1. 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

2. 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

3. 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

4. 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????

5. 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: (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

6. 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

7. 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)

8. 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

9. Pharmacological Actions:
Smooth muscles: Relax smooth muscles (bronchial)
CNS:
Caffeine ( 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

10. Pharmacokinetics
Absorption: Irritant, Food↓, SR, Rectal (unreliable), Variable & irritant.
Distribution: protein bound, Widely distributed Vd ( 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

11. 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)

12. 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

13. 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

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

15. 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

16. 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

17. 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

18. 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

19. 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 ( )
Budesonide: (pulmicort ( )
Side effects:
Oropharyngeal candidiasis
Dysphonia (Solve)
Systemic effects in children with > 500 ug/day (mention)

20. 2. Oral administration: Drugs: prednisone or prednisolone
doses: begin with mg/day for 1-2 days then decrease to 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?

21. 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)

22. 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: mg/1month