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

Cystic fibrosis is genetic metabolic disease (↓ DNase 1, not have enough lead to decreased secretions in various organs especially airways) which leads to decreased secretions in various organs. 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. Hydrolyses proteins in bronchial mucus to improve fluidity

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

Also known as hyaline membrane disease, occurs in premature babies. Surface active agent (surfactant, which covers airways and is essential for gaseous exchange), is only formed shortly before birth, disrupted gas exchange, lungs may therefore collapse and can result in death. The 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.

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

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)

BUT increased oxygen for long-term leads to retinal damage and blindness. 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?

New-born and premature babies: Respiratory centre in brain not yet fully developed to stimulate continuous breathing. Apnoea with bradycardia lasts longer than 15 seconds and occurs repeatedly. May lead to hypoxia and neural damage. Methylxanthine is used to stimulate the CNS, theophylline is used

What are the general causes of rhinitis and rhinorrhoea?

Allergic rhinitis = allergen exposure, IgE mediated inflammation.
Non-allergic rhinitis = physiological response due to stimuli such as heat, smoke, cold.

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

Decongestants (alpha-agonists): oxymetazoline, xylometazoline, ephedrine

Antihistamines: diphenhydramine, loratadine, cetirizine 

Corticosteroids: betamethasone, prednisone, beclomethasone

Mast cell stabilizers: Sodium chromoglycate, ketotifen

Mucolytics: Mesna, acetylcysteine

Antibiotics: Mupirocin, neomycin

Diverse drugs: steam, normal saline, essential oils

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

Sympathomimetic agents, α1 agonists: vasoconstriction of mucosal blood vessels, ↓ oedema of nasal mucosa. Ephedrine, pseudoephedrine and propylhexedrine are nonselective adrenergic agonists (a and b) with additional potent indirect action. The a-adrenergic receptor stimulation (direct-acting or indirect-acting) by these drugs gives rise to decongestion of the mucous membranes of the nose. The drugs with mixed action administered topically act directly, but if they are administered orally, they reach lower concentrations in the biophase, resulting in mainly indirect action.

• 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.

Typically administered topically (nasal spray)

What is rhinitis medicamentosa?  How is it treated?

Also known as 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. Receive local corticoid therapy

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?

The first-generation antihistamines are multipotent competing antagonists and also block muscarinic receptors. Antimuscarinic drugs reduce the secretions of both the upper and lower airways and are, therefore, frequently included in preparations for colds to clear up rhinorrhoea.  They can, however, cause sedation and therefore negatively influence the ability to concentrate. The second-generation antihistamines do not block muscarinic receptors and are useful in the long-term or short-term treatment of allergic rhinitis. Because histamine plays no part in cold rhinitis (but bradykinin does) these drugs do not help to clear up cold rhinitis. They also do not cross the blood/brain barrier and thus rarely cause sedation

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

Corticosteroids: Used in allergic rhinitis, nasal polyps, inflammatory rhinitis and reversal of rhinitis, nasal spray

Anti-allergic drugs: Nasal vestibule staphylococci infection, prophylactic treatment of allergic rhinitis, nasal spray

Salt solution: dilutes mucus during sinusitis, nasal rinse/lavange

• Give your own definition of COPD

COPD stands for chronic obstructive Pulmonary Disease. It is the different combination of bronchial asthma, emphysema, and chronic bronchitis to different degrees.

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

Chronic Bronchitis: It is non-specific COPD characterised by: increased mucus secretion (mucus hypersecretion), decreased mucociliary clearance regular bacterial respiratory infections, structural changes in bronchial walls and a chronic cough due to thick mucus.

Emphysema: Often develops due to smoking and irritants. Emphysema is IRREVERSIBLE widening of respiratory bronchioles and alveoli, due to structural damage. The Damage cannot be reversed. Air is trapped in lungs which makes expiration difficult. The decreased capillary blood vessels impedes gaseous exchange.

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

The types of therapy are: self-management, bronchodilators, inhaled corticosteroids, methylxanthines, oxygen and surgery.

