti-inflammatory therapy NEVER MONOTHERAPY o Prevention of exercise induced bronchospasm MOA: bronchodilation Potential adverse effects o Tachycardia o Skeletal muscle tremor o Hypokalemia o Prolongation of QTC interval in overdose o Diminished bronchoprotective effect? Place in therapy: moderate and severe persistant asthma Clinical pearls o Not to be used to treat acute symptoms or exacerbations Should NEVER take o Tolerance? down regulation of B2 receptors from chronic use more than one puff of o NOT MONOTHERAPY SMART study (salmeterol vs. inhaled steroid, Servent or Advair at one time. Don’t monotherapy showed an increase risk of mortality) dispense script: o May provide more effective symptom control when added to standard doses of Advair 2 puffs bid TOO MUCH! ICS, compared to increasing the ICS dose o Still need short acting beta agonist (like Albuterol) Medication Takes 30 min to work Works within 5 minutes Dosage Form Adult Form Child Dose Salmeterol Diskus DPI: 50mcg/blister 1 blister q12h 1 blister q12h Albuterol SR 4mg tablet 4mg q12h Formoterol Actuator 12mcg/blister 12 mcg cap (puff) q12h 0.3-0.6mg/kg/day, not to exceed 8mg/day. >5y.o. 12 mcg puff q12h Comments May use one dose nightly for symptoms Not to be used to treat acute symptoms or exacerbations. Can use for exercise induced asthma Onset of action within 5 minutes – can be used for exercise induced asthma – must use 15 minutes before challenge MAST CELL STABILIZERS Long term controller MOA: anti-inflammatory. Block early and late reactions to allergens. Stablizes mast cells to inhibit activation and release of mediators from eosinophils and epithelial cells o Inhibits acute response to exercise, cold, dry air, and sulfur dioxide Place in therapy o Alternative to ICS for mild-persistent asthma Biggest use, Pt that always have problem around spring (ragweed season) can give mast cell o Exercise induced AND Seasonal asthma stabilizer but give 1 month before! ADR’s o Unpleasant taste Time to onset: 4-6 weeks to see full effect Education points o Importance of compliance o Spacer may decrease bad taste Asthma 6 Regimen: cumbersome (4x a day with unpleasant taste) Clinical pearls o Safety is primary advantage to these agents o Little data of additive efficacy in combo with ICS Medication Cromolyn Dosage Form MDI 1mg/puff Nebulizer solution 20mg/amp Adult Form 2-4 puffs TID – QID 1 amp TID – QID Child Dose >2y.o. 1-2 puffs TID – QID 1 amp TID – QID Nedocromil MDI: 1.75mg/puff 2-4 puffs BID-QID 1-2 puffs BID-QID >6y.o. Comments One dose prior to exercise (10-60minutes before) or allergen exposure providers effective prophylaxis for 12 hours METHYLXANTHINES (theophylline) Never for preferred therapy MOA o Not fully understood. Bronchodilator?: smooth muscle relaxation by inhibiting phosphodiesterase (↑ cAMP) More important in o Thought to increase diaphragm contractility and mucociliary clearance COPD patients Place in therapy o Alternative to low dose ICS for mild persistent (as monotherapy) o Alternative (in combo with ICS) for moderate persistent Clinical kinetics o Therapeutic range Traditional 10-20mcg/ml Contemporary 8-12mcg/ml • Still derive benefit, but decreases risk of ADRs Potential ADR Caffeine is a methylxanthine o Dose related acute toxicities o ADR at usual doses (hint: transient caffeine like effects) Insomnia, gastric upset, aggravation of GERD, can worsen Drinking caffeine will make ADRs worse hyperreactivity in kids, H/A, nervousness, irritability o >20mcg/ml: N/V/D, H/A, irritability, insomnia o >40mcg/ml: cardiac symptoms o >50mcg/ml: severe CNS manifestations such as seizures may occur seizures have been reported at levels as low as 25mcg/ml Not well controlled with antiepileptics BASIC pharmacokinetics review Terminology o S – salt form o F – bioavailability factor Usually 1 (especially if drug given IV) o Bioavailability of drug = (S) X (F) X total dose Absorption o Non-sustained-release tablet and liquid F=100% Absorption is