13.3 Pharmacokinetics, Pharmacodynamics & Pharmacogenomics Across the Adult Lifespan
Key Takeaways
- Aging increases body fat and decreases total body water, so lipophilic drugs such as diazepam gain a larger volume of distribution and a longer half-life while hydrophilic drugs such as digoxin and lithium reach higher peak concentrations at the same dose.
- Phase I hepatic oxidation by cytochrome P450 declines with age while phase II conjugation is relatively preserved, which is why lorazepam, oxazepam and temazepam are the preferred benzodiazepines when one is unavoidable.
- It takes approximately 4 to 5 half-lives to reach steady state after starting or changing a dose and the same 4 to 5 half-lives to eliminate a drug after stopping it.
- Cockcroft-Gault estimated creatinine clearance, not eGFR, remains the equation on which most drug package inserts base renal dose adjustments, and a normal serum creatinine in a sarcopenic older adult conceals substantial renal impairment.
- CYP2C19 poor metabolizers activate clopidogrel poorly and should receive prasugrel or ticagrelor instead, and HLA-B*57:01 screening is mandatory before abacavir.
Pharmacokinetics, Pharmacodynamics & Pharmacogenomics Across the Adult Lifespan
Plan of Care carries 60 percent of the scored items, and its Pharmacology subsection contains five sub-topics, three of which are pure pharmacologic science: the effects of development and aging on pharmacology, pharmacogenetics, and pharmacokinetics and pharmacodynamics. Those three concepts explain why the same milligram dose behaves differently in a 24-year-old, a 74-year-old and a frail 94-year-old.
The one-line distinction to hold onto: pharmacokinetics is what the body does to the drug; pharmacodynamics is what the drug does to the body.
1. Pharmacokinetics: ADME and How Aging Alters Each Step
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| AGE-RELATED PHARMACOKINETIC CHANGES AND CONSEQUENCES |
| |
| ABSORPTION |
| - Decreased gastric acid, delayed emptying, reduced splanchnic blood flow and mucosal surface. |
| - NET EFFECT: the RATE of absorption slows, but the EXTENT is largely unchanged. This is the |
| LEAST clinically important of the four steps. |
| - EXCEPTION: reduced first-pass metabolism RAISES bioavailability of high-extraction drugs |
| (propranolol, labetalol, morphine, nitrates, verapamil) -> exaggerated first-dose effect. |
| |
| DISTRIBUTION |
| - Body FAT rises (~18 -> 36% in men); total body WATER falls (~10-15%); lean mass falls. |
| - LIPOPHILIC drugs (diazepam, amiodarone, most antipsychotics): LARGER volume of distribution |
| -> PROLONGED half-life -> accumulation with repeated dosing. |
| - HYDROPHILIC drugs (digoxin, lithium, aminoglycosides, ethanol): SMALLER volume of |
| distribution -> HIGHER peak concentration from the same dose. |
| - Serum ALBUMIN falls -> higher FREE fraction of highly protein-bound drugs (warfarin, |
| phenytoin, naproxen, valproate). A "normal" total phenytoin level can hide free-drug toxicity.|
| |
| METABOLISM |
| - Liver mass falls ~20-40% and hepatic blood flow ~40%. |
| - PHASE I (oxidation, reduction, hydrolysis via cytochrome P450) DECLINES with age. |
| - PHASE II (glucuronidation, sulfation, acetylation - conjugation) is RELATIVELY PRESERVED. |
| - CLINICAL RULE: when a benzodiazepine is unavoidable, use a phase II agent - |
| Lorazepam, Oxazepam, Temazepam ("LOT"), which have no active metabolites. |
| |
| EXCRETION |
| - GFR declines roughly 8 mL/min per decade after age 40 in many adults. |
| - Sarcopenia lowers creatinine GENERATION, so serum creatinine stays "normal" while clearance |
| is markedly reduced. ALWAYS estimate clearance; never trust a bare creatinine. |
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Which equation for which purpose? Use CKD-EPI 2021 eGFR (the race-free equation) to stage chronic kidney disease. Use Cockcroft-Gault estimated creatinine clearance for most drug dosing, because the pivotal trials and the resulting FDA package inserts for direct oral anticoagulants, many antimicrobials and other renally cleared drugs used that equation. Reported eGFR is also normalized to 1.73 m² of body surface area, which overestimates clearance in a small, frail patient unless it is de-indexed.
