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Digoxin, a widely prescribed cardiac drug, has a narrow therapeutic window (a very small difference exists between therapeutic and toxic tissue concentrations). While excess digoxin can have serious side effects (eg, cardiac dysrhythmias, heart failure, seizures, death), it is one of the few therapeutic drugs for which antidotal therapy is available.(1) In toxic situations, antibody fragment therapy, which involves the administration of antibodies to digoxin (eg, Digibind, Digoxin Immune Fab), is indicated. In manufacturing of Digibind, papain cleaves digoxin-specific IgG antibody into 2 antigen binding-site fragments (Fab fragments). These fragments bind to digoxin, block the active site of the digoxin molecule, and make it unavailable to its receptor molecule and biologically inactive. The Fab fragment-digoxin complex is then excreted by the kidney.
Total digoxin concentration in blood increases approximately 10 to 30 fold after administration of Fab fragments. On the other hand, the unbound (free) fraction, which is responsible for its pharmacological activity, decreases. Traditional digoxin assays performed by immunoassay (eg, DIG / Digoxin, Serum) measure both Fab fragment-bound (inactive) digoxin and free (active) digoxin (ie, total digoxin), and are unsuitable for managing patients when digoxin-specific Fab fragment therapy has been administered. Assays that only measure free digoxin levels are necessary in such situations.
The kidneys provide the main route of Fab fragment elimination from the body. In patients with normal renal function, digoxin-specific Fab fragments are excreted in the urine with a biological half-life of 15 to 20 hours. Ordinarily, improvement in signs or symptoms of digoxin intoxication begins within a half hour or less after initiation of Fab fragment therapy. Clearance may be delayed in patients with renal failure. In such patients, toxicity may recur if previously bound drug is released from the Fab fragments, resulting in increased levels of free digoxin.
Digoxin-like immunoreactive factors (DLIFs) are endogenous substances that can cross-react with testing antibodies used in some digoxin immunoassays, causing erroneous results. DLIFs may be seen in certain volume-expanded patients such as neonates, patients with renal or liver disease, and in women in the third trimester of pregnancy being treated with digoxin.(2) DLIFs are strongly bound to proteins and, in this assay, are removed prior to testing.
The following ordering guidelines are offered:
-When creatinine clearance is <30 mL/min/surface area: order free digoxin levels daily for 12 days (or until dismissal)
-When creatinine clearance is > or =30 mL/min/surface area (and patient is not on renal-replacement therapy): order free levels daily for 72 hours, as long as last level is not supratherapeutic (these patients are expected to have good clearance and a lower risk for reintoxication)
- Also order total digoxin levels every other day during the time periods above, with a goal of determining whether there is correlation between changes in free and total levels.
Evaluating recrudescent (breakthrough) digoxin toxicity in renal-failure patients
Assessing the need for more antidigoxin Fab to be administered
Deciding when to reintroduce digoxin therapy
Monitoring patients with possible digoxin-like immunoreactive factors (DLIFs)
The target therapeutic is 0.4 to 1.5 ng/mL. Toxicity may be seen when free digoxin concentrations are > or =3.0 ng/mL. Pediatric patients may tolerate higher concentrations.
Therapeutic concentrations for free digoxin are 25% lower than therapeutic values for total digoxin due to the separation of protein-bound digoxin in the assay.
Patients vary in their responsiveness to digoxin.
Renal dysfunction alters the metabolism of digoxin and antibody-bound digoxin.
It takes 6 to 8 hours after digoxin administration for equilibration between serum and tissue; results obtained from specimens collected <6 to 8 hours after the last dose of digoxin should be interpreted with caution.
Digibind (Glaxo Wellcome, Research Triangle Park, NC) is the most common brand of antidigoxin Fab fragments used; other brands are available and may be monitored by this assay.
Therapeutic concentration: 0.4-1.5 ng/mL
Toxic concentration: > or =3.0 ng/mL
Pediatric toxic concentrations may be higher.
1. Jortani SA, Pinar A, Johnson NA, Valdes R Jr: Validity of unbound digoxin measurements by immunoassays in presence of antidote (Digibind). Clin Chim Acta 1999;283:159-169
2. Package insert: DIGIBIND Digoxin Immune FAB (Ovine). GlaxoSmithKline, Research Triangle Park NC, 2003
3. Applied Therapeutic Drug Monitoring. Vol 2. Edited by TP Moyer, RL Boeckx. Washington DC, American Association for Clinical Chemistry, 1984
4. Jortani SA, Voldes R Jr: Digoxin and its related endogenous factors. Crit Rev Clin Lab Sci 1997;34:225-274
5. Datta P, Hinz V, Klee G: Comparison four digoxin immunoassays with respect to interference from digoxin-like immunoreactive factors. Clin Biochem 1996;29(6):541-547
6. Soldin SJ: Free drug measurements. When and why? An overview. Arch Pathol Lab Med 1999;123:822-823