Central Nervous System Medications: Pharmacokinetic and Pharmacodynamic Considerations for Older Adults

Abstract

Most drugs have not been evaluated in the older population. Recognizing physiological alterations associated with changes in drug disposition and with the ultimate effect, especially in central nervous system-acting drugs, is fundamental. While considering pharmacokinetics, it should be noted that the absorption of most drugs from the gastrointestinal tract does not change in advanced age. There are only few data about the effect of age on the transdermal absorption of medications such as fentanyl. Absorption from an intramuscular injection may be similar in older adults as in younger patients. The distribution of lipophilic drugs (such as diazepam) is increased owing to a relative increase in the percentage of body fat, causing drug accumulation and prolonged drug elimination following cessation. Phase I drug biotransformation is variably decreased in aging, impacting elimination, and hepatic drug clearance has been shown to decrease in older individuals by 10–40% for most drugs studied. Lower doses of phenothiazines, butyrophenones, atypical antipsychotics, antidepressants (citalopram, mirtazapine, and tricyclic antidepressants), and benzodiazepines (such as diazepam) achieve the same extent of exposure. For renally cleared drugs with no prior metabolism (such as gabapentin), the glomerular filtration rate appropriately estimates drug clearance. Important pharmacodynamic changes in older adults include an increased sedative effect of benzodiazepines at a given drug exposure, and a higher sensitivity to mu opiate receptor agonists and to opioid adverse effects. Artificial intelligence, physiologically based pharmacokinetic modeling and simulation, and concentration-effect modeling enabling a differentiation between the pharmacokinetic and the pharmacodynamic effects of aging might help to close some of the gaps in knowledge.

Key Points

Changes in distribution, metabolism by cytochrome P450 enzymes, and renal clearance affect exposure to benzodiazepines, antipsychotics, and antidepressants.

Important pharmacodynamic changes include an increased sensitivity to opioids and to the sedative effect of benzodiazepines.

Dosing of central nervous system-affecting drugs requires careful attention in older adults. Polypharmacy should also be taken into account.

Introduction

Included in the Consolidated Appropriations Act 2023 is the Food and Drug Omnibus Reform Act of 2022 (“FDORA”), intended to promote diversity in clinical trial enrollment of older age groups [1, 2], a population that is constantly increasing, and also becomes increasingly older [3, 4]. Older patients have multi-morbidities, presenting 10–15 years earlier in communities with a lower socioeconomic status [5]. In addition, frailty, depicted by muscle weakness, weight loss, slow walking speed, fatigue, and a low activity level (Fried criteria) is common. The physiological changes of frailty are likely to affect the pharmacokinetics and pharmacodynamics further but very few data exist on this [6, 7]. Although physiological age is a better predictor of a drug’s effect, chronological age is often used, described categorically as young-old (age 65–75 years), old (age 75–85 years), and old-old (aged 85 years and over).

Medication treatment for the aging population is effective, in a similar manner as it is in the young population, and as the older patient accumulates diseases and treatments for each disease, polypharmacy becomes common [8]. However, polypharmacy is also associated with a decreased functional status. Although accumulation of the underlying pathology explains deterioration, attention should be focused on the aggregation of adverse effects particularly when considering medications that impact central nervous system (CNS) functions [9–12]. We are challenged with providing benefits for illnesses and well-being on the one hand, and preventing harmful unnecessary and excessive drug exposure on the other hand.

To assimilate knowledge from clinical trials, it becomes apparent that the old-old population has not been included in most trials. Extrapolation from the younger population is not necessarily appropriate, when considering drug disposition (pharmacokinetics) and effect (pharmacodynamics). Moreover, most of the included study participants do not have multiple diseases as real-world patients do [13, 14].

Pharmacokinetics and pharmacodynamics in the aged individual are in many cases measurably different, although similar when considering the effect traits. As most of the drugs in use have not been evaluated in the older population, knowledge of the physiological and pathological changes in older patients that relate to the changed drug disposition and effect is critical for understanding how to treat effectively this patient group. The pharmacokinetic and pharmacodynamic changes that occur in the older population are reviewed here with examples taken from medications that affect the CNS.

