Pharmacological Dose Adjustments in the Geriatric Patient

Katrina R. Viviano, DVM, PhD, Diplomate ACVIM (Internal Medicine)

Clinical Assistant Professor
University of Wisconsin
School Veterinary Medicine
Madison WI

Introduction
As pets live longer, geriatric medicine continues to grow in veterinary medicine. Surveys
estimate that in many small animal practices the geriatric population encompasses 10 to 20% of the
patient population. Geriatric patients are a population at high risk for drug toxicities, adverse drug
reactions, and drug-drug interactions. The clinical drug approval process focuses on evaluating the
safety and efficacy of drugs in relatively young populations, therefore therapeutic use in geriatric
populations often requires dosage adjustments.1 Recall older patients, both human and veterinary,
experience systemic degenerative changes, have a higher disease burden relative to the young, and are
commonly being administered medications and in some cases multiple medications. Relatively little
objective information is available in veterinary species focusing specifically on geriatric
pharmacology, thus the recommendations included below are extrapolated from what is known in
geriatric humans.2
In human geriatric medicine four basic principles are adhered to enhance therapeutic outcomes
in geriatric patients: 1) avoid unsafe medications, 2) recognize when medications worsen daily
activities, 3) use evidence-based medicine to guide first line therapies, and 4) drug therapy should be
tailored to the individual. To avoid polypharmacy, adverse drug reactions, and over medicating
geriatric patients drugs should only to be prescribe when there is an indication. In addition drug
therapy needs to be consistently monitored for efficacy, side effects, and adverse drug events. Avoid
unnecessary drug use including therapy without an indication, duplicate therapy, excessive dose,
excessive duration, and inadequate monitoring). Common medications used in veterinary medicine
that are categorized as unsafe (or most problematic) in geriatric human patients include
benzodiazepines (prolonged sedation) and digoxin (reduced renal clearance) increasing the risk of
toxicity.
The normal physiology of aging leads to changes in body composition (decreased lean body
mass and total body water and an increase in fatty tissue) and a redistribution of regional blood flow.
This altered distribution of tissues and blood in geriatric patients impacts the distribution of drugs. For
example, the distribution of water soluble drugs is limited to the plasma; therefore water soluble drugs
(ex. aminoglycosides or digoxin) should be dosed on lean body weight to avoid excessive plasma
concentrations. Additional intrinsic changes in physiology associated with aging that clinically impact
drug disposition in geriatric patients include decreased renal excretion and decreased hepatic
metabolism. Table 1 summarizes some of the common drugs used in geriatric veterinary patients that
dosage adjustment is recommended.

Renal function: Drug dosage adjustments

The reduction in renal function associated with aging has the most clinically significant impact
on drug disposition. A loss in the body’s ability to eliminate drugs through the kidney results in
increased drug plasma concentrations and increased elimination half-lives when standard dosage
regimens are administered. Drugs excreted primarily by the kidneys often require drug dosage
adjustment to minimize the risk of toxicity in geriatric patients. Dose adjustments are recommended
for drugs primarily excreted by the kidney (fluoroquinolones, aminoglycosides, ACE-inhibitors,
digoxin, chloramphenicol (cats)). Also consider dose reduction of drugs associated with an increased
risk of adverse effects in renal failure patients including cephalosporins, sulfonamides, tetracycline
(except doxycycline), furosemide, cimetidine, metoclopramide, NSAIDs. For example, NSAIDs have
a negative impact on renal blood flow especially during states of low renal blood flow (hypovolemia).
NSAIDs inhibit prostaglandins including those essential for the maintenance of renal blood flow and
autoregulation.
Drug dosage adjustments in patients with compromised kidney function can be done
objectively using therapeutic drug monitoring, using the individual patient’s circulating drug
concentrations to guide dosage adjustment. For some drugs, therapeutic drug monitoring (TDM) is
recommended to make the most accurate dose adjustments for individual patients. Routine therapeutic
drug monitoring is available for phenobarbital, digoxin, and aminoglycoside antibiotics.
For most other drugs TDM is either not available or expensive, requiring dose adjustments to
be made empirically based on available renal function tests (serum creatinine) in association with close
monitoring for therapeutic efficacy and/or toxicity. In humans the gold standard used to guide drug
dose adjustments is creatinine clearance because functional tubular secretion and creatinine clearance
decrease at parallel rates. For drugs excreted in the urine, the elimination half-life remains stable until
the creatinine clearance is reduced by 30-40%. This has lead to the standard recommendation that
dosage adjustments should be made for drugs primarily cleared by the kidney when 67% of a patient’s
renal function is lost.3
In our veterinary patients 24 hour urine collection is not readily available therefore serum
creatinine is used as an estimate of creatinine clearance. Of note, it is important to realize that the
relationship between creatinine clearance and serum creatinine is only linear up to a serum creatinine
of 4 mg/dL. In addition serum creatinine may not significantly change in geriatric patients in
association with a decrease in creatinine clearance because creatinine production is decreased due to
loss of lean body mass concurrent with the decrease in GFR associated with the aging kidney. The
limitations of using serum creatinine alone stresses the importance that drug dosage adjustments made
based on a single serum creatinine concentration is only a rough estimate and monitoring the patient’s
response becomes clinically important.
The two approaches used to make drug dosage adjustments are either by reducing the dose or
by adjusting the dosing interval. Dose reduction maintains the standard dosing interval but decreases
the dose administered. Depending on the relationship of the elimination half-life and dosing interval in
patients with compromised kidney function, an adjustment in dose drug is likely going to result in
some drug accumulation. Therefore drugs commonly adjusted by dose are those with relatively high
safety margins (ex. penicillins and cephalosporins). The dose is adjusted using the patient’s serum
creatinine concentration by using the equation below:

