PCOL 3.2 DRUGS USED IN ASTHMA.pdf

PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 OUTLINE I. II. III. IV. V. VI. VII. Pathogenesis of asthma Basic pharmacology of agents used in the treatment of asthma Clinical pharmacology of drugs used in the treatment of asthma Management of acute asthma Prospects for prevention Treatment of chron...

PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 OUTLINE I. II. III. IV. V. VI. VII. Pathogenesis of asthma Basic pharmacology of agents used in the treatment of asthma Clinical pharmacology of drugs used in the treatment of asthma Management of acute asthma Prospects for prevention Treatment of chronic obstructive pulmonary disease (COPD) Appendix ❖ ❖ ❖ PATHOGENESIS OF ASTHMA Classic Allergic Asthma ❖ ❖ Immune Globulin (IgE) mediated, produced in response to foreign proteins (house dust mites, cockroaches, animal danders, molds, and pollens). ★ “Qualify as allergens on the basis of the induction of IgE antibody production in persons exposed to them” The tendency to produce IgE is at least in part genetically determined, and asthma clusters with other allergic diseases (allergic rhinitis, eczema, food allergy) in family groups Immunopathogenesis of Asthma FIGURE 1 ❖ ❖ Exposure to allergen causes synthesis of IgE, which binds to mast cells in the airway mucosa On re-exposure to allergen, antigen-antibody interaction on mast cell surfaces triggers release of mediators of anaphylaxis: histamine, tryptase, prostaglandin D2 (PGD2), leukotriene (LT), C4, and platelet- activating factor (PAF). 1 | Page ❖ ❖ These agents provoke contraction of airway smooth muscle, causing the immediate fall in forced expiratory volume in 1 second (FEV1) ★ At times, it is called the EARLY ASTHMATIC RESPONSE RE-EXPOSURE to allergen also causes the synthesis and release of variety of cytokines: ● Interleukins (IL) 4 and 5, ● granulocyte-macrophage colonystimulating factor, ● tumor necrosis factor (TNF), and ● tissue growth factor (TGF) from T-cells and mast cells. These cytokines, in turn, attract and activate eosinophils and neutrophils, whose products include: ● eosinophil cationic protein (ECP), ● major basic protein (MBP), ● proteases, and ● platelet-activating factor. These mediators cause: ● Edema ● mucus hypersecretion ● smooth muscle contraction ● increase in bronchial reactivity (associated with the LATE ASTHMATIC RESPONSE, indicated by a second fall in FEV1, 3- 6 hours after exposure.) Once produced, IgE binds to high affinity receptors (FCεR-1) on mast cells in the airway mucosa, so that re-exposure to the allergen triggers the release of mediators stored in the mast cells’ granules and the synthesis and release of other mediators EARLY ASTHMATIC RESPONSE ■ The histamine, tryptase, leukotriene C4, and D4, and prostaglandin D2 released cause the smooth muscle contraction and vascular leakage responsible for the acute bronchoconstriction. LATE ASTHMATIC RESPONSE ■ 3-6 hours after the early reaction ■ This is the second, more sustained phase of bronchoconstriction, associated with the influx of inflammatory cells into the bronchial mucosa and with an increase in bronchial reactivity ■ This late response is thought to be due to cytokines characteristically produced by T2 Lymphocytes, especially interleukins (IL) 5, 9, and 13. ■ These cytokines are thought to attract and activate eosinophils, stimulate IgE production by B lymphocytes, and stimulate mucus production by bronchial epithelial cells ■ It is not clear whether lymphocytes or mast cells in the airway mucosa are the primary source of the mediators responsible for the late inflammatory response but the benefits of corticosteroid therapy are attributed to their inhibition of the production of proinflammatory Apple | Charity | Klemson | Jennah PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 cytokines in the airways and of the response of airway epithelial cells to them NOTE ❖ ❖ ❖ ★ ★ This classic conception of asthma as an allergic disease only applies to a subgroup of patients with asthma, those with evidence of allergy. Allergic asthma accounts for a great proportion of asthma that develops in childhood, but a smaller proportion of adult-onset asthma Other terms used in asthma are: ● “Extrinsic” vs “Intrinsic” ● “Aspirin-sensitive” ● “Adult-onset” ● “Post-viral” ● “Obesity-related” The allergen challenge model fails to account for all the features of the condition in allergic asthmatics. The model only applies to patients with allergic asthma ❖ Inflammatory Mechanism of Asthma FIGURE 2 ❖ Airway epithelial cells, once exposed to activation stimuli (including allergens, viruses, and irritants), release cytokines that promote dendritic cell (DC) mobilization to draining lymph nodes, where they present antigens, and thereby activate naïve CD4 T-cells ● These T-cells then induce B-cell class switching and maturation into plasma cells, which produce IgE ● TH2 cells also migrate into the airway subepithelial mucosa, where they release inflammatory cytokines such as IL-5 and IL-13, which induce goblet cell metaplasia and mucus production, and act as a chemokine for eosinophils, mast cells, and basophils 2 | Page Unbound IgE secreted by plasma cells binds the FCεR-1 receptor on submucosal mast cells and basophils, and when crosslinked by an antigen induces the release of preformed mediators such as histamine and leukotrienes, as well as the release of inflammatory cytokines Bronchial Hyperactivity ● “Asthmatic bronchospasms can also be provoked by non-allergenic stimuli (such as distilled water, aerosol, exercise, cold air, cigarette smoke, and sulphur dioxide)” ● The tendency to develop bronchospasm on encountering non-allergenic stimuli is assessed by measuring the fall in maximal expiratory flow provoked by inhaling serially increasing concentrations of the aerosolized cholinergic agonist, Methacholine ● It is considered fundamental to asthma’s pathogenesis because it is nearly ubiquitous in patients with asthma, and its degree roughly correlates with the clinical severity of the disease ★ It is important to ask the patient other stimuli for his asthma, not just the allergens. ● The mechanisms underlying bronchial hyperreactivity are incompletely understood but appear to be related to inflammation of the airway mucosa. The anti-inflammatory activity of inhaled corticosteroids (ICS) treatment is credited with preventing the increase in bronchial reactivity associated with the late asthmatic response. ● The