28.1 Pharmacokinetic Principles, Dose Adjustment & Drug Interactions in Critical Illness

ABIM Critical Care Medicine Study Guide Exam

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1 Chapter 1: Exam Orientation: Format, Blueprint & Study Strategy

1.1 ABIM Critical Care Medicine Exam: Format, Blueprint & Study Strategy

2 Chapter 2: Acute Respiratory Failure & ARDS

2.1 ARDS Definition, Pathophysiology & Phenotypes 2.2 Lung-Protective Mechanical Ventilation 2.3 Refractory ARDS: Prone Positioning, Neuromuscular Blockade & VV-ECMO

3 Chapter 3: Obstructive Airways, Pulmonary Vascular & Pleural Emergencies

3.1 Severe Asthma & COPD Exacerbations in the ICU 3.2 Massive & Submassive Pulmonary Embolism 3.3 Pulmonary Hypertension & Right Ventricular Failure in the ICU 3.4 Massive Hemoptysis, Complex Pleural Effusions & Thoracic Drainage

4 Chapter 4: Airway, Parenchymal & Nonthrombotic Pulmonary Emergencies

4.1 Airway Management, Upper-Airway Obstruction & Artificial-Airway Complications 4.2 Diffuse Alveolar Hemorrhage, Interstitial Lung Disease, Pulmonary Vasculitis & Noncardiogenic Edema 4.3 Severe Community-Acquired & Viral Pneumonia 4.4 Nonthrombotic Embolism (Air, Fat, Amniotic Fluid, Tumor, Septic) & Acute Chest Syndrome

5 Chapter 5: Mechanical Ventilation Modes, Dyssynchrony & Liberation

5.1 Mechanical Ventilator Modes & Advanced Breath Delivery 5.2 Patient-Ventilator Dyssynchrony & Waveform Analysis 5.3 Ventilator Liberation, Spontaneous Breathing Trials & Post-Extubation Support

6 Chapter 6: Shock Syndromes & Hemodynamic Principles

6.1 Shock Classification, Cellular Pathophysiology & Biomarkers 6.2 Hemodynamic Monitoring: Arterial Lines, CVP & Pulmonary Artery Catheter 6.3 Dynamic Assessment of Fluid Responsiveness & Resuscitation Targets

7 Chapter 7: Vasoactive Therapies & Mechanical Circulatory Support

7.1 Vasopressors & Inotropes: Pharmacology & Clinical Titration 7.2 Temporary Mechanical Circulatory Support: IABP, Impella & TandemHeart 7.3 Venoarterial ECMO (VA-ECMO) & Differential Hypoxemia 7.4 Post-Cardiac Arrest Care, Targeted Temperature Management & Neuroprognostication

8 Chapter 8: Acute Kidney Injury & Renal Replacement Therapy

8.1 KDIGO AKI Classification, Etiologies & Diagnostic Evaluation 8.2 Continuous Renal Replacement Therapy (CRRT) vs Intermittent Hemodialysis 8.3 Indications & Timing for RRT in Critical Illness: AKIKI & STARRT-AKI

9 Chapter 9: Electrolyte, Acid-Base & Endocrine Emergencies

9.1 Severe Dysnatremias: Hyponatremia, Hypernatremia & Osmotic Demyelination 9.2 Potassium, Calcium, Magnesium & Phosphate Disorders 9.3 Complex & Mixed Acid-Base Disorders: Boston vs Copenhagen vs Stewart 9.4 Endocrine Crises: DKA, HHS, Thyroid Storm, Myxedema Coma & Adrenal Crisis

10 Chapter 10: Glycemic Control, Hyperammonemia, Pituitary & Adrenal Disorders

10.1 ICU Glycemic Control & Severe Hypoglycemia 10.2 Non-Hepatic Hyperammonemia & Metabolic Encephalopathy 10.3 Pituitary Emergencies, Adrenal Excess & Critical Illness-Related Corticosteroid Insufficiency

