NR566 Week 2 Study Outline_ Chapter 17: Drugs Affecting the Respiratory System

NR566 Week 2 Study Outline Chapter 17: Drugs Affecting the Respiratory System Bronchodilators: Beta 2 Receptor Agonists (B2RA): Short and long acting beta agonists • B2RA widely used in all ages to treat reversible bronchoconstriction caused by reactive airway disease (RAD) or COPD • Bronchodilators • Short-acting beta agonists: Albuterol (ProAir, Ventolin, Proventil) , metaproterenol (Alupent),  terbutaline (Brethine, Brethaire), bitolterol (Tornalate), pirbuterol (Maxair), and levalbuterol (Xopenex)   • Long-acting beta agonists:  arformoterol (Brovana), salmeterol (Serevent), formoterol (Foradil), and indacaterol (Arcapta Neohaler)   • Drug of choice during pregnancy for asthma Pharmacodynamics    • Act on smooth muscle to reverse bronchospasm, decreases airway resistance and residual volume and increasing VC and airflow • Stimulate beta 2 adrenergic receptors in the lungs to increase cAMP production which relaxes bronchial smooth muscle and inhibits mediators from hypersensitivity cells (mast cells) • All beta agonists stimulate beta 1 activity (increased HR, tremor)f Short Acting Beta Agonists • Albuterol  o Selective beta2 agonist with minor beta1 activity  o Often first-line drug r/t less ADRs than the other drugs in this class o Increases HR by stimulating beta 2 receptors in the heart and vascular smooth muscle • Levalbuterol: (similar to albuterol), where the (S)-isomer from racemic albuterol is removed • Pirbuterol: selective beta 2 agonist, similar to albuterol • Terbutaline: similar to albuterol, selective beta 2 with minor beta 1 activity o Known to inhibit uterine contractions • Metaproterenol: beta 2 selective with some beta 1 activity, less selective than albuterol or terbutaline • Bitolterol: hydrolyzed by esterase in the lung to colterol, or terbutylnorepinephrine, selective beta 2 Long Acting Beta Agonists (Salmeterol, formoterol, indacaterol, and aformoterol) • Salmeterol is more selective for beta2 receptors than albuterol and has minor beta1 activity. o 12 hour half-life o Formoterol: 200-fold greater agonist activity at B2 than albuterol and has minor B1 activity o Aformoterol (R,R)-enantiomer of formoterol, twice as potent as formoterol o Indacaterol: 24 fold greater B2 activity than B1 o Salmeterol and formoterol exert long-lasting broncho protection against allergen, exercise, histamine, and methacholine caused bronchospasm Pharmacokinetics    • Contraindications: Cardiac arrhythmias (tachycardia or heart block caused by digitalis intoxication, angina, narrow-angle glaucoma, organic brain damage (epi only), and shock during general anesthesia with halogenated agents • Monitor closely: HTN, ischemic heart disease, coronary insufficiency, CGH, and Hx of stroke and/or cardiac arrhythmias • Diabetics: potential drug-induced hyperglycemia, insulin dose may need increased • Hyperthyroidism: ADRs are more likely to occur with use of bronchodilators • Digoxin: require close monitoring, albuterol increases the volume of distribution of dig and can cause decreased dig blood levels • Pheochromocytoma: avoid, severe HTN may occur • Older adults: Lower doses r/t increased sympathomimetic sensitivity • Black Box warning for LABAs: The risks of salmeterol (Serevent) and formoterol (Foradil) outweighed the benefits and should not be used singly in asthma for all ages o Two-fold increase in catastrophic events (asthma-related intubations and death)  o The use of LABAs is contraindicated without the use of an asthma controller medication such as an inhaled corticosteroid o Only use long-term in patients who asthma cannot be adequately controlled on asthma controller medications o Use for the shortest duration of time required to achieve control, then maintain on an asthma controller medication o Pediatric and adolescent patient who require addition of a LABA to an inhaled corticosteroid should be a combination product containing both an inhaled ICS and a LABA, to ensure compliance with both medications • Terbutaline pregnancy category B (prevent contractions) (others category C)  • Albuterol safe for all age children  • Metaproterenol can be used in young children • Levalbuterol, as young as 2 (drug insert says 6) • Salmeterol should not be used in children less than age 4 years and never singly.  • Formoterol age 5 and older • Indacaterol and aformoterol are used for COPD, not for use in children or adolescents Drug and Food Interactions  o Many drug interactions o Digitalis glycosides: increased risk of dysrhythmia  o Beta adrenergic blocking agents (Beta Blockers): direct competition for beta sites resulting in mutual inhibition of therapeutic effects  o Including beta blocker eye drops  o Tricyclic antidepressants and MAOIs potentiate effects of beta agonist on vascular system ADRs o Usually transient o Stopping the med is not usually needed, reduce dose then slowly increase o Supraventricular and ventricular ectopic beats have occurred o Tachycardia and palpitations  o Some central nervous system (CNS) excitation effects  o Tremors, dizziness, shakiness, nervousness, and restlessness  o Headaches, rarely insomnia, post inhalation cough o Salmeterol has an increased risk of exacerbation of severe asthma symptoms if the patient is deteriorating o Overuse can lead to seizures, hypokalemia, anginal pain and HTN o Stimulant like effects o GI upset, take po meds with food Clinical Use and Dosing   Bronchospasm • Bronchodilators are used primarily in the treatment of bronchospasm associated with asthma, bronchitis (acute or chronic), and chronic obstructive pulmonary disease (COPD) o Albuterol  MDI dose children over 4 and adults is 2 puffs every 4 to 6 hours o Nebulizer dose children over age 12 and adults is 2.5 mg/dose   For younger children over 15 kg, dose is 0.1 to 0.15 mg/kg/dose o Dose may be repeated once after 5 to 10 minutes, up to 2 times, three doses total during exacerbations o Oral dose in adults is 2 to 4 mg 3 or 4 times a day  For children 6 to 12, 2 mg albuterol 3 to 4 times a day (PO form rarely used in children)  Oral syrup: children under age 6, 0.1 mg/kg 3 times a day (rarely used) o May combine with ipratropium   o Aformoterol (Brovana): nebulizer 15 mcg/ by inhalation BID (not approved for use in children) o Indacaterol (Arcapta Neohaler): powder via a Neohaler device  adults with COPD, one capsule one daily with a Neohaler device o Levalbuterol (Xopenex): inhalation solution (nebulizer) in adolescents over age 12 and adults is 0.63 mg TID (every 6 to 8 hours)  Children: 6 to 11: 0.31 mg TID, do not exceed 0.63 mg TID  Children 4 and younger: 0.31 to 1.25 mg every 4 to 6 hours  Inhaler: one to two puffs repeated every 4 to 6 hours o Metaproterenol (Alupent): MDI, inhalation solution, and syrup forms o Terbutaline: MDI (Brethaire), PO tablets (Brethine), or parenteral form for SC injection o Pirbuterol: only available as MDI (Maxair Autohaler) o Bitolterol (Tornalate): MDI: acute bronchospasm two puffs 1 to 3 minutes apart o Salmeterol (Serevent DISKUS): 1 puff BID  o Do not use alone for persistent asthma, combine with an  inhaled corticosteroid o Packaged with Fluticasone (Advair DISKUS) differing doses o Formoterol: 12 mcg, single use dry powder capsule o Ipratropium: inhaled anticholinergic, may be used in combination with albuterol to treat asthma exacerbation in the ER  Bronchodilator of choice3 in patients taking beta blockers or who do not tolerate beta 2 agonists Exercise-induced bronchospasm (EIB)  o Albuterol or other SABA and salmeterol o Albuterol MDI: 2 puffs 15 minutes before exercise, lasts 2-3 hours o Salmeterol: 2 puffs 30 to 60 minutes before exercise, duration 10 to 12 hours o Cromolyn or nedocromil may be used before exercise, not as effective o Leukotriene modifiers taken daily may decrease EIB symptoms in 50% of patients, but patient will still need to use albuterol  before exercise Xanthine derivatives o Methylxanthines have declined in importance in the Tx of asthma, but some patients may still benefit from the use of theophylline o Theophylline and Caffeine o Bronchodilator Pharmacodynamics o Bronchial smooth muscle relaxation o CNS stimulants o CV effects o Increased gastric acid production o Stimulate skeletal muscle o Increased renal blood flow and GFR o Work directly by an unknown mechanism: mediated by selective inhibition of specific phosphodiesterase o Increased production of cAMP=bronchial smooth muscle and pulmonary vessel relaxation o Theophylline and caffeine: powerful CNS stimulants (insomnia and excitability) o Theophylline has a greater effect on the cardiovascular system o Theophylline directly stimulates the myocardium and increases myocardial contractility and HR o Relaxes vascular smooth muscle, dilates the coronary, pulmonary, and systemic blood vessels o Both