[OS 213] LEC 03 Drugs Acting on the Respiratory System (1)-1

OS 213: Human Disease and Treatment 3(Circulation and Respiration) LEC 03: Drugs Acting on the Respiratory System Exam 2 | Cecilia A. Jimeno, MD | 23 August 2012  Objectives       Understand the pharmacologic basis of drugs used in COPD and ASTHMA Management of other causes of cough, congestion and mucus problems TO ACHIEVE OPTIMAL THERAPY Differentiate Relievers vs controllers (GINA 2006) Understand therapy of COPD Focus: TREATMENT OF NON INFECTIOUS RESPIRATORY CONDITIONS   I. BRONCHOSPASTIC CONDITIONS COMMON DRUGS GIVEN FOR ASTHMA AND COPD Bronchodilators 1. 2. 3. β-adrenergic agonists • SABA, LABA Anticholinergic agents • SAMA, LAMA Methylxanthine (theophylline) – • Short acting (aminophylline theophylline) • Long Acting (Doxofylline) Anti-inflammatory Drugs / Anti-mediator Drugs 1. Corticosteroids • When systemically given, high dose- relievers • Inhaled, low-dose- controllers 2. Leukotriene inhibitors 3. Cromones – esp those with allergy* disease modifying ASTHMA, COPD NORMAL AIRWAYS (ABN PULM NORMAL PULMO FXN FXN =>S/S) (PulmonaryCOUGH/COLD homeostasis) disorders THERAPEUTICS GOAL: Relief, Restoration, Cure(?) Drug Rx: Basic & Clinical Pharm Non-Drug Rx, Alternative Rx  ADR of frequent use of relievers include hypokalemia and arrhythmia, which may result to death. Relievers must be used to intervene and reverse these changes. If not used early, more potent drugs must be used to reverse changes. (Asthma is NOT a progressive disease, unlike COPD. If given proper management, it may revert to normal. In between attacks, pulmonary functions are normal.) Histologic (“airway remodeling”), airway occlusion due to: o mucous plugs (jelly lungs) o mucosal and submucosal edema o smooth muscle hypertrophy o thickening of basement membrane o hypertrophy of submucous glands Functional o hyper reactive airways (drug: Anti inflam corticosteroids) o variable airway obstruction (drug: Bronchodilators) B. CHRONIC OBSTRUCTIVE PULMONARY DISEASE Gel-forming mucins are produced by goblet cells and mucous cells In health, these cells are found in large airways, sparse in small airways  Goblet cells increase in number, mucous cells increase in size Patients usually complain of chronic sputum production End result: impaired mucociliary clearance (terminal and respiratory bronchioles are not cleared by cough) o Increased mucus secretions Table 1. Comparison of asthma and COPD Similarit y Differen ce A. ASTHMA  A pulmonary disorder associated with an inflammatory response to a variety of factors (triggers – e.g. antigens, stress and exercise) o control triggers  control response  avoid asthmatic attack o Stress  increases glucocorticoids but still induces asthma characterized by increased pulmonary inflammation followed by bronchial hyper-reactivity and eventually, decreased lung function due to airway narrowing (due to bronchial muscle contraction), congestion and edema (“airway remodeling” which can be reversible)  MAIN DIFFERE NCE Asthma COPD Both are characterized by airway narrowing secondary to chronic inflammation Eosinophils are Neutrophil infiltrates predominant are predominant in the throughout the peripheral airways respiratory release proteolytic tract enzymes* which destroy the lung parenchyma (emphysema)  loss of support for airways and early closure on expiration *responsible for permanent destruction Treated correctly, You can never go back to can go back to baseline normal normal (PERMANENT AND (REVERSIBLE) PROGRESSIVE) C. IMMUNOPATHOGENESIS OF ASTHMA AND COPD STRUCTURAL AND FUNCTIONAL CHANGES IN ASTHMA Changes are cumulative and are not immediately permanent. Continued usage of controllers must be maintained to prevent worsening of condition (otherwise increase in usage of relievers) Luigi Josiah Shaima UPCM 2016 B: XVI, Walang Kapantay! 1 16 of drug of choice  Anti-cholinergics (short acting ones)  Methylxanthines (quick acting – e. Systemic Glucocorticosteroids (oral. to control inflammation. TREATMENT BASED ON ASTHMA SEVERITY (Old Classfication) Severity Intermitt ent Mild to Moderate Persisten t Severe Persisten t Daily Controller None needed Alternative Controller Reliever (ICS + LABA) combination inhaler ICS high or regular dose + either SR theoph/ LTx/oLABA SABA Prn SABA Prn (OCS + ICS + SABA Prn LABA) + either SR theoph/ LTx/oLABA Table 3. Comparison between Relievers and Controllers NOTE: The two classifications have the same component drugs for asthma treatment despite category differences. there might be a need to switch to LABA (controllers). Theophylline) Figure 1. Short-acting Bronchodilators  Short acting beta agonists (SABA)Sympathomimetics: β2selective. Anti-allergic agentschromones 4. will also inhibit bronchial airway reactivity 2. late phase  inflammatory cells and eosinophils cause further inflammation and airway obstruction  cell wall edema. if used chronically. irritability. can act as controller. with consequent bronchodilation: “bronchodilators” o Short acting beta-agonists: relievers o Examples: β2-adrenergic agents. and there is a decrease in FEV1. give systemic steroids. relief is not persistent. Leukotriene Inhibitors (NSAIDs) 3. 2 16 of . Treatment of asthma based on severity (old classification) SABA: Short-Acting Β Agonist.  Sife effects of SABA include tachycardia. IV. Long-acting SR Bronchodilators  Long acting β2-agonists (LABAs)  Methylxanthines (long acting – e. APPROACHES TO DRUG TREATMENT ASTHMA: Inflammation. Immunopathogenesis of asthma and COPD. death.minutes) due to smooth muscle contraction caused by mast cells degranulation (releasing mediators such as histamine and tryptase). it may progress to COPD. receptor activation): “anti-asthmatics” o Anti-inflammatory action (glucocorticoids) o Addresses the underlying disease condition in order to prevent the need for bronchodilators Luigi Josiah Shaima CONTROLLERS (preventers) 1.  