9/22- Pharmacology of Obstructive Lung Diseases Flashcards
What are the main pathologic features in obstructive lung diseases?
- Bronchoconstriction
- Increased airway inflammation
- Increased mucus production
- Airway Remodeling
- Parenchymal lung destruction (emphysema)
Describe PS bronchial autonomic innervation
- NT
- Mechanism
- End result
Parasympathetic
- NT: ACh
- Binds muscarinic M3 receptors (cholinergic) on sm cells within bronchial walls
- End result: constricts the airways
Describe sympathetic bronchial autonomic innervation
- NT
- Mechanism
- End result
- NT: catecholamines
- Binds adrenergic receptors
- Airway sm cells express B2 adrenergic receps mainly (expressed elsewhere too, but mostly on smooth muscles)
- End result: bronchodilation
Overview of Medications for Asthma - Ant-inflammatories - Bronchodilators - Others
Anti-inflammatories:
- Inhaled Corticosteroids
- Antileukotrienes
- Cromones
- Theophylline (?)
Bronchodilators
- Short and Long-acting ß-agonists
- Short-acting Anticholinergic ICS/LABA
Combination
Anti IgE
(Thus, you can see that bronchodilation may be achieved by promoting sympathetic stimulation or blocking PS)
Overview of Medications for COPD:
- Ant-inflammatories
- Bronchodilators
- Others
Anti-inflammatories:
- Inhaled Corticosteroids
- Roflumilast Bronchodilators
- Short and Long-acting ß-agonists
- Short and Long-acting
Anticholinergics
- Theophylline
What method of administration is preferred for bronchodilators?
Inhalation
- Can be given systemically if really severe/can’t inhale
What is the benefit of combining bronchodilators in COPD?
- May improve efficacy
- May decrease the risk of side effects compared with increasing the dose of a single bronchodilator
Provide examples of classes of bronchodilators?
- Beta 2 agonists
- Anticholinergics
- Methylxanthines
How do the following effect bronchodilation?
- Beta agonists
- Muscarinic antagonists
- Theophylline
- Beta agonists: activation of AC -> more cAMP -> bronchodilation
- Muscarinic antagonists: block ACh activation of bronchoconstriction
- Theophylline: blocks PDE, increasing cAMP levels (by preventing cAMP -> AMP degradation) and blocks adenosine (?)
In addition to relaxing airway sm, what other functions to B2 agonists have?
- Inhibition of plasma exudation and airway edema
- No effect on chronic inflammation
- Don’t want too use to frequently (bad outcomes), so used to supplement long-acting treatment
Provide example drugs for short and long-acting B2 agonists?
(Don’t need to remember drug names at this point)
Short
- Albuterol
- Pirbuterol
Long
- Salmeterol
- Formoterol
- Indacaterol
Describe short-acting beta agonists
- Onset
- Duration
- Frequency
(Albuterol is the most commonly used rescue inhaler)
- Onset: rapid, within 10-15 min
- Duration: max 4-6 hrs
- Most effective when used on “as-needed” basis, or “rescue”
Describe long-acting beta agonists
- Duration
- Frequency
- Effects
(Salmeterol and formoterol)
- Similar to short-acting, but longer duration: 12 hrs
- Dosed 2x/day
- Variable effects on exercise, exacerbation, QOL
- Should only be used as add-on to ICS (immunocorticosteroids?) in asthma
Recommendations on use of LABAs in Asthma?
Not recommended as monotherapy for long-term control
- Consider as adjunctive therapy in patients aged >5 years who require more than a low-dose ICS
- Consider adding an LTRA in patients aged >5 years
Not recommended for treatment of acute symptoms
May be used before exercise to prevent EIB
How to anticholinergics function to alleviate asthma and COPD (mechanism/targeted pathology)?
- Block vagal pathways-decreases vagal tone
- Blocks reflex bronchoconstriction caused by inhaled irritants
- Role in asthma is less clear (than in COPD) may have added benefit in combination with beta2-agonists in acute asthma
- Delivered locally, but may be associated with systemic effects (since cholinergic): most common = dry mouth
Provide examples of short and long acting anticholinergics (don’t memorize names)?