theophylline and caffeine: increase gastric acid production (may cause NV) o Stimulate skeletal muscle: tremors o Theophylline: Acts directly on the renal tubules to cause increased sodium and chloride excretion o Both cause diuresis r/t action on the kidneys (increased blood flow to kidneys) Pharmacotherapeutics o Contraindications to theophylline: hypersensitivity to xanthine, PUD, and underlying seizure disorder o Contraindications to caffeine: hypersensitivity to caffeine or use of caffeine sodium benzoate formulation in neonates o Use Caution: HTN, ischemic heart disease, coronary insufficiency, CHF, or Hx of stroke and cardiac arrhythmias r/t effects on CV system o Toxicity: levels above 25 mcg/mL  May occur if clearance is decreased (hepatic impairment, chronic lung disease, cardiac failure, patients older than 55, and infants under 1) o Theophylline: Pregnancy Category C, crosses placenta, newborns may have therapeutic serum levels if maternal levels are high-normal range (tachycardia, irritability, and vomiting) o May be used in children: infants younger than 1 have decreased theophylline clearance and closely monitor levels should be a range of 5 to 10 mcg/mL o Caffeine citrate is used to treat apnea of prematurity o Pregnancy Category C Theophylline: Drug and Food Interactions o Many drug interactions due to metabolism via CYP 450 isoenzyme CYP1A2, CYP2E1, and CYP 3A3/4 o Increase serum theophylline: allopurinol, VVs, CCBs, cimetidine, cipro, oral contraceptives, corticosteroids, disulfiram, ephedrine, flu vaccine, interferon, macrolides, quinolones, THs, carbamazepine, IZD, loop diuretics o Decrease serum theophylline: aminoglutethimide, barbiturates, charcoal, hydantoins, ketoconazole, rifampin, smoking, sulfinpyrazone, beta agonists, carbamazepine, isoniazid, loop diuretics, lansoprazole, primidone, ritonavir o Lithium: theophylline may increase renal clearance of lithium=reduced levels o Smoking tobacco increases theophylline clearance (may take months to 2 years to normalize theophylline clearance after quitting) o Benzodiazepines are antagonized by theophylline o Beta Blockers may cause additive toxicity o Elimination is effected by diet o Low-CHO/high-protein diet increases clearance (shortens half-life) o High in CHOs and low in protein decreases elimination (lengthens half-life) o Charcoal-broiled foods accelerate the hepatic metabolism of theophylline o Caffeine is metabolized by CYP1A2, CYP2E1, and CYP3A3/4 o Cimetidine, ketoconazole, fluconazole, mexiletine, and phenylpropanolamine (impair metabolism) o Caffeine elimination increased by phenobarbital and phenytoin ADR o Some patients have toxic effects at 15 to 20 mcg/mL (greater than 25 mcg/mL is toxicity) o CNS effects: irritability, restlessness, seizures, insomnia o GI effects: reflux, worsening heart burn o Cardiac effects: palpitations, tachycardia, hypotension, and life-threatening arrhythmias o Others: rash, diuresis, and tachypnea o Toxicity (greater than 20 mcg/mL): NVD, HA, insomnia, and irritability o Toxicity (greater than 35 mcg/mL): hyperglycemia, hypotension, cardiac arrhythmias, tachycardia, seizures, brain damage, and death o Caffeine: cardiac arrhythmias, tachycardia, insomnia, agitation, irritability, NA, NV, gastric irritation Clinical Use and Dosing Theophylline and COPD o Second or Third line drug for asthma and COPD o Recommended for long-term control of asthma and an “alternative, not preferred” therapy in step 2 of asthma care o Alternative treatment in combination with inhaled corticosteroids o Try LABA with ICS before theophylline r/t toxicity issues with theophylline o Dose for asthma and COPD based on weight and serum theophylline levels o Adult (16 and older) is started on 6 mg/kg/24 hours or 400 mg/24 hours o Dose is increased by 25% every 3 days until serum theophylline levels are 10 to 20 mcg/ml o Maximum dose 12-16 years old is 13 mg/kg/day and 10 mg/kg/day in healthy adolescents older than 16 and adults o The initial dose for children ages 5 or older is 16 mg/kg/day up to a maximum of 400 mg/day Apnea of Prematurity o Loading dose of caffeine citrate 10 to 20 mg/kg o Maintenance dose of 5mg/kg/day o If theophylline has been given to the patient in the previous 3 days. the loading dose is decreased by 50-70% o Theophylline: loading dose of 4 mg/kg/dose o Maintenance dose: 4 mg/kg/day o Total daily dose is divided and administered every 12 hours o Both drugs