rapid and complete Peaks in 1-2 hours o Sustained-release products: most are completely absorbed, but the duration of absorption varies Example: If pt. is on luoroquinolone o treat COPD exacerbation and hey are on heophylline chronically, cut Asthma 7 As duration increases, dosing interval may be decreased Variability among products, especially those dosed once daily Peak levels usually obtained 4 hours after dose Hospitals use o Rectal; complete, but erratic absorption aminophylline for IV form o IV: aminopylline is used parenterally o SALTS Form Theophylline Aminophylline Oxtriphylline S (fraction of labeled dose that is theophylline) 1.0 0.8 0.65 o Distribution o Protein binding ~40% o Vd 0.5L/kg in adults and children (range of 0.4 to 0.7L/kg) 0.7L/kg in neonates (up to one year of age) o Dosing weight in obese subjects controversial – use IBW if ABW >30% IBW for calculations If have pt. with asthma who is pregnant and on o Crosses placenta and enters breast milk theophylline, consider d/c theophylline and increasing inhaled therapy. (B/c most inhaled therapies are topical, o Pregnancy category C not systemically sbsorbed.) Clearance o Primarily (>90%) cleared by liver, metabolized by cytochrome P450 (specifically CYP 1A2) o Premature neonates excrete 50% dose unchanged in urine o Non linear pharmacokinetics Renal impairment – no effect on clearance; no dosage adjustments needed o Factors causing increased clearance Smoking Cystic fibrosis Drugs High protein, low carb diets (ATKINS diet) o Factors causing decreased clearance ( level of theophylline) CHF Severe COPD Liver disease Age: neonates and elderly Drugs o When several factors are present; its hard to predict drug levels DRUG Interactions Asthma 8 Take famotidine, zantac, or anitidine instead of cimetidine. No DI with these. Drugs that INHIBIT metabolism of theophylline SIGNIFICANT (>30% inhibition) Drugs that INDUCE metabolism of theophylline ( level of theophylline) Phenytoin Fluoroquinolones (enoxacin, cipro, norflox) Rifampin Cimetidine( doses >1000mg/d) Fluvoxamine (SSRI mainly for OCD) Oral contraceptives Disulfram Propafenone Ticlopidine Zileuton MODERATE inhibitory interations (10-30%) Erythromycin, clarithromycin Isoniazid Allopurinol at large doses (> 300mg BID) Carbamazepine Phenobarbital Ritonavir (for HIV) Moricizine Cigarette smoking St. John’s Wort COPD pts taking theophylline and still smoking, once get them to stop smoking, watch theophylline levels Pro duct sele ctio n o S ustained release products preferred (Immediate release theophylline not used a lot) o Release characteristics of some products may be affected by food o SR products NOT interchangeable o Avoid other oral salt forms Characteristics of selected slow-release formulations FORMULATION Capsule • Slo-bid Gyrocap • Theo-24 Time to peak serum concentration Comments • 3-7 hours after morning dose when given q 12 h • can be opened and sprinkled on a spoonful of soft food for kids who can’t swallow the capsule; contents must be swallowed without chewing; complete absorption occurs with or without food • incomplete absorption occurs when taken after an overnight fast; pH-dependent dissolution causes much more rapid and complete absorption when taken after food or in the evening • scored tablets can be split without affecting absoroption characteristics; complete absorption occurs in the presence or absence of food • Variable depending on whether taken in the am after an overnight fast, after breakfast, or in the pm Tablet • Theo-Dur • 3 to 7 hours after am dose when given every 12 hours • Uni-Dur • 8 to 12 hours after once daily evening dose • Uniphyl • 8 to 12 hours after once-daily evening dose • formulation similar to TheoDur tablets but more slowly absorbed; near complete absorption occurs in the presence or absence of food • incomplete absorption occurs when taken after overnight fast; more complete absorption occurs when taken after food or in the evening Weinberger M