263PathwayFelodipine Metabolism PathwayFelodipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction. Similar to other DHP CCBs, felodipine binds directly to inactive calcium channels stabilizing their inactive conformation. Since arterial smooth muscle depolarizations are longer in duration than cardiac muscle depolarizations, inactive channels are more prevalent in smooth muscle cells. Alternative splicing of the alpha-1 subunit of the channel gives felodipine additional arterial selectivity. At therapeutic sub-toxic concentrations, felodipine has little effect on cardiac myocytes and conduction cells.
This pathway depicts the pharmacological action of felodipine on arterial smooth muscle cells. Felodipine decreases arterial smooth muscle contractility and subsequent vasoconstriction by inhibiting the influx of calcium ions through L-type calcium channels. Calcium ions entering the cell through these channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium decreases the contractile activity of arterial smooth muscle cells and results in vasodilation. The vasodilatory effects of felodipine result in an overall decrease in blood pressure. Felodipine may be used to treat mild to moderate essential hypertension.
. Drug MetabolismPW000595CenterPathwayVisualizationContext66513001100#000099PathwayVisualization292263Felodipine PathwayFelodipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction. Similar to other DHP CCBs, felodipine binds directly to inactive calcium channels stabilizing their inactive conformation. Since arterial smooth muscle depolarizations are longer in duration than cardiac muscle depolarizations, inactive channels are more prevalent in smooth muscle cells. Alternative splicing of the alpha-1 subunit of the channel gives felodipine additional arterial selectivity. At therapeutic sub-toxic concentrations, felodipine has little effect on cardiac myocytes and conduction cells.
This pathway depicts the pharmacological action of felodipine on arterial smooth muscle cells. Felodipine decreases arterial smooth muscle contractility and subsequent vasoconstriction by inhibiting the influx of calcium ions through L-type calcium channels. Calcium ions entering the cell through these channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium decreases the contractile activity of arterial smooth muscle cells and results in vasodilation. The vasodilatory effects of felodipine result in an overall decrease in blood pressure. Felodipine may be used to treat mild to moderate essential hypertension.
. Drug11303Plendil. (2009). e-CPS (online version of Compendium of Pharmaceuticals and Specialties). Retrieved August 13, 2009.263Pathway1304Striessnig, J. Ca 2+ channel blockers. In S. Offermanns, & W. Rosenthal (Eds.). Encyclopedic reference of molecular pharmacology (2004) p. 201-207. Berlin, Germany: Springer.263Pathway4Cardiomyocyte CL:00007466MyocyteCL:00001871CellCL:00000003NeuronCL:00005401Homo sapiens9606EukaryoteHuman62Acinetobacter baylyi (strain ATCC 33305 / BD413 / ADP1)62977Prokaryote10Cell MembraneGO:00058865CytoplasmGO:000573736MembraneGO:00160201CytosolGO:00058295cardiocyteBTO:00015399MuscleBTO:00008871411811HeartBTO:000056273107Nervous SystemBTO:000148414101PW_BS0000143451014PW_BS000034451014PW_BS0000455291016PW_BS00005265111PW_BS0000658511PW_BS000008228361PW_BS00002465110624PW_BS000508397113PW_BS0000399456FelodipineHMDB0015158Felodipine is a long-acting 1,4-dihydropyridine calcium channel blocker (CCB)b. It acts primarily on vascular smooth muscle cells by stabilizing voltage-gated L-type calcium channels in their inactive conformation. By inhibiting the influx of calcium in smooth muscle cells, felodipine prevents calcium-dependent myocyte contraction and vasoconstriction. Felodipine is the most potent CCB in use and is unique in that it exhibits fluorescent activity. In addition to binding to L-type calcium channels, felodipine binds to a number of calcium-binding proteins, exhibits competitive antagonism of the mineralcorticoid receptor, inhibits the activity of calmodulin-dependent cyclic nucleotide phosphodiesterase, and blocks calcium influx through voltage-gated T-type calcium channels. Felodipine is used to treat mild to moderate essential hypertension. 72509-76-333335859483216DB01023CCOC(=O)C1=C(C)NC(C)=C(C1C1=C(Cl)C(Cl)=CC=C1)C(=O)OCC18H19Cl2NO4InChI=1S/C18H19Cl2NO4/c1-5-25-18(23)14-10(3)21-9(2)13(17(22)24-4)15(14)11-7-6-8-12(19)16(11)20/h6-8,15,21H,5H2,1-4H3RZTAMFZIAATZDJ-UHFFFAOYSA-N3-ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate384.254383.069113515-4.731felodipine00Felodipina [inn-spanish];Felodipine [usan:ban:inn];Felodipinum [inn-latin];Dl-felodipine;(+-)-ethyl methyl 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate;3-ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate;4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid ethyl methyl ester;Felodipina;FelodipinumPW_C009456Felodip3541141845Voltage-dependent L-type calcium channel subunit alpha-1CQ13936Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1C gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin- GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA). Calcium channels containing the alpha-1C subunit play an important role in excitation-contraction coupling in the heart. The various isoforms display marked differences in the sensitivity to DHP compounds. Binding of calmodulin or CABP1 at the same regulatory sites results in an opposit effects on the channel functionHMDBP02220CACNA1C12p13.3L29537199134276745351314353852509465805558807512281361316512706Voltage-dependent calcium channel subunit alpha-2/delta-2Q9NY47The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel. Acts as a regulatory subunit for P/Q-type calcium channel (CACNA1A), N-type (CACNA1B), L-type (CACNA1C OR CACNA1D) and possibly T-type (CACNA1G). Overexpression induces apoptosisHMDBP07485CACNA2D23p21.3AJ25136819403927684535141435395250956584992281361326512720Voltage-dependent L-type calcium channel subunit beta-1Q02641The beta subunit of voltage-dependent calcium channels contributes to the function of the calcium channel by increasing peak calcium current, shifting the voltage dependencies of activation and inactivation, modulating G protein inhibition and controlling the alpha-1 subunit membrane targetingHMDBP07499CACNB117q21-q22CH47115219383927694535151435405250966580753228136133651321Voltage-depenent L-type calcium channel1PW_P0003213401845134127061342272011162451797falsePW_R001797Unknown673094561Compoundfalse67313211ProteinComplexfalse7043945614157false42540510regular200190313018451476false5257158subunitregular15070313127061477false4457708subunitregular16080313227201476false3757158subunitregular1507027093212921431193130312031313121313210703M625 500 C655 500 457.5 597 481.5 614 5true1810704M526 715 C526 662 525 617 525 595 148false18falsetrueM 517.4425069997617 546.7957712398443 L 530 555 L 542.5574930002383 563.204228760155720522921797147135704310703Left44270910704Right4767440351.01.00211580250508M187 849 C187 799 237 749 287 749 C435 749 626 749 774 749 C824 749 874 799 874 849 C874 905 874 979 874 1035 C874 1085 824 1135 774 1135 C626 1135 435 1135 287 1135 C237 1135 187 1085 187 1035 C187 979 187 905 187 849 1true6687.0386.038115Vascular Smooth Muscle Cell275995201.01.01601583515Voltage-gated L-type calcium channel (ICaL)265780201.01.01601523925014355333992124944937916