Pulmonary

Question 1

Where is smooth muscle found in the lungs?

Answer 1

airway smooth muscle extends as far distal as terminal brochioles

Question 2

What receptors are expressed in the pulmonary system?

What do the mediate?

Answer 2

SNS

• β2- adrenoceptors – (coupled GalpaS)
  
  • Expressed on SM in bronchioles
  • EPI → β2- adrenoceptors activation → Increased intracellular cyclic AMP
  • widening of the airways (bronchodilation)
    
    • mediate relaxation of smooth muscle in blood vessels, bronchi, the uterus, bladder, and other organs

Non adrenergic Non-cholinergic nerves (NANC)

• Relax airway smooth muscle by releasing Nitric oxide (NO) and vasoactive intestinal peptide(VIP)
  
  • Ex: Bradykinin increase NO in endothelial cells (influence tone)

PSNS

• Stimulation of the vagus nerve leads to bronchoconstriction
• M3 receptors (coupled with Galphaq) are pharmacologically most important
  
  • Found on bronchial smooth muscle
  • Mediate bronchostriction via the activation of IP3 (inositol triphosphate) which increases in the intracellular Ca²⁺ concentrations
  • Mediate mucus secretion (narrow internal diameter)

Question 3

What do adrenergic receptors cause in the lungs?

cholinergic?

Answer 3

Adrenergic β2

• Bronchial smooth muscle RELAXATION
• Results in
  
  • Bronchodilation

Cholinergic

• Bronchial smooth muscle CONTRACTION
• Increased secretion of the bronchial glands
• Results in
  
  • Bronchoconstriction
  • Increased mucus secretion

Also, important to note that the parasympathtic nerves provide baseline tone to the lungs so even in the resting state these drugs can provide some dilation

Question 4

What is asthma? s/s?

Answer 4

• Chronic inflammatory disorder of the airways characterized by:
  
  • Immune-mediated airway inflammation and edema
  • Increased responsiveness of the tracheobronchial tree to a variety of stimuli that parallels the extent of inflammation
  • Variable airflow obstruction (especially outflow obstruction) that is reversible
  • Often but not always in response to known allergens
• Characteristic s/s:
  
  • Sense of breathlessness
  • Tightening of the chest
  • Wheezing
  • Dyspnea
  • Cough
• “More than just bronchospasm” →
  
  • Thickened basement membrane
  • Infiltration of eosinophils
  • Mast cells active
  • SM hypertrophied
  • Internal diameter limited by Muscus plug and mediators

Question 5

What are the phases of asthma? treatments?

Answer 5

• Immediate: nonspecific stim, allergen → mast cell degranulation and release of substances (prostaglandins, Histmaine, leukotrienes → work to promote bronchospasm
  
  • B2-agonist
  • CysLT-receptor antagonist → reduce leukotriene signaling
  • Theophylline → reduce bronchospasm
• Chemotaxins, chemokines → promote the inflammation (late phase box) → recruits more mediators (all contribute to endothelial damage) → hypertrophied SM -→ bronchospasm, wheezing, coughing
  
  • NEED inhaled GLUCOCORTICOID!! Get inflammation under control

Question 6

What are the main pharmacologic classes of drugs we use to treat asthma?

Answer 6

• Signs & Symptoms of asthma result from a combination of inflammation and bronchoconstriction
• Important to address both problems pharmacologically
• Two main pharmacologic classes:
  
  • Anti-inflammatory agents
    
    • Glucocorticoids (prednisone)
  • Bronchodilators
    
    • Beta₂ agonists (albuterol) → acute bronchospasm issue

Question 7

What are some mediators for asthma?

