Pathophysiology & drugs for chronic airway flow limitation Flashcards
Types of chronic airway flow limitation diseases
asthma
COPD
bronchiectasis
bronchiolitis
Sx of chronic obstructive airway diseases
Cough
Sputum
Dyspnea
COPD - sites, cells and mediators
central and peripheral airways, lung parenchyma, pulmonary vasculature
neutrophils, macrophages, CD8, CD4, B lymphocytes
LTB4, IL-8, TNFa
Asthma - sites, cells, and mediators
central and peripheral airways
eosinophils, CD4 Th2, mast cells, neutrophils, epithelial cells
LTD4, IL-4, IL-5, TNFalpha, many others
Bronchiectasis - sites, cells, and mediators
major bronchi, bronchioles
neutrophils
proteases, reactive oxygen, IL-8
Bronchiolitis - sites, cells, and mediators
membranous and respiratory bronchioles, immediately adjacent alveoli
neutrophils, eosinophils, macrophages, lymphocytes, mast cells
immunoglobulins, fibronectin, procoagulants
Changes in airway resistance in obstructive disease
resistance decreases from central –> peripheral
but in disease, resistance changes in peripheral
considerable changes can occur before symptomatic
Subtypes of emphysema
centrilobunar (acinar) - smoking, upper lobe - respiratory bronchioles
Panlobular (acinar) - lower lobe, AAT patients
Bronchiectasis etiologies
• Cystic Fibrosis • Cilial Dysfunction Syndromes foreign bodies tracheomalacia relapsing polychondritis inhalation of noxious fumes/gases infective
FEV1/FVC for pulmonary disease
< 75% - obstructive
> 90% - restrictive
Short-acting beta2 agonists
salbutamol
long-acting (~12 hours) beta agonists
salmeterol
ultra-long acting beta agonists
indacaterol
MOA of beta2 agonists
activation of adenyl cyclase –> increase cAMP –> relaxation of bronchial smooth muscle
Combination therapy for b2 agonists
+ inhaled corticosteroids, which upregulates beta 2 receptors
b2 agonists thought to downregulate beta2 receptors
Anticholinergic prototype
Long-acting muscarinic antagonist: tiotropium (greater selectivity for M3)
MOA of anticholinergics
antagonism at M1, M3 (major) - bronchoconstriction/bronchial secretion
PK of anticholinergics
quaternary compound; systemic absorption low
mostly swallowed, but not absorbed
peak effect 30-90 min, duration 6 h
SE of anticholinergics
dry mouth
nasal irritation
nosebleeds
Leukotriene receptor antagonist prototype
montelukast
MOA of LTRAs
antagonist receptors in the lipoxygenase pathway
LT1 receptor = mediate bronchoconstriction / inflammation
leukotrienes = biologically active FAs derived from arachidonic acid
- bronchoconstriction
- hyperactive airways
- inflammation
- mucus hypersecretion
SEs of LTRAs
headache, vomiting diarrhea
rare: Churg-Strauss syndrome
Methylxanthine prototype
theophylline
MOA of methylxanthines
inhibit phosphodiesterase, which breaks down cAMP adenosine antagonist (contributes more to SE)
SE and contraindications of theophylline
narrow margin of safety
absorption unpredictable
nausea, vomiting, headache, insomnia, tremor, seizures, restlessness, arrhythmias
CI: active/symptomatic CAD (increased inotropy, HR)
Inhaled corticosteroid prototype
Budesonide, fluticasone
MOA of inhaled corticosteroids
affects nuclear gene expression anti-inflammatory inhibit expression of pro-inflammatory cytokines and COX-2 immunosuppression catabolic anti-mitotic water retention
SEs of inhaled corticosteroids
oral candidiasis
dysphonia
sore throat
Monoclonal antibody prototype
omalizumab
sc injection
Combination therapy for obstructive airway disease
inhaled corticosteroids + LABA
- fluticasone + salmeterol
- budesonide + formoterol
corticosteroid upregulation of b2 to counteract downregulation by BA
Inducer of asthma in a previously non-asthmatic individual
western red cedar sap
Mechanism of alveolar breakdown due to smoking
Neutrophil and macrophages recruited to alveolar space, release elastase-containing granules
Chemotaxis
Inactivating alpha-1-antritrypsin
Impairs elastin resynthesis
Non-obstructive causes of bronchiectasis
CF Kartagener's syndrome (ciliary dysfunction) immune deficiencies necrotizing pneumonias (TB, Staph)
Obstructive causes of bronchiectasis
foreign bodies
neoplasms
inspissated mucus
congenital abnormalities
Complication of emphysema
cor pulmonale
