Congestive Heart Failure CHF Table

Bioavailability of loop diuretics is no different in patients with CHF compared to healthy controls [1, 3, 4, 12], Consequently, delivery of total amounts of diuretic to the urinary site of action is normal in CHF and cannot be invoked as a mechanism of resistance to loop diuretics. Despite prior speculation to the contrary, it is unlikely that malabsorption occurs in any but unusual circumstances.

TABLE 4 Time of Peak Diuretic Concentration (mins) as a Reflection of Speed of Absorption in Healthy Subjects and in Patients with CHF

Furosemide

Bumetanide

Torsemide

Healthy subjects

108 ±20

72 ±7

52 ±11

Congestive heart failure

Compensated Decompensated

180 ±30 177 ± 21 144± 150 242 ±25

180 ±19

66 ±54

Though bioavailability is not affected by CHF, the time course of absorption is altered (Table 4). Studies with bumetanide and furosemide show a delay in the time of peak concentration in both serum and urine compared to healthy subjects. Interestingly, torsemide may not have a similar delay. This delay could occur from a prolongation of the lag time for absorption, a slowed rate of absorption, or both. Since the delayed peak concentration is also approximately half of that which occurs in normal subjects, a component of slowed rate of absorption must occur. Slowed absorption is of the greatest degree in patients with decompensated heart failure. In decompensated CHF, the lag time for absorption has been shown to be markedly increased with a diminished peak concentration. Attainment of dry weight resulted in changes of these parameters toward, but not to, normal.

It is conceivable that the observed changes account in part for resistance to oral loop diuretics in CHF, particularly in the decompensated state. Simplisti-cally, if a threshold concentration is needed to elicit a response, then the decrease in peak concentration caused by slowed absorption could be sufficient that the threshold is not reached and no response occurs despite absorption of the same amount of drug as occurs normally. In turn, response would occur only at increased oral doses that would be disproportionately large compared to effective intravenous doses.

It is important to reemphasize that even when an effective oral dose is administered, response to oral drug will be delayed in patients with CHF. If a rapid response is desired, one must administer the diuretic parenterally; otherwise the onset of effect may be delayed several hours and the time at which it occurs is unpredictable.

In general, total body and renal clearance tend to be lower and elimination half-life longer in patients with CHF (Tables 2 and 3); these differences are due to diminished renal function, either intrinsic or secondary to severe heart disease. In patients with CHF with relatively normal renal function, normal amounts of loop diuretic are delivered into the urine. Consequently, in such

Urinary Diuretic Excretion Rate

FIGURE 3. Schematic illustration of the changed pharmacodynamics of response to loop diuretics that occurs in patients with CHF.

Total Na+ 100 mmole

Urinary Diuretic Excretion Rate

FIGURE 3. Schematic illustration of the changed pharmacodynamics of response to loop diuretics that occurs in patients with CHF.

patients resistance to intravenous diuretic cannot be accounted for by pharmacokinetic mechanisms.

Studies have shown dramatic changes from normal in pharmacodynamics in patients with CHF (Fig. 3). This undoubtedly is the major mechanism of resistance in these patients [4]. The mechanism(s) of this change is unknown, but the same possibilities can be invoked as discussed previously, namely, increased solute reabsorption at the proximal and/or distal nephron and changed dynamics of the receptor-diuretic interaction.

Since in most patients with CHF, normal amounts of diuretic are delivered to the site of action, little is to be gained by administering large doses. Single intravenous doses of 80 to 120 mg of furosemide or the equivalent of other loop diuretics should suffice even in patients with modest declines in renal function. If the patient does not respond adequately to such doses, combination of loop diuretics with thiazides should be attempted [6].

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Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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