Respiratory Drugs PDF

Dr. Bilvick Tai Lecturer, School of Pharmacy Sep 17th, 2024 Email: [email protected] 1  To state the drug class, basic mechanism of action, clinical indications, therapeutic effects, adverse effects, and other clinical particulars of...

Dr. Bilvick Tai Lecturer, School of Pharmacy Sep 17th, 2024 Email: [email protected] 1  To state the drug class, basic mechanism of action, clinical indications, therapeutic effects, adverse effects, and other clinical particulars of medications used for managing the following respiratory diseases: ▪ Chronic obstructive pulmonary disease (COPD) ▪ Asthma ▪ Cold ▪ Allergic rhinitis ▪ Influenza 2  Examples: salbutamol, terbutaline  MOA: stimulate beta-2 receptors and cause bronchial smooth muscle relaxation, which result in bronchodilation  Major side effects: nervousness, tremor, hyperglycemia, tachycardia, palpitation, hypokalemia  Notes: ❖ Have bronchodilator effects that last ~4-6 hours ❖ Salbutamol is one of the most commonly used drugs for acute relief of asthma or COPD symptoms 3  Notes: ❖ SABAs can cause tachycardia o May occur within 15 mins after administration o Risk factors: ▪ Overuse (dose and frequency) ▪ Concurrent use of other sympathomimetics ▪ Preexisting cardiovascular disease ❖ SABAs can cause CNS side effects o Include excitement, nervousness, tremor, anxiety, hyperactive behavior, and insomnia o Risk factor: ▪ Overuse (dose and frequency) 4  Notes: ❖ Use SABAs with caution in patients with diabetes mellitus ❖ Use SABAs with caution in patients with glaucoma ❖ Use SABAs with caution in patients with seizure disorders Generic name Common dosage forms Salbutamol Tablet, syrup, inhaler, IV infusion, nebulizer solution Terbutaline Tablet, syrup, nebulizer solution 5  Examples: formoterol, salmeterol, indacaterol, olodaterol, vilanterol  MOA: stimulate beta-2 receptors and cause bronchial smooth muscle relaxation, which result in bronchodilation  Major side effects: nervousness, tremor, hyperglycemia, tachycardia, palpitation, hypokalemia  Important points: ❖ Have bronchodilator effects that last ~12-24 hours ❖ Use LABAs with caution in patients with diabetes mellitus ❖ Use LABAs with caution in patients with seizure disorders 6  Notes: ❖ Formoterol and salmeterol are twice-daily LABAs, whereas indacaterol, olodaterol, and vilanterol are once-daily LABAs ❖ LABA monotherapy is contraindicated in asthma treatment o LABA as monotherapy (without inhaled corticosteroid (ICS)) increases the risk of asthma-related death ❖ LABAs may increase the risk of asthma-related hospitalization in pediatric and adolescent patients 7  Example: ipratropium  MOA: blocks the action of acetylcholine at type 3 muscarinic (M3) receptors in bronchial smooth muscle causing bronchodilation  Notes: ❖ Can be administered via MDI or nebulization o Duration of action of ipratropium MDI is ~2-4 hours; whereas that of nebulization solution is ~4-8 hours ❖ May cause dry mouth, dizziness, and blurred vision ❖ May increase intraocular pressure ❖ May cause urinary retention 8  Examples: tiotropium, glycopyrrolate (glycopyrronium), aclidinium, umeclidinium, revefenacin  MOA: blocks the action of acetylcholine at type 3 muscarinic (M3) receptors in bronchial smooth muscle causing bronchodilation  Notes: ❖ May cause dry mouth, dizziness, and blurred vision ❖ May increase intraocular pressure ❖ May cause urinary retention ❖ The contents of Spiriva capsules are for inhalation only via the HandiHaler device ✓ Capsules should not be swallowed 9  Examples: fluticasone, budesonide, beclomethasone, ciclesonide, mometasone  MOA: exert anti-inflammatory effect  Notes: ❖ Side effects due to the local deposition of ICS in the oropharynx and larynx may occur o E.g. dysphonia (hoarse voice) ✓ Prevention: use a spacer for patients using MDI o E.g. oropharyngeal candidiasis (thrush) ✓ Prevention: use a spacer for patients using MDI; rinse the mouth with water and expectorate the rinsate after each ICS use 10  Notes: ❖ In asthmatic children, both ICS therapy and untreated asthma