Asthma Flashcards
Drugs that trigger or increase susceptibility to asthma
acetaminophen aspirin NSAIDs (cyclooxygenase inhibitors) sulfites benzalkonium chloride nonselective beta blockers
Asthma
reversible airflow obstruction
prolonged expiration
diffuse wheezes
sx worse at night/early morning
Asthma: targets of drug therapy
- narrow airway
- tightened muscles
- inflammation
Asthma: diagnostics
limitation of airflow on PFTs
or
positive bronchoprovocation challenge
Asthma: pathology
bronchial lumen is narrowed due to:
-airway remodeling (hypertrophy of BM, mucus plugging, hypertrophy of smooth muscle, hypertrophic goblet cells)
-inflammation (infiltration of inflammatory cells, edema, cellular debris)
Phases of Asthma: immediate asthmatic response
minutes
bronchoconstriction
lymphocytes and mast cells
histamine and prostaglandins
Phases of Asthma: late asthmatic response
hours
submucosal edema, hyperresponsiveness
neutrophils, macrophages, eosinophils, monocytes
Phases of Asthma: chronic asthma
days
epithelial damage, mucus hypersecretion, hyperresponsiveness
eosinophils, lymphocytes
preeosinophil
Asthma and Exercise
initial bronchodilation then crash in PEF
Intermittent Asthma (initial)
symptoms: = 2 d/wk nighttime awakenings: = 2 d/wk SABA use: =2 d/wk limit on activity: none FEV1: >80% FEV1/FVC: >85% or N exacerbation risk: 0-1/year recommended step: step 1
Persistent Mild Asthma (initial)
symptoms: >2d/wk nighttime awakenings: 3-4/mo SABA use: >2d/wk limit on activity: minor FEV1: >80% FEV1/FVC: >80% or N exacerbation risk: >/= 2/yr recommended step: step 2
Persistent Moderate Asthma (initial)
symptoms: daily nighttime awakenings: >1x/week SABA use: daily limit on activity: some FEV1: 60-80% FEV1/FVC: 75-80% exacerbation risk: >/=2/year recommended step: step 3
Persistent Severe Asthma (initial)
symptoms: throughout the day nighttime awakenings: 7x/wk SABA use: several times per day limit on activity: extreme FEV1: <60% FEV1/FVC: <75% exacerbation risk: >/=2/year recommended step: step 3/4
Risk Factors for Exacerbations
uncontrolled asthma symptoms
high SABA use
>/= 1 exacerbation in the last 12 months
low FEV1
incorrect inhaler technique/poor adherence
smoking
obesity, chronic rhinosinusitis, pregnancy, blood eosinophilia
Risk factors for fixed airflow limitation
no ICS treatment smoking occupational exposures mucus hyper secretion blood eosinophilia pre term birth low birth weight
Risk factors for medication side effects
frequent oral steroids
high dose ICS
P450 inhibitors
Treatment Goals
prevent bronchoconstriction
reduce inflammation
prevent irritant reaction
immunotherapy if severe
Treatment Goals: prevent bronchoconstriction (agents)
early phase - rescue
- beta 2 agonist
- theophylline
- anticholinergic (antimuscarinic)
- mediator antagonist
Treatment Goals: reduce inflammation (agents)
late/chronic phase - controller
-corticosteroids
Treatment Goals: prevent irritant reaction (IgE) (agents)
aka bronchial hyperresponsiveness
late/chronic phase
- lipoxygenase
- leukotriene inhibitors
Asthma: Step 1
SABA as needed
Asthma: Step 2
low dose ICS
alternative: cromolyn, LTRA, theophylline
Asthma: Step 3
low dose ICS + LABA
or
medium dose ICS
alternative: low dose ICS + either LTRA, theophylline, zileuton
Asthma: Step 4
medium dose ICS + LABA
alternative: medium dose ICS+either LTRA, theoyphylline, zileuton
consult with asthma specialist
Asthma: Step 5
high dose ICS + LABA and consider omalizumab for patients who have allergies
consult with asthma specialist
Asthma: Step 6
high dose ICS + LABA + oral corticosteroids and consider omalizumab for patients who have allergies
consult with asthma specialist
What is the therapy target in the arachidonic cascade?
LTD4 (leukotriene)
Effects of Nitric Acid in Asthma
smooth muscle relaxation capillary leakage increased mucus secretion inflammatory cell chemotaxis (eosinophils, T lymphocytes)(iNOS) remodeling (arginase pathway)
Muscarinic Effects (dumbbbelss)
diarrhea urination miosis/muscle weakness bronchorrhea bronchospasm bradycardia emesis lacrimation salivation sweating
Beta 2 Agonist: MOA
beta adrenoreceptor agonist
stimulate adenylyl cyclase–> inc cAMP in smooth muscle–> powerful bronchodilator response
Beta 2 Agonist: agents, method of delivery
albuterol, terbutaline, metaproterenol (~6 hr duration)
salmeterol, formoterol, indacaterol (12-24hr duration)
inhalation
- dec systemic dose (adverse effects)
- effective dose to airway smooth muscle
Beta 2 Agonist: albuterol (SABA)
beta selective bronchodilation
acute asthma attacks
ADE: toxicities, tachycardia
Beta 2 Agonist: salmeterol (LABA)
beta 2 selective bronchodilation, potentiation of corticosteroid action
asthma prophylaxis (NOT acute release)
slow onset
preventative
potentiates corticosteroid effects
ADE: tremor, tachycardia, cardiovascular events
Antimuscarinic (Anticholinergic) Agents
atropine: belladonna alkaloid
ipratropium: little systemic action
tiotropium: longer acting analog
Antimuscarinics: MOA
competitively block muscarinic receptors –> prevent bronchoconstriction
can also reverse bronchoconstriction in asthmatic children and COPD patients
Antimuscarinics: ipratropium, tiotropium
competitive muscarinic antagonists
asthma and COPD
ADE: dry mouth, cough
Methylxanthines
provide stimulant effects
caffeine (coffee)(inc CNS effect)
theophylline (tea)
theobromine (cocoa)(inc cardiac effect)
Theophylline: MOA
- inhibits PDE –> inc cAMP
- blocks adenosine receptors
**adenosine: can momentarily stop the electrical impulse propagation through the heart, esp for PSVT
Theophylline
bronchodilation
inc strength of contraction of the diaphragm
CNS stimulation, cardiac stimulation, vasodilation, inc BP, diuresis, inc GI motility
