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PHRM 825 > lectures 22-23 (asthma) > Flashcards

lectures 22-23 (asthma) Flashcards

exam 3 (56 cards)

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1
Q

extrinsic asthma

A
  • 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
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2
Q

intrinsic asthma

A
  • non-immune triggering mechanism (ex. aspirin, viral infection, cold, physiological stress, exercise)
  • no personal or family history of allergy
  • serum IgE levels are normal
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3
Q

triad of lung disease inducers

A

genetic
environmental
medications

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4
Q

acute bronchoconstriction

A
  • 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
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5
Q

sustained bronchoconstriction

A
  • 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
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6
Q

role of IgE and mast cells in the pathology of extrinsic asthma

A
  • 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
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7
Q

immune cells responsible for the pathology of asthma

A

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

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8
Q

role of vagal (parasympathetic) receptors in bronchoconstriction

A

direct stimulation of subepithelial vagal (parasympathetic) receptors provokes reflex bronchoconstriction

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9
Q

SABA/LABA MOA

A

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

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10
Q

ICS MOA

A

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

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11
Q

leukotriene pathway inhibitors MOA

A

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

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12
Q

methylxanthine/phosphodiesterase inhibitors MOA

A

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)

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13
Q

antimuscarinic MOA

A

stimulation of cholinergic (parasympathetic) nerves causes bronchoconstriction and mucus secretion
antimuscarinic drugs competitively inhibit the action of Ach at muscarinic receptors

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14
Q

mast cell stabilizer MOA

A

inhibit mast cell degranulation
no direct bronchodilator action

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15
Q

anti-IgE mab MOA

A

recognizes the portion of IgE that binds to its receptor (FceR-1 and FceR-2) on immune cells
inhibits IgE binding to mase cells

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16
Q

anti-IL-5 mab MOA

A

IL-5 released from H2 cells attracts and activates eosinophils, mab inhibit IL-5 and its action

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17
Q

anti-IL-5 receptor mab MOA

A

binds to IL-5 receptor and blocks IL-5
inhibits differentiation and maturation of eosinophils in the bone marrow

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18
Q

anti-IL-4 receptor mab MOA

A

IL-4 alpha chain is involved in signaling for both IL-4 and IL-13, key cytokines involved in type 2 inflammation

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19
Q

anti-TSLP mab MOA

A

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

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20
Q

SABAs

A

albuterol (ventolin)
levalbuterol (xopenex)
metaproterenol (alupent)
terbutaline (brethine)
pirbuterol (maxair)

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21
Q

LABAs

A

salmeterol (severent)
formoterol (foradil)
arformoterol (brovana)

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22
Q

ICSs

A

triamcinolone acetonide (azmacort)
beclomethasone dipropionate (vanceril, qvar)
flunisolide (aerobid)
budesonide (pulmicort)
mometasone furoate (asmanex)
fluticasone propionate (flovent)
ciclesonide (alvesco)

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23
Q

leukotriene pathway inhibitors

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A

5-lipoxygenase inhibitor:
zileuton (zyflo)
LTRAs:
zafirlukast (accolate)
montelukast (singulair)

24
Q

methylxanthines

Study These Flashcards
A

theophylline
theobromine
caffeine

25
antimuscarinics
ipratropium (atrovent)
26
mast cell stabilizers
cromolyn (gastrocom, intal) nedocromil (tilade)
27
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)
28
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
29
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
30
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
31
terbutaline
brethine SABA - N-t-butyl analogue of metaproterenol - greater β2 selectivity, 3-fold potency than metaproterenol - good oral bioavailability
32
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
33
levalbuterol
xopenex SABA - R-isomer of albuterol - greater potency but more expensive - used when albuterol has side effects in pediatric patients
34
pirbuterol
maxair SABA - analogous to albuterol except the pyridine ring - comparable duration of action but less potent than albuterol
35
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
36
formoterol
foradil LABA - highest receptor affinity - rapid onset but comparable duration of action to salmeterol - increased lipophilicity and increased resistance to COMT/MAO
37
arformoterol
brovana LABA - R,R enantiomer of formoterol
38
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
39
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
40
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
41
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
42
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
43
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)
44
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
45
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
46
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
47
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)
48
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
49
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
50
type 2 inflammation
high inflammation eosinophilic IL-4, IL-5, and IL-13 PGD2 stimulation of the DP2 receptor
51
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
52
mepolizumab
nucala anti-IL-5 - inhibit IL-5 released from TH2 cells - decreased eosinophil numbers, reduction in clinically significant exacerbations by 40-50%
53
resilizumab
cinqair anti-IL-5 - inhibit IL-5 released from TH2 cells - injection given under supervision
54
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
55
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
56
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

PHRM 825 (9 decks)

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