11 Chapter 11: Acute Coronary Syndromes & Cardiac Arrhythmias

11.1 Acute Coronary Syndromes & Mechanical Complications of Myocardial Infarction 11.2 Critical Tachyarrhythmias: Atrial Fibrillation with RVR, VT & VF 11.3 Critical Bradyarrhythmias, Conduction Blocks & Temporary Cardiac Pacing

12 Chapter 12: Acute Heart Failure, Valvular & Pericardial Emergencies

12.1 Acute Decompensated Heart Failure & Cardiogenic Pulmonary Edema 12.2 Acute Valvular Regurgitation & Prosthetic Valve Emergencies 12.3 Pericardial Tamponade & Acute Aortic Syndromes

13 Chapter 13: Myocardial Disease, Hypertensive & Cardiac Device Emergencies

13.1 Fulminant Myocarditis, Stress & Peripartum Cardiomyopathy, and Hypertrophic Cardiomyopathy 13.2 Hypertensive Emergencies & Ruptured Abdominal Aortic Aneurysm 13.3 Implanted Cardiac Devices, LVAD Emergencies & Electrical Storm

14 Chapter 14: Sepsis & Systemic Infectious Diseases

14.1 Sepsis-3 Definitions & Surviving Sepsis Campaign 2026 Guidelines 14.2 Refractory Septic Shock & Adjunctive Therapies 14.3 Multidrug-Resistant Pathogens & Antimicrobial Stewardship in the ICU

15 Chapter 15: ICU-Acquired & Severe Focal Infections

15.1 Hospital-Acquired & Ventilator-Associated Pneumonia 15.2 Central Line-Associated Bloodstream Infections & Catheter-Associated UTIs 15.3 Intra-Abdominal Sepsis, Necrotizing Soft Tissue Infections & CNS Infections

16 Chapter 16: Focal, Special-Host & Systemic Infections

16.1 CNS Infections Beyond Bacterial Meningitis: Encephalitis, Brain Abscess & Epidural Abscess 16.2 Infections in the Immunocompromised Host, Tropical & Bioterror Infections 16.3 Infective Endocarditis, Device Infections & Other Focal Cardiovascular Infections 16.4 Antimicrobial Pharmacokinetics, Allergy, Toxicity & Infection Prevention 16.5 Gastrointestinal & Hepatobiliary Infections: Fulminant C. difficile, Typhlitis, CMV Colitis & Abscesses

17 Chapter 17: Neurocritical Care & Coma

17.1 Coma, Altered Mental Status & Acute Delirium in the ICU 17.2 Status Epilepticus & Non-Convulsive Status Epilepticus 17.3 Acute Ischemic Stroke & Intracranial Hemorrhage

18 Chapter 18: Cerebrovascular Syndromes, Encephalopathy & Withdrawal States

18.1 Cerebral Venous Sinus Thrombosis, PRES & Reversible Cerebral Vasoconstriction Syndrome 18.2 Alcohol & Sedative Withdrawal, Wernicke Encephalopathy & Drug-Induced Encephalopathy

19 Chapter 19: Intracranial Hypertension & Neuromuscular Weakness

19.1 Intracranial Pressure Monitoring, Cerebral Perfusion & Tiered ICP Management 19.2 Acute Neuromuscular Respiratory Failure, ICU-Acquired Weakness & Brain Death Determination

20 Chapter 20: Traumatic Brain Injury, Spinal Cord Injury & Toxin-Mediated Paralysis

20.1 Traumatic Brain Injury Management & Paroxysmal Sympathetic Hyperactivity 20.2 Acute Spinal Cord Injury, Neurogenic Shock & Autonomic Dysreflexia 20.3 Toxin-Mediated Paralysis & Neuromuscular Crises: Botulism, Tetanus, Tick Paralysis & Myasthenic Crisis

