Pathways

Apparent mineralocorticoid excess (AME), also known as cortisol 11-beta-ketoreductase deficiency, is an extremely rare inborn error of metabolism (IEM) and autosomal recessive disorder of the steroidogenesis pathway. It is caused by a mutation in the HSD11B2 gene which encodes for corticosteroid 11-beta-dehydrogenase isozyme 2, and enzyme that converts cortisol to cortisone in the cell. Without this enzyme being functional, an accumulation of tetrahydrocortisol builds up, while tetrahydrocortisone levels dissipate. AME is characterized excessive thirst and urination, and along with this, symptoms include low levels of aldosterone, failure to thrive and hypertension. Treatment with corticoids that suppress the secretion of cortisol within the body can affect blood pressure and aldosterone levels. Antihypertensive agents are also effective. It is estimated that AME affects less than 1 in 1,000,000 individuals, with less than 100 reported cases as of 2019.

Metabolites of Aprepitant are predicted with biotransformer.

Aprotinin, trade name Trasylol is a bovine serine protease inhibitor of trypsin, chymotrypsin, kallikrein and plasmin. Aprotinin is administered prophylactically to patients undergoing surgery with a high risk of bleeding to block fibrinolysis and prevent the breakdown of blood clots. The inhibition of kallikrein inhibits factor XIIa production to reduce fibrinolysis and coagulation. Inhibition of plasmin slows down fibrinolysis. Hypersensitivity reactions may occur after repeat exposure to Aprotinin.

Aprotinin is an inhibitor that is used to prevent blood loss during cardiopulmonary bypass surgery. It slows the breakdown of fibrin clots to reduce bleeding plasminogen and kallikrein. The drug is slowly metabolized by lysosomal enzymes and is eliminated through the urine over 48 hours.

Aprotinin is a naturally occurring serine protease inhibitor derived from bovine lung. It is administered intravenously as an antifibrinolytic agent for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass in the course of coronary artery bypass graft surgery who are at an increased risk for blood loss and blood transfusion. The clotting process consists of two pathways, intrinsic and extrinsic, which converge to create stable fibrin which traps platelets and forms a hemostatic plug. The intrinsic pathway is activated by trauma inside the vasculature system, when there is exposed endothelial collagen. Endothelial collagen only becomes exposed when there is damage. The pathway starts with plasma kallikrein activating factor XII. The activated factor XIIa activates factor XI. Factor IX is then activated by factor XIa. Thrombin activates factor VIII and a Calicum-phospholipid-XIIa-VIIIa complex forms. This complex then activates factor X, the merging point of the two pathways. The extrinsic pathway is activated when external trauma causes blood to escape the vasculature system. Activation occurs through tissue factor released by endothelial cells after external damage. The tissue factor is a cellular receptor for factor VII. In the presence of calcium, the active site transitions and a TF-VIIa complex is formed. This complex aids in activation of factors IX and X. Factor V is activated by thrombin in the presence of calcium, then the activated factor Xa, in the presence of phospholipid, calcium and factor Va can convert prothrombin to thrombin. The extrinsic pathway occurs first, producing a small amount of thrombin, which then acts as a positive feedback on several components to increase the thrombin production. Thrombin converts fibrinogen to a loose, unstable fibrin and also activates factor XIII. Factors XIIIa strengthens the fibrin-fibrin and forms a stable, mesh fibrin which is essential for clot formation. The blood clot can be broken down by the enzyme plasmin. Plasmin is formed from plasminogen by tissue plasminogen activator. Aprotinin inhibits plasmin, preventing the degradation of the fibrin clot and reducing bleeding. Aprotinin also inhibits plasma kallikrein. This prevents the formation of factor XIIa, thereby inhibiting the intrinsic pathway of the coagulation cascade and reducing coagulation. When blood is subjected to extracorporeal circulation during cardiopulmonary bypass surgery, there are certain changes in normal coagulation and clotting properties. Clotting mechanisms that are activated through surface-media contact increases thrombotic and fibrinolytic activity and is responsible for excessive bleeding. This is why aprotinin targets both coagulation and fibrinolysis, to re-establish normal homeostatic balance of clot formation and clot lysis. Side effects of aprotinin include atrial fibrillation, fever, nausea, low blood pressure, lung problems, kidney disease, blood clots, heart failure, severe allergic reaction (anaphylaxis), stroke, or trouble breathing.