PHA Respiratory Drugs and Corticosteroids (v4) PDF

PHA PHARMA-THERAPEUTICS SHIFT 1 Respiratory Drugs & Corticosteroids...

PHA PHARMA-THERAPEUTICS SHIFT 1 Respiratory Drugs & Corticosteroids LESSON Jude P. Guiang, MD and Katherine C. Manaysay, MD | 29 September 2023 08 TABLE OF CONTENTS ASTHMA BOTH COPD 1. Obstructive Airway Disease 1 Environmental Exposures 1.1. Asthma vs. COPD Pathophysiology Prenatal and 1.2. Pathogenesis of Asthma 1.3. Asthma Treatment Goals postnatal 4 tobacco smoke 2. Anti-Asthmatic Agents Allergens (None given) 2.1. Classification of Asthma Medications Air pollution Endotoxins 2.2. Categories of Asthma Medications Biomass fuel 3. Bronchodilators 18 smoke and 3.1. Overview fumes 3.2. Structure of Sympathomimetic Agents 3.3. Chemistry and Structure-Activity Susceptibility Factors Relationship of Sympathomimetic Amines Genetics 3.4. Mechanism of Smooth Muscle Relaxation Altered growth of B2 Agonists Airway hyper- and 3.5. Mechanism of Action of PK and PD of responsiveness differentiation of Sympathomimetics B2-Selective Agents Introduction of airway and 3.6. Respiratory Deposition Model Male sex in non-breast milk alveoli 3.7. Inhaled Therapies smokers 3.8. Inhalers before 4 mos ○ Low birth Early weight Female sex in 3.9. Muscarinic Antagonists 3.10. Methylxanthines aeroallergen ○ Prematurity non-smokers 3.11. Leukotriene Pathway Inhibitors sensitization ○ IUGR α2-anti-trypsin 3.12. Targeted Monoclonal Antibody Agents Female sex Recurrent deficiency 4. COPD Prenatal respiratory tract 4.1. Pharmacotherapy for COPD Patients antibiotic infections 4.2. Diagnosis and Classification treatment Diet and nutrition 4.3. COPD GOLD Guidelines 2019 5. Other Respiratory Agents Obesity 18 5.1. Simplified Schematic Diagram of the Cough Smoking Reflex Fig 1. Obstructive airway disease 5.2. Cough Pathway 5.3. Origin of Productive Cough 1.1. ASTHMA VS. COPD PATHOPHYSIOLOGY 5.4. Classification of Cough 5.5. Ideal Properties of Cough Preparation Bronchial asthma and COPD are now recognized as one of 5.6. Pharmacological Classification of Cough the most important non-communicable threats to global and Cold Preparations health, social welfare and economic development in all 5.7. Antitussives (Cough Suppressants) 5.8. Mucolytics regions of the world, especially in low to middle-income 5.9. Expectorants countries. 6. Adrenocorticosteroids (Steroids) Main Pathophysiological Feature of Asthma 21 6.1. Adrenal Gland ○ Episodic airway obstruction characterized by expiratory 6.2. Steroid Classes 6.3. Cholesterol and Steroid Synthesis airflow limitation 6.4. Glucocorticoids (Cortisol) Dominant Pathological Feature 6.5. Mineralocorticoids ○ Airway inflammation sometimes associated with airway 6.6. Antagonists of Adrenocortical Agents 34 7. Summary structural changes LEGEND Table 1. Asthma vs. COPD (Lecture Slides) ★ Important / Take Note ✤ Textbook Information ASTHMA COPD ➤ Lecturer’s Verbatim ❐ Other Transes/Resources More intermittent airflow Progressively worsening airflow 1. OBSTRUCTIVE AIRWAY DISEASE obstruction; expiratory airway obstruction Asthma and COPD both have significant burden locally and limitation Need O2 therapy internationally COPD patients Improvement in airways Often presents in 6th decade of ○ Should have a history of chronic history smoking obstruction with bronchodilators life or later ○ Alpha 1- antitrypsin deficiency and steroids ○ Exposure to biomass fuels and pollutants Cellular inflammation with Cellular inflammation Asthma patients eosinophils, mast cells, characterized by presence of ○ Smoking is not an important factor but it may induce T-lymphocytes, and neutrophils neutrophils, macrophages, exacerbation in more severe disease eosinophils, and mast cells ○ Personal and family history of atopy or allergy may occur More prevalent in ages below 40 years old Common in ages above 45 UST MED 2026 | PHARMA-THERAPEUTICS 1  PHA SHIFT 2 | LESSON 1 | Respiratory Drugs and Corticosteroids (prevalent in ages above 60) Growth factors – promote cell survival Eicosanoids – lipid-mediators that have