and Hendeles L. Theophylline in Asthma. NEJM 1996; 1380 - 1388 For general initiation, start at lower doses and titrate up over 9 days to avoid transient side effects Dosing strategy for those WITHOUT risk factors for impaired theo clearance Asthma 9 o Initial dose For infants 6 weeks – 1 year, initial daily dose is calculated using: • 0.2 (age in weeks) + 5 = initial dose in mg/kg/day When to measure level when titrating? -NO SOONER THAN Q 3 DAYS • divide q 6 hours if > 6 months and q 8 hours if < 8 months For children > 1 year and adults begin with 10mg/kg/day with MAX dose of 300mg o First incremental increase (o.k. to do if no side effects seen) 13mg/kg/day; max 400-450mg/day o Second increment 16mg/kg/day; max 600mg/day o Measure serum concentration after 3 days at highest tolerated dose o Dose increases should be made no sooner than q3 days and if the dose is well tolerated For patients with risk factors that may decrease theophylline clearance, use pharmacokinetic equation Not used in practice very much o D = (Css x Cl x τ)/F x S (D=dose, Css = concentration at steady state (average), τ=dosing interval) o Initial dose should not exceed 400mg/day (16mg/kg/day) without checking a serum level ORAL dose adjustments of theo; dose increases should be limited to ~25% of total daily dose Rule of thumb Theophylline maintenance dose adjustments Measured serum conc (mcg/ml) 5-7.5 Dose adjustment Increase dose 25%; recheck serum conc in 3 days Increase dose 25% only if patient is symptomatic; recheck serum conc in 3 days and q 6-12 months 7.5-10 10-20 20-25 25-30 No change; consider decreasing dose if > 15mcg/ml Decrease dose by 10-25%; recheck in 3 days and q 6-12 months Hold one dose; decrease maintenance dose by 25%; recheck in 3 days and q 6-12 months Hold two doses; decrease maintenance dose by 50%; recheck to guide dosage adjustment; consider activated charcoal for toxicity > 30 Monitoring IV; estimated when steady state will occur and obtain level ORAL o Obtain level at steady state (4-5 half lives) o In most cases, concs should not be obtained until a patient has received a given dosage for 3 days o Trough levels more reliable, peaks estimated via kinetics o Peaks may be associated with toxicity o o For SR oral products, can check level mid-interval Once pt stable, check level annually Level warranted if s/sx of tox are present Theophylline (getting levels) Any other time a level is warranted? -Annually -Symptoms of toxicity present -Pediatrics Leukotriene eceptor antagonists Asthma 10 o Children may require more freq monitoring LEUKOTRIENE MODIFIERS usually for kids that have a problem w/ inhaled drugs, good compliance MOA: selective competitive inhibitor of LTD4 and LTE4 receptors (zileuton – 5lipoxygenase inhibitor) Place in therapy o Can be used as monotherapy for mild persistent asthma (alternative to ICS) CAMP study: LT modifiers inferior as monotherapy to ICS o Prefer oral medication Not a preferred agent. Adverse effects o Usually well tolerated o Might have to monitor LFT (Zileuton) Education points o Doesn’t work for everyone o Singulair - FDA indication for allergic rhinitis Clinical Pearls -Singular Other FDA indications Approved for peds 12 months and up Medication Montelukast Dosage Form 10 mg tablet 5 mg chewable tablet 4mg chewable tablet Adult Form 10 mg PM for pts >14yrs Child Dose 4mg PM for children 2-5y.o. 5 mg PM for children 6-14 yrs Comments Well tolerated with no signifcant DI PEDIATRIC INDICATION (> 12 mo) (>2 yrs if using for alleric rhinitis) Administer without regard to meals Zafirlukast 20mg tablet 40mg daily (20mg BID) N/A Administer at least 1 hour before or 2 hours after meals. Competitive inhibitor of Cyp 2C9 Zileuton 300mg tablet 600mg tablet 2400 mg daily (600mg QID) N/A Monitor ALT Not used much 2/2 liver monitoring and DI Cyp 3A4 inhibitor 5-lipoxygena e inhibitor Hard for kids to be compliant with this must take on empty stomach XOLAIR (olimizumab) o Will learn during