• Briefly explain what cystic fibrosis is and how dornase alfa acts to solve the problem.

Cystic fibrosis is a genetic defect leading to reduced secretions in various organs.  The manifestation in the airways is the most prominent and problematic symptom.  In the airways, the mucus secretions are exceptionally thick and sticky which provides the ideal environment for bacterial infections.  The repeated infections cause continuous chemotaxis of neutrophils which then, during disintegration, deposits DNA in the mucus to make it even stickier.  The mucus then becomes virtually impossible to clear and a vicious circle of sticky mucus and further infections results.

Dornase alfa (rhDNase I) hydrolyses extra-cellular DNA from the neutrophils in the bronchial mucus, increasing its liquidity drastically. It is related to the natural enzyme deoxyribonuclease I (DNase I) which is normally produced by the pancreas and salivary glands.

• Briefly explain what neonatal respiratory distress syndrome is, what the general treatment strategies involve and how cortisone and exogenous surfactants solve the problem.

Neonatal respiratory distress syndrome is also known as hyaline membrane disease.  The surface-active material which covers the respiratory unit of the airways is formed only in the last weeks of pregnancy.  When babies are born prematurely, this surface-active material has not yet formed, resulting in disrupted gas exchange and also the possibility that the lungs may collapse.  Treatment must follow rapidly in order to save the life of the premature baby.

The treatment includes:

Monitoring:

The intensive monitoring of respiratory and circulatory status is essential.

Oxygenation, continuous positive airway pressure:

Oxygen (mixed with air at room temperature) is administered in order to ensure oxygenation.  A continuous positive pressure (as obtained with a ventilator) improves respiration and keeps the alveoli open to prevent collapse.  It is critically important that the arterial partial oxygen pressure is continuously monitored.

Sufficient oxygen is a basic requirement for normal respiration.  Therapeutically it is administered generally to prevent or reverse hypoxia (of various causes).  When oxygen is inhaled in excessive quantities and/or over too long a period of time, it has toxic effects.  Paradoxically, oxygen toxicity causes, inter alia, reduced gas exchange, hypoxia and, in extreme cases, death.  In neonates, it can cause retinal damage and blindness.

These surfactants are administered exogenously at room temperature (by means of a catheter into the lungs), prophylactically, or during acute respiratory distress syndrome to the neonate to augment lung surfactant. Eventually, the mortality and long-term oxygen requirement are lowered.  This therapy, however, is relatively expensive and specialised.

Corticosteroids

A short course of corticosteroids is also effective to boost endogenous surfactant production and is a cheaper alternative than the exogenous surfactant.  When the baby is viable and there is an impending miscarriage, it can be administered prophylactically. Systemic administration of betamethasone to the mother just before labour can induce neonatal endogenous surfactant production within 24 hours.

• What is the role of oxygen therapy in neonatal respiratory distress syndrome?  What do the dangers of oxygen toxicity involve?

Sufficient oxygen is a basic requirement for normal respiration.  Therapeutically it is administered generally to prevent or reverse hypoxia (of various causes).  When oxygen is inhaled in excessive quantities and/or over too long a period of time, it has toxic effects.  Paradoxically, oxygen toxicity causes, inter alia, reduced gas exchange, hypoxia and, in extreme cases, death.  In neonates, it can cause retinal damage and blindness.

• Briefly explain what neonatal apnoea is and how the methylxanthines solve the problem.  Which methylxanthine is used?

Neonatal apnoea occurs when the respiratory centre in the medulla of the premature baby has not yet developed sufficiently to stimulate continuous breathing.  The breathing centre is, therefore, still insensitive to the stimulating effect of carbon dioxide.  Apnoea has a duration, typically, of longer than 15 seconds and is accompanied by bradycardia. Repeated episodes of apnoea with hypoxia can eventually lead to neural damage.

Methylxanthines, especially caffeine and theophylline, stimulate the central nervous system and intravenous administrations of these drugs usually help to solve the problem.  Therapy is however, usually discontinued as soon as possible – usually after a few weeks in intensive care.  The neonate then also receives oxygen therapy and the oxygen levels in the blood are continuously monitored.

