Exam 2 - Asthma/COPD

Question 1

What is the pathogenesis of asthma, in terms of triggers and physiological response?

Answer 1

Two phases -

1. Early reaction: As the antigen binds to IgE, the binding triggers a release of histamine, tryptase, leukotrienes, and prostaglandins from mast cells. This causes immediate bronchial smooth muscle contraction and vascular leakage.
2. Delayed reaction (2-8 hours): Sustained bronchoconstriction, activation of TH2 lymphocytes (causes release of inflammatory mediators including granulocyte-macrophage colony-stimulating factor and IL-4,5,13. Goblet cells hypersecrete mucus. Lastly, eosinophils are reaching the cells.

Question 2

What is the role of goblet cells in the pathogenesis of asthma?

Answer 2

Goblets hyper-secrete mucus during asthma.

In healthy cells, Goblet cells make up only 1/7th of the population (the rest are ciliated), but during hyperplasia, we lose the ciliated cells and get more goblet cells. This causes hyper-secretion of mucus and we aren’t able to transport the antigen away (due to loss of ciliated cells).

Cytokines from TH2 cells, bacterial, neutrophils, and oxidants can cause this hyperplasia. EGFR and CLCA are involved in the development of hyperplasia and Bcl-2 is involved in the maintenance of hyperplasia.

Question 3

Why are β2-adrenergic agonists the drugs of choice for acute asthma attacks? What effects do these drugs have on the respiratory system of the asthmatic patient?

Answer 3

β2 agonists relax bronchial smooth muscle (bronchodilation), and that’s where the effected area is for asthma.

These activate Gs pathway and PKA converts myosin LC kinase -> MLCK-(PO4)2, which stimulates relaxation.

They also inhibit the release of mediators from mast cells, inhibit microvascular leakage, and increase microciliary transport of mucus.

Ex of SABAs: Albuterol (optimal β2 selectivity), Terbutaline (causes increased palpitations), and Levalbuterol (more expensive).

Question 4

What are the effects of theophylline on the respiratory system and other systems? What is the relationship of these effects to the therapeutic use and adverse effects?

Answer 4

Theophylline is in tea. It can inhibit the binding of adenosine to A1R, which means the contraction pathway doesn’t start. It also inhibits PDE4, which helps to increase cAMP levels, promoting relaxation.

Theophylline has a very narrow therapeutic range. Some AEs include nausea, vomiting -> cardia arrhythmias, hypotension -> seizures cardiac arrest.

Also theophylline competes with other drugs, which can make it more toxic.

Question 5

What is the rationale for the use of glucocorticoids in the treatment of asthma and the advantage of using inhaled doses over daily oral doses?

Answer 5

The goal of glucocorticoids is to alter the gene expression of proteins that are important in the inflammatory process. The point is the inhibit the synthesis of prostaglandins and leukotrienes. This will in turn decrease the hyperresponsiveness of bronchial smooth muscle cells that occurs in chronic asthma.

Use inhaled so that there are less systemic side effects?

Question 6

What is the rationale for using Cromolyn in the treatment of asthma and how does this rationale compare with that of the β2-adrenergic agonists?

Answer 6

These are of value when taken prophylactically. It’s inhaled as a powder or aerosolized solution. These inhibit mast cell degranulation.

This is used as pretreatment for mild to moderate chronic asthma (mostly exercise induced). It blocks bronchoconstriction that is caused by antigen inhalation, exercise, aspirin, and environmental toxins.

Question 7

What is the mechanism of action of omalizumab, and what’s the rationale for it’s therapeutic use?

Answer 7

Biologics - These usually block receptors or cytokines. It’s used when steps 1-5 don’t work.

Omalizumab is an anti-IgE produce that binds to IgE and therefore blocks the crosslinking of IgE (by antigen binding) on the mast cells. It is approved for Type 2 High Inflammation.

Question 8

What are the differences between the mechanisms of action of the antileukotrienes?

Answer 8

5-Lipoxygenase oxygenation of arachidonate: Block this (FLAP enzyme) so that the production of leukotrienes can’t proceed.
- Zileuton (Zyflo) does this

Zafirlukast (Accolate) & Montelukast (Singulair) - Selective competitors (mimic) at CysLT-1 receptor, causing inhibition of late phase bronchoconstriction.

Question 9

Why do Ipratropium and Tiotropium have some use in treating bronchoconstriction (what is the mechanism)?

Answer 9

LAMAs are used in COPD treatment. Ipratropium (Atrovent) and Tiotropium (Spiriva) are quaternary ammonium compounds that have limited systemic absorption and go straight to the lungs

Ipratropium - Inhibits the contraction pathway by inhibiting ACh binding to M3R.

Question 10

What are the chemical structures of distinct classes of drugs used to treat asthma?

Answer 10

SABAs - t-butyl and alcohol phenyl ring.

LABAs - Has this central N with two long chains w/ aromatic rings attached.

Methylxanthines (Theophylline) - Xanthine ring structure

Cromolyn - Two cromolyn rings

LAMAs - quaternary amines.

Question 11

What are some novel strategies for the treatment of asthma (+ justification)?

Answer 11

???? Seebri Neohaler - glycopyrrolate inhalation powder as stand-alone monotherapy for COPD. This can be used for long-term maintenance treatment of airflow obstruction in pts with COPD.

Question 12

What is the emerging pathogenesis of e-Cigarettes and Vaping?

Answer 12

E-cigarettes have many toxins.

EVALI - exogenous pneumonitis-like reaction. Vitamin-E acetate was being used to solubilize THC, and it was found that this Vitamin E was leading to this inflammatory response in the lungs.

• Involves airway epithelial cells, alveolar macrophages, granulocytes/neutrophils.
• NETosis (process of recruiting lots of neutrophils, then they die and release their DNA) leads to greater increase of inflammation and other respiratory implications.