itself have been associated with deceleration of growth velocity o The effects are most pronounced with severe asthma o Their ultimate adult height is ~1.2 cm less than without ICS ❖ ICS is associated with an accelerated decrease in bone mineral density in adults ❖ ICS can increase intraocular pressure and enhance the formation of cataracts ❖ ICS is associated with increased risk for bacterial colonization, bacterial pneumonia, or mycobacterial lung infections 11  Notes: ❖ The risk of symptomatic adrenal suppression or acute adrenal crisis by ICS therapy is small, esp. when the doses used are within the recommended ranges ❖ Testing for adrenal insufficiency should be performed in children and adolescents who are taking long-term ICS and have symptoms suggesting adrenal insufficiency ❖ The need for screening of asymptomatic patients for adrenal insufficiency is based on the following risk factors: 1. Long-term ICS use at exceedingly “high” doses 2. Long-term use of intranasal glucocorticoids with high-dose ICS 3. Intermittent use of systemic glucocorticoids and long-term high- dose ICS 4. A low BMI 12  Notes: ❖ The pharmacokinetics of ICS administered by MDI or DPI: 13  Notes: ❖ ICS has fewer and less severe adverse effects than OCS ❖ Risk of developing systemic adverse effects from ICS is influenced by the following factors: o Dose delivered o Site of delivery o Delivery system/device o Individual differences in the response to the glucocorticoid o Individual comorbidities ❖ CYP3A4 inhibitors may inhibit the metabolism and increase the serum level of ICSs esp. budesonide, ciclesonide, fluticasone 14  Examples: prednisolone, prednisone  MOA: exert anti-inflammatory effect  Administration: take with or after food  Notes: ❖ Nearly all adult patients with a significant asthma exacerbation should receive a short course of OCS o Reduces the likelihood of a repeat severe exacerbation within the succeeding 2 weeks, and lessens the frequency of persistent severe symptoms evaluated at a 2-week follow-up 15  Adverse effects of systemic glucocorticoids: Dermatologic and Cardiovascular appearance Fluid retention Skin thinning Peripheral edema Weight gain Hypertension Acne Hirsutism Gastrointestinal Cushingoid features Gastritis Peptic ulcer disease Bone and muscle Ophthalmologic Osteoporosis Cataract Myopathy Glaucoma 16  Adverse effects of systemic glucocorticoids: Neuropsychiatric Metabolic and endocrine Euphoria Hyperglycemia Depression Hypothalamic-pituitary-adrenal Insomnia (HPA) axis suppression Psychosis Children Immune system Growth Increased risk of infections impairment 17  Notes: ❖ Methods to limit adverse effects of systemic glucocorticoids: 1. Use the lowest dose of glucocorticoids for the shortest period of time needed to achieve the treatment goals 2. Assess for preexisting comorbid conditions that may increase risk, and optimize the management of those conditions 3. Use preventative interventions when available 4. Monitor patients for adverse effects and pursue corrective interventions when possible 18  Type of inhaler Examples of devices Pressurized metered dose inhaler (pMDI) ------------------- HandiHaler® Ellipta® Turbuhaler® Dry powder inhaler (DPI) Genuair® Accuhaler® Breezhaler® Twisthaler® Soft mist inhaler (SMI) Respimat® 19 Turbuhaler Genuair Accuhaler Ellipta HandiHaler Breezhaler 20 21  Characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases  Major risk factor: o Cigarette smoking  Major signs and symptoms: o Dyspnea, cough, sputum production, wheezing, chest tightness  Diagnosis: o Spirometry demonstrating airflow limitation 22 Grade 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 I walk slower than people of the same age on the level because of breathlessness, or I have to stop for breath when walking on my own pace on the level 3 I stop for breath after walking about 100 meters or after a few minutes on the level 4 I am too breathless to leave the house or I am breathless when dressing or undressing 23 24  Assessment of symptoms and risk of exacerbations: Patient Symptoms Risk Group 0 or 1 exacerbations mMRC 0 to 1 or A (not leading to hospitalization) CAT 5 days o Antibiotic (when indicated) ▪ Can shorten recovery time, reduce the risk of early relapse, treatment failure, and hospitalization duration ▪ Duration of therapy should not normally be 5 days 28  Key points for management: o Antiviral therapy ▪ Recommended for patients with influenza infection who require hospitalization for an exacerbation of COPD ▪ Oseltamivir is preferred o Magnesium sulphate ▪ Suggested for patients who present with a severe exacerbation that is not responding promptly to short-acting inhaled bronchodilators ▪ IV administration has bronchodilator activity ▪ Contraindicated in renal insufficiency, and hypermagnesemia can result in muscle weakness 29  Drug class: phosphodiesterase-4 (PDE-4) inhibitor  MOA: exerts anti-inflammatory effect  Indication: to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations  Major adverse reactions: weight loss, diarrhea  Notes: o Neuropsychiatric effects (e.g. anxiety, depression, insomnia) have been reported with use 30  A heterogeneous disease usually characterized by chronic airway inflammation  Defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness, and cough that vary over time and in intensity, together with variable expiratory airflow limitation  Factors that trigger or worsen asthma symptoms: o Allergens, infections, tobacco smoke, exercise, stress o Medications (NSAIDs, aspirin, beta-blockers) 31  Exercise-induced bronchoconstriction (EIB) in asthma: ❖ Bronchoconstriction which begins by 3 mins after exercise, generally peaks within 10 to 15 mins, and resolves with rest over 30 to 60 mins o Typical symptoms: shortness of breath, chest tightness, and cough ❖ Avoiding exercise in cold, dry air can reduce the stimulus for EIB ❖ SABA is the most effective therapy for quick relief of EIB ❖ Antihistamines, theophylline, and oral beta-2 agonists are minimally effective or ineffective treatment for EIB 32  Term Definition Maintenance Asthma treatment that is prescribed for use every day treatment (or on a regularly scheduled basis) Medication targeting both asthma symptom control and Controller future risk Inhaler taken as needed, for quick relief of asthma Reliever symptoms Anti- Reliever inhaler that contains both a low-dose ICS and a inflammatory rapid-acting bronchodilator reliever (AIR) Maintenance Treatment regimen in which the patient uses an ICS- -and-reliever formoterol inhaler (at maintenance dose) every day, and therapy also uses the SAME medication (at reliever dose) as- (MART) needed 33  Symptoms Daily symptoms, Short course Symptoms most days, or waking with OCS may also less than or waking asthma once a be needed for 4-5 days a with asthma week or more, severely week once a week and low lung uncontrolled or more function asthma Steps 1-2 Step 3 Step 4 Step 5 Add-on LAMA Refer for As-needed Low dose phenotypic Medium dose Preferred low dose maintenance assessment ± maintenance Controller ICS- ICS- biologic ICS-formoterol formoterol formoterol Consider high dose ICS- formoterol Preferred As-needed low dose ICS-formoterol Reliever 34  Symptoms Short course Symptoms most days, or Symptoms OCS may Symptoms twice a waking with most days, or also be less than month or asthma once waking with needed for twice a more, but a week or asthma once a severely month less than more, and week or more uncontrolled daily low lung asthma function Step 1 Step 2 Step 3 Step 4 Step 5 Refer for Low dose ICS- Medium dose phenotypic LABA, or ICS-LABA, or assessment medium dose low dose Low dose ± higher ICS, or very low ICS- Preferred ICS taken Daily low dose ICS- dose ICS- formoterol Controller whenever dose ICS LABA or add- formoterol maintenance SABA taken on therapy, maintenance and reliver e.g. anti-IgE, and reliever therapy anti-IL4R, therapy (MART) (MART) anti-IL5 Reliever As-needed SABA (or low dose ICS-formoterol reliever for MART in Steps 3 and 4) 35  Drug class: leukotriene receptor antagonist  Indication: prophylaxis