Many theories have been proposed to explain the human aging process. Clinical manifestations of normal aging include changes in the biochemical makeup of tissues, reduced capacity of body systems, reduced ability to adapt to physiologic stress, and increased vulnerability to disease.12 Interindividual variability in physiology increases with age13 because individuals experience aging at different rates along with the development of disease processes. eTable 8-1 reviews some common physiologic changes associated with aging, with an emphasis on changes that can affect pharmacotherapy. For more detailed information, readers are referred to excellent reviews.12,14
Age-associated physiologic changes may result in reduced functional reserve capacity (i.e., ability to respond to physiologic challenges or stresses) and reduced ability to maintain homeostasis, thus making older adults susceptible to decompensation in stressful situations.12,14,15 Examples of homeostatic mechanisms that may become impaired include postural or gait stability, orthostatic blood pressure responses, thermoregulation, cognitive reserve, and bowel and bladder function. An event resulting in functional impairment may involve an insult for which the body cannot compensate, and relatively small stresses may result in major morbidity and mortality.12,14,15
The clinical response to a medication in an older adult is the net result of the interaction of a number of complex processes, including pharmacokinetics and pharmacodynamics. Age-related changes in physiology can affect drug pharmacokinetics and pharmacodynamics (see eTable 8-1). Concurrent medications, comorbidities, and frailty also play roles. When applying general knowledge of pharmacokinetic and pharmacodynamic alterations in an older adult in the clinical setting, it is necessary to consider the patient’s overall condition, age, diseases, and concurrent medications.
eTable 8-2 and the following discussion summarize what is known about the effect of aging on each of the four major facets of pharmacokinetics.13,16,17 Of interest, when multivariate population pharmacokinetic analyses are conducted, age by itself seldom is a significant predictor of individual pharmacokinetic parameters (e.g., clearance). Age-associated changes in drug absorption, distribution, metabolism, and elimination are more important predictors of altered pharmacokinetics than is age per se.
eTable 8-2 Age-Related Changes in Drug Pharmacokinetics |Favorite Table|Download (.pdf)
eTable 8-2 Age-Related Changes in Drug Pharmacokinetics
|Pharmacokinetic Phase||Pharmacokinetic Parameters|
- Unchanged passive diffusion and no change in bioavailability for most drugs
- ↓ Active transport and ↓ bioavailability for some drugs
- ↓ First-pass metabolism, ↑ bioavailability for some drugs, and ↓ bioavailability for some prodrugs
- ↓ Volume of distribution and ↑ plasma concentration of water-soluble drugs
- ↑ Volume of distribution and ↑ terminal disposition half-life (t1/2) for lipid-soluble drugs
- ↓ Clearance and ↑ t1/2 for some drugs with poor hepatic extraction (capacity-limited metabolism); phase I metabolism may be affected more than phase II
- ↓ Clearance and ↑ t1/2 for drugs with high hepatic extraction ratios (flow-limited metabolism)
|Renal excretion||↓ Clearance and ↑ t1/2 for renally eliminated drugs and active metabolites|
Most drugs are taken orally; age-related changes in gastrointestinal physiology could affect the absorption of medications. Drug–food interactions, concurrent medication use, and comorbidities affecting gastrointestinal function must also be considered.