in-service MOA: Anti IgE (Binds to IgE) Prevents IgE from binding to high affinity IgE receptors on mast cells and basophils Mediators released are reduced (histamine) Place in therapy: Monitoring: Education points: Usually requires health insurance prior auth 2/2 cost Usual dose: Asthma 11 Everyone with asthma should have access to a short acting agent! Not going to work as well when actually need it if it has been overused No one with asthma should be getting Combivent (ipratropium & albuterol)! Quick acting agents SHORT ACTING BETA AGONISTS Albuterol, Albuterol HFA, pirbuterol, levalbuterol MOA: BRONCHODILATION. Smooth muscle relaxation following adenylate cyclase activation Use 10-15 min before exercise and increase in cyclic AMP production o functional antagonism of bronchoconstriction Place in therapy: DOC for acute bronchospasm (DOC for quick relief, exercise induced) ADRs: tachycardia, skeletal muscle tremor, H/A (poor perceiver: perceive their breathing is Education points: carry with you at all times, over-reliance worse than it really is) o >1 canister per month (not controlled) o >2 canisters / month (RED FLAG, increase risk of death from asthma, call physician!) Clinical pearls o tolerance (down regulation of B2 receptor) tolerance can develop, especially when pt. is using it more than they probably need to Loss of bronchoprotective effect after routine use Xopenex (Levalbuterol) o R enantiomer of racemic albuterol o Beta 2 receptor agonist o Only available via nebulizer solution o Decreased incidence of cardiovascular adverse effects v. Albuterol (claim to fame) Less tachycardia, less anxious Very expensive. o Duration of action: may last up to 8 hours Should try albuterol first. Lasts a lot longer than albuterol. o Usual dose: 0.63mg via neb q 6-8 hours Don’t know role in acute SOB episodes. o Clinical pearls Albuterol has studies. Albuterol lasts 4-6 hours. Must not mix with other neb solutions Medication Albuterol Dosage Form 90 mcg/puff, 200 puffs *DPI 200 mcg/capsule **Nebulizer 5 mg/ml (0.5%) Adult Dose 2 puffs Q 5 min prior to exercise *1-2 caps Q 4-6hrs PRN & prior to exercise **1.25-5 mg in 2-3 ml of saline Q 4-8 hrs Child Dose 1-2 puffs 5 min prior to exercise *1 capsule Q 4-6 hrs PRN & prior to exercise **0.05 mg/kg (min 1.25 mg, max 2.5 mg) in 2-3 ml of saline Q 4-6 hrs 2 puffs tid-qid prn *Not established Bitolterol 370 mcNebg/puff, 300 puffs *Nebulizer 2 mg/ml (0.2%) 2 puffs tid-qid prn *0.5-3.5 mg in 2-3 ml of saline Q 4-8 hrs Pirbuterol 200 mcg/puff, 400 puffs 2 puffs tid-qid prn 2 puffs tid-qid prn Levalbuterol 0.63 mg/3ml, 1.25 mg/3ml sol 0.63 – 1.25 mg nebulized TID < 12 yrs N/A Comments ***May mix with cromolyn or ipratropium neb solutions. May double dose for mild exacerbations. May not mix with other nebulizer solutions Not currently in MDI IPRATROPIUM MOA: ANTICHOLINERGIC (NOT for routine management! Only for acute exacerbation of asthma) Place in therapy: acute exacerbations in combo with SABA. Usually only given in ER. o Evidence has shown if given in ER, can help decrease hospitalizations Asthma 12 NOTES: Inappropriate to use at home! Medication Anticholingeric Ipratropium Can use chronic po steroids for pt. who has constant daily symptoms, constantly have RED-YELLO W peak flow, never get back to normal Dosage Form 18 mcg/puff, 200 puffs *Nebulizer 0.25 mg/ml (0.025%) Adult Dose 2-3 puffs Q 6 hrs *0.25-0.5 mg Q 6 hrs Child Dose 1-2 puffs Q 6 hrs 0.25 mg Q 6 hrs PO STEROIDS MOA: quick acting generalized anti inflammatory Place in therapy: adjunct to inhaled therapy for acute exacerbations o “burst” 3-10days to gain prompt control of inadequately controlled persistent asthma (prevents inflammation from getting worse) o severe persistent asthma (constant symptoms): long term prevention of symptoms o suppression, control, and reversal of inflammation Goal if use po steroids is get them Adverse effects off as soon as o Short term: hyperglycemia, increased appetite, fluid