Answer 7

• Airway hyper-responsiveness and inflammation from an supposed allergen in bronchial mucosa with activation of Th2 lymphocytes and cytokinine release
• Mediators include: (all have been implicated as histologic mediators )
  
  • Eosinophils
  • mast cells,
  • neutrophils,
  • macrophages,
  • basophils,
  • T lymphocytes
• Other probable mediators of acute bronchoconstriction include: cytokines, interleukins (3,4,5), arachidonic acid metabolites leukotrienes and prostaglandins, histamine, adenosine, and platelet activating factor. Some asthmatics are atopic and have IgE synthesis and are considered to have atopic or extrinsic asthma. Medications are aimed at flattening the response to mediators

Question 8

What are advantages to inhalational drug therapy?

Answer 8

• A high local concentration of the drug is achieved in the bronchial tree = exactly where the drug is needed most
  
  • Pulmonary effects are enhanced
    
    • Systemic effects are minimized- impact entire body
  • Drug onset is RAPID (really useful in acute attacks)

Three drug delivery methods:

• Metered-dose inhalers (MDIs)- classic albuterol inhaler
  
  • Lung/hand coordination, ~10% go into lung
• Dry-powder inhalers (DPIs)
  
  • Much less coordination, ~20% in
• Nebulizers
  
  • Mist, enhance amount going into lung, take longer amount of time

Question 9

What are some anti-inflammatory drugs used for asthma?

Answer 9

• Foundation of asthma therapy/control- limit # of acute exacerbations
• Taken daily for long-term control
  
  • 1^st: Inhaled Corticosteroids (glucocorticoids)
  • Cromolyns
  • Leukotriene Inhibitors
  • Anti-IgE Antibodies

Question 10

MOA Glucocorticoids?

Answer 10

*Most effective/important preventive treatment for asthma

• MOA- Suppress inflammation by altering genetic transcription of proinflammatory mediators and increasing production of anti-inflammatory mediators
  
  • Shift production of proteins away pro-inflamm state
    
    • Steroids work by: receptors circulating in cytosol (for any steroid to work→ drug needs to get through plasma membrane to get to cytosol and bind → complex will translocate to nucleus → where it acts to influence transcription of the genes (influences which proteins made)
• Target: glucocorticoid receptor alpha in cytoplasm of airway epithelial cells
  
  • increase transcription of genes for b2 receptors & enhanced receptor responsiveness
    
    • Respond better to albuterol!
  • increase transcription of genes for anti-inflammatory proteins
  • decrease transcription of genes for pro-inflammatory proteins
    
    • decrease airway mucus production
    • decrease Vascular permeability (edema)
  • Induce apoptosis in inflammatory cells
    
    • More cell death → (eosinophils, TH2 lymphocytes)
  • Indirect inhibition of mast cells over time
  • Reverses many features of asthma especially bronchial hyperreactivity
    
    • Not need B2 agonists as much
  • Used as suppressive therapy- they do not change the progression of the disease
    
    • not a cure
• Usually administered by inhalation, but IV and oral are also options

Question 11

Examples of inhaled corticosteroids? Systemic?

Answer 11

Inhaled Corticosteroids → (long term prophylaxis in all patients with moderate to severe asthma)

• Budesonide (prototype, available in nebulized form for kids too young to use MDI or DPI)
• Beclomethasone
• Triamcinolone
• Fluticasone
  
  • Daily to prevent asthma exacerbations

SYSTEMIC:

• IV (status asthmaticus)
  
  • Hydrocortisone
  • Methylprednisolone
• PO (acute exacerbation, chronic severe asthma- limit time course if possible because toxicity increases over time)
  
  • Prednisone
  • Prendnisolone
    
    • Limit systemic corticosteroids → impact growth in children

Question 12

Considerations for administration of inhaled corticosteroids? S/E?