and chronic treatment of asthma in adults and pediatric patients ≥12 months of age  Notes: o Available as FC tablet, chewable tablet, and oral granules (sachet) ✓ Oral granules can be administered directly in the mouth; administer within 15 mins of opening packet o Administer the dose in the evening for asthma management 36  Notes: o Can also be used for symptomatic relief of perennial or seasonal allergic rhinitis o Various neuropsychiatric adverse reactions, which may lead to drug discontinuation, have been reported with montelukast in both adult and pediatric patients ✓ E.g. disturbance in attention, memory impairment ✓ E.g. agitation, aggressive behavior, anxiety, depression ✓ E.g. abnormal dreams, insomnia ❖ In most cases, these reactions are reversible upon discontinuation 37  A phosphodiesterase (PDE) enzyme inhibitor  MOA: o Bronchial smooth muscle relaxation (i.e. bronchodilation) ▪ Due to inhibition of PDE III and, to a lesser extent, PDE IV o Suppression of the response of the airways to stimuli (i.e. non-bronchodilator prophylactic effects)  Its chemical name is 1,3-dimethylxanthine o Forms active metabolites: caffeine (= 1,3,7- trimethylxanthine) and 3-methylxanthine 38  Notes: o Signs and symptoms of toxicity: ▪ Persistent vomiting, seizure, arrhythmias, hypotension o Monitor serum concentration at 6 month intervals for rapidly growing children, and at 12 month intervals for all others o Smoking cessation can decrease theophylline clearance o Use with caution in patients with seizure disorders 39  Used for persistently uncontrolled asthma  Have not been compared in head-to-head trials  Each agent has its own particular indications, dosing, and side effect profile based on clinical trials  Selection of a biological agent depends on factors including: o Age o Serum IgE level o Type-2 asthma phenotype 40  Drug class: anti-IgE monoclonal antibody  MOA: inhibits IgE binding to the high-affinity IgE receptor on mast cells and basophils  Indication: treatment of moderate to severe persistent asthma in patients ≥6 years of age who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with ICS  Common side effect: local injection site reaction 41  Notes: o Administered via subcutaneous injection every 2 or 4 weeks o Dose and frequency based on body weight and pretreatment total IgE serum levels ▪ Dosing should be adjusted during therapy for significant changes in body weight o Should not be used for treating acute bronchospasm o Because of the risk of anaphylaxis, initiating omalizumab therapy in a health care setting is recommended 42  Drug class: interleukin (IL)-5 antagonist  MOA: inhibits IL-5 signaling, and hence reduces the production and survival of eosinophils  Indication: treatment of severe asthma in patients ≥6 years of age with an eosinophilic phenotype  Common side effects: local injection site reaction, headache  Notes: o Administered via subcutaneous injection every 4 weeks o Should not be used for treating acute bronchospasm 43  Drug class: interleukin (IL)-5 receptor antagonist  MOA: binds to IL-5 receptors and inhibits IL-5 signaling, and hence reduces the production and survival of eosinophils  Indication: treatment of severe asthma in patients ≥12 years of age with an eosinophilic phenotype  Common side effects: local injection site reaction, headache  Notes: o Administered via subcutaneous injection every 4 weeks for the first 3 doses, then once every 8 weeks o Should not be used for treating acute bronchospasm 44  Drug class: interleukin (IL)-4 receptor antagonist  MOA: binds to IL-4 receptors and inhibits both IL-4 and IL-13 signaling, and hence inhibits inflammatory responses  Indication: treatment of moderate to severe asthma in patients ≥6 years of age with an eosinophilic phenotype or with OCS- dependent asthma  Common side effects: local injection site reaction, URTI  Notes: o May cause transient eosinophilia o Administered via subcutaneous injection o Should not be used for treating acute bronchospasm 45  Drug class: anti-TSLP monoclonal antibody  MOA: binds