Disease Induced Alterations in Pharmacokinetics

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IMPAIRED RENAL CLEARANCE OF DRUGS If a drug is cleared primarily by the kidney, dose modification should be considered in patients with renal dysfunction. When renal clearance is diminished, the desired effect can be maintained either by decreasing the dose or lengthening the dose interval. Estimation of the glomerular filtration rate (GFR) based on serum creatinine, ideal body weight, and age provides an approximation of the renal clearance of many drugs.

With knowledge of the GFR, initial dosing reductions can be estimated. The accuracy of initial dosing should be monitored by clinical assessment and plasma drug concentration where feasible.

Drug metabolites that may accumulate with impaired renal function may be pharmacologically active or toxic. Although meperidine is not dependent on renal function for elimination, its metabolite normeperidine is cleared by the kidney and accumulates when renal function is impaired. Because normeperidine has greater convulsant activity than meperidine, its high levels in renal failure probably account for the central nervous system (CNS) excitation, with irritability, twitching, and seizures, that can occur when multiple doses of meperidine are given to patients with impaired renal function (see Chapter 21).

IMPAIRED HEPATIC CLEARANCE OF DRUGS The effect of liver disease on the hepatic biotransformation of drugs cannot be predicted from any measure of hepatic function. Thus, even though the metabolism of some drugs is decreased with impaired hepatic function, there is no quantitative basis for dose adjustment other than assessment of the clinical response and plasma concentration. The oral bioavailability of drugs with extensive first-pass hepatic clearance (e.g., morphine, meperidine, midazolam, and nifedipine) may be increased in liver disease.

CIRCULATORY INSUFFICIENCY OWING TO CARDIAC FAILURE OR SHOCK In circulatory failure, neuroendocrine compensation can substantially reduce renal and hepatic blood flow, thereby reducing elimination of many drugs. Particularly affected are drugs with high hepatic extraction ratios, such as lidocaine, whose clearance is a function of hepatic blood flow; in this setting, only half the usual infusion rate of lidocaine is required to achieve therapeutic plasma levels.

ALTERED DRUG BINDING TO PLASMA PROTEINS When a drug is highly bound to plasma proteins, its egress from the vascular compartment is limited to the unbound (free) drug. Hypoalbuminemia owing to renal insufficiency, hepatic disease, or other causes can reduce the extent of binding of acidic and neutral drugs; in these conditions, measurement of free drug provides a more accurate guide to therapy than does analysis of total drug. Changes in protein binding are particularly important for drugs that are >90% bound to plasma protein, where a small change in the extent of binding produces a large change in the level of free drug. Metabolic clearance of such highly bound drugs also is a function of the unbound fraction of drug. Thus, clearance is increased in those conditions that reduce protein binding; shorter dosing intervals therefore must be employed to maintain therapeutic plasma levels.

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