Pathways

Metabolites of Acenocoumarol are predicted with biotransformer.

Acenocoumarol (also known as Nitrowarfarin or Sinthrome) is an anticoagulant that inhibit the liver enzyme vitamin K reductase, which cause Vitamin K1 2,3-epoxide could not be catalyzed by vitamin K reductase to form vitamin KH2, the reduced form of vitamin K. Vitamin K-dependent coagulation factors (II, VII, IX, and X) requires its cofactor, vitamin K to facilitate the activation and gamma-carboxylation. Inhibition of vitamin K reductase results in reduced concentration of vitamin KH2, which will ultimately lead to decreased coagulability of the blood and reduced cleavage of fibrinogen into fibrin.

Acenocoumarol is a vitamin K antagonist derived from coumarin. It is also marketed as Sintrom. Acenocoumarol works as other vitamin K antagonists, by reducing the stores of reduced vitamin K, by inhibiting the vitamin K reductase complex, and preventing the recycling of the vitamin K within the cell. This in turn prevents coagulation factors VIII, IX, X as well as prothrombin, factor II, from activating, which in turn prevents fibrin clots from being formed and stabilized. Acenocoumarol is administered orally, and within 2 days, it is absorbed in the intestine and enters the liver. There, it inhibits the vitamin K epoxide reductase complex, preventing vitamin K1 2,3-epoxide from being recycled into reduced vitamin K. This leads to less reduced vitamin K to be present in order to react with the precursors of coagulation factors II, VII, IX and X through the vitamin K dependent gamma-carboxylase, and prevents those coagulation factors from being produced. Normally, coagulation factor IX is activated by factor XIa, which then, with the addition of coagulation factor VIII, forms the tenase complex that activates coagulation factor X. Activated coagulation factor Xa then joins with coagulation factor V to form the prothrombinase complex which forms thrombin from prothrombin. Thrombin is then necessary to convert fibrinogen to loose fibrin within the blood plasma, as well as converting coagulation factor XIII into its activated form. The fibrin then is able to polymerizes, and is stabilized into a water insoluble clot by coagulation factor XIIIa. The presence of acenocoumaroll and the absence of reduced vitamin K prevents this coagulation cascade from occurring as much due to lack of substrates, and thus helps to prevent blood clotting.

Acenocoumarol is a anticoagulant drug that is used to prevent blood clots to avoid thromboembolic diseases that could result in infarction, ischemic attacks, deep vein thrombosis and myocardial infarction. Acenocoumarol is a derivative from coumarin that is used to inhibit vitamin k reductase, by doing this the carboxylation of vitamin-k depedent factors such as II, VII, IX and X are prevented. As the concentration of reduced form of vitamin K decreases this leads to a depletion of the cofactor for future reactions that are vitamin k dependent. This ultimately leads to interference with coagulation, because of this patients should not give blood during the time they are using Acenocoumarol. Acenocoumarol is rapidly absorbed through oral ingestion and metabolized via oxidation in the liver. Side effects can include bleeding, blood in urine, swelling of clotted blood in the tissue, gastrointestinal bleeding, tachycardia, hypotension, nausea, vomiting, diarrhea and abdominal pains.

Acemetacin is highly metabolized and degraded by esterolytic cleavage to form its major and active metabolite indometacin. Indomethacin is a nonsteroidal anti-inflammatory (NSAID) used for the symptomatic management of chronic musculoskeletal pain conditions and to induce closure of a hemodynamically significant patent ductus arteriosus in premature infants. This drug is not FDA, Canada or EMA approved. It has analgesic, antipyretic, and anti-inflammatory effects. It targets the prostaglandin G/H synthase-1 (COX-1) and prostaglandin G/H synthase-2 (COX-2) in the cyclooxygenase pathway. The cyclooxygenase pathway begins in the cytosol with phospholipids being converted into arachidonic acid by the action of phospholipase A2. The rest of the pathway occurs on the endoplasmic reticulum membrane, where prostaglandin G/H synthase 1 & 2 convert arachidonic acid into prostaglandin H2. Prostaglandin H2 can either be converted into thromboxane A2 via thromboxane A synthase, prostacyclin/prostaglandin I2 via prostacyclin synthase or prostaglandin E2 via prostaglandin E synthase. COX-2 is an inducible enzyme, and during inflammation, it is responsible for prostaglandin synthesis. It leads to the formation of prostaglandin E2 which is responsible for contributing to the inflammatory response by activating immune cells and for increasing pain sensation by acting on pain fibers. Indomethacin inhibits the action of COX-1 and COX-2 on the endoplasmic reticulum membrane. This reduces the formation of prostaglandin H2 and therefore, prostaglandin E2 (PGE2). The low concentration of prostaglandin E2 attenuates the effect it has on stimulating immune cells and pain fibers, consequently reducing inflammation and pain. Fever is triggered by inflammatory and infectious diseases. Cytokines are produced in the central nervous system (CNS) during an inflammatory response. These cytokines induce COX-2 production that increases the synthesis of prostaglandin, specifically prostaglandin E2 which adjusts hypothalamic temperature control by increasing heat production. Because indomethacin decreases PGE2 in the CNS, it has an antipyretic effect. In clinical trials, acemetacin exhibits better gastric tolerability compared to its active metabolite indometacin.

Aceclofenac is a non-steroidal anti-inflammatory drug (NSAID) with marked anti-inflammatory and analgesic properties. It is used to treat osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis. Aceclofenac targets the prostaglandin G/H synthase-1 (COX-1) and prostaglandin G/H synthase-2 (COX-2) in the cyclooxygenase pathway. Aceclofenac displays more selectivity towards COX-2 (IC50 of 0.77uM) than COX-1 (IC50 of >100uM), which promotes gastric tolerance compared to the other NSAIDs. The cyclooxygenase pathway begins in the cytosol with phospholipids being converted into arachidonic acid by the action of phospholipase A2. The rest of the pathway occurs on the endoplasmic reticulum membrane, where prostaglandin G/H synthase 1 & 2 convert arachidonic acid into prostaglandin H2. Prostaglandin H2 can either be converted into thromboxane A2 via thromboxane A synthase, prostacyclin/prostaglandin I2 via prostacyclin synthase, or prostaglandin E2 via prostaglandin E synthase. COX-2 is an inducible enzyme, and during inflammation, it is responsible for prostaglandin synthesis. It leads to the formation of prostaglandin E2 which is responsible for contributing to the inflammatory response by activating immune cells and for increasing pain sensation by acting on pain fibers. Aceclofenac inhibits the action of COX-1 and COX-2 on the endoplasmic reticulum membrane. This reduces the formation of prostaglandin H2 and therefore, prostaglandin E2 (PGE2). The low concentration of prostaglandin E2 attenuates the effect it has on stimulating immune cells and pain fibers, consequently reducing inflammation and pain. This drug is administered as an oral tablet.

Metabolites of Aceclidine are predicted with biotransformer.