lectures 22-23 (asthma) Flashcards
exam 3
extrinsic asthma
- allergic asthma or classical asthma
- hypersensitivity reaction induced by exposure to an extrinsic antigen (ex. dust mites, molds, pollens, etc.)
- commonly associated with other allergies in the patient as well as in other family members
- the onset is usually earlier in life
- elevated serum IgE levels and eosinophil count
- driven by TH2 subset of CD4+ cells
intrinsic asthma
- non-immune triggering mechanism (ex. aspirin, viral infection, cold, physiological stress, exercise)
- no personal or family history of allergy
- serum IgE levels are normal
triad of lung disease inducers
genetic
environmental
medications
acute bronchoconstriction
- immediate asthmatic response
- 30-60 minutes after inhalation of antigen
- 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 the mediators from the mast cells (mast cell degranulation)
- mast cells release histamine, tryptase, leukotrienes (LTC4 and LTD4) and prostaglandin D2 (PGD2)
- mediators cause the smooth muscle contraction and vascular leakage, swelling
- direct stimulation of subepithelial vagal (parasympathetic) receptors provokes reflex bronchoconstriction
sustained bronchoconstriction
- late asthmatic response
- 4-8 hours after the immediate asthmatic response
- caused by the activation of TH2 cells and cytokine production
*ex. IL-5, IL-9, and IL-13
*attract and activate eosinophils
*stimulate mucus hyper-secretion by bronchial epithelial cells
*stimulate IgE production by B lymphocytes - activation of eosinophils
*releases major basic protein (MBP), eosinophil cationic protein (ECP), peroxidase, which cause tissue damage
*amplifies and sustains the inflammation without additional exposure to the triggering antigen
role of IgE and mast cells in the pathology of extrinsic asthma
- acute bronchoconstriction 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 the mediators from the mast cells (mast cell degranulation)
- mast cells release histamine, tryptase, leukotrienes (LTC4 and LTD4) and prostaglandin D2 (PGD2)
- mediators cause the smooth muscle contraction and vascular leakage, swelling
immune cells responsible for the pathology of asthma
dendritic cells- primary antigen presenting/detecting cells that initiate the immune response
naive T cells- with dendritic cells, present antigen to TH2 cells
TH2- signal to mast cells (IL-9), B cells (IL-4, IL-13), eosinophils (IL-5), bronchial epithelium (IL-13)
B cells- IgE production
eosinophils- release of MBP, ECP, peroxidase (tissue damage)
mast cells- degranulation releases histamine, tryptase, LTC4, LTD4, and PGD2
role of vagal (parasympathetic) receptors in bronchoconstriction
direct stimulation of subepithelial vagal (parasympathetic) receptors provokes reflex bronchoconstriction
SABA/LABA MOA
binds to β2 adrenergic receptors in the bronchial smooth muscle
increases cAMP concentration and relax the muscle cells
SABA- PRN FOR ACUTE ATTACKS
LABA- NOT A MONOTHERAPY FOR ASTHMA, DAILY USE WITH ICS
ICS MOA
activation of glucocorticoid receptors
altered gene transcription
reduced production of inflammatory mediators
MAINTENANCE THERAPY for persistent asthma
- not curative –> controller, effective only so long as they are taken
- systemic or oral corticosteroids are reserved for more severe cases
- ICS are the most effective way to minimize systemic adverse effects
leukotriene pathway inhibitors MOA
leukotrienes produced from arachidonic acid by 5-lipoxygenase and involved in many inflammatory diseases and in anaphylaxis
LTB4- potent neutrophil chemoattractant
LTC4 and LTD4- responsible for many symptoms of asthma (bronchoconstriction, increased bronchial reactivity, mucosal edema, and mucus hypersecretion)
5-lipoxygenase inhibitors
cysLT1 receptor selective antagonists
methylxanthine/phosphodiesterase inhibitors MOA
inhibition of PDE3 and PDE4 –> increased cellular cAMP concentration –> bronchodilation and suppression of histamine release
block the action of adenosine (adenosine causes bronchoconstriction and histamine release)
histone deacetylation (suppresses inflammatory gene expression)
antimuscarinic MOA
stimulation of cholinergic (parasympathetic) nerves causes bronchoconstriction and mucus secretion
antimuscarinic drugs competitively inhibit the action of Ach at muscarinic receptors
mast cell stabilizer MOA
inhibit mast cell degranulation
no direct bronchodilator action
anti-IgE mab MOA
recognizes the portion of IgE that binds to its receptor (FceR-1 and FceR-2) on immune cells
inhibits IgE binding to mase cells
anti-IL-5 mab MOA
IL-5 released from H2 cells attracts and activates eosinophils, mab inhibit IL-5 and its action
anti-IL-5 receptor mab MOA
binds to IL-5 receptor and blocks IL-5
inhibits differentiation and maturation of eosinophils in the bone marrow
