Title: Pharmacology RS Final / Treatment of Asthma

Q: The definition of asthma: (2)
A: 1. It is a chronic inflammatory disorder with intermittent narrowing of the airways
2. Characterized by wide variations, over short periods of time, in the resistance to flow in the intrapulmonary airways.

Q: Factors in the treatment strategy of asthma: (5)
A: 1. Asthma is a chronic condition
2. The goal of therapy is normal function
3 Asthma is heterogenous
4. The course is unpredicatable
5. Therapy must be individualized

Q: Asthma is hetergenous in terms of:(3)
A: 1. Cause or trigger mechanism
2. Extent of bronchoconstriction
3. Degree of inflammation

Q: Risks of not treating asthma: (5)
A: 1. Deterioration of the condition
2. Accelerated decline in the function of the patient's lungs as measured by PFTs
3, Increased numbers of attacks of asthma
4. Poorer response to therapy if started late
5. Increased mortality from asthma

Q: Goals of therapy in asthma (8)
A: 1. Minimal symptoms even during sleep
2. No, or infrequent, acute episodes
3. No ED visits or missed days in school or work
4. Rare need for beta-agonist inhaler therapy
5. No limitation of activities- even sports
6. Peal flow rate variability less tha 20%
7. FEV1 consistently >80% of predicted range
8. No or minimal adverse effects from drugs

Q: The pathogenesis of early asthamtic response: (6)
A: 1. Allergens provoke IgE production, the tendency to produce IgE is genetically determined
2. Re-exposire to the allergen causes antigen-antibody interaction on the surface of mast cells, leading to:
3. Release of stored mediators
4. Synthesis of other mediators
5. Activation of neural pathways
6. All of which lead to bronchoconstriction.
PREVENTED BY BRONCHODILATORS

Q: The pathogenesis of late asthmatic response: (5)
A: 1. Occurs 4-5 hours later
2. More sustained phase of brnchoconstriction
3. Influx of inflammatory cells and an increase in bronchial responsiveness
4. The mediators here are cytokines produced by TH2 lymphocytes, especially ILs: 5, 9, and 13
5. These will stimulate IgE production by B lymphocytes and directly stimulate mucus production
PREVENTED BY CORTICOSTERIODS.

Q: The features of the histopathology of a small airway in fatal asthma: (6)
A: 1. Mucus plug with trapped inflammatory cells
2. Goblet cell metaplasia
3. Inflammatory cells infiltrate in submucosal layer
4. Thickened basement membrane
5. Thickened airway smooth muscle
6. Normal parenchymal attachments

Q: Asthma triggers: (9)
A: 1. Exercise
2.Cold air
3. Cigaratte smoke
4. Stress and anxiety
5. Animal dander's (cats, dogs, etc.)
6. Allergens (grass, trees, mold, cockroach)
7. Pollutants (sulfur doxide, ozone, etc.)
8. Fumes/toxic substances
9. Medications (ASA, NSAID's, others)

Q: Subjective diagnosis of asthma: (5)
A: 1. Cough: usually in spasms and to the point of vomiting, nighttume worse than daytime
2. Cough may follow exposure to cold air, exercise, URI (common cold), or exposure to allergen.
3. Dyspnea> cough or wheezing> sputum
4. Past history of bronchitis as a child
5. Family history of asthma of asthma is common

Q: Objective diagnosis of asthma: (6)
A: 1. Reduced FEV1 and FEV1/FVC ratio
2. Reduced Peak Expiratory Flow Rate (FEFR)
3. Reversibility with bronchodilators
4. Heightened response to Methacholine test
5. Increase in expired NO
6. Increase in inflammatory mediators and their metabolic products in body fluids

Q: Step-wise approach to asthma therapy: (5)
A: 1. Mild intermittent--> Short acting beta2 agonist as required for symptom relief
2. Mild persistent --> We add ICS Low dose
3. Moderate persistent --> We add LABA
4. Severe persistent --> We alternate ICS low dose to high dose
5. Very severe persistent --> We add OCS
ICS: inhaled corticosteroids
LABA: long-acting beta agonist
OCS: oral corticosteroids

