| Guidelines for CLINICAL DRUG USE ~ Descriptions of Drug Classes ~ | |||
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Analgesic Agents Most of the analgesics are eliminated by the liver and renal dysfunction has little influence on their disposition. It has been noted, though poorly documented, that patients with renal and hepatic dysfunction manifest an increased sensitivity to a variety of the analgesic agents, particularly to narcotics. Whether this increased sensitivity is related to changed distribution to the sites of activity, additive effects of retained endogenous toxins, or to truly increased sensitivity is unclear. Usually, beginning doses of these agents are reduced in patients with renal and liver dysfunction until the individual patient demonstrates his or her own dose response relationship. Anesthetics (and drugs used during anesthesia) Many of the neuromuscular blocking agents are eliminated by the kidney and require dose adjustment in patients with renal dysfunction. For some of these drugs no data are available to allow development of guidelines for use in patients. Use of any of these drugs in the patient with renal failure requires caution, and it has been recommended that a peripheral nerve stimulator be employed to assess the degree of neuromuscular blockade. Short of this, the clinician must be aware that a patient with renal dysfunction may have slow recovery from anesthesia owing to both retention of anesthetic agents eliminated by the kidney or to additional factors that again are related to renal function. For example, patients with renal disease who either accumulate aminoglycoside antibiotics to high concentrations or who are potassium depleted may have prolonged respiratory suppression in the face of anesthetic agents as a result of the "curare like" effect that can occur with these antibiotics. The same principles apply to patients with liver disease and to drugs eliminated by hepatic routes. Fazadinium appears to have only minor changes in pharmacokinetics in patients with end stage renal disease and may, therefore, be a preferred agent in patients with renal dysfunction. Alfentanil, fentanyl, and propofol have been studied in the elderly. The disposition of the former two drugs was no different than in young patients. However, the pharmacodynamics were clearly altered such that half as much of either drug resulted in the same CNS depression as in young patients. The mechanism of this increased sensitivity is unknown. The initial volume of distribution and the clearance of propofol in elderly patients were about 75% of those in young patients. Thus, with this anesthetic, lower doses should also be used in elderly patients. Antianxiety Agents, Sedatives and Hypnotics Flumazenil is a benzodiazepine antagonist but is included in this section. Anticholinergics and Cholinergics Metoclopramide blocks dopamine receptors in the central nervous system while its effects on the gastrointestinal tract (and those of cisapride) most likely occur as a cholinergic agonist, either directly or by increasing sensitivity to endogenous amounts of acetylcholine. The central effects, combined with peripheral effects on the gut, contribute to its usefulness as an antiemetic. Cisapride does not enter the CNS and thereby avoids CNS side effects. The cholinergic effects hasten esophageal clearance, accelerate gastric emptying, and speed transit through the small bowel. I have elected to classify metoclopramide and cisapride as cholinergic agents since the majority of their therapeutic indications emanate from peripheral cholinergic effects. Anticoagulants, Antifibrinolytics, Antiplatelet and Fibrinolytic Agents It is important to note that patients with decreased renal function manifest intrinsic disorders of platelet function. Patients with liver and sometimes those with cardiac disease may have a decreased ability to synthesize vitamin K dependent clotting factors. Such patients treated with anticoagulants might have a greater tendency to bleed than would normal subjects since there would predictably be a greater overall disruption of hemostasis. Anticonvulsants The disposition of phenytoin and valproic acid shows important changes in patients with decreased renal function and hypoalbuminemic conditions. These changes are a manifestation of decreased protein binding with a concomitant increase in the volumes of distribution of these drugs. This phenomenon has been closely investigated with phenytoin, and it is likely that parallels can be drawn with valproic acid. Both drugs are highly protein bound; in patients with renal dysfunction or with hypoalbuminemia, displacement from serum proteins occurs with a concomitant increase in the volume of distribution. The clinical importance of this phenomenon is that the patient with renal dysfunction manifests the same concentration of free drug in serum at a lower total blood concentration than does the subject with normal renal function. Since most clinical laboratories measure only total concentration of drug in the blood, the importance of the phenomenon is in the proper interpretation of a blood level for these drugs in such patients. In some circumstances it may be desirable to obtain a measurement of the unbound drug concentration. Fundamentally, clinicians should not misinterpret diminished concentrations of total phenytoin in such patients. In summary, in a uremic or hypoalbuminemic