Give a short and critical explanation of the rationale of using fluvoxamine (a selective serotonin reuptake inhibitor (SSRI) in the treatment of Covid patients. Your answer must be properly and appropriately referenced (in-text references as well).

According to National Institutes of Health (NIH, 2021) fluvoxamine is a selective serotonin reuptake inhibitor (SSRI). It is approved by the  Food and Drug Administration (FDA) for the treatment of obsessive-compulsive disorder. It is also used in depression and other conditions.

The studies that have been done, show that fluvoxamine was found to bind to the sigma-1 receptor in immune cells, resulting in reduced production of inflammatory cytokines. It also reduces the expression of inflammatory genes in an invitro study of human endothelial cells and macrophages.

In the Medical letter (Medical letter, 2021:63) it is written that sigma-1 agonism has been shown to inhibit SARS-CoV-2 replication and to modulate the inflammatory response to sepsis. It could theoretically prevent development of life-threatening cytokine storm and acute respiratory distress syndrome in COVID-19.

 According to the article from K. Hashimoto (NIH ,2021) the sigma-1 receptor in the endoplasmic reticulum plays an important role in SARS-CoV-2 replication in cells. Knockout and knockdown of SIGMAR1 (sigma-1 receptor, encoded by SIGMAR1) caused robust reductions in SARS-CoV-2 replication, which indicates that the sigma-1 receptor is a key therapeutic target for SARS-CoV-2 replication.

Reference list:

NIH (National institute of health). 2021. https://www.covid19treatmentguidelines.nih.gov/therapies/immunomodulators/fluvoxamine/ Date of access: 13 Oct. 2021

NIH (National institute of health). 2021. https://pubmed.ncbi.nlm.nih.gov/33403480/ Date of access: 13 Oct. 2021

Medical letter. 2021.https://secure.medicalletter.org/sites/default/files/freedocs/w1623d.pdf Date op access: 13 Oct. 2021

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

• Endothelium-dependent vasodilators  increase the intracellular calsium levels in the endothelium. Endothelium cells respond to vasorelaxants by releasing soluble EDRF. EDRF acts on vascular muscle to cause relaxation and gives a vaso-relaxing effect.
•  An increase in blood flow stimulates endothelium-dependent vasodilation by increasing shear stress on the endothelium, both in conduit 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?

• eNOS and nNOS are expressed constitutively and NO synthesis is relied on calcium regulation. Whereas iNOS is expressed through transcriptional induction when it is exposed to inflammatory mediators therefore NO synthesis is not regulated by calcium.

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

• Sepsis is a systemic inflammatory response that is caused by infection. Some components which are present in bacteria (endotoxins, cytokines and tumor necrosis) cause the formation of iNOS in macrophages, T-cells, hepatocytes . This formation of NO leads to shock, severe hypertension and possible death. 

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

• NO

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

• Intracellular glutathione protecting mechanisms against tissue damage caused by scavenging peroxynitrite. Peroxynitrite causes tissue damage during inflammation.

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

• NO activates COX-2 and causes the synthesis of inflammatory prostaglandins. Prostaglandins have vasodilatory effects and together with NO  can increase vascular permeability and lead to perivascular edema. Excessive NO can cause tissue injury.

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?

• Angiotensinogen levels are increased with estrogens, thyroid hormones, corticosteroids, ANG II. Angiotensinogen is also increased during pregnancy and in women taking estrogen-containing oral contraceptives. The implications of an increased level of angiotensinogen are associated with hypertension.

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

• Drugs that block ACE, will also cause the inhibition of bradykinin breakdown to a non-active metabolite. Increased bradykinin concentrations cause bradykinin 2 receptor mediated bronchoconstriction which cause the adverse side effect of an irritating, dry cough. Therefore, drugs that block angiotensin receptors will not cause the inhibition of the breakdown on bradykinin. Thus, no adverse effects will be seen as bradykinin doesn’t increase.

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

• ACE inhibitors block the conversion of angiotensin I to angiotensin II. Angiotensin II type I receptors are also blocked. This leads to vasodilation instead of vasoconstriction which causes a decrease in blood pressure and peripheral resistance. Aldosterone secretion decreases which cause less salt and water retention and more excretion of salt and water. This excretion lowers cardiac preload, cardiac output and blood pressure. Left ventricular hypertrophy is reversed. ACE inhibitors inhibits bradykinin breakdown. Increased bradykinin concentrations, increase prostaglandin synthesis which decreases blood pressure, increase vasodilation and decreases peripheral resistance.

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?

• They act on Angiotensin II type 1 receptors. Losartan and other similar drugs have no effect on Angiotensin II type 2 receptors.

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

• Yes, the Kinins cause vasoconstriction of veins and  vasodilation of arteries. Yes ,there are many other autacoids that also cause vasodilation such as neurokinin A, neurokinin B, natriuretic peptides, substance P, vasoactive intestinal peptides, Calcitonin gene-related peptide.

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

• Bradykinin 2 receptor.

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

• Natriuretic peptides such as carperitide and urodilatin causes natriuresis and diuresis, decrease the effect of angiotensin and aldosterone. Thus the above mentioned will relieve the oedema associated with congestive heart failure. These natriuretic peptides cause vasodilation which decrease peripheral resistance and blood pressure that can be effective in treating hypertension.

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 metabolizes the natriuretic peptides which lead to a decrease in concentrations of the peptides. In lowering ANP and BNP, their therapeutic effects in congestive heart failure is also lowered. Therefore neprilysin should be inhibited so that the therapeutic positive effects of the natriuretic peptides can dominate.

Give examples of endothelium-derived vasodilators and vasoconstrictors.

• Endothelium derived vasodilators: nitric oxide,PGI2
• Endothelium derived vasoconstrictors: Endothelin

Pathology:

Migraine involves the trigeminal nerves distribution to intracranial and highly possibly extracranial arteries. These nerves release peptide neurotransmitters, whereas calcitonin gene-related peptide (CGRP) is an extreme powerful vasodilator. These neurotransmitters cause vasodilatory effects. The above-mentioned neurotransmitters also cause the extravasation of plasma and plasma proteins in to the perivascular space, which leads to mechanical stretching. The mechanical stretching is the cause of activation of the pain nerve endings in the dura. Migraine involve nausea, vomiting, paresthesias, visual scotomas, hemianopsia and speech abnormalities.

Current treatment and mechanism of action:

Triptans e.g. Sumatriptan: The first line drug therapy for acute severe migraines. These drugs are selective agonist for 5-HT 1D and 5-HT 1B receptors. They activate these receptors on the presynaptic trigeminal nerve ends to inhibit the release of the vasodilating peptides. Triptans should not be used in patients with coronary artery disease because they have the ability to cause coronary vasospasms.

Lasmiditan: Is a highly selective 5-HT 1F receptor agonist and is effective in treating migraines. The agent lacks vasoconstriction actions and is a much more cardiovascular save than the triptans. The drug reduces trigeminal nerve stimulation-induced plasma and plasma protein extravasation in dura vessels. Lasmiditan is used in acute migraines.

Ergot alkaloids e.g. Ergotamine and Ergonovine: The ergot derivates have mixed partial agonist effects at 5-HT2 and at alpha adrenoceptors. These drugs cause a marked smooth muscle contraction but they also block alpha agonist vasoconstriction. The effects mentioned above helps to reduce the vasodilation which causes the migraine.

Anti-inflammatory analgesics e.g. aspirin: These drugs are only helpful in controlling the pain of the migraine and not resolving the migraine itself.