Prescription Danger: How to Avoid Overmedicating Older Adults

According to a review published in the Journal of Clinical Pharmacology, as our population ages, managing medications becomes increasingly complex. Aging bodies undergo changes that affect how drugs are absorbed, distributed, metabolized, and excreted. Decreased stomach acid, slower gut movement, and altered liver function can all impact a drug's effectiveness and safety. To ensure proper care, doctors need to carefully consider these changes and potentially adjust doses, explore alternative administration routes, and closely monitor older adults taking medications. Remember, a little extra caution goes a long way when it comes to medication management in our aging population.

1. Aging and Oxidative Stress: The aging process increases oxidative stress, leading to cellular damage and influencing drug metabolism, which can affect drug effectiveness and safety in older individuals.

2. Age-Related Changes in Absorption: Aging can lead to reduced gastric acid production, gastric motility, and first-pass metabolism, impacting the absorption of drugs and potentially necessitating dose adjustments or alternative routes of administration.

3. Alterations in Distribution: Changes in body composition, such as increased body fat, can affect the distribution of lipophilic drugs, leading to prolonged drug effects, while changes in protein binding can influence the unbound fraction of drugs, affecting their pharmacological actions.

4. Metabolism and Liver Function: Age-related reductions in liver volume, blood flow, and enzyme activity can alter the metabolism of drugs, potentially requiring lower doses to achieve therapeutic effects and avoid adverse reactions.

5. Renal Function and Excretion: The decline in glomerular filtration rate with age can impact the clearance of water-soluble drugs primarily excreted through the kidneys, emphasizing the importance of estimating renal function and monitoring drug accumulation in older individuals.

Leading Age-Related Health Issues

A myriad of age-related health conditions, including sensory impairments, chronic obstructive pulmonary disease, diabetes, dementia, and osteoarthritis, have emerged as leading causes of disability among the elderly.These diseases not only impact the prescription of drugs but also necessitate changes in how societies organize prevention programs and provide medical and pharmaceutical care. Additionally, older individuals often require multiple medications, a practice known as polypharmacy. As the aging process affects the body's organ functions, it also alters the way drugs are absorbed, distributed, metabolized, and excreted, known as pharmacokinetics. These changes, in turn, influence the biochemical and physiological effects of drugs on the body and their mechanism of action, known as pharmacodynamics.

Age-Related Biological Changes

The decline in organ and body functions associated with biological aging is driven by various biological mechanisms, including:

1. Oxidative Stress: Aging increases oxidative stress, leading to cellular damage and influencing drug metabolism.

2. Lipid Peroxidation: Increased lipid peroxidation can alter the pharmacokinetics of certain drugs.

3. Telomere Shortening: Telomere shortening is associated with aging and can impact drug responses.

4. Altered Gene Expression: Changes in gene expression affect drug metabolism and response.

5. Upregulation of Apoptosis: The upregulation of apoptosis contributes to cellular damage, which can affect drug pharmacokinetics and pharmacodynamics.

How Altered Human Organ Functions Affect Pharmacokinetics

Absorption

DECREASED GASTRIC ACID PRODUCTION

One common age-related change is decreased gastric acid production, which can impair drug dissolution and reduce the bioavailability of drugs. For instance, drugs like erythromycin and ketoconazole may be affected. Although the effect is not always clinically relevant, it's essential to consider potential alterations in dosing.

DECREASED GASTRIC MOTILITY

Aging can lead to decreased gastric motility, which results in reduced drug absorption. This change may affect the efficacy of drugs like Vitamin B12, iron, and calcium. In some cases, the standard dose may become inadequate, necessitating potential increases in dosage or alternative routes of administration.

REDUCED FIRST-PASS METABOLISM

The aging process can reduce first-pass metabolism, leading to increased absorption of high-clearance drugs. Drugs like morphine, lidocaine, verapamil, propranolol, and nitroglycerine may have altered pharmacokinetics. In some cases, a "start low, go slow" dosing strategy is recommended, with consideration for transdermal administration.

INCREASED PLASMA CONCENTRATION

Certain drugs may result in increased plasma concentrations due to age-related changes. For example, drugs like hydroxyzine, valaciclovir, captopril, prednisone, and clopidogrel may exhibit this effect. However, it's crucial to note that these changes are often not clinically relevant.

Distribution

INCREASED PROPORTION OF BODY FAT

Aging often leads to an increased proportion of body fat. This change can affect the distribution of lipophilic drugs, potentially leading to prolonged drug effects. Clinicians may need to adjust dosing regimens for drugs that are highly lipophilic to prevent adverse effects.

Absorption in Aging: The Basics

Absorption is the movement of a drug from the site of administration into the systemic circulation. For most oral and rectal drugs, this process primarily occurs in the small intestine. However, in some cases, drug absorption can take place through alternative routes such as the skin, muscles, subcutaneous layers, or even the lungs. The bioavailability of a drug is a key concept in understanding how much of an ingested dose reaches the systemic circulation.