subject, one should not misinterpret a low serum phenytoin concentration as subtherapeutic. The clinician must depend on clinical measures of end points of response. Phenytoin is readily assessed because patients with therapeutic concentrations often have nystagmus and increasing the dose in such patients would result in toxicity. On the other hand, the dose can be safely increased if there is a lack of efficacious effect and the patient does not have nystagmus. It is also important to note that phenytoin follows dose dependent kinetics. As a consequence, increments in dosing should be small and sufficient time should be allowed for the patient to achieve a new steady state. Antihistamines There are few data assessing the pharmacokinetics of classical antihistamines (H1 blockers) much less the influence of disease on handling of these drugs. It appears for the most part that H1 antihistamines are eliminated by the liver, but there are virtually no data available as to the existence of active metabolites. Similar to the psychotherapeutic agents these antihistamines tend to have sedating side effects to which patients with renal and hepatic dysfunction may theoretically be more susceptible. Anti-inflammatory Agents Specific data are presented for the few nonsteroidal anti-inflammatory drugs (NSAIDs) in which the effects of disease on kinetic parameters are clinically important. Data for all the NSAIDs are presented in Table 2. Most of the drugs are extensively metabolized, are highly protein bound with small volumes of distribution, and are poorly dialyzed. Since all of the agents are highly bound to serum albumin, they are likely to demonstrate decreased binding with an increased volume of distribution in uremia and other diseases with decreased albumin concentrations. This hypothesis has been verified with several of these drugs. The clinical implications of this phenomenon are negligible. As with any tightly protein bound drug, these drugs can displace other protein bound pharmacologic agents causing transient increases in concentrations of free drug in the serum. It is important to point out that all of these anti inflammatory agents are inhibitors of prostaglandin synthesis and in a variety of disease states, particularly congestive heart failure, liver disease, hemorrhage, systemic lupus erythematosus with renal involvement, and chronic renal failure, prostaglandins appear to be important in maintaining renal blood flow. In addition, it is now clear that both COX-1 and COX-2 have physiologic and pathophysiologic roles in renal function. As a consequence, prostaglandin inhibition, either COX-1 or COX-2, can result in decrements in renal function. Therefore, any of the nonsteroidal anti-inflammatory drugs could cause worsening renal function in patients with the aforementioned diseases. The effects of different clinical conditions on the kinetics of some of the NSAIDs have been elucidated and mandate dose adjustment. Importantly, many of these effects were not detected until studies of disposition of unbound NSAIDs were performed. Other anti inflammatory agents not covered in the tables include gold and the antimalarials. Gold compounds have inherent nephrotoxicity and should be avoided in any patient with decreased renal function. Sixty to 90% of parenterally administered gold and up to 50% of absorbed auranofin are eliminated by the kidney over a prolonged period of time (half life is approximately 250 days for parenteral gold and 70 to 80 days for auranofin). Therefore, it is predictable that gold would accumulate in patients with decreased renal function. The influence of disease on disposition of antimalarials is discussed under that specific heading. Sulfinpyrazone is included in the section on anticoagulant, antifibrinolytic, and antithrombotic agents. ANTIMICROBIAL AGENTS † Antibacterials Many members of the antimicrobial group of drugs depend on the kidney for their elimination. For a number of these agents, detailed kinetic studies have been performed in patients with varying degrees of renal dysfunction, which allow derivation of relatively precise guidelines. However, one must not overestimate their precision because of the considerable variability among patients. The derived guidelines relate to the "average" patient and serve as a starting point from which individualization of patient care must occur. For some of the agents in this and all other groups, the therapeutic index of the drug is so large that little precision is necessary, and concerns about variability among patients are less. On the other hand, many drugs in this category have a narrow therapeutic index, precision is mandatory, therapeutic end points must be closely followed, and if possible, serum concentrations of drugs should be determined. † Aminoglycoside Antibiotics The aminoglycoside antibiotics have the narrowest therapeutic range of any of the antimicrobial drugs. Their use requires precision of administration; optimal use requires monitoring serum levels. Accumulation of these compounds causes nephrotoxicity and ototoxicity, which can be delayed in onset and from which full recovery may not ensue. All of these compounds demonstrate a slow terminal elimination phase, and drug is excreted in the urine for weeks after discontinuation of therapy. This slow elimination phase contributes to accumulation of any of these compounds. Penicillins, particularly