Lecture 7 - pharmacology of copd Flashcards
describe asthma vs copd
asthma usually occurs in children whereas copd in elderly
asthma can be reversible with use of bronchodilator whereas copd is not
copd is less responsive to inhaled corticosteroid treatment compared to asthma
what are the main goals in the management of copd?
improving health status, reducing symptoms, preserving lung function decline, preventing exacerbations and reducing mortality
what is the characteristics and treatment for mild copd?
characteristics are FEV/FVc <70%
FEV1</ 80%
with or without symptoms and treatment is short acting bronchodilator when needed
what are the characteristics of moderate copd and the recommended treatment?
moderate copd has FEV1 40-59%,
recommended treatment with one or more bronchodilators, rehabilitation and inhaled glucorticosteroids if significant symptoms and lung function resposne
what are the characteristics of severe copd and the recommended treatment?
characteristics: FEV1 < 40%
recommended treatment
regular treatment with one or more bronchodilators
inhaled glucocorticoids if significant symptoms and lung function respond or if repeated exacerbations
treatment of complications
rehabilitation
long term oxygen therapy if respiratory failure
consider surgical treatments
describe where beta2 adrenoreceptors are located, and how the bind/ mechanism of action.
beta2 adrenergic receptors are present in high density in airway smooth muscle cells.
B2 agonists act by binding to B1AR. interaction of the receptor with intracellular G proteins stimulates the production of intracellular cyclic adenosine monophosphate cAMP. this leads to activation of protein kinase A
inhibit myosin light-chain kinase
promote calcium efflux
inhibit the MPK pathway by phosphorylating and inhibiting the rAF-1 kinase
net effect is bronchodialtion
what re examples of short acting and long acting beta 2 adrenoreceptors agonist ?
Short Acting: Salbutamol, Piralbuterol, Levalbuterol
Long Acting: Salmeterol, Formeterol, Arformeterol
where are other sites which Beta 1 adrenoreceptors are present?
β2AR are also present in vascular endothelium, ciliated cells, circulating inflammatory cells (such as eosinophils), and sub-mucosal glands.
what are other effects of b2 agonist other than bronchodilation ?
non-bronchodilator effects, include attenuation of mast cell mediator release, reduction of plasma exudation, and reduced activation of sensory nerves, enhancement of mucociliary transport, attenuation of neutrophil recruitment, and inhibition of smooth muscle cell proliferation.
describe the use of laba, properties and what type of copd patients it is used in.
Option patients that are symptomatic despite regular SABA use
Both are lipophilic, but the relative water solubility of formoterol enables it to diffuse rapidly to the β2AR and cause bronchodilation in between 1 to 3 minutes
Salmeterol’s onset of action is significantly longer.
Long duration of action due to lipophilic properties that allow them to remain in the airway tissues in close vicinity to β2AR
Cochrane review concluded that inhaled long-acting beta2-agonists are effective over the medium and long term for patients with moderate to severe COPD with improved quality of life and reduced exacerbations, but did not significantly reduce mortality or serious adverse events
what are side effects of beta 2 adrenoreceptor agonists?
Tachycardia, tremor (flight or flight!)
Hypokalemia (low potassium, stimulates the Na/K-pump)
Transiently decreases PO2 as they may increase perfusion to poorly ventilated areas supplemental oxygen helpful
LABAs not problematic in COPD (in contrast to Asthma- black box warning)
what does parasympathetic activity mediate and how is mucous secreted?
Para-sympathetic activity mediates both bronchial smooth muscle contraction and the release of mucus into the airway lumen through stimulation of muscarinic receptors
where are M1, M2 and M3 receptors located?
M1 receptors are expressed in peribronchial ganglia, whilst M3 receptors are present on bronchial smooth muscle cells.
M2 receptors are located in the post ganglionic para-sympathetic nerve and act as auto receptors. Agonistic stimulation of these receptors leads to inhibition of further acetylcholine release
optimal inhibition achieved by selectively blocking M1 and M3 receptors
give an example of short acting msucarinic antagonists and their action
Ipratropium bromide
Blocks all muscarinic receptors without sub-type selectivity.
Its onset of action is within minutes, with peak activity occurring between 1 and 2 hours and duration of action approximately 4 hours in the majority of patients
give an example of long acting muscarinic antagonists and their action
Tiotropium
It binds to M1–M3 receptors and is 10 times more potent than ipratropium bromide.
Dissociates slowly from M1 and M3 receptors- long acting effect,
Dissociates relatively rapidly from the M2 receptor- kinetic selectivity.
Onset of bronchodilation occurs within 30 minutes, with peak activity at 3 hours, sustained over more than 24 hours
The Cochrane concluded that Tiotropium effects were superior to LABAs in terms of preventing exacerbations and disease related hospitalization.
what are adverse effects of muscarinic antagonists?
dry mouth
exacerbation of narrow angle glaucoma and myasthenia gravis (autoimmune neuromuscular disease-muscle weakness)
what is inflammation in COPD dominated by? and what are examples of inhaled corticosteroids?
The inflammation in COPD is dominated by neutrophilic infiltration, with an increased numbers of macrophages and CD8 T lymphocytes; neutrophilic infiltration is not as responsive to steroids as the eosinophilic inflammation seen in asthma
Budesonide, Triamcinolone, Fluticasone, Mometasone, Flunisolide, Beclometasone, Ciclesonide
what does the combination of ICS and Saba DO?
Animal studies suggest that the combination of ICS plus LABA behaves synergistically
what does ICS regulate?
ICS may regulate the coupling of β receptors to G proteins and enhancing cAMP activation
what des chronic LABA or SABA exposure lead to?
Chronic LABA or SABA exposure will also lead to reduced β receptor expression, as they are internalized and degraded; ICS reverse this effect through increased gene transcription and synthesis of these receptors
what are methylxanthines (theophylline- drug) an describe the or mechanism of acton
Adenosine receptor antagonist/PDE inhibitor – airways bronchodilation
Inhibition of PDE4 on inflammatory cells, reduces cytokine and chemokine release
Enhancement of histone deacetylation, decreased inflammatory cell gene transcription
what are toxicities of methylxantines
Narrow therapeutic window!
Toxicity: anorexia, abdominal discomfort, anxiety
More severe toxicity: seizures and arrhythmias
what does oxygen administration reduce?
Oxygen administration reduces hematocrit, pulmonary artery pressures, dyspnea, and rapid eye movement related hypoxemia (low oxygen in blood) during sleep
what are common causes of acute execrations of copd?
Tracheobronchial infection, Pneumonia (use of antibiotic to eliminate)
Air pollution
Pulmonary embolism (blood clots in pulmonary vessels)
Rib fractures/chest trauma, Pneumothorax (free air in pleural chest cavity-lung collapse)
Inappropriate use of sedatives, narcotics, beta-blocking agents
Right and/or left heart failure or arrhythmias
what are side effects of protease inhibitors?
Side effects include anaphylaxis and low grade fever (especially in patients with IgA deficiency)
what are the biologic effects of smoking on tnf-a?
amplifies the inflammatory response resulting in activation of epithelial cells, monocytes, macrophages, and neutrophils
induce emphysema through the release of proteinases, including NE and MMP-9,
stimulate mucus secretion,
induce apoptosis of skeletal muscle cells.
Anti-TNFa – not very efficacious and problems with cancers.
Anti IL-8 receptor antibody CXCR2 –low efficacy
Anti-IL-5 and Anti IL-13-small benefits
