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PHRM 825 > Medicinal Chemistry and Pharmacology of Pulmonary Disease > Flashcards

Medicinal Chemistry and Pharmacology of Pulmonary Disease Flashcards

1
Q

Main Treatment Strategies in Asthma

Bronchodilation
(3 drug classes)

A
  • B2 adrenergic agonists
  • methylxanthines
  • anticholinergics
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2
Q

Main Treatment Strategies in Asthma

Anti-inflammation
(2 drug classes)

A
  • glucocorticoids
  • antileukotriene agents
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3
Q

Main Treatment Strategies in Asthma

inhibition of mast cell degranulation
(2 drug classes)

A
  • Cromolyn
  • Omalizumab
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4
Q

Main Treatment Strategies in Asthma

LABA

A

long acting beta agonists

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5
Q

Main Treatment Strategies in Asthma

ICS

A

inhaled corticosteroid

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6
Q

Main Treatment Strategies in Asthma

LTRA

A

leukotriene receptor antagonist

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7
Q

Main Treatment Strategies in Asthma

LAMA

A

long acting muscarinic agents

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8
Q

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

A
  • relax
  • mast
  • microvascular
  • transport
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9
Q

B2 adrenergic receptor agonists

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

B2-agonists activate the ___ pathway which causes relaxation

A
  • Gq
  • Gs
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10
Q

Selective B2- Adrenergic Agonists

SABA examples

A

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

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11
Q

SABA

A

short acting beta agonist

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12
Q

Selective B2- Adrenergic Agonists

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

A

True; terbutaline causes increased palpitations

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13
Q

Selective B2- Adrenergic Agonists

LABA examples

A

formoterol
salmeterol

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14
Q

SABA examples

A

albuterol
terbutaline

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15
Q

SABAs are resistant to ___

A

COMT

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16
Q

LABAs are resistant to ___ and ___

A

COMT and MAO

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17
Q

Selective B2 - Adrenergic Agonists

T or F: salmeterol/formoterol are for acute attacks

A

False

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18
Q

Selective B2- Adrenergic Agonists

  • Inhaled drugs have ___ systemic adverse effects compared to oral B2 agonists
  • inhaled drugs provide a ___ action on brochial smooth muscle
A
  • fewer
  • local
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19
Q

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.

A
  • PRN
  • regular
  • ICS
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20
Q

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

A
  • tremors
  • tachycardia
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21
Q

LABA

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

A

salmeterol and formoterol

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

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22
Q

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.

A

inflammatory
* bronchial
* prostaglandins and leukotrienes
* hyperresponsiveness, chronic

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23
Q

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

A

daily, 4-8 weeks

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24
Q

albuterol and terbutaline

  • SABA inhalation onset ___ and duration ___
  • SABA oral onset ___ and duration ___
A
  • 5 min, 3-4 h
  • 30 min, 3-8 h
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25
Q

salmeterol and formoterol -LABA

  • salmeterol inhalation onset ___ and duration ___
  • fomoterol inhalation onset __ and duration ___
A
  • > 20 min, 12 h
  • 10 min, >12 h
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26
Q

Advair

A

fluticasone + salmeterol combo

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27
Q

Symbicort

A

budesonide and formoterol

28
Q

Dulera

A

mometasone and formoterol

not for acute relief of bronchial spasm. 12 yo+

29
Q

QVAR

A

beclomethasone

30
Q

Pulmicort

A

Budesonide

31
Q

Methylxanthines - Theophylline

  • inhibits ___
  • increases ___ levels
  • antagonizes bronchoconstriction produced by ___

evidence for anti-inflammatory activity at low dose

A
  • phosphodiesterase 4 (PDE4)
  • cAMP
  • adenosine
32
Q

Anti-inflammatory actions of theophylline

  • ____ activation
  • enhances ___ of inflammatory cells
  • enhances anti-inflammatory effects of ___
A
  • HDAC
  • apoptosis
  • glucocorticoids
33
Q

why is theophylline not commonly prescribed

A

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

34
Q

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:
A
  • Mg2+ and Al(OH)3
  • congestive heart failure
  • seizure
  • cimetidine, allopurinol, erythromycin, fluroquinolones (ciprofloxacin), propranolol, and leukotriene inhibitors
35
Q

