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

It refers to the increasing of intracellular Calcium levels in endothelial cells which then leads to the synthesis of Nitric oxide. This NO then diffuses to the smooth muscle resulting in vasorelaxation.

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

 Constitutive enzymes: Are enzymes which are synthesised at a constant rate/ level, therefore the enzyme is synthesised in constant amounts regardless of the physiological amounts of the substrate. Constructive enzymes are regulated by calcium. An increase in cytosolic calcium concentrations will trigger the synthesis of NO. 

Inducible enzymes: Are enzymes which are present in minute concentrations in a cell. When a substrate is added this enzyme will increase.  Inducible enzymes are not regulated by Calcium which results in the accumulation of iNOS protein and synthesis of large amounts of NO.

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

Endotoxin components along with endogenously generated TNF and other cytokines induce the synthesis of iNOS in: macrophages, T cells, hepatocytes, smooth muscle cells, endothelial cells and fibroblasts. This wide range of NO generation leads to hypotension, shock and may also resukt in death. 

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

Nitric Oxide (NO).

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

NO can react with heme and hemoproteins which oxides NO to Nitrate. NO can react with hemoglobin resulting in the transportation of NO throughout the vasculature.

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

NO acts pro-inflammatory as it is an immune regulator. 

Advantage: TH1 cells synthesise NO, which is important with the impaired protective response to injected parasites in animal models after inhibition of iNOS.

Disadvantage: In both acute and chronic inflammatory conditions NO production may magnify tissue injury.

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

Stroke and Parkinson's disease 

1.  COPD has a different degree of combinations such as bronchial asthma, chronic bronchitis and emphysema. This limits the limit air flow as well as gaseous exchange.

2. Chronic bronchitis is a non-specific COPD that is characterised by increased mucus secretion, decreased mucociliary clearance, regular bacterial respiratory infections, structural changes in bronchial walls and a chronic cough due to thick mucus.

Emphysema is often developed from smoking and irritants. Irreversible widening of respiratory bronchioles and alveoli. Air is trapped in lungs which equals difficult expiration. A decreased capillary blood vessels. Impededs gaseous exchange.

3. Treatment includes stop smoking. You may develop bacterial infection such as influenza immunization and broad spectrum antibiotics which can be treated with tetracycline, amoxicillin, ampicillin erythromycin. In the airflow obstruction give bronchodialtors. In mucus secretion dilate mucus with rehydration and steam. In hypoxia give oxygen inhalation. In poor lung capacity light moderate exercise will help.

4. Beta-sympathomimetics can improve mucociliary clearance. Ipratropium inhalation is currently the first line of drug treatment for COPD, the bronchodiatory effect is better achieved with beta-sympathomimetics.

5. Theophylline improves the contraction function of the diaphragm, further improves cardiac contractions and improves ventilatory capacity.

6.  The combination of beta-sympathomimetic, ipratropium and Theophylline may help bring relief however corticosteroids may be given if the above medications don't work. Corticosteroids are mostly ineffective so if needed oxygen therapy should be given.

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

Answer: Associated with sinitus or allergen exposure, IgE, mediated inflammation, physiological response or physiological response to stimuli such as heat smoke and cold and consequences of allergy cold chemical or drug damage 

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

Answer:

•  Alpha1-agonist (naphazoline)
• Corticosteroids ( Budesonide)
• Mast cell stabilizer (ketotifien)
• Antihistamines (loratidine)
• Mucolytics (Mesna)
• Diverse drugs (normal saline)
• Antibiotics (neomycin)

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

Answer: MOA: decongestants present are alpha adrenoceptor sympathomimetics, They therefore cause vasoconstriction, as a result reducing nasal airway resistance and allows breathing through the nose.

Duration of action: they provide quick relief that can last up to 12 hours however, they can only be used for 5-7 days.

Decongestants are administered topically by metered-dose sprays, which is the safes

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

Answer: permanent vasoconstriction causing poor local blood supply to damaged mucous membranes with permanent swelling and inflammation. Tachyphylaxis can be evoked by indirect acting drugs also known as privinism.

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?

Answer: 1st gen antihistamines are used for non allergic rhinorrhea since they reduce inflammation in the nose. They also treat the symptoms.

2nd gen antihistamines are used to treat allergic rhinitis since they inhibit the release of histamine from  mast cells as well as other inflammation mediators. The advantages would be that they have almost no CNS distribution and have a low incidence to patients who have sedation and anticholinergic side effects.