Question 13

What is the pathogenesis of COPD and how does it compare to the pathogenesis of asthma?

Answer 13

Unlike asthma, COPD is not related to an allergic response. It’s more linked to pollutants (smoking). It’s irreversible (unlike asthma).

COPD remodeling: TH1 cells invovled (TH2 in asthma). Get alveolar wall destruction (emphysema), leaving a hollow alveoli, leading to irreversible damage causing shortness of breath.

Key differences between COPD and asthma - COPD has much more fibrosis. COPD involves TH1 and Tc1 cells, but asthma mainly involved Th2.

Question 14

What is the pathogenesis of cystic fibrosis (CF) and how does it affect lung function?

Answer 14

Cystic fibrosis - Completely genetic. CF patients have obstructed lung airflow that leads to an increase in bacterial colonization (ex. pseudomonas). It also leads to obstruction of pancreatic duct in the gut, which interferes with digestion.

CFTR gene is affected. It encodes an ABC transporter that functions as a Cl- channel. CFTR is expressed in airway epithelium, sweat duct epithelium, and pancreatic duct epithelium.

In sweat - If the CFTR gene isn’t working and we therefore don’t have chloride function, we will have increased Cl- in the extracellular space (in mucus and sweat). This causes an additional increased Na+ because they are linked.

In lung - Loss of CFTR function inhibits the ENaC Na+ regulation. This leads to dehydration of lungs because water is trying to balance the influx of Na+ and Cl-.

Question 15

What is the mechanism of action of drugs that are currently used to improve lung function in CF, as well as new, genotype-specific drugs that are under development?

Answer 15

Ivacaftor (Kalydeco) - This potentiates Cl- current through CFTR in response to cAMP. This helps rehydrate the lung.

Mucolytics - Enzymes that can break down mucus into a more liquid form to help hydrate the lungs.

Bronchodilators & Antibiotics are useful, too.

In development:

• Ataluren is used to suppress premature stop codons in order to make the full protein.
• VC-809 is a small molecule chaperone used to help protein folding.
• Bronchitol rehydrates mucus.

Question 16

What makes LABAs “long acting”

Answer 16

These are more resistant to MAO and COMT, which allows them to last longer in the body. They also can be more lipophilic.

Ex of LABAs: Formoterol (resistant to MAO/COMT and has increased lipophilicity).

Question 17

Whats the difference between type 2 low inflammation and type 2 high inflammation?

Answer 17

Type 2 Low Inflammation - Neutrophilic, involves IL6, IL8, and IL17. It’s harder to treat and more likely to have adverse events when treatments have been used.

Type 2 High Inflammation - Eosinophilic, involves IL4, IL5, and IL13. This involves PGD2 stimulation of the DP2 receptor.

Question 18

What are the main pulmonary targets for asthma, COPD, and CF?

Answer 18

Asthma: Bronchodilation, anti-inflammation, inhibition of mast cell degranulation, inhibition of eosinophilia.

COPD: Bronchodilation (muscarinic and adrenergic receptor based) and protease inhibitor strategy

CF: Protein folding, mucus rehydration, bronchodilation & antibiotics.

Question 19

What are the signs and symptoms of asthma?

Answer 19

Signs -

• Expiratory wheezing
• Dry hacking cough
• Allergies
• Low FEV1/FVC that goes up after β-agonist use
• High eosinophil count and blood IgE concentration

Symptoms -

• Episodic symptoms of airflow obstruction (chest tightness, dyspnea, non-productive cough)
• The airway obstruction is reversible

Question 20

What are the intermittent asthma classifications? (frequency of symptoms, nighttime awakenings, SABA use, interference with normal activity, lung function, and exacerbations requiring oral steroids)

Answer 20

Frequency - ≤ 2 days/week

Nighttime awakenings - ≤ 2 times/month

SABA use - ≤2 days/week

Interference w normal activity - none

Lung function - FEV1 normal between exacerbations, FEV1 > 80% of predicted, FEV1/FVC normal

Exacerbations - 0 or 1/year

Question 21

What are the mild persistent asthma classifications? frequency of symptoms, nighttime awakenings, SABA use, interference with normal activity, lung function, and exacerbations requiring oral steroids)

Answer 21

Frequency - > 2 days/week

Nighttime awakenings - 3-4 times/month

SABA use - > 2 days/week, but not daily and < 1 time/day

Interference w normal activity - minor

Lung function - FEV1 > 80% of predicted, FEV1/FVC normal

Exacerbations - ≥ 2/year

Question 22

What are the moderate persistent asthma classifications? frequency of symptoms, nighttime awakenings, SABA use, interference with normal activity, lung function, and exacerbations requiring oral steroids)

Answer 22

Frequency - daily

Nighttime awakenings - > 1 time/week

SABA use - daily

Interference w normal activity - some limitation

Lung function - FEV1 > 60-80% of predicted, FEV1/FVC reduced 5%

Exacerbations - ≥2/year

Question 23

What are the severe persistent asthma classifications? frequency of symptoms, nighttime awakenings, SABA use, interference with normal activity, lung function, and exacerbations requiring oral steroids)

Answer 23

Frequency - throughout the day

Nighttime awakenings - often 7 times/week

SABA use - several times a day

Interference w normal activity - extremely limited

Lung function - FEV1 > 60 of predicted, FEV1/FVC reduced 5%

Exacerbations - ≥2/year

Question 24

What is an EIB?

