3.7.2. Pharmacology of Astma Flashcards
Adrenergic agonists stimulate what?
Stimulate B2-adrenoreceptors, resulting in the relaxation of bronchial smooth muscle
Adrenergic agonists inhibit what?
inhibit the release of mediators, stimulating mucociliary clearance
Albuterol, levalbuterol, pirbuterol, metaproterenol are what kinds of drugs?
B2-selective agonists: Preferred for brochoconstriction
With B2 selective agonists, what is their effect?
Enhanced B2 selectivity = Bronchodilation
How do we administer B2 agonists and how long does it take to activate?
administered by inhalation, active in 1-5 minutes
Long term effect of B2 agonists?
long-term use associated with diminished control of breathing, possibly due to down regulated B-receptors
Effect of B2 agonists on specific pulmonary cells?
Increases surfactant by Type II pneumocyte, ciliary clearence
B2 agonists desensitizes and downregulates a few things. What are they?
Desensitizes neutrophils, eosinophils, T-Cells, decreases cholinergic transmission as well as plasma exudation and mast cell releases
Discuss isoproterenol and what it does?
Isoproterenol: relatively non-selective B-receptor and potent bronchodilator
Discuss Epinephrine and what it acts on?
Epinephrine: available OTC inhalant, acts on B1, B2, and A1 receptors; onset in 5-10 min and duration 60-90 minutes
Salmeterol, formoterol are examples of what?
Long acting B2-agonists
Salmeterol, formoterol are administered as inhalants but with slower onset of action and longer duration. Why?
very lipophilic side chains that slow diffusion out of the airway (very high lipid solubility)
Salmeterol, formoterol, which are 50x more selective than albuterol, are used in the clinical setting primarily for what?
use for prophylaxis of asthma
Discuss the specificity of Terbutaline and it’s effect on the heart
moderately specific B2 agonist that is available as injection or tablet moderately cardiostimulatory
Side effects of Epinephrine and isoproterenol
Epinephrine and isoproterenol have significant B1-receptor activity and can cause increases in cardiac effects (tachycardia, arrhythmias, angina)
most common side-effect of B2-agonists is ____ ____.
most common side-effect of B2-agonists is muscle tremors (skeletal)
A-receptor agonists may cause _____ and _____.
A-receptor agonists may cause vasoconstriction and hypertension
What is the side effect “Tachyphlaxis” and how do we counter it?
Tachyphlaxis, blunted response due to prolonged use, cna be countered by switching to a different agonist or adding methylxanthine or a corticosteroid
Methylxanthines cause what and how?
broncohdilation via action on smooth muscles of the airways
Theophylline has _____ properties and reduces airway responsiveness to ____ and _____.
Theophylline has anti-inflammatory properties and reduces airway responsiveness to histamine and allergens
Methylxanthines does what biochemically?
inhibits PDE (increasing cAMP) at high doses
Methylxanthine pharmacologic effect (4)
- Produce rapid relaxation of smooth muscle in bronchioles 2. decrease response to histamine 3. stimulate ciliary transport of mucus 4. improve contractility of diaphragm
Methylxanthine has effects on other systems besides the pulmonary one. What are those effects?
- chronotropic and inotropic actions on the heart 2. pulmonary and peripheral vasodilation but cerebral vasoconstriction 3. at high doses can lead to nervousness and seizures due to medullary stimulation
Methylxanthine can be used for 3 things?
- as an adjunct to inhaled corticosteroids and B-agonists to improve response 2. treat COPD and emphysema 3. treat apnea in preterm infants (specifically caffeine)
Methylxanthine adverse effects
- Physical: arrhythmias, nervousness, vomitin, and GI bleed 2. Psych: behavioral problems in children 3. Contraindications: combined use with B2 receptors is suspected for increased asthma mortality
Ipratrpoium and atropine are what drugs?
Are muscarinic antagonists
What do muscarinic antagonists do?
competitive antagonists of ACh
Muscarinic antagonists do what?
inhibit constriction of airways and decrease vagal-stimulated mucus secretion
Distinguish between Ipratropium and Tiotropium
Ipratropium is poorly absorbed and does not cross the blood brain barrier, administered as an aerosol and therefore limits its adverse effects - short acting Tiotropium is a long-acting antagonist used to treat COPD
Side effects of atropine
Atropine is readily absorbed, adverse effets include drowsiness, sedation, dry mouth, blurred vision
How does Chromlyn Sodium work?
