Renal Function Caveats

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Use of increased numbers of medications and age-related decline in renal function make older patients more susceptible to adverse medication effects. Drug pharmacokinetics change, and it’s important to remember that drug metabolism is affected by a number of processes.

Renal elimination of drugs is based on nephron and renal tubule capacity, which decrease with age.1 Older individuals will not metabolize and excrete drugs as efficiently as younger, healthier individuals.

According to the Centers for Disease Control and Prevention (CDC), there are more than 36 million adults in the United States older than 65, and overall U.S. healthcare costs related to them are projected to increase 25% by 2030.2

Preventing health problems, preserving patient function, and preventing patient injury that can lead to or prolong patient hospitalizations will help contain these costs.

Quartarolo, et al., recently reported that although physicians noted the estimated glomerular filtration rate (GFR) in elderly hospitalized patients, they didn’t modify their prescribing.3 They also noted that drug dose changes in these hospitalized patients are important to prevent dosing errors and adverse reactions.

New Drugs

The FDA has approved a 300 mg Plavix tablet (clopidogrel) indicated for use as a loading dose in appropriate patients following hospital admission for acute coronary syndrome. A combination product of olmesartan and amlodipine, known as Azor, has been FDA approved as monotherapy or in combination with other treatments for hypertension.

SAFETY

Genetic Dosing Clues

A genetic test to identify which patients have genetic variants to metabolize warfarin has been used to more accurately predict initial individualized doses. This is one of the first steps toward personalized medicine using pharmacogenomics. Approximately one-third of patients metabolize warfarin differently than the rest of the population based on variants of VKORC1 and CYP2C9 genes. These genetic tests are being used to more accurately predict warfarin doses to decrease adverse events and improve patient outcomes.

Get to Know MEDMARX

Each year the United States Pharmacopeia (USP) analyzes medication errors submitted by facilities participating in its national medication error and adverse drug reactions (ADR) reporting program, MEDMARX. Data are compiled, summarized, and presented in an annual report. The report includes types of medication errors, causes, contributing factors, products, and actions taken.

The 2005 MEDMARX Report analyzes more than 11,000 perioperative medication error records submitted to MEDMARX over a seven-year period. The Joint Commission noted how difficult it is for facilities to achieve anticoagulation safety on a national scale. Of the 519 products involved in harmful errors in this report, heparin ranked third, warfarin sixth, and enoxaparin ninth. Of the 17 medication-related deaths reported to MEDMARX in 2005, four involved enoxaparin.

The 2008 Joint Commission Hospital Safety Goals include a new requirement (3E) titled “Reduce the likelihood of patient harm associated with the use of anticoagulation therapy.” All anticoagulants are included: low-molecular weight heparins, unfractionated heparin, warfarin, and others. Full-implementation is expected by Jan. 1, 2009.

One of the first requirements of the phase-in (due April 1) is for the hospital to assign oversight and coordination of developing, testing, and implementing 3E. One of the major implementation expectations is to have a defined anticoagulation management system for each patient receiving one of these agents. This will be another measure on which organizations will be scored during Joint Commission surveys.—MK

There are four major age-related pharmacokinetic parameters:

Usually decreased gastrointestinal absorption changes ;

Increases or decreases of a drug’s volume of distribution leading to increased blood drug levels and/or plasma-protein-binding changes;

Usually decreased clearance with increased drug half-life effect (hepatic metabolism changes); and/or

Decreased clearance (and increased half-life) of renally eliminated drugs.4,5

Renal Effects

Renal excretion of drugs correlates with creatinine clearance. Because lean body mass decreases as people age, the serum creatinine level is a poor gauge of creatinine clearance in older individuals. Creatinine clearance decreases by 50% between age 25 and 85.6 The Cockroft-Gault equation is used to estimate creatinine clearance in older individuals to assist in renal dosing of drugs (See Table 1, above).

The National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative defines chronic kidney disease (CKD) as:

Kidney damage for three or more months, as defined by structural or functional abnormalities of the kidney, with or without decreased GFR, marked by either pathological abnormalities or markers of kidney damage; or

GFR of 60 mL/min/1.73 m2 or less for three or more months, with or without kidney damage.6

In these patients, adjustment of the drug dose or dosing interval is imperative to attain optimal drug effects and patient outcomes. The same is also true for older adults with decreased renal function, whether diagnosed with CKD or not.

In addition, patients with severe renal insufficiency, including those with CKD, may encounter accumulation of active metabolites, as well as accumulation of the parent drug compound. This can lead to significant toxicity in some cases. Examples of active metabolites include:

Normeperidine, an active metabolite of meperidine that can lead to central nervous system stimulation including seizures;

Morphine-6-glucuronide, an active metabolite of morphine and codeine with less analgesic effect. It can lead to a prolonged narcotic effect; or

N-acetyl-p-benzoquinoneimine, a metabolite of acetaminophen responsible for hepatotoxicity.7

Doses of renally cleared drugs should be adjusted in patients with decreased renal function. Initial dosages can be determined using published guidelines.8 TH

Michele B. Kaufman is a freelance medical writer based in New York City.

