EX. 3 - Asthma Flashcards
Episodic bronchospasm resulting form an exaggerated bronchoconstrictor response to various stimuli
Asthma
Asthma is an - of the bronchi
Inflammation
Episodic bronchospasm causes
Dyspnea, cough, and wheezing
Asthma affects -% of adults and -% of children
5% adults
7-10% children
(Over 3,000 fatalities a year)
Types of asthma
Extrinsic (allergic/classical)
Intrinsic
Extrinsic asthma:
Hypersensitivity rxn induced by exposure to an extrinsic antigen (dust, mold, pollen)
Commonly associated w/other allergy in patient/family members
Onset - early in life
Elevated serum IgE levels and eosinophil count
Driven by TH2 subset of CD4+T cells
Intrinsic asthma
Nonimmune triggering mechanism (ex. aspirin, viral infection, cold, psychological stress, exercise)
No personal or family history of allergy
Serum IgE levels - normal
Two phases of extrinsic asthma attacks
Acute bronchoconstriction
(immediate; 30-60 min)
Sustained bronchoconstriction:
(Late; 4-8 hours later after immediate response)
Acute bronchoconstriction
Immediate asthmatic response (IAR)
Occurs after sensitization
Mediated by IgE, produced in response to exposure of foreign particles
(IgE binds to FcER-1 on mast cells in the airway mucosa
Re-exposure to the allergen triggers the release of mediators from the mast cells in a process called
mast cell degranulation
Mast cells release
Histamine
Tryptase
Leukotrienes (LTC4 and LTD4)
Prostaglandin D2 (PGD2)
Mediators of acute bronchoconstriction cause
Smooth muscle contraction and vascular leakage
Sustained Bronchoconstriction
Late asthmatic response (LAR)
(3-6hrs after acute)
Caused by Activation of TH2 cells and cytokine production
Activation of TH2 cells in sustained bronchoconstriction
Ex. IL5, IL9, IL13
Attract and activate eosinophils
Stimulate mucus hypersecretion by bronchial epithelial cells
Stimulate IgE production by B lymphocytes
Activation of eosinophils
Release major basic protein, (MBP), eosinophil cationic protein (ECP) peroxidase, - causes tissue damage
Epithelium remodeling
Hyperplasia
Hypersecretion
Basement membrane remodeling
Thickening
Smooth muscle remodeling
Hypertrophy
Pharm treatments in asthma
Sympathomimetics
ICs’s
(^^MOST COMMON^^)
Leukotriene pathway inhibitors
Methylxanthine drugs
Antimuscarinic Agents
Cromolyn and Nedocromil
Monoclonal antibodies
Sympathomimetics are - while ICS’s are -
Relievers, controllers
Sympathomimetics mechanism
Binds to B2 adrenergic receptors in the bronchial smooth muscle
Increases the cAMP concentration -> relax the muscle cellsS
Types of sympathomimetics
-Nonselective
Epinephrine (IV inject. after severe attack)
-B selective (also affects heart - B1)
Isoproterenol (displaced by B2 selective drugs)
-B2 selective
Most common
Short and long acting agonists
B2 Selective agonist SAR
Bulky N subs-> B2 selective
Subs in the phenyl ring -> B2 selective and resistant to COMT
Mostly racemic -R active
B2 Selective agonists Toxicities
Tachycardia, arrhythmias (less)
Skeletal muscle tremors
Induction of tachyphylaxis - reduction in the bronchodilator response upon regular uses
SABA vs LABA use
SABA - PRN for acute attacks
LABA - additional therapy for patients currently using inhaled glucocorticoids
NOT for acute attacks, but regular daily use
No anti-inflam action (black box warning)
Comonly combined with corticosteroids
Metoproterenol
SABA
Resorcinol analogue of isoproterenol
Somewhat B2 selective
LEAST POTENT B2 AGONIST
5-min onset, 4hr duration
Good oral bioavailability
Terbutaline
SABA
N-t-butyl analogue of metapro
Greater B2 selectivity
3-fold greater potency than metaproterenol at B2 receptors
Good oral bioavailability
Albuterol
SABA
most widely used
Resistant to COMT
5-min onset, 4-8hr duration of action when inhaled
Levalbuterol is R-isomer
(Greater potency, more expensive)
Pirbuterol
Analogous to albuterol except the pyridine ring
Comparable duration of action as albuterol
Less potent than albuterol
Salmeterol
LABA
-Available as powder
Greater lipid solubility; dissolve in cell membranes