retention, possible b/c of horrible side effects weight gain, mood alteration, hypertension, GERD of chronic steroids o Long term: adrenal axis suppression, skin thinning, HTN, DM, Cushing’s syndrome, cataracts, muscle weakness, and rarely – impaired immune function Education points: use as directed Educate patients that it is not an anabolic steroid, it is a glucocorticoid Clinical pearls o Use at lowest effective dose (qod if needed) o Long term use: alternate day AM dosing produces least toxicity NOTES: Take steroid in the morning! Medication Methylprednisolone Dosage Form 2,4,8,16,24,32 mg tablets Prednisolone 5mg tabs, 5mg/5ml, 15mg/5ml Adult Form 2-60mg daily in a single dose or qod as needed for control Short-course “burst”: 4060mg per day as single or 2 divided doses for 310 days Child Dose 0.25-2mg/kg daily in single dose or qod as needed for control Short course “burst”: 1-2mg/kg/day, maximum 60mg/day for 3-10 days Comments Short courses or “bursts” are effective for establishing control when initiating therapy or during a period of gradual deterioration. The burst should be continued until patient achieves 80% PEF personal best or symptoms resolve. This usually requires 3-10 days but may require longer. There is no evidence that tapering the dose following improvement prevents relapse. Prednisone _1,2.5,5,10,20,25,50 mg tabs; 5mg/ml _ If patient has history of severe exacerbations, can give prescription for steroid (prednisone) that they can keep at home. Give specific instructions(action plan) of when to use it to prevent going to hospital or ER. Asthma 13 Can assess a pt. into a category based on what drug they are on. PUTTING IT ALL TOGETHER - STEP WISE APPROACH TO TREATMENT Medications required to maintain long term control Step 4 Severe Persistent Step 3 Moderate Persistent Step 2 Mild Persistent Need SABA. If use albuterol >1-2x/week consider tepping up to next level or reating with anti-inflammat ory Step 1 Mild intermittent (Not a lot of symptoms, not on daily meds, generally in green zone) Preferred treatment: High dose ICS AND Long acting beta agonist AND if needed Corticosteroid tablets or syrup long term (2mg/kg/day, generally do not exceed 60mg/day) (make repeat attempts to reduce systemic corticosteroids and maintain control with high dose ICS) Preferred treatment: (Advair) Low to medium dose ICS AND long acting beta agonist Alternative treatment Increase ICS within medium dose range OR Low to medium dose ICS and EITHER leukotriene modifier or theophylline Preferred treatment: Low dose ICS Alternative therapy (Any long term controller) Cromolyn, leukotriene modifier, nedocromil, OR sustained release theophylline to serum conc (5-15mcg/ml) No daily medication needed Severe exacerbations may occur, separated by long periods of normal lung function and no symptoms. A course of corticosteroids is recommended QUICK RELIEF ALL PATIENTS Short acting bronchodilator: 2-4 puffs SABA prn symptoms Intensity of treatment will depend on severity of exacrbation Use of SABA >2 x / week in intermittent asthma may indicate the need to initiate long term control therapy Two Options for Chronic Add-On: Step up vs. step down therapy Last drug added Step down: review treatment every 1-6 months; a gradual stepwise reduction in treatment is first drug to d/c Step down is used when stepping more often may be possible down Step up: if control is not maintained, consider step up. First, review patient medication technique, adherence, and environmental control Special considerations o Exercise induced bronchospasm Pre-treatment (30 min before exercise, use 1-2 puffs short acting inhaler) Example: Pt. has mild intermittent asthma. Step Up: Start on therapy for mild intermittent Step Down: Start therapy for moderate persistent and then step them down when controlled. Asthma 14 Very safe o Pregnancy may make asthma better, worse, or no change. o o o Beta Agonists Short acting agents will help 2-3 hrs. Cromolyn/nedocromil