THE RESPIRATORY SYSTEM Overview Troublesome cough patients only presenting complaint Can be adequately controlled through a combined

ned approach of appropriate lifestyle changes and medication management Drugs used to treat respiratory conditions can be delivered topically to the nasal mucosa (nasal sprays), inhaled into the lungs (metered dose inhalers), or given orally or parenterally for systemic absorption o Topical delivery is preferred so as to target affected tissues while minimizing side effects COMMON RESPIRATORY DISEASES Bronchial Asthma Caused by hyperresponsive airways An inflammatory disease of the airways characterized by episodes of acute bronchoconstriction occurring: o Shortness of breath o Cough o Chest tightness o Wheezing o Rapid respiration Acute symptoms may resolve spontaneously via: o Non pharmacologic relaxation exercises (i.e. swimming) o Quick relief medications (i.e. short acting 2 adrenergic agonist) Unlike chronic bronchitis, cystic fibrosis or bronchiectasis, asthma is usually not a progressive disease (does not lead to crippled airways) If left untreated, BA may incur airway remodeling, resulting in creased severity and incidence of exacerbation and/or death Deaths due to asthma are relatively infrequent, but significant morbidity results in: o High outpatient cost o Numerous hospitalizations o Decreased quality of life Goals of Therapy Reducing impairment Prevent chronic symptoms

Require infrequent use of inhaled shortacting 2 agonist for quick relief of symptoms (around 2 days a week only) Maintain (near) normal pulmonary function Maintain normal activity levels (including exercise and attendance at work/ school) Meet the expectations and satisfaction of the patients and families with regards to asthma care Reducing risk Prevent recurrent exacerbations of asthma and minimize the need for ER visits or hospitalizations Prevent progressive loss of lung function; for children, prevent reduced lung growth Provide optimal pharmacotherapy with minimal or no adverse effects

Drug Therapy Relievers 2 adrenergic agonist Salbutamol (Ventolin) Salmeterol (*Seretide) Anticholinergics Ipratropium Br Phosphodiesterase inhibitors Theophylline Controllers Corticosteroids Hydrocortisone (Cortizol) Dexamethasone (Decilone) Antileukotrienes Montelukast (Singulair) Zafirlukast (Accolate) Cromones Cromolyn Na Nedocromil Anti-IgE Omalizumab Adrenegic Agonist DOC for mild asthma (occasional and intermittent symptoms) Potent bronchodilators that relax airway smooth muscles Quick relief: o Onset in 5-30min after administration o Provide relief for 4 to 6 hours Have no anti-inflammatory effects

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troublesome

 Should never be used as a sole therapeutic agent for patients with persistent asthma o May be appropriate only in mild intermittent asthma Direct acting 2 selective agonists (pirbuterol, terbutaline and albuterol) o Offer the advantage of providing maximally attainable bronchodilation with little of the undesired effect of 1 stimulation o Not catecholamines so they are not inactivated by cathecol-O-methyl transferase Adverse effects: o Tachycardia o Hyperglycemia o Hypokalemia o Hypomagnesemia Minimized with dosing via inhalation vs. systemic routes Tolerance to the effects of 2 agonists in nonairway tissues can occur but is uncommon in normal dosages All patients with asthma should be prescribed a quick-relief inhaler and regularly assessed for appropriate inhaler technique Long-term control: o Salmeterol xinafoate and formoterol: long-acting 2 agonist bronchodilators Chemical analogs of albuterol but differ by having a lipophilic side chain, increasing the affinity of the drug for the 2 adrenoreceptors Have long durations of action (up to 12 hours of bronchodilation) Have slower onsets of action and should not be used for quick relief in acute asthma attacks For routine administration Useful adjuncts to inhaled corticosteroids for attaining asthma control Their adverse effects are similar to quick relief 2 agonists Appropriate technique: critical to success of therapy and should be reassessed regularly Cholinergic Antagonists Generally less effective than 2 adrenergic agonist

MOA: block the vagally mediated contraction of airway smooth muscle and mucus secretion Not traditionally effective for patients with asthma unless COPD is also present Inhaled Ipratropium (Atrovent) Quaternary atropine derivative Useful in patient unable to tolerate adrenergic agonist Slow in onset Nearly free of side effects Theophylline (Theo-dur) MOA: inhibits phosphodiesterase in airway smooth muscle cells, which increases cyclic AMP A bronchodilator that relieves airflow obstruction in chronic asthma and decreases its symptoms Well absorbed in the GI tract Has been largely replaced by 2 agonists with corticosteroids due to: Narrow therapeutic window High side effect profile Potential for drug interactions Overdose: may cause seizures of potentially fatal arrhythmias A CYP1A2 and 3A4 substrate: interacts adversely with many drugs