21 Chapter 21: Gastrointestinal, Hepatic & Abdominal Emergencies

21.1 Acute Upper & Lower Gastrointestinal Bleeding in the ICU 21.2 Acute Liver Failure & Severe Acute Pancreatitis 21.3 Abdominal Compartment Syndrome & Acute Mesenteric Ischemia

22 Chapter 22: Luminal GI Emergencies & Complications of Cirrhosis

22.1 Esophageal, Gastric & Bowel Emergencies: Perforation, Obstruction, Ogilvie Syndrome & Colonic Ischemia 22.2 Complications of Cirrhosis: Alcohol-Associated Hepatitis, Hepatorenal Syndrome & Pulmonary Vascular Syndromes

23 Chapter 23: Trauma, Burns & Perioperative Critical Care

23.1 Polytrauma Resuscitation, Damage Control & Massive Transfusion 23.2 Severe Burn Injury, Inhalation Injury & Environmental Emergencies 23.3 Perioperative Critical Care for High-Risk Surgical Patients

24 Chapter 24: Thoracic Trauma, Environmental Injury & Obstetric Critical Care

24.1 Thoracic Trauma: Flail Chest, Pulmonary Contusion, Great Vessel & Tracheobronchial Injury 24.2 Environmental Injury: Drowning, Diving, Altitude, Heat, Cold, Electrical & Radiation 24.3 Obstetric & Genitourinary Emergencies and the Physiology of Pregnancy

25 Chapter 25: Transplantation, Donor Management & Post-Cardiac Surgery Care

25.1 Solid Organ Transplant Recipients & Deceased Donor Management 25.2 Post-Cardiac Surgery Critical Care: Bleeding, Tamponade, Low Output & Vasoplegia

26 Chapter 26: Hematologic Emergencies, Toxicology, Critical Ultrasound & ICU Liberation

26.1 Hematologic Emergencies in the ICU: HIT, DIC, TMA & Anticoagulant Reversal 26.2 Critical Care Toxicology, Toxidromes & Specific Antidotes 26.3 Critical Care Point-of-Care Ultrasound (POCUS) 26.4 ICU Liberation, Analgosedation, Goals of Care & Critical Care Ethics

27 Chapter 27: Transfusion Medicine, Hematologic & Oncologic Disorders

27.1 Transfusion Medicine: Products, Thresholds, Reactions & Apheresis 27.2 Red and White Cell Disorders, Hemoglobinopathies, Factor Deficiencies & Hypercoagulable States 27.3 Oncologic Emergencies, Hematopoietic Cell Transplant Complications & Cellular Therapy Toxicity

28 Chapter 28: Clinical Pharmacology, Adverse Drug Reactions & Specific Poisonings

28.1 Pharmacokinetic Principles, Dose Adjustment & Drug Interactions in Critical Illness 28.2 Adverse Drug Reactions: Anaphylaxis, Severe Cutaneous Reactions & Hyperthermic Syndromes 28.3 Specific Poisonings: Sodium-Channel Blockers, Lithium, Valproate, Theophylline, Iron, Sulfonylureas & Methemoglobinemia

29 Chapter 29: Ethics, Research Methods, Administration & Abdominal Ultrasound

29.1 Advance Care Planning, Nonbeneficial Treatment, Informed Consent & Confidentiality 29.2 Critical Care Research Methods, Statistics, IRB Oversight & Quality Improvement 29.3 Abdominal, Vascular & Procedural Point-of-Care Ultrasound

28.1 Pharmacokinetic Principles, Dose Adjustment & Drug Interactions in Critical Illness

Key Takeaways Explain This Topic AI

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.

Last updated: October 2026

The Two Equations That Matter

Loading dose = V d × C target F \text{Loading dose} = \frac{V_d \times C_{\text{target}}}{F} Loading dose = F V d ​ × C target ​ ​

Maintenance dose rate = C L × C target,ss \text{Maintenance dose rate} = CL \times C_{\text{target,ss}} Maintenance dose rate = C L × C target,ss ​

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.