multiple Primarily eosinophilic Predominantly Neutrophilic effects in the airway (high levels of neutrophils is (some patients with COPD Narrowing of airways is the pathognomonic feature of noted with patients that have exhibit high levels of exacerbations associated with eosinophils) asthma. bacterial infection) ○ Physical Examination will produce wheezing brought about by the narrowing of the airways Broad inflammatory mediator More permanent airflow response obstruction, less reversibility and less normalization of airflow obstruction Airways remodeling Emphysema frequently found 1.2. PATHOGENESIS OF ASTHMA Understanding the underlying mechanism of inflammation in asthma is crucial in its management. Inflammatory response in the airways of patients with asthma involves the following: ○ Orchestrated interplay of the respiratory epithelium ○ Innate immune system Fig 3. Airway Narrowing ○ Adaptive immunity that initiates and drives a chronic Right side: Normal Airway inflammatory response ○ Lumen is open and not flooded with secretions Central to this process is an interaction between genes and ○ Smooth and pinkish mucosa the environment resulting in an abnormal immune response to ○ Blood vessels are not engorged allergens and other environmental triggers in genetically Left side: Asthmatic Airway (Bronchoconstriction) susceptible individuals. ○ Airway is obstructed inflamed ○ Hyperemia of the mucosa ○ Engorgement of blood vessels with mucus secretions causing narrowing of the airways ○ Bronchoconstriction caused by the inflammatory reactions ○ Responsible for producing wheezing sound 1.2.2. ASTHMA VS. COPD DIFFERENCES IN INFLAMMATION AND ITS CONSEQUENCES Fig 2. Asthma Pathogenesis 1.2.1. IMMUNOHISTOPATHOLOGICAL FEATURES OF ASTHMA Include epithelial injury and infiltration of inflammatory cells (eosinophils, lymphocytes, mast cells, and phagocytes) Attacks can be resulted from exposure to allergens/ viral infection/bacterial infection/ pollutants Once these agents trigger the inflammatory response, it produces a cascade that will release Interleukins, IgE, Mast cells that release histamine Inflammatory mediators released by these cells are the Fig 4. Differences in Inflammation and its Consequences between Asthma and effectors of chronic inflammation. COPD (Same image used in the Lecturer’s slides) ○ These mediators include cytokines and other products that are classified into: 1.3. ASTHMA TREATMENT GOALS Lymphokines – immunomodulatory cytokines 2 long-term goals of asthma management are released by the T-cells ○ Symptom Control Pro-inflammatory cytokines – promote and amplify To prevent long-term symptoms that interferes with inflammatory response daily living (e.g., coughing or shortness of breath) Chemokines – chemoattractants for leukocytes UST MED 2026 | PHARMA-THERAPEUTICS 2  PHA SHIFT 2 | LESSON 1 | Respiratory Drugs and Corticosteroids We try to allow the person to participate in all 4. Any activity activities of daily living → Risk reduction: limitation due to Yes No To achieve good control of symptoms and maintain asthma? normal activity levels ○ Risk Reduction * Based on SABA (as needed ICS-Formoterol reliever not To minimize future risk of exacerbations, fixed airflow included); excludes reliever used before exercise limitation and medication side-effects * Use this checklist to routinely ask the patient regarding his asthma. Helps identify To prevent repeated asthma attacks whether the symptoms are well-controlled/Partly controlled/Uncontrolled. Provide the best medicine treatment with the fewest possible side effects 1.3.3. ASTHMA ACTION PLAN ○ Always inform and discuss with patients the different side effects of the medication Maintaining lung function near the personal best of the patient 1.3.1. PERSONALIZED ASTHMA MANAGEMENT Fig 5. Personalized Asthma Management Response. (GINA 2021) Assess ○ Confirm whether it is actually asthma or not ○ Identify the medications taken by the patient ○ Addressing non-pharmacologic interventions and comorbidities Adjust ○ Stepwise adjustment of medications based on