Obstructive Pulmonary Diseases and Glucocorticoid Pharmacology

Flashcards covering pathophysiology, medicinal chemistry, and drug pharmacology for asthma and COPD based on lecture transcripts.

Obstructive Pulmonary Disease

A category of lung conditions defined by a limitation in expiratory airflow, resulting in a reduced capacity to move air out of the lungs.

Chronic Obstructive Pulmonary Disease (COPD)

A common, preventable, and treatable heterogeneous lung condition characterized by chronic respiratory symptoms (dyspnea, cough, sputum production) due to airway and/or alveolar abnormalities usually caused by exposure to noxious particles or gases.

Small Airway Disease in COPD

A pathophysiologic process in COPD characterized by airway inflammation, airway wall thickening, fibrosis, inflammatory exudate, and narrowing, leading to increased airway resistance.

Parenchymal Destruction in COPD

Destruction of lung parenchyma (bronchioles and alveoli) characterized by alveolar wall destruction, loss of alveolar attachments, and reduced lung elastic recoil.

Pathological Changes in COPD

Structural changes throughout the respiratory system including mucus hypersecretion, mucosal inflammation, wall fibrosis, narrowed bronchioles, destruction of alveoli, and disrupted alveolar attachments (emphysema).

Oxidative Stress Biomarkers in COPD

Increased chemical indicators such as nitric oxide and hydrogen peroxide produced in response to cigarette smoke, inhaled particles, and inflammatory cells, which promote tissue damage and inhibit antiprotease activity.

Protease/Antiprotease Imbalance

An amplifying pathogenic mechanism in COPD where proteases break down connective tissue elastin in lung parenchyma faster than antiproteases can protect against breakdown.

Primary Inflammatory Cells in COPD

Neutrophils, macrophages, and $\text{CD8}^+$ T lymphocytes that migrate to the lungs and release destructive inflammatory mediators.

Primary Inflammatory Mediators in COPD

Tumor necrosis factor-alpha ($\text{TNF-}\times\text{a}$ or $\text{TNF-}\frac{}{}\text{a}$ / $\text{TNF-}\text{alpha}$), interleukin 8 ($\text{IL-8}$), and leukotriene $\text{B}_4$ ($\text{LTB}_4$), which amplify the inflammatory process and induce structural airway changes.

Gas Trapping and Hyperinflation

Progressive entrapment of air during expiration caused by airflow obstruction, which reduces inspiratory capacity and serves as the main mechanism for exertional dyspnea in COPD.

FEV1 / FVC Spirometry Curve

A spirometric plot recording expired volume over time, highlighting Forced Expiratory Volume in 1 second ($\text{FEV}_1$), Forced Vital Capacity ($\text{FVC}$), Peak Expiratory Flow Rate ($\text{PEFR}$), and a normal $\text{FEV}_1/\text{FVC}$ ratio of $0.8$.

Post-Bronchodilator FEV1/FVC Diagnostic Threshold

A post-bronchodilator spirometric ratio of $\text{FEV}_1/\text{FVC} < 0.70$ required to confirm persistent airflow limitation and diagnose COPD.

V/Q Mismatch in COPD

An abnormal ventilation ($V$) relative to perfusion ($Q$) ratio resulting from parenchymal destruction, serving as the primary cause of hypoxemia in COPD.

Pulmonary Hypertension in COPD

A late-developing physiological abnormality in COPD driven mainly by hypoxic vasoconstriction of small pulmonary arteries that leads to structural vascular changes.

Cardinal Symptom of COPD

Dyspnea, described as progressive, persistent, and worsening with exertion.

Most Effective Intervention in COPD

Smoking cessation, recognized as the single most effective and cost-effective intervention to reduce COPD risk and halt disease progression.

Asthma

A heterogeneous chronic inflammatory airway disorder characterized by variable respiratory symptoms (wheeze, shortness of breath, chest tightness, cough), bronchial hyperresponsiveness, and expiratory airflow obstruction.

