Review Article Drugs 17: 111-123 0012-6667/79/0200-0111/$03.25/0 © ADIS Press Australasia Pty Ltd. All rights reserved.

Drug Prescribing in Renal Failure William M. Bennett Department of Medicine. Division of Nephrology, University of Oregon Health Sciences Center and Veterans Administration Hospital, Portland, Oregon

Summary

Drug prescribing for patients with renal failure should incorporate adjustment of dosage regimens in order to avoid accumulation and thus adverse effects. Drugs usually eliminated by the kidneys require the most modification. Since immediate therapeutic efficacy is of importance. the initial or loading dose is essentially unaltered for patients with renal dysfunction. Maintenance doses can be adjusted by either lengthening the interval between doses or by reducing the size of individual doses. In clinical practice. a combination of both methods is used. Serum levels should be used as guides whenever possible. In interpreting these leve/s, recognition of decreased plasma protein binding and prolonged elimination half-lives in renal failure is imperative. In patients requiring dialysis. consideration must be given to adjustments for drug removal by the artificial membrane. Small molecules unbound to proteins are most easily removed. Specific guidelines for therapy with common drugs prescribed for patients with renal failure are given. These include: (1) narcotics and analgesics; (2) psychotherapeutic drugs; (3) cardiovascular drugs; and (4) antimicrobial agents.

Patients with renal failure of varying degrees often need to be treated with a wide variety of pharmacological agents, both for their renal disease as well as intercurrent illness. Drugs whose route of excretion is primarily renal may accumulate in the presence of renal insufficiency leading to adverse reactions unless dosage regimens are modified. In recent years, it has been widely recognised that the altered physiology of renal failure may also involve other organs vital to drug elimination such as the liver, resulting in complex pharmacokinetic patterns in individual patients. Further complicating therapy in renal patients are

changes in volume of distribution, binding of drug to plasma proteins, irregular gastrointestinal absorption, and dialysis treatments. For the clinician treating patients with renal disease, these and other variables such as interactions between drugs, drug interference with laboratory tests and effects of uraemia on drug serum level determinations often seem overwhelming. Once it is realised that drug prescribing in renal failure follows some general principles, then it is obvious that the best guide to therapy with any drug is a thorough knowledge of its pharmacokinetics and its alteration

112

Drug Prescribing in Renal Failure

with renal disease. The purpose of this review is to elucidate some of these general principles and to provide specific practical guidelines for drugs commonly used in these patients.

1. Clinical Estimation of Renal Function The half-life of elimination for drugs (or metabolites) excreted primarily by the kidney is inversely proportional to the glomerular filtration rate. For such drugs the half-life increases slowly until the glomerular filtration rate reaches approximately 30ml/min (Kunin et ai., 1959) but with more severe degrees of renal dysfunction the half-life markedly increases. Since the blood urea nitrogen and serum creatinine do not follow a straight line relationship with glomerular filtration rate, use of these serum values may be misleading in regard to the actual level of renal function. Only when the serum creatinine and its relationship to creatinine clearance are known for any individual can subsequent serum values be used to infer the likely glomerular filtration rate. For example, if a serum creatinine value of Img/dl is equated to a creatinine clearance value of 100ml/min in a particular patient, a doubling of the serum value to 2mg/ dl will correspond to a halving of creatinine clearance to 50ml/min. However, it may be incorrect to assume that for a different individual a serum creatinine of 1. 5 mg / dl reflects normal creatinine clearance, particularly if the patient is elderly or has a low body weight. Presumption of normal renal function could result in serious overdoses with drugs that have narrow therapeutic:toxic ratios such as digitalis glycosides or aminoglycoside antibiotics. The blood urea nitrogen may be influenced by such extrarenal factors as diet, state of catabolism and corticosteroid therapy, thus making it an unsuitable parameter on which to base drug dosage. Consequently, some measurement or derivation of glomerular filtration rate is necessary to prescribe for patients with renal disease. The endogenous creatinine clearance is customarily used for clinical measurement of glomerular

filtration rate. Its chief advantage is that the measurements do not require constant infusion of solute and the methodology is widely available. The chief disadvantage is the requirement for carefully timed urine collections. Since creatinine excretion is proportional to lean body mass and inversely proportional to age, Cockcroft and GaUlt (I 976) have developed a formula for estimating creatinine clearance without the need for urine collection. The following equation has been validated in 123 patients of both sexes with varying degrees of renal dysfunction: .. - (140 - age) x (body weight in kg) Creatmme = - - - - - - - - - - - - - clearance 72 x serum creatinine The only patient population in which the formula overestimates the measured creatinine clearance is the pregnant female. Theoretically, this might also occur in patients with oedema and ascites because of increases in body water, although this has not been specifically examined (Parker et al., 1977). Both the formula and the measured endogenous creatinine clearance overestimate the true glomerular filtration rate as measured by inulin clearance in patients with marked diminution of renal function, i.e. less than I Oml/ min (Bennett and Porter, 1971). However, for purposes of drug prescribing these differences are small enough to be ignored. No other parameter of renal function other than glomerular filtration rate has been systematically evaluated in relation to prolongation of elimination half-life of drugs in renal failure. It is doubtful that assessment of renal blood flow or tubular function will prove useful in devising dosage regimens for these patients.

