Smooth Muscle (pt 1/4) Asthma Flashcards
What are the clinical characteristics of asthma?
-Small, inflamed internal lumen.
-Increased mucus production.
-Recurrent bouts of SOB, chest tightness, coughing and wheezing
What is the pathophysiology of Asthma?
-Widespread, reversible narrowing of the bronchial airways
-Significant bronchial responsiveness to inhaled stimuli
What is the pathology of Asthma?
-Lymphocytic and eosinophilic inflammation of the bronchial mucosa
-“Remodeling” of the bronchial mucosa: Hyperplasia of the cells of the airway walls and Overproduction of mucus
Describe Mild Asthma
-Occasional
-Occurs on exposure to allergens or certain pollutants (pet dander)
-During exercise
-Triggered by viral URI
Describe Severe Asthma
-Frequent
-Associated with wheezing and dyspnea
-Often at night
-Chronic airway narrowing with chronic respiratory impairment
-Regular overproduction of mucus. End up on multi-agent treatments (PO and rescue)
Explain the effects of Volatile Agents on Asthma.
-1st exposure to gases can trigger an event and cause bronchoconstriction. Once gas circulates, goes to bloodstream, then we get bronchodilation.
T/F: Volatiles are irritants to lung tissue.
True, and effects are more profound in patients with irritated tissues (asthma, COPD).
Will Volatiles help in a true, complete bronchospasm?
If you aren’t moving air, volatiles won’t help.
1) Off of vent and bag them
2) Epi ?
If you can’t move air, deepening the gas may help but probably doesn’t.
In asthma, exposure to an allergen causes the synthesis of what?
IgE, which binds to Mast Cells in the airway mucosa.
What occurs on re-exposure to the allergen?
Antigen-antibody interaction on mast cell surfaces triggers release of mediators of anaphylaxis.
What are the mediators of anaphylaxis?
Histamine, tryptase, prostaglandin D2 (PGD2), leukotriene C4, and platelet-activating factor (PAF) = all inflammatory agents. Inflammation is occurring.
What do the mediators of anaphylaxis (histamine, PGD2, leukotriene) provoke?
Contraction of the airway smooth muscle, causing the immediate fall in FEV1(25%)
Re-exposure to allergen also causes the synthesis and release of a variety of cytokines (cytokines are coming from mast cells and t-lymphocytes), such as?
-Interleukins 4 & 5
-granulocyte-macrophage colony-stimulating factor (GM-CSF)
-Tumor Necrosis Factor (TNF)
-Tissue Growth Factor (TGF)
Released from T-cells and mast cells
What do these cytokines do that are released on re-exposure to an allergen?
These cytokines in turn attract and activate eosinophils and neutrophils, which go on to create products that further the immune response.
What are the products created by cytokine attraction and activation of eosinophils and neutrophils?
-Eosinophil Catonic Protein (ECP)
-Major Basic Protein (MBP)
-proteases
-platelet-activating factor (PAF)
(Immune response)
What do the products of eosinophils and neutrophils (ECP, MBP, proteases, and PAF) cause?
These mediators cause the edema, mucus hypersecretion, smooth muscle contraction, and increase in bronchial reactivity (more intensive narrowing) associated with the late asthmatic response indicated by a second fall in FEV1 3-6 hours after the exposure.
What does increasing cAMP do in relation to Asthma?
Increases bronchodilation.
What two categories of drugs increase cAMP?
-Beta 2 Agonists
-PDE-Inhibitors (Theophylline or Aminophylline)
How do Beta 2 Agonists increase cAMP?
Increase the rate of synthesis of cAMP by adenylyl cyclase (AC)
How do Phosphodiesterase (PDE)-Inhibitors (Theophylline or Aminophylline) increase cAMP?
Interrupt the breakdown of cAMP (slow the rate of degredation). PDE is the enzyme that breaks down cAMP. Allows more to be available.
What is the other way that PDE-Inhibitors can decrease bronchoconstriction?
Theophylline (PDE-Is) also are Adenosine receptor inhibitors. (Adenosine receptors normally = bronchoconstriction). Inhibiting adenosine receptor promotes bronchodilation.
How does antagonization of M3 receptors in the lung tissue affect asthma?
-M3 receptors are in lung tissue
-Antagonizing M3 causes bronchodilation
-M3 normally = bronchoconstriction
-Use Muscarinic antagonists to alleviate bronchoconstriction
Explain the effects of Epinephrine and asthma.
-Can be given many different routes (IV, INH, SQ)
-Stimulates α & β1
-Problematic adverse effects: Tachycardia, Arrythmias, and Angina
-Useful in anaphylaxis
-Displaced by β2 selective agents in Asthma therapy
Explain the effects of Ephedrine and asthma.
-A sympathomimetic
-Compared to Epi: Longer DOA, oral availability, ⬆CNS effects, ⬇ potency
-Displaced by β2 selective agents in Asthma therapy
Explain the effects of Isoproteronol and Asthma.
-Potent bronchodilator
-1960s in the UK
-⬆ in asthma related mortality
-Attributed to cardiac arrhythmias from high dose inhaled isoproteronol
What are the long acting (12+ hrs) B2 agonists used in asthma treatment?