Answer 12

• 10-20% of inhaled corticosteroids reaches airway
• Beta-2 agonist BEFORE steroid inhalation → increases local drug concentration in lung (dilate bronchioles)
• 80-90% inhaled dose reaches oropharynx and swallowed
  
  • Recommend to rinse mouth after
    
    • ~ opportunistic infections (candidiasis)
• Higher airway concentration than same dose given PO
• Generally quite safe with limited systemic side effects
• The patient should always take the lowest effective dose
• SE:
  
  • Adrenal suppression→ mild compared with IV/PO adrenal suppression
    
    • Don’t need to give stress dose with inhaled
  • Oropharyngeal candidiasis
  • Hoarseness/laryngeal dysfx
  • Delayed growth in children – may have some impact (R v B?)
  • Osteopenia/osteoporosis
    
    • Encourage vitamin D/calcium intake & weight bearing exercise

Question 13

What are some adverse effects for systemic corticosteroids?

Answer 13

• Minor when taken acutely (< 10 days) but can be severe when used long-term

Long-term use:

• Myopathy/weakness
• Adrenal suppression
  
  • Taper (do not stop suddenly)
  • STRESS DOSE: Give extra IV/PO dose during times of physiologic stress (surgery/trauma/infection) during treatment and for several months after tapering patient off the drug or pt could die
• Infection risk
• Suppression of growth and development
• Peptic ulcer disease (NSAIDS increase the risk)
• Weight gain, edema, hypokalemia (some diuretics increase risk)
• Hyperglycemia
  
  • Monitor levels in diabetic patients (probably will need to increase insulin dose)

Question 14

What is cromolyn? Administration?

Answer 14

MOA: Stabilizes pulmonary mast cells (inhibits immediate and later phase issues of pathway)

• Inhibits antigen-induced release of histamine and the release of inflammatory mediators from eosinophils, neutrophils, monocytes, macrophages, lymphocytes and leukotrienes (later phase)
• Inhibits immediate allergic response to an antigen
  
  • but not the allergic response once it has been activated!
• Principle use: Prophylactic therapy of bronchial asthma
  
  • Can help prevent exercise induced bronchospasm
  • Does not relieve an allergic response after initiation
    
    • Not used as a rescue inhaler (daily preventative)
• Administered via inhalation 8-10% enters the systemic circulation poor oral absorption
• Dose: Take 4 times daily

Question 15

S/ECromolyn?

Route?

Answer 15

rare, safest of all antiasthma medications

• Infrequent but serious side effects include:
  
  • Cough and/or Bronchospasm
  • Laryngeal edema
  • Angioedema,
  • Urticaria,
  • Anaphylaxis

Route—inhalation

• Nebulizer
• MDI

Question 16

What are leukotriene modifiers? MOA? Examples?

Answer 16

• Leukotrienes are synthesized from arachidonic acid when inflammatory cells are activated
  
  • Leukotrienes C₄, D₄, And E₄ →
    
    • Promote bronchoconstriction, eosinophil infiltration, mucus production, and airway edema
      
      • If we decrease leukotriene signaling → really reduce inflammatory piece
• Leukotriene Inhibitors of pathway→ useful drugs for bronchial asthma because they reduce leukotriene effects
  
  • Less effective than inhaled glucocorticoids
    
    • Additive effect
  • Not effective in the treatment of ACUTE Asthma attacks
  • Few extrapulmonary effects
• Used in place of glucocorticoids (if not tolerated) or if additive effect is needed
• Available agents
  
  • Zileuton (Zyflo)
  • Zafirlukast (Accolate)
  • Montelukast (Singulair)

Question 17

What class is Zileuton?

MOA? Adverse effect?

Answer 17

Leukotriene modifier

• Lipoxygenase inhibitor which blocks the biosynthesis of leukotrienes from arachidonic acid
  
  • Reducing leukotriene signaling (reduced []) →
    
    • Bronchodilation, improves asthma symptoms, and shown long-term improvement in PFT
• Low bioavailability
• Low potency → bad thing (more drug molecules → more SE)
• Significant adverse effects
  
  • Hepatotoxic 2-4%
    
    • Monitor LFT regularly early in tx
  • Neuropsychiatric issues
    
    • Depression, anxiety, agitation, hallucinations, suicidal thinking and behavior
  • Cytochrome P450 interactions
  • Not widely used- not a first line, if others failed

Question 18

What is montelukast (singulair) MOA?

