Psychopharmacology is the study of the effects of drugs on the mind and body. It consists of pharmacokinetics – what the body does to the drug, and pharmacodynamics – what the drug does to the body. Aging can alter both pharmacokinetics and pharmacodynamics. Understanding these processes is essential for optimizing drug therapy in older adults. Having a basic understanding of these processes is also is helpful for non-prescribing providers so that they can recognize the potential impact of medications or medication side effects on mood and behavior, appropriately relay concerns to the prescribing provider, and assist older adults with medication adherence.

Older adults use more prescription drugs than any other age group and are more likely to have multiple chronic disorders, increasing risk for adverse events (Brahma, et al, 2013). This is particularly problematic for women, who are almost twice as likely as men to experience adverse drug reactions (Zucker and Prendergast, 2020) and are underrepresented in clinical drug trials both on the basis of gender and age (van Marum, 2020; Zucker and Prendergast, 2020).

Pharmacokinetics in older adults

Pharmacokinetics refers to the absorption of the drug, which depends heavily on the route of administration (e.g., oral, intravenous, intramuscular, etc.), distribution of the drug via the blood stream across the different body compartments, metabolism, and excretion/elimination (Le, 2022). Age affects all of these processes to varying degrees.

Route of administration and absorption: Absorption depends heavily on the route of administration (e.g., oral (by mouth), intravenous (direct injection to a vein), intramuscular (injection into a muscle), etc.). The ultimate goal is for the drug to reach the blood stream for distribution throughout the body. Thus, drugs with quicker access to the bloodstream (e.g., intravenous, inhalation) will have faster action. Most prescribed medications are administered orally and absorbed in the gastrointestinal (GI) tract, which means slower and more variable response. Most absorption occurs in the lower intestine and thus is dependent on the rate of stomach emptying. Other factors that affect absorption include stomach contents, intestinal transit time, GI bacteria, and pH (Le, 2022).

With age: There are age-related decreases in small intestine surface area, slower emptying of stomach contents, and an increase in stomach pH (more alkaline). While most of these changes have minimal impact on most drugs, changes in pH can slow absorption and increase adverse effects on the stomach. Slowing of passage through the stomach or use of anticholinergic medications (which will be discussed in more detail below) can delay drug movement to the small intestine, delaying and reducing therapeutic effect (Ruscin & Linnebur, 2022a).

Distribution: Once a drug enters the bloodstream, it will be distributed to all body compartments, including the brain, regardless of which compartment is the intended target (Le, 2022). The brain is typically protected by the blood brain barrier, which evolved to protect the brain from toxins. Brain capillaries are tightly covered by cellular membranes from support cells (glia), such that only certain substances can pass through. The blood brain barrier also contains active transporters to allow other substances in (e.g., glucose). Otherwise, a drug must be able to pass through the multiple cellular membrane layers to gain access to the brain from the blood. These cellular membranes are composed of lipids (fats), thus a drug must be dissolvable in fat (lipid soluble) to pass through (Marques et al, 2013). By definition then, the vast majority of psychotropic medications are lipid soluble. Because psychotropic drugs are distributed throughout the body as well as to the brain, they will have the intended therapeutic effect (e.g., treatment of depression) as well as unintended effects (side effects) in the body (e.g., elevated blood pressure). Conversely, a medication to treat a problem with the body (e.g., antihistamine for allergies) will have central nervous system (CNS) side effects (e.g., drowsiness) if they are able to cross the blood-brain barrier.

With age: Body fat generally increases with age while body water content decreases. Higher body fat means that psychotropic drugs (which are all lipid soluble) accumulate in fat may take longer to eliminate from the body (Ruscin & Linnebur, 2022a). The blood brain barrier becomes more permeable with age, meaning substances previously kept out of the brain can pass through.  This increases CNS side effects from medications (Marques, et al., 2013).

Metabolism:  Most drugs are metabolized by the liver and use a shared enzyme system (Le, 2022).