bronchoconstriction itself results not simply from the direct effect of the released mediators but also from their activation of neural pathways. ● This is suggested by the effectiveness of muscarinic receptor antagonists, which have no direct effect on smooth muscle contractility, in inhibiting the bronchoconstriction caused by inhalation of allergens and airway irritants. ● ❖ Asthmatic bronchospasms result from a combination of release of mediators and an exaggeration of responsiveness to their effects. ★ It predicts that drugs with different modes of action will effectively treat asthma The bronchospasms provoked by the exposure to allergens might be prevented by: 1. Reduce the amount of IgE bound to mast cells (Anti-IgE antibody) 2. Reduce the number and activity of eosinophils in the airway mucosa (Anti-IL-5 antibody) Apple | Charity | Klemson | Jennah PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 3. Block the receptor for IL-4 and IL-13 (Anti-IL-4α receptor antibody) 4. Prevent mast cell degranulation (Cromolyn or Nedocromil, sympathomimetic agents, Ca channel blockers) 5. Block the action of the products released (antihistamines and leukotriene receptor antagonists) 6. Interfere with the action of inflammatory cytokines (anti- IL-5 and anti-IL-13 monoclonal antibodies) 7. Relax airway smooth muscles (sympathomimetic agents, phosphodiesterase inhibitors) or inhibit the effect of acetylcholine released from vagal motor nerves (muscarinic antagonist, also described as anticholinergic agents) 8. Reduce level of bronchial responsiveness. Increased responsiveness appears to be linked to airway inflammation and because airway inflammation is a feature of late asthmatic responses, this strategy is implemented both by reducing exposure to the allergens that provoke inflammation and by prolonged therapy with anti- inflammatory agents, especially inhaled corticosteroids (ICS). This therapy, once expected to be effective for all forms of asthma, is now recognized to be more effective for allergic than non-allergic asthma. ❖ ❖ ❖ ❖ ★ BASIC PHARMACOLOGY OF AGENTS USED IN THE TREATMENT OF ASTHMA A. Sympathomimetic Agents: most commonly used; used as RELIEVERS B. Methylxanthine Drugs C. Antimuscarinic Agents D. Corticosteroids: used as CONTROLLERS/ antiinflammatory E. Cromolyn and Nedocromil F. Leukotriene inhibitors G. Targeted Therapy (Monoclonal Antibodies) ◼ EPINEPHRINE ➢ ➢ ➢ A. SYMPATHOMIMETIC AGENTS ➢ Adrenoreceptor agonists ➢ ◼ ➢ FIGURE 3 ❖ Effective, rapidly acting bronchodilator Injected subcutaneously (0.4 mL of 1:1000 solution) or inhaled as a microaerosol from a pressurized canister (320 mcg per puff) Maximal bronchodilation is achieved within 15 minutes after inhalation and lasts 60- 90 minutes ADVERSE EFFECTS: (because epinephrine stimulates α and β1 as well as β2 receptors) Tachycardia Arrhythmia Worsening angina pectoris USES: its current use is thus largely for the treatment of acute vasodilation and bronchospasm of anaphylaxis EPHEDRINE ➢ ◼ Their binding to β-adrenergic receptors (abundant on airway smooth muscle cells) ► stimulates adenylyl cyclase and increases the formation of intracellular cAMP, thereby relaxing airway smooth muscle and inhibiting release of bronchoconstricting mediators from mast cells. They may also inhibit microvascular leakage and increase mucocilliary transport ADVERSE EFFECTS: especially of adrenoceptor agonists that activate β1 as well as β2 receptors, include: Tachycardia Skeletal muscle tremor Decreases in serum potassium levels. MODE: Inhalation ► results in the greatest local effect on airway smooth muscle with the least systemic toxicity Aerosol deposition depends on particle size, the pattern of breathing, and geometry of the airways Size range of 2-5 μm, 80-90% of aerosol is deposited in the mouth or pharynx Only 10-20% of the particles reach the lung parenchyma Particles under 1-2 μm remain suspended and may be exhaled Bronchial deposition of an aerosol is increased by slow inhalation of a nearly full breath and by 5 or more seconds of breath-holding at the end of inspiration Has a longer duration, oral activity, more pronounced central effects, and much lower potency Now used infrequently for treating asthma ISOPROTERENOL ➢ Is a potent nonselective β1 and β2 bronchodilator Mainstay in the treatment of asthma 3 | Page Apple | Charity | Klemson | Jennah PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 ➢ ➢ ★ INHALATION: 80-120 mcg isoproterenol causes maximal bronchodilation within 5 minutes and has a 60- to 90-minute duration of action ADVERSE EFFECTS: cardiac arrhythmia (high doses) With the efficacy of β2-selective agonists, the use of isoproterenol as a treatment of asthma has been displaced - - - Βeta2-Selective Drugs ❖ ❖ ❖ β2-selective adrenoceptor agonist drugs are now most widely used Inhaler or oral administration Have a longer duration of action than epinephrine or isoproterenol ◼ ALBUTEROL, TERBUTALINE, METAPROTERENOL & PIRBUTEROL ➢ ➢ ➢ ➢ ➢ ➢ ❖ ◼ are available at metered-dose inhalers Given by inhalation, cause bronchodilation equivalent to that produced by isoproterenol. Peak within 15 minutes Duration for 3-4 hours As a nebulizer (diluted in saline): Higher doses must be given (2.5-5.0 mg vs 100- 400 mcg) but not necessarily more effective than inhalers. Nebulized therapy should thus be reserved for patients unable to coordinate inhalation from a metered-dose inhaler Mixture of R(levo) and S(dextro) isomers. ONLY the R isomer activates the β-agonist receptor ■ S isomer may promote inflammation hence a purified preparation of the R isomer of albuterol has been developed (Levalbuterol). \ ■ This purified isomer is often used in children with asthma ■ Meta-analyses of clinical trials have not shown it to have greater efficacy or lower toxicity than the standard less expensive racemic mixture of R- and S-albuterol in treating exacerbations of asthma or chronic obstructive pulmonary disease. ALBUTEROL AND TERBUTALINE ➢ ➢ ➢ ➢ ➢ are also available in oral form DOSE: 1 tab two to three times daily is the usual regimen ADVERSE EFFECTS: Skeletal Muscle Tremor Nervousness Occasional Weakness This route of administration presents no advantage over inhaled treatment and produces more pronounced adverse effects and is thus rarely prescribed TERBUTALINE is available for subcutaneous injection (0.25 mg) 4 | Page INDICATION: severe asthma requiring emergency treatment when aerosolized therapy is not available or has been