Fortunately, most drugs are absorbed via passive diffusion, and age-related physiologic changes appear to have little influence on drug bioavailability.17 Nutrients absorbed by active transport, such as vitamin B12, iron, calcium, magnesium, and leucine, may have impaired absorption in older adults.16 There is evidence for a decreased first-pass effect on hepatic or gut wall metabolism that results in increased bioavailability and higher plasma concentrations of drugs such as propranolol and labetalol and reduced bioavailability of some prodrugs such as enalapril and codeine.13,16
Drugs requiring an acidic environment for absorption may have reduced extent of absorption in a relatively small proportion of older adults with increased gastric pH caused by atrophic gastritis or in those taking medications that increase gastric pH.13 The effects of aging on the absorption of modified-release orally administered dosage forms are not known, although changes in gastrointestinal motility or pH might affect absorption from some dosage forms in some patients.13
The distribution of medications in the body depends on factors such as blood flow, plasma protein binding, and body composition, each of which may be altered with age. For example, the volume of distribution of water-soluble drugs is decreased, whereas lipophilic drugs exhibit an increased volume of distribution.13,17 Changes in the volume of distribution can have a direct impact on the amount of medication that must be given as a loading dose. Older adults may also exhibit differences in the distribution of drugs to their sites of action. Tissue perfusion may decrease with aging, slowing the distribution to less highly perfused tissues such as muscle and fat.13 Small changes in protein binding (decreased albumin and increased α1-acid glycoprotein) have been documented with aging, but these changes do not generally have a significant effect on drug distribution except for drugs that are highly extracted by the liver, extensively protein bound, and administered IV.13,17
Blood–brain barrier permeability may also be altered in older adults, thereby affecting distribution of medications into the central nervous system (CNS). Cerebrovascular P-glycoprotein influences the transport of drugs across the blood–brain barrier. Studies using verapamil labeled with carbon-11 (a positron emitter) and positron emission tomography have demonstrated decreased P-glycoprotein activity in the blood–brain barrier with aging. As a result, the brain of elderly individuals may be exposed to higher than normal levels of drugs and toxins.18
The liver is the major organ responsible for drug metabolism, including phase I (oxidative) and phase II (conjugative) reactions. Variations in drug metabolism and consequently drug clearance are a major source of variability in the response to medications in older adults.19 Hepatic metabolism of drugs depends on liver perfusion, capacity and activity of drug metabolizing enzymes, and protein binding, all of which may altered by the aging process.17 For drugs that have high intrinsic clearance (high hepatic extraction ratio) and undergo rapid hepatic metabolism, drug clearance is dependent on hepatic blood flow (flow-limited metabolism). For drugs that have low intrinsic clearance (low hepatic extraction ratio) and are slowly metabolized by the liver, drug clearance is dependent on hepatic enzyme activity (capacity-limited metabolism).
Age-related decreases in hepatic blood flow can decrease significantly the metabolism of high extraction ratio drugs that undergo flow-limited metabolism. Hepatic blood flow may decline by 20% to 50%, and hepatic clearance of propranolol and amitriptyline may be reduced by 40% or more in older adults.17 Other high-extraction-ratio drugs that have been shown to have reduced hepatic clearance in older adults include diltiazem, lidocaine, metoprolol, morphine, and verapamil.20 Interpreting the effect of age on the metabolism of drugs that undergo capacity-limited metabolism is more complex. Hepatic clearance of capacity-limited drugs depends on the fraction unbound in blood and the intrinsic hepatic clearance. Most, but not all, studies have reported reduced liver size and enzyme content in older adults.20 Total hepatic clearance of capacity-limited drugs, however, may be reduced (lorazepam, piroxicam, warfarin), increased (ibuprofen, naproxen, phenytoin) or unchanged (diazepam, temazepam, and valproic acid) with aging.20 Hepatic clearance of the unbound drug, rather than the total hepatic clearance, which includes bound and unbound drug, may be more relevant in understanding the effect of age on hepatic clearance.21
Serum albumin concentrations decline with age. For capacity-limited drugs with extensive protein binding, older adults with reduced serum albumin concentrations may experience a significant increase in fraction unbound, leading to increased total hepatic clearance even though unbound clearance is significantly reduced. Naproxen, for example, has capacity-limited metabolism and is highly bound to albumin. Older adults experience reduced unbound clearance and increased total clearance compared with younger adults.20
Most research on hepatic drug metabolism and aging has focused on age differences in phase I drug metabolism pathways. Generally, phase II metabolic pathways are preserved in healthy older people.20 Frail older adults, however, experience reduced phase II metabolism. Frailty is a risk factor for declining health status and disability. Although frailty has proven difficult to define, it is characterized by reduced lean body mass, muscle loss, malnourishment, reduced function, and reduced endurance.20 Frailty is associated with inflammation, which may downregulate drug metabolism and transport.22
Renal excretion is the primary route of elimination for many drugs and metabolites. Age-related reductions in glomerular filtration rate (GFR) are well documented. However, as many as one third of “normal” older adult subjects may have no reduction as measured by creatinine clearance, and older adults maintaining a high protein diet have a GFR similar to younger adults.23 Additionally, declines in kidney function may be more closely implicated to disease processes such as hypertension and heart disease than aging itself. Therefore, age alone may not have as great impact on renal excretion of drugs than previously thought.16
The estimation of creatinine clearance, although not entirely accurate in individual patients, can serve as a useful screening approximation for the purpose of dosage adjustments. Cockcroft and Gault24 created one of the most commonly used equations for adults with stable renal function whose actual weight is within 30% of ideal body weight:
where age is given in years, actual body weight in kilograms, and serum creatinine concentration in milligrams per deciliter. The resulting creatinine clearance is in units of mL/min. For women, multiply this result by 0.85.