Leukotriene Antagonist LTB4 and cysteinyl leukotrienes LTC4, LTD4 and LTE4: products of the 5-lipoxygenase pathway of arachidonic acid metabolism and part of the inflammatory cascade 5-lipoxygenase: found in cells of myeloid origin such as mast cells, basophils, eosinophils and neutrophils LTB4: a potent chemoattractant for neutrophils and eosinophils Cysteinyl leukotrienes: constrict bronchiolar smooth muscles, increase endothelial permeability and promote mucus secretion Zileuton (Zyflo) MOA: selective and specific inhibitor of 5-lipoxygenase, preventing formation of both LTB4 and cysteinyl leukotrienes Zafirlukast and Montelukast MOA: selective reversible inhibitors of cysteinyl LT-1 receptor, thereby blocking the effects of cysteinyl leukotrienes

Montelukast: market leader in its pharmacologic class with 2 primary advantages: Dosing recommendations for children > 1 year old Availability in chewable/granule formulations All are approved for asthma prophylaxis but not in acute attacks Therapeutic benefits: Modest reduction in 2 agonist and corticosteroid dosing Improved respiratory function Pharmacokinetics: All orally active (zafirlukast: absorption is impaired by food) More than 90%% proteinbound and extensively metabolized Zileuton and metabolites: urinary excretion Zafirlukast and montelukast: Biliary excretion Adverse effects: Elevations in serum hepatic enzymes (requires monitoring and discontinuation when enzymes exceed 3-5 times the normal upper limit) Eosinophilic vasculitis (ChurgStrauss Syndrome) Headache Dyspepsia Inhibit cytochrome P450 (zafirlukast and zileuton) Increase serum levels of warfarin

Requires 4 to 6 weeks to test for efficacy A/E: mild: include bitter taste and irritation of the larynx and pharynx

Anti-IgE Omalizumab (Xolair) A recombinant DNA-derived monoclonal antibody that selectively binds to human IgE Decreases binding of IgE to the highaffinity IgE receptors on the surface of mast cells and basophils Limits the degree of release of mediators of the allergic response Useful in the management of moderate to severe allergic asthma cases that are poorly controlled with conventional therapy Disadvantage in therapy: o High cost of the drug o Limitations in dosage o Lack of available clinical trial data Corticosteroids DOC for patients with moderate to severe asthma who require inhalation of 2 adrenergic agonists more than twice a week Systemic glucocorticoids: short-term treatment for severe asthma Inhaled glucocorticoids: reduce/ eliminates the need for oral glucocorticoids in severe asthma Needs to be taken continuously Actions on the lungs o No direct effect on airway smooth muscles o Decrease the number and activity of cells involved in airway inflammation: macrophages, eosinophils and Tlymphocytes o Prolonged inhalation: reduces hyperresponsiveness of the airway smooth muscle to a variety of bronchoconstrictor stimuli (i.e. allergens, irritants, cold air and exercise) Anti-flammatory steroids Reverse mucosal edema Decrease permeability of capillaries Inhibit the release of leukotrienes

Cromones Effective prophylactic anti-inflammatory agents Not direct bronchodilators: not useful in acute asthma attacks Can block the initiation of immediate and delayed asthmatic reactions Cromolyn (Nasalcrom) Inhaled as microfine powder or aerosolized solution Poorly absorbed: minor ADEs Pre-treatment: blocks allergen- and exercise-induced bronchoconstriction Useful also in treating allergic rhinitis

Pharmacokinetics 80-90% deposited in the mouth and pharynx, or is swallowed Absorbed from the gut and enter systemic circulation through the liver Beclomethasone, triamcinolone, and flunisolide Undergo extensive firstpass effect 10-20% deposited in the airways Oral/Systemic IV methylprednisolone (Solu-medrol) or PO prednisone Useful in the management of status asthmaticus The dose is gradually reduced upon improvement of condition and discontinued in one to two weeks Spacers Large-volume chambers attached to MDIs Used to decrease drug deposition in the mouth Reduce the velocity of the injected aerosol before it enters the mouth, allowing large drug particles to be deposited in the device Improve the delivery of inhaled glucocorticoids and are advised for virtually all patients Rational of use: The smaller, high-velocity drug particles are less likely to be deposited in the mouth and more likely to reach the target airway tissue Adverse effects: Reduced with the use of a spacer Minimizes adrenal suppression by reducing the amount of glucocorticoid deposited in the oropharynx Negligible risk of corticosteroidinduced growth reduction in children

