Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) that is approved by die FOOD and Drug Administration (FDA) for the treatment of obsessive-compulsive disorder and is used for other conditions, including depression. Fluvoxamine is not FDA-approved for the treatment of any infection. (fluvoxamine, 2021)

There’s not enough evidence for the COVID-19 Treatment Guidelines Panel to recommend either for or against the use of fluvoxamine for the treatment of COVID-19. Results from adequately powered, well-designed, and well-conducted clinical trials are needed to provide more specific, evidence-based guidance on the role of fluvoxamine for the treatment of COVID-19. (fluvoxamine, 2021)

Treatearly.org. 2021. fluvoxamine. [online] Available at: <https://www.treatearly.org/fluvoxamine> [Accessed 25 October 2021].

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

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

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

Constituent enzymes are enzymes synthesized by a constant level and constant amounts, so these enzymes are produced in constant quantities without taking into account the concentration of the substrate or the physiological requirements.

An induced enzyme is affected by the presence of an inducer which leads to an increase in gene expression. The concentration of such enzymes increases drastically when a substrate is added.

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

Endotoxin components from the bacterial wall along with endogenously generated tumor necrosis factor and other cytokines induce the synthesis of iNOS in macrophages, neutrophils, T cells as well as hepatocytes, smooth muscle cells, endothelial cells and fibroblasts. This widespread generation on NO results in exaggerated hypotension, shock and in some cases death.

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

Nitric oxide (NO)

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

Scavengers of superoxide anion such as superoxide dismutase may protect NO, enhancing its potency and prolonging its duration of action. Nitrate tolerance.

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

When your body reacts to infection or even injury it leads to the activation of leukocytes and release of inflammatory mediators. which leads to an increase in iNOS levels in leukocytes. The NO produced is an important microbial agent. It helps the immune system to reach the infected area, but also has a disadvantage because it causes vasodilation.

• In which possible neurological and psychiatric diseases is NO involved? 

Parkinson's disease, stroke and amyotrophic lateral sclerosis.

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

Disease like hypertension and heart failure has increased angiotensinogen levels because of the over activity of the RAAS.

An increase in angiotensinogen leads to an increase in the amount of angiotensin I that is converted by renin. There are higher levels of angiotensin I that can be converted into angiotensin II. This causes hypertension, cardiac and vascular hypertrophy and systemic vasoconstriction.

• 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 complete blockage of the angiotensin receptors compared to drugs that inhibits the ACE. Bradykinin does not increase which leads to fewer side effects. ACE inhibitors are non-selective while the angiotensin blockers are selective. This leads to the angiotensin blockers having less effects.

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

ACE inhibitors inhibits the conversion of angiotensin I to angiotensin II and the conversion of Bradykinin to Inactive peptide. Bradykinin will increase which causes an increase in PG synthesis, vasodilation, a decrease in peripheral vascular 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?

It acts on angiotensin II receptors by blocking it (antagonist). It also has action on 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 capillary permeability. Prostaglandins also have a role here.

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

Bradykinin receptors

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

Vasodilators increase glomerular filtration and decrease renin secretion and aldosterone mechanism which leads to a decrease in Na reabsorption, it also inhibits angiotensin II. There is a decrease in the effect of angiotensin, 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.

Neprylisine is ‘n neutral endopeptidase that metabolize natriuretic peptides. Inhibition of this leads to a increase in the circulating levels of natriuretic peptides and an increase in natriuresis and diuresis.

• Give examples of endothelium-derived vasodilators and vasoconstrictors.

Vasoconstrictors: Endothelin

Vasodilators: PGI₂, NO, Vasoactive intestinal peptide