anti-IL-4 receptor mab MOA
IL-4 alpha chain is involved in signaling for both IL-4 and IL-13, key cytokines involved in type 2 inflammation
anti-TSLP mab MOA
blocks interaction of TSLP with its receptor resulting in decreased type 2 inflammatory response (TH2, dendritic cells, mast cells)
inhibits differentiation and maturation of eosinophils in the bone marrow
SABAs
albuterol (ventolin)
levalbuterol (xopenex)
metaproterenol (alupent)
terbutaline (brethine)
pirbuterol (maxair)
LABAs
salmeterol (severent)
formoterol (foradil)
arformoterol (brovana)
ICSs
triamcinolone acetonide (azmacort)
beclomethasone dipropionate (vanceril, qvar)
flunisolide (aerobid)
budesonide (pulmicort)
mometasone furoate (asmanex)
fluticasone propionate (flovent)
ciclesonide (alvesco)
leukotriene pathway inhibitors
5-lipoxygenase inhibitor:
zileuton (zyflo)
LTRAs:
zafirlukast (accolate)
montelukast (singulair)
methylxanthines
theophylline
theobromine
caffeine
antimuscarinics
ipratropium (atrovent)
mast cell stabilizers
cromolyn (gastrocom, intal)
nedocromil (tilade)
monoclonal antibodies
anti-IgE: omalizumab (xolair)
anti-IL-5: mepolizumab (nucala), reslizumab (cinqair)
anti-IL-5 receptor: benralizumab (fasenra)
anti-IL-4 receptor: dupilumab (dupixent)
anti-TSLP: tezepelumab (tezspire)
β2 selective agonists SAR
bulky N substitutions –> more β2 selective
substitutions in the phenyl ring –> more β2 selective and resistant to COMT
mostly racemic mixture (ex. levalbuterol)- only R-isomer is active
β2 selective agonists toxicities
tachycardia, arrhythmias (less concern for β2 selective)
skeletal muscle tremors
induction of tachyphylaxis- reduction in the bronchodilator response upon regular uses
metaproterenol
alupent
SABA
- resorcinol analogue of isoproterenol
- somewhat selective for β2 receptor, least potent
- 5 minute onset and 4 hour duration when inhaled
- good oral bioavailability
terbutaline
brethine
SABA
- N-t-butyl analogue of metaproterenol
- greater β2 selectivity, 3-fold potency than metaproterenol
- good oral bioavailability
albuterol
ventolin
SABA
- most widely used
- salicyl alcohol in the phenyl ring –> COMT resistant
- optimal β2 selectivity
- 5 minute onset and 4-8 hour duration when inhaled
levalbuterol
xopenex
SABA
- R-isomer of albuterol
- greater potency but more expensive
- used when albuterol has side effects in pediatric patients
pirbuterol
maxair
SABA
- analogous to albuterol except the pyridine ring
- comparable duration of action but less potent than albuterol
salmeterol
serevent
LABA
- greater water solubility and moderate lipophilicity
- 20 minute onset and 12 hour duration of action
- moderate resistance to MAO/COMT
- available as a powder
formoterol
foradil
LABA
- highest receptor affinity
- rapid onset but comparable duration of action to salmeterol
- increased lipophilicity and increased resistance to COMT/MAO
arformoterol
brovana
LABA
- R,R enantiomer of formoterol
SABA/LABA application notes
inhalation is the route of choice for attacks
PRN for acute or anticipated attack
- provides for local action on bronchial smooth muscle
- fewer systemic adverse effects compared to oral
patients should not use albuterol more than 2x/week except for exercise induced asthma
adverse effects:
- skeletal muscle tremors
- tachycardia and palpitations (less with β2 selective, high doses of β2 selective agents may stimulate β1 receptors in the heart, reflex tachycardia due to vasodilation caused by activation of β2 receptors)
- vasodilation –> decreased blood pressure –> increased HR
ICS adverse effects
candidiasis:
- can be treated with topical clotrimazole
- can be reduced by having patients gargle water and expectorate after each inhaled treatment
- ciclesonide is a 21-ester prodrug associated with less candidiasis
hoarseness- direct effect of corticosteroids on vocal cords
long-term use may increase the risk of osteoporosis and caratacts
in children, 1cm reduction in their growth only in the first year
zileuton
zyflo
5-lipoxygenase inhibitor
- N-hydroxy group is essential for inhibitory activity
- good oral bioavailability
- alternate to LABA in addition to ICS
- NOT FOR ACUTE ASTHMA ATTACK
- requires periodic monitoring of liver function (liver toxicity)
- cysLTs increase contration, secretion, and permeability
- metabolized and inhibits fome P450 isozymes
- doubles the blood levels of theophylline and increases prothrombin time (PT) with warfarin use
- side effects: headache, dyspepsia
zafirlukast
accolate
- blocks the binding of LTC4, LTD4, and LTE4 to the receptor
- twice daily dosing required
- potential for liver toxicity (requires liver function monitoring)
- no boxed warning
- less commonly prescribed compared to montelukast
- benzofuran ring system with a sulfonamide group and carboxyl group