Answer 24

EIB - Exercise induced bronchospasm

• Pt has history of cough, chest tightness, or endurance problems during exercise.
• Drop of FEV1 by > 15% of baseline
• Bronchial hyperresponsiveness

Question 25

What is the treatment step outline for asthma pts under 5 years old? (4 steps)

Answer 25

1. PRN SABA 2. Low ICS 3. Double low dose ICS 4. Continue & refer to specialist Alternative - 2. LTRA or intermittent ICS 3. Low ICS + LTRA 4. increase ICS frequency, add LTRA or intermittent ICS if haven't yet

Question 26

What is the treatment step outline for asthma pts ages 6-11 years old? (5 steps)

Answer 26

1. PRN SABA 2. Low ICS 3. low ICS-LABA or med. ICS 4. med. ICS-LABA & refer for advice 5. refer for phenotypic assessment +/- add on therapy like anti-IgE Alternative - 1. Take low ICS with SABA when taken or just low ICS 2. LTRA or concomitant low ICS + SABA 3. Low ICS + LTRA 4. High ICS-LABA or add tiotropium or add LTRA 5. Add anti-IL5 or add low OCS

Question 27

What is the treatment step outline for asthma pts ages 12+? (6 steps)

Answer 27

1. PRN SABA 2. low ICS + PRN SABA or PRN concomitant ICS + SABA 3. Daily and PRN combo of low ICS-formoterol 4. Daily and PRN combo of med. ICS-formoterol 5. Daily med/high ICS-LABA + LAMA and PRN SABA 6. Daily high ICS-LABA + OCS + PRN SABA Alternative - 2. Daily LTRA and PRN SABA or Cromolyn/Nedocromil/Zileuton/Theophylline & PRN SABA 3. Med. ICS + PRN SABA or low ICS-LABA (or ICS + LAMA or low ICS + LTRA) & PRN SABA or low ICS + theophylline or zileuton & PRN SABA 4. med. ICS-LABA or med. ICS + LAMA & PRN SABA or med ICS + LTRA & PRN SABA 5. med ICS-LABA or high ICS + LTRA & PRN SABA

Question 28

What's the difference between "difficult to treat" asthma and severe asthma?

Answer 28

Difficult to treat - Pt has symptoms/exacerbations despite being on appropriate GINA step 4 therapy or taking maintenance OCS. Severe asthma - Difficult to treat pts who are still uncontrolled despite addressing factors that are contributing to symptoms (like inhaler technique, social issues, adherence, etc.) & high dose ICS therapy trials with 3-6 month assessment.

Question 29

``` If a patient's labs while on high dose ICS or OCS are as follows, what is the likely asthma assessment: Blood eosinophils > 150 cells/uL FeNO > 20ppb Sputum eosinophils > 2% Allergen-driven asthma ```

Answer 29

Refractory Type-2 asthma - Assess adherence and modifiable risk factors - Treat for other phenotypes if indicated (AERD, ABPA) - Consider costs/route/patient preference prior to initiating biologic agents

Question 30

What are 4 characteristics of type 2 asthma?

Answer 30

- Seen in 50% of severe asthmatics - Involves production of cytokines like IL-4, IL-5, IL-13 by the adaptive immune system in response to allergens - Characterized by FeNO and eosinophils - Usually responds to high dose ICS/OCS, but the patients can be refractory

Question 31

What does a patient need to be eligible for anti-IgE therapy?

Answer 31

- During skin prick/IgE test: Sensitivity to inhaled allergens - Pretreatment serum IgE: 30-700 IU/mL - Pt weighs 66-330lbs (30-150kg) - At least 1 severe exacerbation within the past year

Question 32

What does a patient need to be eligible for anti-IL-5 therapy?

Answer 32

- Blood eosinophils >300 cells/uL | - At least 1 severe exacerbation within the past year

Question 33

What does a patient need to be eligible for anti-IL-4 therapy?

Answer 33

``` At least 1 severe exacerbation within the past year AND At least of of the following: - Blood eosinophils > 300cells/uL - FeNO > 25 ppb -Pt requires maintenance OCS ```

Question 34

After biologics therapy for asthma, what do we do if we had good results vs. if we had bad results?

Answer 34

Good: Re-evaluate every 3-6 months, consider tapering use of OCS or reduction of ICS dose, don't trial withdrawal biologic within 12 months Bad: Review the basics like adherence, technique, risk factors, investigate other things like a chest CT/induced sputum, maybe add low OCS/Macrolides with help by specialist.

Question 35

What's the goal of therapy of severe acute asthma?

Answer 35

- To rapidly reverse the airway obstruction and inflammation - To correct the hypoxemia (Goal oxygen saturation is 93-95% in pts older than 11, 94-98% is pts 11 and under) - To prevent complications like a pneumothorax or respiratory arrest/intubation

Question 36

What's the first line management of severe acute asthma?

Answer 36

- Systemic corticosteroids (oral or IV): 1-2 mg/kg/day; Prednisone/Prednisolone/Methylpredisolone; Max dose is based on age. - Inhaled albuterol +/- ipratropium if pt is in ED (not if hospitalized) - Supportive care: Oxygen supplementation/fluid resuscitation - If pt is having anaphylaxis/angioedema: Epinephrine IM injection

Question 37

What is the second line management of severe acute asthma?

Answer 37

- Continue appropriate systemic corticosteroids - Transition from continuous SABA to PRN (monitor HR and K+) - Magnesium sulfate (IV or inhaled): Slow IV infusion (40-50mg/kg) is most common, also can inhale.

Question 38

What are some things we may see as third/fourth/rescue treatment for severe acute asthma?

