Case Presentations: Drug Dose Adjustments
ACVIM 2008
Lauren Trepanier, DVM, PhD, DACVIM, DACVCP
Madison, WI, USA

There is considerable evidence to support the adjustment of drug dosages in human patients with obesity, advanced age, hepatic failure, or renal insufficiency. In contrast, such studies are lacking in dogs and cats. This presentation will discuss several veterinary clinical cases in which drug dose adjustments were recommended, based upon the following principles:

Drug Dosing in Obese or Geriatric Patients

Obesity is now a common problem in companion animals. Drugs that a highly polar (water soluble) do not distribute to fat, and should be dosed based on estimated lean body weight. Examples of such polar drugs are digoxin and aminoglycosides. Cyclosporine is also dosed on lean body weight, at least in humans. Lean body weight can be estimated from a dog or cat's conformation, or from previous medical records for individual patients. Alternatively, an empirical dose reduction by 15-20% can be estimated for obese patients given polar drugs.

Geriatric patients are also a commonly treated population, and have numerous age-related changes that may alter drug disposition. Older dogs and cats are likely to have subclinical nephron loss that may lead to decreased renal clearance of some drugs. Decreased renal clearance will increase the risk of aminoglycoside and digoxin toxicity, may increase the risk of renal decompensation from enalapril or NSAIDs, and will likely increase the risk of retinal toxicity from enrofloxacin in cats. In elderly patients, it is wise to use conservative doses of renally cleared drugs and monitor clinical response carefully. Older patients also have decreased muscle mass, which may lead to increased serum digoxin concentrations, since digoxin distributes to skeletal muscle. Elderly dogs and cats may also have decreased total body water and poor skin turgor, which may cause erratic SC absorption of some drugs.

Changes in Drug Disposition Due to Hepatic Insufficiency

Both humans and dogs have age-related decreases in hepatic blood flow. This is important for drugs that are efficiently metabolized by the liver, for which drug clearance is related to the rate of their delivery (blood flow) to the liver. Such "flow-limited" drugs include beta blockers such as propranolol, for which lower dosages are often used in older humans. In humans with inflammatory liver disease without cirrhosis, hepatic drug metabolism is fairly well conserved. With cirrhosis or severe hepatic dysfunction, however, drugs that are normally extensively metabolized are not cleared as readily. Based on human data, dosages of some drugs may need to be reduced in dogs and cats with severe liver disease (e.g., hepatic lipidosis, acute hepatic necrosis, cirrhosis). For metronidazole, benzodiazepines, and propranolol, dose adjustments to 25-50% of the regular dose are recommended in humans. If neurotoxicity or inappetance from metronidazole are a concern, lactulose can be substituted when treating hepatic encephalopathy, and amoxicillin/clavulanate or clindamycin can be substituted for systemic anaerobic therapy.

Hypoalbuminemia is a common complication of hepatic insufficiency, and could potentially lead to increased acute effects from highly protein drugs such as NSAIDs and benzodiazepines. When ascites is present, drug dosing should be carefully considered. For example, lipid soluble drugs will presumably not distribute to ascites fluid, so the normal body weight (minus estimated ascites fluid weight) should probably be used to calculate dosages of lipophilic drugs such as propofol or vitamin K. Polar (water soluble drugs) will distribute to ascites fluid unless they are highly protein bound. For drugs such as fluoroquinolones or aminoglycosides, the total body weight (including ascites fluid) should be used to calculate drug dosage. Morphine, a relatively polar opioid with polar active glucuronide metabolites, also appears to distribute to ascites fluid, leading to decreased efficacy in humans if dosed on non-ascitic body weight.1

Dogs and cats with hepatic insufficiency have increased sensitivity to CNS depressants. Therefore, benzodiazepines, barbiturates, and acepromazine should be avoided or used at reduced dosages. Opioids should also be used at reduced dosages, and reversible agents are preferable. For encephalopathic seizures, consider using diazepam or midazolam at 20-30% of standard doses and titrate upwards to effect. Some therapies can worsen hepatic encephalopathy and should be avoided. Avoid stored whole blood and packed red blood cell transfusions (high ammonia levels) in patients with significant liver disease. Instead, use an in-house blood donor or a unit with a distant expiration date. Avoid NSAIDs with significant liver disease, because of the risk of GI bleeding (which is a protein load on the gut, leading to hyperammonemia) and renal decompensation (which will increase BUN and ammonia levels). Furosemide can worsen hepatic encephalopathy by leading to hypokalemia, dehydration, azotemia, and alkalosis. Finally, do not use glucocorticoids in dogs or cats with liver disease until signs of hepatic encephalopathy are controlled. Glucocorticoids are catabolic, and will enhance deamination of proteins and release of NH3.

Changes in Drug Disposition Due to Renal Failure

Renal failure leads to decreased filtration of renally eliminated drugs and active metabolites, as well as decreased tubular secretion of some drugs, such as cimetidine, trimethoprim, and digoxin. Renal failure is also associated with less obvious effects on drug disposition, such as decreased renal P450 and conjugative metabolism of some drugs, impaired binding of acidic drugs (such as furosemide, sulfamethoxazole, and aspirin) to albumin,2 and reduced tissue binding of some drugs (e.g., digoxin).

