Pharmacotherapy Considerations in Elderly Adults

James M. Wooten, PharmD

Disclosures

South Med J. 2012;105(8):437-445. 

In This Article

Pharmacokinetics

Pharmacokinetics describes how the body processes a specific drug after its administration. Every drug has a specific pharmacokinetic profile based on specific parameters such as age, sex, weight, body mass index, hepatic function, and renal function. The more a specific drug is studied in specific patient types (eg, elderly patients), the better the understanding will be of the pharmacology of that drug in those patients. Proper doses can be established and a clear adverse effect profile can be determined.[1,14,15]

Drug researchers are hesitant to conduct large randomized controlled trials in elderly patients. Most elderly patients have several different diseases and take many different medications that cannot be discontinued so that a patient can participate in a drug study. The pharmacology of many medications in elderly adults has not been studied sufficiently, so making accurate predictions about pharmacokinetics in older adults is difficult. Developing an effective pharmacotherapeutic plan for an elderly patient requires a clear understanding of the principles of pharmacokinetics (absorption, distribution, metabolism, and elimination) and how the pharmacokinetics of a drug may be altered in the geriatric population, and this consideration must be applied to every drug that is prescribed.[1,14–18]

Absorption of Oral Medications

The gastrointestinal (GI) tract can change with age and this may affect how certain drugs are absorbed. The aging process can reduce GI motility and GI blood flow. Gastric acid secretion is reduced in older adults and this can result in an elevation in gastric pH. Increased gastric pH and reduced gastric blood flow may cause reduced drug absorption, whereas reduced GI motility may result in more of the drug(s) being absorbed. The age-related absorptive changes seen with fluctuating gastric pH also can be influenced by medication use. Concurrent use of antacids and overuse of proton pump inhibitors may contribute greatly to these changes.[19] Age-related absorptive changes can alter significantly a drug's absorption as well as its onset of action. The absorption of drugs that undergo first-pass metabolism also may be increased in older people. This action is seen with nitrates and the lipophilic [beta]-adrenergic blockers (eg, propranolol).[14,17–19]

The net effect of these changes is difficult to predict and may vary depending on the nature of the drug being prescribed. Age-related changes affecting drug absorption are, by themselves, generally considered minimal, but elderly patients are at high risk for developing other problems that can affect absorption. These problems, which are common in older adults, include swallowing difficulties, poor nutrition, and dependence on feeding tubes.[14,17,18]

Distribution

Drug distribution refers to where the drug goes after it enters the bloodstream. For drugs that are administered orally, the distribution phase begins after absorption and first-pass metabolism. The distribution phase is represented by a theoretically calculated volume; however, no real volume exists. Rather, the apparent volume of distribution of a drug is illustrated by a proportion that relates the amount of drug in the body to the concentration of drug measured in a biological fluid. Some drugs are widely distributed into tissues, body fluids, and the central nervous system by crossing the blood-brain barrier. Other drugs are not distributed well at all, such that the apparent volume of distribution may be close to the actual volume of blood in the body.[1,14,15,17,18]

Various factors influence the volume of distribution of a drug, including protein binding (only unbound drug is distributed), pH, molecular size, and water or lipid solubility (lipid-soluble drugs, in general, have a greater volume of distribution). For instance, phenytoin is a highly protein (albumin)-bound anticonvulsant that may have a significant effect in elderly patients who have reduced albumin levels. This leaves more free phenytoin available to cause various adverse effects.

Understanding how and where a specific drug is distributed is vital information because this determines the dosage necessary to achieve an adequate concentration of the drug at the location where the drug has its primary effect (ie, specific body fluid or specific tissue or organ system). The distribution volume of a drug is determined via phase I trials mandated by the US Food and Drug Administration (FDA) before they approve a drug.[4,14,17,18]

The aging process can have a significant effect on how a drug is distributed in the body. As the body ages, muscle mass declines and the proportion of body fat increases; therefore, drugs that are fat soluble will, in general, have a greater volume of distribution in an older person compared with a young person, but for drugs distributed in muscle tissue, the volume of distribution may be reduced. This effect is observed with diazepam, which is highly fat soluble, and this may necessitate dosing changes until the desired effect is observed.