Age-Related Changes in Gastrointestinal Tract

As we age, several physiological changes occur in the gastrointestinal tract that can significantly affect the bioavailability of orally and rectally administered drugs. These changes include:

1. Reduction in Intestinal Blood Flow and Gastric Acid Production: Aging can lead to a decrease in blood flow within the intestines and a reduction in gastric acid production. These changes may impact the absorption of certain drugs.

2. Decreased Gut Motility and Delayed Gastric Emptying: Aging can also result in decreased gut motility and delayed gastric emptying due to a loss of local neural control. These changes can further affect drug absorption.

Hypochlorhydria and Its Impact

Hypochlorhydria, a condition characterized by low stomach acid production, is more common in older adults. This condition can reduce the absorption of weakly basic drugs, such as ketoconazole. Consequently, understanding the impact of hypochlorhydria is crucial for ensuring the effective absorption of certain medications.

Absorption of Subcutaneous and Intramuscular Drugs

The absorption rate of drugs administered via subcutaneous or intramuscular injections can also be influenced by age-related changes in the body. Two primary factors come into play:

1. Decreased Tissue Blood Perfusion: Reduced blood perfusion in the tissues can decrease the absorption of drugs from their site of administration into the bloodstream.

2. Reduced Muscle Mass: Aging is often associated with a decrease in muscle mass. This reduction can particularly impact drugs administered as depot preparations, affecting their absorption.

Effects on Inhaled Drugs

For drugs administered via inhalation, age-related changes in the body can influence their absorption. Reductions in chest wall compliance, ventilation-perfusion matching, and alveolar surface area may decrease the absorption of drugs through inhalation.

First-Pass Metabolism and Bioavailability

First-pass metabolism is a crucial aspect of drug absorption. It refers to the metabolism of a drug or substance before it enters the systemic circulation, primarily occurring in the liver and, in some cases, in the gut. With advancing age, several changes influence first-pass metabolism and, consequently, drug bioavailability.

1. Reduction in Liver Mass and Blood Flow: Aging results in a reduction in liver mass and blood flow. This, in turn, decreases the capacity of the liver to metabolize drugs, leading to higher bioavailability for some medications, especially those with a narrow therapeutic index.

2. Decreased CYP Enzyme Activity: The activity of key enzymes involved in first-pass metabolism, such as CYP3A4, decreases with age. This further contributes to increased bioavailability for drugs undergoing extensive first-pass metabolism.

Implications for Medication Dosage

As a consequence of age-related changes in drug absorption, dosage adjustments become necessary, especially for drugs with altered bioavailability due to reduced first-pass metabolism. For drugs with a narrow therapeutic index, initiating treatment at a lower dose is recommended to avoid adverse effects. Additionally, alternative routes of administration, such as intravenous, intramuscular, transdermal, and sublingual, can be considered to achieve the desired therapeutic effect.

Dermal Products and Age-Related Changes

The age-related reduction in skin hydration and lipophilic content may theoretically impact the absorption of hydrophilic drugs in dermal products. However, clinical observations have not shown significant differences in transdermal absorption between young and older individuals, suggesting that age-related changes in the skin may not be a critical factor in prescribing these medications.

Distribution: How Aging Affects Volume of Distribution

The term "volume of distribution" plays a crucial role in drug distribution within the body. It represents the ratio of the total amount of drug in the body to drug plasma concentration. Several factors, both drug-related and patient-related, influence this volume of distribution.

Drug-Related Factors

Drug-related factors such as protein and tissue binding, acidity, lipophilicity, water solubility, charge, and size determine the volume of distribution. Water-soluble drugs tend to have smaller volumes of distribution in older people, resulting in higher plasma concentrations. This impacts drugs like gentamicin, digoxin, lithium, and theophylline, where the dose should be reduced. On the other hand, lipid-soluble drugs like benzodiazepines, morphine, and amiodarone have increased volumes of distribution with age. This leads to a prolongation of the terminal elimination half-life, which can result in extended adverse effects after discontinuation of treatment.

Protein Binding

Protein binding is another crucial factor in drug distribution. The two primary drug binding proteins are α-1-acid glycoprotein and albumin. Acidic compounds mainly bind to albumin, while basic drugs bind to α-1 acid glycoprotein. Changes in the concentrations of these proteins may affect the free (unbound) fraction of drugs, ultimately influencing drug effects.

P-glycoprotein (P-gp)

P-glycoprotein is a membrane-associated protein with a primary function as an efflux pump. While the effects of aging on P-gp activity have not been extensively studied, decreased P-gp activity in older individuals may lead to increased drug exposure in the brain. This is particularly significant for drugs actively pumped out of the brain by P-gp, such as domperidone, loperamide, paclitaxel, ondansetron, and cyclosporine A.

Metabolism and Age-Related Changes

Metabolism involves the breakdown of drugs in the body, converting them into more water-soluble substances for excretion. The liver is the primary site for drug metabolism, where enzymes transform lipid-soluble drugs into more water-soluble compounds. Aging can affect the capacity of the liver to remove drugs from the systemic circulation.

