DRUGS USED IN ASTHMA

Asthma is an inflammatory disease of the airways characterized by episodes of acute bronchoconstriction causing shortness of breath, cough, chest tightness, wheezing, and rapid respiration.

1. Selective Beta 2 agonist Short acting: Albuterol, terbutaline, metaproterenol (duration of action less than 6hrs ) Long acting: salmetrol, formoterol (duration of action more than 12hrs) Given by inhalation Mechanism of action Stimulate adenylate cyclase which increases the cAMP resulting in powerful brochodilator response

Clinical uses: Asthma First line therapy in the treatment of asthma, the short acting are used in the acute attacks The long acting are used as prophylaxis and should not be used in acute attacks because their onset of action is too slow. COPD

Adverse effects Tremor At high dose stimulate beta 1 and cause tachycardia Tolerance and tachyphylaxis develop with excessive use of the inhaler Patients with COPD usually have concurrent heart disease, arrhythmia may develop even with normal doses

2. Methylxanthines Purine derivatives Three major methylxanthines are found in the plants, caffeine (in coffee) theophylline (in tea) and theobromine (in cocoa). Theophylline is the only one used in the treatment of asthma Can be given orally and is available as salt and as base Eliminated by CYP 450 in the liver Clearance varies with age (highest in young adolescent), smoking status (higher in smokers), and drugs that induce/inhibit liver enzymes

Mechanism of action Inhibit phosphodiestrase, the enzyme that degrades cAMP They also block the adenosine receptors in the CNS Effects: Bronchodilator CNS stimulation Cardiac stimulation Vasodilation Slight increase in blood pressure Increase in GI motility

Clinical uses Aminophylline is a salt of theophylline used in the treatment of asthma Pentoxifylline is promoted as a remedy for intermittent claudication Adverse effects Common: tremor, insomnia, GI disturbance, N/V, cardiac arrhythmia, seizure

3. Muscarinic antagonists Ipratropium, Tiotropium longer acting Given by aerosal Mechanism of action: They competitively block muscarinic receptors in the airways and effectively prevent the braonchoconstriction caused by vagal discharge. It has no effect on the inflammatory aspect of asthma

Adverse effects: Minimal because the drug is directly delivered to the airway Overdose causes antimuscarinic side effects They don’t cause tremor and tachycardia

4. Cromolyn and Nedocromil They are insoluble drugs, so even massive doses given orally or by aerosol result in minimal side effects Given by aerosol for asthma Cromolyn is the prototype in this group Mechanism of action Decrease the release of mediators from mast cells (leukotrienes and histamine) These drugs are not bronchiodiltors but they prevent bronchioconstriction caused by reaction to an antigen which the patient is allergic to it

Clinical uses Local acting drugs When given orally can prevent some food allergy Nasal and eye drops are available for hay fever and conjunctivitis Adverse effects May cause irritation of airways and cough when given by aerosol Rarely allergy reaction to the drug

5. Corticosteroids Inhaled steroids is used in moderate to severe asthma that are not fully responsive to beta agonist. Early use may prevent the severe, progressive inflammatory changes that are characteristic for asthma. Local administration of steroids by aerosol is relatively safe and inhaled steroids has become the first line management of moderate to severe asthma IV steroids is used for status asthmaticus and their mechanism of action in this condition is not fully understood

beclomethasone, budesonide, fluticasone, (inhaled steroids) Hydrocortisone and prednsilone used in status asthmaticus Mechanism of action Reduce the synthesis of arachidonic acid by phospholipase A2 and inhibit the expression of COX2 It is also suggested that steroids increase the responsiveness of beta receptors in the airways

Effects: Glucocorticoids binds to glucocorticoids response elements in the nucleus resulting in the synthesis of substances that prevent the full expression of inflammation and allergy Reduced activity of phospholipase A2 is thought to be important in asthma because leukotrienes that result from eicosanoids synthesis are extremely potent bronchioconstrictors and also participate in the late inflammatory response

Toxicity Small degree of adrenal suppression Changes in oropharyngeal flora can result in oral candidiasis Other systemic toxicity of steroids include?? Regular use of steroids in children can result in growth retardation but these children eventually reach full predicted adult nature

6. Leukotriene antagonist These drugs interfere with the synthesis or the action of leukotriene A. LEUKOTRIENE RECEPTOR ANTAGONIST Zakirlukast, montellukast are antagonist at LTD4 leukotriene receptor. The LTE 4 receptor is also blocked. These drugs are orally active and have been shown to be effective in preventing exercise induced asthma, antigen- and aspirin induced asthma They are not recommended acute episodes Toxicity is generally low Rarely Churg-Strauss syndrome have been reported

B. ZILEUTON Selectively inhibit 5-lipoxygenase, a key enzyme in the conversion of arachidonic acid to leukotrienes The drug is effective in preventing exercise- induced and antigen-induced and aspirin-induced asthma Toxicity: elevation of liver enzymes

7. Anti Ig E antibody Omalizumab is murine monoclonal antibody to human IgE It binds to IgE on sensitized mast cells and prevent activation by antigens and subsequent release of inflammatory mediators Approved for prophylactic management of asthma It is very expensive and must be administered parentally