Browsing Pathways

Etacrynic acid (also known as ethacrynic acid and Edecrin) is a loop diuretic that can inhibit water reabsorption by binding and inhibiting solute carrier family 12 member 1 (also known as sodium-potassium-chloride cotransporter) in the loop of Henle. Binding of the transporter can prevent import of sodium from lumen from loop of Henle to basolateral interstitium, which lead to more hypertonic environment in lumen than interstitium, and result in prevention of water reabsorption due to diminished osmotic gradient in nephron.

Celecoxib, a non-steroidal anti-inflammatory drug (NSAID), is a selective inhibitor of cyclooxygenase-2 (COX-2), also known as prostaglandin G/H synthase 2. Like other NSAIDs, celecoxib exerts its effects by inhibiting the synthesis of prostaglandins involved in pain, fever and inflammation. COX-2 catalyzes the conversion of arachidonic acid to prostaglandin G2 (PGE2) and PGE2 to prostaglandin H2 (PGH2). In the COX-2 catalyzed pathway, PGH2 is the precusor of prostaglandin E2 (PGE2) and I2 (PGI2). PGE2 induces pain, fever, erythema and edema. Celecoxib antagonizes COX-2 by binding to the upper portion of the active site, preventing its substrate, arachidonic acid, from entering the active site. Similar to other COX-2 inhibitors, such as rofecoxib and valdecoxib, celecoxib appears to exploit slight differences in the size of the COX-1 and -2 binding pockets to gain selectivity. COX-1 contains isoleucines at positions 434 and 523, whereas COX-2 has slightly smaller valines occupying these positions. Studies support the notion that the extra methylene on the isoleucine side chains in COX-1 adds enough bulk to proclude celecoxib from binding. Celecoxib is approximately ten times more selective for COX-2 than COX-1. Celecoxib is used mainly to treat rheumatoid arthritis and osteoarthritis which require something more potent than aspirin. The analgesic, antipyretic and anti-inflammatory effects of celecoxib occur as a result of decreased prostaglandin synthesis. The first part of this figure depicts the anti-inflammatory, analgesic and antipyretic pathway of celecoxib. The latter portion of this figure depicts celecoxib’s potential involvement in platelet aggregation. Prostaglandin synthesis varies across different tissue types. Platelets, which are anuclear cells derived from fragmentation of megakaryocytes, contain COX-1, but not COX-2. COX-1 activity in platelets is required for thromboxane A2 (TxA2)-mediated platelet aggregation. Platelet activation and coagulation do not normally occur in intact blood vessels. After blood vessel injury, platelets adhere to the subendothelial collagen at the site of injury. Activation of collagen receptors initiates phospholipase C (PLC)-mediated signaling cascades resulting in the release of intracellular calcium from the dense tubula system. The increase in intracellular calcium activates kinases required for morphological change, transition to the procoagulant surface, secretion of granular contents, activation of glycoproteins, and the activation of phospholipase A2 (PLA2). Activation of PLA2 results in the liberation of arachidonic acid, a precursor to prostaglandin synthesis, from membrane phospholipids. The accumulation of TxA2, ADP and thrombin mediates further platelet recruitment and signal amplification. TxA2 and ADP stimulate their respective G-protein coupled receptors, thomboxane A2 receptor and P2Y purinoreceptor 12, and inhibit the production of cAMP via adenylate cyclase inhibition. This counteracts the adenylate cyclase stimulatory effects of the platelet aggregation inhibitor, PGI2, produced by neighbouring endothelial cells. Platelet adhesion, cytoskeletal remodeling, granular secretion and signal amplification are independent processes that lead to the activation of the fibrinogen receptor. Fibrinogen receptor activation exposes fibrinogen binding sites and allows platelet cross-linking and aggregation to occur. Neighbouring endothelial cells found in blood vessels express both COX-1 and COX-2. COX-2 in endothelial cells mediates the synthesis of PGI2, an effective platelet aggregation inhibitor and vasodilator, while COX-1 mediates vasoconstriction and stimulates platelet aggregation. PGI2 produced by endothelial cells encounters platelets in the blood stream and binds to the G-protein coupled prostacyclin receptor. This causes G-protein mediated activation of adenylate cyclase, which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic AMP (cAMP). Four cAMP molecules then bind to the regulatory subunits of the inactive cAMP-dependent protein kinase holoenzyme causing dissociation of the regulatory subunits and leaving two active catalytic subunit monomers. The active subunits of cAMP-dependent protein kinase catalyze the phosphorylation of a number of proteins. Phosphorylation of inositol 1,4,5-trisphosphate receptor type 1 on the endoplasmic reticulum (ER) inhibits the release of calcium from the ER. This in turn inhibits the calcium-dependent events, including PLA2 activation, involved in platelet activation and aggregation. Inhibition of PLA2 decreases intracellular TxA2 and inhibits the platelet aggregation pathway. cAMP-dependent kinase also phosphorylates the actin-associated protein, vasodilator-stimulated phosphoprotein. Phosphorylation inhibits protein activity, which includes cytoskeleton reorganization and platelet activation. Celecoxib preferentially inhibits COX-2 with little activity against COX-1. COX-2 inhibition in endothelial cells decreases the production of PGI2 and the ability of these cells to inhibit platelet aggregation and stimulate vasodilation. These effects are thought to be responsible for the adverse cardiovascular effects observed with other selective COX-2 inhibitors, such as rofecoxib, which has since been withdrawn from the market.