• What are the general causes of rhinitis and rhinorrhoea?

Rhinitis (inflammation of the mucous membranes of the nose) and rhinorrhoea (runny nose) are usually the results of allergies, cold, chemical or drug damage, cold air or physical damage.

• Which drug groups can be used for the treatment of rhinorrhoea? Name examples from each group.

α1-agonists, (decongestant) e.g., phenylephrine, ephedrine, phenylpropanolamine,naphazoline,  oxymetazoline and xylometazoline. Vasoconstriction of mucosal blood vessels, ↓ oedema of nasal mucosa

Antihistamines e.g., Diphenhydramine, promethazine, chlorpheniramine, brompheniramine, loratadine,

cetirizine, levocabastine, rupatadine

Corticosteroids e.g., Betamethasone, prednisone, beclomethasone, budesonide, cyclonesonide, mometasone

Mast cell stabilisers e.g., Sodium chromoglycate (Vividrin® eye drops), ketotifen

Mucolytics e.g., Mesna, acetylcysteine

Antibiotics e.g., Mupirocin, neomycin, topical in nostrils

Diverse drugs e.g., steam, normal saline, essential oils such as menthol, eucalyptus oil

• How do the decongestants differ with respect to the mechanism of action and duration of action?  How are they administered typically?

    short-acting drugs (4 to 6 hours), e.g. ephedrine, phenylephrine, propylhexedrine, naphazoline and tetrahydrozoline;

    intermediary acting drugs (8 to 10 hours), e.g. xylometazoline;

    long-acting drugs (12 hours), e.g. oxymetazoline.

• What is rhinitis medicamentosa?  How is it treated?

Rhinitis medicamentosa (privinism) and rebound rhinitis can result from an overdose of local preparations.  Privinism is a condition that may present following chronic treatment with decongestants, where the permanent vasoconstriction with poor local blood supply leads to damage of the mucous membranes of the nose with permanent inflammation and swelling, as well as deregulation of the a‑adrenergic receptors on the blood vessels, rendering them unresponsive towards the a‑agonists. Tachyphylaxis (l‑noradrenalin storage exhaustion) can be evoked by indirect-acting drugs.

• How does the first and second generations of antihistamines differ with respect to the mechanisms according to which rhinitis and rhinorrhoea are relieved?  What are the advantages of the second generation of antihistamines?  Why should they not be used to relieve cold rhinitis?

There is controversy, however, about the use of antihistamines for the treatment of rhinorrhoea during colds.  Here bradykinin, and not histamine, is the mediator of inflammation.  There is, therefore, no rationale for the application of the antihistaminic characteristics of the antihistamine.  It is, however, true that the old generation antihistamines (multipotent antagonists) are used for cold rhinorrhoea in view of their antimuscarinic characteristics to dry all watery secretions.  There is a feeling among certain experts that the disadvantages (side-effects and serious toxicity, especially in children) outweigh the advantages.  For the treatment of allergic rhinitis the usefulness of the antihistamines is, however, clear.

• When are corticosteroids, anti-allergic drugs, mesna and normal salt solution valid and how are they administered?

Topical mesna (nasal spray) is especially meaningful to use when the nasal secretion is sticky.  The mesna helps to make the mucus more liquid.

The use of sodium cromoglycate as a nasal spray is very effective for the prophylactic treatment of allergic rhinitis, but the regular dosage makes it less popular.

Normal salt (saline) solution is very safe and effective as nose drops.  It humidifies the dry, inflamed mucous membranes of the nose during colds, dry weather, allergy (hay fever), nose bleeding, overuse of decongestants and other irritations. Volatile oils can, however, potentially cause reflex larynx constriction in very small babies, which can be fatal.

• Give your own definition of COPD.

chronic obstructive diseases describe different combinations and grades of three obstructive airway conditions, namely bronchial asthma, chronic bronchitis and emphysema.  These conditions limit pulmonary airflow and gas exchange and can therefore lower life quality by causing sleeping disorders, reducing the ability to perform physical activity and, during acute attacks, leading to fear, hypoxia and even death

• Briefly describe the proposed aetiology and pathophysiology of chronic bronchitis and emphysema.

