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/relexation of bronchial smooth muscle)

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

•(*an acute (sudden) decrease in the response to a drug after its administration.[1])

•Patients with COPD usually have concurrent heart disease, arrhythmia may develop even with normal doses

Tolerance

• when a subject's reaction to a specific drug and concentration of the drug is progressively reduced, requiring an increase in concentration to achieve the desired effect.[

Tachyphylaxis• Tachyphylaxis is a sudden onset

drug tolerance which is not dose dependent. Tachyphylaxis can occur both after an initial dose of medication or after an inoculation with a series of small doses. Increasing the dose of the drug may be able to restore the original response.[2] This can sometimes be caused by depletion or marked reduction of the amount of neurotransmitter responsible for creating the drug's effect, or by the depletion of receptors available to which the drug or neurotransmitter can bind.

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(>, pain and cramping in the lower leg while walking or exercising caused by blocked arteries.)

•Adverse effects•Common: tremor, insomnia, GI disturbance, N/V, cardiac arrythmia, 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 bronchoconstriction 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 bronchodilators but they prevent bronchoconstriction 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(Allergic rhinitis) 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, flunisolide, fluticasone, mometasone (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 bronchoconstrictors 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 in acute episodes • Toxicity is generally low • Rarely Churg-Strauss syndrome (allergic granulamotosis-auto immune diseae)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