Pathways

Fenofibrate is a peroxisome proliferator receptor alpha activator used to lower LDL-C, total-C, triglycerides, and Apo B, while increasing HDL-C in hypercholesterolemia, dyslipidemia, and hypertriglyceridemia. Fenofibrate is a fibrate that activates peroxisome proliferator activated receptor alpha (PPARα) to alter lipid metabolism and treat primary hypercholesterolemia, mixed dyslipidemia, and severe hypertriglyceridemia. Fenofibrate requires once daily dosing and has a half-life of 19-27 hours so its duration of action is long. Fenofibrate is completely hydrolyzed by liver carboxylesterase 1 to fenofibric acid. Fenofibric acid is either glucuronidated or has its carbonyl group reduced to a benzhydrol that is then glucuronidated. Glucuronidation of fenofibrate metabolites is mediated by UGT1A9. Reduction of the carbonyl group is primarily mediated by CBR1 and minorly by AKR1C1, AKR1C2, AKR1C3, and AKR1B1. 5-25% of a dose of fenofibrate is eliminated in the feces, while 60-88% is eliminated in the urine. 70-75% of the dose recovered in the urine is in the form of fenofibryl glucuronide and 16% as fenofibric acid.

Fenoldopam is a racemic mixture with the R-isomer responsible for the biological activity. The R-isomer has approximately 250-fold higher affinity for D1-like receptors than does the S-isomer. Fenoldopam is a dopamine (D1) receptor agonist that results in decreased peripheral vascular resistance primarily in renal capillary beds, thus promoting increased renal blood flow, natriuresis, and diuresis. Fenoldopam has minimal adrenergic effects. Fenoldopam is used as an antihypertensive agent postoperatively and also intravenously to treat hypertensive crises. Since fenoldopam is the only intravenous agent that improves renal perfusion, it may be beneficial in hypertensive patients with chronic kidney disease. Fenoldopam administration is via a continuous intravenous (IV) infusion using an infusion pump. In arteries, the tunica media is composed of smooth muscle cells activated by various neurotransmitters, hormones, and mechanical perturbations. The contraction and relaxation of vascular smooth muscle are the mechanisms by which changes in systemic vascular resistance (SVR) occur. Dopamine D1 receptors are located in the tunica media of arteries and exert their effects through a G-alpha stimulatory second messenger system. Upon ligand binding such as fenoldopam binding to D1-receptors, the alpha subunit dissociates from the intracellular domain of the transmembrane receptor and activates adenylate cyclase (AC). AC subsequently converts ATP to cyclic adenosine monophosphate (cAMP). All downstream effects get mediated by cAMP, the chief second messenger in this pathway. Inside the cell, cAMP activates protein kinase A (PKA). PKA phosphorylates MLCK, thus causing its inactivation. Since myosin cannot undergo phosphorylated by MLCK, the cross-bridge formation between myosin and actin does not occur, rendering the arterial smooth muscle cell unable to contract. The result is the dilation of arteries producing decreased SVR, increased renal blood flow, natriuresis, and diuresis. These pharmacologic effects result in a decrease in blood pressure.

Fenoprofen (also named Nalfon) is a nonsteroidal anti-inflammatory drug. Fenoprofen 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 Fenoprofen.

Fenoprofen is an anti-inflammatory analgesic used to treat mild to moderate pain in addition to the signs and symptoms of rheumatoid arthritis and osteoarthritis. Fenoprofen possesses anti-inflammatory, analgesic and antipyretic activity. 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 converts 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. Fenoprofen 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 fenoprofen decreases PGE2 in the CNS, it has an antipyretic effect. Antipyretic effects results in an increased peripheral blood flow, vasodilation, and subsequent heat dissipation.

Metabolites of Fenoprofen are predicted with biotransformer.

Fenoterol is a short acting beta-2 adrenergic receptor agonist that is used as a bronchodilator. This drug causes the relaxation of bronchial smooth muscle allowing for its use for the treatment of asthma. The result of taking this drug is relaxation of the bronchial smooth muscles causing bronchodilaton and increased airflow. Once fenoterol is administered and it binds to the beta-2 adrenergic receptor, the G protein signalling cascade begins. The alpha and beta/gamma subunits of the G protein separate and GDP is replaced with GTP on the alpha subunit. This alpha subunit then activates adenylyl cyclase which converts ATP to cAMP. cAMP then activates protein kinase A (PKA) which in turn phosphorylates targets and inhibits MLCK through decreased calcium levels causing muscle relaxation. PKA can phosphorylate certain Gq-coupled receptors as well as phospholipase C (PLC) and thereby inhibit G protein-coupled receptor (GPCR) -PLC-mediated phosphoinositide (PI) generation, and thus calcium flux. PKA phosphorylates the inositol 1,4,5-trisphosphate (IP3) receptor to reduce its affinity for IP3 and further limit calcium mobilization. PKA phosphorylates myosin light chain kinase (MLCK) and decreases its affinity to calcium calmodulin, thus reducing activity and myosin light chain (MLC) phosphorylation. PKA also phosphorylates KCa++ channels in ASM, increasing their open-state probability (and therefore K+ efflux) and promoting hyperpolarization. Since myosine light chain kinase is not activated, Serine/threonine-protein phosphatase continues to dephosphorylate myosin LC-P, and more cannot be synthesized so myosin remains unbound from actin causing muscle relaxation. This relaxation of the smooth muscles in the lungs causes the bronchial airways to relax which causes bronchodilation, making it easier to breathe. Some side effects of using fenoterol may include chest pain, dizziness, dry mouth, fatigue, and headache.