The aging process also is associated with a theoretical reduction in total body water, which can affect the volume of distribution of water-soluble drugs. Older adults in general produce less albumin, which binds drugs in the bloodstream. Reduction in protein binding can result in an increase in free drug concentration. As the free drug concentration increases (compared with bound drug), more drug becomes available to reach receptors, thus increasing the pharmacologic effect in an elderly individual.[14,17,18]

All of these effects taken together can greatly influence how a drug is distributed, and this ultimately determines the dose that is necessary to produce a desired pharmacologic effect or unwanted adverse effects. If the distribution volume of a drug is reduced in an elderly patient, then the loading dose that is necessary to achieve a desired concentration is reduced and the half-life of the drug (the time it takes for the blood concentration to decline by 50%) may be altered. Failure to take these changes into consideration can result in drug toxicity. Changes in the half-life of a particular drug also will determine the specific dosing regimen for a patient. If a drug's distribution volume is increased, then the opposite effects occur.[14,17,18]

Consideration of how a drug's volume of distribution may be altered in an elderly patient is an important component that helps determine the proper drug dose for an individual. Drugs that have undergone sufficient study in elderly patients to determine how the volume of distribution will change because of aging can be dosed more precisely in this population. For drugs lacking such information, the dose should be reduced and titrated to a specific effect.[8–10,14,15,17,18]

Metabolism

The liver is the primary organ responsible for drug metabolism. The liver can both synthesize various proteins, substrates, and enzymes and convert chemicals (xenobiotics) from one form to another. This detoxification process is complicated, but the result is to convert substances believed to be harmful to the body to a form that can be eliminated more easily. In general, the final by-product of liver metabolism is a water-soluble product that is readily eliminated via the kidney; however, some toxins (eg, acetaminophen) can be converted to toxic components before being converted to the final by-product, which can pose problems if the final product cannot be synthesized.[14,15,18,19]

The liver uses various types of reactions to complete the transformation process. Oxidative reactions (phase 1) may occur via oxidation, reduction, hydrolysis, or other types of chemical conversions. Phase 1 reactions typically involve cytochrome P450 monooxygenase (CYP450) enzymes. There are various types of CYP450 enzymes and they can play a role in drug metabolism. The CYP450 system is also where many drug– drug interactions occur, because various drugs can act as inducers or inhibitors of other drugs undergoing metabolism. Some drugs must be converted via the liver to the active form of the drug (prodrugs). Phase 2 reactions are conjugative. Products of conjugation reactions have increased molecular weight and are usually inactive, unlike phase 1 reactions, which often produce active metabolites. Some drugs undergo both phase 1 and 2 metabolism.[14,15,17,18]

Alteration of the normal metabolic process can significantly affect the pharmacokinetics of a drug. If the normal route of metabolism is slowed in any way, then the half-life of the drug may be prolonged such that the potential for adverse drug reactions (ADRs) increases significantly. If the process is sped up in some way, then the half-life of the drug is reduced and the effectiveness of the drug may be altered. Metabolic capacity can be affected by many variables, including diet, genetics, alcohol, nutritional status, sex, and the presence (or absence) of interacting drugs.[1,4,5,17,18]

The aging process also can affect drug metabolism. Several physiological changes can greatly influence metabolic capacity. In general, hepatic blood flow is reduced in elderly adults, which can significantly affect metabolism because the drug is introduced to the liver at a much lower rate. Liver mass and intrinsic metabolic activity (includes the CYP450 enzyme system) also is reduced during the aging process. Phase 1 reactions are affected much more than are phase 2 reactions. With a reduction of blood flow to the liver and a reduction in metabolic activity, the metabolic process is significantly reduced in older adults.[15,17,18]