SABA.LEC 03: Drugs Acting on the Respiratory System o o Examples: glucocorticoids. non-selective. Frequent use of SABA may cause arrhythmia.g. Inhaled glucocorticoids (prolonged effect – takes 1 to 2 weeks before you get the full effect).. and for immediate relief.  In persistent asthma.. before giving inhaled steroids (which take awhile to take effect). increase in mucus production  If airways are damaged. receptor antagonists Prevent further asthma occurrences RELIEVERS AND CONTROLLERS RELIEVERS 1.  Red flag: the frequency of use of SABA. and sometimes. If it’s used frequently. OCS: Oral UPCM 2016 B: Walang Kapantay! XVI. Doxofylline) 2. IM) – more rapid onset of action Table 2. If severe.g. ICS: Inhaled Corticosteroids. D. check for exacerbation. tremors. bronchoconstriction  Address: bronchial smooth muscle contractions and/or airway edema MECHANISM OF ACTION Direct relaxation of airway smooth muscle. hypokalemia. hyperreactivity.  Early phase quick decrease in FEV1 (within seconds. LABA: Long-Acting Β Agonist. inhibitors of mediator release. inhibitors of mediator synthesis. methylxanthines Target sites of action at the molecular level (mediator synthesis/ release. constriction of airways  If untreated. you need to give anti-inflammatory drugs. But it is not supposed to be given as maintenance monotherapy  SABA are used as needed. anticholinergic agents. CNS (increased alertness. meron na daw) o Never used as single therapyin moderate to severe asthma – steroids are essential o Side effects (due to β1 effects – especially if systemic): more apparent in oral: tachycardia. so there will be a decrease in airway inflammation and decrease in edema). and may also cause bronchodilation indirectly by inhibiting release of mediators from inflammatory cells or neurotransmitters from cholinergic nerves. Classification of chronic asthma severity *Objective measures take precedence over subjective complaints. UPCM 2016 B: Walang Kapantay! XVI. Inhaled short-acting β adrenergic agonists (SABA) o Mild asthma or as relievers o Emergency ‘rescue’ drugs for acute exacerbations o Onset of action in 15-30 mins and provide relief for 4-6 hrs o For symptomatic treatment of bronchospasm in asthma and COPD o as relievers or “rescue” agents to combat acute bronchoconstriction AND ANTIINFLAMMATORY ACTION (last year’s trans says no inflammatory action. Prn = “pro re nata” if the need arises (if there is an attack) CLASSIFICATION OF CHRONIC SEVERITY ON TREATMENT Domains / Estimates Intermitte nt Daytime symptoms Nocturnal awakening Rescue β2 agonist use PEF or FEV1* Monthly Less than monthly Less than weekly > 80% predicted Occasional prn β2 only Persistent Mild to Severe** Moderate Weekly Daily Monthly to weekly Weekly to daily 60 to 80% predicted Regular ICS + LABA combination Nightly Several times a day < 60% predicted Combination ICS + LABA + OCS II. increased wakefulness o Examples: Salbutamol (prototype drug) Albuterol (US). insomnia) ASTHMA Treatment needed to control asthma Table 4. LTx: Leukotriene. however. metabolic o Causes effects in cardiac (tachycardia because they are chronotropic). BRONCHODILATORS Action: relaxes airway smooth muscle   Beta-adrenergic Receptor Agonist (Salbutamol etc) Anti-cholinergic / Anti – Muscarinic (Ipatroprium Bromide etc) Methylxanthines (Theophylline etc) A. which catalyzes conversion of ATP to cyclic AMP (cAMP) Increased cAMP relaxation of airway smooth muscle in lungs and other sites Other effects: attenuation of mast cell degranulation. insulin resistance. Preferentially inhaled. tremors. insomnia). cns. metabolic (increase in blood sugar. CLINICAL AGONISTS USES OF Β-ADRENERGIC  Mainstay for asthma control during acute attack  Potent bronchodilators: relax airway smooth muscle 1. **Patients who are high risk for asthma-related deaths initially classified here  o β2-agonists relax airway smooth muscle directly. improvement of mucociliary transport. 90% of dose is swallowed systemic effects Luigi Josiah Shaima Oral salbutamol is popular because it’s cheaper than the inhaler but more side effects (difficulty of sleeping. cardiac. (Increase airway caliber by relaxing smooth muscles and decreasing the mediators. hypokalemia) o Thus. 3 16 of . hypokalemia. The higher severity level of any domain will be the basis of the final severity level. but right now. Acetylcholine has secondary role in bronchoconstriction. inhaled preparations are preferred so that lungs are directly targeted.LEC 03: Drugs Acting on the Respiratory System Corticosteroids. β-ADRENERGIC RECEPTOR AGONISTS Βetamimetic or sympathomimetic Particularly B2 adrenergic agonists Action: activate adenylyl cyclase. hyperglycemia. palpitation. Terbutaline. SR Theophylline: Sustained-release Theophylline. can be B. pulse rate. pharmacologic) Alternative for patients unable to tolerate inhaled β2 adrenergic agonists (meter dosed inhaler and nebulized forms) UPCM 2016 B: Walang Kapantay! XVI. Long Acting Β-Adrenergics (LABA) o o o o o maintenance for persistent asthma or as controllers Never used as single therapy in moderate to severe asthma – steroids essential (note: has same systemic effects as SABA cos it still is beta-adrenergic. other tissues o Epinephrine for anaphylactic bronchoconstriction. which are structurally narrowed. you cannot use it as a single therapy. controlling vagal tone is more essential for someone with already constricted airways than someone who still has normal airways (asthma) anti-cholinergics are used for people with asthma if they cannot tolerate side effects of SABAs Effects of anticholinergic drugs.) IPRATROPIUM BROMIDE Atropine-like structure but lacks atropine effects on pupils. this is maintained by increase in vagal tone. Formoterol  Unique among LABA’s  now recognized for its rapid action (“SABA property”) and longer half life. not used as reliever because of toxicity o Methylated: cannot be taken orally because it will be quickly metabolized. Anticholinergic drugs inhibit vagally-mediated airway tone leading to bronchdilatation. BP Structure activity relationships: quaternary derivatives (CNS.g. there is already a narrowing of the lumen. 