clinical response and patient preference ○ Modify Environment Fig 6. General Asthma Action Plan. Use this checklist to routinely ask the patient regarding his asthma. Helps identify whether the symptoms are well-controlled/Partly Review Response controlled/Uncontrolled. ○ System of regular objective monitoring 1.3.2. ASSESSMENT OF SYMPTOM CONTROL Patient is Well-Controlled 80-100 peak flow GREEN Table 2. Assessment of Symptom Control (Lecture Slides) No Symptoms ZONE No Nocturnal attacks ASTHMA SYMPTOM CONTROL LEVEL OF SYMPTOM CONTROL Patients continue his medications In the past 4 weeks, has the Well- Partly Uncontrolled patient had: controlled Controlled Use of short-acting medications YELLOW 50-80 peak flow 1. Daytime ZONE Symptoms at night asthma Adjust dose of patient’s medication Yes No symptoms more than twice/week? Multiple doses of short-acting medication do not relieve the symptoms 2. Any night walking due to Yes No RED ZONE Dyspnea asthma? Speaks in phrases Needs to go to the hospital 3. SABA reliever or symptoms Most of the time, the problem with Asthma is COMPLIANCE Yes No Patients with previous respiratory failure more than twice/week? ○ Treat the patient as having severe attacks asthma UST MED 2026 | PHARMA-THERAPEUTICS 3  PHA SHIFT 2 | LESSON 1 | Respiratory Drugs and Corticosteroids ➤ Causes reduction or absence of wheezing 2. ANTI-ASTHMATIC AGENTS sound Examples 2.1. CLASSIFICATION OF ASTHMA MEDICATIONS Short-acting bronchodilators (SABAs) Long-acting Bronchodilators (LABAs) Anticholinergic/Anti Muscarinic Short-acting bronchodilator agents (SAMAs) - short-acting antimuscarinic (SABA) agents Salbutamol Terbutaline - used as a tocolytic Functions Albuterol - salbutamol in the US Persistent symptoms and/or exacerbations BETA-2 AGONISTS Long-acting bronchodilator agents despite optimized treatment with high dose (LABA) controller medications and treatment of Formoterol modifiable risk factors. Salmeterol ➤ For poorly-controlled patients: have Indacaterol symptoms of shortness of breath and dyspnea ADD-ON Oral preparation despite high dose of controllers and modification AGENTS of environment Prednisone - short acting IV and tablet form Examples Hydrocortisone - short acting Long-acting antimuscarinic agent Methylprednisolone - long acting (LAMA) Dexamethasone - long acting Leukotriene receptor antagonists CORTICOSTEROIDS (LTRA) - montelukast group Inhaled form Fluticasone Targeted (monoclonal antibody) therapy Beclomethasone Budesonide - also available in the ➤ Most controllers and relievers are color-coded: nebulized form Controllers - red or brown ➤ Usually given in pediatric patients Relievers - blue MAST CELL STABILIZERS Cromolyn sodium Nedocromil 3. BRONCHODILATORS Aminophylline - only available in IV preparation METHYLXANTHINES Theophylline - Both available in IV preparation, tablet and capsule Montelukast - more popular since LEUKOTRIENE it is the first one in the market ANTAGONISTS Zafirlukast Zileuton IgE ANTIBODY Omalizumab ➤ Monoclonal / targeted agents - ANTI-INTERLEUKIN 5 latest agents used for asthma Reslizumab PATHWAY ANTIBODIES Mepolizumab Fig 7. Bronchodilator agents. Beta-2 agonist agents, Antimuscarinic agents and Benralizumab Methylxanthines all cause bronchodilation through smooth muscle relaxation. 2.2. CATEGORIES OF ASTHMA MEDICATIONS 3.1. OVERVIEW ➤ There are three bronchodilator agents that we prescribe in Functions patients with asthma: 1. Beta-2 agonist agents Reduce airway inflammation Control symptoms ❐ Treatment of acute asthma attacks; Acts on beta Reduce future risks of exacerbations receptors (2025 trans) Reduces decline in lung function 2. Antimuscarinic agents Examples ❐ Less useful in asthma, used for treatment of COPD; CONTROLLERS ➤ Inhaled medications Acts on acetylcholine that reduces vagal tone (2025 Corticosteroids trans) *LABA + ICS (Inhaled corticosteroids) 3. Methylxanthines ○ LABAs are not controllers but are bronchodilator agents (open up the ❐ Long-term/Prevent bronchoconstriction; Acts on airways) phosphodiesterases, adenosines and histone (2025 ○ Called controllers since they are given trans) with ICS ➤ All of which produce smooth muscle relaxation causing Functions bronchodilation but with different mechanisms As-needed relief of breakthrough RELIEVERS symptoms ➤ Produces rapid relief of symptoms UST MED 2026 | PHARMA-THERAPEUTICS 4  PHA SHIFT 2 | LESSON 1 | Respiratory Drugs and Corticosteroids 3.1.1. EXAMPLES OF BRONCHODILATORS ❐ Amine side chain is connected to the main catechol nucleus by two carbons designated as the alpha and the Non-selective beta (not the receptors) (2025 trans) Epinephrine ❐ A bronchodilator becomes B2-specific due to the ○ Have both alpha and beta-2 presence of an amine long chain (2025 trans) properties ❐ Targets the alpha receptors as ➤ B-phenylethylamine - representative or prototype of all sympathomimetic agents well leading to tachycardia (2025 trans) ○ Rarely used for asthma, unless there is a concomitant hypersensitivity causing bronchoconstriction ❐ Used to be a first line agent in SYMPATHOMIMETICS patients with status asthmaticus (2025 trans) Ephedrine Isoproterenol Beta 2-Selective SABA: Salbutamol, Terbutaline, Albuterol LABA: Fenoterol, Formoterol, Salmeterol, Indacaterol, Olodaterol, Vilanterol ❐ Bypasses the effect of alpha receptors and has a longer side chain (2025 trans) Theophylline Aminophylline Theobromine Fig 9. Basic structure of Catecholamines METHYLXANTHINES Doxofylline ❐ Less toxic than theophylline ➤ There are two carbon atoms (carbon 1 and carbon 2) that (2025 trans) connects or links the nucleus to the side chain ○ Carbon 1 is near the amide side chain Ipratropium bromide ○ Carbon 2 is near the nucleus or aromatic ring ANTICHOLINERGIC / Tiotropium - Used in patients with asthma and COPD ANTIMUSCARINIC Aclidinium Alpha Amide. Beta Benzene (ring) Umeclidinium ❐ Bronchodilators are available in two stereoisomers: S and R 3.2. STRUCTURE OF SYMPATHOMIMETIC AGENTS isomer which are chemically and physically the same have different physiologic properties (2025 trans) 3.3. CHEMISTRY AND STRUCTURE-ACTIVITY RELATIONSHIP OF SYMPATHOMIMETIC AMINES ➤ Structural activity of all catecholamines or sympathomimetic agents changes when there is substitution within the prototype structure GREATEST SYMPATHO- When 2 carbon atoms separate aromatic nucleus and MIMETIC ACTIVITY the amide side chain MAXIMAL ALPHA-BETA Depends on the presence of OH group at 3,4 position of ACTIVITY the aromatic nucleus Fig 8. Structure of Sympathomimetic agents. LOSS OF DIRECT Loss of polar OH group of the ➤ Almost similar in structure, differs in the side chains SYMPATHOMIMETIC aromatic nucleus Common aromatic nucleus (benzene ring - 6 carbon ACTIVITY atom) Two hydroxyl groups ➤ From Doc Guiang: ○ in the 3rd and 4th carbon atom of the nucleus Again, for greatest sympathomimetic activity, dapat may dalawang ○ Responsible for alpha and B2 activity carbon [separating the nucleus and amide side chain]. Pero kung Amide side chain (considered as catechols) inalisan mo [carbon atom] or may na modify sa hydroxyl group, mababawasan ang sympathomimetic activity lalo. UST MED 2026 | PHARMA-THERAPEUTICS 5 PHA SHIFT 2 | LESSON 1 | Respiratory Drugs and Corticosteroids 3.3.1. ADRENERGIC BRONCHODILATORS AS STEREOISOMERS Dapat di mawalan ng dalawang carbon. For example, isa lang ang carbon tapos wala pang hydroxyl group, lalong walang sympathomimetic activity ang drug. Increased B receptor activity ○ Disclaimer: Doc said selectivity in the AMINO GROUP lecture, slide said activity SUBSTITUTION Increase in size (bulky substitution) of alkyl substitution Increased (prolonged) duration of ALPHA CARBON action of the non-catecholamines ○ Used in enhancing the effect of ATOM Fig. 10. Stereoisomerism among bronchodilators (Lecturer’s slides) non-catecholamines (e.g. SUBSTITUTION amphetamines) Substitution on either alpha or beta carbon yields optical Blocks substitution by MAO isomers Substitution of an OH group on the B All available drugs in the market contain both isomers carbon ○ Only the R BETA CARBON Decreased action within the CNS due (Left) Levorotatory