Respiratory Pharmacology I Flashcards
Three components influencing bronchoconsriction
- activation of mast cells
- local inflammation
- vagal stimulation
What is central to bronchoconstriction and airway inflammation
mast cell activation
What do agents that increase bronchoconstriction activate?
7-spanning transmembrane receptors linked to internal G-proteins
Activation of Gq subunits results in
phospholipase C activation, increases in IP3, and influx of Ca2+, influx of Ca2+ results in actin-myosin coupling and smooth muscle contraction
Activation of Gi subunits results in
decrease in adenylate cyclase activity and cAMP, incrase in PLC; resulting in bronchoconstriction
Activation of Gs subunits results in
increased adenylate cyclase activity and increases in cAMP; resulting in actin-myosin dissolution
What do bronchodilators do?
induction of smooth muscle relaxation
inhibit smooth muscle contraction
block actions of other inflammatory mediators
Agents that reduce bronchoconstriciton and increase smooth muscle relaxation share which common feature
increase intracellular cAMP concentrations
How do sympathomimetics work
increase cAMP through Gs subunit of GRPRC; relax smooth muscle contraction; decrease release of mediators from mast cells
Sympathomimetics act through?
act through adenoreceptors on smooth muslce (not sympathetic innervation)
Name some sympathomimetics
epinephrine, ephedrine, isoproterenol, albuterol/salbutamol
Specificity of ephinephrine
both alpha and beta effects and cardiac effects preclude its use except in emergencies
Specificity of ephedrine
has more central effects and lower efficacy; has been replaced by selective beta-adrenergic agents
Selective beta-adrenergic agents
albuterol, terbutaline, metaproterenol, pirbuterol
How are selective beta-adrenergic agents delivered
delivered via airway using metered dosing devices (albuterol and terbutaline also available in oral forms)
Difference between airway delivery and oral delivery of selective beta-adrenergic agents
little cardiac side effects with airway delivery; side effects minimal with airway delivery; oral forms associated with tremor, nervousness, and weakness
How may beta-adrenergic agents lead to increased perfusion-ventilation mismatch and decreased oxygenation
beta-adrenergic agents may act on pulmonary vascular beds resulting in vasodilation; this leads to a perfusion of poorly ventilated areas (previously vasoconstricted due to hypoxemia)
How can you avoid an increased perfusion-ventilation mismatch with beta-adrenergic agents
they’re given with oxygen
Long-acting beta-agonists
salmeterol and formoterol
How are long-acting beta-agonists used
used only in combination with inhaled corticosteroids for maintenance therapy; not used alone; not used for acute exacerbations
How do antimuscarinic agents work
reverses vagal contribution to bronchoconstriction; competitively inhibitis muscarinic receptor (block acetylcholine activation)
The effectiveness of antimuscarinic agents is related to
muscarinic contribution to bronchospasm; limited effectiveness in allergic asthma; greater effectiveness in non-allergic conditions such as COPD
Antimuscarinic agents may be an alternative to
long-acting beta-agonists in combination with steroids
Atropine
antimuscarinic agent; effective, but has systemic side-effects even when delivered by inhalation
Ipratropium bromide
antimuscarinic agent; quaternary ammonium derivative with decreased absorption
Tiotropium
longer-acting selective anti-muscarinic approved for COPD
Methylxanthines
theophylline, caffeine, theobromine
Not used very commonly but remains an inexpensive alternative to other therapies
Methylxanthines
Mechanism of action of methylxanthines
relates to inhibition of phosphodiesterase; blocks inactivation of cAMP; results in increased intracellular levels of cAMP
What do methylxanthines do
cause bronchodilation and smooth muscle relaxation; also inhibits activation of inflammatory cells, including mast cells
What can low dose methylxanthines potentiate?
may also potentiate the action of corticosteroids in COPD
Systemic effects of methylxanthines mimic
mimic beta-adrenergic stimulation: cortical arousal and increased alertness, nervousness and tremor, tachycardia, increased CO, rare arrhythmias, stimulation of gastric acid and digestive enzyme secretion, increased diaphragmatic function and ventilatory effort
Theophylline
once commonly used as a mainline asthma drug; now used primarily in combination with steroids; less expensive than many other maintenance therapies
Aminophylline
theophylline-ethylenediamine complex
roflumilast
selective PDE4 inhibitor
Main issues with theophylline
wide variation in blood levels, narrow window of therapeutic range; must closely monitor blood levels to avoid toxicity
Side effects/toxicity symptoms with theophylline
tremor nervousness (therapeutic range) anorexia, nausea, vomiting, abdominal discomfort, headache anxiety (upper therapeutic range) seizures and arrhythmias (>40 mg/L)
Intracellular signaling in mast cells
increased GTP stimulates secretion
increased ATP inhibits secretion
Mast cell mediator blockers
Anti-IgE beta agonists, methylxanthines cromolyn sodium leukotriene synthesis inhibitors leukotriene receptor blockers anti-histamines
Omalizumab (Xolair)
monoclonal antibody that targets the Fc portion of IgE, preventing its attachment to the FcE receptor on mast cells and basophils
MOA of cromolyn sodium and nedocromil sodium
appear to inhibit mast cell degranulation by a poorly understood mechanism; also inhibits other clel types such as eosinophils
How is cromolyn sodium used?
Used prophylactically to inhibit asthma caused by allergen inhalation and exercise because it has no effect on bronchoconstriction; neither as potent or predictable as steroids; used as an adjunct to inhaled steroid therapies
How are anti-histamines used
used prophylactically, especially for allergy-induced asthma; not useful for acute exacerbations of asthma or late phase reactions
LTB C, D, and E act through
Cys-LT1 and Cys-LT2 (7-spanning membrane receptors with g-proteins)
What do leukotriene modifiers do?
cause bronchoconstriction that is slower and more persistent than histamine or cholinergic stimulation; potentiate bronchial reactivity to histamine; increase mucosal edema, hypersecretion of mucous
Two approaches of leukotriene modifiers
- inhibition of 5-lipoxygenase (zileuton)
2. LTD4 receptor antagonists (zafirlukast and montelukast)
Pros and cons of leukotriene modifiers
less effective against inflammation than steroids, but reduce exacerbations of bronchoconstriction; particularly effective in aspirin-induced asthma
What has Zileuton been associated with
liver toxicity
What are anti-inflammatory medications useful for
maintenance therapy of asthma not controlled by periodic use of beta-agonist inhalers
Mainstay of anti-inflammatory therapy
corticosteroids
Corticosteroids inhibit
inflammatory cell activation and cytokine production (NFk-b signaling)
What are steroids used
used early in an exacerbation to decrease late phase reactions
How are steroids best delivered
due to systemic anti-inflammatory and endocrine effects, best delivered in airway; oral and parenteral use limited to urgent cases where bronchodilators are insufficient
Inhaled steroids
beclomethasone, budesonide, ciclesonide, fluinisolide, fluticasone, mometasone, and triamcinolone
What can inhaled steroids be associated with
oropharyngeal candidiasis; may increase risk of osteoporosis and cataracts long term; may slow growth in children
short-acting bronchodilators
epinephrine, isoproterenol, albuterol, terbutaline, metaproterenol
long-acting bronchodilators
salmeterol and formoterol
muscarinic inhibitors
ipratropium bromide, tiotropium
methylxanthines
theophylline, aminophylline, dyphylline, roflumilast
Anti-IgE
omalizumab
Cromolyn
cromolyn sodium, nedocromil sodium
Anti-leukotrienes
zileuton, zafirlukast, montelukast
steroids
prednisone, beclomethasone, fluticasone, ciclesonide