carbenicillin, piperacillin, and ticarcillin, can physically complex with these agents and, therefore, cannot be mixed in the same intravenous infusion. This same phenomenon occurs in patients with ESRD such that co administration of these penicillins results in a decreased serum level of aminoglycoside. More precise guidelines are offered because of the narrow therapeutic index of aminoglycosides. I favor the approach of Sarubbi and Hull, who introduced a regimen for dose adjustment incorporating both changes in dose and changes in dosing interval. Though spectinomycin is an aminocyclitol, its pharmacokinetic properties are closely related to the aminoglycosides, and it has been included in this section. Importantly, it does not appear to share the ototoxicity or the nephrotoxicity of the aminoglycosides. † Cephalosporins In general, these drugs have a wide therapeutic index and the stringent guidelines necessary for drugs such as the aminoglycosides are not required for this group of agents. In patients with liver disease, increased serum bilirubin displaces cefoperazone from protein allowing more to be filtered at the glomerulus. Therefore, the renal contribution to overall elimination increases. Consequently, a patient with combined hepatic and renal disease most likely needs greater reduction in dose than does a patient with isolated liver dysfunction. † Chloramphenicol and Thiamphenicol Chloramphenicol is metabolized by the liver; its metabolites are eliminated by the kidney. These metabolites have no antibacterial activity, but there is some evidence that they may cause central nervous system toxicity, which has been observed to occur more frequently in patients with renal dysfunction. The conjugate of chloramphenicol has a half life in normal subjects of approximately 4 hours, which may be increased to more than 70 hours in patients with ESRD. This occurs in the face of an unchanged half life of the parent chloramphenicol. The parenteral form of chloramphenicol, the succinate ester, can be eliminated unchanged in the urine (average equals 30 percent, range equals 6 to 80 percent). In patients with decreased renal function, the amount eliminated decreases allowing more to be cleaved to chloramphenicol; hence the bioavailability of chloramphenicol succinate (normally 70 percent) increases in patients with renal dysfunction. In ESRD, doses should be decreased by one third when used parenterally while no change is necessary with oral formulations. Patients with cirrhosis have less ability to clear chloramphenicol and they should receive lower doses. Thiamphenicol is a semisynthetic derivative of chloramphenicol; however, its route of elimination differs greatly. Ninety percent of thiamphenicol is eliminated unchanged in the urine as opposed to 10% for chloramphenicol. † Macrolide Antibiotics There is no effect of decreased renal function on the handling of clindamycin, and this drug is not dialyzable; therefore, its administration is unchanged in patients with decreased renal function. On the other hand, clindamycin dosing must be adjusted in patients with liver disease. † Monobactams † Nitroimidazoles † Oxazolidinones † Penicillins The penicillins have a wide therapeutic margin, and dose adjustment for many is not necessary unless high doses are to be administered. It is important to reemphasize that in patients with end stage renal failure, co administration of carbenicillin, piperacillin, and ticarcillin with aminoglycosides can cause a physical complexing of the two antibiotics with a lowering of the serum concentration of the aminoglycoside antibiotic. Nafcillin is, in part, eliminated by the kidney, but the change in handling with decreased renal function is of such a minor magnitude that there is no need to change the dosing regimen. Neither cloxacillin, dicloxacillin, flucloxacillin, or oxacillin have appreciable changes in pharmacokinetics with altered renal function. Slight effects on half life and/or percent of drug bound to serum proteins have been noted, but are of insufficient magnitude to warrant changing dosing regimens. All of these drugs are metabolized to active hydroxymetabolites, which accumulate in uremia. For example, hydroxyflucloxacillin has an elimination half life similar to that of the parent drug of approximately 1 hour in patients with normal renal function. In ESRD, the metabolite's half life is approximately 5 hr. Despite this effect, both the parent drug and the metabolite have a wide therapeutic index and dose adjustment is not necessary. Hemodialysis affects none of these isoxazolyl penicillins. † Polymyxins If possible, this group of drugs should be avoided in patients with renal dysfunction because of their inherent nephrotoxicity. † Quinolones † Streptogramins † Sulfonamides There are a large number of sulfonamide compounds available, but I have elected to detail the kinetics of only those that are used frequently. Most of the sulfonamide group are acetylated with the acetylated metabolite having very little antimicrobial activity. However, it should be realized that this metabolite can still cause crystalluria. Most of these compounds are weak acids and demonstrate pH dependent elimination kinetics, though the magnitude of the effect is unlikely to be clinically important. All sulfonamides are eliminated by the kidney in important amounts and decrements in renal function cause accumulation. These drugs also bind to