ineffective it should be remembered that terbutaline’s longer duration of action means that cumulative effects may be seen after repeated injections Large doses of parenteral terbutaline are sometime used to inhibit uterine contractions associated with premature labor Long-acting β2-selective agonists (LABA) ◼ SALMETEROL AND FORMOTEROL ➢ ➢ ➢ ➢ ➢ DURATION OF ACTION: 12 hours Long duration of bronchodilating actions as a result of high lipid solubility This permits them to dissolve in smooth muscle cell membrane in high concentrations or, possibly, attach to “mooring” molecules in the vicinity of the adrenoceptor These drugs appear to interact with inhaled corticosteroids to improve asthma control. No anti-inflammatory action hence should not be used in monotherapy of asthma Ultra-long-acting β-agonists ◼ INDACATEROL, BAMBUTEROL ➢ ➢ ➢ OLODATEROL, VILANTEROL & need to be taken only once a day Because their prolonged bronchodilation masks symptoms of bronchial inflammation, they should only be used in combination with ICS for asthma Used in monotherapy for COPD TOXICITIES ★ Concerns have been largely put to rest 1. Hypoxemia ● Vasodilating action of β2-agonist treatment may increase perfusion of poorly ventilated lung units transiently, thus decreasing arterial oxygen tension (PaO2) ● This effect is small, easily overcome by the routine administration of supplemental oxygen, AND is made irrelevant after a short period of time by the increase in oxygen tension that follows β-agonist- induced bronchodilation 2. Cardiac Arrhythmia ● In patients presenting for emergency treatment of severe asthma, irregularities in cardiac rhythm improve with the improvements in gas exchange affected by bronchodilator treatment and oxygen administration 3. Tachyphylaxis ● A reduction in bronchodilator response to low-dose-β-agonist treatment can be shown after Apple | Charity | Klemson | Jennah PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 ● ● ★ ❖ several days of regular β- agonist use, but maximal bronchodilation is still achieved well within the range of doses usually given Tachyphylaxis is more clearly reflected by a loss of protection afforded by acute treatment with a β-agonist against a later challenge by exercise or inhalation of allergen or an airway irritant. It remains to be proven whether this loss of bronchoprotective efficacy is associated with adverse outcomes Not a problem in current clinical practice MECHANISM OF ACTION 1. Demonstration of genetic variations in the β-receptor raised the possibility that the risk of adverse effects might not be uniformly distributed among asthmatic patients ○ Single nucleotide polymorphism (SNP) ➔ Change of amino acid code at position 16 from glycine to arginine (Gly16Arg) ➔ Asthma control deteriorated among patients homozygous for arginine at this locus ➔ Studies of LABA treatment have since shown, however, that differences in multiple measures of asthma control are negligible in patient groups with different genotypes at that locus FIGURE 4 ● ● ● ● B. METHYLXANTHINES ❖ ◼ Inhibit phosphodiesterase (PDE) enzyme Theophylline (tea), Theobromine (cocoa), and Caffeine (coffee) ● THEOPHYLLINE ➢ ➢ ➢ ★ ➢ Once a mainstay treatment for asthma has almost ceased with demonstration of greater efficacy of inhaled adrenoceptor agonists for acute asthma and of inhaled anti-inflammatory agents for chronic asthma TOXICITIES: Nausea Vomiting Tremulousness Arrythmia Requires monitoring because of narrow therapeutic index Made all the more necessary by individual differences in theophylline metabolism and frequent drug-to-drug interactions Still used in other countries due to low cost 2. Inhibition of cell surface receptors for adenosine CHEMISTRY ❖ ❖ ❖ ❖ Theophylline is 1,3-dimethylxanthine Theobromine is 3,7-dimethylxanthine Caffeine is 1,3,7-trimethylxanthine A theophylline preparation commonly used for therapeutic purposes is Aminophylline, a theophyllineethylenediamene complex 5 | Page Results in increasing concentrations of intracellular cAMP and, in some tissues, cGMP Cyclic AMP regulates many cellular functions such as stimulation of cardiac function relaxation of smooth muscle, reduction in the immune and inflammatory activity of specific cells INHIBITION OF PDE3: relaxation of airway smooth muscles INHIBITION OF PDE4: inhibiting release of cytokines, thus decreasing immune cell migration and activation SELECTIVE INHIBITORS OF PDE4: Roflumilast, effective for reducing the frequency of exacerbations of COPD although not for the treatment of asthma FIGURE 5 ● 3. Adenosine provokes contraction of isolated airway smooth muscle and release of histamine from airway mast cells Enhancement of histone deacetylation Apple | Charity | Klemson | Jennah PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 Acetylation of core histones is necessary for activation of inflammatory gene transcription ● C. ❖ ❖ Effects on the central nervous system, kidney, and cardiac and skeletal muscles as well as smooth muscle THEOPHYLLINE is the most selective in its smooth muscle effects CAFFEINE has the most marked CNS effects Stimulate secretion of both gastric acid and digestive enzymes ● PHARMACODYNAMICS ❖ Effects on the Gastrointestinal Tract D. Effects on Kidney Weak diuretics (theophylline) Involves both increased glomerular filtration and reduced tubular sodium reabsorption The diuresis is not of sufficient magnitude to be therapeutically useful, although it does counteract some cardiovascular effects and limits the degree of hypertension produced ● ● ● A. Central nervous system effects ● ● ● ● B. Mild cortical arousal with increased alertness and deferral of fatigue (especially for caffeine) The caffeine contained in beverages, approximately 100mg in a cup of coffee, is sufficient to cause nervousness and insomnia in sensitive individuals and slight bronchodilation in patients with asthma The larger the dose necessary for more effective bronchodilation cause nervousness and tremor Very high doses, from accidental or suicidal overdose, can cause medullary stimulation, convulsions, and even death E. ● ● ● ● ● ● Methylxanthines have positive chronotropic and inotropic effects on the heart LOW CONCENTRATIONS: these effects result from inhibition of presynaptic adenosine receptors in sympathetic nerves, increasing catecholamine release at nerve endings HIGHER CONCENTRATIONS (>10 μmol/L, 2 mg/L) are associated with inhibition of phosphodiesterase and increases in cAMP may result in increased