Introduction

The kidney is one of the major routes of drug elimination for a majority of drugs, requiring dose adjustment in case of renal insufficiency. Also many of the drugs metabolized in the liver need an active kidney for elimination of the metabolites which would otherwise get accumulated in case of diminished renal function. It has also been noted in some cases that elimination of certain drugs through the non-renal pathways is altered in case of renal insufficiency. Thus the doses of many drugs need to be reduced in case of renal insufficiency so as to avoid toxicity.

The precise dose adjustment depends on the therapeutic index of individual drugs, with drugs such as penicillin – the wide therapeutic index allows for less precision in dose adjustment when compared to the precision required in aminoglycoside or digoxin dose adjustment, for which, the consequences of drug accumulation can be devastating.

In drugs with narrow margins of safety, dose adjustment must be carried out even when renal function is decreased by only a modest degree, and regimens are sometimes further informed by measuring serum concentrations of the drug.

In addition to the problem of drug accumulation because of compromised elimination pathways, an additional challenge presents itself in patients who are being treated with hemodialysis, hemofiltration, or peritoneal dialysis. The drug may be removed by the procedure itself, thereby requiring compensatory dose supplementation, the extent of which is a function of the amount of drug removed.

General Principles

1. If ≥ 30% of the drug is eliminated unchanged in the urine of patients with normal renal function there might be a need for alteration of dose in patients with impaired renal function. However drugs which are not excreted by the kidneys might also require dose adjustments; a good example is the so-called futile cycle of drug elimination that occurs with acyl­glucuronide conjugates of non steroidal anti-inflammatory drugs such as Ketoprofen.

The implications of renal insufficiency in relation to dosage decision for a drug excreted as an acyl-glucuronide conjugate—the so-called “futile cycle” of drug elimination—wherein the parent drug accumulates even though negligible parent drug is excreted unchanged in the urine.

2. Renal insufficiency often leads to metabolic acidosis with accumulation of organic acids in the blood. These acids

a. May compete with the acidic drugs for protein binding with the subsequent complications associated with drug displacement.

b. May also compete with the acidic drugs for tubular secretion and excretion via the kidneys.

3. Decrease in the serum protein levels associated with certain types of renal insufficiency alters the plasma protein-bound drug concentration.

4. Dialysis in patients with renal insufficiency alters the serum concentration and kinetics of the drug, with disastrous clinical consequences; especially if the drug is restricted to the vascular compartment.

Understanding the pharmacokinetic characteristics of a drug and the influence of renal function on those characteristics is very important while prescribing drugs for the patient suffering from renal impairment.

Pharmacokinetics and Renal Function

1. Loading Dose

Some drugs need a rapid administration of large quantities in certain clinical situations to attain a therapeutic concentration. Without a loading the dose the amount of time required to attain a 90% of the plateau drug concentration is 3.3 times the t_1/2 of the drug. The amount of loading dose can be calculated by the formula - Loading dose = (C_initial) (V_d). Here C_initial is the initial target concentration in th blood and V_d is the volume of distribution.

In patients with renal impairment there may be a change in the V_d necessitating a change in the loading dose. Clincians need to be alert to the changes in the V_{d and} calculate the loading dose accordingly, rather than use a fixed amount as is often seen in practice. The formula for calculating the loading dose in this case is as follows:

or

2. Protein binding

Protein binding of acidic drugs is often decreased in patients with renal insufficiency. For drugs such as warfarin and phenytoin this might lead to a decrease in the bound fraction of the drug while the unbound fraction remains more or less the same because of hepatic clearance. The therapeutic serum concentration might appear lower and hence inadvertently the clinician might increase the dose leading to adverse events.

3. Maintenance dose

This is the dosing regimen that maintains the steady state concentration. It is determined by the formula “Maintenance dose = (C_average)(Cl)”; where C_average is the target average drug concentration and Cl is the clearance of the drug. While administering through the oral route we have to consider the bioavailability of the drugs. Hence depending on the route of administration the formula for calculating the dosing interval varies as follows:

From this we can infer that change in renal clearance warrants a substantial change in the dose as well as dosing interval of the drugs.

4. Half Life

Often we assume that t_1/2 and clearance are the same and one is a direct result of the other. We also assume that a change in t_1/2 leads to a proportional change in the clearance i.e. if t_1/2 is high then the clearance is low and hence there needs to be a proportional decrease in the dose. This assumption can lead to serious consequences in dose adjustments in patients with renal insufficiency.

