Medicinal Chemistry and Pharmacology of Pulmonary Disease

Question 1

Main Treatment Strategies in Asthma

Bronchodilation
(3 drug classes)

Answer 1

• B2 adrenergic agonists
• methylxanthines
• anticholinergics

Question 2

Main Treatment Strategies in Asthma

Anti-inflammation
(2 drug classes)

Answer 2

• glucocorticoids
• antileukotriene agents

Question 3

Main Treatment Strategies in Asthma

inhibition of mast cell degranulation
(2 drug classes)

Answer 3

• Cromolyn
• Omalizumab

Question 4

Main Treatment Strategies in Asthma

LABA

Answer 4

long acting beta agonists

Question 5

Main Treatment Strategies in Asthma

ICS

Answer 5

inhaled corticosteroid

Question 6

Main Treatment Strategies in Asthma

LTRA

Answer 6

leukotriene receptor antagonist

Question 7

Main Treatment Strategies in Asthma

LAMA

Answer 7

long acting muscarinic agents

Question 8

B2 adrenergic receptor agonists - sympathomimetic amines

primary activity - ___ bronchial smooth muscle
secondary activities - inhibit release of mediators from ___ cells, inhibit ___ leakage, increase microciliary ___ of mucus

Answer 8

• relax
• mast
• microvascular
• transport

Question 9

B2 adrenergic receptor agonists

LTC4 and LTD4 or histamine activate ___ pathway which causes contraction.

B2-agonists activate the ___ pathway which causes relaxation

Answer 9

• Gq
• Gs

Question 10

Selective B2- Adrenergic Agonists

SABA examples

Answer 10

albuterol (Ventolin)
levalbutoral (Xopenex)
terbutaline (Brethine)

Question 11

SABA

Answer 11

short acting beta agonist

Question 12

Selective B2- Adrenergic Agonists

T or F: albuterol has optimal B2 selectivity wheras terbutaline is more potent

Answer 12

True; terbutaline causes increased palpitations

Question 13

Selective B2- Adrenergic Agonists

LABA examples

Answer 13

formoterol
salmeterol

Question 14

SABA examples

Answer 14

albuterol
terbutaline

Question 15

SABAs are resistant to ___

Answer 15

COMT

Question 16

LABAs are resistant to ___ and ___

Answer 16

COMT and MAO

Question 17

Selective B2 - Adrenergic Agonists

T or F: salmeterol/formoterol are for acute attacks

Answer 17

False

Question 18

Selective B2- Adrenergic Agonists

• Inhaled drugs have ___ systemic adverse effects compared to oral B2 agonists
• inhaled drugs provide a ___ action on brochial smooth muscle

Answer 18

• fewer
• local

Question 19

Selective B2- Adrenergic Agonists

Regular vs. PRN dosing
* ___ for acute or anticipated attack
* __ dosing confined to oral drugs or salmeterol and formoterol (in combination with ___ only). Used morning/evening.

Answer 19

• PRN
• regular
• ICS

Question 20

Selective B2- Adrenergic Agonists

skeletal muscle ___ , palpitations, ___
* occurs less with B2 selective agents
* high doses of B2 selective agents may stimulate B1 receptors in the heart
* reflex tachycardia may occur due to vasodilation caused by B2 activation

vasodilation → decreased blood pressure → increased heart rate

Answer 20

• tremors
• tachycardia

Question 21

LABA

what 2 drugs are contraindicated as monotherapy for prevention of asthma attacks?

Answer 21

salmeterol and formoterol

monotherapy LABA increases risk of asthma related death; need ICS + LABA

Question 22

Glucocorticoids: Mechanism of Action

alter gene expression of proteins important in the ___ process
* Eosinophils, macrophages, and mast cells in the ___ epithelium and submucosa are decreased.
* Inhibit synthesis of ___ and ___.
* Decrease the ___ of bronchial smooth muscle cells that occurs in ___ asthma.