With age: Changes in liver function with age result in reduced clearance from the body and higher concentrations of drug in blood circulation, meaning longer duration of drug effect and increased potential for drug-drug interactions and toxicity. Blood flow to the liver is also decreased by patients with heart failure and by taking other drugs that affect the cytochrome P-450 enzyme system. (Ruscin & Linnebur, 2022a)

Elimination: Elimination of most drugs is via the kidneys in urine (Le, 2022).

With age: Kidney size decreases by 20-30% between the ages of 30 and 80 (Drenth-Van Maanen, et al., 2019). This is one of the more significant age-related pharmacokinetic changes and means that drugs excreted by the kidney will have longer action in the body (Ruscin & Linnebur, 2022a). This is particularly problematic for drugs with a narrow therapeutic index, which is a measure comparing the level of drug that causes a therapeutic effect to the level of drug that is toxic. A narrow therapeutic index means there is very little difference between the therapeutic dose and the toxic dose, and careful dosing is required. When drugs are eliminated more slowly due to age-related kidney changes, a drug with a narrow therapeutic index, such as lithium, can become toxic if dose adjustments aren’t made.

Pharmacodynamics in older adults

Pharmacodynamics refers to a drug’s mechanism of action in the brain. Age-related changes in pharmacodynamics are complex, with considerable variability across individuals (Drenth-Van Maanen, et al., 2019). For example, one person’s response to a medication can be different than someone else’s due to their past experience with medications. While some age-related changes can make an older person less sensitive to medications, a number of brain changes with age result in increased sensitivity to medications that affect the CNS (Mangoni & Jackson, 2004).

Drug classes of concern for older adults

A number of drug categories pose particular risks for older adults, and these may be over-the-counter (OTC) medications and supplements, as well as prescribed medications. Potentially problematic drug classes for older adults include analgesics, anticoagulants, antihypertensives, antiparkinsonian drugs, diuretics, hypoglycemic drugs, and a variety of psychotropic drugs (Ruscin & Linnebur, 2022b). The American Geriatric Society Beers Criteria® are commonly used to identify potentially problematic drugs (American Geriatrics Society Beers Criteria® Update Expert Panel, 2023). Recommendations are made to avoid use in all older adults or avoid use for certain individuals with certain conditions or under certain circumstances. The strength of the recommendation is also specified, as well as the quality of the evidence behind the recommendation.

Anticholinergic medications: The neurotransmitter acetylcholine is found throughout the body and the brain, and is involved in many physiological functions. In the brain, it is involved in cognition (attention, learning, and memory), as well as sleep. In the body, acetylcholine has widespread effects. Drugs that block the transmission of acetylcholine are referred to anticholinergic, and also have widespread effects (Ghossein et al., 2023). Therapeutic anticholinergic effects include treatment of Parkinson’s disease, urge incontinence, shortness of breath, and vomiting (Ghossein et al., 2023). Adverse effects of anticholinergic medications can be grouped into central effects (i.e., effects in the CNS) and peripheral effects (occurring in the body) (Lopez-Alvarez et al., 2019). An adverse central effect of particular concern for older adults is cognitive impairment. Other central effects include headache, insomnia, and anxiety (Ghossein et al., 2023). Peripheral adverse effects are numerous, and toxic effects are generally summarized by the mnemonic hot as a hare (fever), blind as a bat (dilated pupils), dry as bone (dry mouth, dry eyes, decreased perspiration), red as a beet (flushing), mad as a hatter (cognitive impairment), and full as a flask (urinary retention) (Ghossein et al., 2023). Although anticholinergic effects can be seen throughout the body, a medication with anticholinergic properties can produce CNS effects only if it can cross the blood brain barrier (Lopez-Alvarez et al., 2019).