2. Principles of Drug Therapy in Renal Failure The extent of accumulation of drugs given in the usual doses to patients with renal failure depends on the degree of renal dysfunction. Usually the risk of

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Drug Prescribing in Renal Failure

significant retention is limited to those agents which are primarily excreted by the kidney. Thus, knowledge of a drug's pharmacology is essential prior to prescribing for renal failure patients. Recently, it has become apparent that the situation can be considerably more complex when metabolites with pharmacological activity also depend on the kidney for excretion. For example, norpethidine, a metabolite of pethidine (meperidine) may accumulate in patients with renal failure resulting in a neurological symptom complex characterised by seizures and coma (Szeto et al., 1977). Although pethidine undergoes hepatic biotransformation, norpethidine is primarily excreted by renal mechanisms. Other specific examples are discussed in section 3. 2.1 Importance of a Loading Dose in Renal Failure Patients When patients receive multiple doses of a drug at uniform dose intervals, the average plasma concentration rises until a steady state concentration is reached. Under such circumstances the time required to reach approximately 90 % of the steady state drug concentration is 3.3 times the elimination half-life. Since the half-life may be markedly prolonged in renal failure, effective therapy may be greatly delayed if maintenance doses are adjusted to the renal failure elimination half-life. Thus, a loading dose or at least an increase in the first dose administered to the patient is necessary. This principle is particularly important when planning antibiotic or cardiac glycoside therapy. It appears most practical to administer the usual loading dose to patients with renal failure (Wagner, 1974; Fabre and Balant, 1976). If there is an altered volume of distribution such as with extracellular fluid volume depletion or dehydration, it may be prudent to slightly reduce the initial dose for drugs with a narrow therapeutic: toxic ratio. This applies particularly to cardiac glycosides such as digoxin and ototoxic aminoglycoside antibiotics such as gentamicin, tobramycin, kanamycin and amikacin.

2.2 Principles of Maintenance Dosage Adjustment For glomerular filtration rates above 30ml/min, it is seldom that precise modifications of usual doses are necessary except for certain antibiotics and cardiovascular drugs. The goal of therapy in renal failure patients is to achieve serum concentrations near those obtained in normal individuals. Since serum levels are not available to all clinicians, it is most often necessary to plan clinical therapy in the absence of specific data for a particular drug. For many drugs there are incomplete data in the literature on the effect of renal dysfunction on pharmacokinetics. Even when such data exists in the literature, prospective trials comparing predicted serum levels with those actually obtained often show poor correlation (Barza et al., 1975). This is probably due to the large number of variables which are present in patients with serious disease. In practice, the desired serum level can be reached by one of two methods or some compromise between them.

2.2.1 Lengthening of Dosage Intervals The first method is to lengthen the interval between maintenance doses to correspond to the halflife of elimination in renal failure, while keeping the size of the individual dose constant. This method is convenient and is particularly applicable to drugs with a relatively long serum half-life (Fabre and Balant, 1976). However, when interval extension is applied in severe renal failure to drugs with short half-lives such as the common aminoglycosides, gentamicin, tobramycin and amikacin, prolonged periods of serum concentrations below the therapeutic range may result. Although this peak and trough effect might theoretically result in inadequate therapy for infection, this has not been substantiated by clinical or experimental data. In fact, recent studies have shown that frequent smaller doses of.aminoglycosides may have greater nephrotoxicity in experimental animals (Plamp et al., 1978; Thompson et al., 1977).

Drug Prescribing in Renal Failure

2.2.2 Dosage Reduction Method

Alternatively, the usual dosage intervals can be maintained but the amount of each individual dose reduced in proportion to the patient's degree of renal failure. With this method the difference between peak and trough levels is minimised. The level about which the maximum and minimum concentrations fluctuate can be set by the degree of dosage reduction. If this dose is too high or if the degree of renal function is overestimated, serious toxicity can result. In addition, as mentioned above, for antibiotics such as the aminoglycosides the relatively constant blood levels may enhance nephrotoxicity by keeping receptors for drug transport into proximal tubular cells saturated (Plamp et aI., 1978). In clinical usage therefore, one usually combines some dosage reduction with some lengthening of dosage intervals. To make precise calculations of correct dosage, knowledge of such pharmacokinetic parameters as elimination half-life, overall elimination rate constant and extrarenal elimination rate constant are necessary. Standard sources giving therapeutic guidelines incorporating these parameters are available for most commonly used drugs (Bennett et at., 1977c; Anderson et aI., 1976; Fabre and Balant, 1976; Dettli, 1976). It should be noted that any fIxed formula must be adapted to the. individual situation since many complex variables may modify the recommendations. Data obtained by statistical analyses of groups of patients may not fIt individual clinical circumstances.

