Drug therapy of bronchial asthma By Dr Attia Jabr, 2009 What is asthma? Physiology (Symp., parasymp., CAMP, sensory nerves) Predisposing factors Drugs & asthma Pathogenesis (bronchoconstriction + chronic inflammation + hyperreactivity) Many cytokines + chemokines Immediate phase & late phase Types of asthma Pattern of asthma Goals of treatment of asthma General lines of treatment of asthma

Pharmacological therapy of BA Bronchodilators B2 agonists (▲C.AMP) Methylxanthines (▲CAMP #Adenosine) Anticholinergic (# M3) Anti-inflammatory Corticosteroids Mast cell stabilizers: Na cromoglycate Antileukotriens: Zeuloton, zafirlukast, montelukast PAF antagonist: Ketotifen 3. Anti IgE Antibody: Omalizumab

B2-agonists Types: B2 phenotypes Mechanism of action: Short acting: Salbutamol (acute attack)/4-6h Long acting: Salmeterol (Used for prophylaxis)/12h Administration: Inhalation: (MDI, Nebulizer); Is the best. Why? Oral: children < 5 years-prophylaxis Parenteral: rarely used e.g. in SA Compare between oral and inhalation B2 agonists? Dose-systemic effect-distribution in lung-Compliance-ease of administration-effectiveness Mechanism of action: ↑B2- receptors → ↑AC → ↑CAMP → ↓ Ca→ relax airway smooth muscle → Bronchodilatation (physiological antagonist) ▼Mediators release from mast cells & others ▲Muco-ciliary clearance & ▼Microvascular leakage in the airway

Side effects of B2 agonists: (Systemic + large dose inhalation only) Why side effects are more in poorly controlled asthma? Inhalation safe in pregnancy Tremors Why? Tachycardia & arrhythmias? Why? Throbbing headache Tolerance Why? Nervousness? Why? Hyperglycemia. Why? (with IV) Hypokalemia? Why? (With IV) Weakness? Why? Hypoxemia: ▼PaO2 tension if lung ventilation/perfusion ratio worsens Constipation (with oral treatment) 11. Death????

Dosages of B2-agonists: A. Short acting: Salbutamol (4444) for acute attacks Onset: 4 min by inhalation Duration: 4 hours Oral : 4mg/4h (children < 5 years, severe asthma) IM & SC: 0.4mg/4h IV: 4 micrg/kg (life threatening cases) (5-10 micr/min MDI: 1-2 puffs (100micr) up to 4-8 puffs/20 min for 1 h then/1-4 h Nebulizer: 2.5-5 (4) mg/20 min for 1 h then /4h B. Long acting; Used as a prophylaxis of nocturnal and exercise induced asthma. Can you use salmeterol alone in prophylaxis of asthma? Why? Dose 50 ug/12 h by inhalation only

Drugs: Ipratropium & tiotropium Anticholinergic drugs (Ipratropium) Generally are less effective than B2-agonists. Why? Useful in patients who are unable to tolerate B2 e.g. Thyrotoxic patients, cardiac patients Drugs: Ipratropium & tiotropium Mechanism : competitiely block muscarinic receptors (M1, M2, M3). Which one is important? Quaternary amines: given by inhalation only Kinetics: Delayed onset of action (20-90 min) duration 4h, tiotropium 24 h. Why? Could be combined with B2 agonists in severe asthma

Indications of anticholinergic drugs: Acute, status, prophylaxis (added to B2 agonists in severe asthma) Old age + COPD. Why? Increased parasympathetic tone (Psychogenic) Why some patients respond good while others not? Why increasing the doses above therapeutic is not more effective? Disadvantages & side effects: Rare Local: Dry mouth, Cough Systemic: Atropine; Nausea, constipation urinary retention, glaucoma Kinetics: Delayed onset (30-60 min) MDI: 4-8 puffs (20 ug /Puff ) as needed Nebulizer: 0.5 mg /30 min for 3 doses, then/ 2-4 h as needed Tiotropium: 18 ug /24H (prophylaxis in COPD)