All of these effects are variable, which makes it difficult to measure the extent of hepatic function reduction and then quantitate this effect so that doses can be calculated based on liver function. Because age, sex, genetics, and other variables play such major roles in metabolic capacity, any formula for dose calculation based on hepatic function alone would not be accurate. Although no precise formula can be established based on liver function, the doses of hepatically cleared drugs in elderly patients should be reduced. Dosage adjustments are somewhat arbitrary, but in older adult patients, a general recommendation is to reduce the dosage for those drugs undergoing hepatic metabolism. The dose can then be titrated to efficacy or adverse effects.[1,14,15,17,18]

Excretion

Elimination of drugs from the body occurs primarily via renal excretion. As with metabolism, the half-life of drugs is increased as renal function is reduced. As the body ages, renal function declines, sometimes by a significant degree. This decline is the result of several physiological changes, which include a reduction in blood flow to the kidneys, a decrease in kidney mass, and a reduction in the size and number of functioning nephrons. Unlike hepatic effects, these changes are consistent from one patient to another.[14,17,18]

Different from hepatic changes observed with aging, renal changes can be somewhat predictive, thus allowing drug dose adjustment based on renal function that is either measured or calculated. Calculations based on laboratory measurements (eg, serum creatinine) or other data can be used to estimate a patient's renal function. In fact, pharmaceutical manufacturers use these estimates to provide dosing guidelines to healthcare providers for drugs that are eliminated primarily via the kidneys.

The impact of renal elimination of medications cannot be overstated. Many drugs are completely or partially excreted by the kidneys. Other drugs are metabolized (sometimes to active metabolites) and these metabolites are then excreted renally. A reduction in glomerular filtration rate is a noted consequence of aging. Knowing which drugs are excreted renally and knowing how to adjust the doses of those drugs in patients with renal impairment is imperative to ensure safe and effective drug dosing in all patients.[1,14,15,17–19]

There are several formulas that have been developed and assessed for estimating a patient's renal function. Two such formulas are the Cockcroft-Gault formula and the modification of diet in renal disease (MDRD) formula.[14,17,18] Two of these formulas are reviewed and compared to 24-hour measured creatinine clearance in Table 1. The Cockcroft-Gault formula is the most commonly used calculation, although many practitioners prefer the MDRD formula, which may prove to be more accurate than other formulas even though it has not been used for as long as Cockroft-Gault. In elderly adults, a low serum creatinine is not always indicative of normal renal function. Because older adults have lower muscle mass than younger people, low serum creatinine may not be indicative of normal renal function but rather indicative of a reduction in muscle mass. The same issue is noted in individuals with amputations, malnutrition, or muscle wasting. For patients in whom serum creatinine may not be an accurate indicator of renal function, an actual 24-hour creatinine collection may be necessary.[14,15,17,18]

There is much debate about which formula should be used for estimating creatinine clearance. The Cockroft-Gault formula was developed when the laboratory methods used to measure serum creatinine were not as accurate as today's methods; therefore, comparing the MDRD formula to the Cockroft-Gault formula can be difficult. (Another formula [Chronic Kidney Disease Epidemiology Collaboration equation] also has been suggested and it may offer advantages over the other formulas, although it is unclear which estimate would be best to use in elderly adults). Pharmaceutical manufacturers have long used Cockroft-Gault when recommending dosage adjustments for renally excreted drugs. These recommendations appear on a drug's package insert, which is approved by the FDA. Drug manufacturers will not change their recommendations until required to do so by the FDA. The FDA must compare and contrast the information regarding these formulas to determine what would provide the most accurate estimation of a patient's creatinine clearance.[20,21]

In summary, the altered pharmacokinetics observed in most elderly patients significantly affect the particular pharmacokinetics of a drug. These changes are summarized in Table 2. Although drug absorption is probably least affected by aging, when all of these parameters are taken in concert, significant medication accumulation can occur and this leads to drug toxicity. It can be difficult to calculate the doses of drugs that are hepatically cleared, so arbitrarily reducing the dose and closely monitoring the patient would be appropriate. Doses are more easily calculated for drugs excreted renally based on current drug information. Renally excreted drugs must be monitored closely and their doses must be adjusted when appropriate.

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