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

Cystic fibrosis is a genetic metabolic disease that results in reduced secretions in various organs. Dornase alpha helps by hydrolyzing proteins in bronchial mucous 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 is a breathing disorder in newborns caused by immature lungs. General treatment strategies involve oxygen therapy and ventilation for positive pressure, the exogenous surfactants augment lung surfactant and cortisone initiates the baby’s surfactant production.

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

Oxygen is used to ensure oxygenation, the dangers include retinal damage and blindness.

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

Neonatal apnoea occurs in newborns and premature babies and is when the respiratory center in the brain is not yet fully developed to stimulate continuous breathing. Methylxanthines solve the problem by stimulating the CNS and they are usually administered intravenously. The methylxanthine used is theophylline.

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

The general causes of rhinitis and rhinorrhoea are usually allergies, cold, chemical or drug damage, cold air or physical change.

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

The alpha-1 antagonists, examples include phenylephrine, ephedrine, naphazoline etc.

Antimuscarinic and antihistaminic drugs, first generation histamine include brompheniramine, second generations histamine include loratadine.

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

Decongestants produce their action by activating the postjunctional alpha-adrenergic receptors found on precapillary and postcapillary blood vessels of the nasal mucosa, with regards to their duration of action, they usually start working within 15-30 minutes and will last anywhere from 3-12 hours. They are typically administered as a pill or as nose drops, sprays or gels.

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

Rhinitis medicamentosa is a condition that develops after 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 alpha-adrenergic receptors on the blood vessels making them unresponsive towards the alpha-agonists. Treatment involves gradually decreasing the use of nasal sprays, if congestion is mild a saline spray is recommended.

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

These drugs are valid in allergic rhinitis and they are administered as nasal sprays.

1. Give your own definition of COPD

COPD, which stands for chronic obstructive pulmonary disorder, is a group of lung diseases that block airflow and make it difficult, the lung disease that make up COPD can include the most common ones which are emphysema and chronic bronchitis.

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

The aetiology of chronic bronchitis is non-specific but it is characterized by an increase in mucus production and a decrease in mucosal clearance as well as frequent bacterial respiratory infections. The pathophysiology of chronic bronchitis is structural changes in the bronchial walls.

The aetiology of emphysema is smoking and irritants. The pathophysiology of emphysema is that the alveoli in the lungs are damaged, the inner walls of the alveoli can weaken and rupture.

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

Anticholinergics, which are the 1^st line treatment eg; Ipratropium, tiotropium. You can also add β2 stimulants or slow release theophylline which have broncho dilatory effects, corticosteroid therapy is also helpful, oxygen therapy can also be added.

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

Ipratropium is a M₃ antagonist and it is more effective in treating chronic bronchitis because it interrupts vagally mediated bronchoconstriction, it is indicated for maintenance therapy in stable chronic bronchitis. In terms of bronchial asthma it is not the first option because of its delayed onset of action.

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

Theophylline strengthens the contractions of diaphragm skeletal muscles which in turn improves ventilation response, reduces hypoxia and dyspnea in COPD patients.

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

When not enough air is available in the tissue to sustain bodily functions, oxygen therapy can be used to deliver the oxygen needed.

Blog #2.5

Fluvoxamine is a SSRI (selective serotonin reuptake inhibitor) that can be used to treat obsessive compulsive disorder and for other conditions such as depression (Covid-19 Treatment guidelines, 2021). Fluvoxamine is also an agonist for sigma-1 receptors that control inflammation (Sukhatme et al, 2021).

Covid 19 is usually associated with an increased level of inflammatory mediators including cytokines and chemokines (Sukhatme et al, 2021), therefore it was found that when fluvoxamine binds to the sigma 1 receptors it results in decreased production of inflammatory cytokines (Covid-19 Treatment guidelines, 2021). The proposed mechanism of action of fluvoxamine in Covid-19 treatment includes reduction in platelet aggregation, decreased mast cell degranulation, interference with endolysosomal viral trafficking, regulation of inositol-requiring enzyme 1α-driven inflammation and decreased melatonin levels, which all together have a direct antiviral effect, regulate coagulopathy or mitigate cytokine storm which are the signature trademarks of severe Covid-19 (Sukhatme et al, 2021).

Reference List

COVID-19 Treatment Guidelines. (n.d.). Fluvoxamine. [online] Available at: https://www.covid19treatmentguidelines.nih.gov/therapies/immunomodulators/fluvoxamine/ [Accessed 18 Oct. 2021].

