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335 Cards in this Set
- Front
- Back
inspiration
|
active contraction of inspiratory muscles predominantly the diaphram generates a negative plueral pressure gradient from the atmosphere to the alveolus
|
|
exhalation
|
passive process
relaxation of respiratory muscles and elastic recoil of lung |
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perfusion
|
right ventricle
pulmonary artery pulmonary arteriole pulmonary capillary (perfusion) pulomary venule pulmonary veins left atrium |
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V/Q
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ventilation/perfusion
ideally should equal 1 usually = 0.8 |
|
measure of adequate ventilation
|
partial pressure of CO2 in the arterial blood (pCO2)
|
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PFTs
|
measure airflow through airways, lung size, & gas exchange
normal PFTs values determined by studies of normal individuals and based on age, sex, & race |
|
FRC
|
functional residual capacity
volume of air in the lung after a normal respiration |
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Vt
|
tidal volume
volume of air drawn into the lung during inspiration from end expiratory position = volume of air leaving during expiration ie volume of air in a normal breath |
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ERV
|
expiratory reserve volume
max amount of air that can be exhaled after a quiet expiration completed and requires active contraction of muscles of expiration |
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RV
|
residual volume
volume of air left in lung after maximal expiration (ERV) This air prevents atelectasis (lung collaspe) |
|
Vt + RV
|
Vt(vidal capacity) + RV(inspiratory reserve volume) = inspiratory capacity = max amount of air that can be inhaled from end respiratory position
does not include RV(residual volume still present in lungs after end respiratory position) |
|
TLC
|
total lung capacity
total amount of air in lungs at end of maximal inspiration includes residual volume |
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Vital capacity
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volume of air exhaled by maximal expiration after maximal inspiration
use to measure FEV-1 |
|
flow
|
movement of air into and out of the lung
its the change in volume over time used to define obstructive lung dx |
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FEV-1
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forced expiratory volume in 1 second (forced exhalation following maximal inspiration = vital capacity)
|
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FEV-1>/= 80%
|
normal
|
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FEV-1/FVC
|
forced expiratory volume in 1 second as a % of the vital capacity (maximal expiration volume possible after maximal inspiration
|
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FEV-1/FVC >./= 70%
|
normal
indicates no airflow obstruction want to be able to exhale at least 70% of vital capacity in 1 second |
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FEF 25-75
|
measures mean flow of air on expiration of 25%-75% (middle 1/2) of vital capacity
|
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FEF 25-75 >/= 60%
|
normal
|
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PEFR
|
peak expiratory flow
max expiratory flow at the start of the vital capacity manuver (maximal exhalation following maximal inhalation) easy to measure for outpatients *negative is effort dependent |
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spirometry
|
measurements made from vital capacity maneuver (maximal exhalation following maximal inhalation)
FVC, FEV-1, & FEF25-75 |
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TLC & RV
|
TLC = total amount of air in lungs after maximal inspiration
RV = total amount of air left in lungs after maximal respiration cannot be measured by spirometry |
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TLC < 80%
|
total lung capacity = TLC = total amount of air in lungs after maximal inspiration
defines restrictive lung dx |
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TLC > 120%
|
TLC = total amount of air in lungs after maximal inspiration
indicates hyperinflated lung in emphysema (COPD/obstructive lung dx) |
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RV>120%
|
RV = residual volume = total amount of air left in lungs after maximal expiration
indicates air trapping in asthma due to reduced airway diameter from bronchospasm and airway inflammation |
|
measure lung volumes
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TLC & RV
need helium diffusion, nitrogen washout, or body plethysmography |
|
reduced pulmonary diffusion (<60%) can be a sign of
|
pulmonary vascular dx
interstitial lung dx emphysema anemia |
|
measure diffusion capacity
|
by measuring diffusion of CO (highly soluble in blood, the more CO exhaled after inspiration the poorer the diffusion)
|
|
DLCO/VA
|
single breath of CO/alveolar volume
used to measure diffusion capacity |
|
obstructive lung dx
|
obstruction to flow of air
asthma chronic bronchitis emphysema cystic fibrosis bronchiectasis lymphangioleiomyomatosis (LAM) |
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air flow obstruction from reduced airway diameter due to bronchospasm
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asthma
|
|
air flow obstruction from reduced airway diameter due to inflammation
|
asthma
chronic bronchitis |
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air flow obstruction from reduced driving pressure from reduced elastic recoil
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emphysema
|
|
air flow obstruction from reduced diameter from airway secretions
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cystic fibrosis
bronchiectasis |
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air flow obstruction due to reduced airway diameter from proliferation of abnormal cells in the airway
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lymphangioleiomyomatosis/LAM
|
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most common obstructive lung dx
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asthma
chronic bronchitis emphysema all have reduced FEV-1/FEV-1/FVC/FEF 25-75 |
|
FEV-1 < 80% & FEF25-75 <60% in normal lung volumes (TLC & RV)
|
is diagnostic
|
|
FEV1/FVC <70% in reduced lung volumes (RV and TLC)
|
is diagnostic
|
|
FEV-1= 60-80%
|
mild obstruction
|
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FEV-1 = 40-60%
|
moderate obstruction
|
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FEV-1 < 40%
|
severe obstruction
|
|
in COPD FEV-1. . .
|
correlates with survival!