substitution on beta carbon confers the ATOM to lower lipid solubility greatest peripheral activity SUBSTITUTION Increased agonist activity for both ○ Respiratory smooth muscles are in the peripheral alpha and beta receptors ○ As the airways decrease in size from trachea → primary and secondary bronchi (which are mostly cartilaginous) to AROMATIC NUCLEUS SUBSTITUTION the smaller bronchioles, the lumen diameter decreases and the smooth muscle content increases Maximal alpha beta activity depends on (Right) Dextrorotatory substitution on the alpha carbon the presence of OH group at 3,4 position results in a more potent compound OH at 3,5 position with large amino Dextrorotatory: More toxic INCREASED B2 substituent Levorotatory: Responsible for activating B2 receptors SELECTIVITY ↑ side chain length = ↑ B2 selectivity Decreased lipophilicity 3.3.2. KEYHOLE THEORY OF B2 SPECIFICITY CANNOT CROSS Substitution of polar groups The larger the catecholamine side chain, the more B2 specific BBB Cannot cross the BBB Epinephrine: equal Alpha and Beta Less headache, dizziness, etc. Isoproterenol: strong Beta, little Alpha Unsubstituted compounds Isoetharine: B2 preferential CAN CROSS BBB Alkyl-substituted compounds Can cross the BBB 3.3.3. KEYHOLE THEORY OF B2 SPECIFICITY LOSS OF DIRECT Loss of polar OH groups of the aromatic SYMPATHO- nucleus LOCATION OF B2 RECEPTORS MIMETIC ACTIVITY Substitution in the aromatic nucleus other SMOOTH MUSCLE BLOOD VESSELS MINIMAL B than OH group Relaxation of the RECEPTOR Eye Vasodilation supplying the Except for albuterol with substitution at ACTIVITY position 3 Bronchioles Skeletal muscle Bladder Liver ENHANCED ORAL Uterus Heart EFFECTIVENESS GI Smooth Muscle Loss of one or both OH substituents LIVER OTHER LOCATIONS ENHANCED Reason: COMT cannot metabolize anymore Mast cells: ↓ histamine release DURATION OF Glycogenolysis Adrenergic neurons: ↑ NA release ACTION Application: for pregnant women with premature contractions, we can give bronchodilators because B2 receptors are present in both of them. Terbutaline is the only B2 agent used as a tocolytic. 3.4. MECHANISM OF SMOOTH MUSCLE RELAXATION OF B2 AGONISTS B2 adrenergic receptor agonists stimulates the beta receptor increasing the cAMP concentration in smooth muscle UST MED 2026 | PHARMA-THERAPEUTICS 6  PHA SHIFT 2 | LESSON 1 | Respiratory Drugs and Corticosteroids B2 adrenergic receptor agonists increase the conductance Short-acting bronchodilator (SABA) has 3-4x more of large Ca++ sensitive K+ channels in airway smooth bronchodilating activity compared to anticholinergic agents muscle leading to membrane hyperpolarization and relaxation. (SAMA - Short-acting muscarinic antagonists) Active uptake of Ca from cell intro intracellular stores ○ Can be explained by its interaction with β2-receptors Inhibition of phosphoinositide hydrolysis decreasing Can be diluted with saline via nebulization systolic Ca concentration. ○ Ventolin nebules do not need dilution with saline because Direct inhibition of MLCK preventing interaction of myosin it already contains saline and actin Selective β2-agonists at high doses activates β1-receptors Increase in the amount of cAMP will inhibit the MLCK → therefore patient will manifest with tachycardia and interaction of myosin and actin is prevented → relaxation palpitations If MLCK is activated → activation of the actin-myosin complex → Constriction 3.5.1. SHORT-ACTING VS. LONG ACTING AGENTS SHORT-ACTING Salbutamol/Albuterol Terbutaline BRONCHODILATING Ipratropium AGENT (SABA) Salbutamol + Ipratropium Formoterol LONG-ACTING Fenoterol BRONCHODILATING Procaterol Salmeterol AGENT Indacaterol (LABA) Olodaterol Vilanterol 3.5.2. ADVERSE EFFECTS Fig. 11. Mechanism of Smooth Muscle Relaxation of B2 Agonists (Lecturer’s Table 3. Title. Adverse Effects of β2-agonists (Source: Lecture) slides) ADVERSE SITES MECHANISM EFFECT/S Theophylline inhibits PDE Stimulation of Theophylline inhibits adenosine SKELETAL Tremors β2-receptors in skeletal Beta agonists promote adenylate cyclase MUSCLES muscles Muscarinic antagonists