However, antihistamines should never be used to alleviate cold rhinitis since symptoms which are caused by the bodys response are not related to histamine production. Antihistamines will have no effect. Therefore, we can say that histamine is not the major cause of a runny nose.

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

Answer:

• Corticosteroids: they are acceptable for the use of allergic rhinitis and is administered topically via nasal spray.
• Anti-allergic drugs: they are acceptable for prophylactic treatment of allergic rhinitis, administered topically via nasal spray.
• Mesna: this is acceptable for sticky nasal secretion, since it aids the mucus to become more of a liquid, administered topically via nasal spray.
• Normal salt solution: acceptable for humidifying dry and swollen mucus membranes of your nose during dry, cold weather, allergy like hay fever, nose bleed and other irritants, it is administered topically via nasal drops.

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

Answer: This is a genetic metabolic disease with a decrease in DNASE1  that results in reduced secretion in various organs not most of the worst symptoms are visible in the Airways the mucus is thick and sticky causing recurrent bacterial infections the treatments are daily mucus removal and dornase alpha inhalations hydrolyzes proteins in 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.

Answer: The surface active material that covers the respiratory tract of the airway is only formed during the final weeks of pregnancy. When premature babies are born the surface active material is not formed, this causes gas exchange to be disrupted and the lungs might fall. Treatment needs to be followed quickly in order to save the babys life. 

The general treatment options would be: oxygen as this ensure oxygenation, ventilation for positive pressure and medications (exogenous surfactants like poractant alfa and beractant )

Cortisone increases surfactant production and can be administered prophylactically 

Exogenous surfactants increase the lungs surfactant 

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

Answer: Oxygen is given in order to guarantee oxygenation. A continuous oxygen pressure from the ventilator helps increase respiration and allows the alveoli to stay open and not collapse. The arterial partial oxygen however needs to be continuously monitored.  In order for respiration to take place there needs to be enough oxygen present. It is therefore administered to prevent hypoxia. However, when oxygen is inhaled in large quantities or over a long time it has toxic effects. It can cause inter alia, reduced gaseous exchange, hypoxia and in very severe cases even death. In neonates it can also cause retinal damage which leads to blindness

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

Answer: It occurs when your respiratory center in the medulla of a premature baby has not been able to develop enough to stimulate continuous breathing. Therefore, making the breathing center very sensitive to stimulation and effect of CO2. Apneas typical duration is not longer than 15seconds and comes together with bradycardia. The continuous episodes of apnea can lead to neural damage. 

Methyxanthines like caffeine and theophylline stimulate the CNS. IV administrations tend to aid the problem. Therapy will be stopped usually after a few weeks in the ICU. The neonate will thereafter receive oxygen therapy. It is important to always monitor the oxygen levels in the blood.

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

-  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. 

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

- 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.

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

- ACE inhibitors block the conversion of ANG I to ANG II as well as inhibits the degradation of other substances for example enkephalins, bradykinin and substance P.

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

- They act on AT1 receptors and when ANG II is increased, they act on the AT2 receptors.

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

- Kinins cause vasodilation on arteries due to the direct inhibitory effect of kinins on arterial smooth muscle and is mediated by the release of nitric oxide, vasodilation prostaglandins such as PGE 2 and PGI2.

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

- B2 receptors.

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

- Natriuretic peptides lead to  the following physiological occurrences: Increased renin production, increased ANG2, vasodilation and natriuresis.

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.

- Neprilysin is the catalytic enzyme that break down the Natriuretic peptides to their metabolites and so inactivate them. The rationale of inhibiting them is to ensure an increase in the systemic concentration of the Natriuretic peptides and so ensure that their physiological effects are effective.

9.Give examples of endothelium derived Vasodilators and vasoconstrictors.

Vasodilators: nitric oxide and PG I2

Vasoconstrictors: ET1 and receptor subtypes ETA and ETB.

Migraine pathology:  A condition characterized by painful recurring headaches, sometimes with nausea and vomiting. Migraine typically recurs over a period lasting 4 to 72 hours and is often incapacitating. The primary type is migraine without aura (formerly called common migraine). This condition is commonly unilateral (affecting one side of the head), with severe throbbing or pulsating headache and nausea, vomiting, and sensitivity to light & sound

Treatment: 

1. Triptans -  they are selective agonist for 5HT1D and 5HT1B. They have a vasoconstriction action which prevents vasodilation.
2. Ergot alkaloids – activates 5-HT1D and 5-HT1B receptors on presynaptic nerve endings to inhibit the release of vasodilating peptides. 
3. Nonsteroidal anti-inflammatory analgesic agents – helpful in treating migraine pain