1. Drugs used in asthma By S.Bohlooli, PhD

2. Asthma therapy Short term relievers Bronchodilators Long term controllers Anti-inflammatory agent Leukorienes antagonist

3. Pathogenesis of asthma

4. Pharmacologic significance of lung innervation Reach in Vagal innervation Post-synaptic M3 receptors Pre-synaptic M2 receptors Spare noradrenergic innervation Role of Peptidergic neurons?

5. Basic pharmacology Sympathomimetic agents Methylxanthine drugs Antimuscarinic drugs Corticosteroids Cromolyn & Nedocromil Leukotriene pathway inhibitors Anti-IgE monoclonal antibodies Calcium channel blockers Nitric oxide donors Possible future therapies

6. Sympathomimetic agents Relaxation of airway smooth muscle Inhibition of release of bronchoconstricting substances from mast cells Increasing mucociliary transport Inhibition of microvascular leakage

7. Some sympathomimetic agents Albuterol Terbutaline Metaproterenol Pirbuterol Salmeterol Formoterol

8. the disposition of inhaled drugs

9. Methylxanthine drugs: chemistry

10. Methylxanthine drugs: mechanism of action Inhibition of several family of phophodiesterases Increased intracellular level of cAMP and cGMP Bronchodilation Decreased release of mediators from mast cells Inhibition of adenosine receptors

11. Methylxanthine drugs: Organ effects CNS: alertness, deferral of fatigue, nervousness, insomnia, convulsions Cardiovascular: cardiac stimulation Gastrointestinal tract: secretion of acid and enzymes increases Kidney: weak diuretic Smooth muscle: Skeletal muscle: improving contractility

12. Methylxanthine drugs: clinical use Theophylline Slightly soluble in water Narrow therapeutic window Effects related to plasma concentration

13. Antimuscarinic agents Degree of parasympathetic involvement varies in subjects Ipratropium bromide Tiotropium

14. Corticosteroids Effective on all indices of asthma Lipid soluble corticosteroids: Beclomethasone, butenoside, flunisolide, fluticasone, triamcinolone

15. Potential Adverse Effects Associated with Inhaled Glucocorticoid ADVERSE EFFECTRISK Hypothalamic- pituitary-adrenal axis suppression No significant risk until dosages of budesonide or beclomethasone increased to >1500 ug/day in adults or >400 ug/day in children Bone resorptionModest but significant effects at doses possibly as low as 500 ug/day Carbohydrate and lipid metabolism Minor, clinically insignificant changes occur with dosages of beclomethasone >1000 ug/day CataractsAnecdotal reports, risk unproven Skin thinningDosage-related effect with beclomethasone dipropionate over a range of 400 to 2000 ug/day PurpuraDosage-related increase in occurrence with beclomethasone over a range of 400 to 2000 ug/day DysphoniaUsually of little consequence CandidiasisIncidence <5%, reduced by use of spacer device Growth retardationDifficult to separate effect of disease from effect of treatment, but no discernible effects on growth when all studies are considered SOURCE: Modified from Pavord and Knox (1993) and Barnes (1995).

16. Cromolyn & nedocromil

17. Effective only when taken prophylactically Extremely insoluble salts Alteration in function of delayed chloride channel On nerve: cough On mast cells: inhibition of antigen challenge On eosinophils: inhibition of inflammatory response to inhaled allergens

18. Cromolyn & nedocromil: clinical use Effectiveness should test on 4 weeks trial Blocks bronchoconstriction: Antigen inhalation Exercise Aspirin Occupational asthma Allergic rhinoconjunctivitis Because of lack of serious toxicity have widespread use in children

19. Leukotriene pathway inhibitors

20. Anti-IgE monoclonal antibodies

21. Other possible treatment Calcium channel blockers Nitric oxide donors Antimicrobial therapy of chronic airway infection with chlamydia & mycoplasma pneumeniae