References

Quartarolo JM, Thoelke M, Schafers SJ. Reporting of estimated glomerular filtration rate: effect on physician recognition of chronic kidney disease and prescribing practices for elderly hospitalized patients. J Hosp Med. 2007;2(2):74-78.

Frye RF, Matzke GR. Drug therapy individualization for patients with renal insufficiency. In: DiPiro JT, Talbert RL, Yee GC, eds. Pharmacotherapy A Pathophysiologic Approach. 5th ed. New York, NY: McGraw-Hill; 2002:939-952.

Healthy Aging At-A-Glance 2007. Available at www.cdc.gov/nccdphp/publications/aag/pdf/healthy_aging.pdf. Last accessed Oct. 15, 2007.

Hanlon JT, Ruby CM, Guay D, et al. Geriatrics. In: DiPiro JT, Talbert RL, Yee GC, eds. Pharmacotherapy A Pathophysiologic Approach. 5th ed. New York, NY: McGraw-Hill; 2002:79-89.

Williams CM. Using medications appropriately in older adults. Am Fam Physician. 2002;66(10):1917-1924.

K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Available at www.kidney.org/professionals/kdoqi/guidelines_ckd/p4_class_g1.htm. Last accessed Oct. 15, 2007.

Munar MY, Singh H. Drug dosing adjustments in patients with chronic kidney disease. Am Fam Physician. 2007;75(10):1487-1496.

Brier ME, Aronoff GR. Drug Prescribing in Renal Failure: Dosing Guidelines for adults. 5th ed. Philadelphia, Pa : American College of Physicians; 2007.

In the Pipeline

Bazedoxifene, a selective estrogen receptor modulator, is undergoing Phase 3 clinical trials for the treatment and prevention of postmenopausal osteoporosis (PMO). Wyeth received an FDA approvable letter for use of bazedoxifene for the prevention of PMO. A separate new drug application was filed for treatment of PMO. The Food and Drug Administration (FDA) has not yet commented. Bazedoxifene has shown a non-statistically significant increase in venous thromboembolic events (similar to raloxifene/Evista). No reproductive system or breast safety concerns have been noted.

The FGF-4 gene promotes development of new blood vessels by improving the heart’s oxygen supply. A genetically engineered virus will deliver the gene via an intravascular catheter for angina treatment in women who are maximally medicated and have had bypass surgery, but still have angina. Earlier studies in women and men found no treatment improvement, but when data were broken down by gender, women had a more noticeable difference on exercise treadmill testing duration. It has been given fast-track status by the FDA.

Vildagliptin (Galvus) a dipeptidyl peptidase-4 (DPP-4) inhibitor, is undergoing safety evaluation in patients with renal impairment. This agent, anticipated to be prescribed once daily, is similar in action to sitagliptin (Januvia). Novartis anticipates resubmission of vildagliptin to the FDA in mid-2009. Another DPP-4 inhibitor, saxagliptin, will be nearing FDA submission then.

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The Hospitalist - 2008(01)

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Michele B. Kaufman, PharmD, BSc, RPh

Author(s)

Michele B. Kaufman, PharmD, BSc, RPh

Use of increased numbers of medications and age-related decline in renal function make older patients more susceptible to adverse medication effects. Drug pharmacokinetics change, and it’s important to remember that drug metabolism is affected by a number of processes.

Renal elimination of drugs is based on nephron and renal tubule capacity, which decrease with age.1 Older individuals will not metabolize and excrete drugs as efficiently as younger, healthier individuals.

According to the Centers for Disease Control and Prevention (CDC), there are more than 36 million adults in the United States older than 65, and overall U.S. healthcare costs related to them are projected to increase 25% by 2030.2

Preventing health problems, preserving patient function, and preventing patient injury that can lead to or prolong patient hospitalizations will help contain these costs.

Quartarolo, et al., recently reported that although physicians noted the estimated glomerular filtration rate (GFR) in elderly hospitalized patients, they didn’t modify their prescribing.3 They also noted that drug dose changes in these hospitalized patients are important to prevent dosing errors and adverse reactions.

New Drugs

The FDA has approved a 300 mg Plavix tablet (clopidogrel) indicated for use as a loading dose in appropriate patients following hospital admission for acute coronary syndrome. A combination product of olmesartan and amlodipine, known as Azor, has been FDA approved as monotherapy or in combination with other treatments for hypertension.

SAFETY

Genetic Dosing Clues

A genetic test to identify which patients have genetic variants to metabolize warfarin has been used to more accurately predict initial individualized doses. This is one of the first steps toward personalized medicine using pharmacogenomics. Approximately one-third of patients metabolize warfarin differently than the rest of the population based on variants of VKORC1 and CYP2C9 genes. These genetic tests are being used to more accurately predict warfarin doses to decrease adverse events and improve patient outcomes.

