10-9 Bronchodilators and Asthma Drugs - Martin Lecture & DSA Flashcards
What is asthma?
Asthma is currently viewed primarily as an inflammatory illness that results in bronchial hyperreactivity and bronchospasm
Why are drugs so important in controlling asthma?
recommendations for prevention and treatment of asthma emphasize control of the inflammatory component as the underlying problem
- reserve bronchodilators primarily for symptomatic use.
The inflammatory component and the airway narrowing of asthma are largely reversible
- drug therapy plays a significant role in the management of the disease
Why is inflammation so pervasive in allergic asthma?
immediate hypersensitivity-type reactions can be continuously present at a sub-threshold level
- resulting in mild-to-moderate inflammation without overt bronchoconstriction
If inflammation is continuously present in allergic asthma, why is overt bronchospasm intermittent?
Overt bronchospasm then occurs upon exposure to a specific allergen or to a variety of nonspecific stimuli, e.g., cold air, dust, air pollution, exercise, etc
What is going on in COPD?
disease characterized by the presence of airflow obstruction due to chronic bronchitis or emphysema
- airflow obstruction is generally progressive
- may have airway hyperreactivity
- may be partially reversible
How is drug therapy helpful in treating COPD?
useful in addressing the reversible component of COPD
- induce bronchodilation
- decrease inflammatory reaction
- facilitate expectoration
What are the anti-inflammatory classes of drugs useful in asthma and related respiratory disease?
corticosteroids
cromolyn-like compounds
anti-leukotriene drugs
What are the bronchodilators helpful in treating asthma and related respiratory diseases?
b-adrenergic agonists,
muscarinic receptor antagonists
methylxanthines
In addition to bronchodilators and anti-inflammatories, what other types of drugs are helpful in addressing some respiratory disease?
decongestants, antitussives, expectorants and mucolytic agents
What happens in allergy that causes release of inflammatory mediators?
Allergen-specific IgE binds to Fc receptors on mast cell.
When allergen comes in contact with IgE, the mast cell is activated and releases a large number of mediators.
- enormous variety of mediators is released, each having more than one potent effect on airway inflammation.
Why are antihistamines not very effective in controlling allergic asthma?
many different mediators released
pharmacological blocker of any one mediator is ineffective in alleviating the symptoms or progression of asthma or the inflammatory component of other respiratory diseases
Corticosteroids, which can block many of the key steps in the inflammatory process, come closest to this ideal therapy
Mast cells release many inflammatory mediators, but why do airways become responsive to non-specific stimuli?
asthmatic airways respond to allergen challenge with an immediate airway narrowing and mast cell infiltration.
Reactive hyperemia, edema, and cellular inflammation become evident within hours of challenge
- frequently associated with a second, usually more severe, rise in airways resistance
- influx of white cells and changes in airways function may persist for days and weeks after a single challenge and can result in heightened bronchial sensitivity to a number of stimuli
What changes due to enzyme release from inflammatory cells contribute to bronchial sensitivity?
damage to the respiratory epithelium
enhanced neuropeptide release
exposed afferent nerve endings that can evoke enhanced vagal responses
Other than mast cells, what cells contribute to inflammation in asthma?
Inflammatory cells other than mast cells implicated in the pathogenesis of asthma include eosinophils, neutrophils, macrophages, lymphocytes, and platelets.
To sum, what are the 4 key features of asthma?
- Mast cell activation associated with early bronchospasm
- Inflammatory cell infiltration with subsequently mediator release
- Epithelial cell damage
- Increased responsiveness of the airways to a variety of non‑specific stimuli
What are the immediate mediators from mast cells? What are the effects?
Preformed:
Histamine, TNF-a, Proteases, Heparin
Effects:
Bronchoconstriction, itch, cough, vasodilation, edema
What are the lipid mediators from mast cells? What are the effects?
Mediators - lipids work in minutes
Leukotrienes, Prostaglandins
Effects:
Bronchoconstriction, chemotaxis, mucus secretion
What are the cytokine mediators from mast cells? What are their effects?
Cytokines - start working in hours:
Interleukins, GM-CSF
Effects:
Bronchoconstriction, chemotaxis, inflammatory cell proliferation
Why is aerosol delivery of asthma drugs beneficial?
pathophysiology of asthma appears to involve the respiratory tract alone.
- effective treatment could be achieved if drug administration was restricted to the lungs.
Aerosol application of drugs to the lungs can produce a high local concentration in the lungs with a low systemic absorption
- significantly improving the therapeutic ratio by minimizing side effects.
- both b2-agonists and corticosteroids have potentially serious side effects when delivered systemically.
What percentage of asthmatic patients can be managed by aerosols?
Probably more than 90% of asthmatic patients who are capable of manipulating inhaler devices can be managed by aerosol treatments alone.
What is are some important factors that determine effective deposition of drug into lung?
Particle size:
>10 mm deposit in mouth and oropharynx
<0.5 mm are inhaled and then exhaled
1-5 mm deposit in small airway and are most effective.
Rate of breathing and breath holding are important.
