Drugs and Respiratory System: Asthma & COPD

Drugs and the Respiratory System

• Asthma occurs in the upper airways.
• COPD includes small airways disease and emphysema in the transitional zone.
• Tuberculosis tends to occur in the upper lung lobes.

Allergic Asthmatic Reaction

• Mast cells release histamines when an allergen is encountered.
• Histamine, prostaglandins, leukotrienes, and cytokines are released.
• This causes bronchoconstriction, oedema, mucus secretion, and inflammation.
• White blood cells like eosinophils and T lymphocytes are involved.

Lung Function after Allergen Exposure

• The immediate phase is entirely due to bronchospasm.
• Mediators that contribute to this are PAF and LTs released from allergen-triggered mast cells, which act on bronchiolar smooth muscle to cause contraction.
• The delayed phase is due to airway narrowing from mucosal swelling/oedema.
• This is a result of mediators released from inflammatory cells recruited into airways, initiated by events of the immediate phase.
• There is also a small component of bronchospasm (~10-15%).
• Airway hyperresponsiveness causes are controversial.
• Likely involves combined effects of bronchospasm on an inflamed oedematous airway that is very sensitive/twitchy to any inhaled irritant.
• Reduction in lung function for allergic asthma can be helped with local administration of medication.

Pharmacological Treatment of Asthma: Bronchodilators

• Beta2-agonists are included.
• Muscarinic antagonists are indirect and used in COPD.

Pharmacological Treatment of Asthma: Anti-Inflammatory Agents

• Glucocorticosteroids
• Xanthines
• Cromones (sodium cromoglicate, nedocromil sodium)
• Leukotriene antagonists (e.g. montelukast)
• Anti-IgE (Omalizumab)

Current Symptom Treatments for Asthma

• Short acting b2 agonists include salbutamol, terbutaline, and fenoterol (SABA).
• Long acting b2 agonists include salmeterol and formoterol for asthma/COPD, and indacaterol for COPD (LABA).
• Theophylline is oral and prophylactic, not first line.

Beta2-adrenoceptor Agonists

• Examples include adrenaline, isoprenaline, salbutamol, formoterol, salmeterol, and indacaterol.
• Binding to a G-protein coupled receptor occurs.
• G protein is activated and stimulates enzyme adenylyl cyclase.
• Adenylyl cyclase converts ATP to cyclic AMP.
• Increased cAMP levels activate protein kinase A.
• PKA phosphorylates MLCK, inactivating it, which prevents phosphorylation of myosin light chain.
• Ultimately causes relaxation.
• Beta2-adrenoceptor agonists cause smooth muscle relaxation and inhibit mast cell degranulation.
• They elevate cyclic AMP within effector cells.
• They are administered via the inhaled route (metered dose inhaler, dry powder and nebulizer).
• Side effects include tremor, increased heart rate, and hypokalemia.
• This occurs due to targeting beta-receptors at extra-pulmonary sites.

Muscarinic Antagonists

• They prevent smooth muscle contraction and mucus secretion induced by activation of parasympathetic nerves.
• Bronchoconstriction is inhibited by muscarinic antagonists.
• Examples include ipratropium bromide (6 h) and tiotropium bromide (24 h).
• Mainly used in the treatment of COPD.
• Side effects include dry mouth (can lead to ulceration).
• Less rare effects include 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)

Glucocorticosteroids

• Includes Annexin (Lipocortin).
• Trans-represses of NFKB and AP-1.
• Also affects cytokines, chemokines, adhesion molecules, and inflammatory enzymes (e.g. COX2, NOS).
• Actions include inhibition of leukotriene and cytokine synthesis/release.
• They inhibit recruitment of inflammatory cells (e.g. T cells, eosinophils, mast cells).
• They provide anti-oedema functionality.
• They can increase beta-adrenoceptor function.
• This enhances the bronchodilator effect of beta2-agonists.

Role of ICS (Inhaled Corticosteroids) in Asthma Therapy

• Prevents infiltration and activation of inflammatory cells.
• Reduces mucosal oedema (swelling of airway wall).
• Improves airflow and hence lung function.
• Decreases airway hyper-responsiveness.
• Reduces symptoms.
• Reduces frequency and severity of exacerbations.
• Improves quality of life.