2.3 Use of Serum Levels to Monitor Therapy It is widely recognised that optimum drug doses for achieving therapeutic effects vary widely among individuals. To avoid serious over- or underdosage, serum drug concentrations can be used as therapeutic guides (Koch-Weser, 1972). Usual therapeutic ranges are being increasingly defIned for many groups of drugs used to treat patients with renal failure. These include anticonvuisants, cardiac glycosides, antibiotics, antiarrhythmics and psychotherapeutic drugs.

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Interpretation of serum drug levels should, however, be tempered with clinical judgement. For example, digitalis intoxication can occur with serum levels well within the therapeutic range if significant hypokalaemia or metabolic alkalosis exists. Acute shifts in acid-base balance and potassium often occur in the setting of dialysis, producing cardiac arrhythmias. Thus, the physiological and biochemical milieu must be considered in evaluating serum levels of cardiac glycosides in patients with renal failure. Serum levels can be interpreted fully only if the elapsed time from the last dose and the elimination half-life in,that particular patient are known. To obtain the best estimate of the peak blood concentration, blood should be sampled I to 2 hours after an oral dose and 30 minutes to I hour after an intravenous or intramuscular dose. Many drugs such as phenytoin (diphenylhydantoin), digitoxin and quinidine are bound extensively to serum proteins, predominantly albumin. The bound fraction is pharmacologically inactive, but most techniques for measuring drug concentrations determine the total concentration of the drug in serum. In situations where serum albumin is depressed, such as in nephrotic syndrome, or when the drug binding ability of albumin is decreased by uraemia, the bound fraction may be markedly diminished. Thus, with some agents a normal or low total drug concentration may be associated with serious 'adverse reactions since the free drug concentration is increased. Patients with poor renal function have decreased binding of many drugs to their plasma proteins (Reidenberg, 1976). Anionic or acidic drugs show the most pronounced decreases in binding due to uraemia, perhaps due to occupation of binding sites by endogenous acidic compounds retained in renal failure (Reidenberg, 1976). If this explanation is correct, the substances must not be dialysable since dialysis in vitro does not correct the binding defect for the prototype acidic drug phenytoin (Reidenberg et al., 1971; Shoeman and Azarnoff, 1972). The binding of neutral compounds and organic bases are less affected by uraemia (Reidenberg, 1976).

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Drug Prescribing in Renal Failure

It must be emphasised, however, that decreased plasma protein binding does not necessarily lead to enhanced pharmacological activity. With phenytoin, for example, the elimination half-life may actually be decreased due to increased availability of free drug for conversion to the major metabolite 5-phenyl-5parahydroxy-phenylhydantoin. Although this metabolite depends on the kidney for elimination, it is pharmacologically inactive (Odar-Cederlof and Borga, 1974). Thus, the results of the uraemic state on pharmacokinetics need to be carefully individualised.

2.4 Dialysis and Drug Prescribing for Renal Failure Patients The widespread use of both haemodialysis and peritoneal dialysis to support patients with end stage renal disease has created a further challenge to the clinician prescribing for these individuals. Dialysis may result in depletion of therapeutic concentrations of drugs by causing removal from the blood into the dialysate. 2.4.1 Haemodialysis

Gibson and Nelson (I977) have pointed out in a recent review that the variables which influence drug removal during conventional haemodialysis are molecular weight, water solubility, protein binding, inherent plasma clearance and dialyser clearance. The usual membrane used for haemodialysis in clinical practice is cuprophane or cellulose. As the molecular weight of a drug increases, diffusive transport across these membranes decreases. Thus, the clearance of drugs with molecular weights less than 500 daltons is limited not by membrane factors but by blood and dialysate flow rates. For drugs with larger molecular weights, clearance is more dependent on dialysis membrane surface area (Babb et al., I 971 ). Drugs which are lipid soluble tend to have large volumes of distribution due to penetration into tissues, particularly the central nervous system. Levels of drug in the blood are usually low leading to

Table I. Common therapeutic agents requiring supplemental dosage after conventional haemodialysis Drug group

