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Pharmacotherapy 1 > 3 - Asthma Pathophys and Medchem > Flashcards

3 - Asthma Pathophys and Medchem Flashcards

1
Q

***Explain the pathogenesis of asthma, in terms of triggers and physiological response.

A

early:
1. ANTIGEN binding to IgE –> histamine, tryptase, LTC4, LTD4, PGs from ***MAST CELLS
2. bonrchoconstriction, vascular leakage

delayed 2-8 hr:

  1. sustained bronchoconstriction
  2. TH2 activ’d: **release GM-CSF, **IL4/5/13
  3. mucus hypersecr (goblet)
  4. infiltration by eosinophils
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2
Q

***Explain the role of goblet cells in the pathogenesis of asthma.

A

hypersecretion of mucus in the late/chonic stage.

(cytokines) EGFR and CLCA promote the development of goblet cell hyperplasia and Bcl-2 maintains hyperplasia.

This is a result of the TH2 response.

neutrophils release proteinases–>inflamm–>remodelling

Q576R polymorphism in the IL-4alphaR causes enhanced repsonse to IL-13. AA at increased risk (50% prev of R576). –> antigen hyperreactivity

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3
Q

***Explain why the b2-adrenergic agonists are the drugs of choice for acute asthma attacks. What effects do these drugs have on the respiratory system of the asthmatic patient?

A

bronchodilation! SABAs have quick onset of action.

activate Gs to result in relaxation (leukotrienes and histamine activate Gq, activating myosin LC kinase and resulting in contraction)

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4
Q

***List the effects of theophylline on the respiratory system and other systems. Describe the relationship of these effects to the therapeutic use and adverse effects.

A

*PDE4 inhibition–> increases duration of cAMP effects (relaxation) after beta-2 stimulation.

also adenosine antagoist-blocks receptor. decr in Gq pathways (PLC, Ca, myosin LC kinsase activation and decr’d SM contraction)

also evidence for anti-inflamm activity at low dose:
HDAC activation
enhanced apoptopsis of inflamm cells
decr cyotkine release by inflamm cells

low doses enhance GC activity 
----------
therapeutic range 10-15 mcg/mL
20 mcg - N/V, nervousness, ad discomfot
>25 mcg/mL--arrhythmias, hypoTN, CNS stim
40-100 mcg/mL--Sz, CV arrest
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5
Q

***Explain the rationale for the use of glucocorticoids in the treatment of asthma and the advantage of using inhaled doses over daily oral doses.

A

alter gene expression of proteins po for the inflammx process. (stim lipocortin–>inhib PLA)

decr eosinophils, macrophages, and mast cells in the bronchial epithelium and submosa

inhib synth of PGs and leukotrienes

**decr hyperrresponsiveness of bronchial SM cells that occurs in chronic asthma.

*daily use decr freq and sev of acute attacks

decr systemi cSEss

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6
Q

***Explain the rationale for the use of Cromolyn in the treatment of asthma and compare this rationale with that of b2 adrenergic agonists

A

when taken prophylactically, cromolyn or nedocromil sodium (micropowder bc insoluble) reduce symp sev and freq and bronchodilator use.

daily dosing
decr # and sev of attacks
blocks bronchoconstr caused by antigen inh, exercise, ASA, and toxins 
well-tolerated 
adults-MDI; children-1% aerosol soln
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7
Q

***Explain the mechanism of action of omalizumab, and the rationale for it’s therapeutic use.

A

inhibits binding of igE to FcepsilonR1 on mast cells and basophils. —> inhibi mast cell degranulation. decr inflamm. decr freq and sev of attacks.

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8
Q

***Explain the differences between the mechanisms of action of the antileukotrienes.

A

–> targetting leukotrienes is targetting late-stage of asthma

Zileuton: inhibits 5-lipogenase (inhib syn of LTB4, LTC4, and LTD4)

Zafirlukast/Montelukast: competitive inhib of CysLT-1R: inhibit late-phase bronchoconstriction

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9
Q

Explain why Ipratropium and tiotropium have some use in treating bronchoconstriction (mechanism?).
***

A

comp inh muscarinic R. (ACh, Gq, myosin LC kinase) –> bronchodilation.

quaternary ammonium –> limit systemic abs

**tio has higher affinity and more selective for M1 and M3 receptors, longer doa. structurally, it has 2 bicyclic 2-containing rings while ipra only has 1 phenyl

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10
Q

Recognize distinct classes of drugs used to treat asthma by their chemical structures.**

A

be able to recognize but not in great detail.

