Pharmacology of respiratory system

Question 1

Drugs for asthma

Answer 1

• Want to stop inflammation, constriction, and mucosecretion
• Because there are many compounds that initiate asthma attacks, we cannot block all of them from binding
• So we want physiologic antagonist, one that works downstream of receptor binding and can block a common pathway
• Physiologic antagonists include B2 agonists and theophylline

Question 2

Bronchoconstriction pathway

Answer 2

• Various agonists (Ach, histamine, leukotrienes, PGs, spasmogen) bind to their receptors and cause the conversion of PIP2 to IP3
• IP3 causes release of Ca from SR, the Ca binds to calmodulin and the Ca-calmodulin complex activates myosin kinase
• Activated myosin kinase phosphorylates myosin light chain (MLC) to pMLC which binds to actin and causes contraction of smooth muscle-> bronchoconstriction
• To stop this pathway we can use B2 agonist, which increases intracellular cAMP to activate protein kinases to phosphorlyate active myosin kinase and inactivate it
• Therefore we can stop the pathway where it is common

Question 3

Side effects of B2 agonists

Answer 3

• B/c B2 selective agonists have a higher affinity for B2 receptors, they don’t activate B1 receptors until the concentration is high enough
• They still can cause some tachycardia (due to some binding to B1, and thru binding to B2 in vessels-> vasodilation-> cardiac reflex)
• B2 agonists do the opposite to skeletal muscle than they do to smooth muscle
• That is, they can cause muscle spasms due to the increased cAMP in skeletal muscle

Question 4

Types of B2 agonists

Answer 4

• Short acting (SABA): albuterol

- Long acting (LABA): formoterol, salmeterol

Question 5

Glucocorticoids in asthma

Answer 5

• Used to control inflammaiton, the lipid soluble steroids diffuse thru membranes to bind to the cytoplasmic receptors
• Once bound, the complex moves to the nucleus where it alters transcription/translation by binding to a response element
• One of the genes that glucocorticoids activate is lipocortin, which blocks the activity of phospholipase A2
• Phospholipase A2 produces arachidonic acid which is used to make PGs and LTs, thus blocking the formation of arachidonic acid will limit inflammation
• Since these effects take hours to days they are not beneficial for treating asthma attacks

Question 6

Other benefits to glucocorticoids in asthma

Answer 6

• Besides decreasing inflammation, they also decrease mucus secretion
• Most importantly, they up regulate B2 receptors
• This means that SABAs/LABAs used in conjunction w/ GCCs will be more effective b/c there are more receptors for those drugs to activate

Question 7

Types of glucocorticoids used in asthma

Answer 7

• Fluticasone

- Budesonide

Question 8

Acetylcholine in asthma

Answer 8

• Cholinergic nerve terminals release Ach which can bind to M3 receptors on mucus secreting gland and airway smooth muscle cell
• This would cause increased mucus secretion and bronchoconstriction
• There are also M2 receptors on the nerve terminal (auto receptors), which can bind Ach and causes decreased release of Ach
• Tiotropium is a muscarinic antagonist that works mostly on just M3, leading to reduced bronchoconstriction and mucus production
• Tiotropium doesn’t have high affinity for M2, allowing Ach to bind to M2 and further decrease Ach release

Question 9

Leukotriene antagonists

Answer 9

• LTs are the most potent asthma stimulators (cause bronchoconstriction, mucus secretion, and inflammation)
• Montelukast blocks the LTD4 receptor to prevent these Sxs, and is used in combination w/ GCCs and B2As
• Tiotropium and Montelukast are effective in some pts but not others
• This is b/c their effectiveness depends on the base level of Ach and LTs
• If the base level of these are low the drugs won’t have much of an effect
• If the base level is high these drugs will have a large effect

Question 10

Theophylline

Answer 10

• PDE3 inhibitor that prevents the breakdown of cAMP
• This helps keep a high level of cAMP to keep myosin kinase inactivated
• This is also helpful b/c the increased cAMP in skeletal muscle causes them to contract
• This drug is useful in helping fatigued respiratory muscle contract

Question 11

Omalizumab

Answer 11

-Monoclonal Ab against IgE that prevents IgE from binding to mast cells and basophils so degranulation doesn’t take place

Question 12

Drugs for COPD

Answer 12

• Many of the asthma drugs are used for COPD

- Roflumilast is a specific PDE4 inhibitor that relaxes bronchial smooth muscle

Question 13

Pulmonary HTN

Answer 13

• Bosentan binds to endothelin receptors and blocks the smooth muscle constriction induced by endothelia (leads to relaxation)
• Ambrisentan is a PDE5 inhibitor that relaxes smooth muscle
• Epoprostenol is a prostaglandin inhibitor