Answer 38

``` Terbutaline Aminophyllin/theophylline LTRAs Heliox Antibiotics Sedatives ``` Therapies will vary based on patient and institution. There's not much data supporting exactly what to do.

Question 39

What is the process of the synthesis and metabolism of histamine?

Answer 39

Synthesis: Histidine is decarboxylated to histamine. This reaction is catalyzed by L-histidine decarboxylase. This occurs in mast cells and basophils and is stored in granules for rapid release in response to antigens and cell lysis. Metabolism: Histidine can be metabolized into N-methylhistamine or Imidazole acetic acid, both of which are inactive. Those can be later metabolized into N-methylmidazole acetic acid and imidazole acetic acid riboside, which are also inactive.

Question 40

What is the mechanism by which histamine is stored and released?

Answer 40

There are storage granules in which histamine is complexed with sulfated-polysaccharides, heparin sulfate, chondroitin sulfate, and proteases. All of this is released during mast cell degranulation. There's also histamine in the some areas of the brain and some in the fundus of the stomach, utilized for stimulation of acid secretion. Release of histamine: - Antigen mediated binding of the antigen to antibodies that are bounds to the cell surface causes granules to be released. - Thermal or mechanical stress, cytotoxic agents like venom, and various drugs like high dose morphine also cause granule release. IgE bind to FcϵR -> antigen bind to IgE -> FcϵR cluster -> influx of Ca2+ via CRAC -> granules released

Question 41

How can we differentiate between the effects of histamine due to stimulation of H1 receptors and H2 receptors?

Answer 41

H1 receptor - These are in the CV system, respiratory system, and GI smooth muscle. Through the phosphoinositol pathway, the activation of these receptors causes smooth muscle contraction. Also, H1 receptor is linked to vasodilation and stimulation of sensory nerves, leading to sneezing and itching. H2 receptor - In CV system, GI smooth muscle, and stomach. This receptor is linked to relaxation of vascular smooth muscle and gastric secretion.

Question 42

What are the effects of histamine on the respiratory and cardiovascular systems?

Answer 42

Respiratory - Constriction of bronchial smooth muscle that is mediated by H1. Cardiovascular - Moderate increase in rate and force of contraction of the heart due to H2 receptor & vasodilation due to H1 in endothelium and H2 in smooth muscle.

Question 43

How are the first gen. H1 antagonists are categorized by structure? Which drugs are in which class? Which structures are in which class?

Answer 43

Alkylamines - 3º amine with longer alkyl chain with a couple of rings attached. Ex. Brompheniramine (Dimetapp). Ethanolamines - 3º amine with ether attached and a couple rings. Ex. Diphenhydramine (Benadryl) Ethylenediamines - has 2 3º amines and one of the rings has an ether attached. Ex. Pyrilamine Phenothiazines - has a central ring with a sulfur and a nitrogen. Then an aromatic ring on either side. Ex. Promethazine (Phenergan). Piperadines - Has 6 membered ring, one being a 3º amine. Ex. Cyproheptadine (Periactin). Piperazines - 6 membered ring in the middle with 2 opposite 3º amines. Ex. Hydroxyzine (Atarax).

Question 44

What are the secondary pharmacological effects of 1st gen antihistamines and what are the differences between the therapeutic uses/adverse effects of them? (6 total secondary effects)

Answer 44

Sedation - In the CNS, blocking of H1/H2 receptors casue sedation. Ethanolamines and phenothiazines are the most sedating. (Except in kids, these actually cause stimulation). Anti-cholinergic effects - antihistamines that are more lipid soluble (so CNS access) can have an anti-cholinergic effect, causing dry mouth, decreased urination, etc. In can also help with motion sickness and vomiting. (Diphenhydramine and promethazine have this effect). Local anesthetic - Pyrilamine, promethazine Anti-serotonin - Causes headaches; Cyproheptadine, azatidine α-adrenergic antagonism - Causes hypotension; Phenothiazines Extrapyramidal - Causes dystonia and akathisia (inability to sit still); (Phenothiazine, promethazine)

Question 45

How would we select the appropriate drug for a patient from a list of H1 antagonists?

Answer 45

We can gather patient information and see about history of glaucoma, urinary retention, pregnancy and then decide if a 1st gen drug like diphenhydramine or promethazine is a good choice. Also due to drowsiness/dizziness effect of phenothiazines & ethanolamines, want to make sure patient can tolerate that and can avoid other CNS depressants like alcohol.

Question 46

How can we differentiate 2nd gen H1 antagonists from 1st generation drugs by name and side effect profile?

Answer 46

2nd gens - Have decreased lipid solubility and experience efflux from the CNS by pgp, meaning they have little sedating effect. They also have no anti-muscarinic activity, no anti-emetic activity, and no anti-motion sickness activity. Loratadine (Claratin), Desloratadine (Clarinex), Fexofenadine (Allegra), and Cetirizine (Zyrtec) are all 2nd gen H1 antagonists.

Question 47

What is an example where the 2nd generation antihistamines may not be as efficacious as 1st gen?

Answer 47

In allergies, histamine indirectly stimulates mucus discharge through H1 receptors on nerve endings. This leads to sneezing, rhinorrhoea, etc due to the effect of the CNS H1 receptors. In this case, our antihistamines can help because we can inhibit H1. For the common cold, the virus stimulates the sneezing/rhinorrhoea independent from histamine. This means that because 2nd generation drugs can reach the brain, they may not be as effective to treat the symptoms of the common cold. For seasonal allergic rhinitis and conjuctivits, we can use H1 antagonist eye drops and nasal sprays - Olopatadine (Patanol), Azelastine (Astelin), Ketotifen (Zaditor).

Question 48

What are the roles of T-cells in allergic rhinitis?

Answer 48

T-cells are activated by APCs. T-cells release chemoattractant factors (IL4, IL5, TXA2, etc.) that cause inflammatory cell infiltration. This recruits eosinophils, neutrophils, basophils, and lymphocytes that lead to allergic inflammation and congestion.

Question 49

What is the role of Fluticasone/Budesonide in treating allergic rhinitis?

Answer 49

These have a slow onset and are used to regulate gene expression, thus reducing the inflammatory cell infiltration seen in allergic rhinitis. Fluticasone - Very low systemic absorption from intranasal dose Budesonide - ~1/3 of the dose is absorbed in < 1 hour. Both of these may suppress the HPA axis with prolonged, high doses.

Question 50

What's the mechanism of action of glucocorticosteroids in the treatment of allergic rhinitis?

Answer 50

Glucocorticosteroids alter gene expression that results in the reduction of inflammatory cells like eosinophils, Th2 cells, mast cells, b cells, dendritis cells, and basophils. It also decreases the amount of constitutive cells that secrete mucus and proliferate. GCs also increase the number of regulatory cytokines and T regulator cells.

Question 51

What are 2 drugs that prevent histamine release?

Answer 51

