1
Q
What is Asthma?
A
- CHRONIC INFLAMMATORY disorder of the airways
- Characterized by recurring episodes of hyper-responsiveness to stimuli that causes BRONCHOCONSTRICTION (=airflow obstruction)
- Clinical symptoms: recurring episodes of cough, wheezing, tight chest, dyspnea (=shortness of breath)
- Based on the triggering stimuli characterized as EXTRINSIC (allergenic) or INTRINSIC (non-allergenic).
- Reversible airway limitation!
- Except the damage of airway remodeling.
2
Q
Where is asthma?
A
Asthma induced changes in airway
- bronchi & bronchioles
3
Q
What is Extrinsic Asthma?
A
- MALadaptive immune system response creating memory to allergens.
- External stimuli such as environmental allergens (ie- dust, mold, pollen, animal dander, foods) trigger plasma cells to produce antigen specific IgE antibodies.
- Allergen&IgE binding to mast cells result in degranulation and release of inflammatory mediators.
Allergens have glycoproteins that immune cells recognize as an antigen, substance specific to each allergen. Plasma cells functions as a memory cells producing antibody (IgE) that recognizes only that antigen.
4
Q
What is Intrinsic Asthma?
A
- Non-allergenic asthma.
- Symptoms triggered by non allergenic factors
(e.g. anxiety, stress, cold air, dry air, smoke,
exercise, viruses) - The mechanisms initiating the asthma attack are not completely understood, but likely involve:
– Abnormalities in the autonomic regulation of airway functions – increased responsiveness.
– Immune system responses driving bronchoconstriction.
– Mast cells’ degranulation triggered by stimuli other than allergen specific IgE.
5
Q
What is the acute response of pathophys of Asthma?
A
-bronchoconstriction
occurs within mins
from mast cells - histamine, leukotrienes, PG’s, PAF
6
Q
What is the prolonged response?
A
mast cells & eosinophils & basophil
- vasodilation
- mucus secretion
- edema
- bronchoconstriction
occurs hours after the acute rxns
=> chronic inflammation
7
Q
What is the airway hyper-responsiveness & remodeling?
A
- Fibrosis
- Muscle hypertrophy
- Angiogenesis
- Mucus hypersecretion
8
Q
What is COPD?
A
= Chronic obstructive pulmonary disease
- Slowly progressive airway obstruction due to CHRONIC INFLAMMATION
- Common in smokers. Other causes: air pollution, occupational exposures and genetics (α1-antitrypsin deficiency ~1%).
- Clinical symptoms: cough, mucus hypersecretion, dyspnea (=shortness of breath)
- This disorders includes CHRONIC BRONCHITIS (inflammation of bronchi) and EMPHYSEMA (destruction of alveolar structure => limited air exchange; CO2 export & O2 import reduced)
- Irreversible airflow limitation!
9
Q
What is the COPD pathophys?
A
- Chronic Bronchititis - inflammation & excess mucus
+ Emphysema - alveolar membranes break down
10
Q
What is Emphysema?
A
- air exchange becomes difficult in damaged alveoli
- air becomes trapped
11
Q
What sx’s amenable to drug therapy?
A
- Excessive airway smooth muscle tone
- Inflammation
- Pulmonary edema
- Mucus plugging
- Cough*
12
Q
What are drugs divided based on tx strategies?
A
1) Controllers and 2) Relievers
13
Q
What are drugs divided based on targets?
A
1) Airway muscle tone
=> Bronchodilators
(Beta-adrenergic, Methylxanthines, Anticholinergics,
Leukotriene modifiers)
2) Inflammation
=> Anti-inflammatory agents
(Corticosteroids, Mast cell stabilizers, Anti-IgE Monoclonal-Antibody,
Leukotriene modifiers)
14
Q
What are the bronchodilators?
A
Agents that interact with smooth muscle cells lining the airways (bronchiole) and relax smooth muscles
- Beta-adrenergic (Albuterol/Salbutamol, Terbutaline, Salmeterol, Formoterol)
- Methylxanthines (Theophylline)
- Anticholinergics (Tiotropium, Ipratropium)
- Leukotriene modifiers (Zileuton, Zafirlukast, Montelukast)
15
Q
What is Bronchoconstriction?
A
Activation of parasympathetic nervous system;
Acetylcholine binds to M3 and triggers signaling pathway:
- increased cytoplasmic Ca2+
- Ca2+-calmodulin activates myosin
- myosin binds to actin => actin slide past myosin
=> constriction (that occurs as long as Ca2+ is present)
Adenosine via A1 receptor also increases Ca2+ levels
16
Q
What is bronchodilation?
