NR 566 Week 2 Study Guide {2020} | Chapter 17: Drugs Affecting the Respiratory System

NR 566 Week 2 Study Guide {2020} – Chamberlain College of Nursing 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 Pyrazinamide- an analogue of nicotinamide  Bactericidal – against M. tuberculosis in an acidic environment (pH 5.6).  Useful in tx of TB  Exhibits good activity within macrophages and plays a key role in killing intracellular organisms.  Shortening therapy and preventing relapses  Exact action is UNKNOWN. o Streptomycin – aminoglycoside, used now almost exclusively to treat M. tuberculosis infections.  Bactericidal in alkaline extracellular environment  Added as the 4th drug to the regimen for TB  Sensitive to M. avium and M. kansasii; resistant to all mycobacterium  Irreversible inhibitor of protein synthesis.  Penetrates cells poorly o Ethionamide- similar binding site and mechanism of action as isoniazid.  Ultimately blocks the synthesis of mycolic acids.  Bacteriostatic – M. tuberculosis  Can inhibit some other Mycobacterium species. o Capreomycin – peptide abx  Bactericidal to susceptible mycobacteria.  Inhibits RNA synthesis - decreasing replication of M. tuberculosis.  Resistance easily develops when given as monotherapy (should be given as part of multidrug regimen) o Bedaquiline – unique antimycobacterial, approved by FDA in 2012  For tx of multidrug resistant TB  Inhibits mycobacterial adenosine triphosphate (ATP) synthesis  Active against replicating and dormant mycobacteria  Black-box warning: increased mortality as compared with a placebo tx group.  Only to be used when an effective tx regimen cannot otherwise be provided. o Para-amino salicylic acid- structurally similar to PABA and sulfonamides  Folate synthesis antagonist  Active almost exclusive against M. tuberculosis.  Bacteriostatic  Not used frequently – primary resistance is common, and other drugs are better tolerated and less expensive. • Pharmacokinetics o Oral antimycobacterial drugs are rapidly and well absorbed in GI tract after PO administration. o Isoniazid- 90% bioavailable but should be taken on an empty stomach  Readily diffuses into all body fluids including CSF (90% of serum levels), pleural, and ascitic fluids  Readily diffuses into tissues, organs, saliva, sputum, and feces  Crosses placenta and breastmilk  Metabolism is extensive and highly variable and dependent on acetylator status.  Primarily acetylated by the liver  50% of both blacks and whites are slow acetylators  Alaskan and Asians- majority are rapid acetylators  Fast acetylators metabolize this drug 5 to 6 times faster than slow acetylators  Rate of acetylator does not affect effectiveness but may increase risk for toxic reactions with slow acetylators.  Excreted in the urine- metabolites, and unchanged drug  Elimination is largely dependent on renal function o Rifamycin’s and ethambutol penetrate and concentrate in most body fluids.  Food slow the rate of absorption of rifamycin’s but not the extent of absorption (may be taken with or without food)  Adequate CSF penetration occurs only in the presence of inflamed meninges.  Potent inducers of liver metabolism  Rifampin and rifapentine- metabolized in the liver by deacetylation.  Metabolites are active against M. tuberculosis.  t1/2 life decreases with repeated administration  excreted primarily in the bile - enterohepatic recirculation - feces, urine (small amount)  hepatic insufficiency and age slightly affect metabolism of rifabutin  Renal insufficiency- reduced drug distribution and faster drug elimination - decreased drug concentrations. o Pyrazinamide- widely distributed in body tissues and fluids including the liver and lung.  Reaches high concentrations in CSF  Crosses the placenta and enter breastmilk in small amounts  Poor CSF penetration (good penetration if meninges are inflamed)  70% excreted in urine by glomerular filtration  Hydrolyzed by the liver to a metabolite that also has antimycobacterial activity  Prolonged t1/2 - significant on impaired hepatic and renal functions. o Streptomycin and capreomycin  widely distributed through extracellular fluid  Cross placenta and enter breast milk  Poor CSF penetration except in the presence of inflamed meninges  Excreted almost exclusively by the kidneys o Ethionamide- widely distributed to body tissues and fluids- CSF and serum concentrations are equal  35% metabolized by the liver  Majority of the drug excreted in the urine as inactive metabolites o Ethambutol- mainly excreted as unchanged drug in the urine.  