Term
Know the B2-selective vs non-selective sympathomimetic bronchodilators
Know structural modification that increased B2 selectivity. |
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Definition
B2-selectives: terbutaline, albuterol, pirbuterol. Salmeterol and formoterol are very long acting B2-selective agents.
Increasing bulk of side chain increases B2 selectivity.
Non-selective: isoproterenol (catecholamine) and metaproterenol (non-catecholamine) |
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Term
Beta-agonist Structure
Which modifications lead to longer duration of action? |
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Definition
Benzene ring with side chain.
Modification of benzene ring (3,4-hydroxyl groups) imparts prolonged activity. (example: terbutaline)
Increasing bulk of side chain prolongs action (inhibits degradation by MAO) (Example: albuterol)
Long lipophilic side chains prolong bronchodilation. (Example: salmeterol) |
|
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Term
Beta-agonists Routes of Administration: onset of action, dose response, side effect risk
1. Oral
2. Parenteral
3. Inhalation |
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Definition
1. slow onset of action (peak effect at 2 hrs), larger doses needed, increased tremor and palpitations
2. Rapid onset, increased side effects compared to aerosol but bronchodilation is similar to aerosol
3. 75% effect in 5 minutes; peak effect in 30-90 minutes. Dose response is log-linear (10-fold increase dose provides doubling of bronchodilation)
NOTE: salmeterol has delayed onset and peak effect (180 minutes) |
|
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Term
| What are the non-bronchodilator effects of beta-agonists? |
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Definition
Increased mucociliary clearance
Protection of resp epithelium against bacteria
Suppression of microvascular permeability
Inhibition of cholinergic neurotransmission
Inhibition of mediator release
Anti-inflammatory effects shown in vitro
Enhanced translocation of GC receptor into nucleus |
|
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Term
| Side effects of beta-agonists |
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Definition
Tremor (stimulation of B2 in skeletal muscle)
Cardiac: increased HR, palpitations, prolonged QT, arrhythmias, ischemia
Transient increased hypoxia
Hyperglycemia, hypokalemia, hypomagnesemia
Tolerance (tachyphylaxis) with decreased duration of action (due to downregulation of receptor)
Loss of bronchoprotection to stimuli with chronic use (eg methacholine, exercise) |
|
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Term
B2-adrenergic recetpor polymorphisms
Know 2 common polymorphisms and their clinical effects |
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Definition
B2AR gene is on chromosome 5q32.
Single AA substitutions can impart changes in receptor activity
Arg 16--> Gly 16 at nucleotide 46: severe asthma, nocturnal asthma and enhanced downregulation of B2AR
Gln 27--> Glu 27 at nucleotide 79: decreased airway hyperresponsiveness and attenuated downregulation of B2AR |
|
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Term
Arg 16 homozygotes
1. Who is affected?
2. What are the clinical manifestations? |
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Definition
1. 20% of African Americans
2. Decline in FEV1 and increased exacerbations with chronic use of SABAs. |
|
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Term
| Name the 3 Muscarinic Receptors and what they do |
|
Definition
M1: excitatory
M2: post-synaptic inhibition
M3: mediate smooth muscle contraction and bronchoconstriction |
|
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Term
Quaternary Ammonium Derivatives
Compare/contrast Ipratropium vs Tiotropium |
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Definition
Ipra binds M2 and M3 receptors with equal affinity. So does Tio.
Ipra: shorter duration of action (q6h)
Tio: dissociates from M1 and M3 receptors 100 times more slowly than Ipra and dissociates from M2 10 times faster than Ipra. Longer duration of action (once daily dosing). Slower onset of action than Ipra. |
|
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Term
| Use of Anticholinergics in Asthma |
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Definition
Beta agonists produce greater bronchodilation whenadmin after ipratropiuum than vice versa.
Anticholinergics less effective as single agent than B agonists.
Additive benefit of ipra + B agonists in moderate-severe exacerbations in ED. |
|
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Term
| Theophylline: Mechanisms of Action |
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Definition
Phosphodiesterase (PDE) inhibition: weak, non-selective. Increased cAMP, cGMP.
Adenosine receptor antagonism: potent, this effect may account for some side effects.