Pharmacokinetics

Basic pharmacokinetic variables will be introduced with a discussion on age-related changes to follow. Bioavailability refers to the extent and rate at which the active moiety (drug or metabolite) enters the systemic circulation, thereby accessing the site of action. After a drug enters the systemic circulation, it is distributed to the body’s tissues. Distribution is impacted by blood perfusion, tissue binding (e.g., because of lipid content), regional pH, and the permeability of cell membranes. Drug clearance from the body is the result of elimination by renal excretion and extra-renal pathways, usually hepatic metabolism, and can be defined as the plasma volume in the vascular compartment that is cleared of a drug per unit of time. The drug elimination half-life increases in direct proportion to the drug distribution volume (V_area) [in the absence of any change in systemic drug clearance].

The pharmacokinetic consequence is shown in this relationship:

$$\text{Elimination half}-\text{life}\left(t_{1/2}\right)=\frac{0.693V_{\text{area}}}{\text{Clearance}}$$

The area under the curve represents the total drug exposure integrated over time. Thus, clearance is the ratio of the dose to the area under the curve, so that the higher the area under the curve for a given dose, the lower the clearance. If a drug is administered by a continuous infusion and a steady state is achieved, the clearance can be estimated from a single measurement of the plasma drug concentration, as shown in the equation:

$$\text{Steady}-\text{state drug concentration}(C_{\text{ss}})=\frac{\text{drug input rate}\left(\text{dose}/\text{unit time}\right)}{\text{Clearance}}$$

Drug Absorption Changes in Older Adults

Oral

Advanced age does not influence gastric emptying or the small intestinal transit rate [15], and absorption of most drugs from the gastrointestinal tract is considered the same in older patients as in young patients [16, 17]. However, bioavailability, which is the result of pre-systemic elimination by intestinal wall drug transporters (mainly P-glycoprotein), metabolism at the intestinal wall, and pre-systemic hepatic metabolism [18, 19], is increased in some instances, such as with sustained-release diltiazem [20].

Trans-Dermal and Intra-Muscular Drug Administration

Very few data exist on the changes in absorption of transdermal-administered and intramuscular-administered medications. One of the physiological skin changes in aged skin include changes in permeability. The number of cell layers remains stable, but the epidermis thins, particularly in women and particularly on the face, neck, chest, and the extensor surface of the hands and forearms. In sun-protected sites, the stratum corneum (the outermost layer of the epidermis) thickens and stiffens due to decreased intracellular lipids, with increased cohesion, and the ability for water movement through this layer decreases. In addition, production of sebum (the oily substance that protects the skin from drying out) decreases as much as 60%. These result in a decrease in water and fat emulsion on the skin, and a decrease in water content in the stratum corneum [21, 22].

Interestingly, although the lipid content of the aged skin is reduced globally as much as 65%, the distribution of subcutaneous fat changes; while a reduction is noted in the face, hands, and feet, a relative increase is observed in the thighs, waist, and abdomen [21, 22]. Nonetheless, intra-subject variability was estimated to be less significant, and the major variability in transdermal absorption was best explained by inter-subject variability, primarily by skin conductance of the individual [23]. There are only scarce data about the effect of these changes on the extent of transdermal absorption of medications such as fentanyl. Transdermal absorption of the more hydrophilic drugs (such as hydrocortisone) was reduced in older patients while transdermal absorption of testosterone and estradiol were not decreased [24]. Drug absorption from an intramuscular injection may not noticeably change with age [25, 26].

Drug Distribution in Older Adults

A decrease in muscle mass and an increase in the percentage of total body fat are common in aging. Because of this, fat-soluble drugs have a greater distribution in obese people and in older people. As the elimination of a drug is in direct relationship to drug distribution (longer elimination half-life as the volume of distribution increases), increased drug distribution (e.g., with diazepam) causes drug accumulation during long-term administration; drug elimination after cessation of dosing will be prolonged as well. The clinical consequences are that drug effects may be delayed [27], and as the elimination half-life increases, there will be an increase in steady-state concentrations when compared with a younger individual.