precise mechanism is unclear, inhbits release of mediators from mast cells; suppresses neutrophils, eosinophils, monocytes; inhibits cough reflexes (may be due to inhibition of chloride ion channels)
only anti-asthmatic that inhibits early AND late phase response
Chromlyn Sodium
Function of gluccocorticoids
produce significant increase in airway diameter, probably by attenuating PG and LT synthesis via inhibition of phosphlipase A2 reaction and general inhibition of immune response
What does Prednisone do
Prednisone - Used for acute and chronic asthma exacerbations
Zafirlukast and montelukast do what biochemically?
agonists of the LT receptor LT1; blocks LTC4/D4/E4
General effect and use for Zafirlukast and montelukast
reduces bronchoconstrion and inflammatory cell infiltration for mild persistent asthma
Zileuton does what?
inhibits 5-lipoxygenase, the rate-limiting enzyme in LT biosynthesis
Immediate effect of Zileuton
immediate and sustained 15% improvement in forced expiratory volume (FEV)
Zileuton inhibits microsomal P450’s and decreases the metabolism of ____ ____ and ____.
inhibits microsomal P450’s and decreases the metabolism of terfenadine, warfarin, and theophylline
Prolastin, Aralast are what?
A1-proteinase inhibitors (Prolastin, Aralast)
What do we use A1-proteinase inhibitors (Prolastin, Aralast) for and how often do we give them?
used to treat emphysema caused by a deficiency in a1-proteinase Weekly IV injection to treat patients homozygous for the deficiency
Omalizumab does what?
Omalizumab binds to human IgE’s high-affinity Fc receptor, blocking the binding of IgE to mast cells and basophils and other cells associated with allergic response reduces early phase degranulation of mast cells and late phase release of mediators
Omalizumab lowers serum IgE concentrations, but does not block ____________.
lowers serum IgE concentrations, but does not block alergen-antibody response
Who gets Omalizumab
used in patients >12 yo who are refractory to inhaled gluccocorticoids and asthmatics with allergies SubQ injection every 2-4 weeks
Increased serum levels of IgE Allergens Infections (rhinovirus, parasites, etc) Environmental exposure to all kinds of particulates and toxins Stress, Panic Medicines Food additives, Metabisulfides These are all examples of what?
Extrinsic Asthma triggers
Examples of intrinsic asthma triggers
Normal IgE Patho disturbances Negative responses to common antigenic challenge Cold
Asthma anatomy changes
Increased smooth muscle around airway Inflammation Actual trapping, which is closing of the airway
Cells that contribute to Asthma inflammation
Inflammatory cells Vascular endothelial cells Epithelial cells Smooth muscle cells
Mast cells secrete these: To cause:
Mast cells secrete IgE, peroxidase, chemotactic factors, cytokines, etc. This causes leaking of the endotheial barrier, SMC contraction and inflammatory cells to infiltrate the airspaces
Bronchial gland and mast cells release histamine. This causes:
Bronchial gland and mast cells - histamine. This causes more recruitment of inflammatory cells, SMC contraction and increased granular secretions
Protease production by mast cells and eosinophils do this:
Protease production by mast cells and eosinophils, which increases vascular permeability, further inflammatory cell infiltration, alterations to the ECM, and contributes to the permanent remodeling we see in asthma patients
Leukotriene C4 and D4 released by leukocytes and platelets do this:
Leukotriene C4 and D4 released by leukocytes and platelets, which are both chemoatractants for inflammatory cells. They also cause bronchiospasm, increased mucus production, and increased vascular permeability
Prostaglandin and chemokine release by mast cells and lung epithelial cells do this
Prostaglandin and chemokine release by mast cells and lung epithelial cells, further recruiting inflammatory cells
These 3 things are late asthma events:
Cytokine releases (inflammatory cell recruitment including eosinophils, CD$+T lymphocytes, monocytes, neutrophils). Persistent airflow obstruction Increased airway hyperresponsiveness, SMC growth, etc.
Airway inflammation 3 stages and what happens during them
Acute - Early recruitment of cells to the airway Sub-acute - Recruited and resident cells are activated to cause a more persistent pattern of inflammation Chronic - Persistent level of cell damage and repair processes
Histologic changes we see in asthma
Discuss a metered-dose inhaler
Metered-dose inhaler - usually contains a large volume holding channel (or “spacer”) that fits between the inhaler and the mouth. The inhaler discharges into it and the patient inhales from it
Discuss a nebulizer
Nebulizer - Not as cheap or portable but doesn’t require hand/breathing coordination (therapy can be delivered by face mask)
Discuss a dry-powder inhaler
Dry Powder inhaler - Developed as alternative to chlorofluorocarbon propellants
Two concepts for treating asthma
Drugs that treat symptoms only - Relievers - Bronchodilatory actions, usually rapid onset
Drugs that treat underlying cause - Controllers - Antiinflammatory actions, slower acting, often prophylactic (not for emergencies)