Stop smoking:

• • 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 smoke

If bacterial infection

• • influenza immunization (prevents 2ndary infections)
  • broad spectrum antibiotics (tetracyclines, amoxicillin, ampicillin, erythromycin, co-trimoxazole)

Obstruction of airflow

• • Bronchodilators

Mucus secretions

• • Dilute mucus (rehydration & steam)
  • Rehydration (sufficient intake of liquids) & regular steaming (humidifier)

Hypoxia

• • Oxygen inhalation. 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

Poor lung capacity

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

Bronchial asthma is characterized by inflammation and Ipratropium does not have an anti-inflammatory effect and will thus not be as effective in treating bronchial asthma.

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

Skeletal Muscle effects: Strengthens contraction of diaphragm skeletal muscles. Improves ventilation response, reduces hypoxia and dyspnea in COPD patients.

• What is the role of oxygen therapy in COPD?

If the combination of ipratropium, a b2-sympathomimetic and theophylline does not provide enough relief and the patient is unable to receive enough oxygen, oxygen therapy must be applied.

In which diseases are angiotensinogen levels increased?  What are the implications of this?

Angiotensinogen is increased in hypertension and heart failure. Increased levels of angiotensinogen increases the amount of angiotensin I that can be converted into angiotensin II, thus decreasing the amount of bradykinin in the body, which causes an increase in vasoconstriction. This leads to hypertension, retention of fluid into the urinary tract and ventricular hypertophy.

Why do drugs which inhibit the angiotensinogen system by acting on angiotensin receptors have fewer side effects than those that inhibit ACE?

Drugs that inhibit the angiotensinogen system have a more complete blockage of the angiotensin system than ACE inhibitors, thus there is no increase in bradykinin, which leads to fewer side effects. The angiotensin blockers are also more selective than the non-selective ACE inhibitors, thus it will have less effects since the non-selective ACE inhibitors.

In which way do ACE inhibitors have a two-fold mechanism of action in the treatment of hypertension?

ACE inhibitors first inhibits the conversion of angiotensin I to angiotensin II, which increases bradykinin, which causes vasodilation and thus a decrease in blood pressure. It also decreases peripheral ventricular resistance which leads to a decrease in blood pressure.

At which type of angiotensin receptor do losartan and similar drugs act?  Do they have any effect, direct or indirect, at other angiotensin II receptors?

Losartan acts on the agiotensin II receptors by blocking it, it also has action on the angiotensin I receptors.

What are the physiological effects of kinins on arteries and veins?  Do other autacoids play a role in this action?  Explain.

Kinins are potent vasodilators. It increases cAMP; IP3, DAG, NO, PG and capilliary permeability. Prostaglandins also play a role here.

Which receptor is probably the most involved in the important clinical effects of kinins?

Bradykinin receptors (1&2)

In which way are natriuretic peptides possibly effective in the treatment of hypertension, as well as congestive heart failure?

• VASODILATOR
• increase glomerular filtration
• deacrese renin secretion & Aldosterone mechanism (↓Na reabsorption) & inhibit angiotensin II.
• ↓ effect of Angiotensin and aldosterone and Na secretion.

What is neprylisine and what is the rationale for inhibiting its action in the treatment of heart failure? Can you name the drug being used as such? Refer to Study unit 1 where you have also come across this drug.

it is a neutral endopeptidase which is responisble the breakdown of natiuretic peptides in the kidney liver and lungs.

inhibition of this increases circulating levels of ANP and BNP and thus causes natriuresis and diureses. (Sacubitril)

Give examples of endothelium-derived vasodilators and vasoconstrictors.

vasodilators: PGI₂ & NO

vasoconstrictors: Endothelin - ET₁, ET₂, ET₃

An acute migraine is due to rapid vasodilation which causes pain. Vasoconstrictors combat this, thus the pain caused by the vasodilation goes away.

Serotonin 1D/B receptor agonists are vasoconstrictors (Sumatriptan, Naratriptan, Rizatriptan) in the intracranial cavity and combats the pain in a migraine

Uteroselective ergovine causes vasoconstriction and is used as a migraine prophylaxis

Ergotamine causes vasoconstriction and is used in acute migraines and cluster headaches.