|
|
reversibility of FEV-1 with bronchodilators
|
may indicate asthma
increase in FEV-1 by 15% at time of test and over time on medical therapy |
|
methocholine challenge
|
drop in FEV-1 by at least 20% indicates asthma
useful in cough variant asthma where cough is the only symptom and FEV-1 is typically normal and excercise-induced asthma negative - rules out asthma! |
|
restrictive lung dx
|
inability to achieve a normal TLC
all lung volumes reduced flow is preserved(normal FEV1/FVC) |
|
restrictive lung dx due to neuromuscular dx with weakness and dysfunction of respiratory muscles
|
MS
maximal inspired pressure will be low |
|
restrictive lung dx due to skeletal dx where lung cannot exapnd
|
kyphoscoliosis
|
|
restrictive lung dx due to plueral dx
|
plueral effusion
mesothelioma - a form of carcinoma of the mesothelium lining lungs |
|
restrictive lung dx due to intersitial lung dx
|
pulmonary fibrosis
sarcoid pulmonary edema drug toxicity from amiodarone/bleomycin |
|
measure progression of neuromuscular dx
|
monitor lung volumes
|
|
ABG
|
arterial blood gas
indirect measure of pulmonary function pH, PaO2, PaCO2 |
|
hypoxemia caused by
|
alveolar hypoventialtion via CNS
V/Q mismatch right to left shunt due to atrial septal defect or AV malformations (blood not getting oxygenated) diffusion abnormalities due to pulmonary fibrosis |
|
elevated PaCO2 indicates
|
hypoventilation
not diagnostic of airway dx can be casued by neuromuscular process, drugs affecting CNS which controls RR, obstructive lung dx |
|
oxygen consumption at anaerobic threshold in exercise testing will be decreased in
|
cardiac dx
|
|
bronchietesis
|
localized, irreversible dilation of the part of the bronchial tree
|
|
capacity
|
2 or more lung volumes
|
|
inspiratory reserve volume
|
maximal inspiration
extra volume on top of tidal volume (amount of air inspired in 1 normal breath) |
|
flow
|
change in volume with time
flow is dependent on volume |
|
normal lung volumes/normal lung capacity
|
don't need to use FEV1/FVC
|
|
FEV-1 is
|
effort-dependent
|
|
inspiration
|
negative slope on flow-volume curve
|
|
expiration
|
positive slope on flow-volume curve
if end is clipped (negative slope) there is a problem need evaluation of upper airway top of slope is truncated there is major airway obstruction |
|
in restrictive lung dx
|
all values on time-volume plots are shifted to the left because the total lung volume is down
|
|
TLC < 80%
|
restrictive lung dx
|
|
interstitial lung dx
|
does not affect FEV-1 once adjust to decrease in lung volume
decreases TLC decrease CO2 diffusion |
|
amiodarone AE
|
can lead to fibrosis of the intersitium of the lung
can result in interstitial lung dx which is a restrictive lung dx |
|
decrease in diffusion capacity
|
vascular dx
intersitium of lung fibrosis/scarring anermia decrease in # alveoli in emphysema |
|
LAM
|
obstructive lung dx usually only affects women
Lymphangioleiomyomatosis (LAM) is a rare lung disease that results in disorderly smooth muscle proliferation throughout the bronchioles, alveolar septa, perivascular spaces, and lymphatics, resulting in the obstruction of small airways (leading to pulmonary cyst formation and pneumothorax) and lymphatics (leading to chylous pleural effusion). LAM occurs in a sporadic form, which only affects females, who are usually of childbearing age. |
|
COPD
|
never totally reversible therefore always has an effect on survival
|
|
increase FEV-1 takes
|
1-6 months
used to measure dx progression/response to therapy |
|
reduction in TLC & FEV-1
|
have obstructive and restrictive lung dx at same time
|
|
scoliosis & MS
|
can cause restrictive lung dx
|
|
shunt
|
blood that is not oxygenated and has reach systemic circulation
occurs in septal defects cause hypoxemia |
|
reduced anaerobic threshold is
|
sign of cardiac dysfunction
|
|
bronchodilators
|
SABAs
LABAs theophylline anticholinergics cromolyn & nedorcromil |
|
anti-inflammitories
|
Anti-IgE
leukasotriene pathway inhibitors corticosteriods (INH & PO) |
|
asthma
|
reversible airway obstruction
|
|
inflammation
|
exudative component and cellular component
|
|
exudative component
|
movement of plasma into inflammed tissue via inflammation and leaky capillaries
contains fibrin and Abs mediators: bradykinin, C3, C5a, plasmin, & thrombin |
|
cellular component of inflammation
|
involves leukocytes
access inflammed tissue via extravasation release enzymes, phagocyotize, release inflammatory mediators |
|
acute inflammation is
|
mediated by granulocytes
|
|
chronic inflammation is
|
mediated by mononuclear cells (monocytes) and lymphocytes
|
|
bradykinin
|
kinin system
plasma derived inflammatory mediator induces vasodilation, vascular permability, smooth muscle contraction & pain |
|
C3
|
plasma derived mediator of inflammation
complement system C3a - stimulates histamine release by mast cells C3b - binds to bacteria cell walls and acts as opsonin(marks for target of phagocytosis) |
|
C5a
|
plasma-derived inflammatory mediator
complement system stimulates histamine release from mast cells chemoattractant |
|
Factor XII
|
Hageman Factor
plasma derived inflammation mediator produced by liver activates the kinin, fibrinolysis, and coagulation systems during inflammation |
|
MAC
|
membrane attack complex