influx of calcium MUCH HIGHER CONCENTRATIONS (>100 μmol/L), sequestration of calcium by the sarcoplasmic reticulum is impaired. ○ The clinical expression of these effects on cardiovascular function varies among individuals Ordinary consumption of methylxanthinebeverage: slight tachycardia an increase in peripheral resistance potentially raising blood pressure slightly In sensitive individuals, consumption of a few cups of coffee may cause arrhythmias High doses of these agents relax vascular smooth muscle, except in cerebral blood vessels, where they cause contraction ○ May decrease blood viscosity and may improve blood flow under certain conditions ○ The mechanism of action is not well defined, but the effect is exploited in the treatment of intermittent claudication with pentoxifylline, a dimethylxanthine agent 6 | Page BRONCHODILATION: major therapeutic action in asthma Tolerance does not develop Adverse effects in the CNS limit the dose Inhibit antigen-induced release of histamine from lung tissue ● ● ● ● F. Effects of Skeletal Muscles Improve contractility of skeletal muscle and reverse fatigue of the diaphragm in patients with COPD This effect may account for theophylline’s ability to improve ventilator response to hypoxia and to diminish dyspnea even in patients with irreversible airflow obstruction ● Cardiovascular effects ● Effects on Smooth Muscles ● CLINICAL USE ❖ ❖ ❖ C. Theophylline is the most effective bronchodilator It relieves airflow obstruction in acute asthma and reduces the severity of symptoms in patients with chronic asthma However, the efficacy and safety of other drugs, especially inhaled β2-agonist and inhaled corticosteroids, and the toxicities and need for monitoring of blood concentration of theophylline have made it almost obsolete in asthma treatment ANTIMUSCARINIC AGENTS ❖ ❖ Atropine was discovered as a potent competitive inhibitor of acetylcholine at postganglionic muscarinic receptors, as a bronchodilator Ipratropium: a potent atropine analog that is poorly absorbed after aerosol administration and is therefore relatively free of systemic atropine-like effects MECHANISM OF ACTION: Apple | Charity | Klemson | Jennah PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 ❖ ❖ Competitively inhibits the action of acetylcholine at muscarinic receptors and are therefore sometimes referred to as “anticholinergic agents” In the airways, acetylcholine is released from efferent endings of the vagus nerve, and muscarinic antagonists block the contraction of airway smooth muscle and the increase in secretion of mucus that occurs in response to vagal activity ❖ CLINICAL USES ❖ ❖ ❖ D. Bronchodilators ● Less toxicity from systemic absorption is achieved with ipratropium bromide (a selective quaternary ammonium derivative of atropine), which can be inhaled in high doses because of its poor absorption into the circulation and poor entry into the CNS ● The bronchodilation and inhibition of provoked bronchoconstriction afforded by antimuscarinic agents are incomplete, their use is of clinical value, especially for patients intolerant of inhaled β-agonists Ipratropium appears to be as effective as albuterol in patients with COPD who at have at least partially reversible obstruction Longer-acting antimuscarinic agents: Tiotropium, Aclidinium, and Umeclidinium ● are approved for maintenance therapy of COPD but not approved as maintenance treatment of asthma. CORTICOSTEROIDS MECHANISM OF ACTION ❖ ❖ ❖ ANTI-INFLAMMATORY EFFECT: inhibition of production of inflammatory cytokines. They do not relax airway smooth muscle directly but reduce bronchial hyperreactivity and reduce the frequency of asthma exacerbations if taken regularly. Their effect on airway obstruction is due in part to their contraction of engorged vessels in the bronchial mucosa and their potentiation of the effects of β-receptor agonists. Inhibition of the infiltration of asthmatic airways by lymphocytes, eosinophils, and mast cells CLINICAL USE ❖ corticosteroids consistently show them to be effective in improving all indices of asthma control: severity of symptoms, tests of airway caliber and bronchial reactivity, frequency of exacerbations, and quality of life. 7 | Page ❖ reserved for patients who require urgent treatment: those who have not improved adequately with bronchodilators or who experience worsening symptoms despite highdose maintenance therapy. ● SEVERE ASTHMA EXACERBATIONS, urgent treatment is often begun with an oral dose of 30–60 mg prednisone per day or an intravenous dose of 0.5–1 mg/kg methylprednisolone every 6– 12 hours; the dose is decreased after airway obstruction has improved. ● In most patients, systemic corticosteroid therapy can be discontinued in 5–10 days, but symptoms may worsen in other patients as the dose is decreased to lower levels. INHALATIONAL TREATMENT is the most effective way to avoid the systemic adverse effects of corticosteroid therapy ● Beclomethasone, Budesonide, Ciclesonide, Flunisolide, Fluticasone, Mometasone, and Triamcinolone has made it possible to deliver corticosteroids to the airways with minimal systemic absorption. ● An average daily dose of 800 mcg of inhaled BECLOMETHASONE is equivalent to about 10–15 mg/d of oral prednisone for the control of asthma, with far fewer systemic effects. ● cautions in switching patients from chronic oral to ICS therapy is to taper oral therapy slowly to avoid precipitation of adrenal insufficiency. ● In patients requiring continued prednisone treatment despite standard doses of an ICS, higher inhaled doses are often effective and enable tapering and discontinuing prednisone treatment. Although these high doses of inhaled steroids may cause mild adrenal suppression, the risks of systemic toxicity from their chronic use are negligible compared with those of the oral corticosteroid therapy they replace. ADVERSE EFFECTS OF INHALED TOPICAL CORTICOSTEROIDS: ► Oropharyngeal candidiasis easily treated with topical clotrimazole can be reduced by having patients gargle water and expectorate after each inhaled treatment. CICLESONIDE, a prodrug activated by bronchial esterases, is comparably effective to other inhaled corticosteroids and is associated with less frequent candidiasis. ► Hoarseness can also result from a direct local effect of ICS Apple | Charity | Klemson | Jennah PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 on the vocal cords. chronic use may increase the risks of osteoporosis and cataracts EVEN if majority of