Agents

Antibiotics

Aminoglycosides: streptomycin, kanamycin, gentamicin, tobramycin, amikacin Cephalosporins: cephalothin, cephalexin, cephapirin, cephazolin, cephradine Penicillins: penicillin, ampicillin, carbenicillin, amoxycillin, ticarcillin Chloramphenicol

Antifungal drugs

Flucytosine (5-fluorocytosine)

Antituberculosis drugs

Ethambutol, isoniazid, cycloserine

Miscellaneous antiinfective agents

Metronidazole, quinine, sulphafurazole (sulfisoxazole). co-trimoxazole (trimethoprim-sulphamethoxazole)

Analgesics

Aspirin, paracetamol (acetaminophen)

Sedatives, hypnotics and tranquillisers

Phenobarbitone, lithium

Cardiovascular drugs

Procainamide, quinidine, methyldopa, diazoxide, sodium nitroprusside

Miscellaneous agents

5-fluorouracil, cyclophosphamide, azathioprine, primidone, gallamine

poor removal by conventional haemodialysis. Protein binding also restricts clearance of drug by haemodialysis since the gradient between unbound drug and dialysate is a prime determinant of transfer. Obviously, the type of dialyser and its surface area are important variables. Thus, there are many variables which affect removal of therapeutic agents during dialysis. A useful review of the data needed to predict removal of drugs by conventional dialysis has been published by Gibson and Nelson (I977). Since most clinical situations do not demand such a rigorous approach it is common practice to replace a full maintenance dose of

Drug Prescribing in Renal Failure

the common drugs listed in table I which are significantly cleared by conventional haemodialysis (Bennett et aI., 1977c; Maher, 1977). For drugs that are significantly dialysable, it is wise to omit a dose just preceding dialysis':as well as doses scheduled during dialysis treatments. As a generalisation for the clinician, drugs whose renal excretion represents a high percentage of their elimination from the body will undergo significant decreases in concentration during clinical dialysis. A further consideration, however, is that dialysis may affect drug activity even though it does not remove the drug. The most common example of dialysis influence on metabolic factors affecting drug action is the digitalis intoxication produced by rapid electrolyte shifts of potassium and the divalent cations, Ca + + and Mg + +. Conversely, in some patients dialysis can correct metabolic abnormalities induced by drugs, i.e. large sodium loads (carbenicillin), metabolic acidosis (phenformin), hyperkalaemia (penicillin, potassium salt), and hypermagnesaemia (antacids). 2.4.2 Peritoneal Dialysis The profound effects of drugs on dialysis kinetics has become an important consideration with the resurgence of peritoneal dialysis as a primary therapeutic procedure for chronic renal failure. The physiological effectiveness of the blood supply to the peritoneum, being composed of small arterioles and capillaries, is diminished by vascular disease and can be increased by vasoactive amines such as intraperitoneal isoprenaline (Nolph et aI., 1971; Brown et aI.,1973). In general, the pharmacological considerations applied to peritoneal dialysis are the same as with removal by haemodialysis. Less significant losses are usually observed with peritoneal dialysis despite the longer durations of treatment for drugs of molecular weights less than 500 daltons. With larger molecules, clearances may be similar to haemodialysis. Colistin sulphomethate (colistimethate) is an example of a drug better removed by peritoneal dialysis (Goodwin and Friedman, 1968).

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3. Specific Considerations/or Drugs Used Frequently in Patients with Renal Failure 3.1 Narcotic Analgesics Narcotics are predominantly metabolised in the liver to more polar metabolites. These biotransformed compounds potentially have both pharmacological activity and, more importantly, toxic maniestations if they accumulate in the presence of renal failure. Recently, norpethidine, a metabolite of pethidine, has been shown to accumulate in patients with renal. failure producing seizures in some individuals (Szeto et al., 1977). Thus, pethidine should be used with caution and in reduced doses in renal failure patients. Methadone, on the other hand, undergoes hepatic metabolism to an inactive metabolite which is not known to cause adverse effects. In limited data from patients with renal failure, plasma methadone levels were within normal limits. The absence of significant accumulation of methadone may be due to a shift in the route of elimination from urinary to faecal Onturrisi, 1977). The sensitivity of uraemic patients to the respiratory depressant effects of morphine may be increased because of decreased plasma protein binding in uraemic serum (Olsen et aI., 1975). Thus, morphine should be administered with caution to uraemic patients, particularly those with low serum albumin levels and / or concurrent liver disease. 3.2 Non-narcotic Analgesics The propoxyphene metabolite, norpropoxyphene, may accumulate with repetitive dosing in patients with advanced renal disease but its pharmacological activity is probably low. Codeine, pentazocine and the narcotic antagonist naloxone can be used without dose modification in renal failure patients. None of these drugs or the narcotics undergo significant enough removal during dialysis to require dosage supplementation. Salicylates should be used with caution in patients with renal failure. Pharmacological effects on both

