Block D - COPD

Question 1

COPD definition ?

Answer 1

Chronic Obstructive Pulmonary Disease (COPD) is a chronic slowly progressive disorder characterized by airflow obstruction (manifested by reduced FEV1 and FEV1/VC ratio to below 0.8) that does not change markedly over several months. Most of the lung function impairment is fixed, although some reversibility can be produced by bronchodilator (or other) therapy.

Question 2

pathology ?

Answer 2

Changes in Mucus gland thickness it is viscous

Air Flow limitation due to:-

(i) Mechanical obstruction due to mucus
(ii) Loss of pulmonary elastic recoil caused normally by factors in smoke
(iii) Reduction of the alveolar attachment around the walls of the small air ways which impairs gas exchange.

Question 3

when do circulatory changes occur ?

Answer 3

confined to advanced disease

Question 4

large airway insult ?

Answer 4

Large airway insult I.e trachea and bronchi causes glandular hypertrophy and a reduced number of cilia , the physiological consequence of this is an increased cough with or without sputum

Question 5

small airway insult ?

Answer 5

Small airway insult I.e bronchioles causes goblet cell metaplasia which is a change in the morphology producing more mucus to form an oedema. Smooth muscle hypertrophy occurs and the cells transform into synthetic cells which are able to produce inflammatory mediators. Fibrosis is made up of collagen which reduces elasticity of the airways and there is a change in flow resistance.

Question 6

what occurs when there is an insult to alveoli ?

Answer 6

If there is an insult to the alveoli there is a loss of walls and capillaries become detached so there is reduced gas exchange.

Question 7

what is damage linked to ?

Answer 7

The severity of the inhaled insult varies in a complex way and produces damage of varying severity within different areas of the lung depending on individual exposure and susceptibility. DLCO=diffusing capacity of carbon monoxide.

Question 8

pulmonary vascular changes ?

Answer 8

Pulmonary vascular changes in COPD are characterized by a thickening of the vessel wall that begins early in the natural history of the disease. Thickening of the intima is the first structural change, followed by an increase in smooth muscle and infiltration of the vessel wall by inflammatory cells. As COPD worsens, greater amounts of smooth muscle, proteoglycans, and collagen further thicken the vessel wall.

Question 9

symptoms of COPD ?

Answer 9

Symptoms include cough, sputum, dyspnea (difficulty breathing), and wheeze.

Patients who have chronic cough and sputum production with a history of exposure to risk factors should be tested for airflow limitation, even if they do not have dyspnea.

Question 10

what COPD result in ?

Answer 10

COPD causes airway narrowing, inflammation and mucous production

Question 11

3 forms of chronic bronchitis , what is simple mucoid bronchitis ?

Answer 11

Simple mucoid bronchitis - mucus is clear

Question 12

mucopurulent bronchitis ?

Answer 12

Mucopurulent bronchitis - mucus and pus consequence of bacterial infection

Question 13

chronic obstructive bronchitis ?

Answer 13

Chronic obstructive bronchitis - irreversible remodeling

Question 14

why does bronchitis occur and lead to ?

Answer 14

Bronchitis caused by bacterial and viral infection (much more frequent in COPD patent-chronic) causes bronchoconstriction, hyperplasia of the bronchial smooth muscle and mucus secretion.

Question 15

clinical manifestations of chronic bronchitis ?

Answer 15

• Excessive mucus production
• Bronchospasm, dyspnea and wheezing
• Hypoxia and hypercapnia (Blue in color of lips)-elevated CO2 in blood
• Productive cough - mucus is produced
• Increase body weight

Question 16

complications ?

Answer 16

Normally due to hypoxia

Cor-pulmonale is a chronic condition due to increased blood pressure

Question 17

Cor-pulmonale ?