Methylxanthines Mechanism of action: Theophylline, caffeine, theobromine Mechanism of action: Inhibits phosphodiesterase enzyme (PDE 3,4,5) → increase ▲cAMP ►Broncho-dilatation (compare with B2 agonists) ►Mast cell stabilization→ decrease release of mediators ▲Mucociliary clearance Block adenosine receptors A1, A2B (Not enprophylline) Moderate anti-inflammatory effect: inhibit synthesis and secretion of inflammatory mediators (Mast cells, basophils) Increase release of catecholamines. Improvement of diaphragmatic contractions (▲Ventilation) Inhibiting pulmonary edema by ▼vascular permeability ▲clearance  

Pharmacological Actions: Smooth muscles: Relax smooth muscles (bronchial) CNS: Caffeine (150-250 mg), Stimulant (alertness, ▲intellectual effort, motor activity ) ▲Doses ►irritability, nervousness, tremors, confusion,▼ motor tasks, convulsions) ▲ all, medullary centres, CTZ, VM, VC CVS:. Direct myocardial and direct peripheral dilatation. With large doses the peripheral effects predominate. Except Cerebral BV? Why? Diuretic action: Why? 2 causes GIT: ▲Volume and gastric secretion. SKM: +ve skeletal muscles (▼Fatigue of diaphragm) Others: ▲ BMR, FFA

Pharmacokinetics Absorption: Irritant, Food↓, SR, Rectal (unreliable), Variable & irritant. Distribution: protein bound, Widely distributed Vd (0.4-0.6 L/kg) Metabolism; liver (CYP1A2, 3A4): 80-90% (Importance?) Factors: diseases & drugs, genetic, environmental. Not metabolized to uric acid. (importance?) Excretion: kidney 10% First order kinetics→ Zero order kinetics t1/2: 8h Non-Smokers, 4h, Smokers, 4h Children In premature infants; t1/2 up to 50 h Therapeutic level: (10-20 ug/ml). Narrow TI

Indications of methylxanthines: Bronchial asthma: Why it is delayed to 3-4th line? Acute attack & Status asthmaticus (only in impending respiratory failure) Prophylaxis (nocturnal asthma) Vs salmeterol & ICS Bronchospasm + bronchitis (COPD) Apnea in premature infants (caffeine) Headache & migraine (caffeine)

Adverse effects: Narrow safety margin CNS: Headache, restlessness, agitation, insomnia, nervousness, convulsions> 20 ug/dl (treat?), hyperactivity in some children. Habituation Behavioral toxicity: Anxiety, fear, panic, dysphoria, depression, hyperactivity. CVS: Tachycardia, arrhythmia > 20 ug/dl, hypotension, Rapid IV of therapeutic doses→ syncope and death. GIT: N,V, D, PU (hematemesis), hyperglycemia, hypokalemia Respiratory: Tachypnea, hyperventilation, respiratory arrest.(used in asthma of premature infants) Learning difficulty and increased activity in children. Tolerance

Drug interactions: A. Drugs inhibit liver metabolism: e.g. cimetidine, ciprofloxacin, erythromycin, zafirlukast, heart and hepatic diseases, ketoconazole, COPD, Viral infections, extremes of age B. Metabolism is increased by: Protein diet, Rifampicin, antiepileptics, tobacco smokers (↑50-100%) C. Aminophylline inhibits metabolism of other drugs like Warfarin Contraindications to methylxanthines: Caffeine in hypertensives (large, prolonged doses). Cardiac dysrhythymias and IHD Oral therapy in peptic ulcer History of epilepsy & convulsions

Preparations and doses of theophylline: Dose in acute attack: IV infusion Loading dose = (5 mg /kg/15-30 min) Maintenance dose = 0.2-0.8 mg/kg/h Dose in prophylaxis: Orally Adults: 5-15 mg/kg/day (SR tablets) 300-600 mg/day (increased gradually/3 days) up to 800 mg/day What about the dose in smokers, children, neonates, old age?

