28.1 Pharmacokinetic Principles, Dose Adjustment & Drug Interactions in Critical Illness
Key Takeaways
Loading dose equals the target concentration times the volume of distribution, so it is not reduced for organ failure; maintenance dose is governed by clearance and is adjusted.
Rifampin, phenytoin, carbamazepine, phenobarbital, and St John's wort induce CYP3A4 and lower levels of calcineurin inhibitors, direct oral anticoagulants, and many antimicrobials.
Azoles, macrolides (except azithromycin), protease inhibitors, amiodarone, diltiazem, and verapamil inhibit CYP3A4 and raise concentrations of tacrolimus, statins, and many other drugs.
Continuous kidney replacement therapy removes small, water-soluble, minimally protein-bound drugs, so antimicrobial doses usually need to be increased relative to oliguric kidney failure.
ECMO circuits sequester lipophilic, highly protein-bound drugs such as fentanyl, propofol, midazolam, and voriconazole, raising dose requirements.
The Two Equations That Matter
- The loading dose depends on the volume of distribution, not clearance. Organ failure does not reduce it; capillary leak and large fluid volumes often increase it for hydrophilic drugs.
- The maintenance dose depends on clearance and is what gets reduced in kidney or liver failure.
- Time to steady state is about 4 to 5 half-lives. Without a loading dose, a drug with a long half-life (amiodarone, digoxin, vancomycin in kidney failure) takes days to reach target.
Distribution and Protein Binding
- Hydrophilic drugs (beta-lactams, aminoglycosides, vancomycin, neuromuscular blockers) distribute in extracellular water: the volume of distribution rises with edema, ascites, and resuscitation, lowering peak concentrations.
- Lipophilic drugs (fentanyl, propofol, midazolam, amiodarone) have large volumes of distribution and accumulate in tissue, so context-sensitive half-time lengthens with prolonged infusion: a patient sedated for a week does not wake up with the kinetics of a single dose.
- Hypoalbuminemia increases the free fraction of highly bound drugs (phenytoin, ceftriaxone, warfarin, diazepam). For phenytoin, correct the total level or measure the free level: a total of 10 micrograms/mL with an albumin of 2 g/dL can be a therapeutic or toxic free level.
- Uremia displaces drugs from albumin and alters binding further.
Clearance in Organ Failure
| Situation | Effect |
|---|---|
| Acute kidney injury | Reduced clearance of renally eliminated drugs and active metabolites: morphine-6-glucuronide (prolonged sedation), meperidine (normeperidine seizures), midazolam metabolites, enoxaparin, baclofen, gabapentin, lithium, digoxin |
| Augmented renal clearance | Creatinine clearance above about 130 mL/min in younger, hyperdynamic patients: subtherapeutic beta-lactams and levetiracetam |
| Liver failure | Reduced phase I oxidation more than glucuronidation; reduced first-pass metabolism; altered binding. Use lorazepam rather than midazolam, reduce opioid dosing, avoid hepatotoxins |
| Heart failure and shock | Reduced hepatic and renal blood flow lowers clearance of high-extraction drugs (lidocaine, propranolol) |
| Obesity | Lipophilic drugs need total body weight for loading; dose aminoglycosides on adjusted body weight, give lung-protective tidal volumes on predicted body weight, and use weight-capped enoxaparin with anti-Xa monitoring |
| CRRT | Removes small (below about 1,500 Da), water-soluble, minimally protein-bound drugs with a low volume of distribution. Effluent flow approximates clearance, so doses often exceed those used in oliguric kidney failure |
| Intermittent hemodialysis | Dose after dialysis for dialyzable drugs; consider supplemental doses |
| ECMO | Sequestration of lipophilic and highly bound drugs (fentanyl, propofol, midazolam, voriconazole, dexmedetomidine) in the circuit, plus an expanded volume from priming: higher doses are often needed |
| Hypothermia | Slows enzymatic metabolism: sedatives and neuromuscular blockers accumulate |
Interaction Mechanisms Worth Memorizing
CYP3A4
- Inducers (lower concentrations over days): rifampin, rifabutin, phenytoin, carbamazepine, phenobarbital, primidone, St John's wort, efavirenz. Consequences include transplant rejection from low tacrolimus, breakthrough thrombosis on direct oral anticoagulants, and seizure recurrence.
- Inhibitors (raise concentrations within hours to days): azole antifungals (voriconazole, posaconazole, itraconazole, fluconazole at higher doses), macrolides (clarithromycin and erythromycin; azithromycin is largely spared), protease inhibitors and ritonavir-boosted regimens, diltiazem and verapamil, amiodarone, grapefruit juice. Consequences include calcineurin inhibitor toxicity, statin-induced rhabdomyolysis, and prolonged sedation.
Other Key Pathways
- CYP2C9: warfarin's S-enantiomer; inhibited by metronidazole, fluconazole, and trimethoprim-sulfamethoxazole (major INR rises), induced by rifampin.