The pharmacokinetic data of oxycodone and fentanyl are best described by a two-compartment or three-compartment model. Fentanyl pharmacokinetics does not change with age. Conversely, clearance of oxycodone is reduced by 35–40%; age and lean body mass are significant covariates for the volume of the central compartment and for the elimination clearance [28–30].

Drug distribution across a physiological barrier such as the blood–brain barrier has been recently studied [31] with metoclopramide, a substrate of the blood–brain barrier efflux transporter P-glycoprotein. Metoclopramide, used as an antiemetic, displays CNS adverse effects (extrapyramidal symptoms and tardive dyskinesia) caused by a dopamine D₂ receptor blockade in the basal ganglia, occurring in a higher percentage in older patients. A higher total volume of distribution of [11C]metoclopramide in the basal ganglia has been shown in older people [31]. Variable results were obtained when the aging effect on exposure to the breast cancer resistance protein substrate, rosuvastatin, was studied in older participants [18, 32]. There are no data on changes in other drug transporters in advanced age.

Drug Metabolism in Older Adults

Drug metabolism to inactive or active forms occurs mostly by hepatic liver enzymes. These are categorized to phase I (oxidative and degradative processes) and phase II (synthetic) pathways. The phase I pathways are mediated by cytochrome P450 (CYP) enzymes, while phase II pathways include the glucuronyl transferases, sulfotransferases, and acetyltransferases. It should be mentioned that phase I enzymes reside also in the small intestine (duodenum portion) wall and share part of drug metabolism. The kidneys contribute to metabolism of a few peptide drugs such as insulin.

Hepatic Aging

Anatomically, one can appreciate the 20–40% decrease in liver volume and thickening of the hepatic sinusoidal endothelium. Physiologically, there is a decrease in hepatic blood flow and in the smooth endoplasmic reticulum where metabolism occurs. Activity per se of enzymes of drug metabolism does not change with advanced age, although it does decrease with frailty [7, 33, 34].

Age Effects on Drug Metabolism

The medications that are metabolized by phase I enzymes undergo reduced metabolism in advanced age, profoundly known for CYP3A-metabolized drugs [35]. Less clear is the aging effect on the additional long list of CYP enzymes that catalyze drug metabolism such as CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 [36]. Nevertheless, it is apparent that hepatic drug clearance is decreased in older individuals by 10–40% for most drugs studied [37], reflecting probably the reduced liver volume and the decrease in hepatic blood flow [33, 38]. Steady-state drug concentration increases in direct relationship to a decrease in clearance. There are no data on the effect of aging on renal metabolism of peptide drugs.

A significant proportion of medications that are widely prescribed for older adults are metabolized by enzymes that are encoded by highly polymorphic genes (such as CYP2D6, CYP2C9, and CYP2C19). Pharmacogenetic testing is increasingly used to optimize the medication regimen. The effect of enzymes and transporters’ genetic variability (pharmacogenetics/pharmacogenomics) has not been studied much in this age group [39]. Although pharmacogenetics might explain a smaller part of the inter-individual variability in this population [40–43], a retrospective analysis has shown that frequent hospitalizations in older adults with polypharmacy could be explained by a difference in the major pharmacogenes' polymorphism frequency between cases and controls. [44]

Implementation of the pharmacokinetic principles when prescribing CNS-affecting drugs is critical (for a summary, see Table 1). The phenothiazines, butyrophenones, and atypical antipsychotics rely, mostly, on phase I biotransformation. Consequently, there is a decrease in clearance in older age and a lower dose should be administered for obtaining the same exposure. The total concentration of risperidone and of its active metabolite is higher in advanced age, showing a 35% increase in plasma concentration for every 10 years of age, beginning at 40 years of age [45]. Plasma concentration of olanzapine increases by 10% for every 10 years of age [46]. Evidence also exists of an increase in haloperidol plasma concentrations in older subjects [47], and decreased clearance of clozapine and its active metabolite norclozapine, resulting in increased blood concentrations that have been associated with side effects [48].

