L4 asthma treatment

Question 1

Asthma therapies

Answer 1

• b2-Adrenoceptor agonists
• Glucocorticoids
• Leukotriene receptor antagonists
• Muscarinic receptor antagonists
• Antibody to IgE
• Antibody to interleukin-5

Question 2

Asthma Therapies intermediate

Answer 2

Allergen or stimulus, mast cells, histamine and PGD2 and chemokines, bronchospasm

Reversed by beta-2 adreno agonist

Question 3

Asthma therapies late phase

Answer 3

Chemokines, cytokines relase Th2, mediators like neuropeptides, bronchospasm.

Question 4

b2-Adrenoceptor Agonists

Answer 4

• Fast acting and effective relievers
• Relax airway smooth muscle
• Reverse bronchoconstriction due to range of excitatory mediators
  – histamine, leukotrienes etc.
• Inhibit mediator release from mast cells
• Stimulate cilia beat frequency – increase clearance of mucus

Question 5

Short acting b2 agonists

Answer 5

– salbutamol (VentolinTM, AsmolTM)
– duration of action ~6 hours

Question 6

• Long acting b2 agonists

Answer 6

– formoterol
– duration of action ~12 hours

Question 7

b2-Adrenoceptor Agonists taken and problem

Answer 7

• Usually administered via inhalation
  – targets the airways optimally
  – fewer cardiac, skeletal side-effects
• Major problem: can mask inflammatory activity
  – bronchodilation without reversal of inflammation

Question 8

Glucocorticoids
* Frontline therapy for asthma

Answer 8

• Anti-inflammatory actions
  – ideal for the long-term treatment of asthma
• Usedprophylactically
  – prevent, reduce, reverse airway inflammation
• Used in combination with b2 agonists * Administered via inhalation
  – fluticasone
• Administered orally – prednisolone

Question 9

Glucocorticoids inhaled

Answer 9

fluticasone

Question 10

Glucocorticoids oral

Answer 10

prednisolone

Question 11

Release and Metabolism of Arachidonic Acid

Answer 11

Membrane phospholipids > phospholipase 2 >arachidonic acid»Lipoxygenase and cycloxygenase (respectively) > leukotriens and [prostaglandins and thromboxanes]

(-) Glucocorticoids

Question 12

Glucocorticoids: MechanismofAction

Answer 12

• Stimulate lipocortin synthesis
  – inhibits phospholipase A2 activity
  – prevents release of arachidonic acid
  –↓ synthesis of leukotrienes and prostaglandins
• Inhibit cyclooxygenase activity
  –↓ prostaglandin synthesis
• ↓ influx of inflammatory cells
• ↓ mediator release from eosinophils
• ↑ number of b2-adrenoceptors
• ↓ microvascular permeability

Question 13

Glucocorticoids: Adverse Effects

Answer 13

**Inhaled preparations
**– oropharyngeal candidiasis (thrush)
– use of spacer device reduces incidence of thrush
** Oral preparations
**
– suppression of hypothalamic-pituitary-adrenal axis
* adrenal insufficiency
* ↓ capacity to synthesise corticosteroids
– osteoporosis
* bone maintenance involves endogenous steroids

Question 14

Glucocorticoids: Pro-drug

Answer 14

• Pro-drug activated in the lung
  – fewer adverse effects in non-lung tissue
• Ciclesonide
  – converted to the active metabolite M1 (21-des- isobutyryl-ciclesonide) in the lung
  – glucocorticoid receptor agonist
• receptor affinity ~100 times < M1, fluticasone
  – systemic bioavailability via inhalation ~50%
• reflects amount of drug reaching the lungs
  – oral systemic bioavailability <1%

Question 15

Glucocorticoids: Steroidal Anti-Inflammatory Drugs

Answer 15

fluticasone
ciclesonide

Question 16

Combination Therapy: Anti-Inflammatory and Bronchodilator

Answer 16

Glucocorticoid (fluticasone) + Long Acting b2-Agonist (formoterol)

Question 17

Leukotriene Receptor Antagonists

Answer 17

• Anti-inflammatory and block leukotriene-induced bronchoconstriction
  – montelukast
• Administered orally
  – useful in elderly and young children
• inhalers and spacer devices difficult
• avoid/reduce glucocorticoid use in children
• Provide significant symptom relief and/or steroid-sparing effect in some asthmatics
  – block leukotriene-induced bronchoconstriction – block eosinophil trafficking (LTB4)
  – reduce glucocorticoid dose in adults

Question 18

Muscarinic Antagonists

Answer 18

• Ipratropium
  – block acetylcholine-induced bronchoconstriction in some asthmatics
  – block acetylcholine-induced secretion of mucus
  – no anti-inflammatory actions
• Administered via inhalation
• Not as widely used as – b2 agonists
  – glucocorticoids

Question 19

Muscarinic Antagonist drug

Answer 19

ipratropium

Question 20

Antibody to IgE drug

Answer 20

Omalizumab

Question 21

Antibody to IgE

Answer 21

• Omalizumab
  Antibody to IgE
• Antibody binds to immunoglobulin E (IgE)
  –↓ amount of circulating free IgE
  – ↓ magnitude of clinical response when patients with known specific allergies are exposed to these allergens
• Administered by subcutaneous injection

Question 22

Antibody to IgE use in people

Answer 22

• Licensed for use in adults and adolescents (6 years and older) with moderate to severe persistent asthma
• Omalizumab may be used in allergic asthmatics
  – perennial aeroallergen
  – inadequate control with inhaled/oral glucocorticoids – moderate to severe disease
  –↓ glucocorticoid required to control asthma
  – ↓ incidence of asthma exacerbations
  – ↓hospitalisations

Question 24

Antibody to Interleukin-5

Answer 24

• Eosinophilic asthma
  – increased infiltration of eosinophils into the airway – eosinophils present in the sputum
• Interleukin-5 receptors are present on eosinophils – growth, differentiation, recruitment, activation and survival – airway inflammation

* Antibody to interleukin-5 (reslizumab)

Question 25

• Antibody to interleukin-5 (reslizumab)

Answer 25

– antibody that binds to interleukin-5
– prevents interleukin-5 binding to receptor
– reduces eosinophil recruitment and survival
– reduces eosinophil numbers and mediator release

Question 26

Reslizumab used when, patients and adminitered by

Answer 26

– uncontrolled eosinophilic asthma even with glucocorticoids
– reduces the frequency and severity of asthma exacerbations
* In patients 18 years or older
– lack of established safety and efficacy data in adolescents
* Administered by intravenous injection

Question 27

The What is an important source of PGE2

Answer 27

bronchial epithelium

Question 28

what is a selective inhibitor of phosphodiesterase (PDE) type IV

Answer 28

Roflumilast

Question 29

Salbutamol can induce rapid reversal of

Answer 29

bronchoconstriction