- CYP2C19: clopidogrel requires activation, so omeprazole and esomeprazole reduce its effect; use pantoprazole instead.
- CYP1A2: induced by smoking, so stopping smoking in the ICU raises clozapine and theophylline levels.
- P-glycoprotein: amiodarone, verapamil, clarithromycin, and ketoconazole raise digoxin and direct oral anticoagulant levels; rifampin lowers them.
- Pharmacodynamic interactions: QT prolongation (haloperidol, fluoroquinolones, macrolides, ondansetron, methadone, amiodarone), serotonin excess (linezolid, fentanyl, SSRIs, methylene blue), bleeding (anticoagulant plus antiplatelet plus NSAID), nephrotoxicity (vancomycin plus piperacillin-tazobactam, NSAIDs plus ACE inhibitors plus diuretics).
- Specific traps:
- Allopurinol or febuxostat with azathioprine causes profound marrow suppression.
- Carbapenems with valproate drop valproate levels sharply.
- Linezolid with serotonergic agents risks serotonin syndrome.
- Methylene blue with SSRIs likewise.
- Succinylcholine with hyperkalemia or denervation causes cardiac arrest.
- Nondepolarizing blockers with aminoglycosides, magnesium, or clindamycin prolong paralysis.
- Phenytoin with enteral feeds reduces absorption: hold feeds around doses.
Therapeutic Drug Monitoring
| Drug | Target and caution |
|---|---|
| Vancomycin | AUC/MIC 400 to 600 by Bayesian or two-level estimation; trough-only targets of 15 to 20 mg/L cause excess nephrotoxicity |
| Aminoglycosides | High peak for efficacy, low trough for safety; extended-interval dosing with level-guided intervals |
| Phenytoin | Total 10 to 20 micrograms/mL, free 1 to 2 micrograms/mL; nonlinear (zero-order) kinetics means small dose changes can cause large level changes |
| Valproate | Monitor levels and ammonia; highly protein bound |
| Digoxin | 0.5 to 0.9 ng/mL in heart failure; toxicity is potentiated by hypokalemia, hypomagnesemia, and hypercalcemia |
| Lithium | Narrow index; toxicity worsened by volume depletion, NSAIDs, thiazides, and ACE inhibitors |
| Tacrolimus and cyclosporine | Trough-based; recheck after any interacting drug change |
| Voriconazole | Trough 1 to 5.5 micrograms/mL; neurotoxicity and hepatotoxicity above range, failure below it |
| Posaconazole, beta-lactams (where available), and amikacin | Increasingly monitored in critical illness |
Practical Rules at the Bedside
- Give a full loading dose of antimicrobials, antiepileptics, and amiodarone regardless of organ failure, then adjust maintenance dosing.
- Reconcile the medication list daily and ask what each drug interacts with, especially after starting an azole, rifamycin, macrolide, or anticonvulsant.
- Recalculate for changing kidney function: a patient recovering from acute kidney injury clears drugs faster, and one developing injury accumulates them.
- Use actual rather than estimated function when it matters: measured creatinine clearance in augmented clearance or obesity, since creatinine-based estimates mislead when muscle mass is low.
- Beware the enteral route in shock: absorption is unreliable, and crushed extended-release formulations deliver a bolus dose.
- Document and review drug allergies and intolerances so that a mislabeled allergy does not drive worse therapy.
A 72-year-old woman with septic shock, anuric acute kidney injury, and a weight of 70 kg needs vancomycin. Which dosing approach is most appropriate?
Give 500 mg now and repeat in 12 hours, since she is anuric
Give a full loading dose of about 25 to 30 mg/kg now, then dose by levels
Withhold vancomycin until kidney replacement therapy is started
Give 15 mg/kg every 8 hours and check a trough on day 3
A 58-year-old lung transplant recipient on tacrolimus is started on rifampin for suspected tuberculosis. Which consequence should be anticipated, and what is the appropriate response?
Tacrolimus levels will rise sharply, so the dose should be halved immediately
Tacrolimus levels will fall because of CYP3A4 induction, risking rejection, so levels must be followed closely with dose escalation
Rifampin has no clinically relevant interaction with calcineurin inhibitors
Rifampin will displace tacrolimus from albumin, raising the free fraction and causing nephrotoxicity
A 34-year-old man with status epilepticus on venoarterial ECMO requires sedation with fentanyl and midazolam, and voriconazole is added for suspected invasive aspergillosis. Which pharmacokinetic consideration is most important?
ECMO circuits sequester lipophilic and highly protein-bound drugs, so higher doses of fentanyl, midazolam, and voriconazole are often needed
ECMO increases the clearance of all drugs to a similar degree, so every maintenance dose should be halved and then titrated upward
ECMO has no measurable effect on drug disposition in adults, so standard dosing and monitoring intervals apply unchanged
ECMO removes only small water-soluble drugs, so sedative and antifungal dosing should be reduced to avoid accumulation
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