Asthma Flashcards
What is bronchial hyper reactivity?
Pathologic increase in the bronchoconstrictor response to antigens and irritants; caused by bronchial inflammation
What is an IgE mediated disease?
Disease caused by excessive or misdirected immune response mediated by IgE antibodies.
Example: asthma
What is mast cell degranulation?
exocytosis of granules from mast cells with release of mediators of inflammation and bronchoconstriciton
What is phosphodiesterase (PDE)?
family of enzymes that degrade cyclic nucleotides to nucleotides
ex. cAMP (active) to AMP (inactive)
What is tachyphylaxis?
rapid loss of responsiveness to a stimulus
i.e. a drug
What are some agents/events that can trigger or increase susceptibility to asthma?
Respiratory infection, Allergens Environment (cold air, nitrogen dioxide, tobacco smoke, etc.), emotions, exercise, drugs/preservatives (Acetaminophen, ASA, NSAIDs, sulfites), occupation stimuli
Host factors that increase the risk for asthma…
obesity, African American race, Hispanic ethnicity, low SES
What are some high sulfite containing foods that may trigger asthma?
dried fruit, lemon juice, wine, molasses
Describe asthma
episodic or chronic sxs of airflow obstruction
reversibility of airflow obstruction spontaneous or after bronchodilator
prolonged expiratory and diffuse wheezes on PE
limitation of airflow on PFT or + bronchoprovocation challenge
What is asthma drug therapy aimed at?
narrow airway, tightened muscles, inflammation
Pathology found in asthmatic bronchus?
narrowed lumen:
hypertrophy of the BM, mucus plugging and smooth muscle hypertrophy and constriction contribute
inflammatory cells infiltrate, producing submucosal edema & epithelial desquamation fills airway w/ cellular debris and exposes airway to smooth muscles to other mediators
What are the different phases of asthma?
Immediate asthma response (IAR): minutes –> bronchoconstriction
late asthma response (LAR): hours–> submucosal edema, hyper-responsiveness
chronic asthma: epithelial cell damage, mucus hyper secretion, hyper-responsiveness
What are the long term goals of asthma management?
- achieve good control of sxs and maintain norm. activity levels
- minimize future risk of exacerbations, fixed airflow limitation and side effects
(According to GINA-global initiative for asthma)
Asthma treatment goals in immediate phase? (rescue)
Prevent bronchoconstriction (rescue)
- B2 adrenergic agonist
- theophylline
- anticholinergic (antimuscarinic)
- Mediator antagonist
Asthma treatment goals in late/chronic phase? (controller)
reduce inflammation
-corticosteroids
prevent irritant reaction (IgE)
(bronchial hyper-responsiveness)
-lipoxygenase or leukotriene inhibitors
B agonists, muscarinic antagonists, theophylline and leukotriene antagonists all work to…
alter bronchial tone in asthma
Beta agonists MOA?
stimulate adenylyl cyclase
increase cyclic adenosine monophosphate (cAMP) in smooth muscle cells
increase in cAMP results in a powerful bronchodilator response
Name 3 Beta2 agonists
Albuterol*
Terbutaline
Metaproterenol
(inhalation route decreases the systemic dose & adverse effects while delivering an effective dose locally to the airway smooth muscle)
Duration of action of newer beta2 agonist agents such as salmeterol, formoterol and indacaterol? older agents?
12-24hrs
older agents: 6 hrs or less
Clinical application of Albuterol?
acute asthma attack drug of choice
Effects of albuterol?
prompt bronchodilation
Albuterol toxicities?
tremor, tachycardia
Which short acting beta2 agonists can be given orally or parenterally?
Terbutaline
Name 3 long acting beta agonists
Salmeterol, formoterol, indacaterol
LABA MOA?
beta2 selective agonists, bronchodilation, potentiation of corticosteroid action
Salmeterol clinical application?
asthma prophylaxis
Indacaterol for COPD
effects of Salmeterol?
slow onset, primarily preventative action, potentiates corticosteroid effects
Salmeterol toxicities?
tremor, tachycardia, CV events
What are some antimuscarinic (anticholinergic) agents?
Atropine
Ipratropium
Tiotropium: longer acting analogue of Ipratropium
Ipatropium and Tiotropium MOA?
given as aerosol
competitively block muscarinic receptors in the airways and effectively prevent bronchoconstriction mediated by vagal discharge
reverse bronchoconstriction in some asthma pts and in many pts with COPD
Do antimuscarinic agents have an effect on the chronic inflammatory aspects of asthma?
NO
Toxicities of Ipratropium and Tiotropium?
dry mouth, cough
What are three major Methylxatines, which are found in plants and provide the stimulant effect of 3 common drinks?
Caffeine
Theophylline (tea)
Theobromine (cocoa)
Theophylline MOA?
inhibits phosphodiesterase (PDE) -enzyme that degrades cAMP to AMP, thus increase cAMP
block adenosine receptors
(adenosine as used to momentarily stop electrical impulse propagation through the heart)
Effects of theophylline?