There are few good studies regarding dose adjustments for renal failure in dogs or cats, and values for creatinine clearance, which are used to make rational dosage adjustments in azotemic humans, are almost never known for our patients. Drug dosage adjustments are often made in humans with creatinine clearances less than around 0.7 ml/min/kg (depending on the drug), which corresponds to a serum creatinine of about 2.0 to 2.5 mg/dl in dogs and cats.3,4 For many renally excreted drugs, a crude dose reduction can be made by dividing the standard dose by the serum creatinine (i.e., less drug given at same intervals),5 assuming a normal creatinine of 1.0. This may be roughly accurate for serum creatinine concentrations up to 4 mg/dl, since GFR and serum creatinine are approximately linear up to this point in dogs.3 The exception to reducing the drug dosage is aminoglycosides (and probably fluoroquinolones), for which the dose interval should be extended instead. For example, reduce the dosing frequency by multiplying the dose interval by the serum creatinine (e.g., for a serum creatinine of 2 mg/dl, dose every 48 hours instead of every 24 hours). Drugs that require dose reductions in renal failure include any drug with a relatively narrow margin of safety, which is primarily eliminate by the kidneys, or which has an active metabolite that is eliminated by the kidneys. Penicillins are renally excreted, but toxicity is unlikely. However, dosage reduction is probably appropriate and will also decrease the cost of more expensive beta lactam derivatives drugs (such as ticarcillin, meropenem, ceftazidime, or aztreonam) in patients with azotemia. Cephalosporins such as cephalothin and cefazolin can be nephrotoxic at very high doses in humans, so dose reduction of these two drugs in renal failure may be indicated in dogs and cats. These two cephalosporins can also be nephrotoxic in combination with gentamicin to elderly humans, so avoid this combination in older patients.

Most fluoroquinolones are renally cleared. Given the risk of retinal toxicity in cats, always adjust fluoroquinolone doses in cats with renal insufficiency. Although the optimal method is not established, consider extending the dosing interval. In renal insufficiency, less retinotoxic fluoroquinolones are recommended, with the retinotoxic potential in cats being enrofloxacin >> orbifloxacin > marbofloxacin.6

Aminoglycosides are dose dependent nephrotoxins. Other agents should be used whenever possible in azotemic patients (e.g., marbofloxacin or orbifloxacin, ticarcillin, cefotetan, or meropenem), depending on culture results. When aminoglycosides are necessary, always rehydrate first, and always use concurrent fluid therapy (IV or SC). Consider the use of amikacin at 15 mg/kg SC q. 24h, which is possibly less nephrotoxic than gentamicin in cats. [7] Monitor for tubular damage by examining daily fresh urine sediments for granular casts. Do not use aminoglycosides in patients with urinary obstruction, and do not use furosemide or NSAID's concurrently. Finally, limit aminoglycoside therapy to 5 days or less, whenever possible.

Although oxytetracyclines can cause nephrotoxicity (reported in dogs), doxycycline does not carry the same risk. However, all tetracyclines can increase BUN, independent of any renal damage, due to protein catabolism. This increase in BUN is reversible. Outdated tetracyclines should never be administered to patients, as the breakdown products are nephrotoxic, leading to proximal renal tubular damage.

Chloramphenicol is sometimes useful for infections that are resistant to more commonly used antibiotics. In cats, 25% or more of chloramphenicol is excreted unchanged in the urine; therefore, avoid its use in cats with renal insufficiency, or reduce the dosage. Sulfonamides should also be used with caution in azotemic patients, due to decreased renal clearance and decreased protein binding. It is important to reduce the dose in renal failure, especially for sulfadiazine (found in Tribrissen), which is the least soluble sulfonamide, especially in acid urine. In dehydrated human patients, sulfadiazine can precipitate as drug crystals in the renal tubules and lead to hematuria and even tubular obstruction. When using sulfonamides, always rehydrate first, dose accurately, and avoid concurrent use of urinary acidifiers.

Furosemide should be dosed only with good rationale (e.g., fulminant congestive heart failure) in azotemic dogs and cats. Patients with renal disease that are also treated with furosemide should be monitored closely for dehydration, weight loss, hypokalemia, and worsened azotemia at each recheck.

H2 blockers such as cimetidine, ranitidine, and famotidine are cleared by the kidneys, and lead to CNS disturbances (mania, confusion) in elderly humans with decreased GFR. Therefore, the dosage of these drugs should probably be adjusted in renal failure, either by reducing the dose or the frequency of administration. Metoclopramide is also renally cleared. Standard CRI dosages (1-2 mg/kg/day) can cause tremor and ataxia in azotemic patients, and lower doses (e.g., 0.5 mg/kg/day as a CRI) are better tolerated.