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platelets and the gastrointestinal tract can enhance uraemic platelet dysfunction and gastrointestinal symptoms respectively. These effects occur despite the drug's relatively normal half-life in uraemic patients receiving low dose (250mg) therapy. With doses greater than 500mg there is saturation of liver metabolic pathways and renal elimination of unchanged drug becomes a more important pathway of salicylate removal (Lowenthal et ai., 1974b). Salicylate binding to plasma proteins is also decreased in renal failure. Paracetamol (acetaminophen) metabolites accumulate in patients with renal disease but have no pharmacological activity or known toxic effects. The implication of phenacetin (of which paracetamol is a major metabolite) and paracetamol itself in the pathogenesis of analgesic abuse nephropathy does not preclude use of these compounds for analgesia in patients with established chronic renal failure. 3.3 Psychotherapeutic Drugs

3.3.1 Antianxiety Agents and Hypno-sedatives It is well recognised that patients with severe renal disease undergoing long term management of their condition may be subject to a great deal of emotional stress. This may result in anxiety and depression. For mild to moderate symptoms a benzodiazepine can be safely used. Diazepam or chlordiazepoxide can be given in their usual dosage, watching carefully for excessive sedation. Parenteral diazepam, which is poorly dialysable, is useful to treat symptoms of acute anxiety during the dialysis procedure itself. Insomnia is a frequent complaint of patients with end stage renal disease. Flurazepam. which belongs to the benzodiazepine group of drugs and is metabolised by the liver to inactive metabolites, can usually be safely given in usual doses to renal failure patients. Diphenhydramine. an antihistamine, may also be useful in doses of 25 to 50mg at bedtime, particularly in patients who are kept awake by uraemic pruritus. If diphenhydramine is given more frequently than every 9 to I 2 hours, excessive sedation may result.

Barbiturates. because of their great potential for dependence, should be aroided, particularly phenobarbitone which depends on renal excretion for elimination from the body.

3.3.2 Tricyclic Antidepressants For severe depression, tricyclic antidepressants are the mainstay of therapy. There are no unique side effects of these drugs in the patient with renal failure. Orthostatic hypotension can be a problem when superimposed on dialysis induced extracellular fluid volume depletion. Tricyclic antidepressants may interfere with the antihypertensive action of guanethidine and related drugs, and may cause urinary retention by virtue of their anticholinergic effects. For a depressed patient who has psychomotor retardation, imipramine may be used, while amitriptyline may be more appropriate for more agitated individuals (Viederman and Rusk, 1977). 3.3.3 Antipsychotic Drugs The treatment of major psychoses can be handled pharmacologically similar to non-uraemic patients. Phenothiazine drugs are most useful, although the hypotensive potential and low seizure threshold of chlorpromazine, the propensity for arrhythmias with thoridiazine, and the greater frequency of extrapyramidal reactions caused by fluphenazine, perphenazine, trifluoperazine and haloperidol need to be considered in selecting a drug for the individual patient. 3.4 Cardiac and Antihypertensive Drugs The high incidence of hypertension and coronary atherosclerosis in patients with chronic renal failure and the relative frequency of cardiac arrhythmias in these patients make cardiac and antihypertensive drugs among their most frequently prescribed medications.

3.4.1 ~-Adrenoceptor Blocking Drugs Propranolol is used extensively as an effective antihypertensive drug, an antiarrhythmic, and for symp-

Drug Prescribing in Renal Failure

tomatic treatment of angina pectoris. Propranolol achieves a higher peak plasma level in patients with renal disease than in normal subjects probably because hepatic extraction of the drug is reduced (Lowenthal. et aI., I 974a; Bianchetti et aI., 1976). However, the elimination half-life of propranolol is normal to shortened in patients with chronic renal disease perhaps due to induction of hepatic microsomal enzyme systems. Thus, the usual dose interval of propranolol need not be altered for the presence of renal failure but there may be a need to reduce the dose size. Propranolol is not significantly removed by haemodialysis or peritoneal dialysis, although the procedure may alter the systemic availability of the drug leading to enhanced metabolism. Less experience has been accumulated with other ~-adrenoceptor blockers in renal failure. Sotalol is primarily excreted by the kidneys and the dosage must be reduced in renal failure patients; it also is removed by haemodialysis. Pindolol elimination is both by renal and extrarenal routes. Firm recommendations regarding dosage adjustment in renal insufficiency have not been formulated (Johnsson and Regardh, 1976). 3.4.2 Antiarrhythmic Drugs Quinidine half-life is the same in patients with

renal failure as in normal subjects and no adjustment of dosage is necessary. Procainamide is metabolised to a pharmacologically active metabolite, n-acetylprocainamide, which has antiarrhythmic potency similar to the parent compound. Conventional plasma level determinations do not measure the metabolite. Since n-acetylprocainamide has a long half-life and is eliminated almost entirely by the kidney, the interval between doses of procainamide should be increased to 8 to 12 hours in advanced renal insufficiency. Lignocaine (lidocaine) undergoes hepatic extraction and metabolism similar to propranolol. The active metabolites produced could theoretically accumulate in renal failure and cause central nervous system toxicity; however, this has not been a clinical problem.

