Week 2: pharmacology of respiratory system

Question 1

approach to asthma therapy: mechanism

Answer 1

• there are multiple activators of bronchial smooth muscle contraction: histamine, leukotrienes, prostaglandins, Ach, spasmogen
• using a drug that blocks just one isn’t very effective
• want a physiological antagonist: inhibit a common step in a physiologic process through which multiple agonists exert their effect

Question 2

Cellular mechanism of bronchial constriction

Answer 2

• agonist binds and causes PIP2 to IP3 conversion
• increases release of Ca2+ from SR which binds to calmodulin and activates myosin kinase
• myosin kinase phosphorylates myosin light chain, allowing myosin light chain to bind to actin for contraction

Question 3

Mechanism of b2 agonist in ashtma

Answer 3

• b agonist increase cAMP which activates protein kinase

- protein kinase inactivates myosin kinase so that it can’t phosphorylate myosin light chain

Question 4

Side effects of b2-agonists

Answer 4

• tachycardia due to b1 actions of all b2 selective agonists

- muscle spasms: b2 activates ATP to cAMP, this leads to contraction in skeletal muscle (relaxation in SM)

Question 5

Mechanism of action of glucocorticoids in asthma

Answer 5

• glucocorticoid binds to cytoplasmic receptor inside cells, translocates to nucleus and binds to a response element on gene
• activating gene transcription, can produce lipocortin, which blocks activity of phospholipase A2 (which converts phospholipids to prostaglandin and phospholipase A2)
• also increase b2 receptors
• takes hours to days to act

Question 6

glucocorticoid preparations for asthma

Answer 6

1. beclomethasone: older drug, not used as much
2. fluticasone (Advair/Flovent)
3. Budesonide (pulmicort)
4. Budesonide/formoterol (symbicort): formoterol is a LABA
   - ICS increases B2 and combined with b2 agonist can have better response

Question 7

Tiotropium (spiriva)

Answer 7

• muscarinic antagonist
• blocks parasympathetic stimulation of the lungs (which causes bronchoconstriction)
• given chronically
• acts on M3 receptors to prevent bronchospasm. Has less binding affinity for M2, so quickly dissociates and allows Ach to bind to M2 (autoreceptor feedback) so that Ach doens’t build up

Question 8

Ipratropium

Answer 8

• binds to M2 and M3 receptors
• slows down bronchospasms by binding M3
• also binds to M2 which blocks the autoreceptor feedback of Ach, so Ach continues to build up in synapse

Question 9

Montelukast (singulair)

Answer 9

• Leukotriene antagonist: blocks LTD4 receptor in all cell types activated in asthma attack
• added to b2 selective agonist and ICS as a prophylactic drug
• leukotrienes stimulate mucus secretion, bronchoconstriction, and inflammation

Question 10

Theophylline

Answer 10

• non selective inhibitor of phosphodiesterase (PDE)
• PDE4 triggers inflammation and smooth muscle contraction
• PDE inhibitor blocks the conversion of cAMP to AMP, build up of cAMP increases relaxation of SM

Question 11

Omalizumab (Xolair)

Answer 11

• monoclonal antibody that binds to IgE and prevents the IgE from binding to mast cells and basophils
• degranulation doesn’t take place and antigens that initiate asthma aren’t released

Question 12

Other drugs for COPD

Answer 12

-Roflumilast: PDE 4 inhibitor that relaxes bronchial SM by increasing cAMP

Question 13

Drugs for pulmonary HTN

Answer 13

• Bosentan (Tracleer): binds to endothelin receptors and blocks constrictive action of endothelin 1
• ambrisentan (Lentaris):
• sildenafil (viagra): PDE type 5 inhibitor that allows cAMP to increase
• Epoprostenol: prostaglandin antagonist