MedChem of Asthma, COPD, and Cystic Fibrosis

Question 1

Outline the 6 steps of the stepwise approach to treatment of asthma.

Answer 1

(1) SABA prn
(2) low-dose ICS (or cromolyn, LTRA, theophylline)
(3) low-dose ICS + LABA (or others)
(4) medium-dose ICS + LABA
(5) high-dose ICS + LABA, consider Xolair
(6) high-dose ICS + LABA, oral CS, consider Xolair

Question 2

Describe the biochemical mechanism for bronchial smooth muscle relaxation induce by beta-2 agonists.

Answer 2

Beta adrenergic receptors activate cytoplasmic G-proteins, which ultimately increase intracellular cAMP levels. cAMP activates protein kinase A. PKA, then, phosphorylates a myosin LC kinase that normally allows smooth muscle contraction by phosphorylating myosin. Myosin is now not properly oriented for contraction, and the smooth muscle will relax.

Question 3

Which two examples of SABAs were given in lecture?

Answer 3

albuterol and terbutaline

Question 4

Of the two SABAs, which is more beta-2 selective? What is the consequence of this?

Answer 4

terbutaline, causes increased palpitations

Question 5

Name three LABAs.

Answer 5

formoterol (Foradil), Arformoterol (Brovana), and Salmeterol (Serevent)

Question 6

Which LABAs have the greatest beta-2 selectivity?

Answer 6

formoterol and arformoterol

Question 7

SABAs are resistant to metabolism by ______, while LABAs are resistant to ________ and ________.

Answer 7

COMT, COMT, MAO

Question 8

Of the beta-agonists, which are confined to use for regular dosing?

Answer 8

the LABAs, (ar)formoterol and salmeterol

Question 9

Between the two LABAs, _______ has the quicker onset of action due to its increased ________. Its decreased _________ keeps it in the lungs longer.

Answer 9

formoterol, hydrophilicity (allows it to get to receptor sites faster), lipophilicity

Question 10

Outside of use for EIA, what is the suggested weekly limit for SABA use?

Answer 10

no more than 2x/week, not including EIA use

Question 11

List three of the main effects of inhaled glucocorticoids.

Answer 11

(1) decr. eosinophils, macrophages, mast cells
(2) inhibition of leukotriene/prostaglandin synthesis
(3) decreased airway hyperresponsiveness

Question 12

How often are inhaled glucocorticoids dosed?

Answer 12

once daily

Question 13

What are the three inhaled glucocorticoids mentioned in lecture?

Answer 13

fluticasone, budesonide, mometasone

Question 14

Outline the biochemical mechanism of action of methylxanthines.

Answer 14

There are two ways by which methylxanthines cause bronchodilation. The first is by inhibition of PDE4, which normally hydrolyzes cAMP intracellularly. cAMP levels are increased by this effect, and relaxation occurs by the same mechanism as with beta agonists. Methylxanthines also block the adenosine receptor, paired with Gq. The normal signaling cascade that follows increased intracellular calcium, allowing smooth muscle contraction. This is now blocked.

Question 15

Why is theophylline use becoming less common in practice?

Answer 15

has a very narrow therapeutic range, more extensive adverse effect profile

Question 16

theophylline drug interactions/precautions

Answer 16

(1) magnesium/aluminum will delay absorption
(2) half-life prolonged in CHF patients
(3) may aggravate pre-existing seizure disorders
(4) monitor for agents metabolized by P450

Question 17

What are some stimulants that can cause degranulation of mast cells?

Answer 17

(1) antigens
(2) thermal/mechanical stress
(3) venoms
(4) various drugs, like high dose morphine

Question 18

Degranulation is mediated by _____ antibodies and requires that they be bound to the ______ receptor on the surface of mast cells.

Answer 18

IgE, FCεR

Question 19

What are the three primary mediators of the late phase reaction of asthma?

Answer 19

eosinophils cationic protein (ECP)
platelet activating factor (PAF)
neutrophil proteases

Question 20

Cromolyn salts are only useful in the treatment of asthma when taken _____________.