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3.4.3 Diuretics

Diuretics, which form an essential part of most antihypertensive regimens in patients without renal failure, are less useful in the presence of renal insufficiency. Frusemide (furosemide) and ethacrynic acid, which act on the ascending limb of the loop of Henle, may produce a natriuresis in patients with glomerular filtration rates as low as 5 to I Oml/ min; however, the large doses required may produce ototoxicity. Ethacrynic acid should be avoided in patients with renal disease since its ototoxic potential is greater than that of frusemide. Thiazide diuretics are generally ineffective ~ith glomerular filtration rates below 25ml/min. Metolazone has some efficacy in far advanced renal failure; however, it too is ineffective with glomerular filtration rates less than I Omll min. Since the majority, if not all of the antihypertensive action of diuretics depends on achieving a natriuresis, control of extracellular volume most often must be achieved by dialysis in hypertensive patients with end stage renal disease (Bennett et aI., I 977b). Spironolactone and triamterene may cause fatal hyperkalaemia when given to patients with advanced renal failure and are contraindicated. Mercurials are ineffective and nephrotoxic in patients with advanced renal disease and should be avoided. 3.4.4 A ntihypertensive Drugs

Antihypertensive drugs are generally administered to patients with renal failure according to their response, not to the pharmacokinetic characteristics of the individual drugs. For urgent lowering of blood pressure, diazoxide is especially useful in patients with renal insufficiency. One explanation for this drug's more potent effects in patients with renal failure is the decreased protein binding in uraemia (O'Malley et aI., 1975). Although the extracellular fluid volume excess of the undialysed uraemic patient may blunt the vasodilator action of the drug, diazoxide administered after ultrafiltration dialysis often produces profound hypotension. Sodium nitroprusside administered by constant infusion can control almost any hypertensive emer-

Drug Prescribing in Renal Failure

gency. The metabolism of nitroprusside to thiocyanate presents some risks to patients with renal failure, unless blood levels of thiocyanate are monitored and maintained less than 5 to 1Omg / dl. Thiocyanate has a half-life of one week in the patient with normal renal function. The symptoms of thiocyanate toxicity, which include nausea, vomiting, myoclonie movements and seizures, can be rapidly alleviated by dialysis. Because of the potential for accumulation of thiocyanate, sodium nitroprusside infusions in patients with renal failure are best terminated within 48 hours. No dose adjustments for renal failure are required for c/onidine, methyldopa, hydrallazine, prazosin, guanethidine or minoxidil. However, it may be wise to omit the dose of antihypertensive medication just prior to dialysis in those patients who have problems with hypotension during the procedure. 3.4.5 Cardiac G(vcosides

In renal failure, cardiac glycosides are usually given in reduced amounts at customary dosage intervals after providing adequate body stores with the usual digitalising dose. The half-life of digoxin is 1.6 days with normal renal function and 4.4 days in anuric patients (Jelliffe, 1968). The daily maintenance dose is equal to the non-renal losses (14 % of body stores) plus an additional percentage to replace urinary losses. Since urinary losses are inversely proportional to glomerular filtration rate, patients with far advanced renal disease lose very little digoxin in the urine and these patients obtain satisfactory therapeutic effects with doses of 0.125mg 3 to 5 times a week. Dialysis does not lower digoxin levels but sudden shifts in potassium and/ or hydrogen ions may provoke cardiac arrhythmias; for this reason it is recommended that dialysate potassium be 3.0mmoliL in all digitalised patients. Recently, it has also been shown that heparin causes decreased affinity of cardiac glycosides for plasma proteins during haemodialysis (Storstein, 1977). The relevance of this phenomenon to the frequent arrhythmias seen in haemodialysis patients is unclear.

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DigitOXin is mainly eliminated from the body by non-renal routes. Renal failure, therefore, has little effect on digitoxin pharmacokinetics Oelliffe et al., 1970). The digitoxin half-life in patients with normal renal function is 6 days while an anuric patient has a half-life of 8.5 days. Thus, digitoxin dosage schedules, although theoretically needing minor alterations in renal failure, in practice need not be much different from usual therapy. Digitoxin binding to plasma proteins in uraemia, particularly during dialysis, may be decreased (Storstein, 1977). This may necessitate a slightly lower blood level to avoid toxicity.