Cromolyn sodium - Used for mastocytosis and allergic rhinitis Nedocromil - Used for allergic conjunctivitis (eye drop) These interfere with the CRAC channel (also beta agonists can inhibit antigen induced histamine release)

Question 52

What is the pathway by which histamine acts on the H1 receptor in smooth muscle and vascular endothelial cells?

Answer 52

In smooth muscle: Histamine + H1 -> Gq -> PLC -> IP3 + DAG -> raise Ca2+ -> raise Ca2+-calmodulin -> phospho MLC = contraction of smooth muscle In vascular endothelial cells: Histamine + H1 -> NO releasae -> NO diffuses to vascular smooth muscle -> increase cGMP -> lower Ca2+ = relaxation/dilation

Question 53

What is the pathway by which histamine acts on the H2 receptor in smooth muscle?

Answer 53

Histamine + H2 -> Gs -> raise adenylate cyclase -> raise cAMP = relaxation in smooth muscle

Question 54

What are the clinical uses of specific antihistamines in allergic state?

Answer 54

1. Seasonal and perennial allergic rhinoconjunctivitis 2. Chronic urticaria 3. Motion sickness: Dimenhydrinate (Dramamine), Meclizine (AntivertTM), Promethazine (PhenerganTM). 4. Used with epinephrine to treat anaphylaxis

Question 55

What are the common adverse effects and drug interactions of H1 receptor antagonists?

Answer 55

1. Sedation - When ethanolamines and phenothiazines (1st gen antihistamines) accumulate in the brain; Can interact with other sedatives to increase drowsiness (alcohol, anxiolytics, antipsychotics) 2. Anticholinergic effects - 1st gen drugs; Now they are contraindicated in urinary retention and narrow angle glaucoma.

Question 56

What is the etiology, incidence, and pathophysiology of allergic rhinitis (AR)?

Answer 56

AR - An inflammatory, IgE mediated disease characterized by nasal congestion, rhinorrhea, sneezing, and/or itching. More and more people are getting AR. 30% of adults & 40% of children have AR. It's the most common disease in children. Allergic triad of asthma, AR, and atopic dermatitis is involved. 1. Sensitization: Allergen is processed and presented by cell, recognized by CD4, which activates TH2 cells, leading to B cell production of allergen-specific IgE that is bound to mast cells. 2. Re-exposure: The allergen enters body and binds to the IgE on the mast cell, leading to degranulation and release of inflammatory modulators, causing early & late phase symptoms

Question 57

What are the roles of irritants in AR, non-AR, and other allergic disorders?

Answer 57

Seasonal - Grasses, trees, weeds, molds Perennial - Molds, house dust Episodic - Animal dander (not in normal environment)

Question 58

What is the typical clinical presentation of patient with AR and who is it different than other forms of rhinitis?

Answer 58

AR - Bilateral presentation, sneezing, nasal obstruction, rhinnorhea, postnasal drop (PND), coughing, itching of the nose/eyes/throat, nasal creases, red and watery eyes Non AR - most likely doesn't have the red/watery eyes, sneezing is uncommon, primarily seen in adults, caused by airborne irritants (pollution, chemicals, smoke)

Question 59

What questions could you ask to differentiate between AR and non-AR?

Answer 59

What symptoms are you having? Unilateral or bilateral? Is your nasal discharge clear or colored? How long have you had these symptoms? Does the severity of your symptoms change when you move from indoors to outdoors or vice versa?

Question 60

What are the roles of pharmacologic and non-pharmacologic approaches to treating patients with AR?

Answer 60

Goals - minimize symptoms and side effects from treatment, maintain quality of life INCS - Good at congestion, rhinorrhea, sneezing, and nasal itching. OAH - not great for congestion, moderately good for rhinorrhea, sneezing, and nasal itching. INAH - moderately good for congestion, rhinorrhea, sneezing, and nasal itching LTRA - not the best for AR, minimally treats congestion, rhinorrhea, sneezing, and nasal itching. Oral/inhaled decongestants - great for congestion, minimally good for rhinorrhea, no effect on sneezing or nasal itching.

Question 61

What are the advantages and disadvantages of the drug classes and products used to treat AR patients? (ORAH, INAH, INCS, Montelukast, oral or IN decongestant, immunotherapy, biologics)

Answer 61

Oral antihistamines (2nd gen) - Good for mild to moderate AR, once daily dosing, OTC, well tolerated. Bad because there is less nasal congestion effect and they only impact histamine receptors. INAH - Good for localized therapy and excellent for rhinorrhea. Bad due to risk of drowsiness, has bitter taste, BID dosing. INCS - Most effective at releiving nasal Sx!! Great for most pts with mod. to sev. AR. Has the most complete symptomatic relief. Bad because it requires 3-4 times daily dosing and only effective for mild AR. Montelukast - Good due to daily dosing and can be used in children. Bad due to suicidal ideation and Rx only. Oral or intranasal decongestant - Great at relieving congestion and it increases efficacy of antihistamines when used in combo. Bad because it can only be used for 3 days due to rebound congestion. Immunotherapy - Good b/c it targets specific antigens and can be very effective. Bad because it's super expensive and requires many doctor visits. Biologics - Good for those with AR with very severe Sx and those with asthma or atopic dermatitis. Bad because it's very expensive.

Question 62

What specific pharmacological and non-pharm recommendations would you give to an AR patient? Why? What are the options for future monitoring and follow?

Answer 62

Mild intermittent - oral antihistamine (OAH) +/- decongestant; or intranasal antihistamine (INA) Mod. to sev. intermittent - OAH +/- decongestant; or INA; or LTRA; or intranasal corticosteroid (INCS) Mold persistent - OAH +/- decongestant; or INA; or INCS Mod. to sev. persistent - INCS; OAH +/- decongestant; LTRA (combo therapy if needed) Saline nasal spray may be used to help clear passages of pollen. It can be used PRN. Follow up with AR patient and ask about symptomatic relief, any side effects, quality of life issues, issues with administration of devices, etc.

Question 63

If the patient doesn't respond to first line AR therapy, what is an alternative to first line therapy we could try and why?

Answer 63

Sx controlled but ADRs are bad - switch to alternative agent to minimize ADRs AR with severe congestion - consider routine use of antihistamine decongestant combo AR with persistent rhinorrhea - consider adding ipratropium NS severe AR without good Sx control - consider skin testing and immunotherapy (allergy shots) AR Sx not well controlled and pt has asthma or atopic dermatitis - Consider tx with biologics $$

Question 64

How can you classify AR symptoms?

Answer 64

Intermittent symptoms - <4 days per week or <4 weeks at a time Persistent symptoms - >4 days per week, ≥4 weeks at a time Mild - normal sleep, daily activities, work and school, no troublesome symptoms Moderate to severe - abnormal sleep, impairment of daily activities, sport and leisure, difficulties caused at school or work, and/or troublesome symptoms.

Question 65

When do we want to refer AR patients?

Answer 65

- When the Sx are unilateral with purulent discharge +/- fever - Pts not responding adequately to INCS + oral antihistamine - Symptoms suggestive of undiagnosed or uncontrolled asthma