Table 1.

Major CNS pharmacotherapies with pharmacodynamic, CYP pathways, renal excretion, and pharmacokinetic changes in adults

Drug class	Drug	Main pharmacodynamics	Known pharmacodynamics changed in older adults	Main CYP metabolism	Renal excretion	Known pharmacokinetic changes in older adults
Antipsychotics
Butyrophenone	Haloperidol	Blocks post-synaptic dopamine D2 receptors	Higher frequency of adverse effects such as drug-induced parkinsonism and tardive dyskinesia due to a dopamine receptor blockade	50–60% glucuronidation (inactive); 23% CYP3A4-mediated reduction to inactive metabolites (some back-oxidation to haloperidol); 20–30% CYP3A4-mediated N-dealkylation	30%, mostly as metabolites	Increased plasma concentration
Atypical antipsychotics	Risperidone	High 5-HT2 and dopamine D2 receptor antagonist activity. α1, α2 adrenergic, and histaminergic receptors also antagonized with high affinity		CYP2D6 to active metabolite (9-hydroxyrisperidone)	Active metabolite excreted by the kidney. Risperidone and the active metabolite clearance decreased by ~ 60% in patients with CrCl <60 mL/minute/1.73 m2	Risperidone and its active metabolite total concentration higher in older people, with an increased plasma concentration of ~ 35% in each decade of life with advancing age
	Olanzapine	Antagonism of serotonin 5-HT2A and 5-HT2C, dopamine D1–4, histamine H1, and α1-adrenergic receptors		CYP1A2, CYP2D6	57% (7% as unchanged drug)	Plasma concentration of olanzapine increases 10% for each decade of life with advancing age
	Clozapine	Antagonism of dopamine D2 and serotonin 5-HT2A receptors		CYP1A2 (primary), CYP2C19, CYP3A4 and CYP2D6. Metabolites with limited (desmethyl metabolite) or no activity	~ 50% mostly as metabolites	Decreased clearance of clozapine and its active metabolite norclozapine
Antidepressants
SSRI	Citalopram	Inhibits serotonin reuptake in the presynaptic neurons	Lower numbers in the aged brain of serotonin 5HT1A and 5HT2A receptors. No age-related change in the serotonin reuptake pump	CYP3A4, CYP2C19	10% as unchanged	30% longer elimination half-life
Tricyclic antidepressants	Amitriptyline	Increase synaptic concentration of serotonin and/or norepinephrine by inhibition of their presynaptic reuptake (in addition other receptors might be involved)		Metabolism to nortriptyline (active), probably involving CYP2C19, CYP2D6, CYP3A4, CYP1A2	As metabolites	May have increased plasma concentrations
	Imipramine	Increase synaptic concentration of serotonin and/or norepinephrine by inhibition of their presynaptic reuptake (in addition other receptors might be involved)		CYP2D6 to desipramine (active) and other metabolites	As metabolites	Decreased clearance by 10–40%
Tetracyclic antidepressant	Mirtazapine	Presynaptic α2-adrenergic antagonist resulting in increased release of norepinephrine and serotonin		CYP1A2, CYP2D6, CYP3A4, demethylation, and hydroxylation	75% as metabolites	50% prolongation of elimination half-life and higher exposure
Sedative hypnotics or anxiolytics
Benzodiazepine	Diazepam	Enhancement of the inhibitory effect of GABA on neuronal excitability	Increased sedative effect at a given drug exposure	CYP3A4, CYP2C19 to the active metabolite N-desmethyldiazepam and hydroxylation by CYP3A4 to the active metabolite temazepam. N-desmethyldiazepam and temazepam further metabolized to oxazepam. Temazepam and oxazepam are eliminated by glucuronidation	Predominantly as glucuronide conjugates	30% decrease in clearance
	Lorazepam	Enhancement of the inhibitory effect of GABA on neuronal excitability		Glucuronidation (a phase II pathway)	88% as inactive metabolites	Clearance is not altered
	Midazolam	Enhancement of the inhibitory effect of GABA on neuronal excitability		CYP3A4; 60–70% to active metabolite 1-hydroxy-midazolam (or alpha-hydroxymidazolam)	90%, primarily as glucuronide conjugates of the hydroxylated metabolites	Decreased clearance, with prolonged elimination half-life and increased exposure
Nonbenzodiazepine benzodiazepine receptor agonist	Zolpidem	Enhances the activity of the inhibitory neurotransmitter, GABA, via selective agonism at the benzodiazepine-1 receptor		CYP3A4 (~ 60%), CYP2C9 (~ 22%), CYP1A2 (~ 14%), CYP2D6 (~ 3%), and CYP2C19 (~ 3%) to inactive metabolites	48–67%, primarily as metabolites	50% decrease in clearance
Pain management
Opioids	Fentanyl	Agonist, primarily at the μ-opioid receptor	Higher sensitivity to μ-opioid receptor agonism	CYP3A4 and hydroxylation to inactive metabolites	75%, primarily as metabolites	Clearance changes little with age
	Morphine	Agonist, primarily at the μ-opioid receptor		Conjugation with glucuronic acid primarily to morphine-6-glucuronide (active analgesic), morphine-3-glucuronide (inactive as analgesic)	Primarily as morphine-3-glucuronide	Clearance changes little with age
	Oxycodone	Agonist, primarily at the μ-opioid receptor		CYP3A4 to noroxycodone (has weak analgesic activity), noroxymorphone, α- noroxycodol and β-noroxycodol. CYP2D6- mediated metabolism produces oxymorphone (has analgesic activity)	~10% as parent; ~65% as metabolites [noroxycodone (23%, active), oxymorphone (10%, active), noroxymorphone (14%, weakly active), reduced metabolites (≤18%)]	Markedly reduced clearance