3.5 Antimicrobial Agents The need for antibiotic therapy is frequent in renal failure. For drugs with narrow therapeutic: toxic ratios such as the aminoglycoside antibiotics (gentamicin, tobramycin, kanamycin, amikacin), sequential serum levels are most useful to ensure efficacy. However, it is not as clear that elevated serum levels during the treatment period are important aetiological factors in the ototoxicity and nephrotoxicity which occur with this class of drugs. Other commonly used antibiotics which require dose modification in severe renal failure are penicillin G, carbenicillin, cephalosporins, tetracycline, vancomycin and colistin. A complete classification of antimicrobials based on the need for dosage modification in renal failure is shown in table II (Anderson et al., 1976). References for the recommendations made in this table appear in recent review articles (Anderson et al., 1976; Bennett et al., 1977c; Fabre and Balant, 1976). 3.5.1 Penicillins

The penicillins are generally safe to administer to patients with renal failure since even with modest accumulation, little toxicity is noted clinically. Doses of the isoxazolyl penicillins need not be altered at all. When penicillin G (benzylpenicillin) is given to a patient with a creatinine clearance less than

Drug Prescribing in Renal Failure

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Table II. Antimicrobial use in patients with renal failure

Dosage modification

Drugs

1. No major dosage reduction required

Isoxazolyl penicillins Clindamycin. lincomycin Erythromycin Chloramphenicol Doxycycline Pyrimethamine Isoniazid Amphotericin B

2. Major dosage reduction necessary a) With all degrees of renal failure

b) With moderate to severe renal failure (GFR < 50ml/min)

Aminoglycosides Vancomycin Carbenicillin Ticarcillin Cephazolin Co-trimoxazole Sulphonamides Flucytosine

c) With severe renal failure only (GFR < 1OmI/min)

Penicillin G Ampicillin. amoxycillin Methicillin Cephalothin Cephalexin Ethambutol Quinine. chloroquine Pentamidine

3. Avoid in severe renal failure

Tetracyclines (except doxycycline) Cephaloridine Nitrofurantoin Methenamine

I Omll min, half the usual loading dose should be given every 8 to 12 hours after a normal initial dose. It should be remembered that each million units contains 1.7 mmol of sodium or potassium depending on the preparation used. Maintenance doses of ampicillin and amoxycillin, when used to treat extrarenal infections in patients with glomerular ftltration rates less than I Omll min, can be given at intervals of 12 to 16 hours. However, in the treatment of urinary tract infections, usual doses may be necessary in order to

achieve adequate antibiotic concentrations in the renal interstitium and urine. Carbenicillin and ticarcillin doses should be reduced when the filtration rate drops to 25 to 30mllmin. Since each gram of carbenicillin contains 5mmol of sodium, extracellular fluid volume expansion may result from usual doses in patients with reduced excretory capacity. In patients with end stage renal disease, carbenicillin dose is 2g every 8 to 12 hours. Carbenicillin and large doses of other penicillins may cause hypokalaemic metabolic alkalosis since secreted penicillin acts as a relatively nonreabsorbable anion favouring hydrogen and potassium excretion (Lipner et al., 1975). Massive accumulation of the penicillins may result in neurotoxicity manifested as seizures, myoclonic jerks and change in mental status. 3.5.2 Cephalosporins

Cephalosporins, like the penicillins, have a favourable therapeutic: toxic ratio; thus, major modifications are needed only when creatinine clearance is less than I Omll min. Cephalothin is given in the usual loading dose followed by maintenance doses every 8 to 12 hours. For the orally active agent cephalexin, adequate blood levels are achieved by a loading dose of I g followed by maintenance doses of 500mg every 12 hours. Usual doses are necessary for urinary tract infections. Cephaloridine has greater potential nephrotoxicity than other cephalosporin derivatives and should be avoided in patients with advanced renal failure. 3.5.3 Tetracyclines

The elimination rate constants of all tetracyclines except doxycycline are markedly decreased by renal failure. In addition, this group of drugs is antianabolic and can aggravate azotaemia and uraemia in patients with pre-existing renal disease. Doxycycline does not share this property with the rest of the tetracyclines and can be given in usual doses to patients with renal insufficiency. However, doxycycline is not useful for urinary tract infections in patients whose glomerular filtration rates are less than 20mll min.