plasma derived inflammation mediator complement system C5b + C6 + C7 + C8 + C9 causes cell lysis in bacteria |
|
plasmin
|
plasma derived inflammation mediator
fibrinolysis sytsem breaks down fibrin clots, cleaves C3, and activates Factor XII |
|
thrombin
|
plasma derived inflammation mediator
coagulation system cleaves fibrinogen to produce insoluble fibrin which coagulates (blood clot) |
|
histamine
|
cell derived inflammation mediator
vasoactive amine released from mast cells, basophils, platelets causes arteriole dilation and increased venous permeability |
|
IFN-gamma
|
cell derived mediator of inflammation
cytokine released from T-cells, NK cells maintains chronic inflammation |
|
IL-8
|
cell derived mediator of inflammation
chemokine released by macrophages chemoattractant and activates nuetrophils |
|
leukotriene
|
cell derived mediator of inflammation
eicosaniod released from leukocytes plays a role in leukocyte extravasation (enter inflammaed area) produce reactive O2 species |
|
Nitric oxide
|
cell derived mediator of inflammation
released from macrophages and endothelial cells vasodilator |
|
prostaglandin
|
cell derived mediator of inflammation
eicosanoid released from mast cells vasodilation, fever, pain |
|
TNF-alpha & IL-1
|
cell derived mediators of inflammation
cytokines released by macrophages cause inflammation |
|
macrophages release
|
IL-8, NO, TNF-alpha, IL-1
all mediators of inflammation |
|
nuetrophil
|
granulocyte WBC
phagocytosis |
|
eosinophil
|
granulocyte WBC
in allergic rxns (asthma, hay fever, hives) and parasitic infections |
|
basophil
|
granulocyte WBC
similar to mast cell releases histamine in response to allergins and antigens |
|
agranulocyte WBCs
|
lymphocytes (b-cells, T-cells, NK-cells), monocytes ( in blood stream, phagocytoize, present antigens to T-cells), and macrophages(differentiated monocytes in tissue)
|
|
monomer Abs
|
IgD
IgE IgG |
|
Dimer Ab
|
IgA
|
|
pentamer Ab
|
IgM
|
|
asthma
|
inflammatory response is chronically activated even in the absence of an allergen
chronic expansion of the late phase inflammation |
|
asthma in kids
|
50% also have allergies
|
|
asthma
|
increased # of inflammatory cells and inflammatory mediators in lungs
|
|
differentiate COPD from asthma
|
COPD is clinically defined as low FEV-1 that fails to respond acutely to bronchodialtors unlike asthma
|
|
parasympathetic nervous system
|
releases Ach which acts on muscarinic receptors on lungs causing bronchoconstriction
|
|
sympathetic nervous system
|
releases NE from nerve terminals and EPI from adrenal medulla which act on alpha and beta receptors(B2 receptors in lungs causing bronchodilation)
|
|
receptors in lungs
|
M3 - acted by Ach = bronchoconstriction
B2 - acted on by NE/EPI = bronchodilation A1 = minor contribution to bronchoconstriction acted on by NE/EPI |
|
B2 7 pass g-protein receptors are activated . . .
|
adenyl cyclase produces cAMP which before broken down by phosphodiesterase activates PKA which activeas Ca2+/K+ channel & Na+/K+ ATPase and decreases mysoin-light chain kinase
|
|
NE, EPI, & ephedrine
|
not selective for B2
activate also alpha and beta-1 receptors in heart (increase HR) |
|
B2 agonist functional groups
|
phenyl
catechol (NE/EPI) because they are catecholamines ethanolamine |
|
Beta agonist selective for beta over alpha receptors
|
secondary amine (EPI)
|
|
beta agonist with alpha activity
|
primary amine (NE)
|
|
beta agonist metabolized quickly but has best potency
|
has catechol group
metabolized by COMT (catechol-o-methyltransferase) not PO catecholamines (EPI,NE,dopamine) |
|
beta agonist with B1 & B2 activity
|
isopropyl group at secondary amine(no alpha activity)
is isoproterenol -has catechol, not orally active -INH 5-30 min onset 3-6 hour duration |
|
beta agonist with selective B2 activity
|
T-butyl subsitution at secondary amine(no alpha activity)
|
|
albuterol
|
proventil
very selective for B2 due to N-t-butyle PO (not catechol)/INH |
|
biolterol
|
SABA
Tomalate INH & prodrug (ester of colterol) |
|
Pirbuterol
|
Maxair
|
|
Terbutaline
|
brethaire
PO/INH |
|
B2-selective agonists (N-t-butyl) with no catechol (longer duration of action)
|
albuterol
bitolterol pributerol terbutaline |
|
levalbuterolo
|
R-enantiomer of albuterol
studies have indicated greater anti-inflammatory effects, more effective & safe and fewer cardiac AEs than racemic mixture Very $$$ compared to albuterol |
|
Salmeterol
|
Serevent
LABA binds to 2 places on B2 receptors(ligand binding site & reversibly to transmemebrane domain of B2) onset = 20 minutes 12 hour duration! |
|
Formoterol
|
Foradil
LABA 2 chiral carbons highly lipophillic(enters plasma cell membrane forms a depot where its gradually released into aqueous phase[long DUA] and activates B2[aqueous phase activity not demonstrated by salmeterol that causes rapid onset of action] |
|
LABAs cause bronchodilation and
|
decrease plasma exudation
decrease cholinergic nuerotransmission increased mucocilliary clearance decreased neutrophil function decreased bacterial adherence inhibit mast cell mediator release prevent leakage and edema |
|
LABAs are used to
|
decrease use of SABAs (control symptoms)
decrease nocturnal asthma add to ICS instead of increasing dose and increasing chances of getting AEs |
|