Bronchodilation
Increased strength of contraction of diaphragm
Other effects: CNS stimulation, cardiac stimulation, vasodilation, slight increased in BP, diuresis, increased GI motility
What can be used to revere severe CV toxicity from theophylline?
Beta blockers
Theophylline PK?
oral
short and long acting formulations
eliminated through liver CYP450 enzymes
clearance varies w/ age: highest in young adults, higher in smokers
Clinical applications of theophylline?
asthma, especially prophylactic against nocturnal attacks
Theophylline toxicities?
insomnia, tremor, anorexia, seizures, arrhythmias
How should you dose Theophylline?
gradually increase as tolerated
Name some corticosteroids
Prednisone, Beclomethasome, Budesonide, Fluticasone, Mometasone
all potentially beneficially in severe asthma
When are systemic corticosteroids used?
for acute exacerbations or chronically only when other therapies are unsuccessful
Prednisolone is an…
active metabolite of prednisone
important IV corticosteroids for status asthmaticus
Corticosteroid MOA?
reduce the synthesis of arachidonic acid by phospholipase A2 and inhibit the expression of COX-2, the inducible form of cyclooxygenase
increase the responsiveness of beta in the airway
prevent the full expression of inflammation and allergy by activating glucocorticoid response elements
reduce activity of phospholipase A
Effects of inhaled corticosteroids like Beclomethasone?
Reduces mediators of inflammation, powerful prophylaxis of exacerbations
Beclomethasone toxicities?
pharyngeal candidiasis
minimal systemic steroid toxicity (such as adrenal suppression).
What are some of the beneficial effects of inhaled corticosteroids?
decreased eosinophils/mast cells/t lymphocyte cytokine production
inhibit transcription of inflammatory genes in airway epithelium
reduce epithelial cell leak
upregulate B2 receptor production
reduce airway thickening
What are some potential adverse effects of inhaled corticosteroids?
hoarseness, dysphonia, thrush, growth retardation, skeletal muscle myopathy, osteoporosis, fractures, adrenal axis suppression, immunosuppression, impaired wound healing, HTN, psychiatric disturbances
Use of ICS in children…
does cause mild growth retardation
but these children will generally reach full predicted adult stature
Which systemic corticosteroid has the high anti-inflammatory potency?
dexamethasone
Leukotriene antagonists MOA?
interfere with the synthesis or the action of the leukotrienes
-not as effective as corticosteroids in severe asthma
Name 2 leukotriene antagonists (receptor blockers)
Zafirlukast and Montelukast
-antagonists at the LTD4 leukotriene receptor
orally active
Clinical application of Montelukast?
effective in preventing exercise, antigen and aspirin induced bronchospasm
-not recommended for acute episodes of asthma-
Name a lipoxygenase inhibitor (Leukotriene antagonist). MOA?
Zileuton
orally active drug
selectively inhibits 5 lipoxygenase, which is a key enzyme in the conversion of arachidonic acid to leukotrienes
Zileuton clinical application?
prevents both exercise and antigen induced bronchospasm, affective against “ASA allergy”
Zileuton toxicities?
elevation in liver enzymes
When is cromolyn used?
rarely in US, use prior to gardening or outdoor activity
Anti-igE antiiody
Cromolyn MOA?
poorly understood.
decreased in release of mediators (leukotrienes), can prevent bronchoconstriction, prevent early and late responses to challenge. Cromolyn can help w/ preventing food allergy.
Cromolyn can also be used for…
ophthalmic, nassopharyngeal and GI allergy
Side effect of Cromolyn?
cough
What are some monoclonal abs for use in asthma?
omalizumab, mepolizumab, benralizumab
Omalizumab drug class? MOA?
anti IgE antibody
humanized murune monoclonal ab to human IgE
binds to the igE on sensitized mast cells and prevents activation by asthma triggers and subsequent release of inflammatory mediators
Why is Omalizumab not really used?
very expensive and must be administered parenterally
What pts can Mepolizumab be used in?
tx of asthma in pts who are age 12 or older, have freq. asthma exacerbations and have an eosinophilic phenotype (one marker eosinophil count >150)
admin SQ at 4 wk intervals
small increase in herpes zoster in treated adults
GINA asthma dx…pt must have?
-hx of respiratory sxs that vary over time and intensity
- variable expiratory airflow limitation
- reduced FEV1/FVC
- FEV1 increases >12% w/ bronchodilator tx
GINA recommends what to asthma pts, even though with infrequent sxs, to reduce the risk of serious exacerbations?
ICS
Asthma step wise tx approach, what do you give at each step?
1- maybe ICS 2-low dose IC 3- low dose ICS/LABA 4-med or high ICS/LABA 5-refer for add on tx
SABA for all