The correct relationship between t_1/2 and clearance can be depicted as - t_1/2 = 0.693V_d/Cl . Hence it is clear a change in the t_1/2 might be either a consequence of change in the volume of distribution or clearance of a drug.

A good example of this potential scenario in patients with renal insufficiency is the use of digoxin. In patients with mild to moderate renal insufficiency, the V_d of digoxin is approximately the same as in patients with normal renal function, whereas Cl is about one­half to two­thirds of normal. In such patients, the t_1/2 rises in proportion to the diminished Cl. In patients with severe renal insufficiency, however, V_d is decreased to one­half to two­thirds of normal, and Cl is decreased even more, to about one­third of normal. In this setting, t_1/2 is influenced by both parameters, one causing it to increase (Cl) and one causing it to decrease (V_d), so that the overall prolongation is little different from that in a patient with mild to moderate renal insufficiency. In the patient with severe renal insufficiency, if the change in t_1/2 were erroneously presumed to reflect only the decrease in digoxin clearance and thereby affect only the maintenance dose, a serious dosing error would occur. In such a scenario, no downward adjustment in loading dose would be made in proportion to the diminished volume of distribution, and therefore the initial concentration would be higher than desired; in addition, the decrease in maintenance dose would be underestimated, resulting in the patient’s steady state serum concentration being maintained at a higher level than desired. The hazards of such an error are obvious.

Dosing Regimens

The primary objective in altering the drug dosage in renal dysfunction patients is to maintain the same average drug concentration as in patients without renal dysfunction. For drugs with linear kinetics or first-order kinetics the change in clearance can be compensated for by a proportionate change in the dosing rate.

Modified maintenance dose=(Patient's clearance/Usual clearance)×Usual maintenance dose

Hence if the clearance is one half the normal clearance then the dose should be halved. Such a dose reduction will maintain the steady state concentration at the same level as that in patients with normal renal function.

Regimens with closer dosing frequencies and smaller individual doses result in less difference between peak and trough drug concentrations. For example, for an antibiotic with a long

post-antibiotic effect, having a considerable period of time with low serum concentrations may not be worrisome. In contrast, for a drug that must be maintained within a narrow concentration range to maximize efficacy (e.g., an anti-arrhythmic or an anticonvulsant); a regimen that minimizes fluctuations in serum concentrations would be needed. To choose the best dosing regimen requires the clinician to consider the pharmacology of the drug in question, as well as the goals of therapy. For example, if a patient is not responding to a drug, the clinician should realize that a possible explanation is an inappropriate dosing regimen wherein inadequate serum drug concentrations are maintained.

Similarly, signs of toxicity shortly after administration of an individual dose may indicate too high a peak drug concentration and a need to give smaller doses more frequently.

Dialysis

Dialysis and hemofiltration are additional mechanisms for removing drugs. Dialysis might lead to a requirement for supplemental dosing, usually after the completion of the dialysis procedure. In the case of continuous dialysis the dosing might have to be adjusted upwards as a result of continuous removal of the drug. However dose adjustment might not be needed for all drugs and, the pharmacokinetic and molecular characteristics of a drug must be taken into consideration while calculating dosage adjustment if any.

For example, large molecular size may prevent the drug from passing across the dialysis membrane (including the peritoneum); this is the case with vancomycin and amphotericin. In a second example, drugs that are highly bound to serum proteins have restricted access to the dialysis membrane because only free, unbound drugs can cross this barrier. If >90% of a drug is bound, it is unlikely that dialysis will contribute appreciably to its elimination. Third, drugs that are water soluble are more readily dialyzed; a clue to the water solubility of a drug is elimination predominantly in the urine by the kidney as unchanged drug. Finally, drugs with large volumes of distribution have minimal dialyzability.

Active Metabolites

Many drugs might not be removed via the renal system; however they might be converted to active metabolites which are excreted renally. For example, meperidine is converted to normeperidine, which is not an analgesic like the parent drug but rather a central nervous system stimulant. It accumulates in patients with renal insufficiency. Even in patients with mild decrements in renal function, such as elderly patients, this metabolite can reach sufficient concentrations to cause seizures. The use of meperidine in patients with renal compromise requires lower doses (which may limit its efficacy). A better alternative is to use another analgesic that does not depend on the kidney for elimination of either the parent drug or its metabolite(s).

Conclusion

When renal insufficiency affects the volume of distribution of a drug, the loading dose must be modified. More commonly, one must compensate for decreased clearance of drugs by adjusting the maintenance dose. . Subsequent dosing requires tailoring the regimen to each individual patient, and this in turn must be based on clinical end points and/or measurement of serum concentrations of drugs.

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