Half-life and steady state. After starting a drug or changing a dose, plasma concentrations reach steady state after approximately 4 to 5 half-lives, and after stopping, roughly the same 4 to 5 half-lives are required for elimination. This governs practical decisions everywhere: why a levothyroxine TSH is rechecked at 6 to 8 weeks, why amiodarone with a half-life measured in weeks keeps interacting long after it is stopped, and why a loading dose is used when a therapeutic concentration is needed faster than 4 to 5 half-lives allow.
Therapeutic index. Narrow-therapeutic-index drugs have little separation between effective and toxic concentrations and demand monitoring, cautious titration and heightened interaction vigilance: warfarin, digoxin, lithium, phenytoin, levothyroxine, theophylline, carbamazepine, aminoglycosides, tacrolimus.
2. Pharmacodynamics: Changed Sensitivity at the Receptor
Pharmacodynamic change is independent of concentration. The same serum level produces a different effect in an older adult.
| Increased sensitivity with age | Decreased sensitivity with age |
|---|---|
| Benzodiazepines - more sedation, confusion, ataxia, falls | Beta-adrenergic responsiveness - both beta-agonist and beta-blocker effects on heart rate are blunted |
| Opioids - greater analgesia and greater respiratory depression | |
| Anticholinergics - delirium, urinary retention, constipation, dry eyes and mouth | |
| Warfarin - greater anticoagulant effect per milligram | |
| Antipsychotics - extrapyramidal effects and orthostasis |
Add impaired homeostatic reserve: baroreceptor reflexes blunt (orthostatic hypotension), thermoregulation weakens, thirst perception falls, and postural stability declines. This is why the geriatric prescribing maxim is "start low, go slow - but go", and why undertreatment of pain, depression and osteoporosis is as much a prescribing error as overtreatment.
Anticholinergic burden is cumulative: an older adult taking oxybutynin, diphenhydramine and paroxetine simultaneously carries a burden that no single agent predicts. Use an anticholinergic burden scale and deprescribe.
3. Drug Interactions Worth Memorizing
- Strong CYP3A4 inhibitors (clarithromycin, ketoconazole and other azoles, ritonavir, grapefruit juice, diltiazem, verapamil) raise levels of statins - especially simvastatin and lovastatin - as well as many DOACs, tacrolimus and some benzodiazepines.
- Strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin, phenobarbital, St. John's wort) lower levels of DOACs, oral contraceptives, statins and many others - a classic cause of unexplained treatment failure.
- CYP2D6 inhibitors (paroxetine, fluoxetine, bupropion, quinidine) block conversion of codeine and tramadol to their active metabolites (removing analgesia) and reduce activation of tamoxifen (a reason to choose venlafaxine for hot flashes in a patient on tamoxifen).
- Serotonergic combinations (SSRI or SNRI plus tramadol, linezolid, triptans, or MAO inhibitors) risk serotonin syndrome.
- NSAID triple whammy: an NSAID plus an ACE inhibitor or ARB plus a diuretic precipitates acute kidney injury.
- QT prolongation stacks: macrolides, fluoroquinolones, ondansetron, citalopram, methadone, many antipsychotics.
4. Pharmacogenomics: The Gene-Drug Pairs With Actionable Guidance
Pharmacogenomics explains variability that dose adjustment alone cannot. The Clinical Pharmacogenetics Implementation Consortium (CPIC) publishes the prescribing guidance, and the FDA maintains a table of pharmacogenomic associations in labeling.