the inhaled dose is deposited in the oropharynx and swallowed, AND evenly subjected to first-pass metabolism. ► In children, ICS therapy has been shown to slow the rate of growth by about 1 cm over the first year of treatment, but not the rate of growth thereafter, so that the effect on adult height is minimal. - ❖ ❖ ICS- Inhaled corticosteroids ★ ❖ ❖ ❖ E. Because of the efficacy and safety of inhaled corticosteroids National and international guidelines for asthma management recommend their prescription for patients with persistent asthma who require more than occasional inhalations of a β agonist for relief of symptoms. Corticosteroid is continued for 10–12 weeks and then withdrawn to determine whether more prolonged therapy is needed; inhaled corticosteroids are not curative. ● inhaled corticosteroids are thus properly labeled as “controllers.” They are effective only so long as they are taken. In order to reduce to reduce the risk of longterm, twice daily use of ICS is to administer them only intermittently, when symptoms of asthma flare. ● Taking a single inhalation of an ICS with each inhalation of a short-acting β- agonist reliever (eg, an inhalation of beclomethasone for each inhalation of albuterol) or taking a 5- to 10-day course of twice daily high-dose BUDESONIDE or BECLOMETHASONE when asthma symptoms worsen has been found to be nearly as effective as regular daily therapy in adults and children with mild to moderate asthma CROMOLYN & NEDOCROMIL ❖ ❖ ❖ Cromolyn sodium (disodium cromoglycate) and nedocromil sodium were once widely used for asthma management, especially in children, but have now been supplanted so completely by other therapies that they are mostly of historic interest as asthma treatments MECHANISM: inhibiting mast cell degranulation and, as such, have no direct bronchodilator action but inhibit both antigen- and exerciseinduced bronchospasm in asthmatic patients. When taken regularly (2–4 puffs 2–4 times daily), these agents modestly but significantly reduce symptomatic severity and the need for bronchodilator medications, particularly in young patients with allergic asthma. These drugs are poorly absorbed into the systemic circulation F. ❖ and have little toxicity, but are not as potent or as predictably effective as ICS. MAIN INDICATION OF CROMOLYN: ALLERGIC RHINOCONJUNCTIVITIS. applying cromolyn solution by eye drops twice a day is effective in about 75% of patients, even during the peak pollen season. ANOTHER INDICATION is the rare disease: SYSTEMIC MASTOCYTOSIS. Oral dose of a solution of 200 mg of cromolyn in water (Gastrocrom) taken four times per day helps control the abdominal cramping and diarrhea caused by activation of overabundant mast cells in the gastrointestinal mucosa. LEUKOTRIENE PATHWAY INHIBITORS Leukotrienes result from the action of 5lipoxygenase on arachidonic acid and are synthesized by a variety of inflammatory cells in the airways, including eosinophils, mast cells, macrophages, and basophils. ● Leukotriene B4 (LTB4) is a potent neutrophil chemoattractant. ● LTC4 and LTD4 exert many effects known to occur in asthma, including bronchoconstriction, increased bronchial reactivity, mucosal edema, and mucus hypersecretion. PATHWAYS: 1. Inhibition of 5-lipoxygenase, thereby preventing leukotriene synthesis. ZILEUTON, a 5-lipoxygenase inhibitor Zileuton is approved for use in an oral dosage of 1200mg of the sustained-release form twice daily 2. Inhibition of the binding of LTD4 to its receptor on target tissues (LTD4-receptor antagonists) thereby preventing its action. ZAFIRLUKAST (20mg twice daily) MONTELUKAST 10 mg (for adults) or 4mg (for children) once daily. ❖ ❖ ❖ ❖ improve asthma control and to reduce the frequency of asthma exacerbations. not as effective as even low-dose ICS therapy in inducing and maintaining asthma control, but are preferred by many patients, especially by the parents of asthmatic children, because of often exaggerated concerns over the toxicities of corticosteroids. Can be taken orally, which is an easier route of administration than aerosol inhalation in young children, and MONTELUKAST is approved for children as young as 12 months of age. MONTELUKAST is by far the most prescribed: without regard to meals, taken once daily, and does not require periodic monitoring of liver function, as zileuton does. ❖ 8 | Page Apple | Charity | Klemson | Jennah PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 ❖ - ❖ NOT CONSIDERED FIRST-LINE THERAPY the leukotriene-modifying agents are sometimes given in lieu of inhaled corticosteroids for mild asthma when prescription of an ICS meets patient resistance. The receptor antagonists have little toxicity. ASPIRIN-EXACERBATED RESPIRATORY DISEASE (AERD) a disease that combines the features of asthma, chronic rhinosinusitis with nasal polyposis, and reactions to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit cyclooxygenase-1 (COX-1). occurs in approximately 5–10% of patients with asthma. very small dose of aspirin causes profound bronchoconstriction, nasal congestion, and symptoms of systemic release of histamine, such as flushing and abdominal cramping reaction to aspirin is not associated with any evidence of allergic sensitization to aspirin or its metabolites and because it is produced by any of the NSAIDs that target COX-1, AERD is thought to result from inhibition of prostaglandin synthetase (cyclooxygenase), shifting arachidonic acid metabolism from the prostaglandin to the leukotriene pathway, especially in platelets adherent to circulating neutrophils. G. TARGETED (MONOCLONAL ANTIBODY) THERAPY ❖ monoclonal antibodies targeting IgE and IL-5, and an antibody targeting the receptor for IL- 4 and IL-13. ➢ ➢ ➢ ➢ ➢ ➢ ➢ ❖ ❖ MONOCLONAL ANTIBODIES FOR USE IN ASTHMA. ◼ ❖ Anti-IgE Monoclonal Antibodies OMALIZUMAB ➢ SPECIFIC TARGET: portion of IgE that binds to its receptors (Fcε-R1 and Fcε-R2 receptors) on 9 | Page ❖ dendritic cells, basophils, mast cells, and other inflammatory cells. MECHANISM: inhibits the binding of IgE but does not activate IgE already bound to its receptor and thus does not provoke mast cell degranulation. INDICATION: SEVERE ASTHMA and evidence of ALLERGIC SENSITIZATION DOSE ADMINISTERED: Adjusted for total IgE level and body weight. ADMINISTRATION: subcutaneous injection every 2–4 weeks to asthmatic patients (with this dose it lowers free plasma IgE to undetectable levels and significantly reduces the magnitude of both early and late bronchospastic