DIGOXINTherapeutic drug monitoring

Action and uses

• Digoxin is the most widely used of the digitalis glycosides.• Its primary actions on the heart are those of increasing the force of

contraction and decreasing conduction through the atrioventricular node.• Currently, its main role is in the treatment of atrial fibrillation by slowing

down the ventricular response, although it is also used in the treatment of heart failure in the presence of sinus rhythm.• The primary method of monitoring its clinical effect in atrial fibrillation is

by measurement of heart rate but knowledge of its phar- macokinetics can be helpful in predicting a patient's dosage requirements.

Plasma concentration–responserelationship • <0.5 μcg/L: no clinical effect • 0.7 μcg/L: some positive inotropic and conduction blocking effects • 0.8–2 μcg/L: optimum therapeutic range (0.5–0.9 μcg/L in patients >65) • 2–2.5 μcg/L: increased risk of toxicity, although tolerated in some patients • >2.5 μcg/L: gastro-intestinal, cardiovascular system and

central nervous system toxicity.

absorption

•Digoxin is poorly absorbed from the gastro-intestinal tract, and dissolution time affects the overall bioavailability. The two oral formulations of digoxin have different bioavailabilities:•F (tablets) =0.65•F (liquid) =0.8

Distribution

• Digoxin is widely distributed and extensively bound in varying degrees to tissues throughout the body. This results in a high apparent volume of distribution. Digoxin volume of distribution can be estimated using the equation 7.3 L/kg (ideal body weight (BWt)) which is derived from population data. However, distribution is altered in patients with renal impairment, and a more accurate estimate in these patients is given by:

Vd= 3.8 × ideal BWt (3.1 creatinine clearance (mL/min))

•A two-compartment model best describes digoxin disposition, with a distribution time of 6–8 h. Clinical effects are seen earlier after intravenous doses, since the myocardium has a high blood perfusion and affinity for digoxin. Sampling for TDM must be done no sooner than 6 h post- dose, otherwise an erroneous result will be obtained.

elimination

•Digoxin is eliminated primarily by renal excretion of unchanged drug (60–80%), but some hepatic metabolism occurs (20–40%). The population average value for digoxin clearance is:

digoxin clearance (mL/min) = 0.8 × BWt + (creatinine clearance (mL/min))

•However, patients with severe congestive heart failure have a reduced hepatic metabolism and a slight reduction in renal excretion of digoxin:

digoxin clearance (mL/min) = 0.33× BWt +(0.9 × creatinine clearance (mL/min))• Ideal body weight should be used in these equations

Practical implications

• Using population averages it is possible to predict plasma concentrations from specific dosages, particularly since the time to reach the steady state is long. • Population values are only averages, and individual values may vary. In

addition, a number of diseases and drugs affect digoxin disposition.• As can be seen from the preceding discussion, congestive heart failure,

hepatic and renal diseases all decrease the elimination of digoxin.• In addition, hypothyroidism increases the plasma concentration

(decreased metabolism and renal excretion) and increases the sensitivity of the heart to digoxin.

Practical implications

• Hyperthyroidism has the opposite effect.• Hypokalemia, hypercalcaemia, hypomagnesaemia and hypoxia all

increase the sensitivity of the heart to digoxin.• There are numerous drug interactions reported of varying clinical

significance. The usual cause is either altered absorption or clearance.

CLINICAL MONITORING PARAMETERS

•Monitor symptoms of CHF including left sided failure, pulmonary edema, right sided failure•As excreted by kidney renal functions should be monitored 2-3 times•Serum concentration measurements is also important in many cases