Pharmacokinetics: How the Body Handles Drugs in Older Adults
Pharmacokinetics, which encompasses absorption, distribution, metabolism, and excretion (ADME), is profoundly altered by the physiological changes associated with aging.
Absorption
While absorption is generally considered the least affected aspect of pharmacokinetics, some age-related changes can be clinically relevant, especially for certain drug types. Ageing may lead to increased gastric pH, reduced splanchnic blood flow, and decreased motility, potentially affecting the rate and extent of absorption for some medications.
Distribution
Changes in body composition and plasma protein binding significantly impact how drugs are distributed throughout the body in older adults. Older adults typically have an increased percentage of fat and a decreased percentage of lean muscle mass and total body water. This alters the volume of distribution for lipophilic and hydrophilic drugs. Additionally, decreased levels of serum albumin can increase the concentration of the unbound, active drug, raising the risk of toxicity.
Metabolism
The liver's ability to metabolize drugs, particularly via Phase I oxidative reactions, typically declines with age. Reduced hepatic blood flow and decreased liver mass and enzyme activity slow the breakdown of many drugs, increasing the risk of dose-dependent toxicities. Polypharmacy further complicates metabolism by increasing the risk of drug-drug interactions.
Elimination
Kidney function, a critical factor in drug elimination, typically declines with age. Reduced Glomerular Filtration Rate (GFR) slows the renal clearance of many drugs and their active metabolites, increasing the risk of accumulation, particularly for drugs with a narrow therapeutic index. Serum creatinine levels may not accurately reflect the decline in renal function in older adults.
Pharmacodynamics: How Drugs Affect the Body in Older Adults
Age-related changes in pharmacodynamics relate to the body's response to a drug at its site of action and are often more difficult to quantify than pharmacokinetic changes.
Altered Receptor Sensitivity
Many physiological systems in older adults experience changes in receptor number, affinity, and post-receptor signaling pathways, leading to altered drug sensitivity. This can result in increased sensitivity to some drugs, such as benzodiazepines and warfarin, and decreased sensitivity to others, like beta-adrenergic agonists and antagonists.
Impaired Homeostatic Mechanisms
The body's ability to maintain a stable internal environment is less robust in old age, making older adults more susceptible to a drug's effects. Impaired baroreceptor reflex can increase susceptibility to orthostatic hypotension caused by certain drugs, and compromised temperature regulation can increase the risk of heat-related issues.
Comparison of Ageing's Impact on Pharmacokinetics (PK) and Pharmacodynamics (PD)
| Factor | Pharmacokinetic (PK) Impact | Pharmacodynamic (PD) Impact |
|---|---|---|
| Absorption | Generally minimal changes, but potential for altered rates due to reduced GI motility and pH shifts. | Indirectly affected by delayed onset of action. |
| Distribution | Increased volume for lipophilic drugs (e.g., benzodiazepines), decreased volume for hydrophilic drugs (e.g., digoxin). Reduced albumin can increase free drug levels. | Altered drug concentration at target site may lead to enhanced or diminished effects. |
| Metabolism | Reduced hepatic blood flow and Phase I enzyme activity lead to decreased drug clearance. Bioavailability of drugs with high first-pass metabolism increases. | No direct impact, but altered plasma concentrations directly influence drug effect. |
| Elimination | Decreased renal function (GFR) prolongs elimination half-life for renally cleared drugs, leading to accumulation. | Accumulation of drugs can cause dose-dependent toxicities and exaggerated effects. |
| Receptor Sensitivity | Not applicable. | Increased or decreased sensitivity to specific drugs at their receptor sites. |
| Homeostasis | Not applicable. | Impaired homeostatic mechanisms can exaggerate a drug's effect and increase the risk of side effects. |
Conclusion
The effects of aging on drug pharmacokinetics and pharmacodynamics are complex and varied, requiring a personalized approach to medication management in older adults. While absorption is often minimally affected, significant changes in distribution, metabolism, and elimination—primarily due to shifts in body composition and organ function—can increase drug exposure and toxicity risk. Concurrently, age-related changes in receptor sensitivity and impaired homeostatic mechanisms can alter the body's response to medications, often exaggerating both therapeutic and adverse effects. Healthcare providers must be vigilant in monitoring older patients, especially those on multiple medications, and consider starting with lower doses and titrating slowly to achieve therapeutic goals while minimizing adverse events. Continued research, particularly in the older-old and frail populations, is essential to better inform prescribing practices and improve medication safety.
