Bronchodilators, Corticosteroids, and the Pharmacotherapy of Asthma and COPD Flashcards
1
Q
Drug List 1
A
- b agonist Bronchodilators
- Short-acting b agonists (SABA)
- Albuterol, others
- Long-acting b agonists (LABA)
- Salmeterol, formoterol
- Emergency, non-selective b agonist
- Epinephrine
- Short-acting b agonists (SABA)
- Muscarinic Antagonists
- Ipratropium, tiotropium
- Methylxanthine
- Theophylline
2
Q
Drug list 2
A
- Inhaled Corticosteroids (ICS)
- Beclomethasone
- Budesonide
- Ciclesonide
- Flunisolide
- Fluticasone
- Mometasone
- Triamcinolone
- Oral Corticosteroids
- Methylprednisolone
- Prednisone
3
Q
Drug List 3
A
- Leukotriene Receptor Antagonist (LTRA)
- Montelukast
- Zafirlukast
- Cromolyn compounds
- Cromolyn sodium
- Anti-IgE Antibody
- Omalizumab
4
Q
Bronchospasm
A
- In allergic asthmatics patients, immediate hypersensitivity-type reactions can be continuously present at a sub-threshold level, resulting in mild-to-moderate inflammation without overt bronchoconstriction.
- Overt bronchospasm then occurs upon exposure to a specific allergen or to a variety of nonspecific stimuli, e.g., cold air, dust, air pollution, exercise, etc.
5
Q
Antihistamine
A
6
Q
Inflammatory Mediators in Asthma
A
- Enormous variety of mediators are released. Thus, blocker of a single mediator, e.g., antihistamine, is unlikely to be effective in alleviating the symptoms or the progression of asthma.
- Corticosteroids, which are capable of blocking many key steps in the inflammatory process, come closest to this ideal therapy.
7
Q
Mast Cell Mediators of Inflammatory Processes
Preformed
A
CLASS: Preformed (immediate)
MEDIATOR : Histamine,TNF-alpha Proteases, Heparin
EFFECTS: Bronchoconstriction, itch, cough, vasodilation, edema
8
Q
Mast Cell Mediators of Inflammatory Processes
Lipids
A
CLASS: Lipids (minutes)
MEDIATOR : Leukotrienes, Prostaglandins
EFFECTS: Bronchoconstriction,chemotaxis, mucus secretion
9
Q
Mast Cell Mediators of Inflammatory Processes
Cytokines
A
CLASS: Cytokines (hours)
MEDIATOR: Interleukins, GM-CSF
EFFECTS: Bronchoconstriction. chemotaxis, inflammatory cell proliferation
10
Q
Mast Cell Mediators of Inflammatory Processes
A
11
Q
Normal Airway vs Airway in Asthma
A
12
Q
Aerosol Delivery of Drugs
Factors to Consider
A
- Particle size of aerosol is important.
- Rate of breathing and breath holding.
- Even under ideal conditions, 90% of inhaled drug is swallowed.
- Therefore, ideally the best drugs also have poor absoption from the GI tract and/or rapid first-pass metabolism in the liver.
13
Q
Particle Size in Inhalers
A
14
Q
Aerosol Delivery of Drugs
Devices
A
- Metered Dose Inhalers (MDI)
- with spacer device
- Nebulizers
- Dry powder inhalers
15
Q
Nebulizers
A
16
Q
Classifying Astham Severity in youths 12 and Older
A
17
Q
Stepwise Approach for Managing Astham in youths 12 and Older
A
18
Q
Stepwise Treatment: Kids 5 - 11
A
19
Q
Beta-Adrenergic Agonists
A
- Therapeutic Use in Asthma and COPD:
- Drug of choice for rapid relief of bronchospasm
- Highly effective and safe for intermittent, prophylactic treatment of asthma.
- Current Emphasis:
- Intermittent use on an as-needed basis for relief of acute, severe bronchospasm. Not general prophylaxis.