II. Anti-inflammatory drugs Cromolyn and nedocromil: (mast cell stabilizers) Inhalation only Prophylaxis only Mechanism of action: unknown (only 1/3 patients respond) Stabilization of mast cells (▼inflammatory mediator release) Inhibition of axon-mediated release of neuropeptides (▼cl channels)(▼cough-bronchospam-hyperreactivity) ▼Inflammtory cells Pharmacokinetics: Inhalation (aerosol-nebulizer-powder) 0.5-1% absorbed excreted in bile & urine

Indications: 1. Prophylaxis of mild to moderate persistent asthma (added or alternative therapy) 2. Allergic type of asthma & exercise-induced asthma Used in: Short term: immediate before (exercise-allergies-Cold air) Long term: (▼bronchial hyper-reactivity) Doses: Cromolyn for all ages- Nedocromil for > 12 years Inhalations: Cromolyn 2mg/6h –Nedocromil 4 mg/6h Preparations: for nose, eye, mouth Side effects: Safe for children and pregnant women Bitter taste, Irritation (Bronchospam-cough-wheezes-pharyngeal). Solve? Rarely: Allergy

Corticosteroids Mechanism of action of corticosteroids in asthma Inhibition of synthesis of inflammatory cytokines & chemokines. How? ▼Phospholipase A2 E, ↓lysosomal Inhibition of production and accumulation of inflammatory cells (esinophils & basophils in lung tissue) Inhibition of release & response to inflammatory mediators (T-cells-macrophages-esinophils)►↓late response Inhibition of ag/ab reaction Inhibition of ab formation Increase No & sensitivity of B2-receptors # down regulation Prolonged administration ▼Hyper-responsiveness of airway smooth muscles

Uses of corticosteroids in asthma: Improvement begins after 6-8 h, substantial after 2-3 days, maximum after 1-2 weeks Must be given continuously (can you stop it?) Acute severe asthma: given orally or IV for one week Chronic asthma: Drug of choice for persistent asthma (mild-moderate-severe) Given by inhalation Given orally in severe asthma (short course) Could be combined with Bronchodilators Status asthmaticus: Orally Or IV

Administration of corticosteroids in asthmatic patients: 1. Inhalation: in chronic asthma Advantages: Decrease systemic absorption Decrease side effects Dosage form: MDI, Nebulizer, Dry powder. All inhalations are given twice daily Types & doses Fluticasone: Flexicort; the best (100-300-600) Budesonide: (pulmicort (200-600-1200) Side effects: Oropharyngeal candidiasis Dysphonia (Solve) Systemic effects in children with > 500 ug/day (mention)

2. Oral administration: Drugs: prednisone or prednisolone doses: begin with 60-80 mg/day for 1-2 days then decrease to 40-60 mg/day later on decreased gradually if > 2 weeks Indications: Acute severe astma: (failure of bronchodilators)for 3-10 days Severe chronic persistent asthma (failure of aerosols) Status asthmaticus: Maintenance after IV hydrocortisone Side effects of oral corticosteroids & High ICS in children Adrenal suppression 2. Cushing syndrome 3. weight gain 4. Osteoporosis 5. Hyperglycemia 6. Infection (TB) 7. Hypertension 8. Psychosis 9. ▼Growth of children 10. Peptic ulcer 11. Myopathy 12. cataract & glucoma 13. Withdrwal syndrome 14. Thinning of the skin What are the contraindications of corticosteroids?

Leukotriene pathway inhibitors: Zafirlukast Montelukast Mechanism Block LTC4, D4 receptors Block LTC4,D4 receptors Kinetics T1/2 Oral PPB Liver-bile 10 h 5 h Dose 20/2 4-10 /1 Age > 5y > 1y Indications Prophylaxis only Weaker than ICS Mild PA & Moderate PA (additives or alternative to ICS) NSAID-induced asthma Exercise-induced asthma & irritant (cold air)-allergic asthma Side effects ▲Liver enzymes, Headache, NV, dyspepsia Hypersensitivity, edema Churg-Straus syndrome (vasculitis) DDI: Zafirlukast (CYP450) # warfarin (+hepatitis)

Anti-IGE treatment (Omalizumab) Mechanism: RH monoclonal antibody binds to IgE ▼its binding to mast cells and eosinophils ▼allergic reaction Pharmacokinetics: Administration: SC Half life: 26 days Elimination : liver, RES. Indications: expensive & injection 1. > 12 years with moderate & severe asthma (failure of others) 2. Other allergies: Food allergy- nasal allergy Side effects: Very expensive (600$ for vial) Local reactions (redness-induration-bruising-stinging) Anaphylaxis (0.1%) Cancer? Dose: 175-350 mg/1month