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

Cystic fibrosis is a genetic metabolic disease where a person does not have enough DNase 1 in their body and this leads to the decrease in secretions in various organs.  The manifestation is the worst in the airway, and the mucus secretion are very thick and sticky which makes the perfect environment for the development of an infection. 

Dornase alfa hydrolyses the extra-cellular DNA from the neutrophils in the bronchial mucus, increasing the liquidity of the mucus.

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

NRDS is when the surface-active material that covers the respiratory unit is not formed, as it is only formed in the last couple of weeks in pregnancy and NRDS occurs in premature babies.  Treatment includes monitoring, oxygen and continuous positive airway pressure and drug therapy.

Exogenous surfactants is used to augment surface-active lung surfactant.

Corticosteroids is administered to the mother just before labour as corticosteroids can induce the production of neonatal surfactant within 24 hours.

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

Oxygen therapy ensures that the patient gets constant oxygenation.  Oxygen toxicity and long-term use can cause blindness or retinal damage.  Oxygen toxicity can also induce hypoxia and poor gaseous exchange.

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

Methylxanthines such as caffeine and theophylline is used.  Methylxanthines is used to stimulate the CNS so that constant breathing can take place.  It also stimulates the skeletal muscles, thus it strengthens the contraction of the diaphragm, this improves hypoxia and dyspnoea. 

What are the general causes of rhinitis and rhinorrhoea?

Allergy, cold, chemical, drug or physical damage.

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

Anti-histamines – Diphenhydramine

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

Decongestants are nonselective adrenergic agonists (alfa and beta stimulation).  Decongestants to are administered topically are direct acting and decongestants that are administered orally is indirect acting.

What is rhinitis medicamentosa?  How is it treated?

It is also known as rebound rhinitis.  It can appear after chronic use of decongestants, because of the chronic vasoconstriction and the poor blood supply you have damage to the mucous membranes that cause permanent inflammation and swelling.  There is also the deregulation of alfa-adrenergic receptors in the blood vessels that makes them unresponsive to alfa-adrenergic agonists.

Rhinitis medicamentosa is treated by local corticoids treatment.

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:  They are multipotent competitive antagonists and they also blocks muscarinic receptors.  Due to its anti-muscarinic action it is effective in the treatment of rhinorrhoea.

2^nd generation:  They are only multipotent competitive antagonists, they don’t block muscarinic receptors.  They are only used in the treatment of allergic rhinitis.

The advantages of 2^nd generation anti-histamines is that they do not have as much side-effects as 1^st generation anti-histamines.  They don’t have sedation as a side effect. 

As 2^nd generation anti-histamines have no anti-muscarinic effects they can only be used for allergic rhinitis as it only has effects on allergies (IgE mediated).  With no anti-muscarinic effects has no effect on cold rhinitis.

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

Coricosteroids:  Treatment of privinism, allergic rhinitis.  Administered topically.

Anti-allegic drugs:  Prophylaxis of allergic rhinitis.  Administered topically.

Mensa:  For the use when the nasal secretion is sticky.  Administered topically.

Salt solution:  Humidifies the dry inflamed mucous membranes of the nose during colds, allergies or dry weather.

Give your own definition of COPD.

COPD (Chronis Obstructive Pulmonary Disease) is different combinations and degrees of bronchial asthma, emphysema and chronic bronchitis.

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

Chronic bronchitis is a non-specific airway obstructive disease which is characterised by an increase in mucus secretions, a decrease in mucocilliary clearance, regular bronchial airway infections, structural changes in the bronchial walls as well as a chronic cough due to thich mucus.

Emphysema is the irreversible dilation of the bronchi and alveoli because of a loss of elasticity that is due to structural damage.  The damage is irreversible.  The air is trapped inside the lungs so you have difficult exasperation and there in a decrease in capillary blood vessels that impedes gaseous exchange.  

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

• Drug therapy by means of bronchodilators, and antibiotics if there is an infection.
• Light-moderate exercise to improve poor lung capacity.
• Oxygen therapy the help with hypoxia.
• Prevention of progression by stopping to smoke.

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

Ipratropium is an anti-cholinergic, its MOA is the inhibition of M3 receptors, this inhibits Ach from binding to the receptors which causes bronchodilation and a decrease in mucus production..

Thus ipratropium is more effective treatment of chronic bronchitis as it has positive effects in terms of bronchodilation as well as a decrease in mucus production and chronic bronchitis is characterised by an increase in mucus production.  Ipratropium thus treats both the symptoms of chronic bronchitis.  Bronchial asthma only needs the bronchodilator effects of Ipratropium.

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

The skeletal muscle effects of theophylline has an advantage in COPD as the skeletal muscle contractions causes better contraction of the diaphragm, this causes an improvement in the ventilation response, thus it decreases hypoxia and dyspnoea in COPD.

What is the role of oxygen therapy in COPD?