serum proteins but to a variable extent, and no general statement can be made regarding the influence of renal disease as it might apply to all sulfonamide compounds. Trimethoprim is included in this section. † Tetracyclines All compounds in the tetracycline group demonstrate antianabolic effects, which can cause an increase in the blood urea nitrogen that might be interpreted as nephrotoxicity. In addition, however, these drugs can cause decrements in renal function that would be more accurately assessed by changes in serum creatinine or in creatinine clearance. If tetracyclines are to be used in a patient with renal dysfunction, those which are not removed by hemodialysis are preferable. These drugs include (with half life): chlortetracycline (6 hr) and minocycline (12 to 18 hr). Other tetracyclines specifically including demeclocycline, methacycline, oxytetracycline, rolitetracycline, and tetracycline accumulate during renal failure with increases in half life in patients with ESRD approximately ten times that in subjects with normal kidneys. The latter group of tetracycline antibiotics may be preferred in patients with liver disease. Though a body of literature suggests that handling of doxycycline does not change in uremia, it has recently become apparent that if assessed as free concentration of the drug, clearance decreases with decreasing renal function, and this drug should probably also be avoided in azotemic patients. † Urinary Bacteriostatics In general, urinary bacteriostatics should be avoided in patients with decreased renal function. Methenamine is absorbed and reaches the urine where it is converted at acidic pH to formaldehyde, which is the active moiety. This conversion does not occur systemically, so accumulation in renal insufficiency does not lead to systemic amounts of formaldehyde. Nevertheless, it is best to avoid this drug in severe renal disease because agents used to acidify the urine are contraindicated and, more importantly, the mandelate moiety is contraindicated at any level of renal insufficiency because of its tendency to crystalluria. Nitrofurantoin is 90% bioavailable, has a serum half life of 1 hour, is approximately 60% protein bound, and 47% of the drug is excreted unchanged in the urine. One would predict accumulation of the parent drug in uremia. However, the question becomes moot for there is severe and increased toxicity to nitrofurantoin in patients with decreased renal function, and insufficient drug reaches the urine to be therapeutic in such patients. This drug should be avoided in patients with renal dysfunction. Elimination of nalidixic acid (half life of 6.7 hr) itself is not changed in patients with decreased renal function. Most of the drug is metabolized to 7 hydroxynalidixic acid, which is as active as the parent drug and accumulates in azotemic patients. Therefore, it is probably best to avoid using this drug in patients with renal insufficiency and particularly in those with ESRD. In addition, the drug does not achieve therapeutic concentrations in urine in many patients with decreased renal function. Lastly, the influence of liver disease on the disposition of these drugs has not been investigated. † Vancomycin-like Drugs Though guidelines for use of vancomycin in patients with renal dysfunction have been derived, it is important to emphasize their tenuous aspect. A statistically significant correlation of creatinine clearance with clearance of vancomycin can be found. However, this correlation accounts for only approximately 20% of the variance in vancomycin clearance. Clearly, a number of unidentified and unquantified factors impact on vancomycin handling. The offered guidelines can serve as an initial starting point of therapy, but patients must then be assessed with serum concentrations of vancomycin to devise dosing regimens capable of achieving peak and trough target concentrations of 30 to 40 and 5 to 10 mg/L, respectively. Antifungals Antihelminthics Antimalarials There are few data regarding the pharmacokinetics of antimalarials. It appears that all but chloroquine and proguanil (a prodrug for cycloguanil) are metabolized. Whether or not active metabolites are formed that may accumulate in renal disease is unknown. Antiparasitics Metronidazole, tinidazole, and ornidazole are the only drugs in this category for which any manifestation of renal dysfunction affects handling. None are eliminated by the kidney, but all are dialyzable so that a patient on hemodialysis has a half-life of these drugs one half that of normal subjects; a supplemental dose equal to one half the normal dose should be administered after hemodialysis. Peritoneal dialysis removes negligible amounts of metronidazole or ornidazole. Neither hemodialysis nor peritoneal dialysis removes the alcohol metabolite of metronidazole, which has 30% of the activity of the parent compound. This metabolite, then, accumulates in patients with renal dysfunction. Some authorities feel it may contribute to nephrotoxicity. If further study proves this to be the case, dose adjustment or avoidance of metronidazole will be needed in patients with renal impairment. Antituberculous Agents and Drugs Used for Leprosy Antiviral Agents Antineoplastics and Antimetabolites The antineoplastic and antimetabolite drugs are a particularly difficult group. Many of these drugs are converted to metabolites that, in many instances, remain to be identified. As