20
Q
Beta-Adrenergic Agonists
Overuse
A
Overuse:
- Side effects intensify will overuse, but a greater danger is the tendency to continue to self-medicate during periods when symptoms are escalating.
- To avoid a medical emergency, patients should be encouraged to seek medical attention as soon as possible after they detect a decline in the efficacy of their usual therapeutic regimen.
21
Q
Beta-Adrenergic Agonists
Mechanism of Action:
A
Mechanism of Action:
- Stimulate b2-adrenergic receptor on surface of bronchiolar smooth muscle cells.
- b2-adrenergic receptor couples to Gs protein and activates adenylyl cyclase enzyme leading to increased cellular levels of cyclic AMP.
- Cyclic AMP stimulates phosphorylation cascade that leads to decreased intracellular calcium and smooth muscle relaxation.
- Also inhibit mediator release from mast cells.
22
Q
Selectivity of
Beta-Adrenergic Agonists
A
- Selectivity means these agonists have higher affinity, and thus, higher potency at b2-adrenergic receptors than at b1-adrenergic receptors.
- Selectivity helps limit side effects mediated by activation of b1-receptors
23
Q
Beta 2-Receptor Selectivity
A
24
Q
Rapid Acting-Short Duration
Beta 2-Adrenergic Agonists
A
- Albuterol onset<15 min duration: 2-4 hr
- Levalbuterol same
- l-isomer of albuterol
- Pirbuterol same
- Terbutaline same
- These agents are used as “rescue inhalers”. They are relatively fast at relieving bronchospasm, but have a relatively short duration of action.
25
Long Acting
Beta 2-Selective Agonists (LABA)
* Salmeterol:
* slower onset
* duration \> 12 hours of useful bronchodilation
* useful to control nighttime asthma attacks, also now used BID for prevention
* not suitable for treatment of acute bronchospastic attacks because onset of action is too slow.
* Formoterol
* Similar to salmeterol
* Not for acute attacks
26
Less Selective or Nonselective
Beta -Adrenergic Agonists
* Epinephrine
* Isoproterenol
* Metaproterenol
* Isoetharine
* Because of their very short duration of action and their lack of b2-selectivity, these agents are not frequently used.
* Low-strength epinephrine inhalers sometimes prescribed for mild asthma
* Racemic Epinephrine
* aerosol used for pediatric patients
27
Long-term Use of LABA
* Continued use of a LABA may cause down-regulation of b2 receptors with loss of the protective effect from rescue therapy with a short-acting agent.
* LABA should not be used for monotherapy in patients with persistent asthma, especially in children.
* LABA should be used in asthma only in combination with an inhaled corticosteroid.
* **_“Stop use of a LABA, if possible, once asthma control is achieved and maintain the use of an asthma-controller medication such as an inhaled corticosteroid”._**
28
Oral Therapy with
Beta -Adrenergic Agonists
* Oral administration increases incidence of adverse side effects:
* muscle tremor, cramps, cardiac tachyarrhythmias, metabolic disturbances, hypokalemia
* Appropriate situations for oral therapy:
* brief therapy in children with upper respiratory tract infections who cannot manipulate inhaler
* in severe asthma exacerbations where inhaler cannot be used or when aerosol is irritating
* oral albuterol and terbutaline are available
29
Adverse Side Effects of
Beta -Adrenergic Agonists
* Patients with **cardiovascular** disease or **diabetes** are at higher risk of adverse effects.
* **_Skeletal muscle tremor (most frequent side effect)_**
* CNS: restlessness, apprehension, anxiety, tremors
* CVS: **_tachycardia_**, dysrhythmias, hyper- or hypotension
* hypokalemia
* worsen hyperglycemia in diabetics
* drug interactions with thyroid, digitalis, methylxanthines
30
Epinephrine: Emergency Use
* Epinephrine is the drug of choice for treatment of anaphylactic reactions.