theophylline MOA
|
increases cAMP level by inhibiting phosphodiesterase resulting in bronchodilation
weak and nonselective inhibtor of phosphodiesterase may also inhibit adenosine receptor on mast cells and prvent histamine release methylxanthine(same structure as caffeine just replace CH3 with H) |
|
aminophylline
|
ethylenediamine salt of theophylline
|
|
theophylline increased clearance via CYP450
|
phenobarbitol
phenytoin children marjuana smokers |
|
theophylline decreased clearance via CYP450
|
cimetidine
erythromycin ciprofloxacin allopurinol zileuton zafirlukast viral infections/vaccinations |
|
parasympathic innervation of lung
|
dominates the large and medium size airways
cause bronchoconstriction and increased gland secretion via Ach |
|
M1 receptors
|
peribronchial ganglion cells
|
|
M2 receptors
|
on postganglionic nerves
activated by Ach and promote its uptake |
|
M3 receptors
|
on lung smooth muscle
leads to Ca2+ release from intracellular stores resulting in bronchoconstriction |
|
atropine
|
protype anticholinergic bronchodilator
|
|
ipratropium
|
anticholinergic
quaterneary amine (not lipophillic, poorly absorbed across biological membranes) MDI/nebulizer onset = 30 minutes DUA = 6 hours |
|
tiotropium
|
structural analog of ipratropiem
longer DUA than ipratropium because it dissassociated from M3 receptors more slowly QD dosing! |
|
anticholinergics have lack of efficacy in asthma however are
|
among the most effective therapies in COPD
|
|
Cromolyn Na
|
derived from plant Ammi visnaga
chromone Khellin has bronchodilator activities inhibits antigen-induced bronchospasm and stabalizes mast cells |
|
cromolyn & neocromolyn Na
|
prevent early and late allergic response
reduce airway activity inhibit Cl channels in mast cells & sensory nuerons prevent leukocyte activation in asthma and activation of nuetrophils, esionophils, and monocytes |
|
Alpha-antitrypsin
|
endogenous plasma protein inhibitor especailly of neutrophil elastase which can cause lung tissue destruction in their is a genetic deficiency resulting in emphysema
|
|
proteases in the lung
|
neutrophil elastase produced by neutrophil
gelatinase produced by macrophage/nuetrophil/eosinophil macrophage elastase produced by macrophage |
|
protease inhibitors in the lung
|
alpha-1-antitrypsin inhibits serine proteases and is produced by liver
alpha-2-macroglobulin inhibits matrix metalloproteinases & serine proteases and is produced by liver TIMPs inhbit matrix metalloproteinases and is produced by macrophages and lung |
|
alpha-1-antitrypsin
|
glycoprotein
inhibits serine proteases especially elastase(can cause pulmonary emphasema = panlobular emphaysema via elastin breakdown) |
|
Prolastin
Zemaira Aralast |
3 alpha-1-antitrypsin products derived from human plasma
cost = $100,000/year/patient |
|
Future Agents to tx asthma
|
vasoactive intestinal peptides & atrail natiuretic peptide (both cause vasodilation but are degraded too quickly becasue they are pepetides!)
other PDE inhibitors (cilomilast causes emesis/vomit) other proteinase inhibitors pharmacogenomics (some B2 receptors susceptible to down regulation) |
|
INH drug delivery of LABAs/ICS
|
particles > 10 ums are deposited in mouth and swallowed (90%) and particles < 0.5 ums are exhaled (10%)
decrease gut absorption (less systemic AEs) and increases 1st pass metabolism (inactivation) |
|
omalizumab
|
Xolair
recombinant DNA-derived humanized IgG1 monoclonal Ab that selectively binds to IgE anti-inflammatroy prevents IgE from activating mast cells and basophils humanized mouse Ab |
|
asthma therapy
|
should be direct toward anti-inflammatory because it is a dx of chronic inflammation
|
|
cholesterol
|
synthetic precursor to all steroid hormones including glucocorticosteriods (cortisol)
|
|
aldosterone
|
minerolglucocorticoid
|
|
glucocorticoids
|
synthesized in the adrenal cortex from cholesterol (27 carbons)
secreted during the day = diurnal lipophillic |
|
glucocorticoids levels rise 10 -fold during
|
severe stress (cortisol) along with mineralocorticoid aldosterone from adrenal cortex
|
|
physiological functions of glucocorticoids
|
immunological
metobolic developmental |
|
immunological function of glucocorticoids
|
upregulate expression of anti-inflammatory proteins
down regulate the expression of pro-inflammatory proteins |
|
metabolic function of glucocorticoids
|
cortisol stimulates processes that serve to increase and maintain normal concentrations of glucose in the blood
|
|
developmental functions of glucocorticoids
|
affect fetal development
lung maturation produce surfactant brain development |
|
glucocorticoids inhibit
|
prostaglandins via COX-2
leukotrienes via phospholipase A2 transcription and release of interluekins, ICAM-1, IgE inhibit transcription of pro-inflammatory genes & activate transcription of anti-inflammatory proteins via the glucocorticoid receptor |
|
glucocorticoid receptor
|
cytoplasmic receptor
nuclear receptor transcription factor causes +/- regulation of transcription of target genes effects take hours-days to develop! |
|
glucocorticoid response elements
|
specific DNA sequences targeted by glucocortidcoid receptor that once bound can increase/decrease transcription of downstream genes
|
|
how to glucocorticoids regulate gene expression?
