The Impact of Age on Pharmacokinetics: An Overview
Pharmacokinetics describes how the body absorbs, distributes, metabolizes, and excretes a drug—a process known by the acronym ADME. In older adults, these physiological processes undergo alterations that can significantly affect a drug's effectiveness and safety profile. A reduced homeostatic capacity, coupled with more comorbidities and an increased likelihood of polypharmacy (the use of multiple medications), further amplifies the risk of adverse drug events.
Absorption: The Drug's Journey into the Body
While changes in drug absorption are often considered less clinically significant than other pharmacokinetic changes, they can still play a role.
- Changes in the gastrointestinal tract: Slower gastric emptying and intestinal motility may delay a drug's arrival at its absorption site.
- Altered gastric pH: The decrease in gastric acid secretion that can occur with aging or the use of certain medications like proton pump inhibitors can affect the absorption of weakly basic drugs.
- Reduced blood flow: Decreased blood flow to the digestive tract may also impact absorption, though the overall effect on total drug absorption (bioavailability) is often minimal in healthy older adults.
Factors Influencing Absorption
While normal aging has a modest effect on absorption, other factors frequently seen in the elderly can be influential:
- Comorbidities: Conditions like atrophic gastritis can significantly alter the gastric environment and impact drug dissolution and absorption.
- Polypharmacy: Drug-drug interactions can alter gastric emptying or compete for transport mechanisms, further modifying absorption rates.
Distribution: Where a Drug Travels in the Body
Age-related changes in body composition directly affect how a drug is distributed.
- Increased body fat: Older adults tend to have an increase in body fat and a decrease in lean body mass and total body water. This causes lipid-soluble (fat-soluble) drugs like diazepam to have an increased volume of distribution, leading to a prolonged half-life and extended duration of action.
- Decreased total body water: Conversely, water-soluble drugs like digoxin and lithium have a smaller volume of distribution. This can result in higher plasma concentrations and a greater risk of toxic effects if not properly dosed.
- Plasma protein binding: While plasma protein concentrations generally remain stable with age, conditions like malnutrition or acute illness can lower albumin levels. This can increase the amount of unbound, active drug for highly protein-bound medications like warfarin and phenytoin, raising the risk of toxicity.
Metabolism: The Body's Chemical Processor
Age-related physiological changes to the liver significantly impact drug metabolism.
- Reduced hepatic blood flow and liver size: These changes decrease the liver's ability to metabolize drugs, especially those with a high hepatic extraction ratio.
- Enzyme activity: The activity of Phase I enzymes, particularly certain cytochrome P450 (CYP450) isoenzymes, tends to decrease with age, extending the half-life of drugs metabolized by these pathways. Phase II metabolism, which involves conjugation and glucuronidation, is generally less affected by aging.
- First-pass metabolism: The effect of first-pass metabolism is diminished, meaning a greater proportion of an orally administered drug reaches systemic circulation, potentially increasing its effect. Prodrugs that require hepatic activation, however, may have their activation reduced.
Excretion: Eliminating Drugs from the Body
Declining renal function is arguably the most clinically significant pharmacokinetic change in older adults.
- Decreased glomerular filtration rate (GFR): The filtering capacity of the kidneys diminishes with age due to a reduction in renal mass and glomeruli. This decline is often not reflected by serum creatinine levels, as reduced muscle mass in the elderly lowers creatinine production.
- Prolonged drug half-life: Reduced renal clearance leads to a prolonged half-life for many drugs, causing them to accumulate to potentially toxic levels if dosages are not adjusted.
- At-risk medications: Drugs with a narrow therapeutic index, such as digoxin, lithium, and certain antibiotics, require careful monitoring and dosage adjustment in older adults with reduced renal function.
Comparison of Pharmacokinetics in Young vs. Elderly
| Parameter | Impact in Young Adults | Impact in Elderly Adults |
|---|---|---|
| Absorption | Generally rapid and complete. | Can be delayed; potentially affected by reduced GI motility and pH, but clinically minor in healthy individuals. |
| Distribution | Higher total body water and lean body mass. Lower body fat. | Higher body fat, lower total body water and lean mass, altering Vd for lipophilic and hydrophilic drugs. |
| Metabolism | Robust liver function, higher hepatic blood flow, and more active Phase I enzymes. | Reduced liver size, blood flow, and Phase I enzyme activity, leading to slower metabolism. |
| Excretion | Higher GFR and efficient renal clearance. | Progressive decline in GFR and renal mass, leading to slower clearance and accumulation of renally excreted drugs. |
Optimizing Medication Management in Older Adults
The profound pharmacokinetic impacts for elderly people necessitate a more cautious and individualized approach to medication management.
- Start low, go slow: This principle involves starting with a low dose and increasing it gradually, as needed, to achieve the desired therapeutic effect while minimizing the risk of adverse reactions.
- Comprehensive medication review: Regular review of all medications, including over-the-counter drugs and supplements, is essential to identify and address polypharmacy and potential drug-drug interactions. The Merck Manuals offer a thorough resource on geriatric pharmacokinetics.
- Monitor for adverse effects: Given the heightened risk, close monitoring for adverse effects and drug toxicity is critical, particularly for drugs with narrow therapeutic windows.
- Adjust for comorbidities: Dosage adjustments should account for age-related changes as well as any existing liver or kidney disease, as these can exacerbate pharmacokinetic alterations.
Conclusion
The effects of aging on the body's ADME processes significantly alter how older adults respond to medications. Reduced renal and hepatic function, coupled with shifts in body composition, can lead to increased drug half-lives, higher plasma concentrations, and a greater risk of adverse effects and toxicity. By understanding and accounting for these pharmacokinetic changes, healthcare professionals can optimize medication regimens and promote safer, more effective care for the aging population.