to TSLP and prevents TSLP from interacting with TSLP receptor, and hence reduces inflammation  Indication: treatment of severe asthma in patients ≥12 years of age  Major side effect: local injection site reaction  Notes: o Adverse effects are generally similar between active and placebo groups in research studies o Administered via subcutaneous injection every 4 weeks o Should not be used for treating acute bronchospasm 46  Characterized by a progressive increase in symptoms of SOB, cough, wheezing or chest tightness and progressive decrease in lung function  Represents a change from the patient’s usual status that is sufficient to require a change in treatment  May occur in patients with a pre-existing diagnosis of asthma, or occasionally as the first presentation of asthma  Common exacerbation triggers include: o Viral respiratory infections, pollen, pollution o Poor adherence with ICS-containing medication 47  Main initial therapies for mild or moderate exacerbation in primary care include: 1. Repeated doses of rapid-acting inhaled bronchodilators o E.g. inhaled SABA (e.g. salbutamol) 4- 10 puffs (by pMDI + spacer) every 20 mins for 1 hour 2. Early use of OCS o E.g. prednisolone: ▪ For adults: 1 mg/kg/day (max: 50 mg/day) for 5-7 days ▪ For children: 1-2 mg/kg/day (max: 40 mg/day) for 3 to 5 days 3. Controlled flow oxygen supplementation o Target oxygen saturation for adults: 93-95% o Target oxygen saturation for children: 94-98% 48  Main therapies for severe exacerbation in emergency room include: 1. SABA 2. Ipratropium bromide 3. Oral or IV corticosteroid 4. Controlled flow oxygen supplementation 5. (Consider) IV magnesium sulphate 6. (Consider) high-dose ICS 49  A.k.a. common cold  A mild viral infection of the upper respiratory tract o Usually a self-limiting illness  A separate and distinctly different entity than the following terms: o Influenza, pharyngitis, acute bronchitis, acute bacterial rhinosinusitis, allergic rhinitis, and pertussis  May occur at any time of the year, but the incidence tends to be higher in winter months  A common cause of work and school absenteeism 50  Most common and characteristic initial signs/symptoms: o Nasal discharge, nasal obstruction, and sore throat  Other signs/symptoms: o Cough, fever, sneezing, headache, malaise, pressure/discomfort in ears and face  Medications commonly used for cold treatment: o Analgesics, antihistamines, decongestants, antitussives, expectorants, and mucolytics 51  History of histamine and antihistamine: o Histamine was first prepared synthetically in 1907 o Identified as a natural constituent of mammalian tissues in 1927 o Histamine was named after the Greek word for tissue, histos o Antihistamine activity was first demonstrated by in 1937 o In the 1980s, nonsedating H1 antihistamines were developed for treatment of allergic diseases 52  MOA: o Inverse agonists that compete with histamine for binding to the H1 receptor, and bind the H1 receptor to downregulate its constitutive activity  Benefits in cold: o Nasal itching, sneezing, and rhinorrhea  Common formulations for cold: o Tablet, capsule, or liquid for oral ingestion o Spray for nasal cavity ▪ E.g. azelastine, chlorpheniramine 53  Examples: o Chlorpheniramine, dexchlorpheniramine, pheniramine, brompheniramine, diphenhydramine, promethazine, triprolidine, clemastine, carbinoxamine  Has anticholinergic effects o E.g. dry mouth, dry eye, urinary retention, tachycardia, confusion, increased IOP o Can be problematic in elderly  Effect usually lasts 4 to 6 hours 54  Generally known as sedating antihistamines o They are lipophilic and easily cross the BBB  CNS signs/symptoms are reported by ≥20% patients o Adverse effects on intellectual and motor function are well documented o Not recommended for transportation workers o Use in school-aged children are associated with impaired school performance  Can cause paradoxical agitation in very young children 55  Examples: o Cetirizine, levocetirizine, loratadine, desloratadine, fexofenadine, bilastine  Compared with first-generation