Answer 20

prophylactically

Question 21

T or F: The cromolyn salts are stable but extremely insoluble, and therefore must be taken via inhalation rather than orally.

Answer 21

True

Question 22

How frequently is cromolyn taken in asthma prophylaxis?

Answer 22

daily

Question 23

What are the side effects of inhaled cromolyn?

Answer 23

very well tolerated drug, few side effects that are minor and local

Question 24

How does omalizumab (Xolair) prevent mast cell degranulation?

Answer 24

It is a humanized mouse anti-human anti-IgE antibody. It binds IgE and prevents the necessary binding to FCεR1 receptors on mast cells.

Question 25

Xolair carries a boxed warning for _________.

Answer 25

anaphylaxis

Question 26

To what class does Zileuton belong? What is its role in the treatment of asthma?

Answer 26

selective inhibition of 5-lipoxygenase (decreases leukotriene production)

It is, like cromolyn, a prophylactic drug used in prevention of asthma attacks in chronic asthma patients.

Question 27

Zileuton is metabolized by P450. Because of this fact, which drug must we be cautious of another drug used to treat asthma, ________.

Answer 27

theophylline

Zileuton doubles the blood levels of theophylline due to competition for P450.

Question 28

What other therapy monitoring is necessary for patients taking Zileuton?

Answer 28

warfarin

Zileuton increases prothrombin time.

Question 29

What are the most common side effects noted with Zileuton?

Answer 29

headache, dyspepsia, some cases of liver toxicity

Question 30

In addition to blocking their production, you can block leukotrienes at the receptor site as well. Which receptor are we talking about, and which two drugs currently on the market do this?

Answer 30

CysLT-1 receptor (cysteine leukotriene 1)

Monelukast (Singulair) and Zariflukast (Accolate)

Question 31

Do leukotriene modifiers mainly inhibit the early or the late phase of bronchoconstriction?

Answer 31

late phase

Remember, they are prophylactic drugs with no acute use. Also, leukotrienes do not play a role in the early phase of asthma bronchoconstriction, which is mediated by mast cells (histamine).

Question 32

What is the biochemical mechanism by which CysLT-1 inhibitors inhibit bronchoconstriction?

Answer 32

It is the similar to one of the mechanisms used by methylxanthines, but at a different receptor. Like the adenosine receptor blocked by methylxanthines, the leukotriene receptor is couple to Gq. Inhibition, therefore, reduces intracellular calcium and prevents smooth muscle contraction.

Question 33

Which four classes of drugs are used to treat COPD? (#4 is only for a rare form of COPD)

Answer 33

(1) LAMA
(2) LABA
(3) SABA
(4) alpha-1 antitrypsin replacement

Question 34

Two LAMAs were given. What are they, and how do they differ in their duration of action?

Answer 34

Ipratropium (Atrovent, short acting) and Tiotropium (Spiriva, long acting)

Question 35

Describe the biochemical mechanism of action of LAMAs.

Answer 35

As seen with methylxanthines, and leukotriene receptor antagonists, a Gq coupled receptor is blocked (the Ach receptor). Intracellular calcium is decreased, and contraction is inhibited.

Question 36

What structural aspect of the LAMAs keeps them localized in the lungs?

Answer 36

quaternary ammonium salt prevents systemic absorption

Question 37

What is the newest LAMA approved for use in COPD patients?

Answer 37

Seebri (glycopyrollate)

Question 38

Describe the difference in use of LABAs in COPD vs. asthma patients.

Answer 38

LABAs are not contraindicated as mono therapy in COPD patients, as they are in asthma treatment.

Question 39

What are three examples of LABAs used in treatment of COPD?

Answer 39

salmeterol, formoterol, indacaterol (Arcapta)

Question 40

Ivacaftor (Kalydeco)

use, patients who can use it, dosing frequency

Answer 40

CFTR potentiator used in the treatment of CF, only for patients with certain mutations of CFTR, taken orally BID

Question 41

What are three other classes of drugs often used in the treatment of CF?

Answer 41

(1) mucolytics
(2) bronchodilators
(3) antibiotics