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 ___
A
  • IgE
  • venom, morphine
36
Q

Mast Cell Degranulation Requires:

  1. binding of ___ to FcER
  2. binding of ___ to IgE antibodies
  3. Clustering of ___ receptors
  4. influx of ___ via ___
A
  • IgE
  • antigen
  • FcER
  • Ca2+, CRAC

CRAC = Ca2+ release activated channels

37
Q

Two Phases of Asthma

Early reaction and Late reaction

A
  • early reaction is allergen/mast cell/ T lymphocyte mediated
  • late reaction: ECP, PAF, Neutrophil proteases
38
Q

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

A
  • prophylactically
  • orally

Prophylaxis of mild to moderate chronic asthma, mostly used for exercise induced asthma

39
Q

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

A
  • receptors or cytokines
40
Q

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

41
Q

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
A
  • IgE
  • IL-5
  • IL-5
  • IL-4, IL-4, IL-13
  • thymic

all are approved for type 2 high inflammation

42
Q

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.

A
  • IgE
  • 12, steroids
  • 2-4
  • 96%
43
Q

Inhibition of Eosinophils - Interleukin 5 pathway

IL-5 - ___ and ___ of eosinophils
* Mepolizumab and Reslizumab

A

recruitment and maturation

44
Q

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

A

IL-13
bloody eosinophils

45
Q

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

A

eosinophils

46
Q

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

A
  • cytokine
  • T2
  • eosinophils
  • 4
47
Q

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

48
Q

5-Lipoxygenase Oxygenation of Arachidonate

Lipoxygenase pathways for
the formation of ___

A

leukotrienes

49
Q

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
A
  • LTB4, LTC4, LTD4

LTB4 – potent chemotactic agent

50
Q

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
A
  • CYP450
  • theophylline, warfarin
51
Q

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 ___)

A
  • CysLT-1
  • bronchoconstriction
  • leukotriene
  • bioavailability

Should not be abruptly substituted for inhaled or oral corticosteroids.

52
Q

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
A
  • ICS
  • SABA, SAMA
  • LAMA, LABA
  • antitrypsin
53
Q

Muscarinic Antagonists

Competitively inhibit muscarinic receptors in the lung
Examples: SAMA - ___ LAMA - ___

Both are quaternary ammonium compounds to limit systemic absorption

A
  • ipratropium (Altrovent)
  • tiotropium (Spiriva)
54
Q

Clinical Use of Ipratropium and Tiotropium - dosing

Ipratropium dosing: ___
Tiotropium dosing: ___

A
  • tid/qid (SAMA)
  • qd (LAMA)

PRN dosing is not used in contrast to SABAs

55
Q

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 ___

A

glycopyrrolate
sweating

56
Q

Long-acting B2-adrenergic agonists

T or F: Mono-therapy with LABAs is NOT contraindicated in COPD

57
Q

Remodeling in COPD

  • ___ of small airways
  • ___inflation of lungs
  • alveolar ___ and ___ destruction
  • mucus ___
  • genetic deficiency of ___
A
  • fibrosis
  • hyperinflation
  • enlargement, wall
  • hypersecretion
  • a1-anti-trypsin
58
Q

a1-antitrypsin Replacement Therapy

leads to excessive ___ damage to lung tissue (uninhibited ___ and ___)

A

proteolytic, MMP9, elastase

less than 1% of COPD patients have this genetic deficiency

59
Q

Drugs to Treat Cystic Fibrosis

Ivacaftor (Kalydeco) - CFTR regulator
* BID
* For CF patients 4 months or older with ___mutations in ___

A

gating, CFTR

60
Q

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_

A

Orkambi
Symdeco
Trikafta

61
Q

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

A
  • thick
  • pancreatic enzyme replacement therapy
  • pancrelipase
62
Q

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)

63
Q

Pulmonary Targets Summary

Asthma

A
  • Bronchodilation
  • Anti-inflammation
  • Inhibition of Mast cell
  • Inhibition of eosinophilia
64
Q

Pulmonary Targets Summary

COPD

A
  • bronchodilation - muscarinic receptor and adrenergic receptor based
  • Protease inhibitor strategy
65
Q

Pulmonary Targets Summary

CF

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

PHRM 825 (49 decks)

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