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11
Q

Propose and justify novel strategies for the treatment of asthma**

A

Nucala–humanized anti-IL5 antibody –> reduce levels of eosinophils –> reduce servere asthma attcks

Tralokinumab (phase III asthma)–> anti-IL-13 mab .

Cinquair (lebrikizumab)–> anti-IL-13

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12
Q

Explain the mechanism of action of drugs used to treat COPD.***

A

inh’d AMAs
LABAs
SABAs

–> bronchodilation

alpha1-antitrypsin replacement (rare)–> decr proteolytic damage (MMP9 and elastase) to lung tissue

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13
Q

Explain the pathogenesis of cystic fibrosis (CF), and how it affects lung function.
*****

A

autosomal recessive – mutation in CFTCR (transmembrane conductance regulator), ABC transporter. Cl- channel, gated by PKA phos of R domain.

expr’d in airways, sweat duct, pancreatic duct epithelium.

secrete viscous mucus that obstructs airways, habors pathogens –> lung infx, obstructs pancreatic duct and interferes w digestion

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14
Q

Explain the mechanism of action of drugs that are currently used to improve lung function in CF, as well as new, genotype-specific, drugs that are under development. **

A

Ivacaftor (Kalydeco)–> CFTR regulator: potentiates Cl- current through CFTR in response to cAMP (G551D)

mucolytics: DNAse, N-acetylcystine (open dislfide linkages), hypertonic saline
bronchodilator: albuterol

Abx: tobramycin, azithromycin

ataluren–suppressure premature stop codons

**VX-809 –chapterone for deltaF508 CFTR (corrector–defective CFTR processing, does not get to surface)

bronchitol –inhaled manitol–rehydrate mucus

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15
Q

Describe the role or periostin in asthma pathogenesis.

A

ECM protein induced by IL-13 and IL-4. ligand for alpha-beta itegrins to support adhesion and cell migration –> give immune cells a path to follow

–> promote chornic allergic inflammx in response to TH2 cytokines

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16
Q

Describe airway remodelling in asthma.

A

epithelium-mucuous hperplasia and hypersecretion

BM thickes

SM hyperthropies

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17
Q

Describe airway remodelling in asthma.

A

epithelium-mucuous hperplasia and hypersecretion

BM thickens

SM hyperthropies

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18
Q

What is periostin?

A

matrix protein biomarker

it’s release causes problems

used as a biomarker for epithelium IL-13 activation

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19
Q

Describe remodelling in COPD.

A

fibrosis of small airways

hyperinflation of lungs: alveolar enlarement and wall destruction

mucus hypersecrtion

**genetic deficiency in alpha1-anti-trypsin

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20
Q

How does fibrosis occur in COPD?

A

particles–>epithelial cells release TGFbeta–>fibroblast–> fibrosis

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21
Q

How does emphysema (alveolar wall destruction) occur in COPD?

A

particulates–> activate marcophage (enhanced by epithelial cell cytokines) –> activate Tc1 cells and proteases (nuetorphil elastias and MMP9)

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22
Q

How does mucus hypersecretion occur in COPD?

A

particulates –> actovate macrophage–> activate neutrophils –> proteases increase mucus (??)

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23
Q

How does mucus hypersecretion occur in COPD?

A

particulates –> actovate macrophage–> activate neutrophils –> proteases increase mucus (??)

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24
Q

Describe alpha1-anti-trypsin and its alleles.

A

alpha-1 antitrypsin inhibitis neutrophil elastase and limits lung tissue damage

inhertied disorer with 1/2000 freqency commonly found in N Europe.

ZZ–> clinical disadvantgeous lung fxn

MZ: incr’d height and resp fxn

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25
Q

C/C asthma and COPD cell types

A

fibrosis: greater in COPD, peribronchiolar (asthma subepithelial)

alveolar disruption in COPD only

mast cells incr’d and activated in asthma only

eosinophils incr’d in asthma only

neutrophils increased in COPD only

lymphocytes: TH2 in asthma, TH1 and TC1 in COPD.

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26
Q

Explain the effects of loss of CFTR fxn in the sweat duct epithelium.

A

increased NaCl conc in sweat. (lose Na gradient for ENac). neither Na or Cl is abs’d from the lumen.

