{"id":210,"date":"2019-04-24T15:10:55","date_gmt":"2019-04-24T15:10:55","guid":{"rendered":"https:\/\/sepia2.unil.ch\/pharmacology\/?page_id=210"},"modified":"2020-09-04T04:09:57","modified_gmt":"2020-09-04T04:09:57","slug":"digoxin","status":"publish","type":"page","link":"https:\/\/sepia2.unil.ch\/pharmacology\/drugs\/digoxin\/","title":{"rendered":"Digoxin"},"content":{"rendered":"\n<h4 class=\"inTable wp-block-heading\"> Digoxin pharmacokinetic parameters <\/h4>\n\n\n\n<table class=\"wp-block-table has-fixed-layout\"><tbody><tr><td> Oral bioavailability (F) <\/td><td> 70% <\/td><\/tr><tr><td> Clearance (CL) <\/td><td> 6 L\/h <\/td><\/tr><tr><td> Volume of Distribution (Vd)<\/td><td> 400 L <\/td><\/tr><tr><td> Half-life (t1\/2) <\/td><td> 40 h <\/td><\/tr><\/tbody><\/table>\n\n\n\n<h3 class=\"wp-block-heading\">Description<\/h3>\n\n\n\n<p>Digoxin is used in several cardiac pathologies \nsuch as atrial fibrillation and heart failure. By its positive inotropic\n effect, digoxin increases the cardiac muscular force of contraction. At\n the same time, digoxin has a negative chronotropic effect that \ndecreases heart rate by its influence on the cardiac electrical \nconduction pathway. \n<\/p>\n\n\n\n<p>Digoxin is well <a href=\"\/pharmacology\/absorption\">absorbed<\/a> in the gastrointestinal intestinal tract, and there is no massive <a href=\"\/pharmacology\/metabolism\">hepatic first pass effect<\/a>. Digoxin&#8217;s oral <a href=\"\/pharmacology\/bioavailability\">bioavailability<\/a> remains usually high (70%-80%), even though considerable <a href=\"\/pharmacology\/metabolism\">metabolism<\/a>\n of digoxin within the gastrointestinal tract may occur in some patients\n by hydrolysis in the acidic environment of the stomach or by digestion \nby intestinal bacteria. Therefore, when such a patient is placed on a \nbroad spectrum antibiotic that eliminates many of the intestinal \nbacteria, the bioavailability of digoxin may suddenly increase. \n<\/p>\n\n\n\n<p>Digoxin has a large <a href=\"\/pharmacology\/volumeofdistribution\">volume of distribution<\/a>, due to its high affinity for skeletal and cardiac muscles, intestines and kidney. Digoxin has a distinct <a href=\"\/pharmacology\/distribution\">distribution phase<\/a>,\n which lasts 6-8 hours and thus its disposition is best described by a \ntwo-compartment pharmacokinetic model. Adipose tissue is not a reservoir\n for digoxin; therefore, dosing should be based on the estimated lean \nbody mass. This is often a source of confusion and inappropriate dosing.\n <a href=\"\/pharmacology\/volumeofdistribution\">Binding to plasma proteins<\/a>, mostly albumin, averages 20 to 30%. Digoxin incompletely distributes across the placental barrier.\n<\/p>\n\n\n\n<p>Most of the digoxin is eliminated unchanged by the kidneys. <a href=\"\/pharmacology\/renalclearance\">Renal clearance<\/a>\n of digoxin exceeds the glomerular filtration rate of its free fraction,\n thus indicating a tubular secretion component. Tubular secretion is \nmediated by the multidrug active transporter, p-glycoprotein. This \np-glycoprotein may be inhibited by spironolactone, quinidine, verapamil \nand amiodarone. Renal failure also decreases the <a href=\"\/pharmacology\/clearance\">clearance<\/a> of digoxin, and may cause accumulation to toxic levels if dosage is not adapted thoroughly. A small fraction of digoxin is <a href=\"\/pharmacology\/metabolism\">metabolized<\/a> by the liver and approximately 8% undergoes an <a href=\"\/pharmacology\/biliary-excretion\">enterohepatic cycle<\/a>. The elimination <a href=\"\/pharmacology\/halflife\">half-life<\/a> of digoxin is long. Therefore, in the absence of a <a href=\"\/pharmacology\/repeated-administration\">loading dose<\/a>, the time required to reach steady state, after the initiation of a <a href=\"\/pharmacology\/repeated-administration\">repeated administration<\/a> regimen, is around 5 to 7 days. \n<\/p>\n\n\n\n<p>The <a href=\"\/pharmacology\/renal-excretion\">therapeutic index<\/a>\n of digoxin is very narrow. Severe toxic effects, such as cardiac \narrhythmias (e.g. bradycardia, heart block, ventricular arrhythmias), \nmay occur at plasma concentrations only twice the therapeutic plasma \nconcentration range. <\/p>\n\n\n\n<p><p class=\"hiddenTitle\">Chart Pharmacokinetics<\/p>\n<div>\n\n    <div id=\"chartContainer\">\n        <canvas id=\"chart\"><\/canvas>\n        <div class=\"\" id=\"divSliderContainer\"><\/div>\n    <\/div>\n\n    <script>\n\n        let chart;\n        let baseDataChartValues = [];\n        let dataChart = [];\n        let dataChartStoredValues = [];\n        let labelsChart = [];\n\n        let dose = 1000;\n        let baseDose = 1000;\n\n        let mDose = 1000;\n        let baseMDose = 1000;\n\n        let tau = 24;\n        let baseTau = 6;\n\n        let vd = 400;\n        let baseVd = 50;\n\n        let cl = 10;\n        let baseCl = 10;\n\n        let f = 0.7;\n        let baseF = 0.7;\n\n        let ka = 2;\n        let tH;\n\n        const maxTime = 168;\n\n        function getPlasmaConcentration(h) {\n            let formulaPlasmaConcentration = (dose*f*ka\/(vd*(ka-cl\/vd))*(Math.exp(-cl\/vd*h)-Math.exp(-ka*h))+(mDose*f*ka\/(vd*(ka-cl\/vd))*((1-Math.exp(-Math.floor((h)\/tau)*cl\/vd*tau))\/(1-Math.exp(-cl\/vd*tau))*Math.exp(-cl\/vd*(h-Math.floor(h\/tau)*tau))-(1-Math.exp(-Math.floor((h)\/tau)*ka*tau))\/(1-Math.exp(-ka*tau))*Math.exp(-ka*(h-Math.floor(h\/tau)*tau)))));\n\n            return formulaPlasmaConcentration;\n        }\n\n        \/*\n         *\n         * t1\/2 = ln(2) * (volume of distribution \/ clearance)\n         *\n         *\/\n        function getHalfLife() {\n            tH = Math.log(2)*(vd\/cl);\n            return (Math.round(tH * 100) \/ 100);\n        }\n\n        function updateSlider(updateStored = false) {\n            dataChart = [];\n            if(updateStored) dataChartStoredValues = [];\n\n            for(let i = 0; i <= maxTime; i++) {\n                let concentration = getPlasmaConcentration(i);\n                dataChart.push(concentration);\n                if(updateStored) dataChartStoredValues.push(concentration);\n            }\n\n            chart.data.datasets[0].data = dataChart;\n            chart.data.datasets[1].data = dataChartStoredValues;\n\n            $( \"#slider-f\" ).slider( \"option\", \"value\", tau);\n            chart.update();\n        }\n\n        let sliderF = '<div id=\"slider-f\" class=\"sliderRange\">' +\n                            '<span id=\"custom-handle-f\" class=\"ui-slider-handle customHandle\"><\/span>' +\n                            '<span class=\"spanUnit\" id=\"\">Tau<\/span>' +\n                        '<\/div>';\n\n        $('#divSliderContainer').append(sliderF);\n\n\n   \n\n        $(function() {\n\n            let handle = $('#custom-handle-f');\n\n            $( \"#slider-f\" ).slider({\n                orientation: \"vertical\",\n                range: \"true\",\n                min: 8,\n                max: 96,\n                step: 1,\n                value: tau,\n                create: function() {\n                    handle.text( $( this ).slider( \"value\" ) );\n                },\n                slide: function( event, ui ) {\n                    tau = ui.value;\n                    handle.text( ui.value );\n                    updateSlider();\n                }\n            });\n        });\n\n        Chart.pluginService.register({\n            beforeInit: function(chart) {\n\n                for(let i = 0; i <= maxTime; i++) {\n                    labelsChart.push(i);\n                    dataChart.push(getPlasmaConcentration(i));\n\n                    dataChartStoredValues = dataChart;\n                    baseDataChartValues = dataChart;\n                }\n\n            }\n        });\n\n        chart = new Chart(document.getElementById(\"chart\"), {\n            type: 'line',\n            data: {\n                labels: labelsChart,\n                datasets: [{\n                    label: \"Plasma Concentration\",\n                    data: dataChart,\n                    borderColor: colorDatasetMain.borderColor,\n                    fillColor: colorDatasetMain.fillColor,\n                    strokeColor: colorDatasetMain.strokeColor,\n                    highlightFill: colorDatasetMain.highlightFill,\n                    highlightStroke: colorDatasetMain.highlightStroke,\n                    borderWidth: \"1\",\n                    pointRadius: 0,\n                    fill: false\n                }, {\n                    label: \"Plasma Concentration\",\n                    data: dataChartStoredValues,\n                    borderColor: colorDatasetStored.borderColor,\n                    fillColor: colorDatasetStored.fillColor,\n                    