4 16 of . Thus. and hence can be used as both reliever and controller Other agent: Procaterol STRUCTURE-ACTIVITY RELATIONSHIPS Catecholamines (e. salbutamol.) Salmeterol  chemical analog of salbutamol with a prolonged time of action for at least 12 hrs but has slow onset of action so it cannot be used for acute asthmatic attacks  prolonged action is mainly due to its bulky methyl group in its terminal amino acid.LEC 03: Drugs Acting on the Respiratory System  Terbutaline hypokalemic effect. terbutaline): orally active Ventolin expectorant (salbutamol) is given in children esp. respiratory secretions. Corticosteroids may be used as a single therapy though. This effect is small in normal airways but greater in the airways of COPD patients. when there is difficulty in using inhaler. but oral forms have systemic ADR’s.  Allows greater affinity to β-2 receptor . Substitution on alpha-C atom blocks action by MAO  longer duration of action (long-acting vs. epinephrine): OH group in 3 and 4 position of phenyl ring  methylated by COMT in gut. (note that the airways will never return to its baseline diameter when anti-cholinergics are used. tiotropium (long-acting)  May play an important role in regulating acute bronchomotor response BUT are generally less effective than β-adrenergic agonists better used in COPD Effect on COPD patients more remarkable than in asthma patients o Preferred in COPD patients over LABA drugs o (2014) In COPD. any increase in vagal tone will further narrow airway lumen. short-acting non-catecholamines) Luigi Josiah Shaima “Parasympatholytic”: inhibits vagally-mediated reflexes by antagonizing Ach Action: Blocks acetylcholine in the muscarinic receptor o Blocks Ach-induced smooth muscle contraction and excessive mucus production o Prevents increase in intracellular concentration of cyclic guanosine monophosphate (cGMP) Prototype drugs: Ipratropium bromide (prototype drug. ANTI-CHOLINERGIC DRUGS / used for hyperkalemia ANTI MUSCARINIC ANTAGONISTS 2.longer effect  stimulates β2 receptors and apparently has little or no effect on alpha. β1 or β3  selectivity of salmeterol for β2 versus β1 adrenergic receptors is greater than that of other β agonists. so it also may cause tachycardia. short acting). for instant relief only Non-Catecholamines (eg. etc. So. even without the attack. coffee and chocolate  asthmatics get addicted to these due to small bronchodilator effect Action: blocks adenosine receptor. pulmonary  Adverse effects: nausea and vomiting. especially in the A systematic review of RCTs (10 relevant.LEC 03: Drugs Acting on the Respiratory System May be used in combination with SABA (inhaled). single dose) to β2 agonists seems safe. careful! Some patient’s have taken the tablet orally because they thought it was an oral drug TREATMENT OF ASTHMA COMBINATION TX AND COPD: FIXED dose combinations of anti-cholinergics and βagonists (or anti-cholinergics and steroids) are popular both in asthma and COPD: these have additive effects providing an advantage over increased doses of β agonists in patients with less side effects β-agonists and steroids are clearly indicated for asthma as well as SEVERE / VERY SEVERE COPD (again. 5 16 of . different from the knowledge before where it says that it is not so much indicated for COPD)  Prototype Drug: Theophylline (others: Aminophylline [IVdrip]. has an additive effect Slow onset of bronchodilation (max 30-60 mins) and may persist for 8 hours Selective and long acting like tiotropium more selective formulation than ipatropium but costly! – 150/day Tiotropium (Spiriva). Doxofylline[long acting derivative. number of nebulized treatments. METHYLXANTHINES Related to tea. but with narrow margin]) Inexpensive BUT w/ many side effects and relatively low efficacy o now replaced mostly by β2 agonists in asthma hence.g. seizures). CNS Children are more sensitive to ADR ofβ2 agonists toxicity (agitation. diuresis. nocturnal asthma) Possible mechanisms of action o Phosphodiesterase inhibition o Adenosine receptor antagonism o Stimulation of epinephrine release o Mediator inhibition o Inhibition of intracellular calcium release (for bronchoconstriction) THEOPHYLLINE PDE inhibitors also enhance activity of endogenous autacoids. cardiac arrhythmias. function tests. relapse and adverse events seizures Result of the study: Adding multiple doses (vs. ↑ quality of life C. 6 high elderly (prolonged half-life) and in premature quality) infants (for periodic apnea) Outcome measure: hospital admissions. has a limited role (e. o PDEs catalyze the breakdown of cAMP&cGMP o Inhibition of PDE leads to accumulation of cAMP and cGMP increased signal transduction o Remember: cAMP important in bronchodilatation Luigi Josiah Shaima Effects of Theophylline UPCM 2016 B: Walang Kapantay! XVI. crushed inside inhaler. not younger o Decreases doses of β2 agonists to decrease its side effects: ↓ hospitalizations. gastric discomfort. inhibits cyclic nucleotide phosphodiesterase enzymes (PDEs). improves lung function and may avoid hospital administration – shown for school age children and adolescents.dry powder inhaler. hormones and neurotransmitters that signal via cyclic nucleotide messengers A competitive antagonist at adenosine receptors (adenosine causes bronchoconstriction and potentiates immunologic mediator release from mast cells  