are equally effective in deceasing apnea spells in infants less than 33 weeks gestation Precautions and testing for xanthine derivatives o If serum concentration is between 10 to 15 mcg/mL, maintain dosage if tolerated and recheck at 6 to 12 month intervals o Check levels frequently until therapeutic range is met or adjusting doses (Q 3 days) o Monitor closely for s/s of toxicity o Check theophylline if a new medication is added to the treatment regimen or health status change o Levels need to be timed to measure peak levels of the drug o A serum theophylline level should be drawn 1 to 2 hours after immediate release formulas and 5 to 9 hours after sustained-release formulas o Check when changing brands (bioavailability varies) o Contraindications to theophylline: hypersensitivity to xanthine, PUD, and underlying seizure disorder o Contraindications to caffeine: hypersensitivity to caffeine or use of caffeine sodium benzoate formulation in neonates o Use Caution: HTN, ischemic heart disease, coronary insufficiency, CHF, or Hx of stroke and cardiac arrhythmias r/t effects on CV system o Toxicity: levels above 25 mcg/mL  May occur if clearance is decreased (hepatic impairment, chronic lung disease, cardiac failure, patients older than 55, and infants under 1) o Theophylline: Pregnancy Category C, crosses placenta, newborns may have therapeutic serum levels if maternal levels are high-normal range (tachycardia, irritability, and vomiting) o May be used in children: infants younger than 1 have decreased theophylline clearance and closely monitor levels should be a range of 5 to 10 mcg/mL o Caffeine citrate is used to treat apnea of prematurity Inhaled Anticholinergics o Drugs: ipratropium bromide (Atrovent), ipratropium with albuterol (Combivent), tiotropium bromide (Spiriva), and aclidinium bromide (Tadorza Pressair) o Treatment of COPD o Cause bronchial smooth muscle relaxation (bronchodilator) o Ipratropium may be used in combination with albuterol as the emergent Tx of an asthma exacerbation or when a patient is intolerant to B2Ras o Second-line bronchodilators for asthma and COPD o Use a spacer device and rinse mouth with water after administration to help decrease the incidence of ADRs Pharmacodynamics o Action of each drug is similar o Ipratropium: blocks the muscarinic cholinergic receptors by antagonizing the action of acetylcholine, this decreases the formation of cGMP, which leads to decreased contractility of the smooth muscle of the lungs (action of cGMP on intracellular calcium) o When inhaled ipratropium’s actions are confined to the mouth and airways o Tiotropium and aclidinium bromide: inhibit the muscarinic M3 receptors in the lungs (smooth muscle bronchodilation) Pharmacotherapeutics o Contraindication: hypersensitivity to atropine or atropine derivatives and those with bromide sensitivity o Patients with milk protein hypersensitivity should not be prescribed aclidinium bromide o Tiotropium: contraindication in patients with hypersensitivity to ipratropium or tiotropium o The inhaled anticholinergics (aclidinium, ipratropium and tiotropium), should not be used for the treatment of acute bronchospasms (except ipratropium mixed with albuterol) o Avoid in patients with urinary retention, bladder neck obstruction, or prostatic hypertrophy r/t anticholinergic effects o May increase intraocular pressure in patients with closed-angle glaucoma o Ipratropium bromide is Pregnancy Category B o Aclidinium and tiotropium and Pregnancy Category C o Safety and effectiveness of ipratropium in children under age 12 have not been established o May use in younger children as an adjunct to beta agonist (albuterol) therapy in acute exacerbations of asthma o Aclidinium and tiotropium are only approved for COPD, safety in children not established ADRs o Ipratropium: most common ADR is cough o Hoarseness, throat irritation, and dysgeusia o NV and dyspepsia (r/t anticholinergic effects constipation and urinary retention), and xerostomia (dry mouth) o Inhaled tiotropium (Spiriva HandiHaler): dry mouth is the most common ADR o Mouth irritation, pharyngitis, nasal congestion, sinusitis, HA, and URI o Aclidinium: HA most common ADR o Nasopharyngitis, cough, and rhinitis o Anticholinergic effects: urinary retention, dizziness, drowsiness, and constipation o Urinary retention is increased with the use of inhaled anticholinergics, particularly patients with BPH o If Ipratropium