Liver Volume

A reduction in liver volume is a common age-related change. While this reduction may not be clinically relevant for many drugs, it can significantly impact drugs that undergo extensive first-pass metabolism, such as opioids and metoclopramide. In such cases, lower drug doses may be required to achieve the intended therapeutic effect.

Blood Flow

The extraction ratio of drugs plays a crucial role in their clearance from the body. Changes in liver blood flow can impact drug clearance, particularly for drugs with a high extraction ratio. This age-associated reduction in liver blood flow can affect the clearance of drugs like labetalol, nifedipine, and verapamil. Adjusting the dosage of these flow-limited drugs is recommended in older patients.

Metabolic Capacity

Aging, combined with metabolic genotype, can lead to changes in the systemic exposure of drugs. Some drugs may exhibit up to a 2-fold increase in systemic exposure in older individuals, potentially affecting their therapeutic effect. Dosing adjustments may be necessary for drugs like capecitabine, clomipramine, codeine, ezetimibe, fluvoxamine, paroxetine, venlafaxine, and zolpidem.

Protein Binding and Metabolic Clearance

Metabolic capacity-limited drugs with low protein binding, such as paracetamol and theophylline, may experience a decreased metabolic clearance of 30–50% in older people. For drugs with high protein binding, changes in protein binding can make total clearance unreliable, but free clearance may decrease by around 50%.

Excretion: The Role of Renal Function

Excretion is the process by which the body eliminates metabolic waste, primarily through the urine, faeces, bile, or lungs. Renal excretion is of particular importance, but it can be affected by age-related changes.

Glomerular Filtration Rate (GFR)

The age-related reduction in glomerular filtration rate can influence the clearance of various drugs, especially those that are water-soluble and primarily excreted through the kidneys. Drugs like water-soluble antibiotics, diuretics, digoxin, and certain anticoagulants may be affected by these changes. The clinical significance of these reductions in renal excretion depends on the therapeutic index of the drug. Drugs with a narrow therapeutic index, like aminoglycoside antibiotics, digoxin, and lithium, are more susceptible to adverse effects if they accumulate more than intended.

Choosing the Right Estimation Method

To determine renal function accurately in older patients, various estimation methods are available. The Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas can be used to estimate the glomerular filtration rate. The choice of formula may vary depending on the individual patient's characteristics.

The Role of Frailty in Drug Clearance

Frailty, as defined by the World Health Organization, is a state in which older individuals experience a compromised ability to cope with everyday stressors due to age-related declines in physiological reserve across multiple organ systems. One key aspect of frailty is the presence of sarcopenia, a condition characterized by a progressive decline in skeletal muscle mass. This loss of muscle mass can significantly affect the clearance of certain drugs, particularly those that are highly hydrophilic, such as gentamicin. Sarcopenia can lead to decreased drug distribution into muscle mass, potentially altering the medication's efficacy and safety profile.

How Dementia Alters Medication Effects

Dementia, a prevalent condition among older adults, presents its own set of challenges in medication management. People with dementia frequently experience anorexia and weight loss, leading to reductions in muscle mass and albumin levels. These changes affect drug distribution, with water-soluble medications having a reduced volume of distribution while lipophilic drugs exhibit an increased volume of distribution.

Impact of Altered Body Functions on Medication Intake

The aging process is accompanied by a decline in various body functions, including vision, hearing, swallowing, motor skills, cognition, and self-care abilities. These age-related changes can significantly affect an older person's ability to manage their medications correctly. Research has shown that older individuals encounter numerous practical challenges when it comes to proper medication use. These challenges include difficulties in reading and understanding medication instructions, handling packaging, and preparing medications. They may also forget to take their medications as prescribed. Consequently, patients and their healthcare providers may resort to unconventional medication management practices, such as opening capsules to ease swallowing or administering crushed tablets through feeding tubes.

Pharmacological Considerations in Aging

The aging process doesn't just prompt changes in health; it significantly influences medication management. Older individuals often require multiple medications, a practice known as polypharmacy. This complexity arises due to age-induced alterations in organ functions, affecting drug absorption, distribution, metabolism, and excretion—collectively termed pharmacokinetics and pharmacodynamics.

Conclusion

The ageing population's evolution brings multifaceted challenges in healthcare and medication management. Age-related alterations in pharmacokinetics, along with changes in body functions, significantly influence the safety and efficacy of pharmaceuticals. Recognizing and accommodating these changes are paramount in ensuring optimal medication use in the elderly, demanding continual revision and adaptation of existing guidelines and practices.

Reference Article

Wilting, I., & F. Jansen, P. A. (2020). Prescribing medicines to older people—How to consider the impact of ageing on human organ and body functions. British Journal of Clinical Pharmacology, 86(10), 1921-1930. https://doi.org/10.1111/bcp.14094

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