antihistamines: o Less sedating o Essentially free of the anticholinergic side effects o Fewer significant drug-drug interactions o Require less frequent dosing  Onset of action is within 1 hour for most 56  Levocetirizine is an active enantiomer of cetirizine  Desloratadine is the major active metabolite of loratadine  Fexofenadine: o High-fat meals decrease its bioavailability by ~50% o Fruit juice (apple, grapefruit, orange) may decrease its bioavailability by ~36% o Separate its administration with certain antacids  Bilastine: o Administer 1 hour before or 2 hours after food o Grapefruit juice can decrease its bioavailability by 30% 57  General dosing in adults: o Cetirizine: 10 mg orally once daily o Levocetirizine: 5 mg orally once daily o Loratadine: 10 mg orally once daily o Desloratadine: 5 mg orally once daily o Fexofenadine: 120 mg orally once daily o Bilastine: 20 mg orally once daily 58  History of decongestants: o Ephedra was used in China for at least 2000 years ▪ Contains ephedrine and pseudoephedrine o The decongestant effect of pseudoephedrine was described in dogs in 1927  MOA: o Activate alpha-1 receptors that cause vasoconstriction and reduce nasal blood flow, and lead to shrinkage of swollen nasal mucosa  Benefit in cold: o Nasal congestion 59  Examples: o Pseudoephedrine, phenylephrine  Adverse reactions: o Elevated blood pressure, tachycardia, palpitations o Restlessness, insomnia, anxiety, tremors  May exacerbate diseases and conditions associated with sensitivity to adrenergic stimulation  Contraindication: o Use with or within 14 days of monoamine oxidase inhibitor 60  Phenylephrine is less effective than pseudoephedrine o Most studies suggest that 10 mg of phenylephrine is not more effective than placebo  The sale of medications containing pseudoephedrine is restricted in the U.S.  Dosing of pseudoephedrine in patients ≥12 years: o 60 mg every 4 to 6 hours o Maximum: 240 mg per 24 hours  Dosing of phenylephrine in patients ≥12 years: o 10 mg every 4 hours o Maximum: 60 mg per 24 hours 61  Examples of short-acting one: o Naphazoline, phenylephrine  Examples of long-acting one: o Oxymetazoline, xylometazoline  Compared with oral decongestants, topical ones: o Are minimally absorbed, and have fewer adverse reactions  Adverse reactions specific to topical decongestant: o Nasal irritation o Trauma from the tip of the administration device 62  Prolonged use is associated with rhinitis medicamentosa o Prevention: limit therapy to 3 to 7 days 63 64  Codeine phosphate: o MOA: an opiate that causes cough suppression by direct central action in the medulla to increase the cough threshold o Adverse reactions: nausea, vomiting, sedation, constipation o Codeine is metabolized via CYP2D6 to morphine o Use of codeine is contraindicated for all children younger than 12 years of age 65  Dextromethorphan: o MOA: a NMDA receptor antagonist that causes cough suppression by direct central action in the medulla to increase the cough threshold o Adverse reactions: nausea, vomiting, sedation, GI discomfort o Dosing in patients ≥12 years: ▪ Maximum: 120 mg / 24 hours o Should not be used with or within 14 days of stopping MAOI o Can be abused for its phencyclidine-like euphoric effect 66  Levodropropizine: o MOA: suppresses peripheral cough reflex by decreasing excitability of tracheobronchial receptors o Dosing in patients ≥2 years: ▪ Maximum: 180 mg / 24 hours o Contraindications: ▪ Pregnancy, breastfeeding, severe hepatic impairment; use in children 15 to 23 kg: 45 mg twice daily neuropsychiatric events (e.g. confusion, delirium, ▪ >23 to 40 kg: 60 mg twice daily hallucination) might ▪ >40 kg: 75 mg twice daily occur in children and adolescents o Usual duration of therapy: 5 days 79  Zanamivir  Baloxavir o Administered by oral o Oral administration of a inhalation single dose o Usual duration of therapy: 5 days o May cause diarrhea o May cause bronchospasm o Avoid coadministration of polyvalent cation-containing o Not recommended for use products in patients with asthma or COPD 80