Give a short and critical explanation of the rationale of using fluvoxamine (a selective serotonin reuptake inhibitor) in the treatment of Covid patients.

Fluvoxamine is an SSRI that was approved by the FDA (Food and Drug Administration) to treat OCD and depression. However, it was not approved to treat infections (NIH, 2021). Fluvoxamine has a high affinity for the sigma-1 receptors which inhibit SARS-CoV-2 replication, therefore it can prevent the health of covid patients from worsening (Hashimoto, 2021:2). Fluvoxamine may inhibit enzymes such as CYP1A2, 2C9 and 3A4 which therefore lowers metabolism and increases the concentrations of drugs that are metabolised by them. In conclusion, Fluvoxamine is a safe drug to use in the treatment of COVID-19 patients. However, trials are still occurring as there is not enough conclusive data (Medical letter, 2021:63).

Reference list:

Medical Letter on Drugs and Therapeutics. 2021. https://secure.medicalletter.org/sites/default/files/freedocs/w1623d.pdf Date of access: 23 Oct. 2021.

NIH (National Institute of health): COVID-19 Treatment Guidelines. 2021.  https://www.covid19treatmentguidelines.nih.gov/therapies/immunomodulators/fluvoxamine/ Date of access: 23 Oct. 2021.

Hashimoto K. 2021. Repurposing of CNS drugs to treat COVID-19 infection: targeting the sigma-1 receptor. Eur Arch Psychiatry Clin Neurosci, 271(2):249-258.

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

It is vasodilation caused by vasodilators that originate from the endothelium and are synthesised there. Endothelium-dependent vasodilators such as Acetylcholine and bradykinin increase the intracellular calcium levels in the endothelium leading to the synthesis of NO an endothelial-derived relaxing factor (EDRF) in the endothelium. NO moves to the vascular smooth muscle to cause its vaso-relaxing effect.

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 enzymes that are constantly being synthesized regardless of physiological need, so they have greater physiological and pathological importance because they are persistent in one area. Induced enzymes are enzymes that appear after a substance has been added, so the enzyme is present before the substance, which means the body has to excrete something before the enzyme works, so the effects are small. Endogenous substances may also interact with constitutive enzymes more often due to their more permanent presence in cells than inducible enzymes. Constitutive NOS will have greater pathological and physiological implications than inducible NOS.

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

Sepsis is a systemic inflammatory response caused by infection. Components present on bacteria such as endotoxins, cytokines and tumour necrosis factor-α induce the formation of iNOS in macrophages, smooth muscle cells, neutrophils etc. This NO formation in a wide area leads to severe hypotension, shock and in some cases death.

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

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

Haemoglobin can react with NO in the body and oxidize it to nitrate, thereby deactivating it. NO can also be deactivated by reacting with O2 in the body to form NO2. NO also rapidly reacts with metals in the body which also deactivate it and thereby counteract its detrimental effect on cells. The body releases NOS enzyme inhibitors which bind competitively to arginine binding site in NOS therefore arginine is not converted to nitric oxide.

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

The response to injury or infection leads to the activation of leukocytes and the release of inflammatory mediators, resulting in an increase in iNOS levels and activity in leukocytes. The NO and peroxynitrates produced are an important microbial agent. Function of the immune cell TH1, which synthesizes NO in response to an unknown substance. This is a good protective response, especially when iNOS is inhibited. NO also stimulates prostaglandin synthesis (activates COX2). The vasodilator effects of NO and the effects of COX2 play a role in inflammation, where it causes red skin color, increases vascular permeability and increases edema in acute inflammations. A disadvantage of NO in acute and chronic inflammation is that excessive NO production can lead to tissue damage, psoriasis lesions, airway epithelium in asthma and inflammatory bowel lesions.

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

Stroke, amyotrophic lateral sclerosis and Parkinson’s disease.

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

Hyperthyroidism, hypertension and heart failure causes an increase in angiotensinogen levels. Increased levels of angiotensinogen can lead to increased Angiotensin 1 and 2 .This is because angiotensinogen is the molecule required for ANG 1 and 2 formation. This leads to hypertension due to due to vasoconstrictive effects of increased ANG 2 binding to AT-2 receptors and disorders of fluid and electrolyte balance in the body due to increased aldosterone release.

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

ACE inhibitors may cause a dry cough and angioedema due to the increased levels of bradykinin. Due to the fact that angiotensinogen receptor blockers do not have an effect on bradykinin there is little to no dry cough as a side effect.

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 and also inhibit the degradation of other substances such as bradykinin, substance P and enkephalins. Therefore, the action of ACE inhibitors to inhibit bradykinin and other substances contributes to the treatment of hypertension.

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?

The drugs act at AT1 receptors and when Angiotensin II is increased, they act on the AT2 receptors. They have no direct activity at the AT-2 receptor. They can have an indirect effect on the AT-2 receptor.

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 arteriolar smooth muscle or it is mediated by the release of nitric oxide or vasodilator prostaglandins such as PGE2 and PGI2. The kinins are potent vasodilators of the arteries and veins. Their physiological role is mediated by G-proteins and their second messengers. Autacoids such as bradykinin play a role as bradykinin is a potent vasodilator.

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

B-2 receptor

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

Drugs that combine neprilysin inhibition with ACE inhibition (vasopeptidase inhibitors) include omapatrilat, sampatrilat and fasidotrilat lower the blood pressure in hypertensive patients and improve cardiac function in patients with heart failure. The natriuretic peptides such as carperitide, nesiritide, ularitide, urodilatin cause vasodilation and natriuresis for the treatment of congestive heart failure. They also reduce sodium reabsorption which aids in the bodies fluid balance and thus reduces oedema that is caused by congestive heart failure.

8. What is neprilysin 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 a neutral endopeptidase that is responsible for the degradation of natriuretic peptides in the kidneys, liver and lungs. By inhibiting its action, we can increase circulating levels of ANP and BNP which can lead to diuresis and natriuresis which reduces oedema caused by heart failure and thus reduces the pre and after load on the heart which can all aid in treating heart failure. The drug is Sacubitril.

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

Vasodilators- PGI2 and NO

Vasoconstrictors- Endothelins (ET-1, ET-2 and ET-3) 

MIGRAINE PATHOLOGY:

Migraines involve the release of the peptide neurotransmitter (this peptide is related to the calcitonin gene), from the trigeminal nerve distribution into the intracranial arteries. Vasodilation and extravasation of blood plasma and plasma proteins into the perivascular space is caused by this neurotransmitter. This further causes mechanical stretching and this activates pain nerve endings in the dura. This may be the cause of painful headaches associated with migraines.

TREATMENT:

Anti-inflammatory analgesics such as asprin are often helpful in treating migraine pain.

Beta blockers and calcium channel blockers such as propranolol and verapamil are effective for migraine prophylaxis in some patients.

Anticonvulsants such as valproic acid in the prophylactic treatment of migraines.

Triptans such as sumatriptan are a first-line treatments for migraines, they are partial agonists of serotonin 1B / 1D receptors and selective agonists for 5-HT1D and 5-HT1B and this increases intracranial vasoconstriction, thereby preventing cranial vasodilation, which causes pain by stretching the sensory nerve endings.

Ergot alkaloids such as ergonovine have mixed partial agonistic effects on serotonin-2 receptors and alpha-adrenoceptors; they cause significant smooth muscle contraction, but block alpha-agonistic vasoconstriction.