Long acting agents will Lengthy warm-up period help 10-12 hrs. Seasonal asthma 30-45 min -Anti-inflammatory Prior to onset of symptoms -Mast cell stabilizers (Cromolyn, Nedocromil) -ICS Long term anti-inflammatory initiated prior to anticipated onset of symptoms: start therapy a month before anticipated onset of symptoms Pregnancy (Educate pt. to continue med therapy. Get pt. off po meds + on Stress inhaled meds b/c local effect, not systemic) Pediatrics -Close to adult algorithm -Differ with regard to delivery devices Masks Nebulizers Spacers -Leukotriene Modifiers By mouth Powder Stepwise Approach for Managing Infants and Young children (5 years of age and younger) with acute or chronic asthma symptoms Long-term Control Preferred treatment: Step 4 High-dose inhaled corticosteroid with spacer Severe Persistent holding chamber and face mask AND Long acting inhaled beta 2 agonist AND IF needed, Add systemic corticosteroids tablets or syrup 2mg/kg/day (generally, do not exceed 60mg/day) Make repeat attempts to reduce systemic corticosteroids and maintain control with high dose inhaled corticosteroids Quick Relief Bronchodilator as needed for symptoms (see step 1) up to 3 times a day Asthma 15 Step 3 Moderate Persistent Step 2 Mild Persistent Step 1 Mild Intermittent Preferred Treatment: Bronchodilator as needed for symptoms Low dose inhaled CS with spacer/holding (see step 1) up to 3 times a day chamber and face mask AND Long acting beta 2 agonist OR Medium-dose inhaled CS Alternative treatment: Low dose inhaled CS and either leukotriene receptor antagonist OR theophylline IF NEEDED (particulary in patients with recurring severe exacerbations) Preferred treatment Medium dose ICS AND long acting beta agonist Alternative therapy Medium dose inhaled CS and either leukotriene receptor antagonist or theophylline Preferred treatment: Bronchodilator as needed for symptoms Low-dose inhaled CS (nebulizer or MDI with (see step 1) spacer/holding chamber with or without face mask or DPI) Alternative therapy Cromolyn (neb is preferred) or MDI with holding chamber OR leukotriene receptor antagonist No daily Bronchodilator as needed for symptoms <2 times a week. Intensity of medication needed treatment will depend upon severity of exacerbation. Either: Inhaled short-acting beta 2 agonist by nebulizer or face mask and spacer/holding chamber OR Oral beta 2 agonist for symptoms With viral respiratory infection: Bronchodilator q 4-6h up to 24 hours (longer with physician consults) but, in general, repeat no more than once every six weeks Consider systemic corticosteroid if : severe exac, or hx of previous severe exacerb’s ASTHMA EXACERBATIONS Classify severity based on s/s and objective information Categorize generally into mild, moderate, or severe -NOT exact -Majority of symptoms fall into one category; go with that Defining exacerbations If pt. is acutely feeling worse, it is an Time FRAME exacerbation. If pt. is always in the Symptoms yellow zone, don’t feel good chronically, it is just bad control Peak flow rates Classifying Severity of Asthma Exacerbations MILD MODERATE SEVERE Respiratory Arrest Imminent Asthma 16 Symptoms While talking (infant – softer, shorter cry; difficulty feeding) Prefers sitting While at rest (infant – stops feeding) Sits upright Sentences Phrases Words Alertness May be agitated Usually agitated Signs Usually agitated Respiratory rate Increased Increased Often >30/min Use of accessory muscles: suprasternal retractions Wheeze Usually not Commonly Usually Moderate, often only end expiratory Loud; throughout exhalation Breathlessness While walking Can lie die Talks in Drowsy or confused Paradoxical throacoabdominal movement Usually loud; Absence of wheeze throughout inhalation and exhalation Pulse/minute <100 100-120 >120 Bradycardia Pulsus paradoxus Absent <10mm Hg May be present Often present >25 Absence suggests 10-25mm Hg mm Hg (adult) 20- respiratory muscle 40 mm Hg (child) fatigue Functional