Answer 22

inflammatory
* bronchial
* prostaglandins and leukotrienes
* hyperresponsiveness, chronic

Question 23

Glucocorticoids: Clinical Use in Asthma

___ dosing reduces the frequency and severity of acute attacks in patients with chronic bronchial asthma.
* ___ weeks to experience full effects of the medication

Answer 23

daily, 4-8 weeks

Question 24

albuterol and terbutaline

• SABA inhalation onset ___ and duration ___
• SABA oral onset ___ and duration ___

Answer 24

• 5 min, 3-4 h
• 30 min, 3-8 h

Question 25

# salmeterol and formoterol -LABA * salmeterol inhalation onset ___ and duration ___ * fomoterol inhalation onset __ and duration ___

Answer 25

* >20 min, 12 h * 10 min, >12 h

Question 26

Advair

Answer 26

fluticasone + salmeterol combo

Question 27

Symbicort

Answer 27

budesonide and formoterol

Question 28

Dulera

Answer 28

mometasone and formoterol | not for acute relief of bronchial spasm. 12 yo+

Question 29

QVAR

Answer 29

beclomethasone

Question 30

Pulmicort

Answer 30

Budesonide

Question 31

# Methylxanthines - Theophylline * inhibits ___ * increases ___ levels * antagonizes bronchoconstriction produced by ___ | evidence for anti-inflammatory activity at low dose

Answer 31

* phosphodiesterase 4 (PDE4) * cAMP * adenosine

Question 32

# Anti-inflammatory actions of theophylline * ____ activation * enhances ___ of inflammatory cells * enhances anti-inflammatory effects of ___

Answer 32

* HDAC * apoptosis * glucocorticoids

Question 33

why is theophylline not commonly prescribed

Answer 33

narrow therapeutic range * Usual therapeutic range 10-15 mg/ml; start to see adverse effects at 20 mg/ml. * N/V, nervousness, abdominal discomfort, cardiac arrhythmias, hypotension, CNS stimulation, seizures, cardiac arrest

Question 34

# Theophylline: Drug Interactions/Cautions * ___ and ___ antacids delay absorption * t1/2 prolonged in patients with ___ * may aggravate pre-existing ___ disorders * 6 drugs that increase therophylline levels by competing for same CYP450:

Answer 34

* Mg2+ and Al(OH)3 * congestive heart failure * seizure * cimetidine, allopurinol, erythromycin, fluroquinolones (ciprofloxacin), propranolol, and leukotriene inhibitors

Question 35

# Degranulation of Mast Cells 1. Antigen mediated-binding of allergens to ___ antibodies bound to the cell surface releases inflammatory agents (histamine, kinins, serotonin, leukotrienes, prostaglandins) 2. Other triggers: thermal/mechanical stress, cytotoxic agents like ___, and high dose of ___

Answer 35

* IgE * venom, morphine

Question 36

# Mast Cell Degranulation Requires: 1. binding of ___ to FcER 2. binding of ___ to IgE antibodies 3. Clustering of ___ receptors 4. influx of ___ via ___

Answer 36

* IgE * antigen * FcER * Ca2+, CRAC | CRAC = Ca2+ release activated channels

Question 37

# Two Phases of Asthma Early reaction and Late reaction

Answer 37

* early reaction is allergen/mast cell/ T lymphocyte mediated * late reaction: ECP, PAF, Neutrophil proteases

Question 38

# Inhibition of Mast Degranulation Cromolyn sodium (Intal) and nedocromil sodium (Tilade) * only of value when taken ___ * stable/insoluble salts (cannot be taken __) * inhaled as a microfine powder/aerosolized solution | Reduction in symptomatic severity and bronchodilator use

Answer 38

* prophylactically * orally ## Footnote Prophylaxis of mild to moderate chronic asthma, mostly used for exercise induced asthma

Question 39

# Biologics Therapy and when to use Monoclonal antibody used to modulate biological pathways by blocking ___ or ___ * used when steps 1-5 dont work - failed ICS, leukotriene antagonists * Used for patients with frequent exacerbation