* Give SQ (or IM or IV with dextrose)
* Bronchodilation (mediated by beta 2 receptors)
* Vasoconstriction (mediated by alpha 1 receptors)
* maintains BP & decreases edema
* Inhibition of mediator release (beta 2 receptors)
31
Anaphylaxis Treatments
* Albuterol via nebulizer
* IV fluids
* Oxygen
* Secondary therapy
* H1 antagonist - diphenhydramine
* H2 antagonist - ranitidine
* Corticosteroid - hydrocortisone, methylprednisolone
* Aminophylline
* NE, glucagon - for hypotension
32
Atropine and Ipratropium Bromide
33
Bronchodilators:
Ipratropium bromide
* **A quaternary muscarinic receptor antagonist**
* If given parenterally, effects are like atropine
* But, only given as **_inhaled aerosol_**
* few side effects, even when swallowed because is poorly absorbed from GI and does not cross into brain
* quaternary amine- poor diffusion across membranes
* Parasympathetic - mediated bronchospasm is a significant component of airway resistance in some asthmatics and COPD patients, especially psychogenic exacerbations
34
CNS Airway Control
35
Ipratropium bromide
and Tiotropium
Therapeutic Use
* Therapeutic Use:
* Bronchodilation develops more slowly and is usually less intense than that produced by b-agonists.
* Useful bronchodilation lasts up to 6 hours.
* Principal use of ipratropium is in **COPD**.
* Combined with albuterol = **COMBIVENT**
* Also used intranasally to reduce secretions in the upper and lower respiratory tract in **_allergic rhinitis_** and **_chronic postnasal drip syndrome._**
* **Tiotropium**: newer **_long-acting agent (QD dosing)_** used for maintenance therapy in chronic bronchitis and emphysema; dry powder inhaler device
36
Methylxanthine Bronchodilators:
Theophylline
* **Methylxanthines**
* **_theophylline_**, caffeine, theobromine
* found in coffee, tea, chocolate, cocoa, colas
* **Diverse cellular actions**
* adenosine receptor antagonists
* block cyclic AMP degradation – PDE inhibitor
* lower intracellular calcium
* hyperpolarize cell membranes
37
Theophylline
* **Bronchodilation** is a clinically relevant effect of theophylline
* **Other** **effects** include CNS stimulation, modest peripheral vasodilation, improved skeletal muscle contractility, and a thiazide-like diuresis
38
Theophylline
Therapeutic Use:
* **Therapeutic Use:**
* _Formerly_ a first-line agent for treatment of asthma
* _Now_ has a far less prominent role because:
* benefits are modest
* narrow therapeutic window
* considerable variation in absorption and elimination between different patients
* monitoring of plasma concentrations is often required
* **Nocturnal** asthma can be improved with slow-release theophylline, but inhaled corticosteroids and salmeterol are probably more effective.
* IV formulation = **aminophylline**
39
Anti-Inflammatory Agents
Corticosteroids
* In asthma (and some COPD) an **_inflammatory response_** is responsible for the underlying disease process.
* So many inflammatory mediators are involved that a blocker of any given autocoid or cytokine, e.g., antihistamine, is ineffective in alleviating the symptoms of asthma.
* Corticosteroids block many of the steps involvedin the inflammatory cascade
40
Anti-Inflammatory Agents
Corticosteroids
* Mechanism of Action
* corticosteroids are steroid receptor agonists that bind to intracellular receptors that translocate to the cell nucleus and positively or negatively regulate gene transcription. _This takes time_.
* corticosteroids inhibit the production and release of cytokines, vasoactive and chemoattractive factors, lipolytic and proteolytic enzymes, decrease mobilization of leukocytes to areas of injury, and decrease fibrosis.
* **_General anti-inflammatory response._**
41
Corticosteroid Mechanism
42
Inhaled Corticosteroids
* Beclomethasone dipropionate (Beclovent)
* Budesonide dipropionate (Pulmicort)
* Ciclesonide (Alvesco)
* Flunisolide (AeroBid)
* Fluticasone (Flovent)
* Mometasone (Asmanex Twisthaler)
* Triamcinolone acetonide (Azmacort)
43
Systemic Corticosteroids
* IV or oral
* Prednisone
* Methylprednisolone
* Hydrocortisone
44
Corticosteroids
* Corticosteroids have potentially important adverse side effects.