a consequence, whether or not renal or hepatic dysfunction influences their disposition is unknown. I have attempted to compile the extant literature and interpret it as best as possible. However, one should realize that the data may be fragmentary. Protocols for a number of these drugs entail intermittent administration, and as a consequence, any change in disposition as a result of organ dysfunction may have little impact on the therapeutic index. However, if future protocols employ chronic administration of these drugs, their disposition in patients with disease may require dosage modification. For the drugs that are administered on a daily basis, there have been virtually no studies addressing the need for dosage modification. Antispasticity Agents Antiulcer Agents Histamine H2 antagonists were included in the section on antihistamines, and anticholinergic agents were included in a separate section. For carbenoxolone, disposition has not been evaluated. The effect of antacids on urinary pH can be clinically important in affecting the excretion of weak acids and weak bases. However, the content of sodium and magnesium in antacids is perhaps the most important consideration Patients with renal disease, particularly end stage renal failure, are compromised in their ability to excrete these cations; accumulation of sodium causes problems of volume expansion, and accumulation of magnesium causes neurological sequelae. Clinicians must be aware of the sodium and magnesium contents of the antacids they use. Bisphosphonates Bronchodilators and Pulmonary Agents Cardiovascular Agents The interplay between the cardiovascular system and the kidney is pivotal. Drugs that cause either salutary or detrimental effects on cardiovascular homeostasis can influence global renal function and the ability of the kidney to eliminate drugs. As a consequence, a drug eliminated by the kidney, which affects the cardiovascular system, can importantly influence its own elimination by these effects on overall kidney function. In addition, these effects could influence other drugs administered to a patient and the dynamics of response by the patient to the drugs. One should realize that patients with acute cardiovascular disorders may have rapidly changing renal status and that frequent assessment of renal function may be mandatory. These disorders may dictate frequent changes in dosing regimens. Patients with heart disease often have secondary changes in hepatic function, such as congestive hepatopathy, and these changes can influence the metabolism of drugs eliminated by the liver. Similarly, primary hepatic disease can affect the disposition of the many cardiovascular agents that depend upon hepatic routes of elimination. † Antiarrhythmics Use of antiarrhythmic agents requires particular care because of the narrow therapeutic index of these drugs. Fortunately, we have reliable clinical end points for assessing efficacy and toxicity with a number of these agents. Unfortunately, however, toxicity can manifest as the very same arrhythmias for which these drugs are instituted. As a consequence, the clinician can make the potentially fatal error of misdiagnosing toxicity as lack of efficacy and responding in a manner antithetical to that required. This phenomenon is of particular concern for the class I agents (e.g., quinidine, flecainide, etc.). These agents are usually used to treat ventricular tachyarrhythmias, but their own inherent cardiotoxicity may be the same arrhythmia. It is important to emphasize that the pharmacologic effects of these drugs can often be quantified by measuring the Q T interval, corrected for heart rate, and the duration of the QRS complex. If a patient manifests ventricular tachyarrhythmias with prolongation of the QT interval or widening of the QRS complex, one should suspect a toxic etiology for these arrhythmias rather than lack of efficacy of the drugs. If such toxicity is misdiagnosed and treatment is continued or higher doses are instituted, the consequences could be disastrous. Bretylium, which is used for refractory ventricular tachyarrhythmias, may present particular problems in patients with renal dysfunction because its kinetics appear complex and have not been defined for this group of patients. Therapy with this drug in patients with renal disease should be extremely conservative. Mexiletine and tocainide, drugs with a lidocaine like spectrum of activity but active after oral administration, are both weak bases that demonstrate urine pH dependent elimination, in that their excretion is increased with acidification of the urine. This phenomenon is unlikely to be clinically important, for the urine pH is normally acidic, and the amount of drug excreted in the urine unchanged is less than 10 and 30 to 50 percent, respectively. However, there remains the potential for patients with disorders of urinary acidification to accumulate either of these drugs to toxic levels. It does not appear that decreased renal function per se importantly influences the kinetics of either of these agents. Quinidine is a weak base and its urinary excretion is decreased in an alkaline urine. However, the contribution to elimination by the kidney is minor, and this effect is unlikely to be clinically important. It appears that protein binding of quinidine is increased in uremia, which causes a decrease in the volume of distribution. As a consequence, an elevated