Drugs used in asthma & COPD By Dr. Mahmoud A. Naga

Bronchial Asthma Asthma is an chronic inflammatory disease of the airways with hyper-reactivity characterized by episodes of acute bronchoconstriction causing shortness of breath, cough, chest tightness, wheezing, and rapid respiration. * Types & causes → 1- Antigenic (Extrinsic) asthma → 2. Non-antigenic (Intrinsic) asthma → 1- Exercise-induced asthma. 2. Emotional factors 3- Infections 4- Irritants AS dust 5- Drugs → Parasympathomimetics, non selective β.β & may selective β.β (by large dose), Histamine releasers, PGF2α, Aspirin & NSAIDs → ↑leukotriens & ACEIs → ↑ kinins

* Pathogenesis & pathology 1- First Exposure → antigenic or non-antigenic stimuli stimulates inflammatory cells → air way obstruction by 1- Bronchospasm in s.m.f. of bronchi 2- Congestion and edema of mucosa. 3- Infiltration mucosa by inflammatory cells. 4- Increased mucus secretion that is difficult to expel. 2- Recurrent exposure → chronic inflammation → hyper- reactive airway with exaggerated response to usual stimuli & mediators

Treatment 1- Prevention of exposure to precipitating factors (causes) 2- ttt of bronchospasm → Bronchodilators 3- ↓ mucosal inflammation & hyper-reactivity→ anti-inflammatory drugs 4- Prevent recurrence (Prophylactic ttt) → Mast cell stabilizers * enough alone in mild asthma * In moderate & severe asthma may need prophylactic bronchodilators & steroids

A. Bronchodilators 1.Selective Beta 2 agonist Short acting: Salbutamol = Albuterol, terbutaline, (duration of action less than 6hrs ) Given by inhalation in acute B.A. Long acting: salmetrol, formoterol (duration of action more than 12hrs) Given oral in chronic B.A.

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 – Short act in acute & The long acting are used as prophylaxis in chronic BA and not used in acute as onset of action is too slow. COPD second line as affect heart (tachycardia)

Adverse effects usual dose (beta 2 effect) Tremors, hypotension (with reflex tachycardia) At high dose stimulate beta 1 and cause tachycardia Tolerance and tachyphylaxis develop with excessive use of the inhaler (by receptor down regulation) Patients with COPD usually have concurrent heart disease, arrhythmia may develop even with normal doses

2. Muscarinic antagonists Ipratropium, short act given by inhalation (aerosol), & also oral Tiotropium longer acting, given oral or inhalation Mechanism of action: competitively block muscarinic receptors (M3) in the airways and effectively prevent the braonchoconstriction caused by vagal discharge. It has no effect on the inflammatory aspect of asthma

Use 1.B.A.: it is 2 nd choice after B2 agonist & better to be combined with B2 agonist 2. COPD: it is 1 st choice as no cardiac S.E. Adverse effects: therapeutic dose Minimal because the drug is directly delivered to the airway Overdose causes antimuscarinic side effects (atropine like) They don’t cause tremor and tachycardia

3. Methylxanthines Three major methylxanthines are found in the plants, caffeine (coffee) theophylline (tea) & theobromine (cocoa = Cacao). Theophylline is the only one used in B.A. given orally (chronic) and injection (slow I.V. in acute) Eliminated by CYP 450 in the liver Clearance varies with age (highest in young adolescent & lower in old, neonate), smoking status (higher in smokers), and drugs that induce liver enzymes (increase clearance) or inhibit liver enzymes (decrease clearance) Narrow therapeutic window

Mechanism of action Inhibit phosphodiestrase, the enzyme that degrades cAMP leading to incraese cAMP & bronchodilation They also block the adenosine receptors in the CNS Effects: CNS stimulation Bronchodilator Cardiac stimulation (increase contractility & HR) Slight increase in blood pressure by increase C. OP peripheral Vasodilation (increase renal bl. Flow, diuresis) GIT: may Increase GIT motility & HCL by irritative effect & may cause relaxation by cAMP (as beta2 effect)

Clinical uses 1. B.A. : last choice due to dangerous cardiac S.E. Aminophylline is a salt of theophylline used in B.A. 2. COPD: also last choice due to dangerous cardiac S.E. 3. Cardiac asthma (as increase C. op) 4. Pentoxifylline is Dimethylxanthine for intermittent claudication (leg ischemia, ttt it by V.D.) Adverse effects CNS: tremor, insomnia, seizure CVS: cardiac arrhythmia GIT: GIT disturbance (diarhhea or constipation), N/V & increase HCL

B. Mast cell stabilizers: 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)

Clinical uses Local acting drugs inhalation not bronchiodiltors but they prevent B.A. caused by reaction to an antigen which the patient is allergic to it 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 & may reach bronchospasm (prevent by B2 agonist) Rarely allergy reaction to the drug

C. Anti-inflammatory drugs 1. Corticosteroids Inhaled steroids ( beclomethasone, budesonide, fluticasone ) are 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 ( Hydrocortisone and prednsilone ) are used for status asthmaticus and their mechanism of action in this condition is not fully understood

Mechanism of action & effects Inhibit phospholipase A2 leading to decrease arachdonic acid, PGs & Leucotriens which are mediators of bronchospasm & inflammatory response It is also suggested that steroids increase the responsiveness of beta receptors in the airways Glucocorticoids binds to glucocorticoids response elements in the nucleus resulting in the synthesis of substances that prevent the full expression of inflammation and allergy

Toxicity Inhaled Changes in oropharyngeal flora can result in oral candidiasis systemic toxicity of steroids include? 1. Small degree of adrenal suppression & if stopped suddenly will cause addesonian crisis 2. Cushing with long use 3. Regular use of steroids in children can result in growth retardation but these children eventually reach full predicted adult nature

Leukotriene synthesis inhibitors Leukotriene receptor inhibitors e.g. → Zileuton e.g. → Zafirlukast → twice /d Montelukast → once /d due to longer t 1/2 inhibit 5- Lipoxygenase enzyme * inhibit Leukotriene receptors * used in ttt of B.A. orally active and have been shown to be effective in preventing exercise induced asthma, antigen- and aspirin induced asthma Toxicity: elevation of liver enzymes Toxicity is generally low Rarely Churg-Strauss syndrome have been reported 2. Leukotriene antagonist

3. Anti Ig E antibody = Omalizumab Omalizumab is monoclonal antibody to human IgE It binds to IgE & prevent it from binding to its receptor on sensitized mast cells and prevent activation by antigens and subsequent release of inflammatory mediators Approved for prophylactic management of asthma very expensive and must be given parentally