Bronchodilators: Shorter acting selective beta-2 adrenergic receptor agonists
Albuterol
Levalbuterol
Metaproterenol
Terbutaline
Bronchodilators: Longer acting selective beta-2 adrenergic receptor agonists
Salmeterol
Formoterol
Indacaterol (COPD)
Bronchodilators: Muscarinic receptor antagonists
Ipratropium
Tiatropium
Bronchodilators: Methylxanthines
Theophylline
Roflumilast (COPD)
Leukotriene modulators - LTC4/D4 receptor antagonists
Montelukast
Zafirlukast
Leukotriene Modulators - 5-lipoxygenase inhibitor
Zileuton
Anti-inflammatory drugs: corticosteroids
Budesonide Fluticasone Beclomethasone Flunisolide Mometasone Prednisone (systemic)
Anti-inflammatory drugs: biologicals
Omalizumab (anti- IgE antibody)
Asthma controller use
Inhaled and oral agents: used chonically/daily during asymptomatic periods
Limit frequent, severe asthma attacks. Do not replace relievers which must till be used during asthmatic attack
Asthma Relievers
Bronchodilators - short acting beta-2 adrenergic receptor agonists, used alone or with controllers
Theophylline
Asthma Controllers
Anti-inflammatory - corticosteroids, leukotriene modifiers, anti-IgE antibody
+/- bronchodilators - long-acting beta-2 agonist, anti-cholinergic agent
theophylline
Mild intermittent asthma
Attacks: less than 2 per week
Peak Flow: near normal
Long-term control: n/a
Relief: SABA
Mild persistent asthma
Attacks: >2/wk
Peak Flow: near normal
Long-term control: Low dose ICS
Relief: SABA
Moderate persistent asthma
Attacks: daily
Peak Flow: 60-80% of predicted
Long-term control: Low med dose ICS with LABA
Relief: SABA
Severe persistent asthma
Attacks: continual
Peak Flow: less than 60% of predicted
Long-term control: high dose ICS with LABA + others
Relief: SABA
Inhaled SABA prn for mild intermittent asthma (Step 1)
Take prn for relief of symptoms.
Onset 5-15 min, lasting 4-6 hr
Use 10 minutes prior to predicted trigger (cold, exercise) to prevent onset of symptoms
SABA (inhaled)
Relievers: Albuterol Levalbuterol Metaproterenol Terbutaline
LABA (inhaled)
Salmeterol
Formoterol
Controllers, not relievers
Location of action of inhaled B2 agonists
B2 selective adrenergic receptor agonists preferentially act on pulmonary smooth muscle, compared to cardiac smooth muscle
Relax smooth muscle and dilate airways
B2 receptor antagonists
harmful on airway, negate any beneficial effects on the heart in asthma patients with heart conditions
Propranolol
Nadolol
Timolol
Pindolol
Low dose daily inhaled corticosteroid in mild persistent asthma (Step 2)
Budesonide - high potency Fluticasone - high potency Beclamethasone Mometasone Flunisolide Prednisone (systemic, non inhaled)
Action of corticosteroids
CSR corticoid receptor when occupied –> dimerization, nuclear transport and gene transcription
Suppress inflammatory genes
Express anti-inflammatory genes
ICS not quick acting
Maximal effect on FEV1 may take 1 week or more
Benefits of daily inhaled corticosteroids
Fewer symptoms
fewer severe exacerbations
reduced use of SABA bronchodilators
Improved lung function (improve FEV1 >80% predicted)
Reduced airway inflammation (decline in leukocytes, LTs, cytokines, NO exhalation will decline
Complications of corticosteroids
Impair growth in children
oral candidiasis in adults due to localized mucosal immunosuppression
Post-menopausal systemic dosing can aggravate osteoporosis, overuse can confer risk of osteoporosis
Systemic glucocorticoids used in asthma
Oral or IV
Prednisone
Prednisolone
Dexamethasone
Taper off after control of severe asthma attacks established
associated with impaired wound healing, psychosis, osteoporosis, HTN, glaucoma
Medium dose ICS plus LABA plus SABA prn for moderate persistent asthma (Step 3)
daily attack with FEV1 60-80%
Corticosteroid and B2 receptor agonists
Budesonide/formoterol
Fluticasone/salmeterol
Effects of beta adrenergic receptor agonists: SABA and LABA
Decreased blood potassium levels
increases blood sugar levels
LABA agonists
Salmeterol, formoterol
not for immediate leave or substitution for anti-inflammatory drugs
beneficial with ICS
Don’t use alone as associated with increased risk of death in asthmatic patients
Salmeterol black box warning
increased risk of asthma related death, reserve for patients who are not controlled on low-to-medium dose corticosteroid + rescue inhaler
Leukotrienes
lipid mediates of inflammation
LTC4 and LTD4 promote inflammation, edema, mucus formation, bronchospasm
Phospholipase A2 converts phospholipids to arachidonic acid
5-lipoxygenase converts AA to LTA4.