Narrow margin of safety: toxic/fatal effects Therapeutic level: 10 – 20 μg/mL Can inhaled anticholinergics be added to o Toxicity starts at around 15 which is within the agonists for treating acute childhood and therapeutic level: (GI irritation) to 20 μg/mL: adolescent asthma? cardiac (tachycardia. headaches. arrhythmia). lung penetration than prednisone o Facilitate release of lipocortin Hydrocortisone is used for its rapid action but has o Reverse mucosal edema. as it can have reversal A2. GLUCOCORTICOIDS hydrocortisone but with half the o Systemic (acute) vs Inhaled (maintenance) mineralocorticoid activity. Corticosteroids bind to cytoplasmic glucocorticoid receptors which then bind to glucocorticoid response elements in the promoter region of genes. o Inhibitors of Mediator Release . SYSTEMIC CORTICOSTEROIDS Systemic corticosteroids – for acute exacerbations and persistent asthma (prednisone. o Leukotriene Receptor Antagonists Mainstay in acute asthma.LEC 03: Drugs Acting on the Respiratory System  Theophylline has effects on several other cells in addition to airway smooth muscle. Thus. Cigarette smoking. corticosteroids may bind directly to them.5 h). eosinophils and T-lymphocytes o On prolonged use (months). ANTI-ASTHMATIC / CONTROLLERS   Target sites of action at the molecular level (mediator synthesis/release. hydrocortisone) Prednisone is 4 times more potent than A. If transcription factors such as nuclear factor B and activator protein-1 have been activated by cytokines. some of these effects are mediated via inhibition of phosphodiesterases. irritants. Acute pulmonary congestion. decrease its downside. Used as a reserve drug (unfortunately. let us  Principally. reduces hyperresponsiveness of the airway smooth muscle to a variety of bronchoconstrictor stimuli such as allergens. More expensive and more used. cimetidine. Cirrhosis. 6 16 of . CHF. Viral infection. preventing interaction with inflammatory genes. To further explain at this point. 3. air and exercise Do not directly relax airway smooth muscle: little/ no effect on acute bronchoconstriction Adverse effects on long-term use and sudden withdrawal (may lead to steroid shock  fatal!) Can be systemic or inhaled o Corticosteroid Action. (central in initiation of cascade) and eosinophilMethyl-/prednisolone is longer acting and better chemotaxis. it’s good because it has a wide range of action. barbs. cold. inhibition of cytokine production look at hydrocortisone.Cromones Recall from the lecture on glucocorticoids. rifampin. Drugs: phenytoin. receptor activation): Bronchodilators are not enough as they do NOT affect the inflammation that occurs in asthma especially for patients with moderate to severe type of asthma. Mineralocorticoid cause o Leukotriene Synthesis Inhibitors retention of water (edema). OC Decreased Clearance → Increased half-life o Age (elderly). Decrease the number and activity of cells involved in airway inflammation – macrophages. This of leukotrienes narrowing can be due to: o an allergic reaction Luigi Josiah Shaima UPCM 2016 B: Walang Kapantay! XVI. Drugs: interferon. Aminophylline (IV): usually adjunctive in the emergency treatment of asthma or COPD (especially in situations wherein despite supplemental O2 patient still has difficulty in breathing. the Action: Anti-inflammatory via inhibition of choice of drug is also with consideration of its arachidonic acid release by y phospholipase mineralocorticoid activity. tachycardic with tremors) III. macrolides (erythromycin) Other Agents Doxofylline(PO): longer action agent designed to decrease the side effects assoc with theophylline. preventing synthesis of inflammatory proteins. very narrow therapeutic index/safety margin) Factors that affect Theophylline Clearance or Half-life Increased Clearance → Reduced half-life o Age (children.  (2014) Methylxanthines have multiple targets. there is a need to titrate according to age and lifestyle. For easier use. reducing synthesis of mediators (PGs and LTs) of effect. as it can lead to reversal of action permeability of capillaries and inhibit release which is further narrowing of the airways. methyl-/prednisolone. use β-adrenergic drugs instead! Conversely. methyl-/prednisolone  Maximal benefit at 30-40 mg/day (1 mkd)  Usual maintenance is 10-15 mg/day o Intravenous  for acute asthma exacerbations  Hydrocortisone is preferred due to rapid action. 7. LEUKOTRIENE PATHWAY MODIFIERS    Luigi Josiah Shaima Osteoporosis 8. role was adjunctive. inducing bronchoconstriction. Poor wound healing Hyperglycemia Psychoses Increased risk of infection Hypertension 10. oral steroids use. Rationale: cysteinyl-leukotrienes are produced in asthma with potent effects on airway function. there is still systemic absorption through GI tract Advantages: Minimal ADR’s. airway hyperresponsiveness. o Pharmacokinetics of inhaled corticosteroids ADVERSE DRUG REACTIONS WITH LONGTERM SYSTEMIC USE INHALED (TOPICAL) CORTICOSTEROIDS Inhaledcorticosteroids: for maintenance and prevention(beclomethasone.  B. Peptic Ulcers 9. nebulizers are more convenient because of the continuous flow of drugs into the respiratory tract 1. 2.prophylactic due to its availability in tablet form and favorable outcome. 