inhibit acetylcholine Attributed to β2-receptors induced CARDIO- vasodilation 3.5. MECHANISM OF ACTION OF PK AND PD OF Direct stimulation of SYMPATHOMIMETICS B2-SELECTIVE AGENTS VASCULAR Tachycardia atrial β2-receptors Also limits microvascular leakage therefore minimizing too SYSTEM Stimulation of much mucociliary secretion myocardial β1-receptors Best way of administration is inhalation at high doses Tachyphylaxis So that it can go directly to the lungs rather than the oral form (drug effect There are still drugs, however, that are in tablet form, nebule cannot be Downregulation of form, and injectable form β2-RECEPTORS observed, which β2-receptors ○ Salbutamol comes in oral and nebule form can be due to ○ Terbutaline comes in IV, tablet, or inhaler form drug overuse) RECALL: Terbutaline is used for premature Increased labor/contraction as a tocolytic agent Activation of adipose Free-Fatty Acids Drug deposition depends on the following: tablet form does tissue β2-receptors not have concerns regarding deposition unlike the inhaler form Increased ○ Size of the particle Increased Glucose glycogenolysis ○ Breathing pattern of the patient ○ Geometry of airways METABOLIC ○ Device Increased Insulin *NOTE: Tablet form does not have concerns β2-receptors activation and Lactate regarding deposition unlike the inhaler form, which utilizes a specific devices Stimulation of Bronchodilation: onset: < 5mins; peak: 15 mins, and duration: Decreased β2-receptors, which 3-4 hours Potassium and induces potassium entry Magnesium Indicated in patients with renal failure due to high UST MED 2026 | PHARMA-THERAPEUTICS 7  PHA SHIFT 2 | LESSON 1 | Respiratory Drugs and Corticosteroids potassium levels 3.5.4. MECHANISM OF ACTION OF B2 RECEPTORS BY B2 Also indicated in dialysis AGONISTS patients wherein high potassium levels may Table 4. MOA of β2-receptors by β2-agonists (Source: Lecture) induce arrhythmia Headache, MECHANISM OF β2-AGONIST Restlessness, β2-receptors activation ACTIVATION CNS Dizziness, Attributed to lipophilicity Interacts with Nervousness, of the drug β2-receptors in Insomnia Salbutamol/ Hydrophilic the airway smooth Terbutaline muscles from the 3.5.3. DIFFUSION MICROKINETIC MODEL aqueous phase Aliphatic side chain associated predominantly Salmeterol Lipophilic with the lipid bilayer followed by transmembrane translocation Retained in the plasmalemma lipid bilayer of smooth Formoterol Partially lipophilic but muscles and can also be hydrophilic reach the β2-receptors through the aqueous phase Fig 12. Diffusion Microkinetic Model. Explains why bronchodilating agents differ in 3.5.5. SYNERGISM BETWEEN STEROIDS AND B2 AGONISTS onset of action and duration of action To prevent tachyphylaxis, steroid administration is done The synergism between the two drugs can also enhance the Salbutamol has fast onset of action and short duration of anti-inflammatory effect of steroids action Inhibits proliferation of airway smooth muscle cells because it ○ Once the drug is administered, it will pass through the will cause narrowing of airways hydrophilic portion (aqueous biophase) ○ Fixed airflow obstruction - caused by the repeated ○ Since salbutamol is hydrophilic, it can easily traverse the narrowing and dilation of bronchial smooth muscle cells membrane and can therefore easily reach the receptor Explains why salbutamol is a drug that exhibits Table 5. Title. Synergism Between Steroids and β2-Agonists (Source: Lecture) fast-onset of action Β2-AGONIST STEROIDS LABAs also exhibit differences in terms of onset of action and Increase transcription of duration of action Enhanced binding/activating of β2-receptor gene in the airway ○ Salmeterol - passes through the lipophilic layer, which will glucocorticoid receptors mucosa slow down the drug due to the innate Increase in translocation of Prevents downregulation of tightness/”kasikipan” of the lipophilic membrane glucocorticoid receptors to the β2-receptors Will lead to slow onset of action and long duration of nucleus action ○ Formoterol - is both hydrophilic and lipophilic 3.5.6. PHARMACOLOGIC