Glucocorticosteroids - Side Effects

• If inhaled (e.g., fluticasone proprionate) can cause oral candidiasis (fungal infection), hoarseness, cough, and voice problems.
• If oral or at prolonged high dose (e.g., prednisolone), can cause growth retardation, bruising, immunosuppression, suppression of hypothalamic-pituitary axis, osteoporosis (serum osteocalcin), water retention (also binds to mineralcorticosteroid receptor), diabetes, hypertension, weight gain, and ocular hypertension.

Leukotriene Antagonists and 5-LO Inhibitors

• Leukotrienes cause bronchoconstriction, oedema, cellular infiltration, and mucus production.
• Leukotriene receptor antagonists exist (e.g., Montelukast).
• 5-lipoxygenase (LO) inhibitors exist.
• Zileuton (licensed in USA not UK) is an example.
• Montelukast is a cysteinyl leukotriene receptor antagonist.
• Works relatively long acting (once per day).
• Benefit in severe asthma (combination with GCS).
• Useful for aspirin sensitive and exercise induced asthma.
• Has oral bioavailability.
• Rare side effects include headache and GI disturbance (hepatotoxicity and dyspepsia with zileuton, blocks COX and 5-LO).

Xanthines

• Xanthines inhibit PDE, impairing the metabolism of Cyclic AMP.
• Examples includes Theophylline and Aminophylline.
• Therapeutic window approximately 10-20 mg/ml.
• Side effects include nausea, vomiting, arrhythmias, hypokalemia, hypotension, and seizures.
• Numerous drug-drug interactions which increase/decrease plasma levels.
• Smoking promotes plasma clearance.

Cromones

• Includes Sodium Cromoglicate and Nedocromil sodium (inhaled).
• Mast cell stabilizers.
• Reduce inflammatory cell activation and recruitment.
• Not as effective as glucocorticosteroids.

Omalizumab (Xolair)

• First biological agent.
• Binds to free IgE.
• Must be given as a subcutaneous injection.
• It is very costly.
• Only used in moderate to severe asthmatics whose asthma is not controlled by glucocorticosteroids treatment of asthma.

Asthma Phenotypes

• Antibodies developed to target specific interleukins associated with Th2 immune responses (IL-5, IL-13, IL-4R may have benefit in restricted asthma phenotypes.

Chronic Obstructive Pulmonary Disease

• Smoking, cooking with coal/ biomass fuels.
• Pollution can lead to exacerbations.
• Chronic inflammation of the airways.
• Chronic bronchitis and cough.
• Progressive breathlessness due to development of emphasema.
• Eventual respiratory failure.

Treatment options for COPD

• include quitting smoking
• muscarinic receptor antagonists (tiotropium bromide)
• Reduce the effect with β2 agonists (salmeterol)
• Provide dual bronchodilation.
• Anti-inflammatory drugs
• inhaled corticosteroid (increased risk of Pneumonia)
• PDE4 inhibitor (roflumilast) as add-on therapy for severe COPD
• Anti-tussives (treatment of cough) for Irritation in bronchi/bronchioles
• Codeine can inhibit.
• Dextromethorphan can inhibit.
• But evidence for effectiveness is poor.

PDE4 Inhibitors

• Decrease inflammatory cell activity, airway nerves, and remodelling.

Tuberculosis

• It is a mycobacterial infection, specifically by Mycobacterium tuberculosis.
• More deaths than any other single agent (1.5million/annum/worldwide).
• Historically treatable with streptomycin, isoniazid, rifampicin and ethambutol, but strains with increased resistance and virulence are becoming common.

Active TB

• Presents as chronic cough, blood-containing mucus, fever, and night sweats.
• Weight loss historically called consumption.

Tuberculosis Prevention and Treatment

• Vaccine BCG
• Anti-tuberculosis drugs
• First line drugs: Isoniazid, rifampicin, ethambutol, pyrazinamide
• Second line drugs: capreomycin, cycloserine, ciprofloxacin, streptomycin
• Therapy used:
• 2-month phase of first line drugs
• 4-month phase of isoniazid and rifampicin

Respiratory Drugs List

• Key drugs in this category are: Salbutamol, Salmeterol, Fluticasone propionate, Montelukast, Theophylline, Cromoglycate, Omalizumab, Ipratropium bromide, Tiotropium bromide, and Roflumilast.
• The mechanism of action, site of action, route of administration, rationale for use in respiratory diseases, and side-effects are important to know.