Answer 39

* receptors or cytokines

Question 40

# Asthma Phenotypes Type 2 - ___ inflammation * neutrophilic * IL-6, IL-8, IL-17 * harder to treat and more likely to have adverse events when treatments have been used Type 2 - ___ inflammation * Eosinophilic * IL-4, IL-5, and IL-13 * also - PGD2 stimulation of DP2 receptor

Answer 40

low high

Question 41

# 5 Major types of Biologics – six monoclonals 1. Omalizumab - ___ antagonist 2. Reslizumab and Mepolizumab - ___ pathway 3. Benralizumab - ___ alpha receptor 4. Dupilumab - ___ receptor alpha antagonist - affects both ___ and ___ pathway 5. Tezepelumab - ___ stromal lymphopoietin

Answer 41

* IgE * IL-5 * IL-5 * IL-4, IL-4, IL-13 * thymic | all are approved for type 2 high inflammation

Question 42

# Omalizumab (Xolair) inhibition of ___ * humanized mouse anti-human ___ * >___ yo with moderate+ asthma and unresponsive to inhaled ___ * One injection every ___ weeks * Causes a ___% reduction in free IgE levels.

Answer 42

* IgE * 12, steroids * 2-4 * 96%

Question 43

# Inhibition of Eosinophils - Interleukin 5 pathway IL-5 - ___ and ___ of eosinophils * Mepolizumab and Reslizumab

Answer 43

recruitment and maturation

Question 44

# Inhibition of two pathways - Interleukin 4 alpha receptor Dupilumab (Dupixent) * IL-4 alpha chain is involved in signalling for both IL-4 and ____ * used of persistent asthma * self administered * also used for atopic dermatitis and rhinosinusitis * side effects - increase ___ levels and rare conjunctivits

Answer 44

IL-13 bloody eosinophils

Question 45

# Inhibition of Interleukin 5 alpha receptor Benralizumab (Fasenra) * Severe Eosinophilic Asthma Treatment * Binds to IL-5 receptor (IL-5R) and blocks IL-5 * inhibits differentiation and maturation of ___ in the bone marrow

Answer 45

eosinophils

Question 46

# Thymic stromal lymphopoietin (TSLP) Tezepelumab (Tezspire) * targets TSLP, an epithelial ___ for severe asthma (12+ yo) * decrease ___ and T2 independent inflammation * Inhibits differentiation and maturation of ___ in the bone marrow * One fixed dose – prefilled syringe every ___ weeks by a physician

Answer 46

* cytokine * T2 * eosinophils * 4

Question 47

# Inhibition of Eosinophils DP2 - prostaglandin receptor antagonist Fevipiprant (Novartis) – Failed in Phase III clinical trials ___ is produced primarily from IgE activated mast cells and promotes activation and migration of eosinophils, Th2 lymphocytes, and basophils through activation of the DP2 receptor

Answer 47

PGD2

Question 48

# 5-Lipoxygenase Oxygenation of Arachidonate Lipoxygenase pathways for the formation of ___

Answer 48

leukotrienes

Question 49

# Leukotriene Inhibitors - Zileuton * inhibitor of 5-lipoxygenase and thus inhibits the synthesis of ___, ___, and ___ * decreases ___ stage asthma symptoms * not reccomneded for acute asthma attack * prophylaxis and treatment of chronic asthma

Answer 49

* LTB4, LTC4, LTD4 | LTB4 – potent chemotactic agent

Question 50

# Zileuton Adverse Effects * metabolized by ___ * doubles the blood levels of ___ and causes an increase in prothrombin time if patients taking ___ * some incidents of liver toxicity

Answer 50

* CYP450 * theophylline, warfarin

Question 51

Zafirlukast (Accolate) and Montelukast sodium (Singulair) - Selective and competitive inhibitors of the ___ receptor. Inhibit the late phase of ____ * Prescribing description is to dose in the evening – to counter increased ___ synthesis in the evening * do not take with food (decreased ___)

Answer 51

* CysLT-1 * bronchoconstriction * leukotriene * bioavailability | Should not be abruptly substituted for inhaled or oral corticosteroids.