Answer 17

Cor-pulmonale is enlargement of the right ventricular cardiac muscle (hypertrophy) to counter the hypoxic-induced increase in blood pressure-this is called beneficial hypertrophy. However, in chronic cases of COPD this leads to maladaptive hypertrophy resulting in the apoptosis of cardiac muscle cells and eventually heart failure.

Question 18

emphysema ?

Answer 18

An abnormal permanent enlargement of air spaces distal to the terminal bronchioles, accompanied by destruction of their walls.

Emphysema is long-term destruction of lungs over time caused by chemicals in cigarette smoke and leading to irreversible lung damage, The net result is inefficient gas exchange due to damage of the alveoli.

Question 19

Etiology ?

Answer 19

Cigarette smoking

Question 20

clinical manifestations ?

Answer 20

Dyspnea at rest

• Tachypnea (flushed appearance)
• Patient will be thin due to impaired gas exchange

Question 21

what does cigarrete smoking dmage ?

Answer 21

Substances within cigarettes damage the alveoli sacs.

Question 22

proteases involved in pathogenesis of COPD ?

Answer 22

MMP=matrix metalloproteinases; AAT= α1-antitrypsin; SLPI=secretory leucocyte protease inhibitor; TIMP=tissue inhibitor of metalloproteinases.

Question 23

neutrophils ?

Answer 23

Neutrophils are activated and releases proteases such as elastases which disrupts the lungs, impairs the repair of damage and enhances mucus secretion.

Question 24

theraputics - beta 2 adrenoreceptor agonist ?

Answer 24

b2-adrenoceptor agonists: used for asthma and COPD as they are speciifc they have limited side effects on the heart which expresses low amounts of beta 2 receptors.

include Salbutamol, Salmeterol, Formoterol): mast cell stabiliser, relaxes smooth muscle and causes bronchodilation to improve air flow into the lung:

Question 25

how do these drugs function ?

Answer 25

These drugs function via a cyclic AMP-dependent relaxation of the smooth muscle as cAMP activates protein kinase A which inhibits inflammatory mediators being released from mast cells. In smooth muscle PKA inhibits myosin light chains which mediates constriction and as a result causes dilation to improve air flow. The long acting b-adrenoceptor agonists have lipophilic groups attached which interact with exo-sites on the receptor. This locks the ligand onto the receptor binding site.

Question 26

Gs and beta adrenoreceptor agonists ?

Answer 26

Beta adrenoceptor agonists activate Gs which in turn promotes the stimulation of adenylyl cyclase. This enzyme catalyses the formation of cyclic AMP. cAMP activates protein kinase A, which can Inhibit MCLK Promote calcium efflux Inhibit the MPK pathway by phosphorylating and inhibiting Raf-1 kinase The net effect is relaxation of the bronchial smooth muscle and therefore bronchodilation

Question 27

theophylline ?

Answer 27

Theophylline inhibits the enzyme, phosphodiesterase which functions normally to breakdown cAMP. Therefore cAMP levels increase to cause bronchodilation. Theophylline also blocks the binding of adenosine to adenosine receptors that are normally negatively coupled to adenylyl cyclase. This also causes an increase in cAMP and therefore promotes bronchodilation.

Question 28

muscarininc antagonists ?

Answer 28

Muscarinic antagonists block the binding of acetylcholine to M3 receptors on bronchial smooth muscle to inhibit contraction and therefore bronchoconstriction.

Question 29

Inhibition of inflammatory mediator release from T cells and mast cells by beta agonists ?

Answer 29

This occurs with greater potency than smooth muscle relaxation and involves mast cell stabilisation, lymphocyte activation. This results in reductions in plasma histamine, PAF, chemotactic factors, i.e IL-1 and eosinophil cationic protein.

Question 30

vascular permability ?

Answer 30

Vascular permeability. There is some suggestion that vascular permeability is reduced by b-adrenoceptor agonists.

Question 31

Mucocillary clearance ?

Answer 31

Mucociliary clearance: increase in ciliary beats to clear mucous.