6. Edema Oropharyngeal candidiasis (oral thrush)patients are asked to gargle after taking drug to prevent this Stunted growth in children (if high dose) Are Inhaled Corticosteroids effective in COPD? GENERALLY NO. 3. it is used as maintenance treatment for UPCM 2016 B: Walang Kapantay! XVI. 5.LEC 03: Drugs Acting on the Respiratory System its MINERALOCORTICOID activity (recall again: fast-acting glucocorticoids have greater mineralocorticoid activity than longacting ones) Advantages: quicker onset of action. fluticasone) more useful due to direct targeting of inflammatory site (lungs) enhanced therapeutic index (higher efficacy with less toxicity) Though inhaled. drug is delivered to site where action is most needed Disadvantages: Slow onset of effects Mainstay in prophylaxis and Chronic treatment ADV DADV route of administration o Inhaled  a great advance because it made possible control of symptoms without adrenal suppression or side effects  These drugs are often in combination with other β agonists  Tell Px to always gargle everytime they use it. maintenance of COPD patients are the long-acting Beta agonists and long acting anticholinergics  Main outcome parameter: FEV1  Additional end points: exacerbation frequency. in the past. with short-term benefits  Little benefit in preventing subsequent decline in pulmonary function  Only smoking cessation works!  BUT May work in moderate to severe COPD: o prevents further exacerbations by helping attenuate whatever inflammatory process MIGHT be going on. plasma exudation and mucus secretion Effective as controllers. systemic effects Disadvantages: greater probability of ADRS Routes of Administration o Oral – prednisone. 4. They may develop oral thrush and further exacerbate asthma  MDIs are difficult for children to use because they should be timed with inhalation. budesonide. 7 16 of . again. GLOBAL INITIATIVE FOR ASTHMA After initial medication. REVIEW Controller Medication  Inhaled glucocorticosteroids  Long-acting inhaled β2-agonists  Systemic glucocorticosteroids  Leukotriene modifiers  Long acting Theophylline/doxofylline  Cromones  Long-acting oral β2-agonists  Anti-IgE  Long-Acting Muscarinic Antagonists (COPD) Reliever Medication  Rapid-acting inhaled β2-agonists (SABA)  Systemic glucocorticosteroids  Anticholinergics/SAMA  Theophylline  Short-acting oral β2-agonists TREATING TO ACHIEVE ASTHMA CONTROL Treatment steps (See Appendix II): **In the local setting. for research purpose only  New: “Controlled”. with low doses of fixed-dose ICs+LABA combination inhaler. high-affinity. competitive antagonism of cys-LT1 (leukotriene) receptor b. Step 1 – As-needed reliever medication “Uncontrolled” Luigi Josiah Shaima UPCM 2016 B: Walang Kapantay! XVI. Leukotriene Synthesis Inhibitors  Zileuton (not in clinical use-research pa lang)  inhibit the formation of all 5-lipoxygenase products Levels of Asthma classification Partly Controlled Characteristic Controlled (any present in any week) Daytime None ≥2/week symptoms (≤2/week) Limitations of None Any activities Nocturnal symptoms / None Any awakening Need for rescue / None ≥2/week “reliever” (≤2/week) treatment < 80% predicted or Lung function Normal personal best (PEF or FEV1) (if known) on any day Exacerbation None Uncontroll ed 3 or more features of partly controlled asthma present in any week 1 in any week ≥1/year Goals of Clinical Control of Asthma No (or minimal. Leukotriene Receptor Antagonists (oral)  montelukast and zafirlukast  act through selective. the severity of his asthma must be classified. one can attempt to step down the level of therapy. persistent. <2/week) daytime symptoms  No limitations of activity  No nocturnal symptoms  No (or minimal) need for rescue medication  Normal lung function  No exacerbations This can be reached in a majority of patients with pharmacologic intervention strategy developed in partnership between the patient/family and the doctor.LEC 03: Drugs Acting on the Respiratory System  children with chronic asthma (for adults. then the therapy is stepped up  Old Classification: intermittent vs. C. “Partly Controlled”. for the majority of symptomatic patients. the consensus is to start a step 3. Intermittent asthma uses step 1 control. 8 16 of . Basic premise: When a patient presents himself. and it is a consensus that any symptomatic patient uses step 3 (here in the Philippines because of the tendency of patients to discontinue the glucocorticoids once they realize that they are relieved using the bronchodilators) IV. role was adjunctive) 2 types: a. If (GINA) 2006 patient worsens.  Effects of cysteinyl-leukotrienes on the airways and their inhibition by antileukotrienes. and if asthma is controlled. severe uses step 5. with low doses of a fixed dose ICS + LABA combination inhaler Step 3b – Two Controllers + prn reliever Low-doses of fixed-dose ICS + LABA are recommended as first-line controller in symptomatic patients with persistent asthma o Consensus: if symptomatic. leukotriene modifiers or sustained-release theophylline) (Evidence B) Medium. the higher the starting dose  The low-dose steroid is usually sufficient. and/or worsen periodically.or high-dose inhaled glucocorticosteroid combined with a long-acting inhaled β2-agonist (Evidence B) Selection of treatment at Step 4 depends on prior selections at Steps 2 and 3 Where possible. increase to a medium-dose inhaled glucocorticosteroid (Evidence A) *SYMPTOMATIC PATIENT WHO IS IN MODERATE. Step 3a – Reliever medication plus one or two controllers For adults and adolescents. it may be used for both rescue and maintenance This approach has been shown to result in: o Reductions in exacerbations Luigi Josiah Shaima o Improvements in asthma control in adults and adolescents at relatively low doses of treatment (Evidence A) Additional Step 3c Options for Adolescents and Adults Increase to medium-dose inhaled glucocorticosteroid (Evidence A) Low-dose inhaled glucocorticosteroid combined with leukotriene modifiers (Evidence A) Low-dose sustained-release theophylline (Evidence B) Step 4 – Reliever medication plus two or more controllers In most patients.or high-dose inhaled glucocorticosteroid combined with leukotriene modifiers (Evidence A) Low-dose sustained-release theophylline added to medium. 