Q: Quick relief medications for asthma: (3)
A: 1. Inhaled short-acting beta-2 agonists
2. Inhaled anticholinergics
3. Systemic corticosteroids

Q: Long-term control medications: (5)
A: 1. Topical (inhaled) corticosteroids
2. Inhaled Cromolyn Na and Nedocromil
3. Oral Methylxanthines (theophyllines)
4. Inhaled long-acting beta-2 agonists (LABA)
5. Oral leukotriene modifiers (LTRA)

Q: Effects of Beta-2 adrenergic agonists: (7)
A: --> Medications of choice for acute exacerbations
1. Actively relax airway smooth muscle
2. Inhibit release of mast cell mediators
3. Enhance muco-ciliary activity (clearance)
4. Decrease vascular permeability (plasma exudation)
5. Prevention of microvascular leakage and airway edema
6. Inhibit eosinophil activation and neutrophil function
7. Decreased bacterial adherence

Q: Molecular actions of beta 2 adrenergic agonists: (3)
A: 1. Increased cAMP
2. Activate protein kinase A
3. Phosphorylates kinases
--> All lead to decreased cystolic Ca++

Q: Epinephrine: (3)
A: 1. Obtained from bovine adrenal gland
2. Stimulates alpha, beta1 and beta2 receptors
3. Not effective orally, so it is given subcutaneously

Q: Isopreterenol: (3)
A: 1. Stimulates beta1 and beta2 receptors
2. First (1960s) convenient, pocket-sized multidose inhalers
3. Considerable tachycardia and pounding

Q: Characteristics of short-acting beta2 adrenergic agonists: (3)
A: 1. Rapid onset: 3-5 minutes
2. Maximal effect: 30-60 minutes
3. Duration of action: 4-6 hours

Q: Characteristics of long-acting beta-2 adrenergic agonists: (4)
A: 1. Long acting inhaled bronchodilators :12 hours
2. Supress nighttime attacks
3. Controllers with steroids
4. No tachyphylaxis

Q: Problems of Metered Dose Inhalers (MDI):(5)
A: 1. Cap not removed prior to use in some patients
2. Timing of canister acuation to inspiration is critical (only first air in gets to the right place)
3. Inspiration too rapid (should take 4-5 seconds)
4. Nasal inspiration contains no medication
5. Spacers not used, despite evidence of their great utility

Q: The function of a spacer: (4)
A: 1. A large volume chamber attached to a MDI, used to decrease the deposition of drug in the mouth
2. Serves to reduce the velocity of the injected aerosol before it enters the mouth and allows large drug particles to deposit in the device
3. The smaller, high velocity drug particles, are more likelt to reach the target airway tissue
4. Rinsing the mouth can also decrease the systemic absorption and oropharyngeal candidiasis

Q: Beta 2 adrenegic agonists effects: (4)
A: 1. Medications of choice for acute exacerbations
2. Actively relax the airway smooth muscle
3. Enhance muco-ciliary clearance
4. Decrease vascular permeability

Q: Toxicity of beta-2 adrenergic agonists: (4)
A: 1. Nervousness, anxiety, tremor
2. Due to vasodilation, may increase perfusion of poorly ventilated lung units and might transiently decrease PaO2.
3. Tachyphylaxis
4. Increased mortality due to cardiac toxicity

Q: Methylxanthines: (3)
A: Theophylline, Aminophylline
1. Used to be the mainstay treatment
2. Can be given orally and intravenously
3. CNS and cardiovascular stimulants

Q: Side effects of methylxanthines: (4)
A: 1. Arrythmias
2. Nausea
3. GIT irritation
4. Diarrhea