What is it used to treat?

Metabolized by? PB?

Answer 18

• Leukotriene receptor antagonists block the mechanism of bronchoconstriction and smooth muscle effects.
  
  • blocks the ability of leukotriene to bind to -Leukotriene 1 receptor
    
    • ~ still produce leukotrienes but reduce signal by physically block leukotriene receptors
  • Used to treat asthma in patients < 1 year old
  • Prevents exercise induced bronchospasm >15 years old
  • Treat allergic rhinitis
• Improve bronchial tone, pulmonary function, and asthma symptoms
  
  • Max effect 24 hrs after 1^st dose → not acute use (recommend not d/c)
• Clinical trials:
  
  • Adverse effects = placebo
  • Rare psychiatric effects
• 99% protein bound
  
  • Can see higher unbound drug if taking another highly bound drug → but SE ok
• Undergoes extensive metabolism by CYPP450
  
  • However, drug interactions minimal (phenytoin can decrease drug levels)

Question 19

What is omalizumab? MOA?

Answer 19

• Humanized mouse monoclonal antibody (Anti IgE antibody= class)
• Target: Prominence of IgE mediated allergenic responses in asthma
  
  • Binds to IgE in the blood → neutralizing/inactivating it
  • IgE levels decrease up to a year

Two things happen:

• Decreases quantity of circulating IgE
  
  • Prevents binding of IgE to mast cells → IgE less likely to precipitate inflammatory reaction
• Down-regulation of IgE receptors
  
  • In response to the lower levels of circulating IgE receptors on the mast cells basophils and dendritic cells are down-regulated.
  • This reduces the stimulation of T2 lymphocytes and decreased the late-phase asthmatic response greater than would be expected with IgE alone

Question 20

Administration of Omalizumab? A/E?

Answer 20

• EXPENSIVE: $10,000 per year
• Inconvenient (SQ only)
• ½ life 26 days
  
  • only used in allergy induced asthma when inhaled glucocorticoids have failed
• Adverse Effects:
  
  • Injection site reactions
  • Viral infection
  • Upper respiratory infection and sinusitis
  • Headache
  • Pharyngitis
  • Cardiovascular complications
    
    • increased MI, stroke, heart failure, dysrhythmia, thromboembolism risk → be aware if on chart (aggressive cardiac workup)
  • Possible increased risk of cancer
    
    • Anytime suppressing immune system…
      
      • *Preop: assess closely for infection and CV
• Rare Adverse Effect: triggering of an immune response (anaphylaxis)
  
  • Monitor 2 hours after 1^st 3 doses
  • Monitor 30 minutes after all subsequent doses

Question 21

What are bronchodilators used for? classes?

Answer 21

• Provide symptomatic relief but do not alter the underlying disease process (inflammation)
• In almost all cases, patient taking a bronchodilator should also be taking a glucocorticoid for long-term suppression of inflammation
  
  • Principal bronchodilators are the beta₂-adrenergic agonists
  • ACUTE PHASE- RESCUE

Bronchodilators

• Beta-Adrenergic Agonists
• Anticholinergics
• Methylxanthines

Question 22

MOA of Beta adrenergic agonists?

Answer 22

• Beta adrenergic receptors- coupled to stimulatory Gαs proteins
  
  • Epi → stim Gαs proteins →
• Activate adenlyl cyclase → increases the production of cAMP (adenosine monophosphate)à bronchodilation
  
  • r/t decreased intracellular Calcium
  • and increases membrane K conductance (hyperpolarization)
• Primary effect → dilate the bronchi by a direct action on the B₂ Adrenoceptors:
  
  • Results in smooth muscle relaxation and bronchodilation
  • Stabilization of mast cells → less histamine release
  • Increase mucus clearance by cilia

Question 23

Use of beta adrenergic agonists? examples?