Atopic March

A clinical sequence in allergic individuals characterized by the progression from eczema in infancy to allergic rhinitis and subsequently asthma.

Airway Edema in Asthma

Airway wall swelling caused by microvascular leakage in response to acute inflammatory mediators.

Airway Remodeling in Asthma

Structural airway changes caused by chronic inflammation, including thickening of the sub-epithelial reticular basement membrane, increased airway smooth muscle mass, and mucus gland hyperplasia.

Bronchial Hyperresponsiveness (BHR)

An exaggerated bronchoconstriction response to environmental stimuli that are normally innocuous to healthy individuals, strongly correlated with airway inflammation.

Fractional Exhaled Nitric Oxide (FeNO)

A diagnostic measurement of nitric oxide in exhaled breath used as a biomarker for ongoing lower airway inflammation and predictor of positive corticosteroid response in asthma.

Exercise-Induced Bronchoconstriction (EIB)

Airway narrowing triggered by vigorous physical activity that affects $70\text{--}90\text{\%}$ of asthma patients, associated with inhaling large volumes of cool, dry air.

Nocturnal Asthma

Worsening of asthma symptoms and significant falls in pulmonary function during sleep between bedtime and awakening, linked to diurnal patterns of endogenous cortisol and epinephrine.

Asthma Exacerbation

An acute, short-term worsening of asthma symptoms triggered by exposures, leading to severe bronchospasm, airway edema, mucus accumulation, and poor responsiveness to usual bronchodilators.

Smoking-Induced Asthma Phenotype

A distinct asthma phenotype characterized by neutrophil-predominant airway inflammation that exhibits poor responsiveness to corticosteroid therapy.

Inflammatory Cell Profile: COPD vs Asthma

COPD inflammation is predominantly mediated by neutrophils, macrophages, and $\text{CD8}^+$ T cells, whereas Asthma inflammation is predominantly mediated by eosinophils, mast cells, and $\text{CD4}^+$ Th2 cells.

Inflammatory Mediator Profile: COPD vs Asthma

COPD mediators primarily include $\text{IL-8}$, $\text{TNF-}\text{alpha}$, and $\text{LTB}_4$, whereas Asthma mediators primarily include $\text{IL-4}$, $\text{IL-5}$, $\text{IL-13}$, and $\text{LTD}_4$.

Adrenocorticoids

Steroid hormones synthesized in the cortex of the adrenal gland, divided into mineralocorticoids and glucocorticoids.

Steroid Nucleus

The core carbon framework of adrenocorticoids based on the 21-carbon 5\text{\textalpha}\text{-pregnane} skeleton, consisting of four fused rings labeled A, B, C, and D with standardized carbon position numbering 1 through 21.

Five Structural Features of Natural Glucocorticoids

1) 21-carbon Pregnane skeleton; 2) \text{\textDelta}^4\text{-3-one} group; 3) 17\text{\textbeta}\text{-ketol} group; 4) 17\text{\textalpha}\text{-OH} group; 5) 11\text{\textbeta}\text{-OH} group (or C-11 keto).

\text{\textDelta}^4\text{-3-one} Group

A essential structural moiety in glucocorticoids consisting of a C-4,5-double bond paired with a C-3 ketone on ring A.

17\text{\textbeta}\text{-ketol} Group

A functional group on C-17 composed of a C-20 ketone and a C-21 hydroxyl group ($\text{C-20-keto-C-21-hydroxy}$).

Cortisone

An endogenous steroid containing a C-11 ketone that possesses substantially lower glucocorticoid receptor binding activity compared to hydrocortisone.

Hydrocortisone (Cortisol)

The active endogenous glucocorticoid hormone in humans containing an 11\text{\textbeta}\text{-hydroxyl} group that forms essential hydrogen bonds with the glucocorticoid receptor.

11beta-Hydroxysteroid Dehydrogenase (11beta-HSD)

The enzyme that catalyzes the reversible interconversion of the inactive C-11 ketone in cortisone and the active 11\text{\textbeta}\text{-hydroxyl} group in hydrocortisone.

