Pathways

Cilgavimab is an extended half-life recombinant monoclonal IgG1κ antibody directed against the SARS-CoV-2 spike glycoprotein for COVID-19 prophylaxis in individuals who are unable to undergo COVID-19 immunization. It is produces in Chinese hamster ovary cells derived from a neutralizing antibody isolated from a patient with a natural history of SARS-CoV-2 infection and modified through targeted amino acid substitutions. It is commonly taken with tixagevimab, and was issued FDA emergency use authorization on December 9, 2021. SARS-CoV-2 enters host cells via the interaction between the trimeric spike (S) glycoprotein and host cell angiotensin-converting enzyme 2 (ACE2). Cilgavimab inhibits S glycoprotein by blocking the interaction between it and the host ACE2 protein. This inhibits the binding and entry of the virion into the host cell. This prevents viral replication and propagation.

Spironolactone is a steroidal, non specific, orally administered aldosterone antagonist used mainly for its antihypertensive effects. This drug is used to treat heart failure, hyperaldosteronism, hypertension, adrenal hyperplasia, edema, and nephrotic syndrome. It has also been shown to decrease proteinuria. Spironolactone can be found under the brand names Aldactazide, Aldactone, and Carospir. The main target of spironolactone is the distal convoluted tubule in the nephron of the kidneys where it competitively inhibits mineralocorticoid receptors (MRs) in the principal cells to promote sodium (Na+) and water (H2O) excretion and potassium (K+) retention. Once spironolactone is bound to the MR, it blocks aldosterone from binding which inhibits aldosterone dependent sodium potassium exchange channels and results in the antihypertensive effects seen by causing alterations to the Na+:K+ ratio. Aldosterone is a mineralocorticoid hormone responsible for contributing to the regulation of blood pressure, sodium reabsorption, and potassium excretion and therefore, plays a role in blood pressure via the RAAS pathway. In the principal cells of the distal convoluted tubule, sodium and water reabsorption occur, along with potassium excretion. The sodium channel (ENaC) transports Na+ from the tubule lumen into the principal cells, then the NA+/K+ ATPase pumps the Na+ into the interstitium where it reabsorbed into the blood. K+ ions are pumped into the principal cell from the interstitium via the Na+/K+ ATPase, then the K+ channel transports K+ from the cell into the lumen where it is excreted in urine. Water reabsorption is linked to Na+ reabsorption and occurs via the aquaporins. Activation of the RAAS system leads to increased production of aldosterone, which is produced by the adrenal cortex in the zone glomerulosa. Following binding of aldosterone, the mineralocorticoid receptors undergo dimerization and activation and move into the nucleus where they undergo transcription. Protein is then synthesized in the cytosol. This effect on gene transcription leads to an upregulation of sodium channels in the apical membrane and Na+/K+ ATPase in the basolateral membrane, aiding an increase in Na+ and water reabsorption and K+ excretion. This change in ion concentrations leads to an increased effective circulating volume. By blocking the binding of aldosterone, the RAAS system. This prevents the aldosterone effects on gene transcription, therefore, there is a decrease in Na+ channels and Na+/K+ ATPase in the membrane. Sodium reabsorption decreases, the concentration of Na+ in the lumen becomes high and as a result, water reabsorption also decreases. The effects on Na+/K+ ATPase results in reduced K+ excretion. This effect of spironolactone is important for treating conditions like hypertension because the increased water excretion in urine leads to decreased blood plasma volume, lowering blood pressure. One of the limitations of aldosterone blockage with spironolactone is the increased risk of hyperkalaemia and increased serum creatinine levels. The maximal hypotensive effects seen from spironolactone often require 3-4 weeks to be fully expressed and may persist 1-2 weeks after discontinuation, this is because spironolactone is a prodrug with multiple active metabolites with long half lives such as canrenone which is metabolized in the liver by hepatocytes. Spironolactone has also been shown to have antiandrogenic activity as well contributing to off label uses. Spironolactone has moderate affinity for progesterone and androgen receptors which increases the likelihood of side effects such as loss of libido, menstrual irregularities, gynecomastia, and impotence, Structurally, spironolactone contains elements of progesterone leading to those progestognenic and antiandrogenic adverse effects. Some side effects of using spironolactone may include feeling dizzy, experiencing muscle cramps, feeling tired and low in energy, and experiencing breast pain and enlargement.