20% metabolized by the liver  Marked accumulation may occur in renal failure • Pharmacotherapeutics o Isoniazid- careful monitoring for hepatotoxicity (ETOH drinkers, chronic liver disease, severe renal function, 35y/o, drug abuse, pregnant, immediately postpartum)  Peripheral neuropathy, neurotoxicity may occur  Special caution: patients with preexisting peripheral neuropathy, pregnancy, and (+) HIV. o Ethambutol, streptomycin, capreomycin  Cautious use for patient with renal impairment  Dose adjustments may be required o HEPATOTOXIC: rifamycin’s, Isoniazid, Pyrazinamide, Ethionamide (RIPE) o Ethionamide: use with caution with DM, hepatitis is more likely with these patients o Thrombocytopenia and anemia: rifampin and isoniazid o Gouty arthritis attacks: ethambutol and pyrazinamide (should not be used during a flare up) o Visual disturbances, irreversible blindness- ethambutol (cautious use with eye disorders such as diabetic retinopathy, cataracts, optic neuritis) o CYP enzyme:  Rifamycin’s- potent inducers of liver metabolism  Medications metabolized by CYP enzyme- may lead to subtherapeutic concentrations - tx failure may occur. • Clinical indications & dosing o See textbook pp.766-769 • ADRs/Monitoring: o Hypersensitivity reactions o Isoniazid  Peripheral neuropathy – isoniazid (give Pyridoxine (vit.b6) for prevention)  Hepatitis, Elevated LFTs- jaundice, fatigue – MONITOR LFTs  Isoniazid + rifampin = increased risk for liver damage (4-folds!)  Blood dyscrasias  Metabolic acidosis  Drug fever  Gynecomastia o Rifamycins- mostly GI s/sx (n/v/d, anorexia, flatulence, abd pain)  Hepatotoxicity occurs with isoniazid- MONITOR LFTs  Orange-red discoloration of the body fluids including tears, saliva, urine, sweat, CSF, and feces (harmless)  Hematuria- sign of hypersensitivity reaction (not to be confused with urine discoloration!!!)  Blood dyscrasias  h/a, drowsiness, inability to concentrate  pruritic rash (1%-11% of patients)  visual disturbances  lupus erythematosus  exudative conjunctivitis  thrombocytopenia and neutropenia- observed with rifabutin o Ethambutol – mostly GI s/sx  Common: optic neuritis (serious)- dose related (reversible if drug is dc’d)  Decreased visual acuity, loss of vision  Red-green color blindness  Diminished visual fields  Generally reversible when drug is d/c promptly  May take up to 1 year to recover  Vision tests before, during, and after therapy  Gouty arthritis attacks- elevated uric acid- CHECK/MONITOR URIC ACID  Transient impairment of liver function- MONITOR LFTs  Infrequent peripheral neuropathy o Pyrazinamide – HEPATOTOXICITY (dose related)  Monitor LFTs  Monitor s/sx of hepatotoxicity (jaudince, fatigue)  Hyperuricemia often occurs- may precipitate gouty arthritis attacks  The drug inhibits renal excretion of urates o Streptomycin, capreomycin- OTOTOXICITY  Damage of the CN-VIII (Cranial Never 8)- vertigo, n/v, loss of hearing  Increased risk - higher doses and longer duration of therapy  Nephrotoxicity- common among aminoglycosides  Dose adjustment, monitor kidney function  Dose of 2-3 times weekly (rather than daily)- may reduce the risk for toxicity o Ethionamide  Few ADRs  GI distress (NVD)  Metallic taste  Hepatitis (rare), optic neuritis, and peripheral neuritis (common)  Treat neurological symptoms with pyridoxine o Cycloserine  Neurological effects  Somnolence, psychosis, and suicidal ideation • Patient education o Multidrug therapy is essential for TB- to prevent resistance, and achieve tx success o Directly observed therapy (DOT)- each dose is observed by an HCP or other designated person (strategy to promote compliance) o GI upset is relatively common in the first few weeks of initial phase therapy o First-line drugs, especially Rifampin, must not be d/c’d because of minor adverse effects o May be administered with food o Do not split doses o rifamycin’s may discolor urine, tears, saliva, and sweat o Clothes, dentures, or contacts may become stained o Patients on ethambutol contact provider if eye pain or visual disturbances occur o Good nutrition, rest, appropriate exercise o Monitoring of ADRs, hypersensitivity, resolution of s/sx (is the tx working?) Antimycobacterial guideline for TB  TB disease can be treated by taking several drugs for 6-9 months  10 drugs approved by the USDA and FDA for treating TB  First-line treatment (R-I-P-E)- for dosing, see textbook pp. o Rifampin (RIF) o Isoniazid (INH) o Pyrazinamide (PZA) o Ethambutol (EMB)  Second-line treatment- for dosing, see textbook pp. o Cylcoserine o Ethionamide o Moxifloxacin o Gatifloxacin o Bedaquiline  Treatment regimens include initial phase and continuation phases.  Initial phase has four drugs o isoniazid (INH) rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) o Given for 2 months  Followed by continuation phases, o usually two drugs INH and another drug, most often RIF o Given 4-7 months  Tx of TB begins with accurate diagnosis.