Increased secretion of adrenaline
Inhibits prostaglandins, TNF-alpha
Inhibits intracellular calcium release
Prevents nuclear translocation of NFkappaB
Increases hitone deacetylase activity (?synergy with steroids) |
|
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Term
| Theophylline's effects on airway smooth muscle and inflammation |
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Definition
Relaxes large and small airways (probably via PDE), less effective than beta agonists
Small bronchoprotective effects (methacholine, exercise, histamine)
Anti-inflammatory effects: significance is unclear. Inhibits late phase respone to allergen, decreases airway eos, inhibits proliferation of CD4+/CD8+ T cells, inhibits IL-2 synthesis. Induces apoptosis of T cells. |
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Term
Theophylline metabolism
1. Know cytochromes involved
2. Know the causes of increased clearance (decreased theo level)
3. Know causes of decreased clearance (increased level) |
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Definition
1. Hepatic metabolism by cytochrome p450 system (mostly CYP1A2, but at high concentrations, CYP2E1 is involved)
2. Children, smoking, phenytoin, phenobarbital, rifampin, ethanol, high protein/low carb diet
3. Liver disease, CHF, pneumonia, old age, viral infxn, vaccination, high carb diet, cimetidine, erythro, cipro, zileuton, allopurinol, serotonin reuptake inhibitors.
Note: halve dose when on drugs that decrease metabolism. |
|
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Term
| Side effects of theophylline |
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Definition
headache
Nausea, vomiting, abd discomfort, GER, Gastric acid secretion
Restlessness
Diuresis
At high concentrations: convulsions, arrhythmias |
|
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Term
Antihistamines
How do they act on H1 receptors? |
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Definition
They act as inverse agonists NOT antagonists.
(H1 receptors exist in a state of equilibrium btwn active and inactive states. Antihistamines promote the inactive state.) |
|
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Term
| Non-H1 antihistamine effects |
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Definition
Anti-muscarinic/anti-cholinergic: 1st generation agents
alpha-adrenergic blockade: promethazine
Local anesthesia: diphenhydramine
Anti-serotonergic: cyproheptadine
Anti-inflammatory: require high concentrations for preventing mast cell/basophil mediator release. |
|
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Term
Metabolism of Antihistamines
Know the difference btwn 1st and 2nd generation antihistamines and likely drug interactions |
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Definition
1st gen: hepatic CYP450 (thus potential drug interactions with drugs that inhibit this enzyme, such as macrolides)
2nd gen: most excreted unchanged in urne, feces. Minimal drug interactions |
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Term
Anti-histamines in asthma
What is their effect on bronchoconstriction? |
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Definition
Protective against bronchoconstriction for histamine, AMP, (less so for exercise)
No protection from methacholine, LTD4 |
|
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Term
Side effects of anti-histamines
1st vs 2nd gen |
|
Definition
1st gen: dry mouth, blurred vision, urinary retention, CNS (depressive and excitatory---the latter is more common in children), prolonged QT, torsades de pointes; appetite stim/weight gain (cyproheptadine)
2nd gen: weight gain (ketotifen) |
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Term
Glucocorticoids
Know binding affinity for transcortin and albumin
Know diseases that affect GC metabolism |
|
Definition
More than 90% of cortisol is bound to plasma proteins.
Transcortin: high affinity, low capacity
Albumin: low affinity, high capacity
Hyperthyroidism, CF enhance clearance of GC (so higher doses are required) |
|
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Term
| Know which meds increas/decrease metabolism of glucocorticoids |
|
Definition
Increase metabolism: rifampin, carbamazepime, phenobarbital, phenytoin, antacids
Decrease metabolism: ketoconazole, OCPs, macrolides |
|
|
Term
| Molecular basis of glucocorticoid actions |
|
Definition
GC binds to GC receptor (GR)
Heat shock protein dissociate
GR is phosphorylated and translocates from cytoplasm to nucleus. NLS1 binds to importin-alpha.
GR binds as dimer to GC response elements (GRE) in DNA. Mediated by zinc fingers.
RNA polymerase activated.
Transcription enhanced. |
|
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Term
Anti-inflammatory activity of Glucocorticoids:
GR-GRE interaction leads to transcription and synthesis of which anti-inflammatory proteins? |
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Definition
GLIZ (GC-induced leucine zipper protein). This inhibits NF-kB
MKP-1 (Map kinase phosphatase-1). This inhibits p38 MAP kinase.
IkBa: inhibits NF-kB
(GC also induces B2 receptors and IL-1 receptor antagonist) |
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Term
|
Definition
Binding of GR to negative GRE results in gene suppression.
Negative GREs may be involved with steroid side effects. |
|
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Term
| What is the dominant mechanism of GC's anti-inflammatory effects: gene activation or gene suppression? |
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Definition
| Gene suppression (which leads to inhibition of synthesis of multiple inflammatory proteins) |
|
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Term
Histone Acetyl Transferase (HAT)
What does it do in asthma?
What do glucocorticoids do to HAT? |
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Definition
HAT activates gene transcription and its expression is increased in asthma.