montelukast
singulair
- blocks the binding of LTC4, LTD4, and LTE4 to the receptor
- once a day dosing
- little liver toxicity
- boxed warning for neuropsychiatric issues (agitation, sleeping, and mental health issues)
- dosing in the evening counters neuropsych issues and counters increased leukotriene synthesis in the evening
- more commonly prescribed
- developed from other weakly antagonistic quinoline derivatives
zafirlukast/montelukast adverse effects
both indicated for prophylaxis of asthma in adults and children
not indicated for reversal of acute bronchospasm, but therapy can be continued while treating with β2 agonists
both are cysLT-1R antagonists
headache, nausea, diarrhea
food reduces bioavailability (do not take with meals)
methylxanthine drugs
theophylline (most effective, more specific for smooth muscle), theobromine, and caffeine
differ by the position and number of methyl groups on their xanthine ring system
once a mainstay of asthma treatment but have been replaced by β2 selective agonists
still used in some countries due to its low cost
theophylline
mechanism:
- inhibition of phosphodiesterase –> increase in cellular cAMP –> bronchodilation and suppression of histamine release
- block the action of adenosine
- histone deacetylation
toxicity:
- nausea, vomiting, tremulousness, arrhythmias
- narrow therapeutic index
info:
magnesium/aluminum hydroxide antacids delay absorption
half life is prolonged in CHF patients
aggravates pre-existing seizure disorders
many agents increase theophylline levels by competing for P450 enzymes
ipratropium
atrovent
antimuscarinic agent
- bronchodilator used for acute asthma exacerbations
- more common for COPD
- quaternary amine derivatives of atropine
- poorly absorbed into the circulation after inhaled
- minimal oral bioavailability
- relatively free of systemic atropine-like effect
cromolyn and nedocromil
intal and tilade
mast cell stabilizers
- prophylaxis of mild/moderate asthma
- inhibit mast cell degranulation
- no direct bronchodilator action, should be used as daily dosing
- poorly absorbed into the systemic circulation and have little toxicity, but not as potent or as predictably effective as glucocorticoids
- current indication is allergic rhinoconjunctivitis as eye drops
- cromolyns are stable, insoluble salts and cannot be taken orally (inhaled as a microfine powder or aerosolized solution)
biologics therapy
monoclonal antibody (mab) used to modulate biological pathways
usually by blocking receptors or cytokines
used when steps 1-4 do not work, failed with ICS, leukotriene antagonists, etc
comorbid conditions: smokers and obese patients are less likely to respond, and different types of allergies and sensitivities
used for patients with frequent exacerbations
type 1 inflammation
low inflammation
neutrophilic, TH1 driven
IL-6, IL-8, and IL-17
harder to treat and more likely to have adverse events when treatments have been used
type 2 inflammation
high inflammation
eosinophilic
IL-4, IL-5, and IL-13
PGD2 stimulation of the DP2 receptor
omalizumab
xolair
anti-IgE mab (humanized mouse anti-human IgE antibody)
- recognizes the portion of IgE that binds to its receptor on immune cells
- inhibits IgE binding to mast cells, binds to IgE and causes a 96% reduction in free IgE levels
- reserved for patients with severe asthma and allergic sensitization
- anaphylaxis in 0.1% of patients, injection site reactions, increased incidence of infection, some urticaria/dermatitis/pruitis
mepolizumab
nucala
anti-IL-5
- inhibit IL-5 released from TH2 cells
- decreased eosinophil numbers, reduction in clinically significant exacerbations by 40-50%
resilizumab
cinqair
anti-IL-5
- inhibit IL-5 released from TH2 cells
- injection given under supervision
benralizumab
fasenra
anti-IL-5 receptor
- severe eosinophilic asthma treatment (maintenance therapy)
- binds to IL-5 receptor and blocks IL-5
- inhibits differentiation and maturation of eosinophils in the bone marrow
dupilumab
dupixent
anti-IL-4 receptor
- IL-4⍺ chain is involved in signaling for both IL-4 and IL-13, key cytokines involved in type 2 inflammation
- used for persistent asthma, atopic dermatitis (eczema), and chronic rhinosinusitis (nasal polyps)
- self administered at home SC
- side effects: increase bloody eosinophil levels, rare conjunctivitis
tezeplumab
tezspire
anti-TSLP
- blocks interaction of TSLP with its receptor resulting in decreased type 2 inflammatory response (TH2, dendritic cells, mast cells)
- no limitation-based phenotype or biomarkers
- inhibits differentiation and maturation of eosinophils in the bone marrow
- common side effects: sore throat, joint pain, back pain, rash
- serious/rare side effects: hypersensitivity reactions, including anaphylaxis