Sukhatme, V.P., Reiersen, A.M., Vayttaden, S.J. and Sukhatme, V.V. (2021). Fluvoxamine: A Review of Its Mechanism of Action and Its Role in COVID-19. Frontiers in Pharmacology, 12.

1.) What do you understand by the term 'endothelium-dependent' vasodilation?

Endothelium-dependent vasodilators act by increasing intracellular calcium levels in the endothelium cells leading to the synthesis of NO. NO diffuses to the vascular smooth muscle leading to vaso-relaxation. 

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

NOS1 and NOS3 are commonly associated constitutive expression. Their activity is calcium dependent and requires interaction between the NOS enzyme and calmodulin-bound calcium to facilitate the catalysis of L-arginine and production of NO. 

Inducible expression of NOS has long been associated with immunological function. Immune cells use NO often in conjunction with reactive oxygen intermediates to kill pathogens and cancer cells. NOS2 is minimally expressed or is not abundant intracellularly in macrophages unless immune related stimulation and gene transcription occurs. Once transcribed NOS2 has a high affinity binding site for calmodulin and can function in a calcium-independent manner suggesting that at any time it is expressed it is likely to be active.

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

Endotoxin components from the bacterial wall along with endogenously generated tumor necrosis factor-α and other cytokines induce synthesis of iNOS in macrophages, neutrophils and T-cells as well as hepatocytes, smooth muscle cells, endothelial cells and fibroblasts. The widespread generation of NO results in exaggerated hypotension, shock and some cases 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 mechanism is available to the body to counter this detrimental effect of NO?

NOS enzyme inhibition majority of these being arginine analogs that bind to the NOS arginine binding site.

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

NO can act as a pro-inflammatory in the host immune response and in inflammation. Host response to infection or injury involves recruitments of leukocytes and release of inflammatory mediators like tumor necrosis factor and interleukin-1. This leads to a marked increase in iNOS levels and activity in leukocytes fibroblasts and other cell types.

However in both acute and chronic inflammatory conditions, prolonged or excessive NO production may exacerbate tissue injury. 

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

Stroke, amyotrophic lateral sclerosis and Parkinson's disease. 

 

1.) Production of angiotensinogen is increased by corticosteriods, estrogens, thyroid hormones and ANG II. Elevated during pregnancy and in women taking estrogen containing contraceptives. Decreased blood pressure leads to more conversion of angiotensinogen to angiotensin II mediated by renin enzymes. This will thus increase the synthesis of angiotensinogen.

Implications include increased plasma angiotensinogen concentration that is thought to contribute to hypertension.

2.) Angiotensin receptor blockers and their efficacy in hypertension is similar to that of ACE inhibitors but are associated with a lower incidence of cough. ARB's are preferred for patients who have adverse reactions to ACE inhibitors.

3.) ACE inhibitors not only block the conversion of ANG I to ANG II but also inhibit the degradation of other substances including bradykinin, substance P and enkephalins. The action of ACE inhibitors to inhibit bradykinin metabolism contributes significantly to their hypotensive action. 

4.) Losartan acts at angiotensin AT1 receptors. They also have an effect on AT2 receptors. 

5.) The physiological effect of kinins on veins is contraction and on arteries they cause dilation. Other autacoids like seratonin cause vasoconstriction of the vascular smooth muscle and ergot alkaloids cause vasoconstriction of the blood vessels. 

6.) Bradykinin 2 receptor 

7.) They are not effective as monotherapy in the treatment of  heart failure, however they led to the development of drugs that combine neprilysin inhibition with an ACE inhibitor in order to prevent the increase in plasma ANG II, or with an ARB to block the actions of ANG II. 

The combination of an ANG II receptor antagonist with neprilysin inhibitor (ARNI) increases endogenous natriuretic peptide levels while simultaneously blocking the effects of the increase in plasma ANG II. 

8.) Neprilysin is a natural endopeptidase and its inhibition increases bioavailability of natriuretic peptides, bradykinin and substance P which results in natriuretic vasodilatatory and anti-proliferative effects. The effects are prone to produce a powerful ventricular unloading and antihypertensive response. The drug used is sacubitril. 

9.) Endothelium-derived vasodilator is nitric oxide and a endothelium-derived vasoconstrictor is prostaglandin H2.