Digoxin (CAS 20830-75-5, C₄₁H₆₄O₁₄, MW 780.94 g/mol) is a steroidal cardiac glycoside extracted from Digitalis lanata (woolly foxglove) leaves — the prototypical Na+/K+-ATPase inhibitor with >200 years of continuous clinical use since William Withering’s landmark 1785 monograph “An Account of the Foxglove.” Digoxin’s molecular mechanism of positive inotropy proceeds through a precise four-step sequence: (1) Digoxin binds to and inhibits the α-subunit of the sarcolemmal Na+/K+-ATPase (the sodium pump) on the cardiac myocyte membrane — this is the primary molecular target. (2) Inhibition of the sodium pump reduces Na+ extrusion from the cell → intracellular Na+ concentration rises. (3) The elevated intracellular Na+ reduces the transmembrane Na+ gradient that drives the Na+/Ca2+ exchanger (NCX) — since the NCX uses the energy of Na+ moving down its electrochemical gradient (3 Na+ in, 1 Ca2+ out) to extrude Ca2+ against its gradient, a smaller Na+ gradient means less Ca2+ extrusion. (4) The resulting increase in intracellular Ca2+ is sequestered by the sarcoplasmic reticulum (SR) via SERCA2a → greater Ca2+ loading of the SR → more Ca2+ released during each action potential → increased cross-bridge cycling → stronger, more forceful cardiac contraction — positive inotropy. Critically, this mechanism does not increase myocardial oxygen consumption (unlike β-adrenergic agonists such as dobutamine or milrinone), making digoxin uniquely suited for chronic HFrEF therapy. Additionally, digoxin increases parasympathetic (vagal) outflow to the heart → slows atrioventricular (AV) node conduction velocity and prolongs the AV node effective refractory period → this provides ventricular rate control in atrial fibrillation and atrial flutter. UPOR Biotech provides digoxin as a GMP-certified pharma API (≥95% HPLC) compliant with USP, EP, and BP monographs, with Type II DMF support.

Digoxin has two primary FDA-approved clinical indications, each supported by extensive clinical trial evidence. (1) Heart failure with reduced ejection fraction (HFrEF) — maintenance therapy: The landmark DIG trial (Digitalis Investigation Group, 1997, N=6,800, NEJM) demonstrated that digoxin reduced HF-related hospitalizations by 28% (p<0.001) and all-cause hospitalizations by 6% (p=0.01) in HFrEF patients (LVEF ≤45%) on background ACE inhibitors and diuretics. While digoxin showed a neutral effect on all-cause mortality (p=0.80), the reduction in morbidity and healthcare utilization established its role. Current ACC/AHA 2022 guidelines recommend digoxin as a Class IIa recommendation for symptomatic HFrEF patients (NYHA Class II–III) despite optimal guideline-directed medical therapy (GDMT — ACEi/ARB/ARNI, beta-blocker, MRA, SGLT2i), particularly to reduce hospitalizations. The ESC 2021 guidelines give digoxin a Class IIb recommendation. Digoxin is especially valuable in HFrEF patients who remain symptomatic with elevated heart rate despite beta-blocker therapy. (2) Atrial fibrillation and atrial flutter — ventricular rate control: Digoxin enhances vagal tone at the AV node → slows conduction velocity → reduces ventricular response rate. This effect is most prominent at rest (vagal predominance) and less effective during exercise (sympathetic predominance) — hence digoxin is often combined with a beta-blocker or calcium channel blocker for rate control during both rest and activity. The ESC 2020 AF guidelines give digoxin a Class I recommendation for rate control in AF patients with concomitant HFrEF (where beta-blockers and calcium channel blockers may be poorly tolerated due to hypotension or negative inotropic effects). Retrospective analyses of the AFFIRM and TREAT-AF cohorts have raised concerns about potential increased mortality with digoxin in AF — however, these observational studies carry significant confounding by indication (sicker patients are more likely to receive digoxin). The ongoing RATE-AF trial (digoxin vs bisoprolol) and the DIGIT-HF trial continue to refine the evidence base for digoxin in modern cardiology practice.