- Ipratropium: slow onset (30 min)
- Tiotropium: bronchodilation, long acting (24 hrs)
Overall, slower than B2 agonists, which is why the latter are preferred in rescue situations
What drug is included in the class of methylxanthines?
Theophylline
Describe Theophylline
- Functions
- Mechanism
- Duration
- Dosing
- Metabolism
- Toxicity
- Bronchodilator (mild-moderate) with questionable anti-inflammatory properties
- Mechanism uncertain (probably PDE inhibition)
- Long acting dosage form
- Very narrow therapeutic window (get ASEs easily!)
- Recommended serum concentration = 5-8 ug/mL; dose varies person to preson
- Metabolism: liver
Toxicity:
- GI (most common): irritation, burning, nausea
- CNS stimulation: tremors
- Tachyardia
T/F: Theophylline has numerous drug-drug/disease-drug interactions?
True
What drugs/diseases may increase metabolism of Theophylline (decrease levels)?
- Cigarette smoking
- Young age
- Hyperthyroidism
- Barbiturates
- Phenytoin (ex: if someone stops smoking, may have super high theophylline levels)
What drugs/diseases may decrease metabolism of Theophylline (increase levels)?
- Liver disease
- CHF
- Older age
- Viral infections
- Febrile illness
- Macrolide antibiotic
- Cimetidine
- Quinolone antibiotics
- Propranolol
- Allopurinol
What are classes of anti-inflammatory agents used in asthma/COPD treatment?
- Inhaled Corticosteroids
- Leukotriene Modifiers
- Mast-cell stabilizers (Cromones)
- Anti Ig-E therapy (severe allergic asthma)
Describe inhaled corticosteroids
- Systemic effect
- Effects of chronic use
- Frequency
- Not used in what situations
- When to use in asthma
- When to use in COPD
- Potent local anti-inflammatory with minimal systemic toxicity
- Chronic use decreases airway hyper-responsiveness
- A “preventer”, not a “reliever”
- Daily regularly scheduled - Generally not used in acute exacerbations
- Asthma: 1st line in daily asthma management!
- COPD: Reserved for more moderate-severe disease with frequent exacerbation
What are the cellular effects of corticosteroids?
Inflammatory cell effect
- Decrease numbers of eosinphils (apoptosis), mast cells, and dendritic cells
- Decrease cytokine release by T lymphocytes and macrophages
Structural cell effect
- Decrease cytokines/mediators of ep cells
- Decrease endo cell leak
- Decrease B2 receps and cytokines in airway SM
- Decrease mucus secretion
What are the beneficial effects of inhaled corticosteroids that make them the first-line therapy for persistent asthma?
(1st line therapy even in mild persistent disease)
- Reduce asthma symptom severity
- Improve quality of life
- Improve pulmonary function
- Reduce rescue inhaler use
- Reduce exacerbations/ hospitalizations/ ?mortality
- Reduce bronchial hyperreactivity
- Slow deterioration of lung function
- ? May prevent airway remodeling
Basically: improve lung function and symptoms and health status, decrease exacerbations; decrease mortality
- Significant anti-inflammatory effects
What are some safety/risk considerations of inhaled corticosteroids?
- Small risk for topical adverse events at recommended dosage
- New formulations have lower systemic bioavailability and higher topical potency
Reduce potential for adverse events by:
- Using spacer and rinsing mouth
- Using lowest dose possible
- Using in combination with long-acting beta2-agonists
What are the beneficial effects of inhaled corticosteroids that make them somewhat effective in COPD? Negatives?
- Modest effect on long-term deterioration in lung function (limited because COPD involves neutrophilic inflammation)
- Significant decrease in exacerbations
- Improvement in quality of life
- Modest effect on mortality
- Recommended by guidelines for severe disease and in patients with recurrent exacerbations
BUT: Increase risk of pneumonia
When should oral corticosteroids be used?