Question 32

inhaled route?

Answer 32

inhaled route. A metered dose inhaler is commonly used. Only 10% of the drug enters the lung. For people who cannot use metered inhalers, others include nebulisers and dry powder inhalers.

Question 33

oral route ?

Answer 33

oral route. Only non-catecholamines are effective via this route. Side-effects make this route a last option as it is a higher dose. However, some argue that this path is more effective for small airway bronchodilation.

Question 34

intravenous and intramuscular ?

Answer 34

Intravenous and intramuscular. Necessary for acute asthma ( severe cases). Given as a drip or as a bolus injection. Most commonly used with terbutaline.

Question 35

problems with B2 agonists ?

Answer 35

When given systemically b2-adrenoceptor agonists elicit vasodilation via cyclic AMP-dependent relaxation of vascular smooth muscle. The consequences of this are increased blood flow and a fall in systemic vascular resistance. The fall blood pressure can cause a baro receptor reflex increased cardiac output and tachycardia. Some of the tachycardia is due to a direct action on heart b-adrenoceptors. These agents also increase metabolic processes by beta adrenoreceptors 3, including increased glucose, fatty acids, ketone bodies and high-density lipoprotein. Also associated with systemic administration is an increase in tremor associated with a relaxation of slow-contracting skeletal muscle, leading to diffusion of tetanic contractions in the hand for example.

Question 36

anti allergic drug - glucocorticoids ?

Answer 36

Glucocorticoids: anti-inflammatory, inhibit PLA2 activity. Standard oral steroid is prednisolone, whilst intravenous steroids are hydrocortisone and methylprednisolone. Widely used by inhalation (e.g. beclamethasone, budesonide, fluticasone proprionate) as prophylactic therapy so before an asthma attack. Many argue that glucocorticoids should be the first line therapy in asthma.

Question 37

how are glucocorticoids carried in the body ?

Answer 37

Carried in the body as transcortin.

Question 38

effect on permeabilit increasing mediators ?

Answer 38

LTC4, LTD4, LTE4 (eosinophils, basophils, and macrophages). Secretion is inhibited. PAF synthesis inhibited. PGE1 synthesis blocked (vascular endothelium). Bradykinin formation inhibited (plasma) associated with a cough O2. free radicle formation inhibited (neutrophils, macrophages, eosinophils).

Question 39

primary effector systems ?

Answer 39

Alveolar macrophages (migration, IgG and complement decreased). Mast cells (decrease histamine release). endothelial cells (decrease adhesive response, reduction in vascular permeability). Basophils (local influx inhibited) which help to mount inflammatory response.

Question 40

secondary recruiter systems ?

Answer 40

Neutrophils (IgG receptor decreased, increased apoptosis, decreased adherence to endothelium through ELAM) Eosinophils (Serum ECP decreased, adherence decreased, chemotaxis decreased). Lymphocytes (increased apoptosis and decreased differentiation into Th2 cells, reduction in T4 helper cells, reduction in B-cell cycle). Monocytes (migration inhibited, cell death, reduced production, reduced IgE receptor). platelets (platelet kinetic normalised).

Question 41

leukotriene inhibitors ?

Answer 41

Leukotriene B4 are neutrophil chomoattractant Leukotriene C4 and D4: cause bronchoconstriction, increased bronchial reactivity, mucosal edema and mucous hypersecretion Leukotriene D4 receptor antagonists inhibit these effects: zafirlukast and montelukast 5-lipoxygenase is the enzyme involved in leukotriene synthesis: inhibition by zileuton inhibits the above effects. These agents are less effective than inhaled corticosteroids, but similar efficacy in reducing frequency of asthma exacerbations. Shown to be particularly effective in aspirin-induced asthma.

Question 42

Zileuton ?

Answer 42

MAJOR Side Effect: LIVER TOXICITY!!! (less often used)- zafirlukast has some hepatotoxicity, but less than zileuton

Question 43

MOntelukast ?