9 16 of . for the majority of symptomatic patients. Step 3 as long as not severe o The more severe. and need only be increased if control is not achieved with this regimen (Evidence A) Single inhaler maintenance and relief therapy strategy If a combination inhaler containing formoterol and budesonide is selected.or high-dose inhaled glucocorticosteroid combined with a long-acting inhaled β2-agonist (Evidence A) Medium. combine a o low-dose inhaled glucocorticosteroid o + an inhaled long-acting β2-agonist either in a combination inhaler device or as separate components (Evidence A) Inhaled long-acting β2-agonist must not be used as monotherapy For children. the increase from a medium to a high-dose of ICS provides relatively little additional benefit (Evidence A) The high dose is recommended only on a trial basis for 3 to 6 months when control cannot be achieved with medium dose ICS + LABA and/or a third controller (e. patients require regular controller treatment (step 2 or higher) Step 2 – Reliever medication plus a single controller A low-dose inhaled glucocorticosteroid is recommended as the initial controller treatment for patients of all ages (Evidence A) Alternative controller medications include leukotriene modifiers (Evidence A) appropriate for patients unable/unwilling to use inhaled glucocorticosteroids or one could increase the dose of glucocorticosteroid. the consensus is to start at step 3. or with intermittent asthma A rapid-acting inhaled β2-agonist is the recommended reliever treatment (Evidence A) When symptoms are more frequent.g. where will you start?  GINA guidelines say that as long as it’s not severe.. patients not controlled on Step 3 treatments should be referred to a pulmonary specialist with expertise in the management of asthma for investigation of alternative diagnoses and/or causes of difficult-to-treat asthma Step 5 – Reliever medication plus additional controller options  Addition of oral glucocorticosteroids to other controller medications may be effective (Evidence D) but is associated with severe side effects (Evidence A)  Addition of anti-IgE treatment to other controller medications improves control of allergic asthma when control has not been achieved on other medications (Evidence A) Figure Stepping down treatment when asthma is controlled UPCM 2016 B: Walang Kapantay! XVI. start at step 2 In the local setting.LEC 03: Drugs Acting on the Respiratory System Patients with occasional daytime symptoms of short duration. B. useful in adults who can properly use inhalers. they will get a dose with every breath. Short-acting bronchodilators (SABA) 2. from his/her disease. usually given to children who really have trouble with inhalers. 10 16 of . GINA 2006 Asthma Medications RELIEVERS CONTROLLERS  SABA –  Glucocorticosteroids – inhaled Inhaled and systemic  by 50% Systemic  Leukotriene modifiers ICS Decrease to once Reduce daily by dosing 50% every Reduce 3 months glucocorticoster  LABA – inhaled and oral Maintain LABA dose oids  Theophylline  Anticholiner  Cromones(for children with gics – inhaled allergic asthma)  Theophyllin  Anti-IgE e  Anti-allergic compounds – oral  ICS or SABA – oral to once daily Further reduce ICSDecrease dose or stop LABA anddosing continue decrease ICS-Laba to once daily dosing Summary: Drug Therapy for Asthma Reliever Medications: reverse airflow obstruction 1. Corticosteroids : Inhaled > oral 2.LEC 03: Drugs Acting on the Respiratory System Low-dose ICS Med-high (typically twice a day) dose ICS ICS-LABA Table 5. Leukotriene modifiers Treating to Maintain Asthma Control When control has been achieved. helium O2. with such an array of pharmacologic weapons. UPDATES IN MGMT OF COPD AIMS OF ASSESSMENT OF COPD  Determine Impact of disease on patient’s life  Determine risk of future effects (exacerbations / mortality)  Guide Therapy UPCM 2016 B: Walang Kapantay! XVI. sedatives If still not relieved. short-acting or long-acting bronchodilators: repeated dosing provides temporary relief o A four-fold or greater increase in inhaled glucocorticoids Severity of Asthma Exacerbations Management: Acute Care Setting (ABC’s of treatment!) Oxygen therapy Rapid-acting inhaled Β2-agonist SC Epinephrine (Do not disregard epinephrine!) Plus: systemic/inhaled GCS LT modifiers Others: Mg. ongoing monitoring is essential to: o maintain control o establish lowest step/dose treatment Asthma control should be monitored by the health care professional and by the patient Stepping Up Treatment in Response to Loss of Control Treatment has to be adjusted periodically in response to worsening control which may be recognized by the minor recurrence or worsening of symptoms Treatment options: o Rapid-onset. Spacers for children (those which have difficulty in timing inhalation to pumping and coordination) When? How much? Combi? There is no reason for an asthmatic to suffer. not v. Long-acting sustained-release bronchodilators (LABA) 3. however. So. or even die. Systemic corticosteroids : Oral > IV Controller medications: “preventers” 1. then intubate Luigi Josiah Shaima Delivering Inhaled Asthma Therapy Most common form of asthma therapy Strong logic by inhaled route Important factors: particle size and breathing patterns o deposition in lower RT increasingly occur as particle size decrease from 4 to 2 micra meter dosed inhaler / dry powder inhaler and nebulizers Nebulization is more effective than inhalers of the same drug! If nebulizer is well-applied. Combined Assessment of COPD >2 ASSESS SYMPTOMS  COPD Assessment Test (CAT) or modified British Medical Research Council (mMRC) Breathlessness Scale Table. & should be looked for routinely and treated appropriately Figure. skeletal muscle dysfunction. Goals of COPD Management DRUGS USED IN COPD UPCM 2016 B: Walang Kapantay! XVI. osteoporosis. depression & anxiety. & lung cancer Luigi Josiah Shaima GOALS OF TREATMENT FOR STABLE COPD  REDUCE SYMPTOMS o RELIEVE SYMPTOMS o IMPROVE EXERCISE TOLERANCE o IMPROVE HEALTH STATUS  REDUCE RISK o PREVENT DISEASE PROGRESSION o PREVENT AND TREAT EXACERBATIONS o REDUCE MORTALITY Figure. 