CrCl creatinine clearance, CYP cytochrome P450, GABA gamma-aminobutyric acid, SSRI selective serotonin reuptake inhibitor

Most antidepressants are metabolized by CYP enzymes as well. Decreased clearance is observed in older individuals, and thus drug exposure increases. Citalopram has a 30% longer half-life in older patients [49], while mirtazapine was shown to have a 50% prolongation of the elimination half-life and higher exposure [50]. Conversely, tricyclic antidepressants are often metabolized by CYP enzymes to active metabolites, mostly by CYP3A, CYP2D6, and CYP1A2, and a lower active metabolite concentration might be anticipated. With imipramine, a tertiary amine and its secondary amine metabolite, desipramine, clearance was demonstrated to be impaired by 10–40% in older patients [51].

The benzodiazepines diazepam, clonazepam, and clorazepate are transformed by phase I enzymes as well. Diazepam clearance is decreased by 30% in older people, whereas clorazepate undergoes acid hydrolysis and is decarboxylated to an active metabolite nordiazepam. Lorazepam, rather, undergoes glucuronidation by a phase II pathway, and its clearance is not altered with advancing age. Additional benzodiazepines used as sedative hypnotics, anxiolytics (e.g., chlordiazepoxide), and for conscious sedation (e.g., midazolam) are biotransformed by phase I enzymes, and have thus decreased clearance in older individuals, causing a prolonged elimination half-life and increased exposure [20, 52, 53]. Zolpidem, which is a non-benzodiazepine sedative hypnotic that (similarly to benzodiazepines) increases synaptic inhibition through gamma-aminobutyric acid (GABA)-A receptors, has an approximately 50% decrease in clearance in advanced age patients [54, 55].

As mentioned above, the clearance of fentanyl and alfentanyl, as well as morphine, changes little with age [56, 57]. However, oxycodone, metabolized via CYP3A4/5 and CYP2D6 into active metabolites, has markedly reduced clearance with advancing age [28].