Question 66

Diphenhydramine and Cetirizine characteristics (sedation and anticholinergic effect?

Answer 66

Diphenhydramine (Benadryl) - most sedating and very anticholinergic Cetirizine (Zyrtec) - "non-drowsy" but has one + sedation and one + anticholinergic.

Question 67

What are examples of some antihistamines, INCS, decongestants, INAH, and ocular drops?

Answer 67

Antihistamine - Diphenhydramine, Cetirizine, Allegra INCS - Flonase, Nasonex Decongestants - Pseudoephedrine, phenylephrine (bad) INAH - Azelastine, Olopatadine Ocular drops - Olopatadine (Pataday), Ketotifen, Azelastine (Optivar), Ketorolac (Acular)

Question 68

What are glucocorticoids used for what's generally good/bad about them? (4 main topics)

Answer 68

Corticosteroids are referred to as the "miracle drug" and are used for various conditions, such as brain tumors, skin diseases, join pain or inflammation, asthma, Addison's disease, etc. These are used not to cure the disease, but to alleviate the inflammation (except in replacement therapy, like in Addison's). These have many benefits, but also many risks, so it's important to frequently monitor the pt. Dose should be selected by trial and error and will be selective to each patient. The incidence of side effects from these are dependent on time and dose. It's also important to note that abrupt cessation can lead to adrenal insufficiency. Patients on high dose glucocorticoids should not receive live vaccine (more than prednisone 20mg/day for above or the equivalent) (ex. MMR, varicella, smallpox, rotavirus, live attenuated, flu, yellow fever)

Question 69

What are the appropriate dosage conversions of the commonly used glucocorticoids based on the pharmacologic characteristics?

Answer 69

Hydrocortisone 20mg = Cortisone 25mg = Prednisone 5mg = Methylprednisolone 4mg = Dexamethasone 0.75mg If the pt is on other glucocorticoids, convert to the equivalent dose of hydrocortisone.

Question 70

What is the clinical presentation of Cushing's syndrome in patients and what are the physiological consequences of excess cortisol?

Answer 70

Cushing's syndrome - Can be caused by endogenous or exogenous cortisol (all forms of steroid can cause it). Presentation: Redistribution of body fat (central obesity - 80%), buffalo hump and supraclavicular fat accumulation, muscle wasting and weakness, easy bruising. 4x increase in cardiovascular disease, osteoporosis

Question 71

What is the recommended therapy monitoring parameters for patients receiving exogenous glucocorticoid? (10 complications to monitor for)

Answer 71

Infections - Signs and symptoms of all infections Myopathy - Muscle weakness Osteonecrosis - Hip, shoulder, knee pain Osteoporosis - Bone loss via DEXA scan, height, fractures, pain Psychiatric symptoms - Nervousness, anxiety, euphoria, insomnia, mood swings, poor memory, etc. Fluid & salt retention - BP, edema, electrolytes Metabolic changes - Fasting blood sugar, weight, cholesterol, excessive thirst, etc. Gastric ulcer - Burning pain, bloating, weight loss, nausea, etc. Cataract - Screen before treatment, 3 months after treatment, and yearly Cardiovascular risks - BP, heart rate, edema, cholesterol

Question 72

What is the appropriate treatment strategy to prevent the development of Cushing's syndrome associated with exogenous glucocorticoid administration?

Answer 72

- Use the minimum amount of glucocorticoid for the smallest amount of time necessary. - Give glucocorticoid via administration with the least amount of systemic absorption possible. - Avoid concurrent administration of drugs that can inhibit glucocorticoid metabolism (protease inhibitors, antifungals).

Question 73

What is the clinical presentation of patients with adrenal insufficiency?

Answer 73

Adrenal insufficiency - Inability of the adrenal gland to produce adequate amount of cortisol to regulate the normal body functions in times of stress. Symptoms - Weakness and fatigue, anorexia, nausea, diarrhea, hypoglycemia, amenorrhea, salt craving Signs - Weight loss, orthostatic hypotension, dehydration, personality changes, loss of auxillary/pubic hair

Question 74

What is the recommended key therapy monitoring parameters for patients with adrenal insufficiency?

Answer 74

- If we are suspicious of adrenal insufficiency, we should treat it right away. It's not worth waiting. - Weight loss, fatigue, nausea, myalgia, lack of energy

Question 75

What is the appropriate eduction for patients with adrenal insufficiency?

Answer 75

- Don't stop therapy without consulting healthcare provider - Increase the dose of glucocorticoid during excessive physiologic stress. They will need to double the maintenance dose in the presence of fever, invasive dental procedure or diagnostic procedures, or surgery. - Wear the medical identification bracelet

Question 76

What is the appropriate treatment strategy used to prevent the development of adrenal insufficiency associated with exogenous glucocorticoid administration?

Answer 76

- Assess the patient's risk - Gradually taper to ~20mg (or equiv.) daily in the morning, then change steroid to every other day administration in the AM - Stop the steroid when equivalent physiologic dose is equiv. to prednisone 5-7.5mg/day, hydrocortisone 20mg/day, dexamethasone 0.75mg/day (Pts are at low risk of adrenal insufficiency at physiologic doses) - HPA axis may take up to 1 year to recover after steroid discontinuation, so in times of stress, consider supplementing with an extra dose of steroid - Avoid concurrent administration of drugs that can induce steroid metabolism (ex. rifampin, phenytoin, barbiturates)

Question 77

What are the major drug interactions with the use of systemic glucocorticoids and its management?

Answer 77

Metabolism inducers - Phenytoin, rifampin, barbiturates, carbamazepine (increase the dose of steroid if taking these) Metabolism inhibitors - Protease inhibitors, antifungals (decrease the dose of steroid if taking these)

Question 78

What are the principles of glucocorticoid administration and what are its implications in clinical practice?

Answer 78

Don't administer corticosteroids unless it's absolutely indicated, or more conservative methods have already failed. Then, prescribe the lowest dose to achieve the desired effects, for the shortest duration possible. To relieve pain/distressing symptoms: Start with a low dose and gradually reduce the dose until symptoms worsen (use lowest acceptable dose). If possible, substitute with other medications (like NSAIDs). For life threatening conditions: The initial dose must be high and if no benefits are seen, then double or triple the dose. High and long-term therapy of steroids should only be for life threatening diseases.

Question 79

What are the physiologic doses (replacement doses) of hydrocortisone, prednisone, dexamethasone, and methylprednisolone?

Answer 79

Hydrocortisone - 20mg daily Prednisone - 5-7.5mg daily Dexamethasone 0.75mg daily Methylprednisolone 4mg daily

Question 80

What are some considerations when selecting corticosteroids?

Answer 80

Anti-inflammatory: Want to select steroids with minimal mineralocorticoid activity. Want to use an intermediate acting GC like methylprednisone or prednisone.

Question 81

What are the long term side effects of corticosteroids?

Answer 81

