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

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

Pharmacology of Currently available Anti-Asthmatic Medications

Drugs affecting ANS

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

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

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

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

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

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

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

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

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)

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

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

Pharmacology of potential Anti-Asthmatic Medications

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, 90-95 % of patients are controlled well

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

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-159797, GSK-597901, GSK-159802, GSK-642444 and GSK-678007 (Phase II trials) Produces clinically significant increases in FEV1 Greater therapeutic index

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)

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

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

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

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

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

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.

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

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

Ensure of the proper inhaler technique or Spacer

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