Browsing Pathways

Piroxicam (also named Feldene or Piroxicamum) is a nonsteroidal anti-inflammatory drug. Piroxicam 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 piroxicam. Piroxicam can prevent movement of leukocytes to inflammation site so that thromboxane A2 can't be produced.

Chlorothiazide (also known as Diuril) 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.

The action of ibandronate on bone tissue is based partly on its affinity for hydroxyapatite, which is part of the mineral matrix of bone. Nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, ibandronate and zoledronate) appear to act as analogues of isoprenoid diphosphate lipids, thereby inhibiting farnesyl pyrophosphate (FPP) synthase, an enzyme in the mevalonate pathway of cholesterol biosynthesis. Inhibition of this enzyme in osteoclasts prevents the biosynthesis of isoprenoid lipids (FPP and GGPP) that are essential for the post-translational farnesylation and geranylgeranylation of small GTPase signaling proteins. This activity inhibits osteoclast activity and reduces bone resorption and turnover. In postmenopausal women, it reduces the elevated rate of bone turnover, leading to, on average, a net gain in bone mass.

Polythiazide (also known as Renese or Drenusil) 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.

Methyclothiazide (also known as Enduron or Methyclothiazid) 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.

Simvastatin, the methylated form of lovastatin, is an inactive lactone that is metabolized in vivo to β,δ-dihydroxy acid, its most potent metabolite. Cytochrome P450 (CYP) enzymes, CYP3A4, CYP3A5, and CYP2C8, have been implicated in this activation step; CYP3A4/5 are responsible for ≥ 80% of simvastatin metabolism while CYP2C8 (not shown in pathway) contributes to ≤ 20% of its metabolism. The simvastatin hydroxy acid inhibits cholesterol synthesis via the mevalonate pathway by competitively inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reductase, a hepatic microsomal enzyme, is the enzyme responsible for the conversion of HMG-CoA to mevalonic acid, the rate-limiting step of cholesterol biosynthesis by this pathway. The active hydroxy acid is structurally similar to the reduced reaction intermediate and competes with HMG-CoA for binding to HMG-CoA reductase. Cholesterol biosynthesis accounts for approximately 80% of cholesterol in the body; thus, inhibiting this process can significantly lower cholesterol levels.

Acetylsalicylic acid, also known as ASA or aspirin, belongs to a class of drugs known as non-steroidal anti-inflammatory drugs (NSAIDs). In addition to its anti-inflammatory properties, aspirin also acts as an analgesic, antipyretic and antithrombotic agent. Like most other NSAIDs, aspirin exerts its therapeutic effects by inhibiting prostaglandin G/H synthase 1 and 2, better known as cyclooxygenase-1 and -2 or simply COX-1 and -2. COX-1 and -2 catalyze the conversion of arachidonic acid to prostaglandin G2 and prostaglandin G2 to prostaglandin H2. Prostaglandin H2 is the precursor to a number of other prostaglandins, such as prostaglandin E2, involved in pain, fever and inflammation. The antipyretic properties of aspirin arise from inhibition of prostaglandin E2 synthesis in the preoptic region of the hypothalamus. Interference with adhesion and migration of granulocytes, polymorphonuclear leukocytes and macrophages at sites of inflammation account for its anti-inflammatory effects. The analgesic effects of aspirin likely occur due to peripheral action at the site of injury and possibly within the CNS. Aspirin is unique from other NSAIDs in that it is an irreversible COX inhibitor. Aspirin irreversibly acetylates a serine side chain of COX rendering the enzyme inactive. Enzyme activity can only be regained by production of more cyclooxygenase. This unique property of aspirin and its higher selectivity for COX-1 over COX-2 makes it an effective antiplatelet agent. Platelets contain COX-1, a key enzyme in the production thromboxane A2 (TXA2), which is a potent inducer of platelet aggregation. Since platelets lack the ability to make more enzyme, TXA2 production is inhibited for the lifetime of the platelet (approximately 8 – 12 days). Aspirin is commonly used at low doses to prevent cardiovascular events such as strokes and heart attacks. At higher doses, aspirin may be used as an analgesic, anti-inflammatory and antipyretic. Aspirin may cause gastric irritation and bleeding by inhibiting the synthesis of prostaglandins that enhance and maintain the protective gastric mucous layer.

Etodolac is a non-steroidal anti-inflammatory drug (NSAID) that can be used to treat rheumatoid arthritis and osteoarthritis. Most NSAIDs are non-selective prostaglandin G/H synthase (a.k.a. cyclooxygenase or COX) inhibitors that act on both prostaglandin G/H synthase 1 and 2 (COX-1 and -2). Prostaglandin G/H synthase catalyzes the conversion of arachidonic acid to a number of prostaglandins involved in fever, pain, swelling, inflammation, and platelet aggregation. NSAIDs antagonize COX by binding to the upper portion of the active site, preventing its substrate, arachidonic acid, from entering the active site. The analgesic, antipyretic and anti-inflammatory effects of NSAIDs occur as a result of decreased prostaglandin synthesis. Etodolac was previously thought to be a non-selective COX inhibitor; however, it is now know that it is five to fifty times more selective for COX-2 than COX-1. The first part of this figure depicts the anti-inflammatory, analgesic and antipyretic pathway of etodolac. The latter portion of this figure depicts etodolac’s potential involvement in platelet aggregation. Prostaglandin synthesis varies across different tissue types. Platelets, anuclear cells derived from fragmentation from 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 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. Etodolac 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.

Ketoprofen (also known as (RS)-2-(3-benzoylphenyl)-propionic acid) is a nonsteroidal anti-inflammatory drug (NSAID). It can be used to treat rheumatoid arthritis, osteoarthritis, dysmenorrhea, and to alleviate moderate pain.. Ketoprofen 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. Because of hypothalamus action, antipyretic effects may occur which will lead to vasodilation, increased peripheral blood flow and subsequent heat dissipation.

Ibuprofen is a very common NSAID drug used to treat pain and inflammation. This includes headaches, muscle pain and fever. It is sold under the brand name Advil or Motrin. Ibuprofen is typically ingested orally, although in the USA an intravenous version can be used. It inhibits cyclooxygenase (COX) non-selectively. This enzyme is responsible for the creation of prostaglandins, which allow pain to be felt. Inhibiting COX makes prostaglandin creation more sparse, thus resulting in less pain for the patient using ibuprofen. Arachdonic acid is converted into prostaglandin H2 by using cytosolic prostaglandin G/H synthase (COX). These enzymes are available as COX1 and COX2, and are encoded by PTGS1 (COX1) and PTGS2 (COX2). Ibuprofen may also inhibit fatty acid amide hydrolase (FAAH), which results in the activation of antinociceptive axis, which then metabolizes the endocannabinoid anandamide.