A
Activation of sympathetic nervous system;
noradrenaline/norepinephrine binding to β2 receptor (G-Protein Coupled Receptor), triggers
- Adenylyl cyclase activation, which catalyzes cAMP production
1) promotion of SR Ca2+ pumps
=> decreased cytoplasmic Ca2+
2) prevents activity of enzyme able to activate myosin
=> prevents myosin binding to actin
dilation/relaxation
17
Q
What is B2-adrenergic Agonists?
A
Short acting: Albuterol/Salbutamol ”Ventolin”, Terbutaline “Bricanyl”
Long acting (12 hours): Salmeterol ”Serevent”, Formoterol “Foradil”
18
Q
What is the MOA of B2-adrenergic Agonists?
A
Stimulate adenylyl cyclase thereby increasing the formation of cAMP which acts to relax the airway smooth muscle leading to bronchodilation.
19
Q
What is the RofA of B2-adrenergic Agonists?
A
Typically administered via inhalation
- Albuterol and Terbutaline available in tablet form
- Terbutaline can also be administered subcutaneously
20
Q
What is the indication of B2-adrenergic Agonists?
A
- Extensively used in the treatment of Asthma. (1st approach)
- In inhaled form, Albuterol is the drug of choice for the treatment of acute attacks.
- For severe attacks, subcutaneous injection of Terbutaline or Epinephrine (agonist of both α and b adrenergic receptors) may be required.
- Co-administration with corticosteroids/anti-inflammatory drugs recommended to prevent development of desensitization of b2 receptor, and promote efficacy of b2 agonists.
21
Q
What is the adverse effects of B2-adrenergic Agonists?
A
- β1 receptors on the heart may get stimulated causing tachycardia.
- Skeletal muscle tremor
- Tolerance may develop with very frequent use.
22
Q
What are the drug interactions of B2-adrenergic Agonists?
A
- Not effective on patient taking propranolol for hypertension or other heart/circulatory conditions.
- Co-administration of long term β2 receptor agonists with corticosteroids prevents desensitization.
23
Q
What is Methyxanthines?
A
e.g. Theophylline
24
Q
What is the proposed mech of Methylxanthines?
A
- Inhibits phosphodiesterase resulting in an increase in cAMP. Reduced cytoplasmic Ca2+ and relaxes the airway.
- Inhibits adenosine receptors; systemic & CNS effects. (Adenosine has been shown to cause the constriction of isolated bronchial smooth muscle and provoke mast cell degranulation.)
- Can stimulate the contractility of diaphragm muscles.
25
What is the RofA of Theophylline?
Oral (tablets)
26
What is the indication of Theophylline?
- Used as a second choice for the treatment of acute attacks. However, it has a NARROW therapeutic window and pharmacokinetic slightly unpredictable (vary widely among similar patients) so it should be given under supervision.
- COPD
- May reverse the steroid insensitivity.
27
What is the adverse effects of Theophylline?
- Common: headache, insomnia, tremors
- Serious: anaphylactic shock; nausea & vomiting, stimulates heart, fever, seizures
- Since it is metabolized by CytoP-450 enzymes, drug interactions may result in toxic concentrations.
- Avoid mixing with foods containing theophylline (e.g. coffee, tea, mate, chocolate).
- Caution: increased cardiovascular effects if given with β2 agonists.
28
What are the Anticholinergics?
Ipratropium “Atrovent”(short acting)
Tiotropium “Spiriva”(long acting)
29
What is the MOA of Anticholinergics?
- Blocks muscarinic receptors, preventing bronchial constriction and mucus secretion.
- No effect on inflammation.
30
What is RofA of Anticholinergics?
aerosol
31
What is the indication of Ipratropium?
- The treatment of COPD and chronic bronchitis
- The treatment of acute asthma attacks in children (12+ /18+ years), adults, and those that are intolerant of b agonists.
- Ipratropium enhances the bronchodilation produced by b2 agonists. The combination can be an effective treatment of severe asthma attacks.
32
What is the indication of Tiotropium?
- The treatment of COPD and chronic bronchitis
- The treatment of acute asthma attacks in children (6+ years), adults, and those that are intolerant of b agonists.
- Tiotropium in combo of long term b2 agonists can be an effective management tx of COPD
33
What is the adverse effects of Ipratropium, Tiotropium?
- Aerosol Ipratropium is generally well tolerated, however, excessive use may cause atropine like effects (ie- dry mouth, dilated pupils, tachycardia, stupor, etc.)