``` Infections Myopathy Osteonecrosis Osteoporosis Psychiatric symptoms Fluid & salt retention Metabolic changes Gastric ulcer Cataract Cardiovascular risks ```

Question 82

What is the criteria for being in the green, yellow, and red asthma assessment?

Answer 82

Green - No symptoms, can do all usual activities, peak flow is >80% of personal best. Yellow - Some symptoms, can do some but not all usual activities, peak flow is 50-79% of best Red - Severe symptoms, no improvement with SABA, or >24h in the yellow, cannot do usual activities, peak flow is < 50%.

Question 83

What is the action plan for green, yellow, and red asthma

Answer 83

Green - continue maintenance inhaler, avoid triggers, preventative therapy, use albuterol prn before exercise Yellow - use albuterol q20min for up to an our -> use SABA + oral steroid + call MD Red - SABA, oral steroid, call MD -> go to hospital

Question 84

What are the 3 big signs of COPD?

Answer 84

Chronic bronchitis - Presence of cough and sputum production. These structural changes cause airway narrowing due to fibrosis. Inflammation - Usually in response to irritants like cigarette smoke. Emphysema - abnormal enlargement of airspaces + destruction of alveolar walls. These structural changes destroy the alveoli and reduce their elasticity.

Question 85

3 key concepts about COPD?

Answer 85

It's a preventable disease (although there are risk factors) Non-reversible It's progressive, persistant airflow limitation.

Question 86

What are the 3 hallmark symptoms of COPD and what populations should we consider COPD in?

Answer 86

Symptoms - chronic cough, dyspnea, sputum production Consider if... - > 40 years old with the hallmark symptoms - History of exposure to risk factors (smoking, working around pollution) - Family history of COPD - History of recurrent lower respiratory tract infections

Question 87

What test is required to diagnose COPD? What can we determine with spirometry?

Answer 87

Spirometry - FEV1/FVC <0.7 confirms presence of airflow limitation. We can determine what GOLD class the pt is in from spirometry.

Question 88

What are the GOLD class criteria?

Answer 88

GOLD 1: Mild; FEV1 ≥ 80% predicted GOLD 2: Moderate; 80% > FEV1 ≥ 50% predicted GOLD 3: Severe; 50% > FEV1 ≥ 30% predicted GOLD 4: Very severe; FEV1 < 30% predicted

Question 89

What is the mMRC symptoms assessment?

Answer 89

mMRC - Modified british medical research council; Used to quantify COPD symptoms. Grades 0-4 from "i only get breathless with strenuous exercise" to "I am too breathless to leave the house" mMRC 0-1 is on left half of ABCD chart, mMRC 2+ is on right half of the chart.

Question 90

What is the CAT symptoms assessment?

Answer 90

CAT - COPD assessment test; used to quantify COPD symptoms Score ranges from 0-40. CAT < 10 is on left side of ABCD chart, CAT ≥ 10 is on right side of chart.