Assessment PEF >80% Approx 50-80% or <50% predicted or response lasts <2 personal best hrs PaO2 (on air) Normal (test not >60mm Hg (test <60 mm Hg; usually necessary) not usually possible cyanosis necessary) PCO2 <42mm Hg (test <42mm Hg (test ≥42 mm Hg; not usually not usually possible necessary) necessary) respiratory failure SaO2% (on air) At >95% (test not 91-95% <91% sea level usually necessary) •The presence of several parameters, but not necessarily all, indicates the general classification of the exacerbation •Many of these parameters have not been systematically studied, so they serve only as general guides Guide to rates of breathing in awake children: Age Normal rate <2 months <60/minute 2-12 months <50/minute 1-5 years <40/minute 6-8 years <30/minute Guide to normal pulse rates in children Age Normal rate 2-12 months <160/minute 1-2 years <120/minute 2-8 years >110/minute Dosages of Drugs for Asthma exacerbations in emergency medical care or hospital Medications Albuterol Nebulizer Solution (5mg/ml) Adult Dose Child Dose Inhaled Short-Acting Beta2-Agonists 2.5-5mg q 20 minutes 0.15mg/kg (minimum for 3 doses, then dose 2.5mg) q 20 2.5-10mg q minutes for 3 doses, 1-4h as needed, or then 0.15-0.3mg/kg up 10-15mg/hr continuously to 10mg q 1-4 h as needed, or 0.5mg/kg/hr by continuous nebulizer Comments Only selective beta2-agonists are recommended. For optimal delivery, dilute aerosols to minimum of 4ml at gas flow of 6-8 L/min Asthma 17 Albuterol MDI (90mcg/puff) 4-8 puffs q20 minutes up to 4 hours, then q1-4 hrs as needed 4-8 puffs q 20 minutes for 3 doses, then q 1-4 hrs inhalation maneuver. Use spacer/holding chamber As effective as nebulized therapy if pt is able to coordinate Bitolterol Nebulizer solution (2mg/ml) See albuterol dose See albuterol dose; thought to be half as potent as albuterol on a mg basis Has not been studied in severe asthma exacerbations. Do not mix with other drugs Bitolterol MDI (370mcg/puff) Pirbuterol MDI (200mcg/puff) See albuterol dose See albuterol dose See albuterol dose See albuterol dose; thought to be half as potent as albuterol on a mg basis Has not been studied in severe asthma exacerbations Has not been studied in severe asthma exacerbations Epinephrine 1:1000 (1mg/ml) 0.3-0.5mg q 20 minutes for 3 doses SQ Terbutaline (1mg/ml) 0.25mg q 20 minutes for 3 doses SQ Systemic (injected beta2-agonists) 0.01mg/kg up to 0.30.5mg q 20 minutes for 3 doses SQ 0.01mg/kg a 20 minutes for 3 doses then q 2-6 hrs as needed SQ No proven advantage of systemic therapy over aerosol No proven advantage of systemic therapy over aerosol Anticholinergics Ipratropium bromide neb solution (0.25mg/ml) 0.5mg q 30 minutes for 3 doses then q2-4h as needed 0.25mg q20 minutes for 3 doses, then q 2-4 hours MDI (18mcg/puff) 4-8 puffs as needed 4-8 puffs as needed Prednisone Methylprednisolone Prednisolone Corticosteroids 120-180mg/day in 3 or 4 1mg/kg q6 h for 48 hours divided doses for 48 then 1-2mg/kg/day hours, then 60(maximum 80mg/day until PEF = 60mg/day) in 2 divided reaches 70% of doses until PEF predicted or personal 70% of predicted or best personal best May mix in same neb with albuterol. Should not be used as first-line therapy; should be added to beta2-agonist therapy Dose delivered from MDI is low and has not been studied in asthma exacerbations For outpatient “burst” use 4060mg in single or 2 divided doses for adults (children: 12mg/kg/day, maximum 60mg/day) for 3-10 days Management of exacerbations include inhaled B2 agonist to provide prompt relief of airflow obstruction Do things like dose systemic corticosteroids, for moderate to severe exacerbations + efficiency of B2 agonist: systemic corticosteroids, for patients who rail to respond promptly and completely -double dose of to an inhaled BA inhaled steroid for couple days oxygen, to relieve hypoxemia for moderate to severe exacerbations -adding po steroid monitoring response to therapy with serial measurements of lung function -putting pt. on oxygen if in hospital to manage exacerbation Management of asthma exacerbations at home: Asthma 18 Appendix III. Managing exacerbations – ER / hospital Treating Exacerbations in the ER Oxygen Combinations -Albuterol -Ipratropium IV vs. PO steroids Admit? In general, people who present to ER/hospital can assume that they have moderate-severe exacerbation Goals of therapy (see appendix II) Maintain normal activity levels (exercise/activity) Maintain (near)“normal” pulmonary function Prevent chronic and troublesome symptoms (coughing or breathlessness at HS, early AM, or after exertion) Prevent recurrent exacerbations of asthma and minimize need for ER visits / hospitalizations Provide optimal pharmacotherapy with minimal or no ADRs Meet patients’ and families’ expectations of satisfaction with asthma care MONITORING Subjective o Symptoms Frequency of symptoms Signs/symptoms of dz (goals of therapy) & drug therapy Compliance Asthma 19 Refill history Albuterol or quick relief use o Efficacy of medications Adverse effects experienced (e.g. thrush, sore throat) Objective o Pulmonary function Peak flow rates at home Recommended for all patients with moderate – severe persistent asthma PFT Diagnosis Have “personal best” established o Technique Peak flow Devises Action plan (usually filled out by physician) o Compliance assessment Refill history o Missed work / school days o Impact on ADL / QOL o Psychosocial effects Environmental control o In compliant patients with good technique that are still not controlled, an environmental control plan may need to be instituted. An on-site inspection of the patients home / workplace / school should take place Cockroaches, carpets, pets, dander, dust, mold / mildew, etc. ASTHMA ACTION PLAN o o o o o COPY (see appendix I) Can serve as physician’s order for school nurses All patients with moderate to severe persistent Symptom based Peak flow based Maintaining Control of Asthma Once control is achieved and sustained for several weeks or months, a reduction in p’col therapy – STEP DOWN – is appropriate and helpful to ID the minimum therapy for maintaining control This process SHOULD BE GRADUAL! -Last med added, should be the first subtracted If optimal control of asthma is NOT achieved and sustained at any step of care, several actions may be considered -Pt adherence and technique should be assessed -Temporary increase in anti-inflammatory therapy may be indicated to reestablish control -Other factors that diminish control may be ID and addressed Asthma 20 -Step up to next step of care may be necessary -Consultation with an asthma specialist Factors that can lead to poor control Indoor pets Moist damp rooms Cockroaches Mold Smoking Second hand smoke Unvented stoves Wood burning stoves Unvented heaters Allergic Rhinitis Foods Meds (Beta blockers, ASA/NSAIDs) PATIENT EDUCATION Quick relief medicine versus long term controller medicines o Rationale (for “relief” vs “long-term controller”) o Importance of compliance Devise technique o Amount of drug delivered o content explain importance, describe rationale, demonstrate, patient demonstrates to you, give written instructions o Follow up periodically no substitute for observing technique o Storage, replacement, cleaning Spacer / holding chamber technique Peak flow meter – use, interpret, & adjusting Environmental control and asthma action plan OTC medications for asthma o Types Inhalers – short acting beta agonists (Primatene Mist, Bronkaid Mist, AsthmaHaler Mist) Less specific for lungs, so more adverse effects Shorter duration – lasts < 1 hour Oral – bronchodialtors and/or theophylline o Toxicities Dose related toxicities Increased toxicities if use with similar rx item (theophylline) o Perceptions/ misconceptions o Bottom line: rx Items MORE EFFECTIVE AND LESS TOXIC Follow-up Regular follow-up visits are essential Clinicians can assess if control is maintained and step down is appropriate Follow-up at 1 to 6 month intervals