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

Cystic fibrosis is a genetic metabolic disease (decrease in DNase 1) in which secretion in the body are decreased

Dornase alpha hydrolyses enzymes in the bronchial mucus to improve fluidity

2. 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 also known is hyalin membrane disease. It occurs in premature babies where the surfactants that cover the airways and essential for gaseous exchange only develop shortly before birth, lung fall and lead to death

Cortisone- betamethasone is given to the mother prophylactically before birth to initiate the baby’s surfactant production

Exogenous surfactant- boractant and poractant alpha to augment lung surfactant

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

To ensure oxygenation

The toxicities are retinal damage and blindness

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

Neonatal apnoea occurs in premature and newborn babies where the respiratory centre in the brain isn’t fully developed yet to ensure continuous breathing. Bradycardia and apnoea last longer for 15 seconds and occur repeatedly. Lead to neural damage and hypoxia

Methylxanthines such as theophylline is administered by IV to stimulate the CNS.

1. What are the general causes of rhinitis and rhinorrhoea?

Rhinitis-cold and flu, sinusitis, allergen exposure, response to stimuli such as heat, smoke, cold

Rhinorrhoea- allergy, cold, chemical or drug damage, cold air or physical damage  

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

1^st generation antihistamines e.g., diphenhydramine

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

Short acting (4 to 6 hours) – e.g., ephedrine

Long acting (12 hours) – e.g., Oxymetazoline

Decongestants causes vasoconstriction of the mucosal blood vessels and decreases oedema of the nasal mucosa

Can be administered topically or orally, typically they are administered topically as they distribute the drug best this way, it drops easily into the GIT and the metred dose sprays are the safest. The oral decongestants lead to more side effects and slower commencement of action.

4. What is rhinitis medicamentosa?  How is it treated?

Rhinitis medicamentosa is caused by overuse of a decongestant, the permanent vasoconstriction with poor blood supply leads to damage of the mucous membranes of the nose with permanent inflammation and swelling as well as deregulation of alpha receptors on the blood vessels rendering them unresponsive to the alpha agonists.

It can be treated by corticosteroids

5. 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?

1^st generation antihistamines are multipotent competing agonists and block muscarinic receptors. Thus, reducing the secretions of both upper and lower airways and frequently included in cold preparations to clear up rhinorrhoea. They however cause sedation and thus negatively affect the ability to concentrate.  

2^nd generation antihistamines do not block muscarinic receptors and are useful for long term or short-term treatment of allergic rhinitis. 2^nd generation antihistamines do not have sedation as a side effect

 Histamine plays no role in cold rhinitis, but bradykinin does these drugs do not help clear up cold rhinitis.

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

• Corticosteroids- valid for allergic rhinitis, inflammatory rhinitis, nasal polyps, and reversal of rhinitis medicamentosa and administered topically (nasal sprays)
• Anti-allergic drugs- prophylactic treatment for allergic rhinitis administered as a nasal spray
• Mesna- used when nasal secretion is sticky administered topically

1. Give your own definition of COPD.

A group of diseases including emphysema, chronic bronchitis and bronchial asthma that causes a blockage in the airways as well as breathing problems

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

Chronic bronchitis- a non- specific obstructive airway disease that causes an increase in mucus secretion and decrease in mucous clearance, it also has frequent bacterial respiratory infections, structural changes in bronchial wall and has a chronic cough due to the sticky mucus

Emphysema- develops by smoking and irritants, causes irreversible dilation of the respiratory bronchioles and arterioles due to structural damage, air is trapped in the lungs- difficult exhalation and causes a decrease in capillary blood vessels and thus causing poor gaseous exchange  

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

• If caused by smoking - Smoking cessation
• If caused by bacterial infection -Immunization against influenza and broad-spectrum AB with infection – ampicillin, amoxicillin, erythromycin
• Airway obstruction- Bronchodilators
• Secretions- dilute mucus
• Hypoxia- oxygen inhalation
• Poor lung capacity- regular light to moderate exercise    

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

Ipratropium is an anticholinergic drug thus it blocks the release of Ach and reduces mucus production, chronic bronchitis is characterized by increase in mucus secretions whereas bronchial asthma is not thus ipratropium is better

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

Theophylline improves function of contraction of the diaphragm and thus increases ventricular capacity reducing hypoxia and dyspnoea and COPD  

6. What is the role of oxygen therapy in COPD?

Prevent Hypoxia, improve air flow and gaseous exchange

1. What do you understand by the term “endothelium-dependent” vasodilation?  Explain.

Endothelium is responsible for vasodilation.

An increase in blood flow stimulates endothelium-dependent vasodilation by increasing shear stress on the endothelium, both in conduit and resistance vessels.

2. When we talk about the NOS enzyme, what is meant by “constitutive” and “inducible” enzymes and what are the pathological and physiological implications thereof?

Constitutive enzymes are always present and are produced at constant rates no matter the demand as well as constantly synthesized regardless of physiological and pathological implications.