Answer 23

• Most effective drugs for relief of acute bronchospasm and prevention of exercise-induced bronchospasm
• Use in asthma: both quick relief and long-term control
• Receptor selectivity b2
• Bind to beta 2 200-400 times more strongly than b1 (greater affinity to B2)
  
  • Short-acting
    
    • Albuterol, Levalbuterol
  • Long acting
    
    • Salmeterol, Terbutaline (PO/IV)
      
      • Once larger does → see B1 effects

Question 24

B adrenergic agnost onset, Side effects?

What can oral preparations cause?

Answer 24

• Rapid onset
  
  • 15-30 minutes (peak affect)
• Good for use as Rescue inhaler
• Given via:
  
  • inhalation or aerosol
  • Powder or Nebulized
  • Orally or injected (SC)

Side Effects

• Minimized by inhalation delivery
• Tremor
  
  • B2- skeletal muscle, increase speed of contraction (high doses)
• Increased heart rate
  
  • B1 activity in higher doses
  • Also B2 on BV → dilation → drop in EDBP causes baroreceptor response
• Vasodilation
• Metabolic changes
  
  • Hyperglycemia (mobilize glucose)
  • Hypokalemia (shift K into cell)
  • Hypomagnesemia

Oral preparations

• Excessive dosage: angina pectoris, tachydysrhythmias

Question 25

What is albuterol?

meterd dose? nebulizer? DOA?

Isomers?

Answer 25

• Preferred selective beta 2 agonists
  
  • Give 2 puffs before case if asthmatic!!! Prevention
• Administered via metered dose:
  
  • 100 mcg/puff
  • 2 puffs q 4-6 hours
• Nebulizer:
  
  • 2.5-5.0mg in 5ml of saline
• Duration of Action
  
  • 4 hours with some relief evident up to 8 hours
• 2 isomers
  
  • R-albuterol levalbuterol more affinity for beta 2
    
    • Levalbuterol→ better for CAD (want to avoid any B1 stim)
  • S-albuterol more affinity for beta 1

Question 26

What is metaproterenol?

Answer 26

• beta 2 agonists for treatment of asthma
• Administered via metered dose
• Not to exceed 16 puffs/day

Question 27

What is bitolterol?

Answer 27

• Selective beta 2 that resembles albuterol
• Longer lasting
• CV side effects are rare
• Daily metered dose is 16-20 puffs/day
  
  • *COPD pts → decrease exacerbations, admissions
• Each dose is 270mcgs

Question 28

What is terbutaline?

Answer 28

long term B2 agonist

• Administered oral, SC, inhalation
• Treat asthma
• SC administration resembles the response of epi at B2 receptors
  
  • If need SQ epi but don’t want effects → good alternative
• Dose SQ
  
  • Child: 0.01mg/kg
  • Adult: 0.25mg q 15 min
• Metered dose inhaler: 16-20 puffs/day
  
  • Each dose is 200 mcgs

Question 29

What is salmeterol?

Answer 29

• Formoterol
  
  • Combination drug -Fluticasone (steroid) and Salmeterol
• Have a lipophillic side chains that resist degradation/bind to the receptor tightly
  
  • (allow drug to stick around longer, bind receptor tighter, Longer DOA)
• Duration in 12-24 hours
• Good for prevention (not for acute flare-up)
• BLACK BOX warning - May increase the risk of fatal or near fatal asthma attack.
  
  • Noticed Rebound hyperbronchospastic episodes → now combine with corticosteriods, won’t see salmeterol given by itself

Question 30

What are methylxanthines?

Clinical application?

Drug examples?

