1. Pharmacology of Anti- Asthmatic Medications
Dr. S. Mahmood alqallaf
Head, Pharmacuy Program
CHS

2. Current Medications Drugs affecting ANS: -Beta-2 Agonists
-Antimuscarinic
Corticosteroids
Methylxanthines e.g. Theophylline
Cromlyns e.g. Sodium Cromoglycate
Leukotriene antagonists
Anti-Ig E agents

3. Pharmacology of Currently available Anti-Asthmatic Medications

4. Drugs affecting ANS

5. Sympathetic ANS Parasympathetic ANS
Stimulation: Bronchoconstriction & increased mucous secretion
Stimulation:
Bronchodilation

6. Beta-2 Agonists
Short-acting Salbutamol (Albuterol)
Long-acting: Salmeterol, Formoterol
Acting by stimulation of beta-2 adrenoceptors in the airways smooth muscles causing their relaxation and producing bronchodilation
Have also been shown to have anti-inflammatory properties

7. Short-acting: Salbutamol (Albuterol)
Used to treat acute asthma attacks, because of its rapid onset of action and ability to relieve symptoms
Used on an as-needed basis because continuous administration is thought to reduce effectiveness
May also be used before exercise to prevent symptoms of exertion-induced bronchoconstriction

8. Long-acting: Salmeterol, Formoterol
Have slow onset of action and prolonged duration of action
Prescribed to provide partial, steady-state bronchodilation
Some studies have indicated that partial tolerance develops in children

9. Antimuscarinics e.g. Ipratropium bromide
Block the effects of acetylcholine, that promotes bronchoconstriction & mucus secretion.
This action is via the M1 and M3 muscarinic receptors located in the smooth muscle and submucosal glands in the airways

11. Corticosteroids Beclomethasone Budesonide Fluticasone
The most effective maintenance treatment for asthma and represent the standard of Care
Inhalation is the preferred and most common route of administration
Systemic corticosteroids are sometimes required

12. MOA Suppressing Proinflammatory genes
Activating Anti-inflammatory genes
Inhibiting T-cell activation (and subsequent cytokine release)
Promoting apoptosis of inflammatory cells

13. When administered continuously as prophylactic therapy, they improve lung function and reduce the frequency and severity of asthma exacerbations
Studies showed 80% reduction in hospitalization
Corticosteroids resistance (no clinical improvement after treatment with high-dose oral glucocorticoid, prednisolone 40 mg daily for 2 weeks)
Alternative drugs to be used, but they have major side-effects

14. Anti-Leukotrienes e.g. Montelukast, Zafirlukast, Zileuton
Leukotrienes (LTs) are lipid mediators released from most of the inflammatory cells present in the airways
LTs directly mediate bronchoconstriction and have proinflammatory effects
The anti-leukotrienes appear to lack the adverse effects associated with long-term corticosteroid therapy (effect on growth & bone mineralization)

15. Leukotriene Receptor Type 1
MOA
Arachidonic Acid
LT A4
LT B4 C4 D4 E4
Leukotriene Receptor Type 1
Phospholipase A2
5-lipoxygenase
Receptor antagonists (Lukast drugs)
Inhibitors of 5-lipoxygenase (Zileuton)
Bronchoconstriction, Edema, Inflammation, Inflammatory cells infiltration

17. Anti-Ig E agents e.g. Omalizumab
Human monoclonal antibody that binds to the IgE
on mast cells and basophils
Causes desensitization of these cells to allergens
inhibiting the release of inflammatory mediators
Indicated for severe persistent asthma not
controlled on high-dose ICS/LABA therapy

18. Pharmacology of potential Anti-Asthmatic Medications

19. Do we need new anti-asthmatic mediations?
None of the treatments for asthma change the natural history of the disease or are curative (symptoms return soon after treatment is stopped)
However, % of patients are controlled well

20. Medications under Research
Inhaled corticosteroids
Long acting beta-2 agonists
ICS/LABA combination therapy
Phosphodiesterase 4 inhibitors
Anticytokine agents
Long acting Anticholinergics
M3 antagonist-b2 agonist (MABA) bronchodilators
Cell adhesion inhibitors
Biological agents

21. Long-acting beta-2 agonists
Carmoterol, Indacaterol (Phase III trial)
Fast onset & long duration of action (24-30 hrs) allowing once daily dosing
Others: GSK , GSK , GSK , GSK and GSK (Phase II trials)
Produces clinically significant increases in FEV1
Greater therapeutic index

22. long-acting antimuscarinic agents
Aclidinium (Phase III trial)
Potent anticholinergic activity comparable to both tiotropium and ipratropium
Faster onset of action & significantly longer duration of action (24 hours)
LAS-35201, GSK656398, GSK233705, NVA-237 (Phase I or II trials)

23. M3 antagonist-b2 agonist (MABA) bronchodilators
Formoterol + tiotropium
+ tiotropium
Salmeterol
Carmoterol + tiotropium
The combination of a LABAa with tiotropium is superior to either single agent alone

24. ICS/LABA combination therapy
Carmoterol + budesonide
Twofold more effective than the formoterol/
budesonide combination
Indacaterol+ mometasone
Superior delivery profile than formoterol/
budesonide owing to its once-daily dosing

25. Phosphodiesterase 4 inhibitors
e.g. Cilomilast and Roflumilast
PDE4 is expressed in macrophages, neutrophils, T cells and airway smooth muscle cells
PDE4 inhibition elevates cellular levels of cAMP, which in turn suppresses the inflammatory response and causes bronchodilation
Controlled clinical trials suggested some efficacy in mild to moderate asthma and to prevent exercise-induced asthma in adults

26. Anticytokine agents Daclizumab: IL-2 antagonist
Currently marketed for the prevention of kidney transplant rejection
Acts by inhibiting IL-2-dependent activation of T cells
In development for several other indications, including the treatment of persistent asthma
Mepolizumab: IL-5 antagonist
IL-5 is essential for the maturation of eosinophils and their release from the bone marrow
It is well documented that IL-5 is highly expressed in the bronchial mucosa of asthmatics

27. Cell adhesion inhibitors
R-411, IVL-745 (Phases I or II trials)
Reducing the infiltration of cells into asthmatic airways by blocking cell adhesion pathways is a novel approach to asthma therapy.
Acts by blocking Integrin receptors
This receptor promote cell adhesion and communication, leading to increases in migration, activation, and survival of inflammatory cells

28. Biological agents
Etanercept was significantly more effective than placebo in improving pulmonary function, asthma symptoms, and quality of life
Infliximab treatment resulted in significantly greater improvements in the PEF and reduced rates of exacerbations compared with placebo
These are preliminary findings & suggest that larger trials are needed to confirm the efficacy of therapies directed against TNF-α.

30. Pharmacogenomics
Several genes have been identified that predict susceptibility to asthma
These genes may operate by causing elevated IgE, airway hyper-responsiveness or atopy
Other genes have been identified that may predict response to β2-agonists, ICS and anti- leukotrienes
The use of pharmacogenomics to predict which patients might respond best to a particular medication is the goal of current research

31. Vaccination
There is now interest in vaccination approaches that divert the immune system in asthmatic patients back to normal

32. Ensure of the proper inhaler technique
or Spacer

33. Conclusion Currently available medications achieve 90-95 % control
ICS + beta-2 agonists are the cornerstone in the treatment
Many new promising compounds are under different phases of research which might help in a better control of the disease
Proper inhaler technique should be demonstrated to every patient & assessed frequently