responses to antigen challenge) MOST IMPORTANT CLINICAL EFFECT: reduction in the frequency and severity of asthma exacerbations, while enabling a reduction in corticosteroid requirements. ● patients most likely to respond are those with a history of repeated exacerbations, a high requirement for corticosteroid treatment, and poor pulmonary function. ● exacerbations most often prevented are the most severe; omalizumab treatment reduced exacerbations requiring hospitalization by 88%. Because exacerbations drive so much of the direct and indirect costs of asthma, these benefits can justify omalizumab’s high cost. proven effective as a treatment for CHRONIC RECURRENT URTICARIA (for which the drug is now approved) and for PEANUT ALLERGY. Anti-IL-5 Therapy ● T2 cells secrete IL-5 as a pro-eosinophilic cytokine that results in eosinophilic airway inflammation. ➔ Although not central to the mechanisms of asthma in all patients, a substantial proportion of patients with severe asthma have airway and peripheral eosinophilia driven by up-regulation of IL-5-secreting T2 lymphocytes (EOSINOPHILIC ASTHMA) Two humanized monoclonal antibodies ● targeting IL-5: ○ MEPOLIZUMAB ○ RESLIZUMAB ● humanized monoclonal antibodies targeting IL-5 receptor: ○ BENRALIZUMAB effective in preventing exacerbations in asthmatic patients with peripheral eosinophilia, leading to their approval as add-on, maintenance therapy of severe asthma in patients with an eosinophilic phenotype. Apple | Charity | Klemson | Jennah PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 ◼ RESLIZUMAB ➢ ◼ MEPOLIZUMAB ➢ ◼ carries a small (0.3%) risk of anaphylaxis, and a period of observation following infusion is recommended. although not associated with anaphylaxis, has resulted in reports of hypersensitivity. In addition, reactivation of herpes zoster has been reported in some patients who received mepolizumab. ❖ reaching because they indicate that perhaps as many as half of patients with mild to moderate asthma do not respond to ICS therapy. The proportion of non-ICS responders among patients with severe “STEROID-RESISTANT” asthma could be much higher. An investigational IL-13 receptor antagonist, LEBRIKIZUMAB, for example, has been shown to be more effective in asthmatic subjects with elevated serum levels of periostin (one of the genes up-regulated in the “T2-high molecular phenotype”). DUPILUMAB ➢ Clinical trials of dupilumab (an antibody directed against the IL-4α co-receptor for both IL-4 and IL-13; not yet approved) have shown it to reduce exacerbation frequency and improve measures of asthma control in patients with and without systemic eosinophilia and, further, to markedly reduce the severity of allergic dermatitis. H. FUTURE DIRECTIONS OF ASTHMA THERAPY ❖ ❖ ❖ ❖ ❖ Persuasive evidence of the existence of different asthma phenotypes requiring different approaches to therapy is the demonstration of differences in the pattern of gene expression in the airway epithelium of asthmatic and healthy subjects. Compared with healthy controls, half of the asthmatic participants overexpressed genes for: Periostin CLCA1 serpinB2, genes known to be upregulated in airway epithelial cells by IL-13, a signature cytokine of T2 lymphocytes. The other half of the asthmatic participants did not. overexpression of genes upregulated by IL-13 are referred to as having a “T2-HIGH MOLECULAR PHENOTYPE” of asthma. Did not overexpress these genes, are described as having a “NON-T2” or “T2-LOW” molecular phenotype. ● The T2-high asthmatic subjects on average tended to have more sputum eosinophilia and blood eosinophilia, positive skin test results, higher levels of IgE, and greater expression of certain mucin genes. ● The response to ICS treatment of these two groups was quite different. Six weeks of treatment with an ICS improved forced expiratory volume in 1 second (FEV1) only in the T2-high subjects. The implications of these findings are far 10 | Page CLINICAL PHARMACOLOGY OF DRUGS USED IN THE TREATMENT OF ASTHMA ❖ ❖ 1. National and international guidelines for asthma emphasize the need for adjusting the intensity of asthma therapy to the underlying severity of the disease and the level of control achieved by the patient’s current treatment. An underlying principle common to these guidelines is that asthma should be considered in TWO TIME DOMAINS: SYMPTOMS AND IMPAIRMENT: cough, nocturnal awakenings, and shortness of breath that interfere with the ability to exercise or to pursue desired activities. ➢ MILD ASTHMA: occasional inhalation of a bronchodilator may be all that is needed to control these symptoms. ➢ SEVERE ASTHMA: treatment with a long-term controller, like an ICS, is necessary to relieve symptoms and restore function. For relief of distress in the present domain, the key information is obtained by asking specific questions: Frequency and severity of symptoms Frequency of rescue use of an inhaled β agonist Frequency of nocturnal awakening Ability to exercise Measuring lung function with spirometry 2. ASTHMA RISK FOR FUTURE EVENTS, such as exacerbations or progressive loss of pulmonary function. ➢ Satisfaction with the ability to control symptoms and maintain function by frequent use of an inhaled β2 agonist does not mean that the risk of future events is also controlled. In fact, use of two or more canisters of an inhaled β agonist per month is a marker for increased risk of asthma fatality. Apple | Charity | Klemson | Jennah PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 ➢ ➢ ➢ ➢ I. The best predictor of the risk for future exacerbations is the frequency and severity of their occurrence in the past. In general, patients with poorly controlled symptoms have a heightened risk of exacerbations in the future. some patients seem unaware of the severity of their airflow obstruction (sometimes described as “POOR PERCEIVERS”) and can be identified only by measurement of pulmonary function. Reductions in the FEV1 correlate with heightened risk of future attacks of asthma. Other possible markers of heightened risk are: ○ unstable pulmonary function (large variations in FEV1 from visit to visit, large change with bronchodilator treatment), ○ extreme bronchial reactivity, ○ high numbers of eosinophils in blood or sputum. ○ high levels of nitric oxide in exhaled air. Assessment of these features may identify patients who need increases in therapy for protection against future exacerbations. ❖ ❖ III. ❖ ❖ BRONCHODILATORS ❖ ❖ ❖ ❖ ❖ II. ❖ ❖ rapidly