Lecture 22/23 Flashcards
drugs used in asthma
extrinsic asthma
hypersensitivity reaction induced by exposure to an extrinsic antigen
commonly associated with other allergies and genetics
onset is early in life
elevated serum IgE levels and eosinophil count
driven by TH2 subset of CD4+ T cells
two types: acute and sustained
acute bronchoconstriction
immediate response within 30 to 60 mins after antigen inhalation
occurs after sensitization, mediated by IgE
acute asthma pathway
mast cell degranulation –> release of histamine, tryptase, leukotrienes, and PGD2 –> smooth muscle contraction and vascular leakage –> direct stimulation of subepithelial vagal receptors –> reflex bronchoconstriction
sustained bronchoconstriction
late asthmatic response 3 to 6 hours after the immediate response
caused by the activation of TH2 cells and cytokine production and activation of eosinophils
sustained asthma pathway
activation of TH2 cells and cytokine production –> activation of eosinophils –> release MBP, ECP, peroxidase –> tissue damage –> amplify and sustain inflammation
intrinsic asthma
nonimmune triggering mechanism
example - aspirin, viral infection, cold, physiological stress, and exercise
no personal or family history of allergy
serum IgE levels are normal
IgE in acute
produced in response to foreign proteins
mediates sensitization
binds to FceR-1 on mast cells
mast cells in acute
in airway mucosa
release histamine, tryptase, leukotrienes, and PGD2
vagal (parasympathetic) receptors
direct stimulate provokes reflex bronchoconstriction in acute asthma
sympathomimetics
bronchodilators
types - nonselective, B selective, B2 selective
increases the cAMP concentration –> relaxation of muscle cells
nonselective sympathomimetic
example - epinephrine
IV injection to relieve a severe attack
B selective sympathomimetic
example - isoproterenol
displaced therapeutically by B2 selective drugs
affects the heart
B2 selective sympathomimetic
SABA and LABA drugs
most used for asthma treatment
SAR - bulky N-substitutions = B2 selective; phenyl ring substitutions = B2 selective and resistant to COMT
inhaled corticosteroids (ICSs)
anti-inflammatory steroids (controllers)
effective only so long as they are taken
systemic or oral are reserved for severe cases
most effective way to minimize adverse effects
leukotriene pathway inhibitors
either 5-lipoxygenase inhibitor or LTD4 antagonists
improve asthma control and reduce the frequency of asthma exacerbations
not as effective as IGC
5-lipoxygenase inhibitor
example - zileuton
alternative to LABA in addition to ICS
not for acute asthma
blocks LTB4 (a potent neutrophil chemoattract)
requires liver monitoring
LTD4 antagonists
also know as selective antagonists for the cysLT1 receptor
examples - Zafirlukast, Montelukast
blocks the binding of LTC4, LTD4, and LTE4 to the receptor
once a day dosing with good bioavailability
methylxanthine
examples - theophylline, theobromine, and caffeine
still used in some countries due to low cost (replaced by B2 selective agonists)
methylxanthine mechanism
inhibit phosphodiesterase –> increase cAMP concentration –> block adenosine –> suppress histamine release and increase bronchodilation
antimuscarinic agents
inhibit the action of acetylcholine at muscarinic receptors to prevent constriction and mucus secretion
used in pts intolerant of inhaled B agonists
example - ipratropium
ipratropium
bronchodilator
type of antimuscarinic agent
derivative of atropine
poorly absorbed in the circulation after inhaled due to minimal oral bioavailability
mast cell stabilizers
examples - cromolyn, nedocromil
inhibit mast cell degranulation
contraindication with direct bronchodilator actions
alternative use - allergic rhinoconjunctivitis as eye drops
monoclonal antibodies
target either IgE or IL5
examples - omalizumab, mepolizumab, reslizumab, benralizumab
omalizumab
inhibits IgE binding to mast cells
reserved for patients with severe asthma and allergic sensitization
mepolizumab, reslizumab, bentralizumab
anti-IL5 monoclonal abs
maintenance therapy of severe asthma in patients with eosinophilic phenotype
prevents the release of TH2 cells that attract and activate eosinophils
SABA
short acting b2 agonists
examples - albuterol, terbutaline, metaproterenol, pirbuterol
used - prn for acute attacks
albuterol
most widely used
resistant to COMT due to salicyl alcohol in phenyl ring
5min onset with 4-8 hour duration when inhaled
terbutaline
greater b2 selectivity with 3 fold greater potency than metaproterenol
good oral bioavailability
metaproterenol
somewhat selective for b2 receptor
least potent b2 agonist
5min onset with 4 hour duration when inhaled
pributerol
analogous to albuterol except for pyridine ring
comparable duration of action to albuterol, but with less potency
LABA
long acting b2 agonists
examples - salmeterol, formoterol, and in-combo with ICSs
uses - additional therapy for patients who is currently using IGCs; daily regular use
salmeterol
available as powder
LABA
greater lipid solubility due to dissolve in cellular membranes
20 min onset with 12 hour duration of action
formoterol
LABA
available as powder
more rapid onset than salmeterol with a comparable duration
resistant to COMT and MAO
LABA does NOT
treat acute attacks
have inflammatory action
have usage in monotherapies
ICSs
triamcinolone acetonide
beclomethasone dipropionate
budesonide
mometasone furoate
fluticasone propionate
ciclesonide