|
modulate the chromatin structure of targeted genes
|
|
2 mechanisms of glucocorticoid transcriptional activation/deactivation are
|
glucocorticoid receptor binding to glucocorticoid response elements (DNA) & modulation of the chromatin structure of target genes (codensed chromatin/DNA bound tightly to + charged histones are usually inactive genes) - rate of transcription is influenced by tightness of binding to histones
|
|
promoter
|
regulatory region of DNA located upstream of a gene that allows transcription of that gene
|
|
glucocorticoid response element
|
short sequence of DNA in the promoter that binds to glucocorticoid receptor complex and regulate transcription
|
|
glucocorticosteriods will activate/repress a gene based on
|
presence of other regulatory elements of that gene and the expression of cellular factors that regulate gene activity
|
|
HATs
|
histone acetyltransferases recurited by glucocorticoid receptor to modify chromatin structure via loosening histones on DNA in order to activate gene transcription
|
|
HDAC
|
histone deacetylases recruited by glucocorticoid receptor to restore histone basic character and tightness bound to DNA to repress gene transcription of pro-inflammatory mediaotrs (primary anti-inflammatory action!!!!)
acetyl group has - charge |
|
flucticasone propionate
|
flonase
rapid deactivation in liver by 1st pass metabolism reduces systemic side effects |
|
ICS used in asthma
|
hydrocortisone
prednisone methylprednisolone dexamethasone |
|
glucocorticoid resistant asthma
|
poorly responsive to ICS
|
|
glucocorticoid resistant/dependent asthma
|
common
requires high inhaled/PO doses for dx control complete corticosteriod resisitance is rare |
|
mechanisms of glucocorticoid resistance
|
reduced nuclear translocation of the glucocorticoid receptor and/
disruptions in histone modifications in chromatin or glucorticoid receptor regulated genes |
|
taper glucocorticoid high dose therapy up cessation
|
limit acute adrenal insufficiency
therapy causes a negative feedback loop so less glucorticoids are being produced from adrenal glands because glucocorticoid act on the anterior pituitary to stop producing ACTH & the hypothalamus to stop producing CRF |
|
PO/systemic glucocorticoids must
|
have low activity at mineral corticoid receptor aka more cortisone-like not cortisol-like
functional specificity of hormones is not perfect! |
|
mineralcorticosteriods
|
aldosterone
act on kidenys to regulate electrolytes via reabsorption of Na+ and water stimulate Na+ retention |
|
glucocorticosteriods
|
regulate carb metabolism
major glucocorticosteriod is cortisol |
|
asthma
|
genetic predisposition AND environmental actions
air flow obstruction is reversible (unless not tx) |
|
inflammatory cells in asthma
|
mast cells
eosinophils T-cells B-cells neutrophils macrophages epitherlial cells |
|
asthma
|
most common chronic childhood dx
boys>girls viral-provoked asthma: 30-70% grow out of it women>men |
|
asthma + atopy as child
|
strong indicator asthma will persisit into adulthood
atopy is a risk factor for asthma |
|
hygiene hypothesis
|
children exposed to more infection/recieve fewer antibiotics less likely to develop asthma because the TH2 lymphocytes (allergies) and TH1(fight infection) are in balance
|
|
air flow obstruction is result of
|
airway inflammation AND airway hyperresponsiveness
similar pathways/linked |
|
acute "early phase" inflammation
|
often allergy mediated but not always
leads to "late phase" rxn hours after exposure |
|
"early phase" inflammation/acute response
|
IgE in allergies attaches to mast cells, release histamine/inflammatory mediators = vasodilation, bronchoconstriction, mucus production, microvascular leak of exudate
|
|
"late phase" inflammation
|
recuritment of inflammatory cells(esionophils, CD4 cells, PMNs, and macrophages
retained CD4 TH2 cells release inflammatory cytokines |
|
Eosinophils
|
major role in inflammation
release cytokines & leukotrienes bind to endotherlim via VCAM/ICAM |
|
CD4 TH2 cells
|
produce IL-4, IL-5, IL-13 and cytokines that decrease TH1 cytokines
|
|
CD4 TH1 cells
|
role in infection as apposed to inflammation like CD4 TH2 cells
produce IL-2 and INF-gamma |
|
mast cells
|
degranulation important in acute inflammation (IgE mediated release of histamine, lueukotrienes, prostaglandins, & PAF)
|
|
alveolar macrophages
|
release PAF, luekotrienes and chemotactic factor
|
|
histamine
|
inflammatory mediator
smooth muscle constriction mucus production mucosal edema |
|
PGD2
|
bronchoconstrition
|
|
PG12
|
prostacyclin
vasodilator |
|
LTC4, LTD4, LTF4
luekotrienes |
bronchospasms
mucous secretions vascular leak |
|
LTB4
luekotriene |
granulocyte chemotaxis
|
|
PAF
|
platelet activating factor
bronchospasms airway edema eosinophil chemotaxis |
|
arachidonic acid pathway produces
|
prostaglandins
luekotrienes thromboxane |
|
vagus
|
parasympathetic innervation of bronchial smooth muscle
maintains normal airway tone |
|
cholinergic bronchoconstriction
|
maximal bronchoconstriction due to stimulation of the vagus
|
|
Diagnose asthma based on
|
history
symptoms PFTs (FEV1,FEV1/FVC,FEF25-75) |
|
asthma exacerbation caused by
|
inadequate use of medication
lack of risk factor modification (allergies/smoking) |
|
exercise-induced asthma
|
problem in cold, dry air
due mast cell degranulation not all excerise-induced dyspnea = asthma, need methylcholine challenge |
|
noctural asthma
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FEV-1 lowest between 3-4 AM and best at 3-4 PM (circadian rhythm)
marker of poor asthma control! contributing factors include GERD, allergies (dust mites), sinus dx |
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most common cause of exacerbations of asthma
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viral infections
-rhinovirus -influenza -RSV |
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sinus dx
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common is asthmatics
control of sinus dx can help control asthma |
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GERD
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common is asthma
contributed to nocturnal asthma(aspirate stomache contents into trachea and excess acid stimulates esophageal vagal afferents resulting in bronchialconstriction by airway vagal efferents |
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asthma + pregos
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poor control results in low birth weight, preme
need control of asthma and oxygen sat >/=95% at all times!!! |
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take long-term QD PEF
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moderate-severe asthma
hx of severe excerbations |
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PEF green zone
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>/= 80% of personal best
good asthma control |
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PEF yellow zone
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50-79% of personal best
caution |
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PEF red zone
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</=50% of personal best
medical alert! |
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maintance therapy for asthma
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ICS
LABAs methylxanthines luekotriene modifiers cromolyn & neocromil immunodulators |
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quick relief therapy for asthma
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SABAs
anticholinergics (only Ipratropium, tiotropium has yet to be tested in asthma patients) PO/systemic coritcosteriods |
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nonselective SABAs
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EPI (Primatene)
Metaproterenol (Alupent) |
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B2 selective SABAs
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albuterol (ventolin/proventil/proventil HFA)
bilolterol (tornalate) pibuterol (maxair) terbutaline (brethine) levalbuterol (xopenex) |
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> 1 cainster/month of SABA
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over-reliance
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>/= 2 canisters/month of SABA