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Drug Prescribing in Renal Failure

Table III. Summary of drug prescribing in renal failure

1. Glomerular filtration rate - needs to be measured by endogenous creatinine clearance or by application of the formula: (140 - age) x (body weight in kilograms) 72

x serum creatinine

2. Principles of drug therapy in renal failure a) In order to ensure efficacy, the loading dose or initial dose should be near normal b) Maintenance doses can be adjusted by lengthening the interval between doses or by reducing the size of individual doses c) Serum levels can be used to guide therapy for drugs with narrow therapeutic: toxic ratios. Decreased protein binding in uraemia can result in toxicity with normal blood levels d) Haemodialysis and peritoneal dialysis may remove enough drug to interfere with therapy and to require supplementation e) Large molecular weight, protein binding and lipid solubility tend to retard clearance 3. Drugs used frequently in patients with renal failure which require specific considerations (see text) a) Analgesic and narcotic drugs b) Psychotherapeutic drugs c) Cardiac and antihypertensive drugs d) Antimicrobial agents

With minocyciine, the situation is less clear. Welling et al. (I975) found no elevation of blood urea nitrogen in patients with mild to moderate renal impairment; however, George et al. (I 973) reported that minocycline administration significantly aggravated the uraemia of patients with renal failure. A markedly increased half-life in severe renal impairment has been reported in some studies, but normal values have been reported in others. If tetracyclines must be prescribed in patients with renal failure, doxycycline and minocycline are preferable. 3.5.4 Aminoglycosides

The aminoglycoside antibiotics are almost entirely cleared from the body by the kidneys; thus dosage

schedules need to be adjusted to prevent ototoxicity, neuromuscular blockade and possibly further renal damage. Since this class of drugs is prescribed mainly in the setting of life-threatening infections, the usual loading doses are administered to ensure adequate immediate serum levels. Repetition of the loading dose every third half-life will usually result in adequate peak and trough blood levels. If the serum creatinine and renal function are stable, the elimination half-life can be estimated by multiplying the serum creatinine by 3 to 4. However, this interval extension method may result in wide swings of blood levels and considerable periods with blood antibiotic concentrations below the therapeutic range. Alternatively, the individual maintenance dose can be reduced to onethird or one-half of normal and given at the usual dosage interval, although this method has a greater risk of drug accumulation. For gentamicin and tobramycin a reasonable compromise is to administer a loading dose of 1.7 to 2mg/kg followed by a maintenance dose of 0.75 to I mg / kg every second elimination half-life; I mg/kg should be replaced following each haemodialysis or peritoneal dialysis treatment. 3.5.5 Sulphonamides, Macrolides and Chloramphenicol Dosages of short acting sulphonamides should be

reduced for treatment of extrarenal infections. However, if adequate concentrations are needed to treat urinary tract infections in patients with low glomerular ftitration rates, normal doses may be necessary. Erythromycin, lincomycin, ciindamycin and chloramphenicol need little if any dosage adjustment in uraemia. The metabolites of chloramphenicol may depress erythropoiesis and add to the anaemia of patients with renal failure (Suhrland and Weisberger, 1963). 3.5.6 Vancomycin

Vancomycin has proven to be useful in treating Gram-positive infections in patients with severe renal failure. It has a markedly prolonged half-life and is influenced by dialysis. In severe renal failure a dose of

122

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1g every 6 to 7 days will provide adequate levels in the blood to treat such serious infections as staphylococcal arteriovenous fistula infections and Grampositive bacterial endocarditis (Morris and Bilinsky, 1971; Bennett et aI., 1977a). Doses can be given every 48 to 72 hours for clearances between 10 and 25ml/min; 24 to 48 hours for clearances between 25 and 50ml/min; and every 24 hours with clearances between 50 and 75ml/min. 3.5.7 Nitrofurantoin Nitrofurantoin should be avoided in patients with renal failure with creatinine clearances less than 20ml/min, because a retained metabolite may produce polyneuritis (Toole and Parrish, 1973). 3.5.8 Amphotericin Band Flucytosine Treatment of fungal infections with amphotericin B is not altered by the presence of renal dysfunction; however, nephrotoxicity and renal tubular acidosis may be superimposed on the pre-existing renal problem. Maintenance doses of flucytosine (5fiuorocytosine) should be given every 24 to 48 hours in patients with end stage renal disease following the usual loading dose. 3.5.9 Antituberculosis Drugs Regimens for antituberculosis drugs need not be changed in patients with renal failure if isoniazid or r(fampicin are used. In severe renal failure, ethambutol dosage should "7 reduced to 5mg/kg/ day to avoid ophthalmological adverse reactions.

Acknowledgements The author would like to acknowledge the excellent secretarial assistance of Jennifer Paquet. Dr Bennett is supported in part by Research Grant number 5 ROI GM 22928-02 from the National Institute of General Medical Sciences and MRIS No. 90 I from the Veterans Administration Hospital, Portland, Oregon.

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Author's address: Dr William M. Bennett, Department of Medicine. University of Oregon Health Scienq:s Center. Portland, Oregon 97201 (USA).