Answer 30

phosphodiesterase inhibitors

MOA: Unclear:

• Possible nonspecific inhibition of Phosphodiesterase isoenzymes (Types III and IV)
  
  • → prevents cAMP degradation in airway smooth muscle as well as in inflammatory cells (more cAMP around → bronchodilation)
• Possible adenosine receptor blockade at adenosine A ₁ and A ₂ receptors
  
  • Adenosine can promote bronchospasm so block that
• May also have an anti-inflammatory effect
• Drug Effect:
  
  • Airway relaxation and bronchodilation

Clinical Applications

• COPD
• Asthma
  
  • Who aren’t resp to 1^st line drugs

​Drug examples: Theophylline, Aminophylline

Question 31

Administration of theophylline?

Metabolism?

Answer 31

Theophylline

• Therapeutic plasma level: 10-20mg/ml
• Toxic level: >20mg/ml
  
  • VERY NARROW
• Wide ½ life variation in different patients (esp. smokers who metabolize 50% faster)
• Susceptible to drug-drug interactions - cytochrome P450
  
  • Increase levels (of theophylline):
    
    • Cimetidine, Cipro, and antifungals (cytochrome P450 inhibitors)
    • Caffeine (also a methylxanthine) → avoid caffeine!
      
      • Increases levels and promotes CNS and CV toxicity
  • Decrease Levels:
    
    • Phenobarbitol and phenytoin (remember these are cyp 450 inducers)
• Metabolized in the liver and excreted in kidney
• Available in sustained release formulation only

Question 32

S/E Theophylline?

Answer 32

Side Effects (almost always at toxic levels)

• Cardiac arrhythmias
• Nausea/vomiting
• Irritability
• Insomnia
• Seizures
• Brain damage
• Hyperglycemia
• Hypokalemia
• Hypotension
• Death from CV collapse
  
  • Preop: investigate SE

Question 33

MOA Anticholinergic?

Uses?

Answer 33

• MOA
  
  • Competitive antagonists at muscarinic acetycholine receptors (nonselective)
  • Promote smooth muscle relaxation & decreased mucus gland secretion by antagonizing endogenous Ach
• Muscarinic 3 subtype → most important
  
  • Block M3 → SM relaxation, less mucous production (improves symptoms)
• Uses
  
  • Treatment of COPD
  • Secondary line of treatment for asthma in patients resistant to beta agonist or significant cardiac disease

Muscarinic receptor antagonists- M3

M1 and M3 coupled to Gαq → increases Ca → bronchospasm

M2 (good guy) → provides negative feedback

Would love M2 agonist, but don’t have that.

M3 antagonist would be more effective

Question 34

Atropine? administration?

Answer 34

naturally occurring alkaloid

• Formally considered 1^st line treatment for asthma
• Administered 1-2 mg diluted in 3 to 5 ml of saline via nebulizer
• Problem: Highly absorbed across respiratory epithelium layer
  
  • Causes: systemic anticholinergic effects (opposite of rest and digest)
    
    • Tachycardia, nausea, dry mouth, GI upset, difficulty urinating

Question 35

What is ipratropium bromide?

dose?

pk?

Answer 35

• Quaternary ammonium salt derivative of atropine
  
  • → does not cross biological membranes (if inhalational, stays in bronchioles)
• Antagonizes the effect of endogenous acetylcholine at M3 receptor subtypes
• Administered via metered dose inhaler
• Dose:
  
  • 40-80mcg in 2-4 puffs of via nebulizer
• Slow onset: 30-90 minutes
• Duration of action 4-6 hours
• Not significantly absorbed compared to atropine
• Inadvertent oral absorption
  
  • Dry mouth and GI upset

Ipratropium has been shown to increase exercise tolerance, decrease dyspnea, and improve gas exchange.

Question 36

What is tiotropium?

Answer 36

• Quaternary ammonium salt
• Long acting anticholinergic
• Not significantly absorbed across resp epithelium which results in few side effects
• Approved by FDA for COPD (1^st line- improve exacerbations and admissions)

Question 37

What are glucocorticoid/LABA combinations?