Lipinski's Rule of 5 for Glucocorticoids

Molecular weight \text{\textle} 500\text{\textcomma}\text{Da} (optimal \text{\texttilde} 350\text{\textcomma}\text{Da}), Hydrogen Bond Acceptors \text{\textle} 10, Hydrogen Bond Donors \text{\textle} 5, and $-2 < \text{Log } P < 5$ (optimal \text{\texttilde} 3).

Delta1-Double Bond Modification

Insertion of a C-1,2 double bond (\text{\textDelta}^1) that increases glucocorticoid anti-inflammatory activity 4-fold, reduces mineralocorticoid activity, and slows metabolic reduction to extend duration of action.

Prednisolone

A synthetic \text{\textDelta}^1 derivative of hydrocortisone administered systemically that exhibits 4 times the anti-inflammatory potency of hydrocortisone, reduced mineralocorticoid activity, and a medium duration of action.

Prednisone

A synthetic \text{\textDelta}^1 oral prodrug derivative of cortisone with 4 times hydrocortisone's anti-inflammatory potency that requires hepatic conversion to prednisolone for biological activity.

9alpha-Halogen Modification

Addition of a 9\text{\textalpha}\text{-fluoro} or 9\text{\textalpha}\text{-chloro} group that increases glucocorticoid potency \text{\texttilde} 10\text{-fold} via an inductive effect that enhances 11\text{\textbeta}\text{-OH} hydrogen bonding, while simultaneously increasing mineralocorticoid activity.

9alpha-Halogen Size Rule

The rule stating that glucocorticoid activity is inversely proportional to the atomic size of the 9\text{\textalpha}\text{-halogen}; larger halogens (such as a 9\text{\textalpha}\text{-bromo} group) decrease activity.

Fludrocortisone

A 9\text{\textalpha}\text{-fluoro} substituted corticosteroid derivative that exhibits powerful mineralocorticoid (salt-retaining) activity alongside high glucocorticoid activity.

16alpha-Hydroxyl Modification

Introduction of a 16\text{\textalpha}\text{-hydroxyl} group that counteracts mineralocorticoid activity, eliminating salt retention and improving glucocorticoid selectivity.

Triamcinolone

A synthetic corticosteroid combining a \text{\textDelta}^1 double bond, 9\text{\textalpha}\text{-fluoro}, and 16\text{\textalpha}\text{-hydroxyl} group, offering 5 times hydrocortisone's anti-inflammatory potency with zero sodium-retaining activity.

16-Methyl Modification

Addition of a methyl group at position 16 (16\text{\textalpha}\text{-CH}_3 or 16\text{\textbeta}\text{-CH}_3) that abolishes mineralocorticoid activity, sterically inhibits oxidation of the 17\text{\textalpha}\text{-OH}, and prolongs duration of action.

Dexamethasone

A long-acting synthetic glucocorticoid containing a \text{\textDelta}^1 bond, 9\text{\textalpha}\text{-fluoro}, and 16\text{\textalpha}\text{-methyl} group, featuring 25 times the anti-inflammatory potency of hydrocortisone and no salt retention.

Betamethasone

A long-acting synthetic corticosteroid isomer of dexamethasone containing a 16\text{\textbeta}\text{-methyl} group, possessing 25 times the anti-inflammatory potency of hydrocortisone and zero salt retention.

Glucocorticoid Inactivation Pathway

Metabolic inactivation occurring via reduction of the C-3 ketone by 3\text{\textalpha}\text{-hydroxysteroid dehydrogenase} and reduction of the C-4,5 double bond by 5\text{\textbeta}\text{-reductase}.

C-17 Side Chain Oxidation

Metabolic oxidation of the C-17 side chain by C-17 oxidase to form a 17-keto steroid, requiring both a free 17\text{\textalpha}\text{-OH} group and a free C-21 hydroxyl group.

Esterification at C-17 or C-21

Chemical esterification at the C-17 or C-21 hydroxyl positions that blocks metabolic oxidation by C-17 oxidase and prolongs the duration of action.

