Patient Case: High Risk Medication Dosing in Older Adults

Joanne is a 79 year-old woman on a medication regimen that has a very high risk of adverse drug events.

Joanne has a history of anxiety, insomnia, and incontinence. When looking at her medication regimen, I noticed the medication that she was taking for anxiety, escitalopram, was being used at a higher dose than recommended. Due to specializing in the care of older adults and with the use of the GalenusCare safety analytics tool, I was able to identify this problem and make recommendations to improve the safety of her regimen.

Physiologic Changes in Older Adults

As we age, there are several changes to the function of our body which can impact how we process certain medications. These changes may lead to increased sensitivity to the side effects of medications or reduced therapeutic response. In addition, as we age, we are more prone to multiple medical conditions and drug-drug interactions.

When considering these changes and how they relate to medications, the impact is put into two categories for consideration: pharmacodynamics and pharmacokinetics. Pharmacodynamics are how drugs affect the body. Pharmacokinetics are how the body affects drugs.

Pharmacodynamic Changes in Older Adults

Pharmacodynamic changes may be harder to understand in older adults. For example, older adults seem to be less sensitive to β-1 and β-2 receptors. This means that they may not respond as well to β-1 or β-2 agonists such as dobutamine or salbutamol. Scientifically, it is not yet fully understood why this occurs. Theories include changes in hormones, increased permeability of the blood-brain barrier, and changes to receptor and neurotransmitter concentrations. In addition, the ability to maintain homeostasis may be impacted by aging and therefore older adults may take longer to regulate things like heart rate, temperature, and electrolyte levels.

Other pharmacodynamic changes include:

Pharmacokinetic Changes in Older Adults

Pharmacokinetics contain four main components:

Absorption is primarily affected by multi-drug, drug-disease, and drug-food interactions which can occur at any age. In older adults, the impact of aging on absorption has mixed results. Some medications, such as levodopa, show increased absorption while others, such as vitamin B and iron, have reduced absorption. Medications that are passively absorbed seem to be less impacted by changes in aging. It is worth noting that gastric motility decreases with age and therefore while absorption itself may not be changed, the time it takes to get to where a medication needs to be absorbed may take longer. In addition, medications such a calcium carbonate need an acidic environment to be absorbed. Older adults may have a higher pH in the stomach and therefore may benefit from calcium citrate which does not require acid to be absorbed.

Distribution of medications on the other hand is significantly affected by age. Older adults tend to experience an increase in body fat by about 20-40% while also experiencing a decrease in lean body mass – or total body water – by 10-15%. This can lead to changes in distribution of both hydrophilic (water loving) and lipophilic (fat loving) medications. Specifically, it may increase the concentrations of hydrophilic drugs and reduce the clearance of lipophilic drugs. Therefore, lipophilic drugs may have increased duration of action, such as diphenhydramine which has a high risk of side effects in older adults. At the same time, hydrophilic drugs, such as digoxin and lithium, may require lower doses because the plasma concentration is higher.

Other considerations with distribution include protein-binding capacity. Drugs such as diazepam and warfarin rely on albumin binding for distribution. Albumin may be lower in older adults, especially those with poor diets. Therefore, medications which bind to proteins may be more likely to be “free” in the blood stream and therefore contribute to more side effects. For medications like warfarin which have a narrow therapeutic index, this can lead to serious adverse events.

Drug metabolism happens primarily in the liver which may change with age. Many drugs undergo what is known as first-pass metabolism. This is when a drug is metabolized before it enters the bloodstream. Changes to this process may alter the concentrations of the drug in the blood. Medications that rely heavily on first pass metabolism have low bioavailability. This means that most of the drug is metabolized before it enters the bloodstream. Therefore, any disruption in that metabolism may lead to significantly higher levels of that drug in the blood than expected. Aging adults may experience reduced blood flow to the liver as well as a lower overall liver mass. A decrease in the number of enzymes in the liver, specifically CYP450 enzymes, may reduce metabolism. Furthermore, competitive and non-competitive drug interactions may also significantly impact first-pass metabolism.

The final step in pharmacokinetics is drug elimination, which is the process of the drugs being removed from the body. Most often, this is done through the kidneys which excrete the remaining drug through the urine. Kidney function often starts to decrease at about middle age and continues to worsen with age. As the body ages, kidneys may get smaller and have reduced filtering capabilities. In those with high blood pressure or diabetes, kidney function may decline more quickly. This decline in kidney function is often why drug doses are lowered in older adults. 

High-dose Escitalopram

As mentioned above, I noticed Joanne was taking a high dose of escitalopram. In the general adult population, escitalopram doses range from 5-20 mg daily. However the FDA recommends that the highest dose of escitalopram is 10 mg per day in patients over 60. This is because in clinical trials, patients over the age of 60 experienced a 50% increase in the elimination half-life of escitalopram. This means escitalopram lasted longer in the body in older adults, possibly due to the reduced kidney function that occurs with age.

Due to it lasting longer in the body, escitalopram may start to accumulate with time. This means that older adults may be more susceptible to side effects from this medication at doses higher than 10 mg per day. Lower sodium levels, known as hyponatremia may already be more common in older adults and the dose accumulation of escitalopram may further exacerbate this risk. Sedative side effects such as dizziness and drowsiness may increase the risk of falls and hospitalization. Perhaps most concerning is a rare but serious change to the heart rhythm known as QT prolongation that can occur with high-dose escitalopram. If QT prolongation occurs and worsens over time, it can lead to a deadly arrhythmia known as Torsades de Pointes.

Summary

Based on the known age-related changes and FDA guidance, I recommended that Joanne’s dose of escitalopram be lowered from 20 mg to 10 mg per day and monitoring for changes in her mood. In addition, I was able to recommend a discontinuation of a highly anticholinergic medication, oxybutynin, to help reduce her overall risk of adverse events. To learn more about why anticholinergic medication are dangerous in older adults, revisit our patient case here.

Making these two changes, I was able to reduce Joanne’s overall risk for falls, ER visits, and hospitalizations. By reducing the dose of escitalopram, I may have also been able to prevent premature mortality by reducing the risk of QT prolongation.