11 16 of . I walk slower than people of the same age because of breathlessness or have to stop for breath when walking at my own pace 3 I stop for breathing after walking about 100 yards or after a few minutes on level ground 4 I am too breathless to leave the house or I am breathless when dressing ASSESS RISK OF EXACERBATION  Exacerbation: acute event characterized by a worsening of the patient’s respiratory symptoms that are beyond normal day-today variations and leads to a change in medication  Best predictors of having exacerbation (2+ / yr) o History of previous treated events o Increase as airflow limitation worsens ASSESS COMORBIDITIES  Cardiovascular diseases. metabolic syndrome.LEC 03: Drugs Acting on the Respiratory System ASPECTS OF DISEASE  Symptoms  Degree of airflow spirometry)  Risk of exacerbations  Comorbidities  limitation (using may influence mortality and hospitalizations. mMRC Breathlessness Scale Gra de Description of Breathlessness 0 I only get breathless with strenuous exercise 1 I get short of breath when hurrying on level ground or walking up a slight hill 2 On level ground. Cromones (for allergic induced) Pharmacologic Action Inhibition of mediator release from bronchial mast cells (mast cell stabilizers) Reversal of leukocyte activation and trafficking in asthmatic airways Suppression of activating effects of chemotactic peptides on human neutrophils. 12 16 of .  and frequent exacerbations that are not adequately controlled by long-acting bronchodilators o Acute exacerbations associated with accelerated disease progression o Airway inflammation o Continues after smoking cessation o Responds incompletely to CS o Neutrophil predominant o Theophylline: nonselective PDE inhibitor o PDE4 is expressed in airway smooth muscle & pro-inflammatory cells o Targeting PDE4 could arrest airway remodelling in COPD o Studies show  in induced sputum neutrophils. eosinophils. eosinophils. and monocytes Inhibition of parasympathetic and cough reflexes Useful for the treatment of both allergic rhinitis and allergic asthma (REMEMBER: drugs can precipitate asthma) Complete mechanism of action is not known: alter the function of delayed chloride channels in the cell membrane inhibiting cellular activation Inhibit the liberation of the mediators of anaphylaxis that are released by the degranulation of mast cells after antibody-antigen interaction Prototype Cromones:Cromolyn Na and Nedocromil Effective prophylactic anti-inflammatory agents but are not useful in managing acute asthmatic UPCM 2016 B: Walang Kapantay! XVI.  severe & very severe airflow limitation. lymphocytes o V.LEC 03: Drugs Acting on the Respiratory System >2    Bronchodilators o For both beta2 agonists & anticholinergics. ADDITIONAL RESPIRATORY DRUGS 1. long-acting formulations are preferred over short-acting formulations o The combined use of short or longacting beta2 agonists and anticholinergics if symptoms are not improved with single agents o Monotherapy with either long acting anticholinergic or long acting B agonists for symptomatic patients with FEV1< 60% o  exacerbations o quality of life o + mortality and hospitalizations o inhaled bronchodilators are preferred over oral bronchodilators o Based on evidence of relatively low efficacy and greater side effects. treatment with theophylline is not recommended unless other bronchodilators are not available or unaffordable for long term treatment Corticosteroids o no evidence to recommend a shortterm therapeutic trial with oral corticosteroids in patients with COPD to identify those who will respond to ICS or other medications o Long term treatment with ICS is recommended for patients with severe and very severe airflow limitation and for patients with frequent exacerbations that are not adequately controlled by longacting bronchodilators o Long-term monotherapy with oral corticosteroids is not recommended in COPD Luigi Josiah Shaima Long term monotherapy with ICS is not recommended in COPD because it is less effective than the combination of ICS + LABA Phosphodiesterase-4 inhibitor o Roflumilast used to reduce exacerbations for patients with the following symptoms  chronic bronchitis. g. ambroxol. IV form). beclometasone.However. decongestants can be used. Fexofenadine nasal decongestants . Antihistamines (H1 receptor blockers) First gen Second gen New 2nd gen Clemastine. Cetirizine Desloratadine.. (carbocisteine?) Note: has a sedative effect 2. elastase) with powerful effects on mucus secretion  Mast cell derived chymase is a potent mucus secretagogue 1. TREATMENT OF COMMON COLDS/ALLERGIC RHINITIS STEPS IN THE TREATMENT OF COLDS/ ALLERGIC RHINITIS 1. may be useful when administered before contact with an allergen (prophylaxis) B. characterized by sneezing. To a certain extent. 