Answer 37

• Available combinations (long acting B2 w/ steroid)
  
  • Fluticasone/salmeterol (Advair)
  • Budesonide/formoterol (Symbicort)
• Indicated for long-term maintenance/prevention in adults and children
  
  • Convenient but limited dosage flexibility
  • Reduce symptoms, reduce the risk of exacerbation and help reduce corticosteroid dose
• Not recommended for initial therapy
  
  • Many patients are controlled adequately on inhaled glucocorticoid
• Black box warning: increased risk of asthma related death

Question 38

Management of chronic asthma?

Answer 38

• Treatment goals:
  
  • Reducing impairment
  • Reducing risk
• Long-term drug therapy
  
  • Agents for long-term control (eg, inhaled glucocorticoids)
• Agents for quick relief of ongoing attack (eg, inhaled SABAs) Stepwise therapy
  
  • Step chosen for initial therapy is based on pretreatment classification of asthma severity (SE and tolerance)
  • Moving up or down a step is based on ongoing assessment of asthma control
• Important to reduce exposure to allergens and triggers
  
  • Sources of allergens: smoke, house dust mites, pets, cockroaches, mold
• Factors that can exacerbate asthma: tobacco smoke, wood smoke, household sprays

Question 39

Drugs used for acute severe exacerbations of asthma?

Answer 39

Requires immediate attention

• Goal:
  
  • relieve airway obstruction and hypoxemia, and normalize lung function as quickly as possible.

Initial therapy consists of:

• Giving oxygen to relieve hypoxemia
• Giving a systemic glucocorticoid to reduce airway inflammation
  
  • Changing types of proteins made (6 hrs) → get on board.
  • Enhance B2 agonist in the long term
• Giving a nebulized high-dose SABA (short acting B2 agonist) to relieve airflow obstruction
• Giving nebulized ipratropium to further reduce airflow obstruction.

OR Meds:

• Ketamine: best choice!
  
  • Enhanced sympathetic tone (more epi → then bronchodilates)
• Propofol
  
  • Bronchodilates too but ketamine better
• Deepen VA: limited if severe bronchospasm b/c want to go in…
• Epinephrine → stim B2 and alpha 1 → try after everything else first
  
  • Succ’s used for laryngospasms NOT bronchospasms

Question 40

What is COPD?

Answer 40

In COPD neutrophils, macrophages, CD8+ T lymphocytes, and eosinophils, are more prominent. Asthma eosinophils play prominent role, followed by mast cells, CD4+ T lymphocytes, and macrophages.

• COPD contrasts with asthma in that the obstruction is either not reversible or incompletely reversible by bronchodilators
  
  • Cell death and destruction of the alveoli is due to impaired lung parenchyma, degraded matrix, and toxic actions of inflammatory cells (specifically macrophages and neutrophils)
• Results in enlargement of air spaces, fibrosis, and increased mucus production
• Inflammation process in COPD
  
  • -Steroids have limited effect (less inflammation, more structural damage)
  • Inhaled corticosteroids help in reducing frequency of exacerbations
• Bronchodilators:
  
  • modest role in air outflow with patient suffering from chronic breathlessness “worsened by exertion”

Question 41

Pharmacotherapy to help with COPD?

Answer 41

Started on monotherapy initially.

Either:

1. Long acting inhaled beta-2 agonist (salmeterol)
2. Long acting anticholinergic (tiotropium)
3. An inhaled glucocorticoid (budesonide) last choice
   
   1. If that does not work may add a second class of drug (usually a combination of LABA and steroid)

Newer drug: Roflumilast (Daliresp)

• Selective phosphodiesterase type 4 inhibitor (normally phosphodiesterase breakdown cAMP)
  
  • MOA: increases cAMP levels → resulting in reduced cough, inflammation and mucus (reduce exacerbations)
  • SE: diarrhea, weight loss and loss of appetite, nausea, headache, back pain and depression