Alendronate (also known as alendronic acid) is a type of bisphosphonate medication with nitrogen that can inhibit FPP synthase, which can block the pathway that produce geranyl-PP and farnesyl pyrophosphate. Geranyl-PP and farnesyl pyrophosphate are the compounds that are required for small GTPase signalling proteins undergo post-translational farnesylation and geranylgeranylation. Therefore, lack the formation of geranyl-PP and farnesyl pyrophosphate can prevent osteoclast activity, which lead to prevention of reduced bone resorption and turnover.

Sulindac, sold as Clinoril, is a non-steroidal anti-inflammatory drug (NSAID). These drugs are typically used to treat conditions associated with pain and inflammation, such as rheumatoid arthritis, headaches or migraines, and dysmenorrhoea. Sulindac is believed to be a non-selective NSAID, meaning that it inhibits both prostaglandin G/H synthase 1 and 2 (COX-1 and COX-2). In this pathway, sulindac, a prodrug, is administered orally. Once in the body, it is metabolized to form the active form of sulindac, which then inhibits the COX-1 and COX-2 enzymes. These enzymes are normally responsible for the formation of prostaglandin G2 from arachidonic acid, well as the formation of prostaglandin H2 from prostaglandin G2. These prostaglandins are responsible for inflammation and fever, as well as muscle contractions in labour and menstruation. With the COX-1 and COX-2 enzymes being inhibited by sulindac, prostaglandins cannot be produced, and inflammation and fever can be reduced. Compared to other NSAIDs, sulindac is less likely to damage the kidneys and cause gastrointestinal effects such as ulcers, but is more likely to damage the liver and pancreas.

Diclofenac (also named Voltaren) is a nonsteroidal anti-inflammatory drug (NSAID). It can be used to treat prostaglandin G/H synthase related fever, swelling, pain and inflammation. Diclofenac can block prostaglandin synthesis by the action of inhibition of prostaglandin G/H synthase 1 and 2. Prostaglandin G/H synthase 1 and 2 catalyze the arachidonic acid to prostaglandin G2, and also catalyze prostaglandin G2 to prostaglandin H2 in the metabolism pathway. Decreased prostaglandin synthesis is caused by presence of diclofenac.