**beta blockers are useful in reversing severe cardiovascular toxicity from theophylline.
elimination through liver CYP450 enzymes
Theophylline: clearance
highest in young adolescents
higher in smokers
varies with concurrent use of other drugs that inhibit/induce hepatic enzymes
Theophylline: clinical applications, effects, ADEs
asthma (prophylactic against nocturnal attacks)
bronchodilation
cardiac stimulation
inc skeletal muscle strength
ADE: insomnia tremor anorexia seizures arrhythmias
Theophylline: dosage
start low
go slow
check drug levels
Corticosteroids: prednisone, prednisolone
systemic (oral)
acute exacerbations
or
chronically when other tx unsuccessful
Corticosteroids: beclomethasone, budesonide, dexamethasone, flunisolide, fluticasone, mometasone
aerosol
common 1st line for mod-sev asthma
Corticosteroids: prednisolone and hydrocortisone
IV
for status asthmaticus
Corticosteroid: MOA
- reduce synthesis of arachidonic acid by phospholipase A2
- inhibit/red expression of COX-2 (inducible form of cyclooxygenase)
inc responsiveness of beta adrenoreceptors
reduces mediators of inflammation
Inhaled Corticosteroids: clinical applications, ADEs
prophylaxis if asthma (drugs of choice)
ADEs:
pharyngeal candidiasis
minimal systemic steroid toxicity (eg: adrenal suppression)
Systemic Corticosteroids: clinical applications
treatment of severe refractory chronic asthma
Inhaled Corticosteroids: beneficial effects
dec eosinophils
dec mast cells
dec T lymphocyte cytokine production
inhibition of transcription of inflammatory genes in airway epithelium
reduced endothelial cell leak
Inhaled Corticosteroids: beneficial effects
dec eosinophils
dec mast cells
dec T lymphocyte cytokine production
inhibition of transcription of inflammatory genes in airway epithelium
reduced endothelial cell leak
upregulates beta 2 receptor production
reduced airway epithelial subbasement membrane thickening
Inhaled Corticosteroids: potential adverse effects
hoarseness, dysphonia, thrush
growth retardation, skeletal muscle myopathy
osteoporosis, fractures, aseptic necrosis of hip
posterior subcapsular cataract formation and glaucoma
adrenal axis suppression, immunosuppression
impaired wound healing, easy bruising, striae
hyperglycemia/hypokalemia, HTN
psychiatric disturbances
Look at systemic corticosteroid comparison chart slide 44
dexamethasone might be the best but idk
Are ICS medications routinely prescribed or written for PRN use?
Routinely prescribed - they’re late phase
Leukotriene Antagonists: MOA
interfere with the synthesis/action of leukotrienes
not as effective as corticosteroids in severe asthma
Leukotriene Antagonists: zafirlukast, montelukast
leukotriene receptor blockers - antagonists at LTD 4 receptor
prevent exercise, antigen, aspirin induced bronchospasm
NOT recommended for acute episodes
designed to be most useful for nighttime symptoms
Leukotriene Antagonists: zileuton
selectively inhibits 5-lipoxygenase (converts arachidonic acid to leukotrienes)
prevents exercise and antigen induced bronchospasm
effective against “aspirin allergy”
ADE: elevation of liver enzymes
Aspirin Allergy
bronchospasm resulting from ingestion of aspirin
divert all eicosanoid production to leukotrienes when cyclooxygenase pathway is blocked
Leukotriene Antagonists: clinical application
prophylaxis of asthma
Cromolyn and Nedocromil
anti IgE antibody
rarely used in the US
use prior to gardening or outdoor activity
prophylaxis of asthma
(also ophthalmic, nasopharyngeal, GI allergy)
ADE: cough
Cromolyn: MOA
dec in the release of mediators (leukotrienes, histamines) from mast cells
prevents bronchoconstriction/ acute bronchospasm
prevent early and late response to challenge
some efficacy preventing food allergy
Monoclonal Antibodies: Omalizumab
anti-IgE antibody
binds to IgE on mast cell –> prevents activation by asthma triggers and inflammatory mediator release
prophylactic for severe, refractory asthma
reduces frequency of exacerbations
parenteral
long term toxicity
Monoclonal Antibody: Mepolizumab, Benralizumab, Reslizumab
antibody to IL-5
severe eosinophilic asthma 12+ years old
frequent exacerbations
**marker for eos phenotype: : absolute eos count in peripheral blood >/=150
enables a reduction in the oral glucocorticoid dose
SQ
**sm inc in herpes zoster in treated adults (vaccine at least 4 wks prior to initiation)