Renal Aging

Many drugs undergo elimination via the kidneys. The size of kidneys, primarily the cortex, decreases with age by as much as one third, and renal glomeruli decrease in number and size. Shunting of blood from afferent to efferent arterioles causes a further decrease in blood flow to the glomeruli. An age-related decrease in glomerular filtration rate is the result, in the range of 0.5–1.0 mL/min/year. An accompanying decrease in renal blood flow is greater than the decrease in glomerular filtration rate; in addition, angiotensin II-mediated vasoconstriction is maintained while endothelial-mediated vascular relaxation by prostaglandins is impaired, explaining the increase in filtration fraction with age [58]. Non-steroidal anti-inflammatory drugs, inhibiting further the prostaglandin production, have thus been implicated as a cause for acute kidney injury, especially in older adults.

Renal Drug Clearance Changes with Age

The renal clearance of medications, such as gabapentin, can be estimated by the glomerular filtration rate, including for drugs that are reabsorbed or secreted by the renal tubules. This estimate used to be determined by the following Cockroft–Gault equation for creatinine clearance [59] (multiplied by 0.85 for women):

$$\text{Creatinine Clearance}\left(\text{ml}/\text{min}\right)=\frac{\left(140--\text{age}\right)\left(\text{weight in kg}\ast \right)}{72\left(\text{serum creatinine in mg}/\text{dl}\right)}$$

*Note: ideal body weight should be used, as using actual body weight might cause an overestimation of renal function in malnourished/underweight patients

Many drugs have labeling information for a dosing adjustment based on creatinine clearance. Subsequently, the MDRD (Modification of Diet in Renal Disease) and CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) [60] equations were developed to more accurately estimate renal disease and not require information on weight [61]. The different formulae can provide varying estimates in older adults with the Cockroft–Gault equation usually providing lower estimates, and it is important to adjust dosing based on the renal estimation used during drug evaluations [62].

When drugs require metabolism before renal elimination, an increase in the metabolite concentration will be evident upon a decrease in glomerular filtration, which figures importantly when the metabolite has pharmacological activity. An example is the clearance of morphine-6-glucuronide, the active metabolite of morphine, which is reduced with aging via a reduction in renal clearance [63, 64].

Stader et al. conducted virtual clinical trials for different drugs, using physiologically based pharmacokinetics, to explore the pharmacokinetic parameters that determine drug exposure changes in the older population. Ten drugs were investigated including midazolam, metoprolol, lisinopril, amlodipine, rivaroxaban, repaglinide, atorvastatin, rosuvastatin, clarithromycin, and rifampicin. It was found that a physiological decrease in hepatic and renal blood flow and the decrease in glomerular filtration rate were responsible for drug exposure changes in older people. Exposure increased by 0.9% per year beginning at the age of 20 years. The volume of distribution of these drugs were not affected by age [65].

Changes in the Pharmacodynamics of CNS Medications with Age by Receptor Sites of Action

Neurotransmitter systems, important in drug action in the CNS, include the dopamine, serotonin, acetylcholine, noradrenaline, GABA, and opiate systems.

Dopamine

Dopamine receptors decrease in number with advancing age, more specifically, a decrease in D₁ and D₂ [66–69] is associated with impairments in motor functionality, as well as mental function and attention. A dopamine D₂ activity blockade is related to the action of antipsychotics although it is clear that antipsychotic act at additional receptors [70]. Risperidone, olanzapine, and haloperidol have similar efficacy in older patients compared to younger patients [71]. The role of antipsychotics for the treatment of agitated dementia is less clear and their use should probably be reserved for cases of significant risk or distress [72–76], as an increased risk of sudden death in older patients, likely due to cardiac arrhythmia, was associated with these drugs [77]. Importantly, when considering adverse effects such as parkinsonism and tardive dyskinesia due to a dopamine receptor blockade, clinicians should be aware of, and inform patients, that a higher frequency is observed in older patients compared with younger patients [78, 79].

Serotonin

Serotonin 5HT_1A and 5HT_2A receptors are found in lower numbers in the aged brain [80, 81]. In Alzheimer’s disease, there is even increase in this trend. However, no change in the serotonin reuptake pump has been observed. Serotonin reuptake inhibitors have been the prominent treatment for depression, related, at least partially, to serotonin receptor activity [82]. As same drug exposure is the therapeutic goal in the older individual, as in the young individual, decreased doses are required in older patients to achieve the desired exposure.