Get to Know MEDMARX

Each year the United States Pharmacopeia (USP) analyzes medication errors submitted by facilities participating in its national medication error and adverse drug reactions (ADR) reporting program, MEDMARX. Data are compiled, summarized, and presented in an annual report. The report includes types of medication errors, causes, contributing factors, products, and actions taken.

The 2005 MEDMARX Report analyzes more than 11,000 perioperative medication error records submitted to MEDMARX over a seven-year period. The Joint Commission noted how difficult it is for facilities to achieve anticoagulation safety on a national scale. Of the 519 products involved in harmful errors in this report, heparin ranked third, warfarin sixth, and enoxaparin ninth. Of the 17 medication-related deaths reported to MEDMARX in 2005, four involved enoxaparin.

The 2008 Joint Commission Hospital Safety Goals include a new requirement (3E) titled “Reduce the likelihood of patient harm associated with the use of anticoagulation therapy.” All anticoagulants are included: low-molecular weight heparins, unfractionated heparin, warfarin, and others. Full-implementation is expected by Jan. 1, 2009.

One of the first requirements of the phase-in (due April 1) is for the hospital to assign oversight and coordination of developing, testing, and implementing 3E. One of the major implementation expectations is to have a defined anticoagulation management system for each patient receiving one of these agents. This will be another measure on which organizations will be scored during Joint Commission surveys.—MK

There are four major age-related pharmacokinetic parameters:

Usually decreased gastrointestinal absorption changes ;

Increases or decreases of a drug’s volume of distribution leading to increased blood drug levels and/or plasma-protein-binding changes;

Usually decreased clearance with increased drug half-life effect (hepatic metabolism changes); and/or

Decreased clearance (and increased half-life) of renally eliminated drugs.4,5

Renal Effects

Renal excretion of drugs correlates with creatinine clearance. Because lean body mass decreases as people age, the serum creatinine level is a poor gauge of creatinine clearance in older individuals. Creatinine clearance decreases by 50% between age 25 and 85.6 The Cockroft-Gault equation is used to estimate creatinine clearance in older individuals to assist in renal dosing of drugs (See Table 1, above).

The National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative defines chronic kidney disease (CKD) as:

Kidney damage for three or more months, as defined by structural or functional abnormalities of the kidney, with or without decreased GFR, marked by either pathological abnormalities or markers of kidney damage; or

GFR of 60 mL/min/1.73 m2 or less for three or more months, with or without kidney damage.6

In these patients, adjustment of the drug dose or dosing interval is imperative to attain optimal drug effects and patient outcomes. The same is also true for older adults with decreased renal function, whether diagnosed with CKD or not.

In addition, patients with severe renal insufficiency, including those with CKD, may encounter accumulation of active metabolites, as well as accumulation of the parent drug compound. This can lead to significant toxicity in some cases. Examples of active metabolites include:

Normeperidine, an active metabolite of meperidine that can lead to central nervous system stimulation including seizures;

Morphine-6-glucuronide, an active metabolite of morphine and codeine with less analgesic effect. It can lead to a prolonged narcotic effect; or

N-acetyl-p-benzoquinoneimine, a metabolite of acetaminophen responsible for hepatotoxicity.7

Doses of renally cleared drugs should be adjusted in patients with decreased renal function. Initial dosages can be determined using published guidelines.8 TH

Michele B. Kaufman is a freelance medical writer based in New York City.

References

Quartarolo JM, Thoelke M, Schafers SJ. Reporting of estimated glomerular filtration rate: effect on physician recognition of chronic kidney disease and prescribing practices for elderly hospitalized patients. J Hosp Med. 2007;2(2):74-78.

Frye RF, Matzke GR. Drug therapy individualization for patients with renal insufficiency. In: DiPiro JT, Talbert RL, Yee GC, eds. Pharmacotherapy A Pathophysiologic Approach. 5th ed. New York, NY: McGraw-Hill; 2002:939-952.

Healthy Aging At-A-Glance 2007. Available at www.cdc.gov/nccdphp/publications/aag/pdf/healthy_aging.pdf. Last accessed Oct. 15, 2007.

Hanlon JT, Ruby CM, Guay D, et al. Geriatrics. In: DiPiro JT, Talbert RL, Yee GC, eds. Pharmacotherapy A Pathophysiologic Approach. 5th ed. New York, NY: McGraw-Hill; 2002:79-89.

Williams CM. Using medications appropriately in older adults. Am Fam Physician. 2002;66(10):1917-1924.

K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Available at www.kidney.org/professionals/kdoqi/guidelines_ckd/p4_class_g1.htm. Last accessed Oct. 15, 2007.

Munar MY, Singh H. Drug dosing adjustments in patients with chronic kidney disease. Am Fam Physician. 2007;75(10):1487-1496.

Brier ME, Aronoff GR. Drug Prescribing in Renal Failure: Dosing Guidelines for adults. 5th ed. Philadelphia, Pa : American College of Physicians; 2007.