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additional AE risks
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SABA tolerance
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from chronic SABA administration
downregulation & decreased binding afffinity |
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Rule of 2 for SABA
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no more than 2x during the day during the wk
no more than 2x during the night during the month don't use more than 2 canisters/year (might not be applicable because HFA inhalers could expire) |
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SABAs AEs
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tachycardia
palpitations skeletal muscle tremor hypokalmeia increased lactic acid HD hyperglycemia reduced with INH |
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S-albueterol
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may oppose bronchodilation of r-albuterol
may be pro-inflammatroy may increase airway reactivity may contribute to paradoxical bronchospasm |
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R-ablueterol
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levalbuterol
increased potency vs. racemic albuterol reduction in AEs? expensive lacking sufficient clinical data |
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Salmeterol
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Serevent/Advair
HFA MDI = Serevent Diskus = Advair onset: 15-30 min DOA > 12 hours |
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Fomoterol
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Foradil & Symbicort
aerolizer = Foradil onset: 5 minutes DOA = 12 hours |
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Salmeterol + Fluticasone
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Advair diskus & HFA MDI
dry powder inhaler = 1 puff BID HFA MDI = 2 puffs BID |
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Formoterol + Budesonide
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Symbicort = pMDI
2 puffs BID |
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SMART safety study
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resulted in boxed warning for serevent & advair about increase in asthma-related death due to salmeterol and greater incidence in african americans
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LABA monotherapy
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NOT for asthma use w/ICS
can use for COPD |
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max dose of Salmeterol
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100 mcg/day =
2 puffs of Serevent (1 puff BID) 2 puffs of Advair DIiskus (1 puff BID) 4 puffs of Advair HFA (2 puffs BID) |
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max dose of formoterol
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24 mcg/day =
2 doses of Foradil = 4 puff of Sympbicort (2 puffs BID) |
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Foradil
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formoterol
store capsules in fridge prior to dispensing cousel patient not to swallow capusle aerolizer |
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Ipratropium Bromide
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relieve acute bronchospasm
NOT FDA-approved for asthma NOT for excerise-induced asthma NOT for peanut allergies |
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Ipratropium Bromide
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reaches max bronchodilation slower than SABA
alt. for intolerance to beta agonists DOC for bronchospasm due to beta blockers |
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Ipratropium Bromide
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Atrovent/Combivent/Duoneb
inhaler & nebulizer |
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Ipratropium bromide AEs
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dry mouth
respiratory secretions can increase wheezing in some individuals |
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Systemic corticosteriods
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short-term burst therapy for 3-10 days to gain control of acute excerbation
can also be used long-term therapy for severe persistent asthma if ICS doesn't work |
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systemic corticosteriods
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hydrocortisone
prednisone methylprednisolone dexamethasone |
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taper systemic corticosteriods if use
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>5 mg/day for >2 weeks
taper over same # of days of tx start PO then go INH |
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least toxicity of corticosteriods for long-term use
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dose on alternate days in the morning
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AEs of chronic systemic corticosteriods
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HPA suppression
growth retardation skeletal muscle myopathy osteoporosis pancreatitis immunosuppresion pyschiatric distrubances hypokalemia hyperglycemia Na & water retention (bind to mineralcorticoid receptor and act like aldosterone) moon face impaired wound healing |
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Ciclesonide
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Alvesco
once daily dosed ICS |
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ICS AEs
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thrush
dysphonia reflex cough and bronchospasm osteoporosis (caution in post-menopausal women) disseminated varicella dermal thinning, increased brusing |
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dexamethasone
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highly absorbed
NOT ICS |
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ICS
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use spacers/holding chambers
rinse & spit after lowest possible dose Vit. D & Ca2+ supplemention |
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cromolyn & nedocromil
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exercise induced asthma
asthma + allergies low toxicity ICS is more effective used as intial anti-inflammatory in children inhibits early and late asthma therapuetic response occurs in 2 weeks |
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theophylline
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bronchodilator
usually used for noctural asthma minimal anti-inflammatory effect many DIs |
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Drugs decrease theophylline clearance
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cimetidine
macrolides allopurinol propanolol quinolones thiabendazole ticlopidine zileuton systemic viral illness |
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increase theophylline clearances
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rifampin
carbamazepine phenobarbital phenytoin charcoil-broiled meat high-protein diet smoking sulfinpyrazone |
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luekotriene modifiers
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ASA induced asthma
excerise induced asthma monotherapy for mild asthma cold air hypoventialtion good for non-compliance issues less effective than ICS |
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Zafirlukast
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Accolate
leukotriene receptor antagonist food decreases bioavailability(take 1 hour before or 2 hours after) |
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Zafirlukast
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BID
children >/= 7 years old monitor LFTs competitive inhibitor fo CYP2C9 |
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montelukast
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Singulair
leukotriene-receptor antagonist FDA approved for allergies QD children >/= 1 year old |
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montelukast for 12 23 months old
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4 mg granules hs
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montelukast for 2-5 year olds
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4 mg granules or 5 mg chewable hs