Question 52

# Drugs to treat COPD * Bronchodilators are the first-line treatment * ___ used for patients with exacerbations and high eosinophil counts * used as needed: ___ and ___ * if regular use is required: ___ and ___ * Rare - a1-___ replacement

Answer 52

* ICS * SABA, SAMA * LAMA, LABA * antitrypsin

Question 53

# Muscarinic Antagonists Competitively inhibit muscarinic receptors in the lung Examples: SAMA - ___ LAMA - ___ | Both are quaternary ammonium compounds to limit systemic absorption

Answer 53

* ipratropium (Altrovent) * tiotropium (Spiriva)

Question 54

# Clinical Use of Ipratropium and Tiotropium - dosing Ipratropium dosing: ___ Tiotropium dosing: ___

Answer 54

* tid/qid (SAMA) * qd (LAMA) | PRN dosing is not used in contrast to SABAs

Question 55

# Recent anti-Muscarinic LAMA - Seebri BID LAMA * (FDA) has approved Seebri Neohaler (____) inhalation powder 15.6 mcg as a stand-alone monotherapy for COPD. * inhalation dose much lower than oral use dose * random: 1st drug approved to treat excessive ___

Answer 55

glycopyrrolate sweating

Question 56

# Long-acting B2-adrenergic agonists T or F: Mono-therapy with LABAs is NOT contraindicated in COPD

Answer 56

True

Question 57

# Remodeling in COPD * ___ of small airways * ___inflation of lungs * alveolar ___ and ___ destruction * mucus ___ * genetic deficiency of ___

Answer 57

* fibrosis * hyperinflation * enlargement, wall * hypersecretion * a1-anti-trypsin

Question 58

# a1-antitrypsin Replacement Therapy leads to excessive ___ damage to lung tissue (uninhibited ___ and ___)

Answer 58

proteolytic, MMP9, elastase | less than 1% of COPD patients have this genetic deficiency

Question 59

# Drugs to Treat Cystic Fibrosis Ivacaftor (Kalydeco) - CFTR regulator * BID * For CF patients 4 months or older with ___mutations in ___

Answer 59

gating, CFTR

Question 60

Small molecule chaperones for DeltaF508 CFTR – lumaftor, tezacaftor and elexacaftor * ___ – a combination of Lumacaftor and ivacaftor. Lumacaftor not approved as a monotherapy * ___ - Tezacaftor combination with Ivacaftor * ___ – Elexacaftor, tezacaftor and ivacaftor (Newest_

Answer 60

Orkambi Symdeco Trikafta

Question 61

# Drugs to Treat Cystic Fibrosis Pancreatic Enzyme Products * ___ mucus obstructs pancreatic enzyme floww * PERT: ____ * ___ - derived from porcine pancreatic glands | Dose is individualized based on stool behavior

Answer 61

* thick * pancreatic enzyme replacement therapy * pancrelipase

Question 62

# Loss of CFTR function in airway epithelium Dehydration of airway surface liquid causes thickening of mucus. CFTR function inhibits ENaC-mediated Na+ influx. When this is broken = greater influx of Na+ and water (less water in mucus)

Answer 62

Question 63

# Pulmonary Targets Summary Asthma

Answer 63

* Bronchodilation * Anti-inflammation * Inhibition of Mast cell * Inhibition of eosinophilia

Question 64

# Pulmonary Targets Summary COPD

Answer 64

* bronchodilation - muscarinic receptor and adrenergic receptor based * Protease inhibitor strategy

Question 65

# Pulmonary Targets Summary CF

Answer 65

* protein folding/channel correctors * mucus treatment and pancreatic enzyme (PERT) * bronchodilation and antibiotics