Acetylcholine

Memory and cognition were associated with brain cholinergic dysfunction [83–89], and Alzheimer’s disease has been associated with the deprivation of CNS cholinergic neurons and function [90, 91]. However, cholinesterase inhibitor treatments, such as donepezil, have limited clinical effectiveness [92, 93], which might be explained by a lack of acetylcholine (due to the paucity of cholinergic neurons), or that the central cholinergic drought is not the main pathophysiology process accounting for the disease.

Adrenergic

There is increased adrenergic activation in the CNS [94]. Although central α-adrenoreceptors are not changed with age, central β-adrenoreceptors are reduced. Changes in the norepinephrine presynaptic reuptake, where some antidepressants exert their effect, such as bupropion (a combined noradrenaline/dopamine reuptake blocker antidepressant), have not been well studied. For a few drugs, such as nortriptyline [95, 96], there was no difference in efficacy in older patients with depression. Thus, it appears that at least slightly lower doses should be administered in older patients to achieve the same plasma exposure and the same effect.

GABA

The GABA neurotransmitter system in the brain has not been well described. Barbiturates, benzodiazepines, and antiepileptic drugs such as gabapentin increase GABA-A receptor action to inhibit the chloride ion channel. The efficacy and adverse effect profile of antiepileptic drugs are similar in older patients as in young patients [97, 98]. In contrast, the sedative effect of benzodiazepines is larger in older people at a similar drug exposure [99]. The reduced clearance of benzodiazepines, causing higher exposure at a given dose, in addition to a greater sensitivity, may account for severe adverse events such as hip fractures associated with benzodiazepine sedative hypnotics, and with Z drugs, in older adults [100–104].

Opioids

Opiate receptor changes have not been well studied in the older population. Binding of pentazocine (a partial μ-receptor agonist and a κ-agonist) was shown to decrease in the frontal cortex with advancing age [105], but the relevance of these findings to understanding of the endogenous opioid system is not obvious. It was shown during anesthesia with the μ-opiate receptor agonists, fentanyl, alfentanyl, and remifentanyl, that older individuals are more sensitive to CNS depression [57, 106]. Older patients are also more sensitive to opioid adverse effects such as an increased risk of falls [102, 107, 108]. However, when studying respiratory depression, there was no difference in the sensitivity to morphine between young and old individuals [109].

Adverse Effects in Older Patients

Polypharmacy is associated with a higher chance for adverse drug reactions [110–113]. Most importantly, medications having anticholinergic and sedative effects cause higher adverse effects in older patients. Specifically, use of medications with anticholinergic properties is associated with cognitive function impairment; antidepressants and benzodiazepines increase the risk of falls; and the use of benzodiazepines increases the risk of hip fractures [10, 11].

Future Perspectives

Artificial intelligence might help in closing some of the gaps in knowledge. Hall 2nd et al. have used supervised machine learning to study drug concentrations in older patients [114]. A physiologically based pharmacokinetic modeling and simulation might be exploited to describe drug disposition in older individuals, facilitating “virtual clinical trials” in combination with clinically observed data [65, 115] for the improvement of geriatric pharmacotherapy.

Conclusions

There are many knowledge gaps on changes in the pharmacokinetics and pharmacodynamics of medications in the older population. However, it is clear that the disposition of medications and the response to medications affecting the CNS in older individuals are often quantitatively different when compared with younger people. Polypharmacy should also be taken into account, and for every candidate drug for an older patient, treatment risks should be carefully considered along with the benefits. Further data from clinical studies in older adults including the old-old population (aged 85 years and over) is essential.

Declarations

Funding

Open access funding provided by Technion - Israel Institute of Technology.

Conflict of Interest

Naomi Gronich has no conflicts of interest that are directly relevant to the content of this article.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Availability of Data and Material

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Code Availability

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Author Contributions

NG had the idea, performed the literature search and data analysis, and wrote the manuscript.