Positive effects with the use of inhaled steroid use far outweighs the risk Oropharyngeal candidiasis Especially in immunosuppressed patients

Chronic Obstructive Pulmonary Disease (COPD) Also known as emphysema or chronic bronchitis The 4th most common cause of preventable deaths in the United Sates A chronic, irreversible obstruction of airflow SMOKING: greatest risk factor and directly linked to the progressive decline of lung function as demonstrated by forced expiratory volume (FEV) Foundation of Therapy Inhaled bronchodilators (anticholinergics and 2 adrenergic agonist) Increase airflow Alleviate symptoms Decrease exacerbation of the disease Inhaled anti-inflammatory steroids Restricted to use in patients with moderate to severe reduction in airflow for whom optimal bronchodilator therapy has failed to improve symptoms Stages of COPD Stage I: MILD FEV1 greater than 80% predicted Short-acting bronchodilator as needed Stage II: MODERATE FEV1 of 50-80% predicted Regular treatment with one or more bronchodilators + inhaled glucocorticoid Stage III: SEVERE FEV1 of less than 30% predicted Regular treatment with: One or more bronchodilators Inhaled glucocorticoid Antibiotics for acute exacerbations of COPD (characterized by increased volume and purulence of secretions) Long-term oxygen therapy

Cough and Colds Coughing An important defensive respiratory response to irritants Cited as the #1 reason patient seek medical care May represent several etiologies, such as the common cold, sinusitis and/or an underlying chronic respiratory disease Pharmacotherapy Mucolytics MOA: reduces thick mucus by dissolving disulfide bonds responsible for the increased viscosity of mucin-containing compounds E.g. carbocisteine (Solmux), erdosteine (Erdotin), acetylcysteine (Parvolex) Expectorants MOA: expels mucus from the respiratory tract by signaling the body to increase the amount of hydration of secretions Result: clearer, less viscous secretions that serves as lubricant for the respiratory tract E.g. guaifenesin (Robitussin) Antitussives MOA: inhibit coughing by decreasing the sensitivity of cough centers in the CNS to peripheral stimuli; also decreases mucosal secretion E.g. codeine, hydrocodone and hydromorphone (at doses lower than those required for analgesia) Dextromethorphan (Delsym) Synthetic derivative of morphine Suppresses the response of the cough center With no analgesic effect or addictive potential Less constipating than codeine Common drugs for the common cold: Phenylpropanolamine HCl (nasal decongestant) Chlorphenamine maleate (first-generation antihistamine/ mild sedative) Paracetamol (antipyretic/ mild analgesic) Usually available in combination preparation Note: The best treatment for seasonal cough and cold remains to be the combination of increased lukewarm/

warm fluid intake, vitamin C supplement and rest. Medications are only for symptomatic treatment. Allergic Rhinitis Inflammation of the mucous membranes of the nose Characterized by itchy, watery eyes, runny nose (rhinorrhea) and a nonproductive cough An extremely common condition that significantly decreases patient-reported quality of life Attack may be precipitated by inhalation of allergens like: o Dust o Pollen o Animal dander The foreign material interact with mast cells that are coated with IgE generated in response to a previous exposure to the allergen The mast cells then release mediators (i.e. histamine, leukotrienes and chemotactic factors) which promote bronchiolar spasm and mucosal thickening from edema and cellular infiltration First line treatment: o PO antihistamine o PO decongestant Systemic effects from PO preparations have prompted interest in topical intranasal drug delivery o Sedation o Insomnia o Cardiac arrhythmias (rare) Drug Therapy Antihistamines (H2 receptor blocker) Most frequently used agents in the treatment of sneezing and rhinorrhea associated with allergic rhinitis E.g. diphenhydramine (Benadryl), chlorpheniramine (Chlor-Trimeton), loratadine (Claritin ), fexofenadine (Telfast) Alpha-adrenergic antagonist Nasal decongestant MOA: constrict dilated arterioles in the nasal mucosa and reduce airway resistance As aerosol: rapid onset of action systemic effect E.g. phenylephrine (Neo-Synephrine), oxymetazoline (long-acting)