The Beers criteria (American Geriatrics Society Beers Criteria® Update Expert Panel, 2023) list the following drug categories as containing medications with strong anticholinergic properties: antidepressants (tricylics), antiemetics, first generation antihistamines, antimuscarinics (for urinary incontinence), anti-parkinsonian agents, antipsychotics, antispasmodics, and skeletal muscle relaxants.  Regarding antidepressant medications, these are largely tricyclic medications, with the exception of the selective serotonin reuptake inhibitor (SSRI) paroxetine (See also Lopez-Alvarez et al., 2019 for a list of neuropsychiatric drugs with anticholinergic properties). First generation antihistamines include several OTC medications: e.g., diphenhydramine (Benadryl; Sominex), deoxylamine (Unisom), and chlorpheniramine (Chlor-Trimeton)

Medications with anticholinergic properties are widely prescribed to older adults because they are effective and other options are sometimes not available (Lopez-Alvarez et al., 2019). Given age-related changes in pharmacokinetics and pharmacodynamics and increased permeability of the blood-brain barrier, the adverse effects of anticholinergic medications are particularly problematic for older adults. This is compounded by polypharmacy (discussed below). When more than one drug with anticholinergic properties is taken, the effects accumulate and this is referred to as anticholinergic burden (Hilmer, A. & D. Gnjidic, 2022). Anticholinergic burden in older adults is associated with increased risk of falls, cognitive impairment, and increased all-cause mortality (Ruxton et al., 2015). However, if the anticholinergic effect is the therapeutic effect, the benefits may outweigh the risks for some individuals and conditions.  Both should be discussed so that the patient can make an informed decision.

Polypharmacy

There is no standard definition of polypharmacy but it is often defined as the use of five or more drug therapies (Masnoon, et al, 2017). Numerical definitions, however, do not take into account the degree to which medications prescribed are necessary for the patient’s conditions. Distinction can be made between appropriate polypharmacy, where all medications have a specific therapeutic intent and adverse drug reactions are minimized, and inappropriate polypharmacy, where medications are prescribed that are not clinically indicated (Varghese, et al., 2023). Problematic, or inappropriate, polypharmacy also includes what has been referred to as a prescribing cascade, which occurs when medication side effects are misinterpreted as a new medical problem, resulting in additional medications, rather than a change or adjustment to the original medication (Rochon et al., 2021). Polypharmacy is increasing over time, with prescription medication and supplement use almost doubling between 2005 and 2011 (Qato et al., 2016). In older persons, this causes increased risks of adverse events and potentially harmful drug-drug interactions. Polypharmacy is particularly problematic for women, who comprise the majority of long-term care residents, many of whom are prescribed ten or more medications (Rochon et al., 2021).

Role of non-prescribing providers working with older adults.

All persons working with older adults, regardless of specialty, can play a role in minimizing pharmacologic-related harm to older adults. The following are recommended for consideration:

• Be aware of which broad classes of medications are of potential harm to older adults.
• Ask about all medications older adults take, including OTC medications and supplements.
• Provide non-pharmacologic interventions to reduce need for multiple medications. This can include assisting with behavioral sleep hygiene, psychological pain management, and psychotherapeutic treatment of depression, anxiety, or other mental health conditions.
• Educate older adults about medication effects, side effects, and usage.
• Educate older adult about OTC medications and supplements.
• Work with patients on medication adherence.
• Alert prescribing physicians regarding concerns about inappropriate prescribing, non-adherence, or symptoms you are seeing that may be attributed to medications.
• Work with older adults to make lifestyle changes, such as with diet and exercise, which can reduce the need for medication management of conditions such as diabetes, hypertension, and high cholesterol.
• Work with older adults to learn what matters to them and facilitate their ability to communicate that to their physician (e.g., is their incontinence problematic enough to outweigh the potential negative impact of anticholinergic medication on cognition).

Written by Suzanne Musil, PhD, ABPP, MyMichigan Health 2024

ADDITIONAL REFERENCES IN PROGRESS

For a great online module on psychopharmacology, check out the Foundational Competencies in Older Adult Mental Health Certificate Program from the E4 Center and CATCH-ON.