-Salmeterol
-Formeterol
-Indacaterol (COPD) only
Explain the effects of long acting B2 agonists on asthma.
-Highly lipid soluble
-Synergistic with corticosteroids
-No anti-inflammatory effects
-Cannot be used as monotherapy
-BBW for inc risk of death/near death from an asthma attack, especially in AAs.
What is the BBW associated with long-acting B2 agonists?
BBW for inc risk of death/near death from an asthma attack, especially in African Americans.
What kind of drug is Albuterol?
Beta 2 selective (not specific. Prefers B2)
What is the overall goal with the use of Albuterol in Asthma?
To relax airway smooth muscle and promote dilation.
What is the physiology behind the relaxing effects of Albuterol?
-Inhibits bronchoconstricting mediators from mast cells
-Inhibits microvascular leakage (decreasing edema)
-Increases mucociliary transport via increased ciliary activity (increases removal of mucus)
-Stimulates adenylyl cyclase, increasing cAMP
Interrupt the cascade of events to promote bronchodilation.
What are the different routes of Albuterol?
PO, MDI, Nebulized
What form of Albuterol is a larger molecule, so you can give a bigger dose?
Nebulized form is a larger molecule, can give a bigger dose than the MDI
How long does the bronchodilation last from Albuterol?
Short-lived bronchodilation (DOA 3-4 hrs). May have to use multiple times/day
What are the systemic effects associated with Albuterol?
-Increases shunt (perfusion without ventilation)
-Tachycardia (hits some B1s)
-Vasodilation (B2 mediated)
-Arrhythmias (B1)
-Tremors
-Can cause Hypokalemia (Activates Na/K Pump. Can be used in tx of HyperK+)
Which method of delivery provides the best local effect on airway smooth muscle with the least systemic toxicity?
Inhalational Therapy
What percentage of the total dose of INH therapy is deposited in the mouth or pharynx?
80-90%
How is absorption in the bronchi increased with INH therapy?
Absorption in the bronchi is increased with slow full breath followed by 5 sec of breath holding
-Have to seal lips, breathe in, have to hold lungs to disperse it throughout lung tissues and get down deep in lungs.
Describe the proper technique for use of a MDI.
Patients are supposed to exhale, place lips around MDI, draw tidal breath in, squeeze, and then hold breath.
What drugs are the Methylxanthines?
-Theophylline
-Aminophylline
-Theobromine
-Caffeine
Which methylxanthine is no longer popular due to:
1) safer INH Beta2 agonists & INH anti-inflammatory agents
2) Narrow therapeutic index - measured trough levels (decreases compliance)
Theophylline
Which methylxanthine is less potent than theophylline and has a short 1/2 life?
Aminophylline
What is the MOA of the Methylxanthines (-phylline drugs)
-PDE-Is: inc cAMP by decreasing its degradation. (dilation)
-Inhibiting PDE also decreases release of cytokines and chemokines, therefore decreasing immune cell activation
-Inhibition of cell surface adenosine receptors (relaxation)
-Enhancement of histone deacetylation (researching this - blocks inflammatory genes)
What does inhibition of Cell Surface Adenosine receptors do?
-Relaxation of airway smooth muscle
-Inhibits histamine release
What are the respiratory effects associated with the Methylxanthines?
-Bronchodilation
-Inhibit antigen induced release of histamine
-Inhibition of inflammatory response
What are the CNS effects associated with the Methylxanthines?
-Mild cortical arousal
-⬆ alertness
-Deferral of fatigue
-Nervousness, anxiety
-Tremor & HA
-Medullary stimulation*
-Convulsions* & Death*
What are the CV effects associated with the Methylxanthines?
-(+) Chronotropy = Tachycardia
-(+) Inotropy = ⬆BP, ⬆SVR, & ⬆CO
-Adenosine receptor antagonism
-⬆ in SNS catecholamine release
-⬆cAMP = ⬆ Ca2+
-Decrease blood viscosity
-Potential for arrhythmias
What are the GI/GU/Endo effects associated with the Methylxanthines?
-Stimulate secretion of gastric acid
-Stimulate digestive enzymes
-Weak diuretics (not therapeutic)
-Anorexia, N/V, ABD pn
What are the skeletal muscle effects associated with the Methylxanthines?
Improve contractility & reverse fatigue of the diaphragm in patients with COPD
What are the toxic effects from high doses or ODs of Methylxanthines?
Medullary stimulation
Convulsions & Death
Which methylxanthine is more effective on smooth muscle, and which is more effective on neural tissues?
Theophylline = smooth muscle
Caffeine = neural tissues
What are the pharmacokinetics of Methylxanthines?
-Slightly water soluble
-Well absorbed
-Narrow therapeutic window
-Requires blood draws to monitor therapeutic levels
-⬆ provider workload
-Patient compliance issue
-Metabolized in the liver
-Plasma clearance varies
-PO/IV
-Tolerance does not develop
-Adverse effects (esp CNS) may limit the dosing
-Improves long-term control of asthma, When taken as the sole maintenance treatment, or When added to inhaled corticosteroids.