20-minute onset and 12hr duration of action
Formoterol
LABA
-Available as powder
-More rapid onset than salmeterol with a comparable duration of action
Resistant to COMT and MAO
Inhaled corticosteroids (ICSs)
Maintenance therapy for persistent asthma
Not curative
“controller”
Effective only so long as they are taken
_ or _ corticosteroids are reserved for severe cases
Oral or systemic
_ is the most effective way to minimize the systemic adverse effects
Inhaled corticosteroids
ICs’s Adverse effects:
Candidiasis - can be treated with topical clotrimazole
Can be reduced by having patients gargle water and expectorate after each inhaled treatment
Ciclesonide - 21 ester prodrug, associated with less candidiasis
Hoarseness - direct effect of corticosteroids on the vocal cords
Long term - use may increase the risk of osteoporosis and cataracts
In children, I cm reduction in the growth only for the first year
Produced form arachidonic acid by 5-lipoxygenase
Involved in many inflammatory diseases and in anaphylaxis
LTB4 - potent neutrophil chemoattractant
LTC and LTD4 - responsible for many symptoms of asthma, such as bronchoconstriction, increased bronchial reactivity, mucosal edema, and mucus hypersecretion
Leukotrienes
Improve asthma control and reduce the frequency of asthma exacerbations
Not as effective as inhaled glucocorticoids
Effective when taken orally, easier than inhalation for children
Reduce significantly the response to aspirin in aspirin-induced asthma (5-10% of asthma patients)
Leukotriene pathway inhibitors
Zileuton
Leukotriene pathway inhibitor
5-lipoxygenase inhibitor
Racemic mix
N-hydroxy group is essential for inhibitory activity
Good oral bioavailability
Alternative to LABA in addition to ICS
NOT for acute asthma attack
Requires periodic monitoring of liver
Monetlukast
Blocks the binding of LTC4, LTD4, and LTE4 to the receptor
Once a day dosing
Good oral bioavailable
Reduces the frequency of asthma exacerbations
Little toxicity
Theophylline (most effective; more specific for smooth muscle)
Theobromine
Caffeine
Once a mainstay for asthma tx, replaced by B2
Still used in some countries due to low cost
Methylxanthine drugs
Methylxanthine MOA
Inhibition of phosphodiesterases (PDE3 and PDE4)-> increase in the cellular cAMP concentration -> bronchodilation and suppression of histamine release
Block the action of adenosine, which causes bronchoconstriction and the release of histamine
Histone deacetylation, which suppresses inflammatory gene expression
Toxicity of Methylxanthine drugs
Nausea, vomiting, tremulousness, arrhythmias
Narrow therapeutic index
“Anticholinergic agents”
MOA:
Stimulation of cholinergic (parasympathetic) nerves causes bronchoconstriction and mucus secretion
Antimuscarinic drugs competitively inhibit the action of acetylcholine at muscarinic receptors
Clinically valuable patients who are intolerant of inhaled B agonists
Antimuscarinic agents
Ipratropium
Antimuscarinic agent
Bronchodilator
Quaternary amine derivative of atropine
Poorly absorbed into the circulation after inhaled
Minimal oral bioavailability
Relatively free of systemic atropine-like effects
Cromolyn and nedocromil
Once widely used for asthma management, especially in kids
Inhibit mast cell degranulation
No direct bronchodilator action; should be used prophylactically (daily dosing)
Poorly absorbed in the systemic circulation; little toxicity; not as potent as glucocorticoids
Current use; allergic rhino conjunctivitis eye drops
Mast cell Stabilizers
Omalizumab
Recognizes the portion of IgE binding to its receptor (FCER-I and FCER-2) on immune cells
Inhibits IgE binding to mast cells
Reserved for patients with severe asthma and allergic sensitization
Anti-IgE monoclonal antibody
IL-5 release from TH2 cells attracts and activates eosinophils
Anti-IL-5 monoclonal antibodies (Mepolizumab and Reslizumab)
Anit-IL-5 receptor monoclonal antibody Benralizumab
Used as a maintenance therapy of severe asthma in patients with an eosinophilic phenotype
Anti-IL-5 Therapy