Chronic bronchitis    

Chronic bronchitis is a non-specific obstructive airway disease of which the exact aetiology is unclear, but which is associated with long-term exposure to irritants, e.g. cigarette smoke, dust and irritating gases. The symptoms and signs of chronic bronchitis are associated with mucus hypersecretion, reduced mucociliary clearance, regular bacterial airway infections and structural changes in the bronchial walls.  Chronic bronchitis sufferers also develop a chronic cough in reaction to the excessive sticky phlegm.  Because the vagus reflex is a typical result of the stimulation of irritant receptors in the airways, an overactive parasympathetic nervous system plays an important role in chronic bronchitis.

Emphysema    

Emphysema comprises a nonreversible dilation of the respiratory bronchiole and alveoli (loss of elasticity) as a result of structural damage to the walls. The air is, therefore, caught in the respiratory space of the lungs and is exhaled with difficulty, disrupting ventilation of the lungs.  Furthermore, there is also sometimes a decrease in capillary blood vessel provision which further hampers gas exchange.  As in the case of chronic bronchitis, cigarette smoke is a very important cause, especially in heavy smokers or genetically susceptible individuals (e.g. persons with a₁-antitrypsin deficiency).

• Which types of therapy are included in the treatment of a COPD patient?

Smoking:

Giving up smoking is extremely important and is necessary to prevent progression.  Psychotherapy, consultation and encouragement (rather positive than cautionary), as well as support, possibly with other drugs, is important to wean the smoker.  There is however, controversy over the efficacy of nicotine-containing drugs to assist in ending the smoking habit.

Bacterial infection:

Annual prophylactic immunisation against influenza (very effective) and a single immunisation against pneumococci (less effective) can be considered.  Broad-spectrum antibiotics (tetracyclines, cotrimoxazole, amoxicillin, ampicillin or erythromycin) can, as required, be used against, especially, pneumococci and Hemophilus Influenzae.

Airflow obstruction:

Airflow obstruction can be treated by means of drugs as for bronchial asthma.  The choice of drug is, however, somewhat different, as discussed below.  The use of a mixing chamber together with aerosols and regular airflow monitoring, by means of a peak-flow meter, holds many advantages.

Secretes:

Rehydration (sufficient intake of liquids) and regular steaming (e.g. humidifier at night) dilutes the mucus and promotes mucus clearance.

Hypoxia:

The morbidity and mortality in serious grades of COPD improve drastically with 18-24 hours/day O₂ inhalation therapy. It is therefore strongly recommended in cases of continued hypoxia (various types of portable O₂ containers are available).  Some patients require O₂ inhalation therapy only with exercise or during sleep.

Weak lung capacities:

Mild and regular exercise improves lung capacities and life quality but must be done with caution where there are already heart complications.

• Why is ipratropium more effective in the treatment of chronic bronchitis than in the treatment of bronchial asthma?

Although the inhalation of b₂-sympathomimetics is effective to counteract bronchial constriction and it possibly improves mucociliary clearance, anticholinergic therapy (ipratropium inhalation) is currently favoured as a first-line drug for the treatment of COPD. Specifically, with COPD (chronic bronchitis and emphysema) the bronchodilatory effect is usually better than what is achieved with b₂‑sympathomimetics.  This can be understood, especially in the light of the role of the parasympathetic nervous system in chronic bronchitis, as discussed above. 

• In which way do the skeletal muscle effects of theophylline have advantages in the treatment of COPD?

    Theophylline has the special advantage that it improves diaphragm contractility and reduces diaphragm exhaustion, improves cardiac contractility, lowers pulmonal resistance, improves mucociliary clearance and improves the ventilatory response.

• What is the role of oxygen therapy in COPD?

If the combination of ipratropium, a b₂-sympathomimetic and theophylline does not provide enough relief, inhalation or oral administration of corticosteroids can be tried.  The corticosteroids are however, mostly ineffective, but a few patients react within two weeks.  If necessary, oxygen therapy must be applied.