Respiratory disease treatment

Asthma, COPD, Coughs, and Tuberculosis Features

• Learn the important features of asthma, COPD, coughs, and tuberculosis.

Bronchodilator Pharmacology

• Learn the pharmacology of directly-acting bronchodilators like salbutamol.
• Understand the pharmacology of indirectly-acting bronchodilators like ipratropium bromide.

Anti-Inflammatory Drug Pharmacology

• Understand anti-inflammatory medications pharmacology.
• Examples of anti-inflammatory drugs: glucocorticosteroids, xanthines, cromones

Antituberculosis Drugs

• Appreciate the use of antituberculosis drugs.

Pulmonary Drug Side Effects and Toxicities

• Learn the major side effects and toxicities linked to pulmonary drugs.

Respiratory System Locations of Diseases

• Asthma and Bronchitis location occurs near the Bronchi.
• COPD (small airways disease and Emphysema occur at the Respiratory Bronchioles.
• Tuberculosis tends to occur in the upper lung lobes.

Allergic Asthma and Antigens

• Mast cells release histamines when an allergic asthmatic inhales an antigen.
• Histamine, Prostaglandins, Leukotrienes, and Cytokines, are produced.
• Bronchoconstriction, Oedema, Mucus secretion, and Inflammation occurs.
• White blood cells like eosinophils and T lymphocytes are involved.

Lung Function and Allergen Exposure Phases

• Immediate phase of lung function change occurs because of bronchospasm.
• Mediators like PAF and LTs are released from allergen-triggered mast cells targetting bronchiolar smooth muscle.
• The delayed phase of lung function change is airway narrowing caused by mucosal swelling/oedema, and events of the immediate phase.
• Airway narrowing occurs as mediators released from inflammatory cells are recruited into airways.
• Bronchospasm in the delayed phase accounts for 10-15% of the change.
• AHR causes are controversial, but possibly involve combined effects of bronchospasm on an inflamed oedematous airway.

Pharmacological Treatments

• Asthma drug pharmacological treatment includes bronchodilators such as beta2-agonists and muscarinic antagonists
• Asthma anti-inflammatory agents include Glucocorticosteroids, Xanthines, Cromones, Leukotriene antagonists, and Anti-IgE

Current Asthma Treatment

• Short acting B₂ agonists (SABA): salbutamol, terbutaline, fenoterol
• Long acting B₂ agonists (LABA: Asthma/COPD: Salmeterol, formoterol; COPD: Indacaterol)
• Theophylline *oral, prophylactic, not first line

Beta2-Adrenoceptor Agonists Summary

• Beta2-adrenoceptor agonists Summary: Salbutamol, terbutaline, fenoterol, formoterol, salmeterol, indacaterol.
• Beta2-adrenoceptor agonists promote Smooth muscle relaxation and inhibits mast cell degranulation.
• Increases cyclic AMP within effector cells.
• Administered via the inhaled route using metered dose inhaler, dry powder and nebulizer.
• Side effects include; tremor, increased heart rate, and hypokalemia.

Muscarinic Antagonists Action

• Prevents smooth muscle contraction and mucus secretion.
• Inhibits bronchoconstriction induced by muscarinic antagonists.
• Two examples are ipratropium bromide (6 h) and tiotropium bromide (24 h).
• Mainly used in the treatment of COPD.
• Side effects include dry mouth, urinary retention, constipation, and acute angle glaucoma.

Current Anti-Inflammatory Therapy

• Glucocorticosteroids (Inhaled and oral)
• Theophylline (oral)
• Leukotriene receptor antagonists? (oral)
• Anti-IgE: Omalizumab (subcutaneous)
• Cromones: Sodium cromoglycate, nedocromil (inhaled)

Glucocorticosteroid Action

• Glucocorticosteroids in asthma performs trans-repression of NFKB and AP-1
• Actions of glucocorticosteroids include inhibiting leukotriene and cytokine synthesis/release
• Glucocorticosteroids inhibit recruitment of inflammatory cells (e.g. T cells, eosinophils, mast cells) recruitment
• Reduces oedema
• Increases beta-adrenoceptor function (enhances bronchodilator effect of beta2-agonists)

ICS - Asthma Therapy Role

• ICS prevents infiltration and activation of inflammatory cells.
• Reduces mucosal oedema or swelling of airway wall.
• Improves airflow and hence lung function
• Decreases airway hyper-responsiveness
• Improves quality of life and reduce symptoms.
• Reduce frequency and severity of exacerbations

Glucocorticosteroids

• When inhaled there is oral candidiasis (fungal infection), hoarseness, cough, and voice problems.
• When oral or used over prolonged high dose, there are Growth retardation, bruising, Immunosuppression, Suppression of hypothalamic-pituitary axis, Osteoporosis, water retention, diabetes, Hypertension, weight gain, and ocular hypertension

Anti-Leukotriene Drugs

• Some 5-lipoxygenase (LO) inhibitors include eg Zileuton (licensed in USA not UK)
• Leukotriene Receptor antagonists include Eg Montelukast (cysteinyl leukotriene receptor antagonist)
• Relatively long acting when taken once per day
• Side effects: Rare, headache and GI disturbance

Xanthines

• Increase plasma levels and promote plasma clearance.
• Xanthines inhibit PDE
• Examples: Theophylline and Aminophylline
• Therapeutic window ~ 10-20 µg/ml
• Side effects include Nausea, vomiting, arrhythmias, hypokalemia, hypotension, seizures
• Smoking promotes plasma clearance

Cromones

• Includes Sodium Cromoglicate and Nedocromil sodium when inhaled
• Mast cell stabilizers
• Reduces inflammatory cell activation and recruitment
• Not as effective as glucocorticosteroids

Omalizumab (Xolair)

• First biological agent to treat asthma
• Binds to free IgE
• Must be given as a subcutaneous injection
• Very costly
• Only used in moderate to severe asthmatics when asthma is not controlled by glucocorticosteroid

COPD Pathology

• Caused by smoking, cooking with coal/biomass fuels as well as pollution
• Inflammation of the airways
• Chronic bronchitis and cough
• Progressive breathlessness due to emphasema
• Eventual respiratory failure

COPD Treatment Options

• Quit smoking
• Palliative such as Muscarinic receptor antagonists or B₂ agonists
• Provide dual bronchodilation
• PDE inhibitor as add-on therapy for severe COPD

Tuberculosis

• A mycobacterial infection disease caused by Mycobacterium tuberculosis.
• Kills more than any other single agent (1.5million/annum/worldwide).
• Treatable with streptomycin, isoniazid, rifampicin and ethambutol
• Can become resistant, becoming increasingly common
• Active TB is a chronic cough
• Causes blood-containing mucus, fever and night sweats
• Causes weight loss historically called consumption

Tuberculosis Prevention and Treatment

• BCG vaccine
• Anti-tuberculosis drugs
  • First line drugs: Isoniazid, rifampicin, ethambutol and pyrazinamide
  • Second line drugs: capreomycin, cycloserine, ciprofloxacin and streptomycin.
• Used to reduce emergence of resistant strains, combination Therapy with:
  • 2-month phase of first line drugs
  • 4-month phase of isoniazid and rifampicin

Respiratory Drugs List

• What is the mechanism of action, site of action, route of administration, rationale for use in respiratory diseases and side-effects of these drugs? Salbutamol, Salmeterol, Fluticasone propionate, Montelukast, Theophylline, Cromoglycate, Omalizumab, Ipratropium bromide, Tiotropium bromide and Roflumilast