Respiratory Pharmacology - Pfister

Question 1

What are the two goals sought in treatment of asthma?

Which phase of mast cell activation do they correspond to?

Answer 1

Bronchodilators to reverse the initial bronchoconstriction (mast cell degranulation)

Anti-inflammatories to counter the late-phase obstruction (delayed mast cell mediator release)

Question 2

What is the mechanism of action and indication for Cromolyn sodium?

What are its side effects, and how popular is it?

Answer 2

Cromolyn sodium stabilizes mast cells through an unknown mechanism, and is used for chronic control of asthma.

It is inhaled, has few side effects, yet isn’t available in the US.

Question 3

Omalizumab

What is its mechanism of action?

What are its indications?

Answer 3

Omalizumab

Inhibits IgE receptors (FceRI/II) to inhibit mast cells and other inflammatory processes.

For very severe asthma, with concomitant allergic rhinitis.

Question 4

Omalizumab

How is it administered?

What are its adverse effects?

Answer 4

Omalizumab

Subcutaneously, once every 2-4 weeks.

Same as any mAb: Injection site reaction, anaphylaxis.

Question 5

What are three classes of bronchodilators?

What do they accomplish?

Which is the treatment of choice for asthma?

Answer 5

Beta-2 agonists, methylxanthines, and anticholinergics.

Relax airway smooth muscle to cause bronchodilation (or prevent bronchoconstriction).

Beta-agonists are the drug of choice.

Question 6

Distinguish between albuterol, salmeterol, and formoterol.

Answer 6

Albuterol is a short-acting beta-agonists (SABA), used as a rescue inhaler.

Salmeterol & formoterol are long-acting beta-agonists (LABAs), used for management of chronic asthma.

Question 7

Compare and contrast the pharmacokinetics of SABAs and LABAs.

Why might salmeterol, for example, have a comparably long half-life?

Answer 7

SABAs act quickly and last 3-6 hours.

LABAs take longer to cause effect (inappropriate for rescue), and last for at least 12 hours.

Salmeterol’s aliphatic side-chain binds a beta-2 receptor exosite for binding stability.

Question 8

What is the pathway activated by beta-2 agonists in airway smooth muscle?

How is this helpful in fighting Asthma & COPD?

Answer 8

Beta-2 receptor is a G_s, activates AC/cAMP/PKA to reduce intracellular calcium.

This causes relaxation of the smooth muscle cell, reducing bronchial tone.

Question 9

Asides from bronchodilation, what beneficial effects to beta-2 agonists have?

Answer 9

Prevent mediator release from mast cells

Prevent bronchial mucosal edema

Enhance mucociliary clearance

Reduce reflex bronchoconstriction (?)

Question 10

What side effects can be associated with beta-2 agonists?

Why is this, and how can they be reduced?

Answer 10

Muscle tremor, tachycardia, hypokalemia, restlessness, hypoxemia. Also, tolerance with chronic use.

Mostly due to extrapulmonary beta receptor activation. Give drug as an inhalant.

Question 11

Why is it meaningful to ask a patient how often they use their rescue inhaler?

How frequently should a LABA be used?

Answer 11

Increased SABA usage indicates the need for anti-inflammatory therapy.

LABAs are generally used twice daily (~12hr duration)

Question 12

Why aren’t LABAs considered first-line treatments for asthma?

Answer 12

They are too slow to be used for immediate relief, and may be associated with higher mortality (especially in children)

Question 13

What role may pharmacogenetics play in the context of asthma treatment?

Answer 13

There are multiple polymorphisms of the beta-2 receptor. Some may correspond to more adverse effect with SABA/LABA use.

Question 14

Theophylline

What class of drug does it belong to?

What are its mechanisms of action?

Answer 14

Theophylline

It is a methylxanthine (like caffeine)

Weak, nonspecific PDE inhibition and adenosine receptor antagonism, which both promote bronchodilation.

Question 15

Theophylline

How is it administered?

What are its side effects?

Answer 15

Theophylline

Administered orally.

Broad side effects (headache, palpitations, dizziness, nausea, hypotension), some related to the adenosine receptor antagonism (seizures, arrhythmias). Less popular than beta-agonists.

Question 16

Anticholinergics

Name a couple of examples and distinguish them.

What effects of acetylcholine do they block?

Answer 16

Anticholinergics

Ipratropium & tiotropium (short and long-lasting, respectively)

Block ACh-mediated construction (via M₃-PLC pathway) and mucus secretion.

Question 17

How is ipratropium administered?

Describe its pharmacokinetics.

What are its side effects?

Answer 17

Inhaled.

Effect onset over 30-90min, effects last 4-6 hours.