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montelukast for >/= 6 year olds
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5 mg chewable TABs hs
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montelukast for > 14 years olds
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10 mg TAB hs
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Zilueton
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Zyflo
decreases theophylline clearance 5-lipo-oxygenase inhibitor 2 600 mg TABs BID >/= 12 years old CYP34A inhibitor monitor ALTs hepatic enzyme DO NOT USE IN LIVER DISEASE |
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post-marketing for luekotriene modifiers
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churg-strauss syndrome see w/leukotriene receptor antagonists
neuropsychiartric events |
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Omalizumab
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Xolair approved in 2003
tx moderate-severe persistant asthma + skin tests/invitro activity to aeroallergen add when not controlled on ICS >/= 12 years old |
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Xolair dosing
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150-375 mg SC for 2-4 weeks
max of 150 mg/ING site base does on total serum IgE level and kg |
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Xolair AEs
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INJ site rxns
viral infetions URT infections HDs pharyngitis anaphylaxis |
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step down
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if asthma is well controlled for at least 3 months
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MDI for kids
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> 5 years old
if less than 5 years old use w/spacer or holding device |
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breath-acutated MDI
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for kids > 5 years old not be alble to generate enough inspiratory flow
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DPI
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for kids > 5 years old
may not work in kids w/low inspriatory flow |
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NEB
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patients of any age
useful in infants & young children |
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Step 1
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Intermittent Asthma
SABA PRN (<2x/wk) up to 3 treatments at 20 minute intervals @ a time |
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Step 2
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persistent asthma
SABA PRN + low dose ICS or cromolyn, LTRA, neodromil, theophylline SQ allergen for allergic asthma |
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Step 3
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persistant asthma
SABA PRN low dose ICS + LABA or medium dose ICS alt. low dose ICS + LTRA/theophylline/Zilueton SQ allergen for allergic asthma |
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Step 4
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Persistent Asthma
SABA PRN medium dose ICS + LABA/LTRA/Zilueton/Theophylline SQ allergen for allergic asthma |
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Step 5
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Persisitent Asthma
SABA PRN high dose ICS + LABA consider Xolair for allergies |
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Step 6
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Persistant Asthma
PRN SABA high dose ICS + LABA + PO corticosteriods Xolair for patient with allergies |
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BEST study group
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beclomethasone along just as effective as beclomethasone + albueterol
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Acute Asthma excerbation with good response (PEF>80%) w/no wheezing/SOB for 4 hours
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at time of excerbation take up to 3 tx of 2-4 puffs @ 20 minute intervals
may continue SABA Q3-4 hours for 1-2days |
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Acute Asthma excerbation with incomplete response (PEF = 50-80%) w/persisten wheezing/SOB
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at time of excerbation take up to 3 tx of 2-4 puffs @ 20 minute intervals
then add PO corticosteriod & SABA tx contact MD |
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Acute Asthma excerbation w/poor response (PEF<50%)
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at time of excerbation take up to 3 tx of 2-4 puffs @ 20 minute intervals
add PO corticosteriod use SABA ASAP call 911 |
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Severe Acute Asthma
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SABA Q20 minutes or continues
systemic corticosteriods (PO/IV) IPRATROPIUM (improve lung function 10-15%) oxygen |
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Mg Sulfate
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causes bronchodilation after B2 agonists and anticholingerics have failed for severe acute asthma
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aminphylline
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bronchodilator
combo of theophylline & ethylerediame |
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BEST study
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shows that ICS(beclomethasone) may be as effective in acute relief as albuterol
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COPD
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decreased FEV-1 that is not fully reversible
inflammatory & destructive lung disease |
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blue bloater
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daily coughing w/sputum
chronic bronchitis |
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pink puffers
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alveolar destruction
emphysema |
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Chronic Bronchitis
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chronic cough w/sputum
>4 days/wk >/= 3 months of the year for at least 2 consecuative years cystic fibrosis dx ruled out |
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emphysema
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permanent abnormal airspace englargement due to destruction of alveolar walls
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COPD
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4th leading cause of death in the US
approx. 20 pack/year history but VERY variable |
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ZZ phenotype
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alpha-1-antitrypsin deficiency
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Genetic factors contributing to development of COPD
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polymorphism of epoxide hydrolase
vitamin D binding protein matrix metalloproteinase-9 hyperresponive airways |
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inflammation in COPD due to
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neutrophil
macrophage CD8 lymphocytes as opposed to esoinophil, mast cells and CD4 TH2 cells in asthma |
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inflammatory mediators in COPD
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TNF1-alpha
IL-8 LTB4 result in airway inflammation |
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increased lung oxidants generated by smoking
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hydrogen peroxide
nitric oxide cause direct tissue damage and inflammation |
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smoking causes increased protease release from
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neutrophils and macrophages causing more tissue damage
collagenase gelatinase cathespin-G matrix metalloproteinases |
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bullae
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enlarged airway space caused by destruction of alveoli in emphysema