Finerenone, under the brand name Kerendia, is indicated to lower the risk of eGFR decline, end stage kidney disease, cardiovascular death, heart attack, and hospitalization for heart failure in chronic kidney disease associated with type 2 diabetes. Finerenone is an oral drug that has been shown to help in reducing inflammation, fibrosis, and improving proteinuria, along with severe congestive heart failure and diabetic nephropathy. Finerenone is the only non steroidal MRA to be FDA approved, and it more selective and longer lasting compared to other MRAs, providing a dose dependent relationship over older MRAs. Finerenone is a non steroidal, or specific, mineralocorticoid receptor antagonist (MRA) that minimizes adverse effects such as hyperkalemia compared to non specific/steroidal MRAs. Binding of Finerenone to mineralocorticoid receptors (MRs) prevents the binding of coactivators of the MRs such as aldosterone, cortisol, and 11-deoxycorticosterone; preventing receptor activation. Aldosterone is a mineralocorticoid hormone responsible for contributing to the regulation of blood pressure, sodium reabsorption, and potassium excretion and therefore, plays a role in blood pressure via the RAAS pathway. In the principal cells of the collecting duct, sodium and water reabsorption occur, along with potassium excretion. The sodium channel (ENaC) transports Na+ from the tubule lumen into the principal cells, then the NA+/K+ ATPase pumps the Na+ into the interstitium where it reabsorbed into the blood. K+ ions are pumped into the principal cell from the interstitium via the Na+/K+ ATPase, then the K+ channel transports K+ from the cell into the lumen where it is excreted in urine. Water reabsorption is linked to Na+ reabsorption and occurs via the aquaporins. Activation of the RAAS system leads to increased production of aldosterone, which is produced by the adrenal cortex in the zone glomerulosa. Aldosterone acts on receptors in collecting and distal tubules of the nephron causing increased reabsorption of Na+ and increased secretion of K+. Aldosterone binds to mineralocorticoid receptors in the cytosol of the principal cells in the collecting duct. The mineralocorticoid receptors undergo dimerization and activation and move into the nucleus where they undergo transcription. Protein is then synthesized in the cytosol. This effect on gene transcription leads to an upregulation of sodium channels in the apical membrane and Na+/K+ ATPase in the basolateral membrane, aiding an increase in Na+ and water reabsorption and K+ excretion. This change in ion concentrations leads to an increased effective circulating volume. Aldosterone can also stimulate MRs in the heart. Once Finerenone binds to the MR, there is a protrusion of MR helix 12 which disables MR activation, therefore blocking the binding of aldosterone. By blocking the binding of aldosterone, the RAAS system. This prevents the aldosterone effects on gene transcription, therefore, there is a decrease in Na+ channels and Na+/K+ ATPase in the membrane. Sodium reabsorption decreases, the concentration of Na+ in the lumen becomes high and as a result, water reabsorption also decreases. The effects on Na+/K+ ATPase results in reduced K+ excretion. This effect of Finerenone is important for treating conditions like hypertension because the increased water excretion in urine leads to decreased blood plasma volume, lowering blood pressure. Finerenone has also been shown to be a therapeutic agent for patients with albuminuria, and to be responsible for decreased BNP levels. BNP is a hormone secreted by cardiomyocytes in heart ventricles in response to increased blood volume. Side effects of using oral Finerenone may include confusion, nausea and vomiting, nervousness, irregular heartbeat, stomach pain, and/or numbness/tingling in the hands, feet, and lips.

Podofilox, also called podophyllotoxin or Condylox, is a topical agent used for the treatment of external genital warts (Condyloma acuminatum) and perianal warts.This drugs comes from the roots of podophyllum plants. It is very irritating to skin and mucous membranes, has keratolytic actions and may have antineoplastic properties. The exact mechanism of action is not well understood, but it does appear that Podofilox and its derivatives may bind and inhibit topoisomerase II during late S and early G2 stages of the cell mitosis. The drug possibly binds and stabilizes the temporary break caused by topoisomerase II. This disrupts the reparation of the break through which double-stranded DNA passes and therefore, stops DNA unwinding and replication. This drug is also studied as a possible tubulin alpha-4A and tubulin beta chains inhibitor. It is available as a topical solution.

