Prescribing in the Older Adult: Doing More by Doing Less

Must know

• Pharmacokinetic Alterations: Fat and Water DistributionTotal body water decreases by 10% to 15% in older adults, while total body fat increases by 20% to 40%.

  • Total body water decreases by 10% to 15% in older adults, while total body fat increases by 20% to 40%.
  • Hydrophilic (water-soluble) psychotropics like lithium distribute into a smaller volume of distribution, producing higher peak serum concentrations and elevated toxicity risk at standard adult doses.
  • Lipophilic (fat-soluble) psychotropics like diazepam, chlordiazepoxide, and long-acting antipsychotics distribute into an expanded fat mass, significantly increasing their volume of distribution.
  • An increased volume of distribution for lipophilic drugs prolongs their elimination half-life, leading to drug accumulation, daytime somnolence, cognitive slowing, ataxia, and falls.
  • Serum albumin levels often decrease in frail older adults, reducing protein binding for highly bound drugs like valproate and increasing the active free drug concentration.
  • Always follow the clinical rule to start low and go slow, initiating lipophilic and hydrophilic psychotropics at 50% of the standard young adult starting dose while titrating to therapeutic targets.
• Safety AlertLithium toxicity occurs at lower serum concentrations in older adults due to reduced total body water and decreased renal clearance. Always obtain baseline renal function (eGFR and serum creatinine) before starting lithium, start at low doses such as 150 mg to 300 mg daily, and maintain target geriatric serum levels between 0.4 and 0.6 mEq/L rather than standard adult targets.

  • Lithium toxicity occurs at lower serum concentrations in older adults due to reduced total body water and decreased renal clearance. Always obtain baseline renal function (eGFR and serum creatinine) before starting lithium, start at low doses such as 150 mg to 300 mg daily, and maintain target geriatric serum levels between 0.4 and 0.6 mEq/L rather than standard adult targets.
• Renal Function: eGFR vs. Serum CreatinineSerum creatinine remains deceptively normal in older adults due to age-related loss of muscle mass, masking a renal function decline of up to 30 percent or more.

  • Serum creatinine remains deceptively normal in older adults due to age-related loss of muscle mass, masking a renal function decline of up to 30 percent or more.
  • eGFR (estimated glomerular filtration rate) is the gold standard metric for evaluating renal clearance and driving psychotropic dosing decisions in geriatric patients.
  • eGFR greater than 60 mL/min indicates adequate renal clearance where most psychotropics require no dosage adjustment.
  • eGFR less than 60 mL/min defines moderate renal impairment that requires dose reduction or drug switching for renally cleared psychotropics, including lithium, gabapentin, and paliperidone.
  • eGFR less than 30 mL/min represents severe renal impairment requiring significant dose decreases or complete avoidance of renally excreted psychotropics.
  • Lithium toxicity risk increases dramatically in older adults when renal clearance drops, requiring frequent lab monitoring of eGFR and serum drug levels.
• Dosing Thresholds by eGFR LeveleGFR greater than 60 mL/min: Standard psychotropic dosing is generally safe.

  • eGFR greater than 60 mL/min: Standard psychotropic dosing is generally safe.
  • eGFR 30 to 50 mL/min: Moderate clearance reduction. Reduce starting doses of renally cleared medications by 25 to 50 percent or select hepatically metabolized alternatives.
  • eGFR less than 30 mL/min: Severe clearance reduction. Avoid lithium if possible, or use extreme caution with reduced doses and frequent blood level monitoring.
• Serum CreatinineFast mental label: Deceptive muscle breakdown marker.

  • Fast mental label: Deceptive muscle breakdown marker.
  • Geriatric limitation: Normal values mask significant renal impairment due to low muscle mass.
  • Boards are testing: Why you should never rely on serum creatinine alone in older adults.
  • Fast mental label: True renal clearance metric.
  • Geriatric value: Accurately reflects functional nephron clearance regardless of muscle mass.
  • Boards are testing: The primary lab value used to adjust renally excreted psychotropics.
• Liver Metabolism: CYP450 Enzyme ChangesHepatic blood flow decreases by 20% to 50% in older adults, while overall liver mass decreases by 20% to 40%.