What are the anti-muscarinics used in the treatment of Asthma?
-Ipatropium Bromine
-Atropine
-Tiotropium
What is the MOA of anti-muscarinics used in the tx of asthma?
-Competitively inhibits Ach at the M3 of the ANS
-Blocks airway smooth muscle contraction
-Blocks the ⬆ of mucous secretion that occurs with vagal stimulation
What is the overall effect of the use of anti-muscarinics in Asthma?
Bronchodilation
What is unique about the Inhalational form of anti-muscarinics in the tx of asthma?
-Does NOT enter the CNS
-Poorly absorbed into the circulation
-Don’t have to worry about systemic SLUDGE effects (poorly absorbed into the circulation)
-Can be used if intolerant to B2 agonists
-Adjunct therapy for asthma exacerbation (used in combo therapy).
-Enhances effects of Albuterol in acute, severe attacks
-NOT an anti-inflammatory med.
-Blocks Smooth muscle contraction and mucus production only
What are the 3 corticosteroids you need to know?
-Prednisone (PO/IV)
-Beclomethasone
-Budesonide
What is the MOA for corticosteroids in Asthma?
-Broad, anti-inflammatory.
-Inhibit production of cytokines,
-Block lymphocytes, eosinophils, and mast cells from infiltrating the airways (!!)
-Block chemical mediators of asthma
-Doesn’t directly relax sm, but decreases bronchial reactivity. Not working on cAMP, but working on inflammatory immune response.
-Potentiates Beta agonists. Given in combo with Albuterol.
What are the pharmacodynamics associated with the use of Corticosteroids?
-↓bronchial reactivity
-Effective only as long as they are taken
-↓ Contraction of the engorged vessels in the bronchial mucosa
-Taper oral doses slowly to avoid adrenal insufficiency
-Oropharyngeal candidiasis (thrush - risk with INH form. Use mouthwash)
Blocks swelling & immune response to increase lumen size.
What are the intended and adverse effects associated with Corticosteroids?
-Systemic effects are worse in PO Form
-↓ the frequency of asthma exacerbations if taken regularly
-↓ airway reactivity & ↑ quality of life
-Severe adverse effects when taken chronically
-Reserved for urgent treatment
-INH/aerosols are the best way to avoid the adverse effects
-↑risk of cataracts & osteoporosis in adults with long term usage
-Slow the rate of growth in children
What are Leukotrienes?
Mediators associated with bronchoconstriction.
-Antagonism = bronchodilation.
What is the MOA of the Leukotriene-Receptor Antagonists (Montelukast aka Singulair)?
-LDT4 Receptor Antagonist
-Oral therapy for pts whose symptoms persist more than 2X a week or awaken from sleep by asthma more than 2X a month
-Widely used in the treatment of children with asthma in the US (age 6 and older)
-Improve asthma control
-Decrease exacerbations
-Once a day dosing (increased compliance)
PO is easier for kids than multiple INH doses/day.
Use of ____ or more canisters of an inhaled B agonist per month is the marker of increased risk of asthma fatality.
2
What are Beta 2 Agonists used for in the treatment of Asthma?
-Rescue inhaler
-Lone therapy for someone with mild asthma
-Supplementation required for severe asthma (corticosteroid)
IF….additional treatment is needed
-Symptoms require “rescue” therapy more than twice a week OR
-Nocturnal symptoms occur more than twice a month OR
-FEV1 is less than 80% predicted
How is Theophylline used in the treatment of Asthma?
-Reserved for patients who are poorly controlled with inhaled anti-inflammatory agent (pulmicort) and PRN Beta2 Agonist (Albuterol)
-Aminophylline: safer profile.
How are Anti-muscarinics (Ipratropium Bromide) used in the treatment of Asthma?
Largely used as an alternative for patients intolerant to Beta2 Agonists
How are Corticosteroids used in the treatment of Asthma?
Inhaled corticosteroids are started IF:
-Significant airflow obstruction persists despite bronchodilator therapy (urgent)
In severe asthma, standard inhaled corticosteroid may not be enough
-Double the dose of corticosteroid?
OR combine with another drug:
-Theophylline
-Montelukast (Singulair)
-Long acting Beta2 receptor agonist
What makes up a Combo Inhaler?
Corticosteroid + Long Acting B2 Agonist
Advair (flucticasone + salmetrol)
Symbicort (budesonide + formeterol)
What are the advantages of Combo Inhalers?
-Convenient
-Effective: Prompt improvement in pulmonary function
-Decrease asthmatic exacerbations
What are the disadvantages of Combo Inhalers?
-Mild-mod asthma should be treated with low-dose INH corticosteroid alone
-If NOT well controlled, the possible ⬆ in the risk of asthma fatality should be discussed in presenting options for treatment (Higher INH corticosteroid vs. adding long acting β2 agonist)
-BBW
What is the BBW associated with Combo Inhalers
Mild-mod asthma should be treated with low-dose INH corticosteroid alone due to increased risk of death with combo therapy.