effective, safe, and inexpensive. occasional symptoms of asthma require no more than an inhaled bronchodilator taken on an as-needed basis. If symptoms require this “RESCUE” therapy more than twice a week, if nocturnal symptoms occur more than twice a month, or if the FEV1 is less than 80% of predicted, additional treatment is needed. ○ The treatment first recommended is a low dose of an ICS, although a leukotriene receptor antagonist may be used as an alternative. An important caveat for patients with mild asthma is that although the risk of a severe, life-threatening attack is low, it is not zero. ACTION PLAN FOR SEVERE, FRIGHTENING ATTACKS: to take up to four puffs of ALBUTEROL every 20 minutes over 1 hour. If no improvement is noted after the first four puffs, additional treatments should be taken while on the way to an emergency department or other higher level of care. MUSCARINIC ANTAGONISTS Limited place in the treatment of asthma. The effects of short-acting agents (eg, IPRATROPIUM BROMIDE) on baseline airway resistance are nearly as great as, but no greater than, those of the sympathomimetic drugs, so 11 | Page ❖ 1. 2. ❖ they are used largely as alternative therapies for patients intolerant of β-adrenoceptor agonists. The airway effects of antimuscarinic and sympathomimetic drugs given in full doses have been shown to be additive only in reducing hospitalization rates in patients with severe airflow obstruction who present for emergency care. The long-acting antimuscarinic agents TIOTROPIUM and ACLIDINIUM have not yet earned a place in the treatment for asthma. Their use of effectiveness is seen in COPD patients level of care. CORTICOSTEROIDS inhaled corticosteroids (ICS) should be started in asthmatic patients whose symptoms occur frequently, OR if significant airflow obstruction persists despite bronchodilator therapy. SEVERE AIRFLOW OBSTRUCTION (eg, FEV1 < 50% of predicted) ○ INITIAL TREATMENT: high dose of an ICS in combination with an LABA is appropriate. Once clinical improvement is noted, usually after 4–6 weeks, the dose of treatment should be stepped down to no more than is necessary to control symptoms and maintain pulmonary function. Two options for asthma inadequately controlled by a standard dose of an ICS are to: Double the dose of ICS or Combine it with another drug a. theophylline or a leukotriene receptor antagonist: modestly increases asthma control b. long-acting inhaled β2-receptor agonist (LABA, eg, salmeterol or formoterol) combine it with another drug. most impressive benefits in terms of asthma control. Such combination is more effective than doubling the dose of the ICS. ● Combinations of an ICS and an LABA in a single inhaler are now available in fixeddose preparations eg: ○ fluticasone + salmeterol [ADVAIR]; ○ budesonide + formoterol [SYMBICORT] ○ mometasone + formoterol [DULERA]; ○ fluticasone and vilanterol [BREO]). Apple | Charity | Klemson | Jennah PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 BUDESONIDE + FORMOTEROL [SYMBICORT] ● The rapid onset of action of FORMOTEROL enables novel use of its combination with a low dose of BUDESONIDE. ● The combination of 80 mcg of budesonide plus 12.5 mcg of formoterol taken twice daily and additionally for relief of symptoms (ie, taken as both a “CONTROLLER” and a “RELIEVER”) is as effective an inhalation of a four-times- higher dose of budesonide with albuterol alone taken for relief of symptoms. IV. LEUKOTRIENE ANTAGONISTS; CROMOLYN & NEDOCROMIL ❖ ❖ ❖ A leukotriene pathway antagonist taken as an oral tablet is an alternative to ICS treatment in patients with symptoms occurring more than twice a week or those who are awakened from sleep by asthma more than twice a month. This place in asthma therapy was once held by cromolyn and nedocromil, but neither is now available for asthma in the USA. The leukotriene receptor antagonist MONTELUKAST is the most widely prescribed of these treatments, especially by primary care providers. This drug, taken orally, is easy to administer and is rarely associated with troublesome adverse effects. This maintenance therapy is widely used for treating children in the USA, particularly those who have concurrent symptomatic ALLERGIC RHINITIS, which is also effectively treated by montelukast. V. ◼ ➢ RESLIZUMAB, ❖ ❖ The treatment of acute attacks of asthma in patients reporting to the hospital requires close, continuous clinical assessment and repeated objective measurement of lung function. MILD ATTACKS: ○ inhalation of a β-receptor agonist is as effective as subcutaneous injection of EPINEPHRINE. SEVERE ATTACKS: ○ require treatment with oxygen, ○ frequent or continuous administration of aerosolized albuterol, and ○ systemic treatment with PREDNISONE or METHYLPREDNISONE (0.5 mg/kg every 6–12 hours). Even this aggressive treatment is not invariably effective, and patients must be watched closely for signs of deterioration. General anesthesia, intubation, and mechanical ventilation of asthmatic patients cannot be undertaken lightly but may be lifesaving if respiratory failure supervenes. PROSPECTS FOR PREVENTION ❖ ❖ AND Other options for treatment of SEVERE ASTHMA uncontrolled by ICS/ LABA therapy, especially if associated with peripheral eosinophilia, are the monoclonal antibodies reviewed earlier 12 | Page ❖ ❖ the monoclonal humanized anti-IgE antibody, and with any of the monoclonal anti-IL-5 antibodies is reserved for patients with CHRONIC SEVERE ASTHMA inadequately controlled by ICS/LABA treatment. reduces lymphocytic, eosinophilic bronchial inflammation, oral and inhaled corticosteroid dose requirements, and the frequency and severity of exacerbations. It is reserved for patients with demonstrated IgE mediated sensitivity (by positive skin test or radioallergosorbent test [RAST] to common allergens) and an IgE level within a range that can be reduced sufficiently by twice-weekly subcutaneous injection. ◼ MEPOLIZUMAB, BENRALIZUMAB. ➢ MANAGEMENT OF ACUTE ASTHMA TARGETED THERAPY OMALIZUMAB ➢ LIMITATIONS OF USE: 1. high cost 2. parenterally: 2- to 4-week intervals. 3. anaphylactic reactions or other hypersensitivity reactions, albeit in a small percentage (<0.5%) of patients, so they cannot be self-administered but must be monitored for a period of time after the injection in a setting equipped to manage anaphylaxis. 