Pharmacokinetics is the study of the absorption, distribution, metabolism, and excretion (ADME) of drugs. Changes associated with aging affect the pharmacokinetics of medications. Once taken, a medication must obtain therapeutic levels in the bloodstream to exert a clinical action. This section discusses how normal changes of aging and alterations due to age-related conditions affect the body’s response to polypharmacy.
Drugs are administered orally, parenterally, or topically. Drugs taken orally are absorbed in the gastrointestinal (GI) tract. Drugs administered parenterally are absorbed by the vascular circulation, while topical drugs are absorbed by skin or mucosa. Incomplete absorption of orally administered drugs occurs mainly because of lack of absorption from the gut. If a drug is too hydrophilic (easily absorbed by or dissolved in water) it will have trouble crossing the cell’s lipid membrane. If a drug is too lipophilic (fat-soluble) it will not be soluble enough to cross the water layer surrounding the cell (Marieb & Hoehn, 2016).
Following administration of a drug by any route, some fraction of the unchanged drug will reach the systemic circulation. The amount of drug reaching the systemic circulation after administration is referred to as its bioavailability. In general, absorption is unchanged in later adulthood; however, there are some important changes to consider related to aging.
Age-related changes can impede absorption due to decreased blood flow to the tissues and the GI tract and changes in gastric pH (Marieb & Hoehn, 2016). In most older adults, this normative change of aging has no clinical consequence; however, the use of certain medications can enhance this effect and alter absorption significantly. For example, proton pump inhibitors (PPIs) such as omeprazole lower gastric pH and can inhibit Vitamin B12 absorption (Marieb & Hoehn, 2016). Elders should take PPIs for the least time necessary to ameliorate the condition they are meant to treat. An older adult taking a PPI for a prolonged period of time should have periodic monitoring of vitamin B12 or take supplements.
Chronic illness and age-related variations in plasma proteins may also cause significant problems with medications that are highly protein bound, such as phenytoin and levodopa/carbidopa. Blood levels can vary, especially if food intake and dosing are not consistent. For example, if phenytoin is taken with a high-protein meal, less medication is absorbed, because phenytoin binds with the protein in the stomach.
Decreased cardiac output in older adults and those with chronic conditions may reduce subcutaneous and intramuscular drug absorption, thus affecting the pharmacokinetics of injectable medications. Transdermal medications are absorbed through subcutaneous fat, which is reduced with aging (Wynne, 2011).
Test Your Knowledge
Age-related changes that impact bioavailability of a medication include:
- Decreased blood flow to the digestive tract.
- Increased oxygen levels in the blood.
- Decreased subcutaneous fat.
- Increased absorption in the gut.
We’re Overmedicating Elders [7:08]
Once a medication is absorbed into the bloodstream, it is distributed throughout the body and exerts both desired and undesired effects. Distribution dynamics can be affected by body weight and body composition, which changes with age. Distribution of a medication is also affected by impaired absorption, which influences its onset, strength, and duration.
In general, as we age, total body water and muscle mass decrease while percentage of body fat increases. These changes can lead to drugs having a longer duration of action and increased effect. Drugs that were effective may become compounded and overexceed their therapeutic threshhold causing increased side effects.
Protein binding refers to the amount of medication bound to albumin in the blood. It is a theoretical concept that explains variability in pharmacologic distribution. Medications that are highly protein-bound have an affinity for albumin. A bound drug is inactive whereas an unbound drug exerts a pharmacologic effect. Think of the albumin as hands that hold onto drug—the more albumin, the more hands, the less active drug available.
Serum albumin comes from dietary protein and is often decreased in older adults, creating unique issues with medications that are highly protein-bound, such as levodopa, warfarin, and phenytoin. Serum albumin is decreased 15% to 20% compared to the levels in healthy younger adults and is perhaps even lower during times of illness. If an older adult has low albumin, there are fewer “hands” to hold the drug and render it inactive, leaving more drug free and active. This is one reason older adults need a lower dose of medication than younger adults, especially if the drug is highly protein-bound.
Following absorption across the gut wall, drug metabolism occurs almost entirely in the liver. Liver metabolism greatly reduces the bioavailability of medications through a process called first-pass elimination, which is the rate at which circulating drugs are metabolized as they traverse the liver before they reach the systemic circulation. First-pass elimination can actually inactivate some drugs, thus requiring alternative routes of administration.
The liver can also excrete the drug into the bile. With age and chronic illness, liver size and hepatic blood flow are decreased, therefore dosing of medications that are significantly metabolized by the liver should be adjusted. In addition, alcohol use should be assessed when prescribing any medications to elders because liver health or disease can modify the drug’s effectiveness.
Age-related changes in renal function are an important factor in the clearance of drugs from the body. About two-thirds of the population experiences a decline in creatinine clearance with aging. This can lead to a prolonged half-life for many drugs and cause the build-up of toxic levels if the dose and frequency are not adjusted (Katzung, 2012). Renal impairment requires dosage adjustment of medications that are metabolized and excreted by the kidneys. There are two laboratory values commonly used to estimate renal function: creatinine clearance and glomerular filtration rate. Blood urea nitrogen (BUN) and creatinine are commonly tested together and should be tested annually for elders taking more than six medications.
Pharmacodynamics is the effect of the medication on the body (Wynne, 2011, Katzung, 2012). Increased drug actions not explained by changes in pharmacokinetics are often listed as pharmacodynamic actions. For example, receptors and receptor sites in elders, or in those with long-standing illness, may be reduced or limited in function, having the effect of increasing or decreasing sensitivity to drug action. Patients with diabetes mellitus often have decreased insulin receptors, which impact overall glucose levels as well as effects on other medications.
Medication is metabolized according to our individual enzyme systems, which are related to our genes and DNA. Some reactions to medications can be predicted genetically. This is referred to as pharmacogenetics. Pharmacogenetics studies and predicts how an individual’s genetic inheritance affects the body’s response to drugs. Known genetic variants predict that certain individuals will not respond to commonly used medications such as statins, antihypertensives, and SSRIs.
Through the use of pharmacogenetics, more accurate methods of matching a drug with the appropriate patient will be available, as well as better determination of the correct dosage of a certain drug tailored to the individual. Genetic mapping holds great promise (and will soon be available as a tool) for predicting diseases and drug reactions, but it is still too expensive to be widely available.
Test Your Knowledge
Pharmacodynamics refers to the:
- Interaction of multiple medications.
- Way the body metabolizes the medication.
- Energy released by a medication.
- Effect of the medication on the body.