The recommendation technique is that a slow, deep breath be taken and held for 5 - 10 sec
How much of a dose of aerosol drugs for asthma reach the lung? Why is this important in formulating drugs for asthma, etc.?
under ideal conditions only 2 - 10 % of drug is deposited in lungs
- most of the remainder is swallowed
to have minimal systemic side effects, an aerosolized drug should be either poorly absorbed from the GI tract or be rapidly inactivated by first-pass liver metabolism.
- ipratropium Br is complexed to a salt and permanently charged, and cannot be absorbed will in the GI tract or cross membranes well
What are the different devices for aerosol delivery?
Metered Dose Inhalers (MDI) - with spacer device
Nebulizers
Dry powder inhalers
How do MDIs work?
pressurized canister with a metering valve that delivers drug with hydrofluoroalkane (HFA) propellant, co-solvents, and/or surfactants
Spacer devices that attach to the MDI markedly improve the ratio of inhaled to swallowed drug and reduce need for coordination.
Valved holding chambers (VHCs) have one-way valves that prevent the patient from exhaling into the device, minimizing the need for coordinated activation and inhalation.
What are the advantages of MDIs? Disadvantages?
low cost and portability
disadvantages include need for hand-lung coordination making it more difficult for young children and the elderly to use
What are the advantages of nebulizers?
preferred for severe asthma exacerbations with poor inspiratory ability
do not require hand-lung coordination
Nebulizer therapy can be delivered by face mask to young children or older patients who are confused.
What are the advantages and disadvantages of dry powder inhalers?
require relatively high air flow to suspend the powder
can be irritating when inhaled
What are the 2+ major classes of bronchodilators?
b-Adrenergic Agonists:
Short-Acting b__2-selective adrenergic agonists (SABA)
Long-Acting b__2-selective adrenergic agonists (LABA)
also:
Nonselective agonists
Epinephrine (*important emergency uses)
What are beta 2 agonists preferred for?
preferred therapy for bronchoconstriction
DOC for rapid relief of bronchospasm
Highly effective and safe for intermittent, prophylactic treatment of asthma.
These are the only agents shown to be immediately effective for relieving bronchoconstriction during acute, severe asthma.
What is the current emphasis for beta adrenergic agonists?
Intermittent use on an as-needed basis for relief of acute, severe bronchospasm in asthma and COPD
Not general prophylaxis
What is the MOA for beta adrenergic agonists?
Stimulate b2-adrenergic receptor on surface of bronchiolar smooth muscle cells.
b2-adrenergic receptor couples to Gs protein and activates adenylyl cyclase enzyme leading to increased cellular levels of cyclic AMP.
Cyclic AMP stimulates phosphorylation cascade that leads to decreased intracellular calcium and smooth muscle relaxation.
Also inhibit mediator release from mast cells.
What are the problems associated with overuse of beta adrenergic agonists?
Side effects intensify with overuse
- greater danger is the tendency to continue to self-medicate during periods when symptoms are escalating
- decreasing receptor sensitivity to agonist activity with increasing use
To avoid a medical emergency, patients should be encouraged to seek medical attention as soon as possible after they detect a decline in the efficacy of their usual therapeutic regimen
What are the rapid acting short duration beta 2 adrenergic agonists? What is their onset and duration?
Albuterol
Levalbuterol - l-isomer of albuterol
Pirbuterol
Terbutaline
onset<15 min
duration: 2-4 hr
What popular term applies to rapid acting-short duration
b2-adrenergic agonists? What are they good at?
These agents are used as “rescue inhalers”
They are relatively fast at relieving bronchospasm,
but have a relatively short duration of action.
What are some long acting b2-selective agonists (LABA)?
salmeterol
formoterol
What is the onset and duration of salmeterol and formoterol?
Long Acting b2-Selective Agonists (LABA)
slower onset
duration > 12 hours of useful bronchodilation
What are salmeterol and formoterol used for?
useful to control nighttime asthma attacks, also now used BID for prevention
not suitable for treatment of acute bronchospastic attacks because onset of action is too slow
What are some less or nonselective b-adrenergic agonists?
epinephrine
isoproterenol
metaproterenol
isoetharine
racemic epinephrine
What are epinephrine, isopreterenol, metaproterenol and isoetharine used for?
Because of their very short duration of action and their lack of b2-selectivity, these agents are not frequently used.
Low-strength epinephrine inhalers sometimes prescribed for mild asthma
What is racemic epinephrine used for?
aerosol used for pediatric patients
What can happen with long-term use of LABA?
Continued use of a LABA may cause down-regulation of b2 receptors with loss of the protective effect from rescue therapy with a short-acting agent.
What should LABAs be used with?
LABA should not be used for monotherapy in patients with persistent asthma, especially in children.
LABA should be used in asthma only in combination with an inhaled corticosteroid.
When should use of LABAs be stopped?
Stop use of a LABA, if possible, once asthma control is achieved and maintain the use of an asthma-controller medication such as an inhaled corticosteroid
What should be anticipated with beta adrenergic agonists used in oral therapy for bronchodilation?
Oral administration increases incidence of adverse side effects:
muscle tremor, cramps, cardiac tachyarrhythmias, metabolic disturbances, hypokalemia