Answer 43

Montelukast UNIQUE Side effect: Eosinophilia and Churg Strauss Syndrome (eosinophilic granulomatosis in small blood vessels).

Question 44

Montelukast work ?

Answer 44

LTD4 receptor antagonists (Montelukast) block the LTD4 receptor and prevent binding of LTD4 to inhibit bronchoconstriction.

Question 45

Zileuton work ?

Answer 45

Zileutin inhibits lipoxygenase to block the synthesis of leukotrienes.

Question 46

Xanthines work ( theophylline)?

Answer 46

Adenosine antagonist. (A) These drugs can block the inhibitory action of adenosine upon adenylyl cyclase, and thus allow intracellular cyclic AMP to accumulate and promote relaxation; (B) phosphodiesterase inhibitor (blocks reduction in intracellular cyclic AMP) and relax smooth muscle; (c) effects via catecholamines (increases catecholamine release); (d) other effects, xanthines have been shown to antagonise the actions PGE2 and PGF2a.

Question 47

mechanism of action thyophylline ?

Answer 47

Theophylline inhibits the enzyme, phosphodiesterase which functions normally to breakdown cAMP. Therefore cAMP levels increase to cause bronchodilation. Theophylline also blocks the binding of adenosine to adenosine receptors that are normally negatively coupled to adenylyl cyclase. This also causes an increase in cAMP and therefore promotes bronchodilation.

Question 48

problems

Answer 48

With oral theophylline side-effects include, anorexia by increasing lypolysis, vomiting and mild CNS stimulation. Doses should be low to avoid gastroadominal problems. CNS stimulation is a problem when maintainance administration is increased to quickly. Most serious toxicity is a risk of seizures by CNS stimulation. Intravenous routes increase arrhythmia, palpitations, and tachycardia at doses above 30mg/l.

Question 49

Roflumilast ?

Answer 49

Roflumilast is a selective drug is a type 4 PDE inhibitor used in the treatment of COPD The active component is believed to be Roflumilast-oxide. It inhibits PDE4 to increase cAMP levels – PKA to reduce inflammation by blocking inflammatory mediators, with little inhibitory activity against other PDE isoforms (there are 11 members of the PDE family expressed in different parts of the body).

Question 50

anti muscarininc ?

Answer 50

Ipratropium: primarily M3 receptor which is short acting Tiotropium (longer acting): primarily M1 and M3 receptors Treatment of COPD, potential use in asthma but not approved.

Question 51

side effects ?

Answer 51

Side Effects: dry mouth, exacerbation of narrow angle glaucoma and myasthenia gravis.

Question 52

protease inhibitors ?

Answer 52

COPD is driven by macrophages and neutrophils with the net release of inflammatory mediators (chemokines) and proteases that promotes alveoli destruction and mucus secretion. There are also fibrotic lesions that reduce the elasticity of the lung-this is driven by Transforming growth factor released from the epithelial cells, TGF promotes the differentiation of fibroblasts into myofibroblasts. Myofibroblasts release collagen that causes scarring at sites of injury (caused by smoke activated neutrophils) and leading to irreversible changes in the lung structure that are responsible for the symptoms of the disease. Therefore, new therapeutic approaches include, Inhibitors of TGF Protease inhibitors Chemokine antagonists Protease inhibitors are helpful in patients with emphysema caused by alpha 1 anti-trypsin deficiency. SE: anaphylaxis and low grade fever (especially in patients with IgA deficiency)

Question 53

biologics ?

Answer 53

Tralokimab (anti-IL-13), lebrikizumab, (anti-IL-13). IL-13 is produced by TH2 cells and activates esoinophils and mast cells in the allergic response Mepoluzimab (anti-IL-5 antibody) prevent eosinophelia Omalizumab (anti-IgE antibody) prevent mast cell activation