Inducible enzymes are only produced when it is needed that is in the presence of other enzymes, pathological and physiological implications can affect the synthesis of the enzymes.

 iNOS is not regulated by calcium, but after synthesis is constitutively active. In macrophages and several other cell types, iNOS is normally not readily detectable until inflammatory mediators induce the transcription of the iNOS gene, resulting in accumulation of iNOS and synthesis of large quantities of NO.

3. Explain how NO contributes to the fatal pathology of septic shock.

It is a systemic inflammatory response caused by infection. Endotoxins from the bacterial cell wall, together with TNf-α and other cytokines, induce the synthesis of iNOS to NO. Excessive increase in NO leads to hypotension or shock or in some cases it can lead to death.

4. Which autacoids’ mechanism of action depends on effects on the guanylyl cyclase-cGMP system?

Nitric Oxide

5. NO may be toxic to the cell.  Which mechanisms are available to the body to counter this detrimental effect of NO?

The body releases NOS enzyme inhibitors which compete with NOS for the binding site of arginine to prevent arginine from being converted Nitric oxide.

6. Name a way in which NO can act pro-inflammatory.  Give examples of where it will have advantages or disadvantages.

NO also appears to play an important protective role in the body via immune cell function. When challenged with foreign antigens, Th1 cells respond by synthesizing NO.

NO also stimulates the synthesis of inflammatory prostaglandins by activating COX-2. Through its effects on COX-2, its direct vasodilatory effects, and other mechanisms, NO generated during inflammation contributes to the erythema, vascular permeability, and subsequent edema associated with acute inflammation.

In both acute and chronic inflammatory conditions, prolonged or excessive NO production may exacerbate tissue injury. Psoriasis lesions, airway epithelium in asthma, and inflammatory bowel lesions in humans all demonstrate elevated levels of NO and iNOS, suggesting that persistent iNOS induction may contribute to disease pathogen.

7. In which possible neurological and psychiatric diseases is NO involved? 

• Parkinson's disease,
• Stroke
• Amyotrophic lateral sclerosis

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

Hypertension

The production of angiotensinogen is increased by corticosteroids, estrogens, thyroid hormones, and ANG II.

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

ACE inhibitors block the bradykinin metabolism and thus the increase in bradykinin levels leads to a common side effect of ACE inhibitors which is a dry cough whereas Angiotensin receptor blockers do not influence bradykinin metabolism and thus no dry cough is experienced.

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

ACE inhibitors block the conversion ANG I and ANG II as well the metabolism of bradykinin to an inactive metabolite. ANG II causes an increase in Blood pressure thus by blocking the conversion of ANG I to ANG II ACE inhibitors decrease blood pressure

4. 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 and other similar drugs are specific competitive antagonists at angiotensin AT1 receptors

They do influence AT2 receptors when ANG II is increased

5. 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 and increase the blood flow in the body.

Autocoids such as Histamine and Serotonin also play a role in this action.

Histamine - H1 and H2 receptors dilatate blood vessels and capillaries

Serotonin- 5-HT2receptors for vasoconstricting activity in most blood vessels and 5-HT1 for vasodilating activity

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

Beta 2 receptor

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

Natriuretic peptides increase sodium and water excretion and causes vasodilation. The excretion of sodium and water decreases volume of fluid leading to a decrease in blood pressure while the vasodilation causes blood to flow easier and thus reduces blood pressure.

8. 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.

Neprylisine is a neutral endopeptidase responsible for degradation of natriuretic peptides in kidneys, liver, and lungs. Neprylisine inhibitors prevent the degradation of natriuretic peptides, increases ANP and BNP and causes natriuresis and and diuresis.   

A drug used as such is Sacubitril.

9. Give examples of endothelium-derived vasodilators and vasoconstrictors.

Vasodilators: Nitric oxide and PGI2

Vasoconstrictors: ET1

Migraine pathology:

Migraines involves the trigeminal nerve distribution to intra-cranial arteries. The trigeminal nerves release peptide neurotransmitters especially calcitonin gene-related peptide (CGRP), which is a strong vasodilator. Extravasation of plasma and plasma proteins into the perivascular space causes mechanical stretching and in turn activities the pain nerves in the dura.

Treatment:

Triptans eg Sumatriptan– They are selective agonists for 5-HT1D and 5-HT1B, this causes vasoconstriction and prevents the vasodilatory effects of the migraine as well as the pain associated with it, they also modulate neurotransmitter release thus reducing the amount of CGRP.

Ergot alkaloids eg Ergotamine – Partial agonist at 5-HT and at alpha adrenoreceptors especially in vessels thus preventing the vasodilation associated with migraines

Anti-inflammatory analgesics eg Aspirin- Control the pain associated with a migraine

Calcium channel blockers eg Verapamil- effective in the prophylaxis of migraine

Beta blockers eg Propranolol – effective in the prophylaxis of migraine