Typical of muscarinic blockade: Dry mouth, constipation, cycloplegia, dyspepsia, cognitive impairment (hot as a hare, red as a beet, blind as a bat, dry as a bone, mad as a hatter)

Question 18

What drugs could be added to beta-agonists?

Answer 18

Ipratropium has additive effect, mix them when beta-agonists aren’t adequate alone.

Inhaled corticosteroids have synergistic effect with beta-agonists, they are mixed often.

Question 19

How do steroids alleviate asthma?

How don’t they?

Answer 19

Actviation of the GC receptor causes suppression of inflammatory elements (like NF-kB) via histone deacetylase-2 (HDAC2).

Also downregulate inflammatory cells, mediators, and mucus, as well as increasing beta-2 receptors.

Steroids have no effect on smooth muscle contraction/dilation.

Question 20

Recall why beta-agonists and inhaled corticosteroids go so well together.

Name a couple of real world combinations.

Answer 20

Both upregulate the expression of the other’s receptor.

Fluticasone + Salmeterol = Advair

Budesonide + Formoterol = Symbicort

Question 21

When are oral steroids indicated? Which ones?

IV? Which ones?

Answer 21

For severe asthma (step 6), in short courses. Prednisone/prednisolone.

For severe acute asthma. Hydrocortisone (“rapid” onset)

Question 22

What side effects are associated with steroids in general?

With inhaled steroids?

Answer 22

ACTH/HPA suppression, which can be catastrophic.

Dermal thinning, cataracts*, osteroporosis*, vocal cord atrophy.

Question 23

What are the indications and frequency of use for ICS?

Answer 23

First-line for patients who use a beta-agonist more than twice weekly. (step 2)

Used twice daily.

Question 24

How do leukotriene inhibitors block asthma?

What are some examples?

Why are they useful against aspirin-induced asthma?

Answer 24

Block the effects of LTs: Bronchoconstriction, edema, mucus, eosinophilic inflammation.

Zileuton (blocks 5-LO), Montelukast/zafirlukast (antagonize cys-LT₁ receptor).

Aspirin-induced asthma results from arachidonate shunting to the leukotriene pathway. These block it.

Question 25

How are leukotriene antagonists administered? What are their indications? What are their adverse effects?

Answer 25

Oral. For mild-moderate asthma as an add-on for patients in which ICS have failed. Rare hepatic dysfunction.

Question 26

Review the steps of asthma treatment. Order the following indications from least to most severe usage. High dose ICS Low dose ICS SABA LABA Oral corticosteroid

Answer 26

SABA \< Low dose ICS \< LABA \< (med dose ICS) \< High dose ICS (+ omalizumab) \< Oral corticosteroid

Question 27

What are the first-line treatments for COPD?

Answer 27

Anticholinergics or beta-agonists.

Question 28

Why do anticholinergics have greater application in COPD than asthma?

Answer 28

The bronchodilatory effects are greater in COPD, because of the structural (rather than smooth muscle mediated) narrowing.

Question 29

Compare the use of ICS in COPD and Asthma. What about oral steroids?

Answer 29

ICS are first-line for asthma, but not for ICS. ICS relieves symptoms of COPD, but do not improve mortality. Oral steroids reserved for serious asthma, while COPD is generally unresponsive to oral steroids.

Question 30

What drugs, besides anticholinergics and ICS, are used to treat COPD? Give examples for each class.

Answer 30

Antibiotics (Azithromycin) Mucolytic (N-Ac to break disulfide bonds) PDE4 inhibitors (Roflumilast)

Question 31

How is cystic fibrosis treated? Is there a cure?

Answer 31

Antibiotics for the infections, bronchodilators, anti-inflammatories, as well as **Dornase and Ivacaftor\***. No, no cure. Survival rarely exceeds 30yrs of age.

Question 32

_Dornase Alpha_ What is its mechanism of action? How is it administered?

Answer 32

_Dornase Alpha_ Recombinant DNAase which breaks down DNA released by neutrophils which contributes to viscosity. This improves mucous clearance. Inhaled.

Question 33

_Ivacaftor_ What is its mechanism of action? How widely used is it?

Answer 33

_Ivacaftor_ Opens the mutated chloride transport channel. Not widely used, only 5% of mutated channels respond to it. Also very expensive.

Question 34

What major problem of delivery is associated with inhalant use? What devices help avoid this?

Answer 34

Many inhalants deposit the drug into the pharynx where it is swallowed and does not act on the lung. Spacers reduce particle velocity and size for better pulmonary direction. Dry powder inhalers also deposit less on the pharynx, as do nebulizers.

Question 35

By what routes can an inhaled drug enter systemic circulation?

Answer 35

Ingestion leading to GI absorption. Dispersal to the circulation from the lungs.