Martin Asthma Lecture

Question 1

beta agonist Bronchodilators

Answer 1

Short-acting b agonists (SABA)
Albuterol, others

Long-acting b agonists (LABA)
Salmeterol, formoterol

Emergency, non-selective b agonist
Epinephrine

Question 2

Muscarinic Antagonists

Answer 2

Ipratropium, tiotropium

Question 3

Methylxanthine

Answer 3

Theophylline

Question 4

Inhaled Corticosteroids (ICS)

Answer 4

Beclomethasone
Budesonide
Ciclesonide
Flunisolide
Fluticasone
Mometasone
Triamcinolone

Question 5

Oral Corticosteroids

Answer 5

Methylprednisolone

Prednisone

Question 6

Leukotriene Receptor Antagonist (LTRA)

Answer 6

Montelukast

Zafirlukast

Question 7

Cromolyn compounds

Answer 7

Cromolyn sodium

Question 8

Anti-IgE Antibody

Answer 8

Omalizumab

Question 9

Bronchospasm

Answer 9

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.

Question 10

Inflammatory Mediators in Asthma

Answer 10

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.

Question 11

Mast Cell Mediators of Inflammatory Processes

Answer 11

Preformed (immediate): Histamine, TNF-alpha, Proteases, Heparin –> Bronchoconstriction,
itch, cough, vasodilation, edema

Lipids (minutes): leukotrienes, prostaglandins –> bronchoconstriction, chemotaxis, mucus secretioin

cytokines (hours): interleukins, GM-CSF –> bronchoconstriction, chemotaxis, inflammatory cell proliferation

Question 12

Aerosol Delivery of Drugs

Answer 12

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.

Question 13

Aerosol Delivery of Drugs

Answer 13

Metered Dose Inhalers (MDI)
with spacer device

Nebulizers

Dry powder inhalers

Question 14

classification of pts who are not taking long-term control meds

Answer 14

intermittent FEV1 > 80%

mild FEV1 > 80% and minor limitation to normal activity

moderate FEV1 60-80

severe FEV1 less than 60

Question 15

Stepwise treatment kids 5-11

Answer 15

Step 1: SABA PRN

Step 2: low dows ICS (alternative: cromolyn, LTRA, nedacromil, oro theophylinie)

Step 3: lowdose ICS + either LABA, LTRA, or theophylline OR medium dose ICS

Step 4: medium dose ICS + LABA. Alternative: ;med dose ICS + either LTRA or theophyline

Step 5: High-dose ICS + LABA . alternative: High-dose ICS + either LTRA or theophyline

Step 6: high dose ICS + LABA + oral systemic corticosteroid. alternative: high-dose ICS + either LTRA or theophylline + oral systemic corticosteroid

Question 16

beta Adrenergic Agonists use in asthma and COPD

Answer 16

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.

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.

Question 17

beta adrenergic agonists MOA

Answer 17

Stimulate 2-adrenergic receptor on surface of bronchiolar smooth muscle cells.
beta 2-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.

Question 18

Selectivity of beta-Adrenergic Agonists

Answer 18

Selectivity means these agonists have higher affinity, and thus, higher potency at beta 2-adrenergic receptors than at beta 1-adrenergic receptors.
Selectivity helps limit side effects mediated by activation of beta 1-receptors.

Question 19

Rapid Acting-Short Duration beta 2-Adrenergic Agonists

Answer 19

Albuterol onset under 15 min duration: 2-4 hr

levalbuterol, pirbuterol, terbutaline

These agents are used as “rescue inhalers”. They are relatively fast at relieving bronchospasm, but have a relatively short duration of action.

Question 20

Long Acting beta 2-Selective Agonists (LABA)

Answer 20

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

Question 21

Less Selective or Nonselective beta -Adrenergic Agonists

Answer 21

Epinephrine
Isoproterenol
Metaproterenol

Isoetharine
- Because of their very short duration of action and their lack of beta 2-selectivity, these agents are not frequently used.
- Low-strength epinephrine inhalers sometimes prescribed for mild asthma
Racemic Epinephrine
- aerosol used for pediatric patients

Question 22

Long-term Use of LABA

Answer 22

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”.

Question 23

Oral Therapy with beta -Adrenergic Agonists

Answer 23

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

Question 24

Adverse Side Effects of beta-Adrenergic Agonists

Answer 24

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

Question 25

Epinephrine: Emergency Use

Answer 25

Epinephrine is the drug of choice for treatment of * anaphylactic reactions. Give SQ (or IM or IV with dextrose) Bronchodilation (mediated by b2 receptors) Vasoconstriction (mediated by a1 receptors) maintains BP & decreases edema Inhibition of mediator release (b2 receptors)

Question 26

Anaphylaxis Treatments

Answer 26

Albuterol via nebulizer IV fluids Oxygen ``` Secondary therapy - H1 antagonist - diphenhydramine - H2 antagonist - ranitidine - Corticosteroid - hydrocortisone, methylprednisolone - Aminophylline NE, glucagon - for hypotension ```

Question 27

Ipratropium bromide

Answer 27

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

Question 28

Ipratropium bromideand Tiotropium therapeutic use

Answer 28

Bronchodilation develops more slowly and is usually less intense than that produced by beta-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

Question 29

Methylxanthines

Answer 29

Methylxanthine Bronchodilator 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 ```

Question 30

Theophylline

Answer 30

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 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 *

Question 31

Inhaled Corticosteroids

Answer 31

``` Beclomethasone dipropionate (Beclovent) Budesonide dipropionate (Pulmicort) Ciclesonide (Alvesco) Flunisolide (AeroBid) Fluticasone (Flovent) Mometasone (Asmanex Twisthaler) Triamcinolone acetonide (Azmacort) ```

Question 32

Systemic Corticosteroids

Answer 32

IV or oral Prednisone Methylprednisolone Hydrocortisone

Question 33

who should get corticosteroids?

Answer 33

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 beta -adrenergic agonist therapy 3 - 4 or more times weekly are candidates for inhaled steroid therapy. 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. Asthmatic patients maintained on inhaled corticosteroids show improvement of symptoms and lower requirements for “rescue” with a bronchodilator.

Question 34

Corticosteroids Systemic Therapy

Answer 34

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.

Question 35

Corticosteroids:Potential Side Effects

Answer 35

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

Question 36

Combination Products

Answer 36

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

Question 37

Chronic Obstructive Pulmonary Disease (COPD)

Answer 37

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

Question 38

Chronic Obstructive Pulmonary Disease (COPD) treatment choices

Answer 38

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.

Question 39

Cromolyn Compounds

Answer 39

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.

Question 40

Cromolyn Compounds:Therapeutic Use

Answer 40

Cromolyn compounds do 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.

Question 41

Leukotriene inhibitors

Answer 41

Montelukast LTD4 receptor antagonist Alternative or adjunctive therapy to low-dose corticosteroids for mild persistent asthma. Useful as * oral prophylaxis in exercise-induced asthma.

Question 42

corticosteroids in general

Answer 42

``` 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 involved in the inflammatory cascade. ``` 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.