total serum concentration of quinidine in uremia may result in the same amount of free drug as in patients with normal renal function. Therefore, slightly higher total serum concentrations should not be misinterpreted clinically. A drug that presents particular difficulty in patients with renal dysfunction is procainamide. Not only is procainamide itself retained in patients with renal dysfunction, but its active metabolite, N acetylprocainamide, is even more highly dependent on the kidney for elimination. As a consequence, patients with renal dysfunction accumulate both procainamide and its active metabolite. Because the parent drug and its metabolite appear to have different spectra of activity, it is virtually impossible to suggest dosing guidelines or to speculate on interpretation of drug levels when both the parent drug and its metabolite are present. Again, one must rely on clinical measures of response. Since N acetylprocainamide is more dependent on the kidney for elimination, the change in its clearance with decreased renal function is considerably greater than is the change in handling of procainamide itself. As a consequence, one may reach a steady state concentration of procainamide before achieving a steady state concentration of the metabolite. One must be particularly wary of the possible difference in time course of attaining steady state with each of these compounds, and not fall into the trap of assuming that they occur in parallel. Because of the difficulties with this drug and its active metabolite, it is probably best avoided in patients with renal dysfunction. Diuretics In terms of clinical use, diuretics are most easily grouped into two categories. Amiloride, spironolactone, and triamterene are all potassium retaining diuretics that should be avoided in patients with decreased renal function. Though some clinicians use these agents in patients with only mild renal disease, it is important to point out that syndromes of renal tubular acidosis of the distal type (RTA, type IV) are being recognized more frequently. These disorders are characterized by mild to moderate uremia, a hyperchloremic metabolic acidosis, and hyperkalemia. Superimposition of potassium retaining diuretics could prove disastrous in this setting, which offers a further argument for avoidance of these drugs in any patient with a decrement in renal function. The remaining diuretics, excluding osmotic agents, are organic acids. All of these drugs are bound to serum proteins and gain access to their intraluminal sites of action predominantly by active secretion at the organic acid transport site of the proximal nephron. With decreasing renal function, accumulated endogenous organic acids compete for this pathway, which decreases access of the diuretics to their sites of action. The loop diuretics are sufficiently potent to continue to achieve a response until extremely severe renal dysfunction supervenes. However, this response is achieved at considerably higher doses than in patients with normal kidneys. These high doses presumably provide concentrations of these drugs in the blood that are high enough to overwhelm the inhibited proximal tubular transport system, and the high doses achieve amounts of loop diuretics at the active site sufficient to cause a diuresis. Drugs of Abuse Amphetamine and its congeners and phencyclidine are weak bases, which demonstrate urine pH dependent elimination characteristics. Alkalinization of the urine increases the nonionized congener of these drugs, which increases reabsorption in the distal nephron and collecting duct and decreases elimination. Conversely, in an acidic urinary environment, the ionized species predominates and excretion is enhanced. Clinically, the most important ramifications of this phenomenon are in overdose settings, in which patients may either have an acidification defect owing to another disease, or because they have taken sodium bicarbonate to decrease elimination of these drugs. In such circumstances, attempts to acidify the urine can be therapeutic. This is particularly true for amphetamine. However, only 9-10% of phencyclidine is excreted unchanged, and changes in urinary pH are unlikely to influence excretion in important quantitative amounts. Since disulfiram is only used to treat alcoholism, it is included in this section. Drugs for Erectile Dysfunction Hormonal Agents and Cytokines Hypoglycemic Agents The oral sulfonylurea group of drugs has posed particular problems in patients with renal disease. Profound and longlasting hypoglycemia has occurred when acetohexamide or chlorpropamide have been used in patients with renal dysfunction because of accumulation of the active drug and/or the metabolite. As a consequence, tolbutamide has been proposed as the agent of choice in such patients. It is eliminated by the liver, and decrements in renal function do not change the clearance of this drug. However, it is important to point out that the potential still exists for displacement interactions with this drug, because it is highly protein bound. As a consequence, even though tolbutamide may be the agent of choice for patients with renal disease, it should still be used with caution. A series of newer agents appear to offer no clear cut advantage (or disadvantage) to the more conventional agents. Protein binding of all of them is high, and volumes of distribution are comparable (0.2 0.3 