Q: MOA of Methylxanthines: (3)
A: 1. Phosphodiesterase inhibition
2. Adenosine receptor stimulation
3. Anti-inflammatory activity

Q: Problems with methylxanthines: (5)
A: 1. Optimal dosing is very difficult
2. Wide inter-individual variation in the rate of hepatic metabolism
3. Half life: 3-16 hours
4. Food and drug interactions (erythromycins and ciprofloxacin)
5. Blood assay is a routine

Q: Atropine: (3)
A: 1. An anticholinergic agent
2. Can be inhaled, but; can cause systemic side effects
3. Impairs mucociliary clearance leading to dryness, and consequently, impaired clearance of airway secretions

Q: Ipratorium bromide inhaler: (4)
A: 1. An anticholinergic agent
2. Poorly absorbed from respiratory mucosa
3. Does not impair clearance of airway secretions
4. Causes minimal cardiac or central effects

Q: Uses of Ipratropium bromide: (3)
A: 1. Metered dose inhaler and as a solution for nebulization
2. Mainly for COPD, not for asthma, because of slow onset (10-15 minutes) and low potency
3. Might be very useful in special conditions (beta blocker-induced asthma, resistant attacks, cardiac patients)

Q: Anti-inflammatory agents and alternative therapy: (4)
A: 1. Corticosteroid
2. Inhibitors of mast cell degranulation
3. Leukotriene pathway modifiers
4. Immunomodulatory agents

Q: Corticosteroids: (8)
A: 1. Inhibit the synthesis and release of many chemical mediators (histamine, PGs and cytokines)
2. Supress the inflammatory cell influx and process
3. Relax bronchial smooth muscle
4. Enhance beta-adrenergic responsiveness (upregulate beta receptors)
5. Increase synthesis of adrenergic mediators
6. Decrease quantity and viscosity of the secretions
7. Inhibit IgE synthesis
8. Decrease microvascular permeability

Q: MOA of corticosteroids: (4)
A: Highly lipophilic, enter the cytosole
1. Bind to cytosolic receptors
2. The drug-receptor complex enters the nucleus
3. Decrease transcription of genes coding for pro inflammatory cytokines
4. Take several hours to days to work

Q: Uses of corticosteroids: (2)
A: 1. Short systemic use in severe refractory attacks
2. Long term use for "steroid dependant" asthma

Q: Ways of administration of corticosteroids: (2)
A: 1. Systemic use (either oral or injectable)
2. Inhalation: Aerosol treatment is the most effective way to avoid the systemic adverse effects.

Q: Local side effects of corticosteroids: (4)
A: 1. Hoarseness of voice (dysphonia)
2. Sore throat
3. Cough
4. Candida infection

Q: Systemic side effects of corticosteroids: (8)
A: 1. Osteoporosis
2. Cataracts
3. Glaucoma
4. Growth retardation
5. Adrenal suppresion
6. CNS effects and behavioral disturbances
7. Increased susceptibility to infections
8. Teratogenicity

Q: Cromolyn Na and Nedocromil Na: (8)
A: 1. Inhibits the release of inflammatory mediators from mast cells (mast cell stabilizers)
2. Phrophylactic for mild to moderate asthma
3. Regular use (4 times daily)
4. Not for acute asthma
5. Phosphorylates a cell membrane protein, so mediator release is inhibited despite antigen-IgE interaction
6. Might decrease Ca++
7. Might decrease neural pathways, plasma exudation and inflammation in general
8. COMPLETE absence of side effects

Q: Leukotrienes: (4)
A: 1. Synthesized by mast cells and eosinophils
2. They are 1000-fold more potent than histamine in stimulating airway smooth muscle constriction
3. They also promote microvascular leakage, mucus secretion and eosinophil chemotaxis
4. Pathway augmented by COX inhibitors (such as NSAIDs)

Q: Aspirin sensitivity: (3)
A: --> 3-5% of adults with asthma, have aspirin sensitivity
1. This reaction is not an allergic response, can be induced by many different chemicals and it does not involve IgE antibody response
2. Patients produce high levels of cysteinyl leukotrienes in response to COX inhibitors, probably by shunting of arachidonic acid into leukotriene pathway
3. Abnormality of the promotor region of the gene for LTC4 synthase, leading to overexpression of the enzyme leading to increased conversion of LTA4 to LTC4.