- Caution with glaucoma, prostatic hypertrophy, heart disease
- Recent studies suggest increased risk for dementia within anticholinergic users
34
What are the Leukotriene Modifiers?
- Leukotrienes are products of arachidonic acid metabolism.
- Leukotrienes (LTC4, LTD4) CAUSE BRONCHOCONSTRICTION, increased bronchial reactivity, mucosal edema, and the secretion of mucus.
- The leukotriene modifiers; drugs that INHIBIT THE SYNTHESIS of leukotriene, and drugs that BLOCK THE RECEPTORS leukotriene act upon.
- Not for acute bronchodilation.
35
What are Leukotrienes functions?
- Bronchoconstrictor --> smooth muscle
- Vasoactive --> BV's (vasodil, edema)
- Chemotactic --> Eosinophils, Neutrophils
- Secretagogue --> mucous gland & epithelial cell
36
What is the Leukotriene Synthesis Inhibitor?
Zileuton “Zyflo”
37
What is the MOA of Leukotriene Synthesis Inhibitor?
Inhibits 5-lipoxygenase, which is the enzyme that catalyzes the formation of leukotrienes from arachadonic acid.
38
What is ROA of Leukotriene Synthesis Inhibitor?
Orally active drug, administered 4 times a day.
39
What is the indication of Zileuton?
- The treatment of persistent asthma in adults, and Aspirin- or NSAID-induced asthma.
- Prevents exercise and antigen-induced brochospasm.
40
What is the AE's of Zileuton?
Liver enzyme levels should be checked periodically for possibly hepatotoxicity.
41
What are the drug interactions of Zileuton?
Inhibits CYP450 which may interfere with the metabolism of other drugs (e.g. theophylline, warfarin).
42
What are the Leukotriene R. Blockers?
Zafirlukast “Accolate”, Montelukast “Singulair”
43
What is the MOA Leukotriene R. Blockers?
Selective reversible inhibitors of the cysteinyl leukotriene-1 (CysLT1) receptor, thereby preventing leukotriene induced bronchoconstriction and airway wall edema. Prevents also chemotactic; infiltration of neutrophils and eosinophils.
44
What is the ROA of Zariflukast?
Orally active, administered twice daily.
45
What is the indication of Zariflukast?
- Used for the preventative treatment of mild to moderate asthma.
- Less effective than corticosteroids.
- Should not be administered to children under 8 years of age.
46
What is the Adverse Effects/Drug interaction of Zafirlukast?
- Head ache, GI disturbance
- Inhibits CYP450 which may interfere with the metabolism of other drugs (e.g. theophylline, warfarin).
- Liver enzyme levels should be checked periodically for possibly hepatotoxicity.
47
What is the ROA of Montelukast?
Orally active, administered once daily
48
What is indication of Montelukast?
- Modestly effective in the treatment of persistent asthma in children and adults.
- Less effective than corticosteroids.
- Can be used as a preventative treatment in adults and children 6 years of age and older.
49
What is the Drug interaction/Adverse Effects of Montelukast?
- Recently found to inhibit CYP450 which may interfere with the metabolism of other drugs.
- Liver enzyme levels should be checked periodically for possibly hepatotoxicity.
50
What is Leukotriene modifiers?
reduces leukotriene levels &/or actions
51
What is B2 agonists?
stimulates B2-adrenergic receptors of bronchi
52
What is Methylxanthines?
inhibits phosphodieterase & adenosine r's
53
What is the Anticholinergic drugs?
reduced vagal tonus via M3 r. block
54
What is anti-inflammatory agents?
- Reduce inflammation, edema and mucus production
- Counteracting airway inflammation reduces asthma attacks and COPD flares/progression
- Corticosteroids (Beclometasone, Fluticasone, Budesonide, Methylprednisolone, Dexamethasone, Prednisone)
- Mast cell blockers (Cromolyn sodium, Nedocromil)
- Anti-IgE Monoclonal-Antibody (Omalizumab)
- Leukotriene modifiers (Zileuton, Zafirlukast, Montelukast)
55
What are Corticosteroids?
= steroid hormones produced in the adrenal cortex
- Glucocorticoids; regulate glucose metabolism
- Mineralocorticoids; salt & water balance
“The King” of anti-inflammatory approaches
56
What are the Corticosteroids?
Beclometasone “Qvar”, Fluticasone “Flovent”, Budesonide “Pulmicort” (inhaled)
Methylprednisolone (i.v.), Dexamethasone (oral) & Prednisone (oral)
57
What is the most effective tx for long term control of asthma?
Corticosteroids
58
What is the MOA of Corticosteroids?
- Blocks the release of arachidonic acid, and hence the production of leukotrienes.