4. Development of herpes zoster infection, and administration of the varicella-zoster vaccine to adults age 50 or older 4 weeks prior to initiation with MEPOLIZUMAB is recommended. ❖ Growing up from birth on a farm with domestic animals or in a household where cats or dogs are kept as pets appears to protect against developing asthma. Microbial exposures during INFANCY foster development of a balanced immune response and then mimicking the effects of natural environmental exposures through administration of harmless microbial commensals (probiotics) or of nutrients that foster their growth (prebiotics) in the intestinal tract during the critical period of immune development in early infancy. Identifying the particular microbes whose growth should be fostered, or the microbial products responsible for inducing appropriate maturation of immune function, has become an active focus of epidemiologic, basic, and translational research. Apple | Charity | Klemson | Jennah PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 TREATMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ❖ ❖ ❖ ❖ COPD resembles asthma in that it is also characterized by airflow limitation, although the obstruction of COPD is not fully reversible with treatment. The airflow limitation of COPD, believed to reflect an abnormal inflammatory response of the lung to noxious particles or gases, especially to cigarette smoke, absolutely progresses if the exposure continues and appears to progress, albeit more slowly, even if the exposure ceases. Although COPD differs from asthma, many of the same drugs are used in its treatment. Although asthma and COPD are both characterized by airway inflammation, reduction in maximum expiratory flow, and episodic exacerbations of airflow obstruction, most often triggered by viral respiratory infection, they differ in many important respects. ■ ■ ■ ■ ❖ ❖ ❖ ❖ ❖ COPD occurs in older patients, associated with neutrophilic rather than eosinophilic inflammation poorly responsive even to high-dose ICS therapy Associated with progressive, inexorable loss of pulmonary function over time, especially with continued cigarette smoking. Despite these differences, the approaches to treatment are similar, although the benefits expected (and achieved) are less for COPD than for asthma. RELIEF OF ACUTE SYMPTOMS: ○ inhalation of a short-acting β agonist (eg, ALBUTEROL), ○ inhalation of an anticholinergic drug (eg, IPRATROPIUM BROMIDE), or ○ inhalation of the two in combination is usually effective PERSISTENT SYMPTOMS of exertional dyspnea and limitation of activities: ○ regular use of a long-acting bronchodilator, whether an LABA or a long-acting anticholinergic, or the two together, is indicated. THEOPHYLLINE ○ may have a particular place in the treatment of COPD ○ may improve contractile function of the diaphragm, thus improving ventilatory capacity. ROFLUMILAST ○ nonmethylxanthine, ○ a selective phosphodiesterase inhibitor that improves pulmonary 13 | Page ❖ function and reduces exacerbation frequency, is now approved as a treatment for COPD The place of ICS therapy is less central to treatment of COPD than of asthma, in part because of its lower efficacy for this condition and in part because of reports of its use being associated with heightened risk of bacterial pneumonia. ○ Its use is thus recommended only for patients with severe airflow obstruction or with a history of prior exacerbations. CHECKPOINT!! 1. In asthma, re-exposure to allergen causes the synthesis and release of the following, EXCEPT? a. IL3 b. IL4 c. IL5 d. TNF 2. In early asthmatic response released of the following cause the smooth muscle contraction and vascular leakage responsible for the acute bronchoconstriction, EXCEPT? a. Histamine b. Tryptase c. leukotriene D4 d. prostaglandin H2 3. Which of the following is a non-allergenic stimulus? a. distilled water & cold air b. exercise & aerosol c. cigarette smoke &sulphur dioxide d. All of the above e. None of the above 4. Most commonly used drug in the management of Asthma and used as reliever. a. Methylxanthine Drugs b. Sympathomimetic Agents c. Antimuscarinic Agents d. Corticosteroids 5. Which of the following is used as monotherapy for COPD? a. Indacaterol & Olodaterol b. Salmeterol & Formoterol c. Vilanterol & Bambuterol d. a and b only e. a and c only 6. Anti asthma drug that have positive chronotropic and inotropic effects on the heart? a. Methylxanthine Drugs b. Sympathomimetic Agents c. Antimuscarinic Agents d. Corticosteroids Apple | Charity | Klemson | Jennah PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 7. Which of the following drugs are approved for maintenance therapy of COPD but not approved as maintenance treatment of asthma? a. Tiotropium b. Aclidinium c. Umeclidinium d. All of the above e. None of the above 8. A drug indicated for severe asthma proven effective as a treatment for chronic recurrent urticaria and for peanut allergy. a. Dupilumab b. Mepolizumab c. Omalizumab d. Reslizumab 9. 15. The treatment of acute attacks of asthma in patients reporting to the hospital requires close, continuous clinical assessment and repeated objective measurement of liver function. a. TRUE b. FALSE 1.a | 2.d | 3.d | 4.b | 5.e | 6.a | 7.d | 8.c | 9.b |10.c | 11. a| 12.a | 13.b | 14. a | 15.a The following are True regarding COPD, EXCEPT? a. COPD occurs in older patients b. COPD is associated with eosinophilic rather than neutrophilic inflammation. c. Poorly responsive even to high-dose ICS therapy d. Associated with progressive, inexorable loss of pulmonary function over time, especially with continued cigarette smoking. 10. A potent atropine analog that is poorly absorbed after aerosol administration and is therefore relatively free of systemic atropine-like effects. a. Aclidinium b. Umeclidinium c. Ipratropium d. Tiotropium 11. Growing up from birth on a farm with domestic animals or in a household where cats or dogs are kept as pets appears to protect against developing asthma. a. TRUE b. FALSE 12. Leukotriene B4 (LTB4) is a potent neutrophil chemoattractant. a. TRUE b. FALSE 13. Relizumab is a monoclonal antibody drug that targets the IL-5 receptor? a. TRUE b. FALSE 14. Although COPD differs from asthma, many of the same drugs are used in its treatment. a. TRUE b. FALSE 14 | Page Apple | Charity | Klemson | Jennah PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 APPENDIX A. Immunopathogenesis of Asthma B. Inflammatory Mechanism of Asthma 15 | Page Apple | Charity | Klemson | Jennah PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 C. SUMMARY: Drugs used in Asthma 16 | Page Apple | Charity | Klemson | Jennah