Browsing Pathways

Sodium valproate, also known as valproic acid, is a fatty acid derivative and anticonvulsant first synthesized in 1881-1882 from an analogue derived from the Valerian herb; however, its mechanism of action is not fully elucidated (yet). Traditionally, researchers and clinicians consider it to be an anticonvulsant due to its effects in the brain: it blocks voltage-gated sodium channels and potentiates gamma-aminobutyric acid (GABA) activity. Over the past centuries, investigations show valproate may also have neuroprotective, anti-manic, and anti-migraine effects. It is a compound of interest in the field of oncology for its anti-proliferative effects and has undergone some clinical trials. Currently, valproate is indicated for use as a monotherapy or adjunct medication in seizure management, for migraine prophylaxis, and for mitigation of acute mania associated with bipolar disorder. Off-label, clinicians may use valproate to manage bipolar disorder or for emergency treatment of status epilepticus. Valproate can be administered orally, in which case it undergoes hepatic first-pass metabolism to enter the bloodstream ___________________ https://go.drugbank.com/drugs/DB00313

Nifedipine is predominantly metabolized by CYP3A4. Nifedipine is predominantly metabolized to 2,6-dimethyl-4-(2-nitrophenyl)-5-methoxycarbonyl-pyridine-3-carboxylic acid, and then further metabolized to 2-hydroxymethyl-pyridine carboxylic acid. Nifedipine is also minorly metabolized to dehydronifedipine. (DrugBank)

Chlorothiazide is an oral diuretic drug which acts in the kidney, specifically in the distal convoluted tubule of the nephron. It is used as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. It is also indicated in the management of hypertension either as the sole therapeutic agent or to enhance the effectiveness of other antihypertensive drugs in the more severe forms of hypertension. In the distal convoluted tubule (DCT), the regulation of ions such as sodium, potassium, calcium, chloride and magnesium occurs. In epithelial cells of the DCT, the basolateral membrane consists of the Na+/K+ ATPase, which pumps Na+ into the interstitium-blood area and K+ into the epithelial cell; the Na+/Ca2+ exchanger, which pumps Na+ into the cell and Ca2+ into the interstitium-blood; and the chloride transporter which transports chloride into the interstitium-blood. The apical membrane contains a calcium channel that transports calcium from the lumen into the epithelial cell, a potassium channel that transports K+ out of the epithelial cell, and a Na+/Cl- cotransporter which transports Na+ and Cl- into the epithelial cell. Chlorothiazide targets this Na+/Cl- cotransporter. Chlorothiazide is transported from the blood into the epithelial cells, then is transported into the urine through the multidrug-resistant associated protein-4. In the lumen it has access to the Na+/Cl- transporter and inhibits it preventing Na+ reabsorption. The inhibition of Na+ reabsorption results in a low cytosolic concentration of Na+ and increases the solute concentration of the lumen. This decreases the lumen-epithelial cell concentration gradient and as a result, less water would be reabsorbed from the urine. This effect is valued in conditions such as hypertension because it allows more water to be excreted in urine rather than be absorbed in the blood which increases blood volume. Side effects such as frequent urination, muscle spasms, blurred vision, constipation, diarrhea, vomiting, loss of appetite, and headache can occur from taking chlorothiazide. This drug is administered as an oral tablet or as an intravenous injection.

Cimetidine is an H2 receptor antagonist drug that is mainly used to treat peptic ulcers and heartburns. It works by acting as a competitive inhibitor and blocks the action of histamine on Histamine H2 receptors. This ultimately reduces gastric acid secretion in the stomach lumen by parietal cells that is caused by histamines interaction with the H2 receptor. This receptors activation causes downstream cascading signals that target the transporters pumping out hydrogen ions which leads to the secretion of acid in the stomach lumen.

Captopril is a potent, competitive inhibitor of angiotensin-converting enzyme (ACE), the enzyme responsible for the conversion of angiotensin I (ATI) to angiotensin II (ATII). ATII regulates blood pressure and is a key component of the renin-angiotensin-aldosterone system (RAAS). Captopril may be used in the treatment of hypertension. (DrugBank) Major metabolites are captopril-cysteine disulfide and the disulfide dimer of captopril. Metabolites are produced by Cytochrome P450 3A4 in the liver and may undergo reversible interconversion. These metabolites are excreted via the Organic anion transporter 1 (OAT1).

Famotidine is an histamine H2 receptor antagonist used to treat stomach ulcers and Gastroesophageal Reflux Disease (GERD). After being taken orally, it is absorbed in the GI tract and travels through the blood to get to the stomach epithelium. Famotidine binds reversibly to the histamine H2 receptor blocking histamine from binding instead. This blocks the downstream Gs cascade which produces cyclic adenosine monophosphate (cAMP) which is an activator for the potassium-hydrogen ATPase pump (H+/K+ ATPase pump). The pump is responsible for secreting hydrogen ions into the stomach lumen increasing the acidity of the stomach environment. By blocking adenylate cyclase signalling pathway from the histamine H2 receptor less hydrogen ions are secreted into the stomach lumen increasing the pH. The less acidic environment doesn't irritate the stomach as much. The H+/K+ ATPase pump can still be activated through gastrin and acetylcholine through the phospholipase C signalling pathway, but blocking the adenylate cyclase pathway helps reduce the acidity.

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