  • Hepatic blood flow decreases by 20% to 50% in older adults, while overall liver mass decreases by 20% to 40%.
  • Phase I metabolism involving CYP450 oxidation, reduction, and hydroxylation decreases significantly with age, prolonging drug elimination half-lives and raising toxicity risks.
  • Phase II metabolism involving glucuronidation, acetylation, and sulfation remains largely preserved in normal aging.
  • LOT benzodiazepines (lorazepam, oxazepam, temazepam) undergo Phase II glucuronidation directly and bypass Phase I CYP450 oxidation, making them preferred when benzodiazepine therapy is unavoidable.
  • CYP2D6 inhibition by fluoxetine and paroxetine blocks the breakdown of co-administered substrates like metoprolol, causing severe bradycardia, hypotension, and falls.
  • First-pass hepatic extraction is reduced in older adults, which increases the oral bioavailability and peak plasma concentrations of highly extracted psychotropics.
• Aging Liver PhysiologyHepatic mass: Decreases by 20% to 40% in older adults, reducing overall metabolic capacity.

  • Hepatic mass: Decreases by 20% to 40% in older adults, reducing overall metabolic capacity.
  • Hepatic blood flow: Decreases by 20% to 50%, reducing first-pass clearance and increasing systemic bioavailability.
  • Serum liver enzymes: AST, ALT, and alkaline phosphatase remain in normal ranges in healthy aging; elevations signal primary liver pathology rather than normal age-related changes.
• Phase I Metabolism (Oxidation)Mechanism: Utilizes CYP450 isoenzymes for oxidation, reduction, hydroxylation, and demethylation.

  • Mechanism: Utilizes CYP450 isoenzymes for oxidation, reduction, hydroxylation, and demethylation.
  • Aging effect: Significantly reduced due to decreases in liver mass, perfusion, and enzyme activity.
  • Clinical impact: Slower drug clearance, prolonged elimination half-life, and drug accumulation.
  • Affected drugs: diazepam, alprazolam, chlordiazepoxide, flurazepam, tertiary TCAs, and fluoxetine.
• Phase II Metabolism (Conjugation)Mechanism: Converts drugs into water-soluble metabolites via glucuronidation, acetylation, and sulfation.

  • Mechanism: Converts drugs into water-soluble metabolites via glucuronidation, acetylation, and sulfation.
  • Aging effect: Preserved and minimally altered by normal aging.
  • Clinical impact: Predictable clearance without significant accumulation.
  • Preferred drugs: lorazepam, oxazepam, and temazepam (the LOT benzodiazepines).
• SignpostsFor depression in older adults, choose SSRIs with minimal CYP450 inhibition such as sertraline or escitalopram (or citalopram with a maximum dose of 20 mg daily to avoid QTc prolongation). Avoid fluoxetine due to its long half-life and paroxetine due to anticholinergic effects and CYP2D6 inhibition.

  • fluoxetine and paroxetine are potent CYP2D6 inhibitors. Co-prescribing them with CYP2D6 substrates like metoprolol, carvedilol, or risperidone blocks substrate clearance, causing elevated drug levels, severe bradycardia, profound hypotension, and falls.
  • Long-acting benzodiazepines cleared by Phase I oxidation (diazepam, chlordiazepoxide) accumulate in geriatric adipose tissue, causing prolonged sedation, ataxia, confusion, and hip fractures.
  • Selecting diazepam or alprazolam for an elderly patient who requires short-term anxiolysis. Boards expect you to select lorazepam, oxazepam, or temazepam because they bypass Phase I oxidation.
  • Assuming normal AST and ALT levels indicate youthful hepatic drug clearance in an older adult. Liver enzymes measure acute cellular injury, not functional metabolic clearance rate.
  • For depression in older adults, choose SSRIs with minimal CYP450 inhibition such as sertraline or escitalopram (or citalopram with a maximum dose of 20 mg daily to avoid QTc prolongation). Avoid fluoxetine due to its long half-life and paroxetine due to anticholinergic effects and CYP2D6 inhibition.

  Board trap. Selecting diazepam or alprazolam for an elderly patient who requires short-term anxiolysis. Boards expect you to select lorazepam, oxazepam, or temazepam because they bypass Phase I oxidation.

  Safety. fluoxetine and paroxetine are potent CYP2D6 inhibitors. Co-prescribing them with CYP2D6 substrates like metoprolol, carvedilol, or risperidone blocks substrate clearance, causing elevated drug levels, severe bradycardia, profound hypotension, and falls.