Oxygen therapy in COPD is to improve hypoxia.

Anti-Inflammatory Effect of Fluvoxamine and Rationale for Use in COVID-19

In a murine sepsis model, fluvoxamine was found to bind to the sigma-1 receptor in immune cells, resulting in reduced production of inflammatory cytokines.¹ In an in vitro study of human endothelial cells and macrophages, fluvoxamine reduced the expression of inflammatory genes.² Further studies are needed to establish whether the anti-inflammatory effects of fluvoxamine observed in nonclinical studies also occur in humans beings and are clinically relevant in the setting of COVID-19.

NIH (National institute of health). 2021. https://www.covid19treatmentguidelines.nih.gov/therapies/immunomodulators/fluvoxamine/ Date of access: 22 Oct. 2021

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

Endothelium-dependent vasodilation is due to substances that induce vasodilation but are synthesised by the endothelium.  Stimuli found in the endothelium cells cause NO synthesis, and NO causes vasodilatation.  

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 produced at a constant rate, thus it is not dependent on the substrate concentration.  Inducible enzymes is only produced when it s exposed to a substrate or when they add adaptive value.

Constitutive enzymes are constantly present and thus they are more likely to be affected by pathology.

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

Septic shock causes a NO inflammatory response to the infection.  Endotoxins released by the septic shock leads to the synthesis of iNOS.  A rapid and big increase in NO can lead to hypertension or even 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?

NO can be inactivated by the reaction with oxygen to form nitrogen dioxide.

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

NO causes vasodilation and it plays a role in prostaglandin synthesis in the COX2 pathway, this results in an inflammatory response.  The inflammatory response contributes to erythema, vascular permeability and oedema that is associated with acute inflammation.

Advantage:  NO also appears to play an important protective role in the body via immune cell function.

Disadvantage : Excessive secretion of NO can worsen tissue injury and have an influence on disease pathology. 

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

Stroke.

Parkinson's disease.

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

Hypertension and Heart failure.  Increased levels of angiotensinogen means there are more angiotensin I that can be converted into angiotensin II.  Increased levels of angiotensin I being converted into angiotensin II leads to the breakdown of bradykinin, this causes an increase in vasoconstriction.  The vasoconstriction leads to hypertension.

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

Drugs that inhibits the angiotensinogen system are more selective than ACE inhibitors.  ACE inhibitors are non-selective and also have an effect on bradykinin.  Angiotensinogen system inhibitors only inhibit the angiotensinogen system and have no effect on bradykinin so there are less side effects.   

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

ACE inhibitors decreases angiotensin II production.  Bradykinin (a potent vasodilator) can not be broken down into inactive metabolites thus it remains and increases prostaglandin synthesis and this leads to vasodilation.

The increase in the synthesis of prostaglandin leads to a decrease in PRV, and this leads to a decrease in 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 is an Angiotensin II receptor antagonist ( it blocks AT1 receptors).  They fully block the angiotensin system, but there is no increase in bradykinin.

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 of arteries and veins.  Yes, other autacoids play a role in this action, such as NO (nitric oxide) that is released after the activation of bradykinin.

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

Bradykinin 2 (B2) receptor.

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

They are effective vasodilators, thus they decreases peripheral resistance and cardiac output which leads to a decrease in blood pressure, thus it is effective in the treatment of hypertension as well as congestive heart failure.

8.) What is neprilysine and what is the rationale for inhibiting its action in the treatment of heart failure? Can you name the drug being used as such? 

Neprilysine is an enzyme that metabolizes BNP and ANP. By inhibiting neprilysine there will be an increase in ANP and BNP, thus an increase in vasodilation, this leads to a decrease in peripheral resistance and cardiac output. 

Sacubitril, it can be used with Valsartan, which is a Angiotensin II receptor antagonist.  Valsartan is used for heart failure.

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

Vasodilators : PGI2 and NO

Vasoconstrictors : ET1, ET2, ET3

Migraine Pathology:

A migraine is characterized by variables that may include nausea, vomiting, visual scotomas.  It is followed by a severe throbbing headache that lasts between 1 and 2 hours.  Trigeminal nerve distributes to the intracranial arteries where they release calcitonin gene-related peptide (CGRP), a potent vasodilator.  Vasodilation of the intracranial arteries causes a migraine.

Migraine treatment:

Triptans : They are partial 5-HT1D/B agonists, they increase intracranial vasoconstriction that counteracts vasodilation that causes pain in migraine.

Ergot alkaloids : They are mixed partial agonists at 5-HT2 and alpha receptors, they cause vasoconstriction.

Beta-blockers : (Clonidine)  It is a agonist at alpha2 receptors in the CNS.  It reduces sympathetic tone and increases parasympathetic tone resulting in vasoconstriction.

Calcitonin gene-related peptide(CGRP) blockers : (Telgepant, Olcegepant) They block the vasodilatory action of CGRP.