6 - Respiratory Pharm Flashcards
What is asthma?
A reversible obstructive lung disease characterized by bronchoconstriction due to hyperresponsiveness of the airways to physical, chem, and pharmalogical stimlu.
A chronic inflammatory condition with acute exacerbations.
Can be life-threatening if not managed well.
What is COPD?
An obstructive disease that over time makes it hard to breathe.
Involves inflammation and thickening of the airways, It also involves destruction of the tissue of the lung where oxygen is exchanged.
Sometimes referred to as chronic bronchitis or emphysemia (most will have symptosm of both conditions)
Third leading cause of death in the US.
What causes bronchoconstriction and immediate, early allergic reaction? What causes late phase reactions and inflammation?
Mast cell degranulation resulting in histamine, leukotriends, cytokines, and proteases.
What causes late phase allergic reaction and inflammation?
Mast cell secretion and release of cytokines and chemokines.
Describe the early and late phase bronchoconstriction reactions?
The treatment of asthma acn be broken down into the use of what three things?
- Quick relievers: medications that quickly reverse symptoms of asthma (short-acting bronchodilators)
- Exacerbation of asthma: short courses of oral steroids (anti-inflamm)
- Long-term controllers: medications to prevent airway narrowing over time (inhaled corticosteroids, long-acting bronchodilators, leukotriene modifiers).
Describe airway narrowing that occurs with asthma?
Airway narrowing causes the symptoms of asthma.
Due to smooth muscle hypertrophy and constriction, muous gland hypertrophy, and hypersecretion.
Vascular engorgement and leakage causes airway wall edema and subepithelial BM thickening and fibrosis.
What are asthma triggers?
- Anger
- Pets
- Exercise
- Pollen
- Bugs in the home
- Chemical fumes
- Cold air
- Fungus spores
- Dust
- Smoke
- Strong odors
- Pollution
*
What is the function of Omalizumab? Who is it given to?
Prevents interaction between IgE receptor and allergen by binding free IgE and thus preventing mast cell degranulation and the resulting inflammation.
Used in pts with severe asthma who remain poorly controlled despite high doses of inhaled steroids combined with long=acting bronchodilators.
What is the function of bronchodilators? What are the three main classes of bronchodilators?
Relax constricted airway smooth muscle. Short acting beta agonists cause immediate reversale of airway obstruction in asthma. Short and long acting B-agonists prevent bronchocontriction (And provide bronchoprotection).
Three classes:
- B2 adrenergic agonists
- Theophylline
- Anticholinergic agents
Bronchodilators are the treatment of choice for asthma. What are the two most effective bronchodilators?
Inhaed B2 agonists:
- Albuterol (short acting)
- Salmeterol and formoterol (long acting)
Have minimal side effects when used correctly
How long do the short acting (albuterol) and long acting (salmeterol and formoterol) inhaled B2 agonists last (duration of action)? Describe how the onset of action differs between salmeterol and formoterol?
Albuterol: duration of 3-6 hours
Salmeterol and formoterol: provide bronchodilation and bronchoprotection for >12 hours.
- Salmeterol has a long aliphatic chain and it’s long DOA may be due to binding within the receptor binding flect that anchors the drug in the binding cleft = slow onset of action
- Formoterol doesn’t bind to this site so it has a quicker onset of action
What is the mechanism of action of albuterol, salmeterol, and formoterol?
Directly stimualtes B2 receptors in airway smooth muscle
- acuses activation of Gs - adenylyl cyclase - cAMP - PKA pathway
- PKA phohsphorylates target substracts
- Decreases calcium
What are other effects of B2 agonists in the airways besides bronchodilation?
- Prevent mediator release from mast cells
- Present bronchial mucosal edema
- Enhance mucociliary clearance
- Reduce reflex cholinergic bronchoconstriction
What are adverse effects of B2 selective agonists?
Dose related; result of excessive activation of extrapulmonary B receptors.
Pts with underlying CV disease are at risk for reactions.
Likelihood of adverse effects decreased by giving the drugs via inhalation.
- Muscle tremor (skeletal muscle B2 receptors)
- Tachy (atrial B2 receptors)
- Hypokalemia (B2 effect on skeletal muscle uptake of K+
- Restlessness
- Hypoemia (increase V/Q mismatch due to reversal of hypoxic pulmonary vasoconstriction)
What can occur when using B2 agonists for a prolonged period of time?
Tolerance (desensitization, subsensitivity)
May be due to down-regulation of the receptor.
What we’ve seen is that tolerance develops to the adverse effects but not the bronchodilator effects.
- Tolerance of non-airway B2 receptor-mediated responses such as tremor and CV/metabolic responses is readily induced in normal and asthmatic subjects.
What does increased use of short-acting B2 agonists indicate? Are long-acting B2 agonists used alone?
The need for more anti-inflammatory therapy.
Long-acting B2 agonists should NOT be used as monotherapy.
What is the MOA of Theophylline?
Oral methylxanthine; works as a non-selective phosphodiesterase (PDE) inhibitor and adenosine receptor antagonist.
- adenosine constricts airways by releasing histamine and leukotrienes
What are side effects of Theophylline?
Less likely to be used due to numerous side effect:
- cardiac arrythmias and seizures
- headache, palpitation, dizziness, hypotension, tachy, severe restlessness, agitation, seizures
What are considered first-line therapy in all but the mildest (least severe) of patients with asthma? What is the only treatment for asthma exacerbations?
First-line in all but the least severe: Inhaled corticosteroids.
Asthma exacerbations: oral corticosteoids - for a short period of time, 3-10 days.
What is the mechanism of the anti-inflammatory action of corticosteroids in asthma?
Acetylation of core histones causes an increased expression of genes encoding multiple inflammatory proteins.
Corticosteroids bind the cystosolic glucocorticoid receptor and translocate to the nucleus and bind coactivators to inhibit HAT activity in two ways:
- directly
- and by recruiting histone deacetylase-2 (HDAC2) which reverses histone acetylation, leading to the suppression of activated inflamamtory genes
What effect do steroids have on B2 adrenergic responsiveness?
Steroids increase the transcription of B2 receptor gene, prevent down-regulation of B2 receptors, and increase B adrenergic responsiveness.
B2 agonsts enhance the action of the GR receptor, increase nuclear translocation of liganded GR receptors, and enhance binding of GR to DNA.
B2 agonists and corticosteroids enhance each other’s beneficial effects in asthma therapy.
What are the different leukotriene modifiers?
5-lipoxygenase (5-LO) enzxyme inhibitors: zileuton
Antagonists of the cys-LT1 receptors: montelukast and zafirlukast
What drug can induce asthma?
Aspirin hypersensitivity
A small proportion (1-5%) of asthmatics become worse with aspirin and other COX inhibitors. This is most likely because the pathway is shifted to the right causing production of leukotrienes.
This is a well-defined subtype of asthma that’s usually preceded by perennial rhinitis and nasal polyps.