• Phase I Oxidation vs Phase II ConjugationThink: Phase I decreases with age; Phase II is preserved.

  • Think: Phase I decreases with age; Phase II is preserved.
  • Priority: Choose Phase II cleared medications to prevent drug accumulation in older adults.
  • Boards are testing: Recognition that LOT benzodiazepines (lorazepam, oxazepam, temazepam) bypass age-related CYP450 oxidation decline.
  • Mini example: An 82-year-old patient needs short-term anxiolysis. Select lorazepam over diazepam because lorazepam undergoes Phase II glucuronidation.
  • Think: High CYP450 inhibition causes severe drug interactions; low CYP450 inhibition is safe in polypharmacy.
  • Priority: Avoid fluoxetine and paroxetine in older adults taking cardiac or psychotropic co-medications.
• Quick Answerlorazepam is the best choice because it undergoes Phase II glucuronidation, which remains intact in older adults.

  • lorazepam is the best choice because it undergoes Phase II glucuronidation, which remains intact in older adults.
• Key Cluelorazepam, along with oxazepam and temazepam, is cleared exclusively through Phase II hepatic glucuronidation. Phase II conjugation pathways are preserved in aging, preventing drug accumulation, excessive sedation, and ataxia.

  • lorazepam, along with oxazepam and temazepam, is cleared exclusively through Phase II hepatic glucuronidation. Phase II conjugation pathways are preserved in aging, preventing drug accumulation, excessive sedation, and ataxia.
  • A. diazepam undergoes Phase I CYP2C19 and CYP3A4 oxidation, generating active long-acting metabolites that accumulate and cause falls.
  • C. alprazolam requires Phase I CYP3A4 oxidation, which is impaired in older adults, leading to prolonged elimination half-life and toxicity.
  • D. chlordiazepoxide is a long-acting benzodiazepine cleared by Phase I oxidation that accumulates in geriatric fat tissue and carries a high risk of delirium.
• Active Recall Checkpoints1. What percentage decrease in hepatic blood flow and liver mass occurs in normal aging?

  • 1. What percentage decrease in hepatic blood flow and liver mass occurs in normal aging?
  • 2. Which liver metabolic pathway decreases significantly with age: Phase I oxidation or Phase II conjugation?
  • 3. What three benzodiazepines make up the LOT group that bypasses Phase I oxidation?
  • 4. Why does reduced first-pass hepatic extraction increase systemic drug exposure in older adults?
  • 5. Which two SSRIs are potent CYP2D6 inhibitors that should generally be avoided in geriatric polypharmacy?
• Practice Question: Best Lab for Renal AssessmenteGFR is the single most accurate lab metric for evaluating renal clearance in older adults.

  • eGFR is the single most accurate lab metric for evaluating renal clearance in older adults.
  • Serum creatinine alone is deceptive in elderly patients because age-related loss of muscle mass reduces creatinine production, masking up to a 30% reduction in renal filtration.
  • An eGFR greater than 60 mL/min indicates adequate renal clearance for standard psychotropic dosing.
  • An eGFR below 60 mL/min requires dosage reduction, extended dosing intervals, or selecting non-renally cleared alternatives.
  • Lithium is eliminated almost entirely unchanged by the kidneys, making baseline and routine eGFR monitoring essential.
  • Other renally cleared psychotropics requiring renal dose adjustments in aging include gabapentin, pregabalin, topiramate, and paliperidone.
• Serum Creatinine versus eGFRSerum creatinine: Serum creatinine is a breakdown product of skeletal muscle. Because older adults experience sarcopenia and decreased muscle mass, baseline creatinine production is reduced. Consequently, serum creatinine can remain within the normal laboratory reference range even when kidney function has dropped significantly.

  • Serum creatinine: Serum creatinine is a breakdown product of skeletal muscle. Because older adults experience sarcopenia and decreased muscle mass, baseline creatinine production is reduced. Consequently, serum creatinine can remain within the normal laboratory reference range even when kidney function has dropped significantly.
  • eGFR: Estimated glomerular filtration rate incorporates age, sex, and serum creatinine to estimate actual renal clearance. It provides the true measure of functional nephron capacity.