Acute exacerbation of asthma and COPD
- Role in chronic, daily management is limited
- Minimize use!
What are some side effects of oral corticosteroids?
(Not uncommon)
- Osteoporosis
- Glaucoma
- Diabetes
- Adrenal suppression
- Skin fragility, bruising
What are the most active leukotrienes in asthma (and COPD?) treatment?
- LTC4
- LTD4
- LTE4
(- LTB4- more neutrophilic infiltrate?)
What are the effects of leukotrienes that are blocked by leukotriene modifiers?
Leukotriene modifiers block:
- Plasma exudation
- Bronchoconstriction
- Mucus secretion
What is the main unique benefit of leukotriene modifiers?
They are safe
- Used more in kids to avoid steroid use?
What are the classes of leukotriene modifiers?
5-lipoxygenase (5-LO) inhibitors
- Zileuton (rarely used; liver tox)
LT-receptor antagonists
- Zafirlukast
- Montelukast
What are characteristics of Zileuton
- Class/mechanism of action
- Pros/cons
- 5-LO synthesis inhibitor
- Con: significant drug interactions with other meds that are metabolized in the liver
What are characteristics of Zafirlukast and Montelukast
- Class/mechanism of action
- Duration
- Frequency
- Pros/cons
- LTE4, C4, D4 receptor antagonists
- Longer acting than Zileuton
- 1-2 daily doses
T/F: Leukotriene modifiers typically have a uniform level of effectiveness in all pts? Explain
False
- Fewer than 1/2 are positive responders; should be discontinued if no response within 1 mo
- Uncovering of Churg-Strauss syndrome seen
What drug is anti-IgE?
Omalizumab
When should anti-IgE treatment (Omalizumab) be considered?
Moderate to severe persistent asthma when concomitant allergy seems important in the causation or provocation of the asthmatic process
What are methods of drug delivery? Most common?
- Metered Dose Inhalers (most common)
- Nebulizers
- Dry Powder Inhalers
- Oral Pills
- Used for leukotriene modifiers
- Not liked for beta agonists
- Intravenous medications
Pros/cons of metered dose inhalers (MDI)?
- Most commonly used method of drug delivery for lung diseases
- Technique of use is most important to achieve optimal effect
- Only 10-30% of each puff deposits in lung
Pros:
- Convenience
- Wide safety margin
- Effective in microgram doses
- Spacers increase effectiveness
Cons:
- Improper technique common (at about 50%)
- Can be overused
Optimal particle size for metered dose inhalers?
2-5 um
- Too large: systemic absorption if swallowed
- Too small: none/minimal clinical effect; systemic absorption
Describe nebulization
- Medication format
- Comparison to MDI
- Pros
- Medications are a mist (not liquid); more easily inhaled into lungs
- Has been found to be equivalent drug delivery to using MDI with spacer
Pros:
- Much higher doses can be delivered
- Does not require patient coordination
- Method of choice in ERs
Describe dry powder inhalers
- Activated by what?
- Deliver medication to the lungs as patients inhale through the device.
- Do not contain propellants or any other ingredients– only the medication
- Breath-activated
What respiratory medications are delivered orally?
- Theophylline
- Oral steroids
- Leukotrienes
- B-2 agonists: not as good a delivery method for this class because higher doses are required which cause higher side effects and less bronchodilation
How is COPD graded?
- Severity, risk, lung function
Grade A
- Mild-moderate stage with minimal symptoms
- 0-1 exacerbations/yr
Grade B
- Mild-moderate stage with severe symptoms
- 0-1 exacerbations/yr
Grade C
- Severe-very severe with minimal symptoms
- 2+ exacerbations/yr
Grade D
- Severe-very severe with severe symptoms
- 2+ exacerbations/yr
What is PDE4 inhibitor used for?
COPD (recently approved)
- Blocks PDE4 in neutrophils
- Possible effect on neutrophilic inflammation
- Approved for severe COPD pts (history of exacerbation)
- Potential adverse effects: diarrhea, weight loss
