3 - Asthma Pathophys and Medchem Flashcards
***Explain the pathogenesis of asthma, in terms of triggers and physiological response.
early:
1. ANTIGEN binding to IgE –> histamine, tryptase, LTC4, LTD4, PGs from ***MAST CELLS
2. bonrchoconstriction, vascular leakage
delayed 2-8 hr:
- sustained bronchoconstriction
- TH2 activ’d: **release GM-CSF, **IL4/5/13
- mucus hypersecr (goblet)
- infiltration by eosinophils
***Explain the role of goblet cells in the pathogenesis of asthma.
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
***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?
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)
***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.
*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
***Explain the rationale for the use of glucocorticoids in the treatment of asthma and the advantage of using inhaled doses over daily oral doses.
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
***Explain the rationale for the use of Cromolyn in the treatment of asthma and compare this rationale with that of b2 adrenergic agonists
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
***Explain the mechanism of action of omalizumab, and the rationale for it’s therapeutic use.
inhibits binding of igE to FcepsilonR1 on mast cells and basophils. —> inhibi mast cell degranulation. decr inflamm. decr freq and sev of attacks.
***Explain the differences between the mechanisms of action of the antileukotrienes.
–> 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
Explain why Ipratropium and tiotropium have some use in treating bronchoconstriction (mechanism?).
***
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
Recognize distinct classes of drugs used to treat asthma by their chemical structures.**
be able to recognize but not in great detail.
Propose and justify novel strategies for the treatment of asthma**
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
Explain the mechanism of action of drugs used to treat COPD.***
inh’d AMAs
LABAs
SABAs
–> bronchodilation
alpha1-antitrypsin replacement (rare)–> decr proteolytic damage (MMP9 and elastase) to lung tissue
Explain the pathogenesis of cystic fibrosis (CF), and how it affects lung function.
*****
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
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. **
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
Describe the role or periostin in asthma pathogenesis.
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
Describe airway remodelling in asthma.
epithelium-mucuous hperplasia and hypersecretion
BM thickes
SM hyperthropies
Describe airway remodelling in asthma.
epithelium-mucuous hperplasia and hypersecretion
BM thickens
SM hyperthropies
What is periostin?
matrix protein biomarker
it’s release causes problems
used as a biomarker for epithelium IL-13 activation
Describe remodelling in COPD.
fibrosis of small airways
hyperinflation of lungs: alveolar enlarement and wall destruction
mucus hypersecrtion
**genetic deficiency in alpha1-anti-trypsin
How does fibrosis occur in COPD?
particles–>epithelial cells release TGFbeta–>fibroblast–> fibrosis
How does emphysema (alveolar wall destruction) occur in COPD?
particulates–> activate marcophage (enhanced by epithelial cell cytokines) –> activate Tc1 cells and proteases (nuetorphil elastias and MMP9)
How does mucus hypersecretion occur in COPD?
particulates –> actovate macrophage–> activate neutrophils –> proteases increase mucus (??)
How does mucus hypersecretion occur in COPD?
particulates –> actovate macrophage–> activate neutrophils –> proteases increase mucus (??)
Describe alpha1-anti-trypsin and its alleles.
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
C/C asthma and COPD cell types
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.
Explain the effects of loss of CFTR fxn in the sweat duct epithelium.
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.
***C/C COPD and asthma
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
Explain the effects of CFTR fxn loss in the airway epithelium.
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
What are tx stragies of asthma?
bronchodilation
anti-inflammation
inhibition of mast cell degradnulation
What drug classes are used for bronchodilation in asthma?
beta2 ag
methylxanthines
anticholinergics
What drug classes are used for anti-inflammx in asthma?
clucocorticoids
antileukotriene agents
What drug classes are used to inhibit mast cell degranulation?
cromolyn-type drugs
omalizumab (Xolair)
***C/C asthma and COPD cell types
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.
What are the activities of sympathomimetic amines in asthma?
- bronchorelax
2. inhibit mast cell degran, inhib microvascular leakage, incr microciliary transport of mucus.