1. reduce disulfide bridges that bind glycoproteins to other proteins such as albumin Also act as antioxidants and may decrease airway inflammation Orally available drugs are well-tolerated. Diphenyhdramine. Ketotifen An antihistamine drug used for the prophylaxis of diverse allergic conditions Prevents allergic reactions by similar mechanisms which are independent of its antihistaminic properties Used as an adjunct for the treatment of asthma Probably related to its effect on eosinophils DRUGS FOR OTHER RESPIRATORY PROBLEM A. fluticasone) May be more effective than antihistamines in relieving the nasal symptoms of both allergic and non-allergic rhinitis 4. Corticosteroids May be in combination with antihistamine (e.5 days) Rationale for combination of antihistamines with alpha-adrenergic agonist for decongestant Rx? 3. the statement “Huwagpabayaanangsipon” is true if there is congestion. especially chronic. and. cystic fibrosis  In chronic bronchitis. Non-pharmacologic treatment: Rest. activation of neutrophils to release enzymes (e. nasal itching. pseudoephedrine Aerosol/Nasal drops: for those with contraindications for oral decongestants.g. treatment is directed both to treating symptoms and blocking either the release or effects of the mast cell mediators Pharmacologic Therapy for Common Colds/ Allergic Rhinitis Pharmacologic therapy for common colds is debatable because it can be relieved by adequate rest and water therapy. which needs antibiotics for treatment. Cromolyn Na a mast cell stabilizer.. watery rhinorrhea and congestion In allergic rhinitis. might lead to sinusitis. Alpha-adrenergic agonists Luigi Josiah Shaima UPCM 2016 B: Walang Kapantay! XVI. Chlorpheniramine Loratadine. 13 16 of . TREATMENT OF COUGH MUCOREGULATORS used to reduce mucus hyper-secretion occurs in chronic bronchitis and asthma. hypersecretion is due to: chronic irritation by cigarette smoke. if symptoms persist. oxymetazoline (much preferred since rapid action w/ few systemic effects) Use limited for only a few days due to rebound nasal congestion. but of little benefit in acute respiratory conditions (throwaway drugs) Examples: N-acetylcysteine (also inh. water therapy especially if viral in nature 2. ergo NOT for long-term treatment of allergic rhinitis – never for more than 7-10 days (2014. If patient does not respond to steam inhalation and hydration.constrict dilated arterioles in the nasal mucosa Oral: phenylephrine. IM. Ascertain if the colds are due to allergic rhinitis Rhinitis – inflammation of the mucus membranes of the nose. Mucolytics Decrease sputum viscosity Usually derivatives of cysteine.LEC 03: Drugs Acting on the Respiratory System attacks because they are not direct bronchodilators Block the precipitation of immediate and delayed asthmatic reactions Given in dry powder form 2. phenylpropanolamine.gloratidine + betamethasone claricor) typically given as local or topical agents Optimal effects (improvement) expected in 1-2 wks (e. the usual medications prescribed are the same as those used for treatment of allergic rhinitis. Congestion. Butamirate Citrate (sinecod) Paucity of information on potential therapies Centrally acting antitussive but is neither chemically (approach via muscarinic Ach. in hemoptysis (might exsanguinate) DO NOT suppress in bacterial lung infections. effect. A synthetic narcotic analgesic Are often emetics (ipecac. for Opioid analgesics (opiates) Prototype drug: codeine or methymorphine suctioning among patients on an endotracheal tube or those with tracheostomy Less addiction potential than other opiates  For hospitalized patients An effective cough suppressant  Expensive Side effects: c. asthma. guaifenesin) Antitussive potency is equivalent to codeine Adequate hydration may have similar outcome Has NO analgesic or addictive potential Current Therapies For Mucus Hyper-secretion Produces only marginally less constipation and (Limited Use) inhibition of mucociliary clearance Few dedicated therapies available 3. but has minimal side effects that is why it is thickens sputum and inhibits ciliary activity. IM. Duration of treatment: 3-6 mucosal secretion months b. bronchiectasis (suppurating bronchial inflammation) or chronic bronchitis where antitussives can cause harmful sputum thickening and retention Luigi Josiah Shaima END OF TRANSCRIPTION UPCM 2016 B: Walang Kapantay! XVI. N-acetylcysteine (also INH. Levodropropizine (Levopront) Species difference: data from small animal models Non-opioid with peripheral MoA of modulation of cloud interpretation sensitive C-fiber activity COUGH SUPPRESSORS What is cough? o A protective reflex mechanism that removes foreign material and secretions from the bronchi and bronchioles o Common symptom but mechanisms are poorly understood o Before treatment with antitussives. P2Y2 or CysLT1 or pharmacologically related to opioids receptors) 4. 14 16 of . Dextromethorphan (vicks) evidence for their efficacy (throw-away drugs) Related to levorphanol Throw away drugs! Little or no effect.LEC 03: Drugs Acting on the Respiratory System Clinical studies in chronic bronchitis. IV form) – may Most drugs have CENTRAL mechanism of action: decrease exacerbations or hospitalizations in COPD decreased sensitivity of the medullary/ CNS and may improve pulmonary function. available in the market reducing clearance of thickened sputum  Has only had limited clinical trials in MILD o Constipation Example: Morphine: effective but indicated only in 2. Expectorants intractable cough with bronchial carcinoma drugs that enhance the clearance of mucus when administered orally Commonly prescribed but with little or no objective 2. merely improve effects of pulmonary function) suppresses the symptom a. Lagundi – small body of evidence on its therapeutic o Decreases secretions in the bronchioles. identify underlying cause that may require therapy When to suppress?May suppress cough in these situations: o Dry painful cough of neoplasia or pleural disease o Irritative cough in inflammation of the respiratory tract (epiglottitis). symptoms cough centers to peripheral stimuli and  and quality of life. asthma and Antitussive Agents bronchiectasis: disappointing (meaning it does not DO NOT influence the underlying condition. Mesna– to allow greater mucus mobilization 1. 15 16 of .LEC 03: Drugs Acting on the Respiratory System APPENDIX I: Steroid action on mediators derived from arachidonic acid (eicosanoids) Luigi Josiah Shaima UPCM 2016 B: Walang Kapantay! XVI. LEC 03: Drugs Acting on the Respiratory System APPENDIX II: STEPS TO ACHIEVING ASTHMA CONTROL Luigi Josiah Shaima UPCM 2016 B: Walang Kapantay! XVI. 16 16 of .