Digoxin distribution volume

The distribution volume of some drugs also can be altered when renal function is impaired. As described in Chapter 3, Sheiner ef al. (27) have shown that impaired renal function is associated with a decrease in digoxin distribution volume that is described by the following equation ... 

As shown in Figure 2.5 the back-extrapolated estimate of Co can be used to calculate the apparent volume (Vdiextrap)) hypothetical single compartment into which digoxin distribution occurs ... 

In this case, the apparent distribution volume of 536 L is much larger than is anatomically possible. This apparent anomaly occurs because digoxin has a much higher binding affinity for tissues than for plasma and the apparent distribution volume is the volume of plasma that would be required to provide the observed dilution of the loading dose. Despite this apparent anomaly the concept of distribution volume is clinically useful because it defines the relationship between plasma concentration and the total amount of drug in the body. Further complexity arises from the fact that only one of three different distribution... 

FIGURE 2.5 Siimilation of plasma (solid line) and tissue (heavy dashed line) digoxin concentrations after intravenous administration of a 0.75-mg loading dose to a 70-kg patient with normal renal function. Cq is estimated by back extrapolation (dotted line) of elimination-phase plasma concentrations. is calculated by dividing the administered drug dose by this estimate of Cq, as shown. Tissue concentrations are referenced to the apparent distribution volume of a peripheral compartment that represents tissue distribution. (Reproduced with permission from Atkinson AJ Jr, Kushner W. Annu Rev Pharmacol Toxicol 1979 19 105-27.)... 

This presumably reflects a reduction in tissue levels of Na/K-ATPase, an enzyme that represents a major tissue-binding site for digoxin (28). In other cases in which distribution volume is decreased in patients with impaired renal function, the relationship between the degree of renal insufficiency and reduction in distribution volume has not been characterized nor have plausible mechanisms been proposed. 

Digoxin Decreased volume of distribution Lower loading dose Lower maintenance dose... 

Altered tissue binding may also affect the apparent volume of distribution of a drug. For example, the distribution volume of digoxin has been reported to be reduced by 30% to 50% from normal values in patients with renal disease. It has been postulated that this reduction in the distribution volume is secondary to a decrease in tissue... 

Digoxin is not extensively metabolized. The volume of distribution for digoxin is 6 to 7 1/kg. Digoxin distributes into lean body tissue but not appreciably into adipose or fatty tissues. For this reason ideal body weight should be used to dose digoxin. Digoxin is 20 to 30% bound to albumin. The distributive phase of digoxin is 6 to 8... 

Distribution Decrease in the volume of distribution of hydrophilic drugs and increase in the volume of distribution of lipophilic drugs Decline in fat-free mass and increase in body fat with aging Important for some drugs Diazepam and flunitrazepam may have increased plasma half-life. Water soluble drugs as digoxin and teophylline have higher peak plasma concentrations and shorter half-lives... 

Digoxin in the blood is virtually conflned to the plasma where, in the therapeutic range, only a relatively small percentage (30%) is protein-bound (P7). After a single intravenous injection of digoxin only 3% remains in the blood after 1 hour in normal subjects (M6). Since only 30% is excreted during the first 24 hours after injection, the data indicate a large volume of distribution. 

We ask the laboratory to measure the plasma digoxin concentration at 12 hours after the first dose, and find it to be 1 pg/1. Can we get any idea of the apparent volume of distribution ... 

Drugs that show extensive tissue binding are said to have an apparent volume of distribution many times the total body size. For example, digoxin (see Chapter 35), which binds to plasma protein to the extent of 23%, has an apparent volume of distribution of 8 1/kg. The volume of distribution of drugs that do not bind to plasma or tissue proteins varies between the extracellular fluid volume (16 liters) and the total body water (42 liters). Insulin, sodium, and iodine are confined to the extracellular water, whereas caffeine and ethanol are distributed in the total body water. 

Volume of distribution is commonly calculated for a particular patient using body weight (70 kg body weight is assumed for the values in Table 3-1). If a patient is obese, drugs that do not readily penetrate fat (eg, gentamicin and digoxin) should have their volumes calculated from ideal body... 

DIGOXIN POTASSIUM-SPARING DIURETICS AND ALDOSTERONE ANTAGONISTS Eplerenone and spironolactone may T plasma concentrations of digoxin Uncertain spironolactone possibly L the volume of distribution of digoxin Monitor digoxin levels watch for digoxin toxicity... 

The value of the volume of distribution is determined mainly by the physiological processes of perfusion and protein binding, but it seldom has a true physiological meaning. For example, the volume of distribution of frusemide, a drug which is highly bound to plasma albumin, is of the order of 15 litres, and that of alcohol is about 35 litres however, the value for digoxin, which is extensively distributed and bound in extravascular tissues, is of the order of 450 litres. 

Examples of changes in tissue binding are the tissue displacement of digoxin by quinidinef" and the decrease in tissue binding of digoxin in uremia.As a result in both cases, the volume of distribution of digoxin is decreased. 

The apparent volume of distribution of digoxin is reduced in hypothyroidism (145) and in renal insufficiency (146). This leads to increased plasma concentrations after a loading dose and hence an increased risk of toxicity, but does not affect the plasma concentration at steady state. The opposite occurs in hyperthyroidism. 

Because digoxin has a large apparent volume of distribution, plasma exchange, hemodialysis, and hemoperfusion are not effective methods of removing digoxin from the body. 

Hemoperfusion has been used to treat digitalis overdose (SEDA-5, 174) but once a cardiac glycoside has been distributed to the body tissues hemoperfusion is unlikely to be of benefit. For digitoxin, which has a lower apparent volume of distribution than digoxin, charcoal hemoperfusion may be more valuable. 

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