Tissue specific isomerases convert to LTB4 and LTC4, LTD4, LTE4
Zileuton
LT modifier
inhibits 5-lipoxygenase
inhibits LT biosynthesis
2x daily
approved for children older than 12
Zafirlukast
LT modifier
Antagonist of cysteinyl LT receptors
2x daily, approved for children older than 5
Montelukast
LT modifier
antagonist of cysteinyl LT receptors
1 x daily, approved for children older than 1
LT receptor antagonists in mild persistent asthma (step 2)
alternative to ICS
LT receptor antagonists/inhibitor in moderate persistent asthma (step3)
alternative or additive to ICS + LABA
Adverse effects of Zileuton
Liver toxicity - elevated ALT
Flu like symptoms - chills, fever, fatigue, myalgias
Adverse effects of zafirlukast and montelukast
Liver toxicity - discontinue therapy (Zafirlukast only)
Hypersensitivity - angioedema, rash, eosinophilia
Clinical indication for Leukotriene modifiers
first line for patient who will not take or cannot tolerate inhaled corticosteroids
Aspirin sensitive asthma
excessive leukotriene production
tend to benefit from leukotrienes modifiers are added to inhaled and/or oral glucocorticoids
Exercise induced asthma
zileuton, montelukast, zafirlukast all prevent exercise-induced bronchospasm
Omalizumab
recombinant humanized monoclonal antibody targeted against IgE
IgE bound to omalizumab cannot bind to IgE receptor on mast cells and basophils
Used to blunt allergic reaction only when environmental or occupational allergens provoke asthma
Omalizumab boxed warning
anaphylaxis as early as 1st dose also beyond 1 year after beginning treatment
Theophylline in asthma
oral
If asthma not adequately controlled with conventional doses of ICS + LABA
If pt adheres to oral drug, but not inhaled and montelukast is ineffective
Inhalation difficult (toddlers) and montelukast ineffective
Additive in ICU patients failing to respond to IV corticoids, etc
Cellular actions of theophylline
inhibition of PDE4 thus inhibiting breakdown of cAMP
Blockade of adenosine receptors
Adverse effects of theophylline
CNS stimulation, nervousness, restlessness, insomnia, tremors, anorexia
Cardiovascular: palpitations, arrhythmias, convulsions
COPD vs asthma
alveolar disruption and much worse fibrosis in COPD
Smokers - COPD
younger than 35 - asthma
chronic productive cough - COPD
Breathlessness - persistent and progressive = COPD, variable = asthma
Nocturnal breathlessness - asthma
Diurnal or day-to-day variation of symptoms - asthma
Ipatropium and tiatropium MOA
inhibit muscarinic M1-M3 receptors
relieve parasympathetic tone, relieving bronchoconstriction, decrease mucus discharge
foundation for treatment of COPD
Can be used in asthma, but less effective than B2 adrenergic receptor agonists (SABA or LABA)
Vagus nerve
innervates airways, releases ACh causing pulmonary sm. m. constriction and increase mucus discharge
Ipratropium
inhaled
short acting - 6 hrs, dose 3-4 x/day
quick onset - 15 min
Less selective M1-M3 antagonist
Quaternary amine +
peripheral effects
NOT CNS due to charge
Tiotropium
Inhaled
Long acting, once per day dose
Onset 30 min
More selective, M1 and M3
Quaternary amine +
Peripheral effects
NOT CNS due to charge
Gold stages for COPD
I - intermittent symptoms
II - persistent symptoms
III - frequent exacerbations
IV - respiratory failure
Stage I bronchodilators for COPD
Short acting
Ipratropium, albuterol or combination
Stage II bronchodilators for COPD
Long acting and short acting
Tiotropium and albuterol
Salmeterol or formoterol + ipratropium, albuterol, or combination
Stage III bronchodilators for COPD
Long acting - 2 mechanisms
Tiatropium + salmeterol or fomoterol
Stage IV bronchodilators for COPD
Add inhaled corticosteroid to long acting
Tiatropium
Budesonid/formoterol
Fluticasone/salmeterol
Roflumilast
PDE4 inhibitor
reduce risk of COPD exacerbation in patients with frequent exacerations
Leukotriene modifiers in COPD
No role of leukotriene modifiers and mast cell stabilizers in management of COPD
Glucocorticosteroids in COPD
chronic treatment with systemic glucocorticosteroids avoided because of unfavorable benefit to risk ratio