L/kg). Glibornuride, gliclazide, glibenclamide (also called glyburide), and glipizide are extensively metabolized and do not appear to have active metabolites. On the other hand, up to 50 percent of a dose of glisoxepide is excreted into the urine unchanged. I agree with the recommendation of Balant that acetohexamide, chlorpropamide, and glisoxepide be avoided in patients with any renal dysfunction and that insulin be used for all patients with a ClCr less than 30 ml per minute. Biguanides are eliminated in large part in the urine unchanged. In addition, patients with renal or hepatic dysfunction are more susceptible to lactic acidosis from these compounds, so they should be avoided in patients with impairment of either system. Though inhibitors of aldose reductase do not lower blood glucose concentrations, their usefulness is in patients with diabetes mellitus. Therefore, they are included in this section. Hypouricemic Agents and Drugs Used for Gout It is important to note that most patients with decreased renal function develop hyperuricemia. Rarely, a patient develops gout as a consequence. Other than these few patients who develop overt gout, the hyperuricemia does not need to be treated. There is no evidence that this increase in uric acid causes further decrements in renal function. Treatment of such patients entails no therapeutic benefit, subjects the patient to the potential risks of the hypouricemic agents, and therefore, is not justified. Immunosuppressants (see also Antineoplastic agents) Psychotherapeutic Agents Phenothiazines, tri or tetracyclic antidepressants, and butyrophenones demonstrate great variability in disposition among individuals. They tend to have large volumes of distribution. The glucuronide metabolites of tricyclic antidepressants accumulate to concentrations five to 15 times greater in patients with renal dysfunction than in patients with normal renal function. Whether the metabolites have an independent pharmacologic effect is unknown. These drugs tend to be highly bound to serum proteins, and therefore, the potential exists for displacement interactions and for decreased binding in patients with diminished levels of binding protein or renal dysfunction. As with any drug, one should be aware of the potential for accumulation of the parent drug and the active metabolites and closely follow the patient with renal dysfunction for clinical end points of salutary effect and of toxicity. Patients with liver disease are at risk for changes in metabolism of both the parent drug and the metabolite. It is important to note that most of these agents have a central depressant effect, particularly at the onset of administration. Patients with renal dysfunction (particularly ESRD), liver disease, and the elderly tend to be susceptible to central nervous system (CNS) depressants and therefore might similarly manifest increased sensitivity to these drugs. Steroids Glucocorticoids are commonly used in patients with renal disease, and little is known of their handling. Recent data indicate the pharmacokinetics to be complex. Prednisone and prednisolone are interconverted, so both must be assessed. Both drugs demonstrate dose dependent protein binding, and therefore, studies must address handling of the unbound drug. Though aminoglutethimide is not a steroid, it inhibits mineralocorticoid synthesis and is included in this section. Sympathetics and Drugs Affecting the Sympathetic Nervous System Though dopamine decarboxylase inhibitors are not themselves sympathomimetics, they are only used clinically with levodopa, and they are therefore included in this section. Thyroid and Antithyroid Agents This group of drugs has been poorly characterized, and the data presented must be viewed as tenuous because they involve very few subjects. Further studies of these drugs are clearly needed. Carbimazole is converted quantitatively to methimazole, which has an elimination half life of approximately 5 hours. Only about 7 percent of methimazole is excreted unchanged in the urine. Consequently, renal dysfunction does not affect disposition in an important manner. However, there is one report of a subject, with a creatinine clearance of 23 ml/min associated with an elimination half life of methimazole of 21 hours. This report used a non specific assay that quantified both parent drug and metabolites and may therefore be misleading. Methimazole has at least one active metabolite, 3 methyl 2 thiohydantoin, which has an elimination half life of 9 to 13 hours. Whether renal dysfunction influences disposition of this metabolite is unknown. A similar paucity of data exists for propylthiouracil. Again, a negligible amount (less than 2 percent) is excreted unchanged in the urine, and one would not predict important changes in disposition with decreased renal function; although, as with methimazole, one patient has been reported who appeared to have a prolonged elimination half life. Propylthiouracil differs from methimazole by having a shorter elimination half life (1 to 2 hours) and by being 80 percent protein bound (as opposed to zero). The difference in half-life is clinically unimportant, for the biological half life is considerably longer than the kinetic. On the other hand, the greater protein binding of propylthiouracil, along with its lower lipid solubility at physiologic pH, imparts the important potential advantage of decreased distribution into breast milk. | |||