Desired Pharmacokinetic Properties of Inhaled Corticosteroids (ICS)

High lipophilicity ($ ext{Log } P ext{ extge} 4$), low systemic bioavailability, high plasma protein binding, and rapid systemic clearance into inactive metabolites.

Glucocorticoid Acetonides

Lipophilic cyclic ketals formed between 16\text{\textalpha}\text{,}17\text{\textalpha}\text{-dihydroxyl} groups and an aldehyde/ketone, which abolish mineralocorticoid activity and are biologically active unless masked by a C-21 ester.

C-20 Fluoromethyl Thioester Group

A functional group ($\text{-SCH}_2\text{F}$) at C-20 that confers potent local anti-inflammatory action when inhaled while remaining susceptible to metabolic hydrolysis at the 17\text{\textbeta} position.

6alpha-Fluoro Modification

Addition of a fluorine atom at position 6\text{\textalpha} that selectively increases glucocorticoid receptor activity without augmenting mineralocorticoid action.

Budesonide

A non-halogenated inhaled glucocorticoid containing a 16\text{\textalpha}\text{,}17\text{\textalpha}\text{-acetal} formed with butanal that reduces mineralocorticoid activity, increases lipophilicity, and provides high local airway efficacy.

Fluticasone Propionate

An inhaled corticosteroid featuring a C-20 fluoromethyl thioester, 17\text{\textalpha}\text{-propionate ester}, 9\text{\textalpha}\text{-fluoro}, and 6\text{\textalpha}\text{-fluoro} groups, prescribed for twice-daily (BID) dosing.

Fluticasone Furoate

An inhaled corticosteroid containing a 17\text{\textalpha}\text{-furoate ester} derived from 2-furoic acid with high lipophilicity ($ ext{Log } P = 4.17$) and high receptor affinity, allowing once-daily (QD) administration.

Fluticasone Furoate vs Fluticasone Propionate Comparison

Structural comparison showing that the bulkier furoate ester of fluticasone furoate ($ ext{Log } P = 4.17$, once daily) occupies the receptor pocket more completely than the propionate ester ($ ext{Log } P = 3.89$, twice daily).

Beclomethasone Dipropionate

A lipophilic diester prodrug ($\text{C-17,21-dipropionate}$) containing a 16\text{\textbeta}\text{-methyl} group, 9\text{\textalpha}\text{-chloro} group, and \text{\textDelta}^1 double bond, showing approximately $20\text{\%}$ systemic bioavailability upon inhalation.

Autonomic Regulation of Airway Tone

Control of bronchial diameter balance where sympathetic norepinephrine/epinephrine stimulates \text{\textbeta}_2 receptors to cause bronchodilation, and parasympathetic acetylcholine stimulates muscarinic receptors to cause bronchoconstriction and mucus secretion.

beta2-Adrenergic Receptor Agonist MOA

Binding of agonists to \text{\textbeta}_2 receptors activates G-proteins, stimulating adenylyl cyclase to convert ATP to cyclic AMP (cAMP), which inhibits calcium influx and prevents smooth muscle contraction.

Cellular Effects of beta2-Agonists

1) Airway smooth muscle relaxation (bronchodilation); 2) Mast cell stabilization (inhibiting degranulation and histamine/leukotriene release); 3) Modulation of goblet cells to decrease mucus secretion.

Short-Acting beta2-Agonists (SABA)

Bronchodilators with rapid onset (within minutes) and short duration ($3\text{--}6\text{,hours}$) used as rescue therapy for acute symptoms (e.g., Albuterol, Levalbuterol).

Long-Acting beta2-Agonists (LABA)

Bronchodilators with slower or rapid onset and prolonged duration ($12\text{--}24\text{,hours}$) used for long-term maintenance therapy (e.g., Salmeterol, Formoterol, Indacaterol, Olodaterol).

beta2-Agonist Permeability Coefficient Kinetics

Kinetic model illustrating how hydrophilic Albuterol ($P_{\text{coeff}} = 0.002$) acts rapidly with short duration, amphiphilic Formoterol ($P_{\text{coeff}} = 3$) acts rapidly with long duration, and lipophilic Salmeterol ($P_{\text{coeff}} = 63$) diffuses slowly into lipid membranes yielding slow onset and long duration.