–> salty sweat is cardinal sign of CF.

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27
Q

***C/C COPD and asthma

A 
COPD: late adulthood onset
3rd leading cause of death in US 
85% d/t smoking
chronically symptomatic
progressive
emphysema + chronic bronchitis

asthma:
childhood onset
triggers
episodic

28
Q

Explain the effects of CFTR fxn loss in the airway epithelium.

A

CFRR fxn inhibitrs ENaC-mediated Na+ influx.

Incr’d ENaC activity -> increases H2O uptake into epithelial cells, dehydrating mucus.

dehydration of airway surface liquid –> thickens mucus.
(ASL = periciliary layer and mucus)

CaCC=Ca2_ activated Cl- channel

29
Q

What are tx stragies of asthma?

A

bronchodilation
anti-inflammation
inhibition of mast cell degradnulation

30
Q

What drug classes are used for bronchodilation in asthma?

A

beta2 ag
methylxanthines
anticholinergics

31
Q

What drug classes are used for anti-inflammx in asthma?

A

clucocorticoids

antileukotriene agents

32
Q

What drug classes are used to inhibit mast cell degranulation?

A

cromolyn-type drugs

omalizumab (Xolair)

33
Q

***C/C asthma and COPD cell types

A

fibrosis: greater in COPD, peribronchiolar (asthma subepithelial)

alveolar disruption in COPD only

mast cells incr’d and activated in asthma only

eosinophils incr’d in asthma only

neutrophils increased in COPD only

lymphocytes: TH2 in asthma, TH1 and TC1 in COPD.

34
Q

What are the activities of sympathomimetic amines in asthma?

A
  1. bronchorelax

2. inhibit mast cell degran, inhib microvascular leakage, incr microciliary transport of mucus.

35
Q

What is the molecular action of beat-2 agonists?

A

Gs –> AC –> cAMP –> PKA –> PLCK(PO4)2 –> RELAXATION

36
Q

What is the molecular action of beta-2 agonists in respiratory dz? leucko

A

Gs –> AC –> cAMP –> PKA –> MLCK(PO4)2 –> RELAXATION

cAMP activates PKA and opens calcium-activated K-channels, hyperpolarizing the cells. —> deactivation of myosin LC kinase –> bronchodilation

Conversely LTC4 and LTD4 (leukotrienes) bind to CysL-1R or histamine binds to H1R and activates the Gq (PLC, IP3, Ca2+_ pathway that activate myosin LC kinase and leads to muscle contraction.

37
Q

What are the SABAs? Differentiate between them using structure and activity.

A

albuterol -t-butyl and salicyl alcohol ring provide optimal beta2-selectivity

terbutaline -t-bury analog of metaproterenol hence more potent beta2-selecitivity –> **increased palpitations

38
Q

What are the SABAs? Differentiate between them using structure and activity.

A

albuterol -t-butyl and salicyl alcohol ring provide optimal beta2-selectivity

terbutaline -t-bury analog of metaproterenol hence more potent beta2-selecitivity –> **increased palpitations

39
Q

What makes LABAs longer-acting than SABAs?

A

more resistant to MAO and COMT

SABAs are just resistant to COMT

40
Q

Why should LABAs not be used as monotherapy?

A

increased in asthma-related mortality

41
Q

What are the LABAs? Differentiate between them using structure and activity

A

(ar)formoterol: N-isopropyl-p-methoxyphenyl, unqie m-formaide and p-hydroxyphenyl ring. greater water solubility and mod lipophilicity. res to MAO and COMT. ***More RAPID ONSET.

salmeterol–N-phenylbutoxyhexyl, beta-hydroxyl and salicyl phneyl substituents. *highest receptor affinity. increased lipophilicty and res to MAO and COMT. **longer duration. do not use as monotherapy.

42
Q

What is an important counselling point regarding formoterol capsules?

A

do not take PO !!

43
Q

What is an important counselling point regarding formoterol capsules?

A

do not take PO !!

44
Q

What is the max that patients should be using albuterol (except for EIA) per week?

A

2x

45
Q

What are adverse effects observed with inhaled BAs?

A

skeletal muscle tremors

tachycardia and palpitations:
occur less with beta-2 selective
-high doses of beta-2 selective may stim beta1 R in heart
-may be some reflex tachycardia d/t vasodilation caused by activation of beta2 receptors

**salmeterol monotherapy increases asthma-related mortality

46
Q

What are examples of ICS + LABA combo products?