Rosuvastatin, sold as Crestor, Rosulip and Zuvamor, belongs to the class of drugs known as statins. It is taken orally to inhibit the endogenous production of cholesterol in the liver. Statins do this by inhibiting the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme is typically responsible for the conversion of HMG-CoA to mevalonic acid, the third and rate-limiting step of cholesterol, LDL and VLDL synthesis. Rosuvastatin has a similar structure to 3-hydroxy-3-methylglutaryl-CoA, and acts to competitively inhibit the action of HMG-CoA reductase. Statins such as rosuvastatin are used to lower the risk of cardiovascular disease due to higher than normal levels of LDL ad VLDL, which are sometimes known as bad cholesterol. Cardiovascular disease can include heart attacks, angina, strokes and artery disease, and LDL and VLDL levels are a risk factor for its development. Because rosuvastatin is not highly metabolized by Cytochrome P450 enzymes and is taken up quickly due to its hydrophilicity, it has less drug interactions than other statins. It is also the most potent statin, meaning a smaller dose is required. However, it does not prevent CVD any better than other statins.

Quinethazone, also known under the brand-name Hydromox, is a pharmacologically-active small molecule that belongs to a class of drugs called thiazides. Thiazides and thiazide-like drugs are diuretics commonly employed to control hypertension. The short term mechanism of action is relatively well-understood: thiazides inhibit sodium-chloride co-transport into the renal distal convoluted tubule of the nephron and therefore increase fluid loss which decreases extracellular fluid (ECF), plasma volume, and ultimately blood pressure. In the case of quinethazone, it inhibits the sodium-chloride symporter, solute carrier family 12 member 3. Thiazides also inhibit sodium ion transport. However, the long-term mechanism of action isn’t as well-characterized and it is thought that other processes beyond regulating plasma and ECF volumes are involved as these two volumes return to baseline within 4-6 weeks of first use of thiazides.

Bendroflumethiazide (also known as bendrofluazide (BAN) or Aprinox) is an organic compound that used for diuretic. It can inhibit the solute carrier family 12 member 3 (also known as sodium-chloride symporter) in the nephron to prevent water reabsorption. Solute carrier family 12 member 3 is also used for sodium reabsorption that count for 5% of total amount. Solute carrier family 12 member 3 transports chloride and sodium from lumen to epithelial cell, and sodium/potassium ATPases facilitate the export of sodium to basolateral interstitium to provide sodium gradient that will increase the osmolarity in interstitium, which lead to establishment of osmotic gradient for water reabsorption.

Pravastatin inhibits cholesterol synthesis via the mevalonate pathway by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reductase is the enzyme responsible for the conversion of HMG-CoA to mevalonic acid, the rate-limiting step of cholesterol synthesis by this pathway. Pravastatin bears a chemical resemblance to the reduced HMG-CoA reaction intermediate that is formed during catalysis. Structure-activity relationship studies have demonsotrated that statins bind to HMG-CoA reductase at the same site as the reduced reaction intermediate and are held in place by similar chemical interactions. Cholesterol biosynthesis accounts for approximately 80% of cholesterol in the body; thus, inhibiting this process can significantly lower cholesterol levels. Pravstatin was derived from the microbial transformation of mevastatin, which is a natural compound produced by Penicillium citinium and the first statin ever studied. Unlike lovastatin and simvastatin, pravastatin is relatively hydrophilic and does not require hydrolysis for activation. Increased hydrophilicity accounts for its decreased penetration of lipophilic peripheral cells, increased selectivity for hepatic tissues and decreased side effects relative to simvastatin and lovastatin.

Bumetanide, trade name Bumex, is a loop diuretic that increases urine production by inhibiting the reabsorption of water in the nephron. In the thick ascending limb of the loop of Henle, the sodium-potassium-chloride cotransporter (NKCC2) is competitively inhibited at the chloride binding site blocking sodium transport from the lumen to the interstitium. This results in the lumen becoming hypertonic and a decreased osmotic gradient thereby reducing the water reabsorption. In the nephron, the think ascending limb reabsorbs 25% of sodium and is a good target for diuretics.