GC at high concentrations can activate or, at low concentrations, can inhibit HAT |
|
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Term
| What are the effects of inhaled corticosteroids in the airways and in asthma? |
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Definition
1. Decrease inflammation: decrease mast cells, cubmucosal T cells, eos, CD25+ and HLA-DR+ lymphs
2. Reduce late phase response and airway hyperresponsiveness
3. Reduce morbidity and mortality (control sx, improve pulm fxn and prevent exacerbations) |
|
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Term
| What are the molecular mechanisms of GC resistance? |
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Definition
GR modification
Increased GR-beta expression
Increase pro-inflammatory transcription factors (AP1, JNK, STAT5, JAK3)
Defective histone acetylation
Increased p-glycoprotein (increased efflux of steroids)
Familial GC resistance |
|
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Term
GR-beta
1. Is it assoc with GC sensitivity or resistance?
2. Name phenotypes assoc with increased expression of GR-beta. |
|
Definition
1. GC resistance
2. Fatal asthma, Nocturnal asthma, nasal polyposis |
|
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Term
| Adverse effects of Systemic steroids |
|
Definition
Metabolic: low K+, hyperlipidemia, hyperglycemia
Endocrine
Immune: decreased IgG,
Derm
Musculoskeletal: ASN, myopathy
Eye: posterior subcapsular cataracts, glaucoma
Cardiovasc: HTN, atherosclerosis
Heme: lymphopenia, eosinopenia, neutrophilia
Psych/Neuro: psudotumor cerebri, mood disorders, psychosis |
|
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Term
Steroid induced myopathy:
Acute vs Chronic
1. Know the cellular derangement
2. Know how CPK is affected |
|
Definition
Acute: necrosis, high CPK
Chronic: Atrophy, normal CPK |
|
|
Term
| What is the mechanism of dysphonia assoc with inhaled steroid use? |
|
Definition
|
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Term
1. What is the mech of action of Chromones?
2. What are their anti-inflammatory effects?
3. What do they do for cough from ACE inhibitors? |
|
Definition
1. Inhibit IgE-mediated calcium channel activation
Inhibit chloride transport and chloride channels
2. inhibit mast cell mediator release, block activation of eos, inhibit neutrophil activation, chemotaxis and mediator release, inhibit IgE production.
3. Inhibit (tachykinin antagonism) |
|
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Term
| Which types of bronchoconstriction do chromones protect against? |
|
Definition
| Antigen, exercise, cold air, fog, hypertonic saline, adenosine, sulfur dioxide, metabisulfites, bradykinin, substance P, neurokinin A but NOT methacholine or histamine |
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Term
Anti-leukotriene therapies
1. What is their effect on early and late phase response to allergen?
2. Do they inhibit exercise-induced bronchospasm?
3. What is their effect on ASA-induced bronchocontriction?
4. What is their effect on LTD4-induced bronchoconstriction? |
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Definition
1. Attenuate both
2. Inhibit
3. Inhibit effect of threshold ASA dose
4. Inhibit |
|
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Term
| What are the anti-inflammatory effects of anti-leukotrienes? |
|
Definition
Reduce eos in peripheral blood, sputum
Reduce exhaled NO |
|
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Term
| What are the common adverse effects of Zileuton and Zafirlukast? |
|
Definition
Zileuton: 3% incidence of increased ALT and interactions with warfarin and theophylline (so need to reduce doses of these meds)
Zafirlukast: live toxicity with high doses (rare with low dose); reduce warfarin dose |
|
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Term
Name the type of Biologic by the last part of its name
ximab
zumab
mubab |
|
Definition
ximab: Chimeric Ab
zumab: humanized Ab
mubab: fully human Ab |
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Term
Omalizumab
1. What part of IgE does it bind to?
2. Does it bind to membrane bound IgE?
3. When are peak serum concentrations attained after injections?
4. How soon does reduction in free IgE occur? |
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Definition
1. It binds to C epsilon 3 domain of IgE (which is very close to high and low affinity binding sites)
2. No. It binds to free IgE.
3. 7-8 days after injection
4. 84-99% reduction in free IgE occurs within 1 hour of dosing! |
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Term
Omalizumab
1. What kind of immune complexes are formed when Omalizumab binds to IgE?
2. Does total serum IgE (measured conventionally) increase or decrease? |
|
Definition
1. IgG-IgE immune complexes, which can be trimers or hexamers
2. Increases. Commercial assays can't distinguish free IgE from IgG-IgE complexes. |
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Term
Mechanism of action of Omalizumab
1. Which one of the following is responsible for Omalizumab's therapeutic effect? Reduction in free IgE or Reduction of membrane bound IgE |
|
Definition
| 1. Reduction of membrane bound IgE |
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Term
| Omalizumab's reduction of surface IgE depends on spontaneous rate of dissociation of IgE from FceRI and cell life expectancy: true or false |
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Definition
True. Basophil life expectancy = 1 wk, so effect on basophils occurs in days to weeks.