Azilsartan medoxomil is a prodrug, it is metabolised in azilsartan during the absorption of the drug in the gastrointestinal tract. Azilsartan is in the angiotensin-receptor blocking (ARB) drug class. This drug selectively binds to AT1 receptors as an antagonist, blocking vasoconstrictor and the aldosterone secretion that angiotensin II provokes (RAAS). Angiotensin II usually binds to angiotensin II type 1 receptor (AT1 receptor) to stimulate the synthesis of aldosterone and promote renal tubular reabsorption of sodium. This molecule also inhibits secretion of renin. The antagonist (azilsartan) of those AT1 receptor provokes a decrease in blood pressure. This drug is available as a tablet.

Tasosartan is a selective angiotensin II (AngII) receptor type 1 (AT1) inhibitor. It is used for the treatment of hypertension and heart failure. This drug causes the blockade of the renin-angiotensin-aldosterone system (RAAS) at the level of the AT1 receptor. Tasosartan is an antagonist of the AT1 receptors localize in the vascular muscles and the adrenal gland. This drug thus causes dilatation, reduced secretion of avsopressin (ADH), and reduced production and secretion of aldosterone.

Letermovir is an antiviral medication that treats cytomegalovirus (CMV) infections and disease in adult CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant.It was approved by the FDA on November 8, 2017 and is the first of the DNA terminase complex inhibitors for CMV. Cytomegalovirus requires a DNA terminase complex for processing of viral DNA. This complex consists of multiple subunits (pUL51, pUL56, and pUL89). Viral DNA is produced in a single repeating strand which is cut by the DNA terminase complex into individual genomes which can then be packaged into the mature viral particles. Letemovir inhibits the DNA terminase complex, preventing the viral DNA from cutting the DNA and packaging it inside the viral capsid. Thie produces immature, non-infective viruses.

Saprisartan is an Type-1 angiotensin II (AT1) receptor antagonist, its chemical structure comes from losartan. This drug is a noncompetitve antagonism of AT1. It blocks the renin-angiotensin-aldosterine system (RAAS) when binding the AT1 receptor that mediates the important actions of angiotensin II. By inhibiting those actions, saprosartan leads to a decrease in sodium reabsorpion and a decrease in vasoconstriction, those two actions decrease the blood pressure.

This drug is administered as the prodrug (candesartan cilexetil), this molecule is quickly converted in candesartan, the active metabolite while it is absorbed in the gastrointestinal tract (ester hydrolosis). Candesartan selectively inhibits the binding of angiotensin II to Type-1 angiotensin II receptors (AT1) in vascular smooth muscle and adrenal glands. In consequence of this interaction, AT1-mediated vasoconstrictive and aldosterone-secreting effects of angiotensin II are inhibited (inhibition of the RAAS). The last inhibition may increase sodium and water excretion while decresing the excretion of potassium. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin comes in the blood by the granular cells (kidneys). This protein cleaves the angiotensinogen to angiotensin I, which is cleaved by angiotensin converting enzyme (ACE) to angiotensin II. Angiotensin II increases blood pressure by increasing sodium and water reabsorption in the kidneys via aldosterone secretion. Angiotensin II can bind two receptors: type-1 angiotensin II receptor (AT1) and type-2 angiotensin II receptor (AT2). AT1, a G-protein coupled receptor, mediates the vasoconstrictive and aldosterone-secreting effects of angiotensin II. Candesartan cilexetil is available as a tablet.

Tixagevimab is an extended half-life recombinant monoclonal IgG1κ antibody directed against the SARS-CoV-2 S protein for COVID-19 prophylaxis in individuals unable to undergo COVID-19 immunization.Tixagevimab, in combination with cilgavimab, was issued an FDA emergency use authorization on December 9, 2021. The combination of drugs was packaged as EVUSHELD and was granted marketing authorization by the EMA on March 28, 2022, then it was approved in Canada later on April 14, 2022. Certain SAR-CoV-2 Omicron subvariants may be associated with resistence to EVUSHELD. SARS-CoV-2 enters host cells via the interaction between the trimeric spike (S) glycoprotein and host cell angiotensin-converting enzyme 2 (ACE2). Cilgavimab inhibits S glycoprotein by blocking the interaction between it and the host ACE2 protein. This inhibits the binding and entry of the virion into the host cell. This prevents viral replication and propagation.