What is the molecular action of beat-2 agonists?
Gs –> AC –> cAMP –> PKA –> PLCK(PO4)2 –> RELAXATION
What is the molecular action of beta-2 agonists in respiratory dz? leucko
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.
What are the SABAs? Differentiate between them using structure and activity.
albuterol -t-butyl and salicyl alcohol ring provide optimal beta2-selectivity
terbutaline -t-bury analog of metaproterenol hence more potent beta2-selecitivity –> **increased palpitations
What are the SABAs? Differentiate between them using structure and activity.
albuterol -t-butyl and salicyl alcohol ring provide optimal beta2-selectivity
terbutaline -t-bury analog of metaproterenol hence more potent beta2-selecitivity –> **increased palpitations
What makes LABAs longer-acting than SABAs?
more resistant to MAO and COMT
SABAs are just resistant to COMT
Why should LABAs not be used as monotherapy?
increased in asthma-related mortality
What are the LABAs? Differentiate between them using structure and activity
(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.
What is an important counselling point regarding formoterol capsules?
do not take PO !!
What is an important counselling point regarding formoterol capsules?
do not take PO !!
What is the max that patients should be using albuterol (except for EIA) per week?
2x
What are adverse effects observed with inhaled BAs?
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
What are examples of ICS + LABA combo products?
Advair: fluticasone + salmeterol
Symbicort: budesonide + formoterol
Dulera: mometasone + formoterol
not sure use in acute bronchial spasm
not for use in pts under 12 yoa
What are he methylthanxines and natural sources of them? Sx?
coffee: caffeine
cacoa: theobromine
tea: theophylline
bicyclic with 4 amine groups. diffe in number nd position of their methyl groups.
What are agents that increase theophylline levels by competition for same CYP450 isozyme?
cimetidine allopurinol eryhtromycin fluoroquinolones (cipro) propranolol leukotriene inhibitions-Zileutin****
What are some drug interactions/cautions for use of theophylline?
Mg and AlOH antacids delay abs
half-life prolonged in CHF pts
may aggravate Sz disorders
What are the mechanisms of mast cell degranulation?
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
What are the effects of mast cell degranulation in asthma?
early stage borncoconstriction, activate TH2 cells
mediators activate eosinophils and neutrophils for late stage response –> ECP, PAF, neutrophil proteases –> activate eosinophils
compare the rationale of using cromolyn in asthma with that of b2 adrenergic agonists
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.
describe omalizumab’s place in thearpy and admin.
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.
What are adverse effects of Xolair?
**black box: anaphylaxis
inj site rxns
incr’d infxs
somme immunogenicity: urticaria, dermatitis, pruritus
What pathway is lipoxygenase involved in?
aracidonate –lipooxygenase–>5-HPETE–> LTA4 –> LTB4 or LTC 4–> LTD4 –> LTE4
What is the fxn of LTB4?
potent chomtatic that attcks pro-inflamm cells –> neutrophils and eosinophils
What are the fxns of CysLTs?
contract airways and some vasuclar SM, stimulate mcuus secr, incr microvascula permeability
Describe the moa and use fo Zileuton?
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
What are adverse effects of Zileuton use?
metab’s by CYP450
**double blood levels of theophylline
incr in prothrombin time in pts on warfarin
SEs: HA, dyspepsia
some liver tox
Describe the moa and use of Zafir- and Montelukast.
comp inhib of CysLT-1R, inhib late-phase bronchoconstr
ind for prophylaxis of asthma in adults and children***
not ind for rescue
What are the AE and cautions for Zafir- or Montelukast.
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.
Describe the dosing of ipra and tiotropium
ipra: regualr dosing tid to qid
tio once d as inhaled powder
**no prn dosing
What is glycopyrrolate?
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.
What are thoughts on LABA monotherapy in COPD?
not contraind’d!
formoterol, salmeterol (also in asthma)
indacaterol (Arcapta) in COPD only once daily
What are the alpha1-antitrypsin replaement therapies?
prolastin
aralast
zemaira