Digoxin has one of the narrowest therapeutic indices in clinical pharmacology: 0.5–2.0 ng/mL (0.6–2.6 nmol/L) — serum concentrations only 4× above the therapeutic threshold can be lethal. This demands rigorous therapeutic drug monitoring (TDM) for every patient. Pharmacokinetic determinants of the narrow index: digoxin has a large volume of distribution (Vd 6–7 L/kg) reflecting extensive binding to skeletal and cardiac muscle Na+/K+-ATPase (not plasma protein — protein binding is only 20–25%); elimination is predominantly renal (70–85% excreted unchanged via glomerular filtration and P-glycoprotein-mediated tubular secretion) with a half-life of 36–48 hours in normal renal function; any decline in renal function (aging, acute kidney injury, CKD, drug-induced) proportionally reduces digoxin clearance and increases serum levels. Critical drug interactions at P-glycoprotein (P-gp): amiodarone, verapamil, quinidine, clarithromycin/erythromycin, itraconazole, ritonavir, and cyclosporine each inhibit intestinal and renal P-gp, reducing digoxin clearance and increasing serum concentrations by 50–100% — these interactions require preemptive digoxin dose reduction (typically 30–50%) and repeat TDM within 5–7 days. Electrolyte-dependent toxicity: hypokalemia (K+ <3.5 mmol/L) reduces Na+/K+-ATPase activity directly and potentiates digoxin binding to the pump → toxicity at otherwise therapeutic digoxin levels; hypomagnesemia similarly sensitizes the myocardium; hypercalcemia increases intracellular Ca2+ synergistically with digoxin → increased arrhythmia risk. TDM clinical indications: (a) at steady state — 5–7 days after initiation or any dose change (t½ 36–48 h × 5 half-lives ≈ 7–10 days to steady state), (b) whenever a P-gp-interacting drug is added or removed, (c) with any change in renal function (monitor serum creatinine and eGFR), (d) with any sign/symptom suggestive of digoxin toxicity: gastrointestinal (nausea, vomiting, anorexia — often the earliest signs), neurological (confusion, weakness, visual disturbances — xanthopsia/yellow-green halos around objects is classic but late), and cardiac (arrhythmias — especially atrial tachycardia with block, bidirectional ventricular tachycardia, accelerated junctional rhythm, and any bradyarrhythmia). Treatment of toxicity: for severe toxicity (life-threatening arrhythmias, K+ >5.0 mmol/L, hemodynamic instability, digoxin level >10 ng/mL, or ingestion >10 mg in adults/>4 mg in children), the antidote is Digoxin Immune Fab (Digibind, DigiFab) — digoxin-specific ovine Fab antibody fragments that bind and neutralize free digoxin with rapid renal elimination of the Fab-digoxin complex. Dosing is calculated from the total body digoxin load (serum level × Vd × body weight) or estimated from the ingested dose. For mild-moderate toxicity, supportive care with ECG monitoring, electrolyte correction (especially potassium and magnesium), and drug cessation is often sufficient given digoxin’s 36–48 hour half-life.

Digoxin is a dual-domain natural product — its structure can be divided into two pharmacologically distinct regions, each with a non-interchangeable role, which makes precise analytical quality control essential for API suppliers. Domain 1 — The Aglycone: Digoxigenin (C₂₃H₃₄O₅, MW 390.51 g/mol). Digoxigenin is a C23 steroid nucleus (cyclopentanoperhydrophenanthrene) with four fused rings in A/B cis, B/C trans, and C/D cis configuration — this ring junction stereochemistry is biologically determined and critical. Two substituents on the steroid nucleus constitute the Na+/K+-ATPase pharmacophore: (a) The C17β α,β-unsaturated γ-lactone ring (butenolide): this is the single most critical structural feature for cardiac glycoside activity. The conjugated lactone forms specific hydrogen bonds with amino acid residues within the α-subunit binding pocket of Na+/K+-ATPase. Saturation of the α,β-double bond, ring-opening of the lactone, or epimerization at C17 (β→α) each abolish cardiotonic activity. The lactone is also the site of metabolic inactivation — saturation by gut bacteria (Eubacterium lentum) in ~10% of patients produces dihydrodigoxin, which has negligible activity and explains the “digoxin reductase” phenotype. (b) The C14β hydroxyl group: forms a critical hydrogen bond within the Na+/K+-ATPase binding cavity. The β-orientation is essential — C14α-OH epimers are pharmacologically inactive. Digoxigenin differs from digitoxigenin (the aglycone of digitoxin) by one additional hydroxyl group at C12β — this single OH difference reduces lipophilicity, reduces hepatic metabolism (digitoxin is extensively metabolized by CYP3A4, digoxin is not), and shifts elimination from hepatic (digitoxin t½ ~7 days) to renal (digoxin t½ ~36–48 hours). Domain 2 — The Trisaccharide: Tridigitoxoside. Three digitoxose sugar molecules (2,6-dideoxy-D-ribo-hexose, each C₆H₁₂O₃) are linked β-1,4 sequentially to each other and via a β-glycosidic bond to the C3-OH of digoxigenin. The sugars do not directly participate in Na+/K+-ATPase binding — digoxigenin alone binds with comparable affinity — but they are pharmacokinetically essential: (i) the trisaccharide increases aqueous solubility (digoxin is slightly soluble in water at 0.007 mg/mL vs digoxigenin which is essentially insoluble), (ii) the sugars protect the C3-OH from glucuronidation (phase II metabolism), extending the elimination half-life, (iii) the trisaccharide creates a molecular shape recognized by P-glycoprotein (P-gp, ABCB1) at intestinal enterocytes (limiting oral bioavailability to 60–80%) and renal proximal tubules (mediating active tubular secretion), (iv) the trisaccharide reduces CNS penetration relative to the aglycone alone, partially protecting from central nervous system toxicity. Structure-function implications for API quality: Given this structural precision, digoxin API must be controlled for both aglycone identity (digoxigenin vs digitoxigenin — the digitoxin impurity ≤1.0%) and glycosidic integrity (gitoxin ≤0.5%, related glycosides ≤2.0% total per USP/EP). HPLC analysis with a pharmacopeial reference standard is the definitive quality method. UPOR Biotech’s GMP-manufactured digoxin undergoes rigorous structural verification — IR, HPLC retention time, TLC Rf, and specific optical rotation — against USP/EP reference standards for every batch, ensuring your finished product’s pharmacophore and pharmacokinetic profile are consistent.

Every shipment of Digoxin from UPOR Biotech includes a comprehensive documentation package supporting pharmaceutical quality assurance and regulatory filing requirements. Core batch documentation: (1) Certificate of Analysis (COA) — HPLC purity ≥95.0%, full impurity profile: digitoxin ≤1.0%, gitoxin ≤0.5%, any individual unspecified impurity ≤0.5%, total impurities ≤2.0%, heavy metals ≤10 ppm with elemental impurities per USP <232>/ICH Q3D (Pb ≤2 ppm, As ≤1 ppm, Hg ≤1 ppm, Cd ≤1 ppm), residual solvents per USP <467>/EP <5.4>/ICH Q3C, microbial panel per USP <61>/<62> and EP <2.6.12>/<2.6.13>. (2) Material Safety Data Sheet (MSDS/SDS) — GHS-compliant, including handling precautions for potent cardioactive compound. (3) HPLC Chromatogram — signed and dated by the QC analyst and QA reviewer, with system suitability parameters, retention times, resolution (digoxin-digitoxin ≥2.0 per USP), and peak purity check. (4) USP/EP/BP Monograph Compliance Certificate — confirming the batch meets all pharmacopeial specifications. GMP and quality system documentation: (5) GMP Certificate — stating compliance with ICH Q7A (Active Pharmaceutical Ingredients), 21 CFR Parts 210/211, EU GMP Part II, and WHO GMP guidelines. (6) Type II Drug Master File (DMF) Support — a Letter of Authorization (LoA) granting FDA/regulatory cross-reference to UPOR’s DMF is available upon execution of a signed Confidentiality Agreement (CDA/NDA). This supports ANDA, NDA, and 505(b)(2) filings. (7) ISO 9001:2015 Certificate — quality management system. (8) FDA Facility Registration — confirming UPOR’s manufacturing site is registered with the US FDA. (9) Stability Data Package — real-time (25°C/60%RH, 36-month) and accelerated (40°C/75%RH, 6-month) stability study data per ICH Q1A(R2). Supply chain integrity documentation: (10) Certificate of Origin — confirming the Digitalis lanata botanical raw material source, country of harvest, and extraction site. (11) Complete Lot Traceability Report — from Digitalis lanata leaf harvest lot → extraction batch → purification batch → finished API batch, with dates, yields, and in-process control data. (12) BSE/TSE-Free Statement — confirming no animal-derived materials in the manufacturing process. (13) Non-GMO Statement. (14) Allergen Statement. (15) HALAL Certificate. (16) KOSHER Certificate. Free sample available for qualified B2B buyers upon execution of a standard Non-Disclosure Agreement. MOQ: 1 kg. All documents are provided in English. For DMF cross-reference, please contact UPOR’s regulatory affairs team with a signed CDA for prompt LoA issuance.