- Increase the sensitivity of β2 adrenergic receptors and prevents their desensitization.
- Prevents long term changes in airways structure & function.
59
What is the ROA of Corticosteroids?
AEROSOL is the PREFERRED mode of administration to limit systemic side effects, however severe exacerbations of asthma may require intravenal (methylprednisolone) or oral (prednisone, dexamethasone) administration.
60
What is the indication of Corticosteroids?
- Aerosol used in most moderate cases of asthma and COPD.
- 1st line of anti-inflammatory therapy for all ages.*
61
What are the aerosal admin adverse effects of Corticosteroids?
has minor side effects: oropharyngeal candidiasis (thrush), and hoarseness.
- Reduced by good mouth hygiene: gargling
62
What is the systemic admin adverse effects of Corticosteroids?
cause more severe side effects.
- Common and reversible: edema, weight gain, psychological (mood swings, insomnia, anxiety, etc.), increase risk of infection, delayed wound healing, elevated blood pressure, loss of glucose control in diabetics, glaucoma, muscle weakness.
- Common and permanent: osteoporosis and cataracts in adults, and growth retardation in children.
- Chronic use may result in the suppression of the adrenal glands and endogenous production of corticosteroids.
- Adverse effects of oral medication reduced with alternate day therapy and morning administration.
- Treatment regime needs to be stopped gradually.
63
What is Mast Cell Blockers?
Cromolyn Sodium “Intal”
- Approved for the treatment of asthma of all ages.
Nedocromil “Alocril”
- Approved for the treatment of asthma in patients of 12+ years of age
64
What is MOA Mast Cell Blockers?
- Poorly understood
- Inhibits the release of mediators from mast cells, possibly by blocking ion-channels required for degranulation.
65
What is the ROA of Mast Cell Blockers?
Aerosol, administered 2-4 times/day
66
What is the indication of Cromolyn Sodium & Nedocromil?
- Anti-inflammatory drug of choice for the treatment of allergenic asthma; Cromolyn for children (>2-3 years old).
- Treatment of mild-moderate asthma and exercise induced asthma.
- Does not reverse ongoing broncho-constriction, BUT, regular use reduces bronchial hyper-reactivity and inhibits acute and chronic responses.
- Trial period of 4-6 weeks is required to determine its efficacy.
- Less potent than inhaled glucocorticoids in controlling asthma.
67
What is the AE's of Cromolyn Sodium & Nedocromil?
Generally well tolerated
Throat irritation, dryness, cough, nasal secretions and congestion, nausea
Serious adverse effects are rare.
Anaphylaxis; hives, low blood pressure, tightness in chest
Less than 2% experience reversible dermatitis, myositis, or gastroenteritis.
68
What is Anti-IgE Monoclonal-Antibody?
Omalizumab (Xolair®)
69
What is the MOA of Anti-IgE Monoclonal-Antibody?
Selectively binds human free IgE in the blood and interstitial fluids, and thus prevents IgE binding to receptors on cells and reduces IgE levels. Both acute and prolonged inflammatory responses reduced.
70
What is the indication of Anti-IgE Monoclonal-Antibody?
Used for allergic asthma in adult and ≥12 years old patients with persistent symptoms.
71
What is the ROA of Anti-IgE Monoclonal-Antibody?
Subcutaneous (sc) injections
72
What is the AE's of Anti-IgE Monoclonal-Antibody?
Anaphylaxis in some patients.
73
What is the summary of anti-inflammatory agents?
- Mast-cell blockers (to prevent degranulation)
- Corticosteroids
- Anti-IgE antibody
Pharmacology (Winter)
flashcards
Decks in class (23)
# Cards
-
Drugs of Abuse (Part 1)73
-
Drugs of Abuse (Part 2)52
-
Parkinson's Disease Drugs36
-
Antipsychotic Drugs & Mood Stabilizers53
-
Antidepressants31
-
Anxiolytics & Hypnotics70
-
General & Local Anesthetics29
-
Antiepileptic Drugs65
-
Adrenal Physiology & Pharmacology38
-
GI Drugs27
-
Dermatological Drugs48
-
Osteoporosis Drugs37
-
Estrogens, Progestins & Androgens81
-
Thyroid Disorders33
-
Allergies44
-
Asthma & COPD drugs73
-
Pediatric Pain Management59
-
Anticancer146
-
Autoimmune Drugs66
-
Cannabinoids & Medical Marijuana78
-
Adverse Drug Reactions & Pharmacogenomics41
-
Diabetes Drugs - Part 133
-
Diabetes Drugs - Part 233