CHARACTERISTICS OF LABA Hydrophilic component is responsible for fast onset Table 6. Pharmacologic Characteristics of LABA (Source: Lecture) of action Lipophilic component, on the other hand, is ONSET OF DURATION OF HALF-LIFE responsible for long duration of action LABA ACTION ACTION (hours) Can be used as a reliever (along with SAMAs and (mins.) (hours) SABAs) Salmeterol 10-30 12 12-15 Controller effect can also be observed once Formoterol 1-3 12 10 steroids are given Olodaterol 5 24 7.5 Villanterol 5.008 + 0.5 24 2.5 Indacaterol 4.0 + 0.2 24 >30 ★ Indacaterol - longest half-life among LABA ★ Formoterol - shortest onset of action ★ Salmeterol and Formoterol - long acting agent given twice a day since they have 12 hours duration of action UST MED 2026 | PHARMA-THERAPEUTICS 8  PHA SHIFT 2 | LESSON 1 | Respiratory Drugs and Corticosteroids ★ Olodaterol, Villanterol, Indacaterol - long acting agent given 3.6 RESPIRATORY DEPOSITION MODEL once a day since they have 24 hours duration of action ❐ PHARMACOLOGIC CHARACTERISTICS OF LABA (2025 Trans) Formoterol has the shortest onset of action. Sustained-action bronchodilators such as Salmeterol and Formoterol are administered twice daily dosing due to its 12 hours duration of action ○ On the other hand, Salmeterol is not suitable for acute relief of asthma since it has a long onset of action and is limited by the ceiling dose of 50ug, twice a day Oledaterol, Villanterol, and Indacaterol are given once a day due to its 24-hour duration of action. Useful in controlling nocturnal symptoms and exercise-induced asthma It has been reported in several studies that monotherapy with LABA increases asthma-related death. Monotherapy with a LABA given on a long-term basis leads to downregulation of beta-receptors Fig 13. Respiratory Deposition Model ○ Associated with beta-agonist tolerance (Lecturer’s Slide) ○ May result in increasing doses of beta-agonists, higher prevalence of adverse effects and even ➤ The deposition of a participle depends on the respiratory death deposition model Therapy with inhaled LABA may cause cardiovascular stimulation, skeletal muscle tremors and hypokalemia ➤ It depends on different factors, such as the geometry of the Reliever medications are usually bronchodilators that airways, the inhaler device, and the size of the particle quickly relieve bronchospasm ➤ We want the drug to be therapeutic and to act in the airways ○ Generally do not treat underlying inflammatory process of asthma ➤ Studies have shown that to be effective, there must be certain ○ Mainly SABA such as Salbutamol and factors that we have to consider if we prescribe an inhaler Terbutaline and SAMA such as Ipratropium device Salbutamol and Terbutaline are used at “AS NEEDED ➤ Inhalation - best mode of delivery for asthma agent BASIS” with lowest dose & frequency required ➤ Medication used for asthma is also used for COPD patients, Table 7. Pharmacodynamics of Reliever Medications for Asthma (Source: 2025 especially short-acting bronchodilators and antimuscarinic Trans) agents PHARMACODYNAMICS OF RELIEVER MEDICATIONS FOR ➤ Factors that affect the delivery of a drug are the aerosol ASTHMA velocity, aerosol duration, particle size and the device Rapid Onset (Inhaled resistance SABA > SAMA Form) ➤ In prescribing an inhaler device, we want to achieve the desired Bronchodilation SABA (3-4x) > SAMA therapeutic effect ➤ We want the drug to go to the area where it is needed and not Potency (Inhaled Form) SAMA < SABA to be delivered or deposited in the trachea or nose (pharyngeal Oral SABA/theophylline < inhaled Onset of action area) SABA ➤ The drug to be deposited in the lowermost area Oral SABA/theophylline > inhaled Side Effects ➤ An inhaler device that imits 0.3 x Th2 high Anti-IL 5 therapy ANTI-IgE MONOCLONAL 10^9/L or 300/uL) ANTI-IL5 AGENTS Elevated total ANTIBODY (OMALIZUMAB) Allergic/T2 Omalizumab IgE>30 IU Inhibits binding of IgE but does Eosinophilic asthma Dupilumab: Allergic skin tests not activate IgE bound to its with or without systemic Immunotherapy, and elevated specific