When serum creatinine is expressed in μmol/L, creatinine clearance in units of mL/min can be calculated by the following equation:
The Modified Diet in Renal Disease equation and the Chronic Kidney Disease Epidemiology Collaboration equation have become more widely used for estimation of GFR.25,26 The validity of each of these equations for use in estimating GFR in older adults has been advocated and challenged.27–29 However, dosing guidelines for medications that primarily are renally cleared are still based on estimated creatinine clearance determined using the Cockcroft and Gault equation, and current consensus is to continue to use of this equation for renal drug dosing in older adults. New methods based on serum creatinine and cystatin C continue to be developed, so this recommendation may change in the future.30
Consensus guidelines for oral dosing of primarily renally cleared drugs in older adults have been developed. Medications to avoid in older adults with creatinine clearance below 30 mL/min (0.5 mL/s) include chlorpropamide, colchicine, cotrimoxazole, glyburide, meperidine, nitrofurantoin, probenecid, spironolactone, and triamterene. Oral medications with recommended dosage adjustments for reduce renal function in older adults include acyclovir, amantadine, ciprofloxacin, gabapentin, memantine, ranitidine, rimantadine, and valacyclovir.31 Some hepatically metabolized medications can yield active, primarily renally excreted metabolites, such as N-acetylprocainamide, normeperidine, and morphine-6-glucuronide, which can accumulate with advancing age because of reduced renal function.
Sidebar: Clinical Controversy...
When using the Cockcroft and Gault equation to estimate creatinine clearance in older adults, some clinicians round the value up to 1 if the patient’s serum creatinine concentration is less than 1 mg/dL (88 μmol/L). Rounding the serum creatinine concentration may provide an underestimation of creatinine clearance and result in improper dose adjustment of renally eliminated medications. It is important to realize that the equation is merely an estimate, and attempts should be made to determine creatinine clearance accurately when contemplating the use of certain medications (e.g., gabapentin).
Age-related changes in pharmacokinetics are well characterized compared with changes in pharmacodynamics. Understanding the effects of age on pharmacodynamics has proven to be complex.
There is a general trend of altered drug response or increased “sensitivity” in older adults. Possible mechanisms that have been proposed include (a) changes in concentrations of the drug at the receptor, (b) changes in receptor numbers, (c) changes in receptor affinity, (d) postreceptor alterations, and (e) age-related impairment of homeostatic mechanisms.32,33 Differences in pharmacodynamics with age may be due to altered sensitivity (greater change in effect for a given change in drug concentration) but may also be due to differences in baseline performance or different concentrations of drug at the site of action between young and older adults.17 Most studies of pharmacodynamic differences with age have focused on drugs acting on the CNS and cardiovascular system.
Older adults are particularly sensitive to the CNS effects of drugs. Changes in brain size and weight as well as changes in neurotransmitter systems have been reported with advancing age. In addition, drugs may penetrate the CNS more easily.32 For example, there are multiple changes to the dopaminergic system with age, including decreased levels of the dopamine transporter, decreased number of dopaminergic neurons, and decreased density of several types of dopamine receptors. These changes are consistent with the increased sensitivity of older adults to the adverse drug effects of antipsychotics.33 Increased sensitivity to the CNS effects of medications in older adults has been demonstrated for benzodiazepines, anesthetic agents, opioid analgesics, antipsychotics, lithium, and anticholinergic medications.32,33
Aging is associated with numerous changes in the structure and function of the cardiovascular system that may predispose older adults to altered pharmacodynamic response to drugs acting on the cardiovascular system. Older adults are more likely to experience orthostatic hypotension as an adverse drug event.33 Age-related changes in pharmacodynamics have been reported for calcium channel blockers (increased hypotensive and bradycardic effects), β-blockers (reduced blood pressure response), diuretics (reduced effectiveness), and warfarin (increased risk of bleeding).32,33