strokeColor: colorDatasetStored.strokeColor,\n                    highlightFill: colorDatasetStored.highlightFill,\n                    highlightStroke: colorDatasetStored.highlightStroke,\n                    borderWidth: \"1\",\n                    pointRadius: 0,\n                    fill: false\n                }]\n            },\n            options: {\n                scales: {\n                    xAxes: [{\n                        scaleLabel: {\n                            display: true,\n                            labelString: 'H [hour]'\n                        }\n                    }],\n                    yAxes: [{\n                        scaleLabel: {\n                            display: true,\n                            labelString: 'C [mg\/l]'\n                        }\n                    }]\n                },\n                responsive: true,\n                maintainAspectRatio: false\n            }\n        });\n\n    <\/script>\n\n<\/div><\/p>\n\n\n\n<h3 class=\"wp-block-heading\">Clinical implications<\/h3>\n\n\n\n<p>Usually a <a href=\"\/pharmacology\/repeated-administration\">loading dose<\/a>\n is administered at the beginning of a long- term therapy. This dose is \nadministered in fractionated amounts over one day, in order to reach \ntherapeutic concentrations rapidly avoiding as much as possible toxic \npeak plasma concentrations. In the absence of renal failure, the loading\n dose is taken as 3-4 times the maintenance dose.\n<\/p>\n\n\n\n<p>Due to its narrow therapeutic index and the readily \navailable methods to measure its plasma concentration, digoxin is a very\n good candidate for <a href=\"\/pharmacology\/dosage-individualization\">therapeutic drug monitoring<\/a>\n (TDM). Therefore, TDM is widely used to adapt individual digoxin dosage\n regimens. In order to evaluate the steady state concentration, the \nplasma concentration should be measured 5 to 7 days after initiation or \ndosage modification of a <a href=\"\/pharmacology\/repeated-administration\">repeated administration<\/a>\n regimen. The blood sample must be drawn at least 8 h after the last \ndose, so that the concentration reflects the elimination phase and the \ntissular impregnation. The therapeutic interval for through \nconcentration is 0.8 to 2 microgram\/L.\n<\/p>\n\n\n\n<p>Since most of the digoxin is <a href=\"\/pharmacology\/renal-excretion\">excreted<\/a>  unchanged in the urine, patients with renal impairment (e.g. elderly  patients) are initially given lower doses of digoxin. Thereafter, dosage  is further adapted to the individual according to TDM.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Digoxin pharmacokinetic parameters Oral bioavailability (F) 70% Clearance (CL) 6 L\/h Volume of Distribution (Vd) 400 L Half-life (t1\/2) 40 h Description Digoxin is used in several cardiac pathologies such as atrial fibrillation and heart failure. By its positive inotropic effect, digoxin increases the cardiac muscular force of contraction. At the same time, digoxin has &hellip; <\/p>\n<p class=\"link-more\"><a href=\"https:\/\/sepia2.unil.ch\/pharmacology\/drugs\/digoxin\/\" class=\"more-link\">Continue reading<span class=\"screen-reader-text\"> &#8220;Digoxin&#8221;<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"parent":10,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"footnotes":""},"class_list":["post-210","page","type-page","status-publish","hentry"],"_links":{"self":[{"href":"https:\/\/sepia2.unil.ch\/pharmacology\/wp-json\/wp\/v2\/pages\/210","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/sepia2.unil.ch\/pharmacology\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/sepia2.unil.ch\/pharmacology\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/sepia2.unil.ch\/pharmacology\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/sepia2.unil.ch\/pharmacology\/wp-json\/wp\/v2\/comments?post=210"}],"version-history":[{"count":13,"href":"https:\/\/sepia2.unil.ch\/pharmacology\/wp-json\/wp\/v2\/pages\/210\/revisions"}],"predecessor-version":[{"id":1378,"href":"https:\/\/sepia2.unil.ch\/pharmacology\/wp-json\/wp\/v2\/pages\/210\/revisions\/1378"}],"up":[{"embeddable":true,"href":"https:\/\/sepia2.unil.ch\/pharmacology\/wp-json\/wp\/v2\/pages\/10"}],"wp:attachment":[{"href":"https:\/\/sepia2.unil.ch\/pharmacology\/wp-json\/wp\/v2\/media?parent=210"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}