A

Advair: fluticasone + salmeterol
Symbicort: budesonide + formoterol
Dulera: mometasone + formoterol

not sure use in acute bronchial spasm
not for use in pts under 12 yoa

47
Q

What are he methylthanxines and natural sources of them? Sx?

A

coffee: caffeine
cacoa: theobromine
tea: theophylline

bicyclic with 4 amine groups. diffe in number nd position of their methyl groups.

48
Q

What are agents that increase theophylline levels by competition for same CYP450 isozyme?

A 
cimetidine
allopurinol
eryhtromycin
fluoroquinolones (cipro)
propranolol
leukotriene inhibitions-Zileutin****
49
Q

What are some drug interactions/cautions for use of theophylline?

A

Mg and AlOH antacids delay abs
half-life prolonged in CHF pts
may aggravate Sz disorders

50
Q

What are the mechanisms of mast cell degranulation?

A

antigen-mediated–antigens bind to IgE on mast cell surface (FcepsilonR) –> clustering of FceR –> influx of Ca2_ via CRAC –> ATP

non-antigen-mediated–thermal or mechanical stress, venoms or various drugs

51
Q

What are the effects of mast cell degranulation in asthma?

A

early stage borncoconstriction, activate TH2 cells
mediators activate eosinophils and neutrophils for late stage response –> ECP, PAF, neutrophil proteases –> activate eosinophils

52
Q

compare the rationale of using cromolyn in asthma with that of b2 adrenergic agonists

A

cromolyn and LABAs can be taken prophylactically to decr attack freq and sev. LABAs are bronchodilators primarily and cromolyn decreases inflammx.

unlike a SABA, cromolyn can’t be used acutely. Can’t regranulate a mast cell. might be useful before encountering triggers.

53
Q

describe omalizumab’s place in thearpy and admin.

A

humanized mouse anti-human IgE antibody given via SC inj.

ind for pts >= 12yo w mod to sev persistent asthma unresponsive to inhaled steroids. (pos rxn to aeroallergin)

1 inj q2-4 wk

96% reduction in free IgE levels.

54
Q

What are adverse effects of Xolair?

A

**black box: anaphylaxis
inj site rxns
incr’d infxs
somme immunogenicity: urticaria, dermatitis, pruritus

55
Q

What pathway is lipoxygenase involved in?

A

aracidonate –lipooxygenase–>5-HPETE–> LTA4 –> LTB4 or LTC 4–> LTD4 –> LTE4

56
Q

What is the fxn of LTB4?

A

potent chomtatic that attcks pro-inflamm cells –> neutrophils and eosinophils

57
Q

What are the fxns of CysLTs?

A

contract airways and some vasuclar SM, stimulate mcuus secr, incr microvascula permeability

58
Q

Describe the moa and use fo Zileuton?

A

sel inhibi of 5-lipoxygenase –> inhib synt of LTB4, LTC4, LTD4

decr all sx of asthma, esp late stage

not rec’d for acute attack

ind for prphylaxis and tx of chronic asthma

59
Q

What are adverse effects of Zileuton use?

A

metab’s by CYP450

**double blood levels of theophylline

incr in prothrombin time in pts on warfarin

SEs: HA, dyspepsia

some liver tox

60
Q

Describe the moa and use of Zafir- and Montelukast.

A

comp inhib of CysLT-1R, inhib late-phase bronchoconstr

ind for prophylaxis of asthma in adults and children***
not ind for rescue

61
Q

What are the AE and cautions for Zafir- or Montelukast.

A

both are metab’d by liver
AE: HA, N/D

food reduces BA–do not take w meals.

**should not be abruptly substituted for inh’d or po CSs.

62
Q

Describe the dosing of ipra and tiotropium

A

ipra: regualr dosing tid to qid
tio once d as inhaled powder

**no prn dosing

63
Q

What is glycopyrrolate?

A

the AI in Seebri Neohaler!! a bid LABA used for long-term maintenance treat of airflow obstruction in pts w COPD.

can be used as monotherapy.

64
Q

What are thoughts on LABA monotherapy in COPD?

A

not contraind’d!

formoterol, salmeterol (also in asthma)

indacaterol (Arcapta) in COPD only once daily

65
Q

What are the alpha1-antitrypsin replaement therapies?

A

prolastin
aralast
zemaira

Pharmacotherapy 1 (26 decks)

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