is sprayed in the eyes, may experience temporary eye irritation, pain, mydriasis, blurred vision, cycloplegia (paralysis of the ciliary muscle), irritant conjunctivitis, and visual disturbances o Rare allergic and anaphylactoid reactions may occur o Urticaria, maculopapular rash, bronchospasm, pruritis, laryngospasm, oropharyngeal edema, and angioedema of the tongue, lips, and face o Use with caution in patients with Hx of sensitivity to other drugs and soybeans, legumes, or soy lecithin appears to be correlated with hypersensitivity to ipratropium bromide o Patients with milk protein hypersensitivity should not be prescribed aclidinium bromide Drug Interactions o Ipratropium and tiotropium are minimally absorbed into systemic circulation after inhalation, no major drug interactions o Do not mix cromolyn sodium and ipratropium bromide via nebulizer because a precipitate will form Clinical Use and Dosage COPD o Ipratropium MDI: 18 mcg/spray: Two inhalations (36 mcg) 4 times a day (total of eight sprays/day) o If needed may take up to 12 puffs/day (maximum of 216 mcg/24 hours) o Ipratropium Nebulizer: one unit dose vial (500 mcg) 3 to 4 times/day via nebulizes, doses are 6 to 8 hours apart o Ipratropium may be mixed with albuterol (must be used within 1 hour) o Aclidinium bromide (Tadorza Pressair): inhalation powder administered via inhaler, 400 mcg/spray o One inhalation BID o Tiotropium (Spiriva) is a dry powder capsule given via HandiHaler device o Two inhalation of a single 18 mcg capsule once daily o Ipratropium/albuterol combination (Combivent): second-line use for patients with COPD o 2 puffs QID o Prescribed for patients already on a bronchodilator who continue to have bronchospasms who may benefit from a second bronchodilator o Each inhalation is 103 mcg of albuterol sulfate and 18 mcg of ipratropium bromide Two inhalations four times a day o May take addition inhalations must not exceed 12 inhalations in 24 hours o Very economical for patients who need both meds Asthma o Ipratropium for asthma maintenance is two to three inhalations 4 times a day o Should not be used for EIA o For children under 12, one or two inhalations every 6 hours o Ipratropium solution: o Adults 250 mcg via nebulizer four times a day o Children under 12 is 250 to 500 mcg every 8 hours o Infants are dosed at 125 to 25o mcg three times a day o Acute exacerbation of asthma: ipratropium mixed with albuterol o Ipratropium/albuterol (Combivent): second-line quick relief mediation in asthma o 103 mcg of albuterol sulfate and 18 mcg of ipratropium bromide o Dose in adults two to three inhalations four times a day o Children under 12 one to two inhalations every 6 hours o Nebulizer solution of albuterol (2.5 mg/3 mL) and ipratropium (0.5 mg/3 mL) o 3 mL every 4 to 6 hours for adults o Children under 12: 1.5 to 3 mL every 8 hours Leukotriene Modifiers o Induces numerous effects that contribute to inflammatory process o Smooth muscle contractions o Decrease inflammation o Leukotriene-receptor agonists (LTRAs) and 5-lipoxygenase pathway inhibitors were developed under the theory that cysteinyl leukotriene play a significant role in the chronic inflammation associated with asthma and allergy o Leukotrienes induce numerous effects that contribute to the inflammatory process (smooth muscle contractility, neutrophil aggregation, degranulation, and chemotaxis, vascular permeability, and lymphocytes o Drugs for use in asthma: zafirlukast (Accolate), zileutin (Zyflo, Zyflo CR), and montelukast (Singular) Pharmacodynamics Leukotriene-Receptor Agonists (Zafirlukast and Montelukast) o Zafirlukast: synthetic, selective, and competitive LTRA of leukotriene D4 and E4 o Have been identified as component of slow reacting substance of anaphylaxis o Montelukast: selective LTRA that inhibits cysteinyl leukotriene receptor (CysLT1) o Binds with high affinity and selectivity to the receptor (CysLT1) o Evidence that cysteinyl leukotriene contribute to the pathophysiology of asthma and allergy o Contribute to: Airway edema, smooth muscle constriction, and cellular changes associated with inflammatory process 5-Lipoxygenase Pathway Inhibitors (Zileuton) o Zileuton in an inhibitor of 5-lipoxygenase (enzyme that catalyzes the formation of leukotrienes from arachidonic acid o By inhibiting 5-lipoxygenase zileuton inhibits the formation of LTB4, LTC4, and LTE4 (component of slow reacting substance of anaphylaxis)