Benazepril is preferred over enalapril in azotemic patients, since benazepril undergoes some hepatic clearance, and does not accumulate in azotemic dogs and cats. [8, 9] However, any ACE inhibitor can adversely affect GFR if systemic hypotension is produced. It is important to monitor blood pressure, BUN, creatinine, and electrolytes in all patients on ACE inhibitors (e.g., initially after one week, then every 1 to 3 months depending on clinical status). NSAID's can also have adverse effects on GFR, as well as show decreased renal clearance and decreased protein binding in renal failure. If patients with renal failure require analgesia, buprenorphine or tramadol may be safer choices. If an anti-inflammatory effect is needed, consider conservative NSAID dosages, and monitor carefully for dehydration, inappetance, and increases in BUN and creatinine. Coxibs have the same potential adverse renal effects as do non-selective NSAIDs (COX-2 is important for renal blood flow), and are not safer in renal insufficiency.

Table 1. Conditions that may require drug dosage adjustment in dogs and cats.

Condition

Drugs

Dose adjustment

Evidence

Obesity

Aminoglycosides
Digoxin

Dose on lean body weight

Pharmacokinetics of gentamicin in obese cats10
Pharmacokinetics of digoxin in obese humans11

Advanced age

Aminoglycosides

Evaluate renal function and adjust dosing interval

Studies in elderly humans

Enrofloxacin in cats

PK modeling of ciprofloxacin in humans12

Hepatic insufficiency

Metronidazole

Use reduced (e.g., 25-50% of standard) dosages in significant hepatic failure

Empirical recommendations in humans

Benzodiazepines

Pharmacokinetics of midazolam in cirrhotic humans13

Propranolol

Pharmacokinetics of beta blockers in cirrhotic humans14 (Note: PK of atenolol, which is renally cleared, was not affected)

Ascites

Beta lactam antibiotics
Aminoglycosides
Fluoroquinolones

Dose based on total body weight, including ascites

Studies in human patients15,16

Hypoalbuminemia

NSAIDs
Benzodiazepines

Probably not necessary with maintenance dosing, due to increased renal clearance of extra free drug

Pharmacokinetics of highly protein bound drugs in humans with nephrotic syndrome without azotemia17

Renal failure

Benazepril (but not enalapril)

No dosage adjustment necessary

Studies in experimentally induced renal insufficiency in dogs and cats8,9

Aminoglycosides

Avoid or prolong dosing interval based on trough serum drug concentrations

Gentamicin pharmacokinetics in azotemic dogs18,19

Fluoroquinolones

Prolong the dosing interval

Based on modeling of ciprofloxacin in humans12

Famotidine

Prolong dosing interval or reduce dose

Studies in human patients20

Metoclopramide

Reduce CRI to 25%-50% of standard dosage

Anecdotal experience

Meloxicam

Dose adjustments not necessary for short term use in humans

Pharmacokinetics in humans21

Trimethoprim-sulfadiazine

Avoid use in dehydrated patients or with urinary acidifiers

Numerous clinical reports in humans of obstructive crystalluria

References

1.  Yokokawa N, et al. Postgrad Med J, 1991. 67 Suppl 2: S50-4.

2.  Dreisbach AW, JJ Lertora, Semin Dial, 2003. 16(1): 45-50.

3.  Finco DR, et al. J Vet Pharmacol Ther, 1995. 18(6): 418-21.

4.  Miyamoto K. J Feline Med Surg, 2001. 3(3): 143-7.

5.  Riviere JE. J Am Vet Med Assoc, 1984. 185(10): 1094-7.

6.  Wiebe V, P Hamilton. J Am Vet Med Assoc, 2002. 221(11): 1568-71.

7.  Christensen EF, JC Reiffenstein, H Madissoo. Antimicrob Agents Chemother, 1977. 12(2): 178-84.

8.  King JN, et al. J Vet Pharmacol Ther, 2002. 25(5): 371-8.

9.  Lefebvre HP, et al. J Vet Intern Med, 1999. 13(1): 21-7.

10. Wright LC, et al. J Vet Pharmacol Ther, 1991. 14(1): 96-100.

11. Abernethy DR, DJ Greenblatt, TW Smith. Am Heart J, 1981. 102(4): 740-4.

12. Czock D, FM Rasche. Eur J Med Res, 2005. 10(4): 145-8.

13. Pentikainen PJ, et al. J Clin Pharmacol, 1989. 29(3): 272-7.

14. Rocher I, et al. Int J Clin Pharmacol Ther Toxicol, 1985. 23(8): 406-10.

15. Esposito S, et al. Int J Clin Pharmacol Res, 1987. 7(3): 181-6.

16. Gerding DN, WH Hall, EA Schierl. Ann Intern Med, 1977. 86(6): 708-13.

17. Gugler R, DL Azarnoff, DW Shoeman. Klin Wochenschr, 1975. 53(9): 445-6.

18. Frazier DL, DP Aucoin, JE Riviere. J Am Vet Med Assoc, 1988. 192(1): 57-63.

19. Riviere JE, et al. Toxicol Appl Pharmacol, 1984. 75(3): 496-509.

20. Lin JH, et al. Eur J Clin Pharmacol, 1988. 34(1): 41-6.

21. Gates BJ, et al. Expert Opin Pharmacother, 2005. 6(12): 2117-40.

Speaker Information
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Lauren Trepanier, DVM, PhD, DACVIM, DACVCP
University of Wisconsin-Madison
Madison, WI


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