* Aerosol delivery of the steroid has significantly improved the safety of treatment for moderate to severe asthma.
* Asthmatics who require inhaled b-adrenergic agonist therapy 3 - 4 or more times weekly are candidates for inhaled steroid therapy.
45
Corticosteroids
Preparations
* Available preparations have equivalent efficacy and potential side effects, but differ in the amount of drug aerosolized per inhaler activation, i.e., high-dose and low-dose.
* Therefore, the dose of inhaled steroid must be empirically determined for each patient.
46
Corticosteroids
for Asthmatics
* Asthmatic patients maintained on inhaled corticosteroids show improvement of symptoms and lower requirements for “rescue” with a bronchodilator.
47
Corticosteroids
Systemic Therapy
* **Systemic Therapy**
* Systemic (i.v. or oral) steroid therapy is used in severe asthmatic attacks requiring hospitalization.
* For severe asthma, **_prednisone_** or **_methylprednisolone_** is given i.v., followed by oral doses and gradual tapering of the dose.
* For acute, sever exacerbations, oral prednisone is administered for 1 -2 weeks.
* Longer treatments require tapering of the dose to account for hypothalamic-pituitary-adrenal suppression.
48
Corticosteroids:
Potential Side Effects
* HPA suppression - low risks until high doses
* Bone resorption - modest risks
* Carbohydrate and lipid - minor risks
* Cataracts and skin thinning - dose-related
* Purpura - dose-related
* Dysphonia - usually resolves
* Candidiasis - use spacer device and rinse mouth
* Growth retardation - of concern in children
49
Combination Products
* Fluticasone propionate + Salmeterol (Advair Diskus, Advair HFA)
* Budesonide + Formoterol
* (Symbicort HFA)
* Mometasone + Formoterol (Dulera)
* **_Not useful for acute bronchospastic attack_**
* Cost Range: ~$145-$175/month
50
Chronic Obstructive Pulmonary Disease (COPD)
* Emphysema and chronic bronchitis
* Smoking cessation
* Alveolar destruction is the main pathophysiological component (irreversible component)
* Some patients have inflammation and bronchospasm (reversible components)
* Drug therapy is applicable to the reversible component of COPD
51
52
Chronic Obstructive Pulmonary Disease (COPD)
Inhaled ipratropium bromide or tiotropium
* Inhaled ipratropium bromide or tiotropium
* especially useful in patients with a vagally-mediated psychogenic component.
* Inhaled beta 2-adrenergic agonists
* As with asthma, continuous (overuse) of bronchodilators may be associated with worsening of symptoms.
* A subgroup of COPD patients may benefit from corticosteroid therapy, but generally mixed results of steroids in COPD.
53
Cromolyn Compounds
* **Cromolyn sodium (Intal)**
* Cromolyn sodium is an **_anti-inflammatory_** agent that indirectly inhibits antigen-induced bronchospasm and directly inhibits the release of histamine and other autocoids from sensitized mast cells.
* May suppress the activating effects of chemoattractant peptides on eosinophils, neutrophils, and monocytes.
54
Cromolyn Compounds:
Therapeutic Use
* Cromolyn compounds d**_o not directly relax smooth muscle_**, therefore they are not useful for control of acute bronchospasm.
* Cromolyn compounds are primarily **_prophylactic_**. When inhaled several times daily, they inhibit both the immediate and late asthmatic responses to antigenic challenge or exercise.
55
Corticosteroids vs. Bradykinin/Angiotensin
56
Leukotriene inhibitors
* Zafirlukast
* LTD4 receptor antagonist
* **_Montelukast_**
* LTD4 receptor antagonist
* Alternative or adjunctive therapy to low-dose corticosteroids for mild persistent asthma.
* Useful as **_oral prophylaxis_** in exercise-induced asthma