New dose = Standard dose (Normal serum creatinine / Patient’s serum creatinine)

Adjusting the dosing interval maintains the standard dose but extends the dosing interval. Drugs
commonly adjusted by dosing interval are likely to result in sometime at subtherapeutic concentrations
for a portion of the dosing interval therefore interval adjustment is most effective for drugs that remain
efficacious at low concentrations but minimizes toxicity. Examples would be the concentration
dependent antibiotics with a post-antibiotic effect; the aminoglycosides and fluoroquinolone. The new
dosing interval is based on the patient’s serum creatinine concentration as the estimate of creatinine
clearance using the following equation:

New interval = Standard interval (1 / (Normal serum creatinine / Patient’s serum creatinine))
Liver function: Drug dosage adjustments
With a progressive loss of liver function comes the risk for adverse clinical events, although for
most drugs unless fulminate liver failure is present it is difficult to accurately predict the need for
dosage adjustments associated with liver disease. Dose adjustment should be considered in patient in
liver failure for some drugs metabolized by the liver including metronidazole, chloramphenicol (dog),
phenobarbital, and benzodiazepines.

References

1. Cross J, Lee H, Westelinck A, et al. Postmarketing drug dosage changes of 499 FDA-approved new
molecular entities, 1980-1999. Pharmacoepidemiol Drug Saf 2002;11:439-446.
2. Aucoin DP. Drug therapy in the geriatric animal: the effect of aging on drug disposition. Vet Clin
North Am Small Anim Pract 1989;19:41-47.
3. Riviere J. Dosage adjustments in renal disease. Ames (IA): Iowa State University Press; 1999;283-
295.
4. Dowling PM. Geriatric pharmacology. Vet Clin North Am Small Anim Pract 2005;35:557-569.
Table 1. Common drugs used in geriatric veterinary patients that dosage adjustment is recommended
based on kidney or liver dysfunction

Drugs Rationale
Antimicrobials
Aminoglycosides* Nephrotoxic
Fluoroquinolones* Drug accumulation with kidney disease
Sulfonamides* Risk of toxicity, including nephrotoxicity
Cephalosporins/Penicillins* Drug accumulation with kidney disease
Tetracyclines (except doxycycline) * Drug accumulation and nephrotoxicity
Chloramphenicol Cats – 25% excreted unchanged in urine
Metronidazole Dose-reduction recommended in patients with
significant liver impairment (7.5 mg/kg q 12hr)
NSAIDs Potential - nephrotoxicity and hepatotoxicity
Carprofen* Idiosyncratic hepatoxicity
Deracoxib* High doses unpredictable kinetics
Etodolac* Narrow therapeutic index
Meloxicam* Chronic use – increase in elimination half-life

Diuretics
Furosemide* Increased elimination half-life with kidney disease

Cardiac drugs
Digoxin* Accumulates with kidney disease - cardiotoxicity
and neurotoxicity

Enalapril, Benazepril* Decreased renal clearance of active metabolite

Atenolol* Decreased renal clearance with kidney disease

Lidocaine* Decreased hepatic clearance

H2-Blockers
Cimetidine Parenteral administration – 75% excreted
unchanged by the kidneys

Famotidine Parenteral administration – 67% excreted

unchanged by the kidneys

Antiemetics
Metoclopramide Primary renal excretion

Anticonvulsants
Potassium bromide* Primary renal elimination
Phenobarbital* Decreased hepatic metabolism, hepatotoxicity
Antifungals
Fluconazole Primary renal elimination
*
Drugs in which dose adjustment is recommended in geriatric patients.4