Q: Leukotriene pathway modifiers: (2) ++
A: 1. Inhibitors of 5-lipoxygenase enzyme:
such as Zileuton which is used for acute and chronic treatment, 4 times daily, and is hepatotoxic
2. Antagonists of Cysteinyl Leukotriene receptors:
such as Montelukast and Zafirlukast,, some patients improve and others do not. --> Churg-Strauss Syndrome

Q: Churg-Strauss syndrome: (3)
A: 1. Rare reaction in newly treated asthmatic patients
2. A common finding is systemic vaculitis with eosinophilic infiltration and granuloma formation
3. Can also be due to unmasking of vasculitis after steroid withdrawal.

Q: Symptoms of Churg-Strauss syndrome: (5)
A: 1. Severe inflammatory reaction
2. Pulmonary infiltration
3. Neuropathy
4. Skin rash
5. Cardiomyopathy

Q: Advantages of Montelukast: (4)
A: 1. Decreased the percentage of patients needing systemic use of corticosteroids by 39%
2. Decreased nighttime awakenings
3. Decreased percent of patients having asthma attacks by 37%
4. Decreased need for beta-agonists by 21%

Q: Omalizumab: (5)
A: 1. It is a humanized monoclonal anti-IgE antibody raised in mice
2. Not recognized as foreign by human immune system
3. Targeted against the portion of IgE that binds to its receptors (FC-R1 and FC-R2 receptors) on mast cells and other inflammatory cells
4. IgE-anti-IgE complexes are cleared from the blood without deposition in the kidneys or joints
5. Given as IV or SC injection every 2-4 weeks

Q: What are immunomodulation biotherapeutics? (2)
A: 1. Monoclonal antibodies directed against cytokines (Il-4, IL-5, and IL-13)
2. Antagonists of cell adhesion molecules, protease inhibitors, and immunomodulators aimed at shifting CD4 lymphocytes from the TH2 to the TH1 phenotype or at selective inhibition of the subset of TH2 lymphocytes directed against particular antigens

Q: General therapy of asthma: (4)
A: 1. Oxygen
2. Hydration: oral or IV
3. Expectorants
4. Antimicrobials

Q: Possible future therapies for asthma: (2) ++
A: 1. There is evidence that sthma may be aggravated (or even caused) by chronic airway infection with Chlamydia pneumoniae or Mycoplasma pneumoniae.
- this may explain the reports of benefit from the treatment with macrolide antibiotics (erthromycins)
- if confirmed, would stimulate the development of new diagnostic methods and antimicrobial therapies
2. Feeding Lactobacillus caseii to infants born to allergic parents reduced the rate of allergic dermatitis at age 2 years, offers reason for hope

Q: Status asthmaticus: (3)
A: 1. Life threatening exacerbation of asthma symptoms that is unresponsive to standard therapy, preceded by rapid increase in the daily use of bronchodilator drugs
2. Provocative factor usually present
3. Needs aggressive treatment in the hospital

Q: Treatment of status asthmaticus: (5)
A: 1. Oxygen
2. Inhaled short-acting Beta2 agonists
3. Oral or parentral corticosteroids
4. Subcutaneous beta2 agonists
5. Inhaled ipratropium may be effective in some patients

Q: Ensifentrine (PRL554): (2)
A: 1. A unique inhaled drug, effective and well-tolerated as a bronchodilator, bronchoprotector, and anti-inflammatory drug, in patients with COPD or asthma
2. RPL554 is a dual inhibitor, blocking the activity of 2 phosphodiesterase enzymes: PDE3 and PDE4