Question 91

What are 3 predictors of exacerbations?

Answer 91

History of previous treated exacerbations, worsening airflow limitation, hospitalization required v. outpatient management only

Question 92

What is the initial COPD treatment depending on which group the patient falls in (ABCD)?

Answer 92

Group A - PRN LABA/SABA Group B - Long-acting (LABA or LAMA) Group C - LAMA Group D - LAMA or LAMA/LABA if highly symptomatic or ICS + LABA if eosinophils > 300 cells/uL

Question 93

For COPD patients, what does follow up treatment look like after initial therapy?

Answer 93

If the pt didn't respond adequately to initial treatment, we need to decide whether to target dyspnea or exacerbations, then we can decide what treatment to proceed with. After initial treatment therapy, we don't look at the GOLD stage to adjust the follow up therapy.

Question 94

What is follow up treatment for a COPD patient who wants to help their continued dyspnea?

Answer 94

If started on LABA or LAMA -> LABA + LAMA If started on ICS + LABA -> ICS + LABA + LAMA If pt gets pneumonia, then try to stop ICS and just go to LAMA + LABA If these treatments don't work, then may switch inhaler type or investigate other reasons why symptoms aren't getting better.

Question 95

What is the follow up treatment for a COPD patient who wants to help their continued exacerbations?

Answer 95

If started on LABA or LAMA -> LABA + LAMA or ICS + LABA if eosinophils > 300 or > 100 + 2 moderate exacerbations or 1 hospitalizations. If LABA + LAMA doesn't work -> ICS + LABA + LAMA If ICS + LABA + LAMA or LABA + LAMA (already took off ICS) doesn't work -> Consider adding Roflumilast if FEV < 50% + chronic bronchitis and Azithromycin in former smokers As usual, if pt gets pneumonia, then take of the ICS.

Question 96

What are the causes of exacerbations? What are the 3 phases of treatment?

Answer 96

Respiratory tract infections (viral or bacterial), air pollution, unknown causes 1. Short-acting bronchodilators: Albuterol +/- ipratropium MDI or nebulizer 2. Systemic corticosteroids: Prednisone 40mg PO daily for 5 days 3. Antibiotics if they have the cardinal symptoms or require mechanical ventilation: Macrolides, amoxicillin/clavulanate, tetracyclines; 5-7 days

Question 97

What are the cardinal symptoms in COPD? What symptoms do the pts have to show to get antibiotics?

Answer 97

Sputum purulence, sputum volume, dyspnea Antibiotics are warranted if patients show all symptoms, or just 2/3, but sputum purulence must be one of them.

Question 98

What is the discharge criteria for patients who were hospitalized for COPD exacerbations?

Answer 98

- Able to used long-acting bronchodilators + inhaled corticosteroids - SABA therapy is no longer required more than every 4 hours - Pt can walk across the room again - Pt can eat and sleep without frequent awakenings - Clinically stable for 12-24 hours - pt understand the correct use of their meds - Follow up and home care arrangement have been completed

Question 99

What questions can you ask the patient to assess asthma control?

Answer 99

During the past 4 weeks, has the patient had: - Daytime symptoms more than 2x per week? - Is the reliever needed more than 2x per week? - Any night awakenings due to asthma? - Any activity limitation due to asthma? Patients can be well controlled (no symptoms), partly controlled (1-2 symptoms), or uncontrolled (3-4 symptoms).

Question 100

What are 6 asthma modifiable risk factors?

Answer 100

- Poor adherence/technique - High SABA use (> 200-dose cannister/month) - FEV1 < 60% predicted - Exposure to allergens or smoke - Comorbidities like obesity, food allergy, sinusitis, etc. - Psychological or socioeconomic problems

Question 101

What is the standard asthma treatment follow up? For initiating controller therapy or stepping down in therapy

Answer 101

Initiating: 2-3 month follow up of response, assess the level of control, FEV1 at start and end after 3-6 months Stepping down: Symptoms controlled for 3 months, low risk for exacerbation, do not eliminate ICS

Question 102

What are things that you measure at each follow up appointment for COPD?

Answer 102

Functional capacity - Timed walking at rest, oxygenation at rest Symptoms - mMRC, CAT Smoking status - Ask the patient Pharmacotherapy (regimen) - assess adherence, inhaler technique, effectiveness of regimen, side effects

Question 103

What are things that you measure annually for COPD?

Answer 103

Lung function and airflow limitation - spirometry Exacerbations - Frequency, severity, type, likely causes

Question 104

What are the 4 main ways to prevent asthma?

Answer 104

Vaccinations - flu, pneumococcal if pt is ≥ 19 years old Exposure to triggers - environment, inflammation Physical activity - breathing exercises & regular activity Smoking cessation - pts and caregivers of pt

Question 105

What are the 4 main ways to prevent asthma?

Answer 105

Smoking cessation - pt/caregivers, use pharm and non-pharm options Vaccinations - flu and pneumococcal Physical activity - Breathing exercises and regular activity Pulmonary rehabilitation - for gold group B and D

Question 106

What patients will likely need to taper their steroid?

Answer 106

- They has glucocorticoid equiv. to prednisone ≥ 7.5mg/day for more than 3 weeks (if pt was on for less than 3 weeks, they can stop without taper) - If they were taking even ≥ 5mg prednisone at night for more than a few weeks - If they appear to have Cushing's - Be more cautious if they look frail or if they are dangerously ill Regardless, monitor the pts signs and symptoms.

Question 107

What is the treatment strategy for patients with chronic adrenal insufficiency?

Answer 107

- Hydrocortisone 15-25 mg/day or cortisone 20-35mg/day (because they resemble endogenous cortisol with high MC activity and short half-life) Dosing regimen: Give 2/3 dose in the morning and 1/3 at night to maintain cortisol levels throughout the day.