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cardinal feature of COPD
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loss of elastic recoil of lung
airway obstruction by mucous and edema, bronchospasm, and remodeling loss of airway tethering(keep airways open) by alveolus reduced FEV-1 |
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elevated TLC is caused by
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hyperinflation in COPD due to loss of alveoli and bullae development
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decreased Vt
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tidal volume decreases because diaphram is flattened due to hyperinflation and not capable of maximum cotnraction in COPD
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Ve =
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RR x Tv
if Vt(tidal volume) is low, RR must increase to maintain Ve |
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chronic hypoxemia causes
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pulmonary HT and right-sided HF
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Systemic inflammation involed in COPD not just the lung and causes
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cachexia and muscle wasting
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causes of acute exacerbation of COPD
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infection
ongoing smoking poor air quality |
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COPD occur in
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bronchioles and further down respiratroy trunk
asthma occurs in bronchi |
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Diagnose emphysema
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with chest x-ray
biopsy (not common) |
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mild COPD
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FEV1/FVC < 70%
FEV1 >/= 80% |
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moderate COPD
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FEV1/FVC < 70%
FEV1 = 50-80% |
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severe COPD
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FEV1/FVC <70%
FEV1 = 30-50% |
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very severe COPD
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FEV1/FVC < 70%
FEV1 < 30%/presence of chronic respiratory failure |
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tx COPD nonpharm
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exercise 3-7 times/week
Influenza vaccines can reduce death by 50% pneumococcal vaccine - for 2-64 yr if FEV1 <40% - for >/=65 yr & previous vaccination was > 5 years earlier & was younger than 65 oxygen increases survival |
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oxygen for COPD
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resting PaO2 < 55 mmHg
evidence of right heart failure, polycythemia orimparied nuerpyschiatric function w/PaO2 <60 mmHg |
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pharm tx for COPD
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no tx has been shown to modify the long term decline in lung function or prolong survival
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Ipratropium
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Atrovent
dose/PRN 2 puffs QID up to 24 puffs/day longer onset than SABA but similar improvements |
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Arformoterol
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Brovana
indicated for long-term maintaince of bronchoconstriction in COPD dose: 15 mcg BID via jet nebulizer 1st long acting B2 for nebulizer! decreased need for short acting therapy (albuterol/ipatropium) fomoterol is also now available as a nebulizer |
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Tiotropium Br
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Spiriva
long acting DPI 18 mcg QD administered vis handihaler |
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Tiotropium AEs
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dry mouth
constipation urinary retention tachycardia blurred vision |
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UPLIFT
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demonstrated improvement in FEV1, SGRQ, & reduction in hospitalizations, exacerbations, & respiratory failure
NO reduction in rate of decline |
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combivent
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albuterol = 103 mcg
ipratropium = 18 mcg need to titrate ipratropium 1st! |
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methlyxanthines
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not 1st line for COPD!
use when intolerat to bronchodilator or not achieving optimal response with LABAs & anticholinergics |
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Theophylline in COPD improves Vital capacity, FEV-1, minute ventilation, and gas exchange
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200 mg BID titrated Q3-5 days up to 400-900 mg/day
range: 10 mcg/mL(8mcg/mL - 15 mcg/mL) monitor once or twice a year |
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ICS in COPD
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only for documented spirometric response or FEV-1 < 50% (stage 3 & 4) who have repeated excerbations
trial of 6 wks - 3 months |
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TORCH
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improvements in FEV-1, health status, and frequency of excerbations with ICS + bronchodialor [advair diskus]
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Advair Diskus
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salmeterol 50 mcg
Fluticasone 500 mcg |
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Systemic corticosteriods for COPD
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not recommended
only benefit if esonifphils in sputum or good response to sympathomimetrics - might have asthma use short course(2 weeks) in acute exacerbations[reduces hospitlization and improves outcomes] |
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AAT dose
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60 mg/kg IV weekly
prolastin/aralast/zemaira |
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tx mild COPD
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short-acting bronchodilator
combivent/albuterol |
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tx moderate COPD
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short-acting bronchodilator + LABA
add rehabiltiation |
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tx severe COPD
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short acting bronchodilator + LABA + ICS if repeated excerbations
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tx very severe COPD
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short acting bronchodilator + LABA + ICS + oxygen if respiratory failure
PaO2 < 55 mm Hg or PaO2 < 60 mm Hg with right sided heart failure, polycythemia, or impaired neuropsychiatric function |
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COPD excerbation uncomplicated
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azithromycin, clarithromycin, doxycycline, 2nd or 3rd generation cephlosporin if increased sputum production and purulence & dyspnea
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COPD excerbation
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IV-PO corticosteriods for 9-14 days [taper if therapy is 2weeks]
increase dose and frequency of bronchodilators spacers/air driven neulizers iv methylxanthines if needed oxygen so O2 sat. > 90% Positive Pressure Ventilation |
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Positive Pressure Ventilation is not for
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altered mental status
severe acidosis(hypercarbic) respiratory arrest CV instability |
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best expectorant
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water
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complicated COPD excerbation
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use levofloxacin
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