Caution: Not for long-term therapy (for 3 to 5 days only. May cause rebound nasal congestion on discontinuation of therapy (rhinitis medicamentosa) THE GASTROINTESTINAL SYSTEM Gastroesophageal Reflux Disease (GERD) GER is a normal physiologic phenomenon occurring especially after a meal GERD occurs when the amount of gastric juice that washes into the esophagus exceeds the normal limit, without associated esophageal mucosal injury Occurs in as much as 25 40% of healthy adult Americans at least once a month (7 10% experience it on a daily basis) Common manifestation: pyrosis (heartburn) Schematically, the esophagus, the lower esophageal sphincter (LES) and stomach can be envisioned or a simple plumbing circuit o Esophagus = antegrade pump o LES = valve o Stomach = reservoir Abnormalities contributing to GERD can stem from any component of the system o Poor esophageal motility decreases clearance of acidic material o A dysfunctional LES can allow reflux of large amounts of gastric juice o Delayed gastric emptying can increase volume and pressure in the reservoir (stomach) until the valve mechanism (LES) is defeated Peptic Ulcer Disease (PUD) Its pathogenesis is not fully understood but major causative factors are recognized: o Chronic NSAID use o Infection with gram-negative Helicobacter pylori o Increased HCl secretion o Inadequate mucosal defense against gastric acid Treatment approaches include: o Eradicating H. pylori infection o Reducing gastric acid secretion o Providing agents that protect the gastric mucosa from damage

Pharmacologic Treatment Option Antimicrobial agents Optimal for H. pylori infections Documentation of infection involves: Endoscopic biopsy of the gastric mucosa Serologic testing Urea breath test Successful eradication is about 50 90% possible using combination therapy Ideal triple therapy include: PPI Metronidazole or amoxicillin Clarithromycin Quadruple therapy include: PPI Metronidazole Tetracycline Bismuth subsalicylate Treatment usually last for two weeks with >90% eradication rate Bismuth salts Do not neutralize stomach acids but inhibit pepsin and increase mucus secretion, thus, from a barrier against diffusion of acid into the ulcer Antibiotic monotherapy Results in only 20 40% eradication May result in antimicrobial resistance H2 receptor antagonists Inhibit gastric acid secretion (partially effective against nocturnal acid secretion) Competitively block the binding of histamine to the H2 receptors Reduce the intracellular concentrations of cAMP 4 members: cimetidine (Tagamet), ranitidine (Zantac), famotadine (H2 Bloc), and nizatidine (Axid) They can potentially inhibit basal, foodstimulated and nocturnal gastric acid secretion even after just a single dose Prototype: cimetidine No longer widely used due to its adverse effect profile and drug interaction

Actions Act selectively on H2 receptors Competitive histamine antagonists and are fully reversible Fully inhibit gastric acid secretion induced by histamine and gastrin Only partial inhibition of secretion induced by acetylcholine and bethanecol Now slowly being eclipsed by PPIs in PUD treatment Therapeutic Uses Peptic ulcers Recurrence is common after treatment is stopped (60 100% per year) PPIs are better for NSAID-induced PUD Acute stress ulcers Usually in IVform, H2 antagonists are effectively in managing this disease associated with major physical trauma in high-risk patients in the ICUs GERD Low dose for OTC use Ineffective in 50% of patients Takes at least 45 minutes to exhibit acid relief Tolerance is observed within two weeks of therapy Pharmacokinetics Given orally Distributed widely (including breast milk and across the placenta) Excreted through urine (70% unchanged for cimetidine) Short serum half-life (increased with renal failure) Cimetidine: 30% of the dose is slowly inactivated by hepatic microsomal mixedfunction oxygenase system Cimetidine Inhibits CYP450 Can potentiate the action of warfarin, diazepam, phenytoin, quinidine, carbamazepine, phenyotin, quinidine, theophylline and imipramine Ranitidine Compared to cimetidine, longer-acting 5 10x more potent Has minimal side effects

Does not produce the antiangdrogenic or prolacting-stimulating effects of cimetidine Does not inhibit the mixed-function oxygenase system in the liver Famotidine Similar to ranitidine in terms of pharmacologic function 20 50x more potent than cimetidine 3 20x more potent than ranitidine Nizatidine Principally eliminated through the kidneys Bioavailability is nearly 10)% due to minimal first-past effect Not available in IV form