Reduced First-Pass Metabolism
For many orally administered medications, the liver significantly metabolizes a portion of the drug before it reaches the systemic circulation, a process known as first-pass metabolism. As a person ages, liver mass and hepatic blood flow decrease, which can lead to a less efficient first-pass effect. This reduction means that a larger fraction of the original drug dose can pass through the liver unmetabolized and enter the bloodstream, resulting in a higher systemic concentration. This effect is particularly pronounced for drugs with a high hepatic extraction ratio, such as certain beta-blockers and opioids. The increased bioavailability and resulting higher plasma concentrations can elevate the risk of toxicity and adverse effects, even with standard dosing.
Gastrointestinal Changes Affecting Drug Absorption
Beyond liver metabolism, several age-related changes in the gastrointestinal (GI) tract can also influence drug absorption, though their overall clinical impact is often considered less significant for most passively absorbed drugs.
Delayed Gastric Emptying
Older adults commonly experience a slowing of gastrointestinal motility and delayed gastric emptying. While this can delay the onset of action for medications absorbed primarily in the small intestine, for some drugs, it may prolong their exposure to the absorption site. This can paradoxically increase the total amount of drug absorbed (bioavailability) over a longer period, especially for medications that are slowly dissolved or depend on prolonged contact with the intestinal mucosa for absorption.
Altered Gastric pH
As people age, there is a natural decline in gastric acid secretion, leading to a higher (less acidic) gastric pH. This change can have a dual effect on drug absorption, depending on the chemical properties of the medication. For weakly acidic drugs, higher gastric pH may reduce their absorption, while for weakly basic drugs, the higher pH can lead to an increased rate of absorption by promoting dissolution. A clinically relevant example is calcium carbonate, which requires an acidic environment for optimal absorption; thus, older adults may absorb less calcium from this source.
Reduced Splanchnic Blood Flow
Blood flow to the digestive tract (splanchnic blood flow) decreases with age. For drugs with high first-pass metabolism, this reduced blood flow contributes to the overall decline in hepatic metabolism, which, as mentioned, increases bioavailability. For other drugs, reduced splanchnic blood flow can potentially slow the rate of absorption from the intestinal wall into the circulation.
Factors Beyond Initial Absorption
It is crucial to understand that drug absorption is just one part of the pharmacokinetic process. Higher plasma drug concentrations in older patients are often compounded by other age-related changes, especially in distribution and elimination.
- Decreased Lean Body Mass and Total Body Water: Older adults tend to have a higher ratio of body fat to lean body mass and less total body water. This alters the volume of distribution for drugs. Water-soluble drugs (e.g., digoxin) are concentrated in a smaller fluid volume, leading to higher plasma concentrations. Conversely, fat-soluble drugs (e.g., diazepam) have a larger volume of distribution and a longer half-life, increasing the risk of accumulation with repeated dosing.
- Reduced Renal and Hepatic Clearance: The kidneys and liver become less efficient at clearing drugs from the body with age. Reduced renal function prolongs the half-life of many drugs excreted through the kidneys. Similarly, decreased liver function reduces the rate of drug metabolism. These factors all lead to a slower removal of drugs from the body, contributing to higher drug concentrations over time.
Comparison of Pharmacokinetic Changes in Older vs. Younger Patients
| Pharmacokinetic Parameter | Change in Older Patient | Effect on Drug Levels | Notes |
|---|---|---|---|
| Absorption | Reduced first-pass metabolism | Increases systemic bioavailability for highly cleared drugs | Clinically significant for specific medications (e.g., propranolol, some opioids). |
| Absorption | Delayed gastric emptying | Delays onset of action or, for some drugs, can increase total absorption. | Clinically relevant for drugs with time-sensitive effects. |
| Absorption | Increased gastric pH | Increases absorption of some weakly basic drugs, decreases absorption of weakly acidic drugs. | Can influence effectiveness of drugs like ketoconazole or calcium carbonate. |
| Distribution | Increased body fat | Increases volume of distribution for fat-soluble drugs, increasing half-life. | May lead to accumulation and prolonged effects of drugs like diazepam. |
| Distribution | Decreased total body water | Decreases volume of distribution for water-soluble drugs, increasing plasma concentration. | Requires dose reduction for drugs like digoxin to prevent toxicity. |
| Metabolism | Decreased hepatic function | Slows metabolism, prolonging drug half-life. | Overall decline in liver function reduces drug clearance, increasing drug concentrations. |
| Elimination | Decreased renal function | Slows excretion of renally-cleared drugs. | The most common cause of drug accumulation and toxicity in older patients. |
Conclusion
The seemingly simple question of what increases the rate of drug absorption in older patients reveals a complex interplay of age-related physiological changes. While reduced hepatic first-pass metabolism is a direct cause for increased bioavailability and, therefore, higher systemic absorption for many drugs, other gastrointestinal factors also play a role. Importantly, these absorption-related changes are often compounded by alterations in drug distribution and elimination, culminating in higher overall drug concentrations in the body. This highlights the critical importance of careful medication management, including starting at low doses and titrating slowly, in geriatric care to prevent adverse drug events and maximize therapeutic benefits. Healthcare providers must consider these unique pharmacokinetic profiles when prescribing medications for older adults. For more detailed information on polypharmacy and pharmacokinetics in older adults, consult resources such as the Merck Manuals.