Mechanism of beta2-Agonist-Induced Tremor

A adverse effect caused by direct stimulation of \text{\textbeta}_2 adrenergic receptors located in skeletal muscle.

Mechanism of beta2-Agonist-Induced Hypokalemia

A side effect caused by an intracellular shift of potassium ions ($\text{K}^+$) mediated by \text{\textbeta}_2 receptor activation.

Mechanism of beta2-Agonist-Induced Hyperglycemia

A side effect resulting from hepatic \text{\textbeta}_2\text{-mediated} glycogenolysis leading to increased glucose release into the blood.

Muscarinic Antagonist MOA

Antagonists block acetylcholine at $M_3$ receptors, inhibiting $\text{G}_q\text{-protein-PLC-IP}_3$ signaling and keeping intracellular calcium low to prevent smooth muscle contraction and reduce goblet cell mucus secretion.

M1, M2, and M3 Receptor Functions

$M_1$ enhances cholinergic signaling in ganglia; $M_2$ provides presynaptic negative feedback to inhibit ACh release; $M_3$ mediates bronchoconstriction and mucus secretion in airway smooth muscle and goblet cells.

Ipratropium

A short-acting muscarinic antagonist (SAMA) that non-selectively blocks $M_1$, $M_2$, and $M_3$ receptors, with an onset of \text{\texttilde} 15\text{--}30\text{,min} and duration of $4\text{--}6\text{,hours}$.

Tiotropium

A long-acting muscarinic antagonist (LAMA) with high selectivity for $M_3$ receptors and $M_2\text{-sparing}$ properties due to slow dissociation from $M_3$ and rapid dissociation from $M_2$, offering a $12\text{--}24\text{,hour}$ duration.

Methylxanthines (Theophylline)

Naturally occurring xanthine alkaloids that cause bronchodilation by non-selectively inhibiting phosphodiesterase (PDE) to increase cAMP and blocking adenosine receptors, limited by a narrow therapeutic index.

Reslizumab (Cinquair)

An intravenous monoclonal antibody that targets the $\text{IL-5}$ cytokine, blocking its interaction with eosinophils to reduce eosinophilic airway inflammation in severe asthma.

Benralizumab (Fasenra)

A subcutaneous monoclonal antibody that binds directly to the $\text{IL-5}$ receptor alpha on eosinophils, inducing direct eosinophil depletion in eosinophilic asthma and COPD.

Dupilumab (Dupixent)

A subcutaneous monoclonal antibody that targets the $\text{IL-4}$ receptor alpha subunit, inhibiting both $\text{IL-4}$ and $\text{IL-13}$ downstream signaling pathways.

Omalizumab (Xolair)

A subcutaneous monoclonal antibody that binds free serum and tissue $\text{IgE}$, preventing $\text{IgE}$ from binding to mast cells and basophils to reduce mediator release.

Tezepelumab (Tezspire)

A monoclonal antibody cytokine inhibitor that blocks thymic stromal lymphopoietin (TSLP) released by epithelial cells, suppressing downstream dendritic cell-mediated inflammation across all asthma phenotypes.

Leukotriene Modifying Agents

Therapeutic agents consisting of 5-lipoxygenase inhibitors (Zileuton) that block leukotriene synthesis, and cysteinyl leukotriene receptor 1 ($\text{CysLTR}_1$) antagonists (Montelukast, Zafirlukast) that block leukotriene-mediated bronchoconstriction and mucus secretion.

Single Inhaler Triple Therapies for COPD

Fixed-dose combination inhalers containing an ICS, LAMA, and LABA; examples include Breztri Aerosphere (Budesonide + Glycopyrrolate + Formoterol) and Trelegy Ellipta (Fluticasone furoate + Umeclidinium + Vilanterol).