Browsing Pathways

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.

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.

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.

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.

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.

Ketorolac (also named Toradol) is a nonsteroidal anti-inflammatory drug (NSAID). It can be used to relieve pain (analgesic), reduce fever (antipyretic) and swelling. Ketorolac 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. Since prostaglandin is the messenger molecules in the process of inflammation; hence, inhibition of prostaglandin synthesis can reduce the pain, fever and inflammation.

Lovastatin (also known as Mevacor or Mevinolin) is a statin drug (hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors) that can be used for lowering cholesterol, treating hypercholesterolemia and preventing myocardial infarction and stroke. Lovastatin is produced by fermentation of Aspergillus terreus. HMG-CoA catalyzes the conversion of HMG-CoA to mevalonic acid, the rate-limiting step of cholesterol biosynthesis. Lovastatin, like simvastin, is a prodrug. These prodrugs are converted to their active form by in vivo hydrolysis of the lactone ring. The hydrolyzed lactone ring resembles the tetrahedral reaction intermediate produced by HMG-CoA reductase and the bicyclic portions of these compounds bind to the coenzyme A site of the enzyme. The active drug concentrates in the liver during first-pass circulation. Cholesterol biosynthesis accounts for approximately 80% of cholesterol in the body; thus, inhibiting this process can significantly lower cholesterol levels.

Hydroflumethiazide (also known as Esidrix or Oretic) 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.

Suprofen (also named Profenal and Maldocil) is a nonsteroidal anti-inflammatory drug (NSAID). It can be used to relieve pain (analgesic) and reduce fever (antipyretic). Suprofen is also a type of ophthalmic anti-inflammatory medicines which may be used to help prevent eye constrict for pupil during surgery. Suprofen 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. Since prostaglandin is the messenger molecules in the process of inflammation; hence, inhibition of prostaglandin synthesis can reduce the pain and inflammation (e.g. in the eyes).

Bromfenac (also named Prolensa, Bromday or Xibrom) is a nonsteroidal anti-inflammatory drug (NSAID). It can be used to reduce ocular inflammation and pain after cataract surgery. Bromfenac is also a type of ophthalmic anti-inflammatory medicines. Bromfenac 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 in many animal model's cell is caused by presence of bromfenac.