Mast cells survive in tissues for months, so reduction of surface IgE is primarily by IgE dissociation from cell. |
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Term
Omalizumab and FceRI expression: True or False
1. There is a weak correlation btwn total serum IgE and FceRI expression
2. FceRI downregulation takes months to achieve
3. Omalizumab reduces FceRI expression by 80-99%. |
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Definition
1. False. The correlation is strong.
2. False. It occurs within days.
3. True. This occurs on basos, mast cells and dendritic cells. |
|
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Term
What is the effect of omalizumab on:
1. Early and late phase allergen response?
2. Airway tissue eos
3. Sputum eos
4. Priming |
|
Definition
1, 2, 3: Omalizumab reduces all of these.
4. Omalizumab suppresses priming effect. |
|
|
Term
Omalizumab adverse effects
1. Rate of malignancy vs placebo
2. Anaphylaxis: when does it occur?
3. Other? |
|
Definition
1. 0.5% omalizumab vs 0.2% placebo
2. It may occur with the first dose OR after years of therapy. Also, it may occur HOURS after dosing.
3. Cardiovascular events |
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Term
| Know the omalizumab joint task force recommendations, including observation period. |
|
Definition
1. Informed consent
2. Patient education re: anaphylaxis
3. EpiPen Rx
4. Assess PEF or FEV1 before each injection
5. Observe in office for 2 hrs for 1st 3 injections; 30 minutes therafter. |
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Term
Biologics: know what these antagonize
1. Inflixumab
2. Adalimumab
3. Etanercept
4. Anakinra |
|
Definition
1. TNF-alpha
2. TNF-alpha
3. TNF receptor (Recombinant TNF receptor-IgG fusion protein)
4. IL-1 receptor |
|
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Term
1. TNF-inhibitors are FDA approved for treatment of which 5 diseases?
2. For which diseases is Anakinra effective? |
|
Definition
1. RA, Crohn's, psoriasis, ankylosing spondylitis, JRA
2. Autoinflammatory syndromes (FCAS, Muckle Wells, NOMID) and Stills, Schnitzers syndrome |
|
|
Term
1. What are the adverse effects of TNF inhibitors?
2. What in vivo test should you do before starting them and during therapy?
3. Which cardiac problem occurs?
4. What type of neuro problems occur? |
|
Definition
1. TB (reactivation or new infxn), increased rate of extrapulmonary or disseminated cases.
2. Do PPD prior to starting therapy and annually.
3. CHF
4. Demyelinating disorders (MS, optic neuritis) |
|
|
Term
Other biologics
1. Efalizumab
2. Alefacept
3. Abatacept
4. Natalizumab |
|
Definition
1. Anti-LFA-1 (binds to CD11a). Approved for psoriasis. Can cause anemia, low plts
2. LFA-3-IgG1 fusion protein, reduces CD45RO+ T cells. Approved for psoriasis. Lymphopenia common.
3. CTLA4-IgG1 fusion protein. Approved for RA.
4. mAB to alpha4 integrin. Approved for MS, Crohn's. Reports of multifocal leukoencephalpathy |
|
|
Term
Pregnancy and Asthma: True or False
1. Pregnancy is associated with worsening, improving or no change in asthma
2. Poorly controlled asthma is associated with low-birth-weight infants. |
|
Definition
1. All of the above (rule of thirds)
2. True. It is also assoc with perinatal mortality, preeclampsia, preterm birth. Oral steroids are assoc with these outcomes. Unclear if this is due to severe asthma or the steroids. |
|
|
Term
Know the preferred asthma meds in pregnancy
1. Beta agonist
2. ICS
3. What is the role of theo? |
|
Definition
1. albuterol
2. budesonide
3. Safe, but considered an alternative tx |
|
|
Term
Rhinitis meds in pregnancy: Know the pregnancy categories (A-N)and risks
1. topical decongestants
2. Oral decongestants
3. Antihistamines
4. Intranasal steroids
5. Cromolyn
6. LTRA |
|
Definition
1. C. Minimize use
2. C. Risk of gastrochisis. Avoid in 1st trimester.
3. B. Cetirizine, loratadine, chlorpheniramine, tripelennamine
4. B. Budesonide
5. B
6. B. Limited data. Use if effective before pregnancy. |
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