Module 46

Question 1

What is the major problem that occurs if a patient uses a ß-agonist too frequently?

Answer 1

• The overuse of ß-agonists leads to tachyphylaxis, i.e. the response to a ß-agonist is significantly attenuated (e.g. there is downregulation of ß-receptors)
  Therefore, if a patient has an acute asthma attack the ß-agonist will not be effective, which can have tragic consequences

Question 2

In the treatment of asthma, what are the various devices used to administer inhalational drugs, and what are the advantages and disadvantages of each?

Answer 2

• pressurized metered dose inhalers (MDI)
  ○ Advantage: not affected by humidity and are reliable
  ○ Disadvantage: requires coordination between actuating the device and inhalation. Spacers can be used to decrease this disadvantage
  
  • dry powder devices (DPI) such as the Turbuhaler
    ○ Advantage: no coordination is required
    ○ Disadvantage: they can be affected by high humidity, and the dose, unless a diluent is used, is so small that it is difficult to be sure that anything was inhaled
  • Nebulizer
    ○ Disadvantage: it is not portable and is expensive. Some patients think it must work better because it is more elaborate, but in most cases the MDIs and DPIs work just as well.

Question 3

What % of a drug administered by metered dose inhaler actually enters the lungs? What happens to the rest of the drug?

Answer 3

Only about 10-20% of the drug enters the lungs and the rest stays on the oropharynx and is swallowed.

Question 4

What is the advantage of budesonide and fluticasone over beclomethasone (administered by metered dose inhaler) for the treatment of asthma?

Answer 4

• Given that most of the drug is swallowed, it is a major advantage if the most of the swallowed steroid is metabolized by the liver so that systemic side effects are minimized. The oral bioavailability of budesonide and fluticasone is much lower than that of beclomethasone; therefore, the systemic effects are less.
  
  • However, some of the drug is absorbed directly from the lungs; therefore, there will always be some systemic effects. In addition, fluticasone is very potent, and in the presence of a P450 inhibitor, the systemic effects of fluticasone can be quite significant.

Question 5

Contrast the effects of steroids and ß-agonists in the treatment of asthma.

Answer 5

• ß-agonists cause immediate bronchodilation and are useful for acute therapy. However, asthma is an inflammatory condition, and the ß-agonists do not treat the basic lung inflammation.
  
  • In contrast, steroids require turning on the synthesis of many genes, and they take about 24 hours to be effective. However, they are important for the treatment of chronic asthma to decrease inflammation.
    Tachyphylaxis can develop to ß-agonists if the underlying inflammation is not treated. However, some patients only have asthma when exposed to some trigger such as horses, and in such cases it is appropriate to simply treat the symptoms with a ß-agonist when there is exposure to the allergen without using a steroid.

Question 6

How does salmeterol differ from other ß-agonists?

Answer 6

• It is a long acting ß-agonist that is not recommended for acute treatment. However, it can be useful for the treatment of severe asthma when patients develop symptoms in the middle of the night as the short acting agent wears off.

Question 7

Critique the attached paper that was published in The Lancet and shows a benefit of the combination of fluticasone and vilanterol for the treatment of patients with chronic obstructive lung disease.

Answer 7

• This was a double-blind placebo controlled trial involving 23,835 patients. The primary outcome was a decrease in mortality, and no decrease in mortality was found. However, among secondary outcomes the study found a statistically significant decrease in moderate and severe exacerbation. But the absolute annual rate of severe exacerbations was 0.05 vs 0.07 for placebo. Although this was very significant statistically, it is not clinically significant, especially given the cost and side-effects of medication.
  It shows the danger of having a sample size so large that you can find clinically unimportant differences. In addition, 47% of the subjects continued to smoke. The important intervention in these patients is to somehow get them to stop smoking! The study was funded by GlaxoSmithKline, who market the drugs.

Question 8

What is Prolastin and for whom would it be appropriate therapy?

Answer 8

• Prolastin is alpha-1 antitrypsin. It is used for patients who have a genetic deficiency in the enzyme and develop severe lung disease mediated by enzymes such as neutrophil elastase.
  ○ Prolastin is prepared from blood plasma of donors. No randomized placebo-controlled study has been done to prove that it works because such a study would be unethical.
  
  • It is very expensive, and to be eligible for receiving it in Canada there are several criteria: you must be shown to have the genetic deficiency, you must no longer smoke cigarettes, you must have lung disease but it cannot be too severe.
    ○ That is because Prolastin presumably protects against further damage, but it does not heal damage that has already occurred.
  • It is likely that many patients who have the deficiency will not have severe lung disease as long as they do not smoke, and it certainly would be counter productive to treat patients if they are not willing to stop smoking.

Question 9

What is another option for treating severe allergic asthma?

Answer 9

• Omalizumab is an antibody that binds to IgE and it is useful for treating asthma that involves a specific allergen.
  
  • It is also useful for the treatment of chronic idiopathic urticaria.
    I would not ask the name of the drug on an exam but you should know that IgE is involved in many types of allergic reactions and there is an antibody that neutralizes it.

Question 10

Why is the incidence of asthma and peanut allergy increasing?

Answer 10

• Of course the answer to that is not known for sure, but it may be part of the hygiene hypothesis.
  
  • This hypothesis states that lack of exposure to parasites and other pathogens, especially in childhood, makes an individual more susceptible to allergies. The theory behind this is that there are a limited number of lymphocytes in the body and their specificity is shaped by exposure to pathogens.
  • If the immune system is exposed to fewer pathogens it is more likely the individual will have lymphocytes that recognize “self”.
    It also appears that, contrary to previous advice, exposure to allergens such as peanuts at an early age decreases the risk of the development of allergies to these specific allergens