Metabolizer phenotypes: ultrarapid, normal (extensive), intermediate and poor. The direction of the clinical consequence depends on whether the drug is a prodrug (needing activation) or an active drug (needing clearance).
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| HIGH-YIELD PHARMACOGENOMIC ASSOCIATIONS |
| |
| GENE / ALLELE DRUG CLINICAL CONSEQUENCE AND ACTION |
| =============== ================ =============================== |
| CYP2C19 (LOF) Clopidogrel PRODRUG. Poor metabolizers form less active metabolite |
| -> stent thrombosis. FDA BOXED WARNING. Use prasugrel |
| or ticagrelor instead. |
| --------------------------------------------------------------------------------------------- |
| CYP2D6 (UM) Codeine, tramadol PRODRUGS. Ultrarapid metabolizers convert too much to |
| morphine/O-desmethyltramadol -> respiratory depression. |
| POOR metabolizers get NO analgesia. Avoid both drugs. |
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| CYP2D6 Tamoxifen PRODRUG activated to endoxifen. Avoid strong CYP2D6 |
| inhibitors (paroxetine, fluoxetine, bupropion). |
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| CYP2C9 + VKORC1 Warfarin Variants predict lower dose requirement and higher |
| bleeding risk during initiation. |
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| HLA-B*57:01 Abacavir MANDATORY screening before use. Positive -> potentially |
| fatal hypersensitivity. NEVER prescribe if positive. |
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| HLA-B*58:01 Allopurinol Severe cutaneous adverse reactions (SJS/TEN/DRESS). |
| ACR conditionally recommends testing in patients of Han |
| Chinese, Thai, Korean (with CKD stage 3+) and African |
| American descent before starting. |
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| HLA-B*15:02 Carbamazepine SJS/TEN. Screen patients of Southeast Asian ancestry. |
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| TPMT / NUDT15 Azathioprine, Deficient activity -> severe, prolonged myelosuppression.|
| 6-mercaptopurine Test before starting; reduce dose or avoid. |
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| DPYD 5-FU, capecitabine Deficiency -> severe, sometimes fatal toxicity. |
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| SLCO1B1 Simvastatin Reduced hepatic uptake -> higher systemic exposure -> |
| myopathy risk. Prefer a different statin or lower dose. |
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| G6PD deficiency Rasburicase, Oxidant drugs -> acute hemolysis. Screen before |
| primaquine, rasburicase and antimalarials. |
| dapsone, nitrofurantoin |
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[!IMPORTANT] Two board-style traps. First, direction matters: for a prodrug, a poor metabolizer gets too little effect, whereas for an active drug cleared by the same enzyme, a poor metabolizer gets too much. Reason it out rather than memorizing "poor metabolizer equals toxicity." Second, ancestry-based testing recommendations are risk stratification, not stereotyping: the alleles are more prevalent in certain populations, but self-reported race is a crude proxy, and where testing is inexpensive and the reaction is catastrophic - as with HLA-B*57:01 and abacavir - screening is universal.
An 82-year-old woman weighing 46 kg is admitted for a hip fracture. Her serum creatinine is 0.9 mg/dL and her reported eGFR is 74 mL/min/1.73 m². The AGPCNP is preparing to start apixaban for newly detected atrial fibrillation. Which pharmacokinetic principle should guide the dosing decision?
A 61-year-old man of Korean descent with chronic kidney disease stage 3b is being started on clopidogrel after drug-eluting stent placement. Pharmacogenomic testing performed by the cardiology team reports a CYP2C19 poor metabolizer phenotype. What is the most appropriate action?
A 78-year-old man with insomnia and mild anxiety is being considered for short-term benzodiazepine therapy after non-pharmacologic measures failed. If a benzodiazepine is prescribed despite the risks, which agent and rationale are most appropriate?