Allergic/T2 receptors eosinophil Omalizumab IgE Add-on therapy with allergic Lack of elevated Tiotropium, Add-on therapy: severe asthma sensitization peripheral and macrolides (likely to Th2 low Reslizumab: 0.3% risk for sputum eosinophil be poor responders anaphylaxis and low FeNO to steroids) Dose administered is adjusted Mepolizumab: hypersensitivity, to total IgE level (SC injection every 2-4 weeks) 0.3% risk for reactivation of herpes zoster 3.12.6. COMMON ADVERSE EFFECTS Benralizumab anaphylaxis Dupilumab: with or without Table 18. Common Adverse Effects systemic eosinophilia LEUKOTRIENE RECEPTOR B2 AGONIST Reduces frequency and Prevents exacerbation in ANTAGONISTS severity of asthma patients with eosinophilic Abdominal Pain exacerbation asthma Anxiety Responders to this type of Arrhythmia Arthralgia treatment: patients with history Tremors Asthenia of repeated exacerbations, high Headache Depression requirement for steroids, or Hyperglycaemia Diarrhea poor pulmonary function Hypokalaemia Fever Rash Headache Sleep Disturbance Nausea NOTE: Both anti-IgE monoclonal antibodies and anti-IL-5 agents Tachycardia Vomiting prevent exacerbation of asthma. Both can cause anaphylaxis Skin reactions (0.3% risk) Sleep Disturbances XANTHINE DERIVATIVES MONOCLONAL ANTIBODIES Arrhythmia 3.12.4. TARGETED MONOCLONAL ANTIBODY THERAPY Seizures Diarrhea Table 16. Targeted Monoclonal Antibody Therapy (Lecturer’s Slides) Allergy Dizziness ANTIBODY Β2-AGONIST STEROIDS Dizziness GERD Dyspnea Omalizumab Humanized IgG1 IgE Headache Myalgia Hypokalaemia Mepolizumab Humanized IgG1 IL-5 Malaise Nausea Hypersensitivity Benralizumab Humanized IgG1 IL-5 receptor Vomiting Sleep Disturbances Reslizumab Humanized IgG4 IL-5 Rash Lebrikizumab Humanized IgG4 IL-13 UST MED 2026 | PHARMA-THERAPEUTICS 17  PHA SHIFT 2 | LESSON 1 | Respiratory Drugs and Corticosteroids 4. COPD Whether patient is not relieved with their dyspnea symptoms 4.1. PHARMACOTHERAPY FOR COPD PATIENTS or is in exacerbation, use either a LABA or a LAMA and follow up Assessment of airflow limitation through spirometry ○ If after patient is still dyspneic or admitted again Mainline drugs: LABA, LAMA because of exacerbation, add either a LAMA or a LABA ○ ICS is additional and case-dependent depending on the agent initially administered ○ LABA: promotes bronchodilator → B2 receptors Review the technique of the patient with regards to the use ○ LAMA: inhibits bronchoconstriction → M3 receptors of inhaling devices (Compliance issues in COPD patients) In COPD, ICS is an add on treatment for patients who are 4.2. DIAGNOSIS AND CLASSIFICATION still symptomatic despite LABA/LAMA combination Table 19. GOLD Severity Classification (2025 Trans) Table 20. Factors to Consider when initiating ICS Treatment PATIENT CATEGORY C PATIENT CATEGORY D STRONG SUPPORT CONSIDER USE AGAINST USE High risk, less symptoms High risk, more symptoms History of 1 moderate Repeated pneumonia hospitalization for exacerbation of events GOLD: 3 or 4 GOLD: 3 or 4 COPD exacerbation COPD* Exacerbations: ≥ 2/year Exacerbations: ≥ 2/year ≥ 2 moderate COPD mMRC: 0-1 mMRC: ≥ 2 Blood eosinophils Blood eosinophils exacerbations per CAT Score: cream/lotion Topical steroids: Eczacort, Elica, etc. 5 𝑚𝑔 𝑃𝑟𝑒𝑑𝑛𝑖𝑠𝑜𝑛𝑒 4 𝑚𝑔 𝑀𝑒𝑡ℎ𝑦𝑙𝑝𝑟𝑒𝑑𝑛𝑖𝑠𝑜𝑙𝑜 20 𝑚𝑔 𝑃𝑟𝑒𝑑𝑛𝑖𝑠𝑜𝑛𝑒/𝑑𝑎𝑦 = 𝑥 ○ Given by allergists to patients with atopic dermatitis, psoriasis, simple zits Pediatricians usually use medium to low potent 20 mg Prednisone = 16 mg Methylprednisolone ○ Usually low potent ○ Class 7 to Class 3 Ex. You have a pediatric patient weighing 20 kilos. The dose ○ Afraid of using high potent because the areas where the of prednisone is 1-2 mg/kg/day. What is the dose equivalent of steroids are applied become hypopigmented and thin prednisone to methylprednisolone? → parang opposite na dalmatians First step: Get the needed dosage of Prednisone. Children are more prone to this ○ Prednisone is 1-2 mg/kg/day ○ If the patient is 20 kg, and you use 1 as the therapeutic 6.4.10. GENERAL PRINCIPLES IN STEROID THERAPY dose, you will need 20 mg per day. High doses of