L4 asthma treatment Flashcards
Asthma therapies
- b2-Adrenoceptor agonists
- Glucocorticoids
- Leukotriene receptor antagonists
- Muscarinic receptor antagonists
- Antibody to IgE
- Antibody to interleukin-5
Asthma Therapies intermediate
Allergen or stimulus, mast cells, histamine and PGD2 and chemokines, bronchospasm
Reversed by beta-2 adreno agonist
Asthma therapies late phase
Chemokines, cytokines relase Th2, mediators like neuropeptides, bronchospasm.
b2-Adrenoceptor Agonists
- 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
Short acting b2 agonists
– salbutamol (VentolinTM, AsmolTM)
– duration of action ~6 hours
- Long acting b2 agonists
– formoterol
– duration of action ~12 hours
b2-Adrenoceptor Agonists taken and problem
- Usually administered via inhalation
– targets the airways optimally
– fewer cardiac, skeletal side-effects - Major problem: can mask inflammatory activity
– bronchodilation without reversal of inflammation
Glucocorticoids
* Frontline therapy for asthma
- 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
Glucocorticoids inhaled
fluticasone
Glucocorticoids oral
prednisolone
Release and Metabolism of Arachidonic Acid
Membrane phospholipids > phospholipase 2 >arachidonic acid»Lipoxygenase and cycloxygenase (respectively) > leukotriens and [prostaglandins and thromboxanes]
(-) Glucocorticoids
Glucocorticoids: MechanismofAction
- 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
Glucocorticoids: Adverse Effects
**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
Glucocorticoids: Pro-drug
- 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%
Glucocorticoids: Steroidal Anti-Inflammatory Drugs
fluticasone
ciclesonide
Combination Therapy: Anti-Inflammatory and Bronchodilator
Glucocorticoid (fluticasone) + Long Acting b2-Agonist (formoterol)
Leukotriene Receptor Antagonists
- 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
Muscarinic Antagonists
-
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
Muscarinic Antagonist drug
ipratropium
Antibody to IgE drug
Omalizumab
Antibody to IgE
- 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
Antibody to IgE use in people
- 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
Antibody to Interleukin-5
- 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)
