CONTENTS
drug interactions
- Medication stewardship
- P-glycoprotein
- Displacement from a carrier protein
- CYP enzymes
- Renal tubular secretion
- (Note: bolded medications are more relevant to critical care.)
pharmacokinetic strategies for bedside practitioners
- Basic pharmacokinetic equations
- Loading dose for PO scheduled medications
- Conversion between loading bolus and continuous infusion rate
- Rapid titration of quasi-titratable infusions
- The number of potential drug-drug interactions is equal to n(n-1)/2, where n represents the number of medications the patient is currently taking. As shown below, this is a parabolic function that increases dramatically with an increasing number of drugs.
- The first and most basic step to avoid drug-drug interactions is to avoid unnecessary medications. For example, when patients are admitted, medications utilized for chronic illness can often be held. (This is discussed further in the chapter on medication reconciliation in the ICU: 📖)
basics
- P-glycoprotein is a drug efflux pump located within numerous barriers in the human body:
- Intestine: P-glycoprotein limits drug absorption. It may also enhance the time the drug is exposed to CYP3A4.
- Liver, kidney: P-glycoprotein promotes drug elimination.
- Blood-brain barrier: P-glycoprotein pumps drugs out of the brain.
- Placenta: P-glycoprotein pumps drug away from the fetus.
- Lymphocyte: P-glycoprotein pumps drug out of the cell.
- P-glycoprotein inducers primarily act to reduce bioavailability.
- P-glycoprotein inhibitors may increase bioavailability and/or reduce clearance.
- Except for digoxin and dabigatran, interactions may have a limited impact unless there is simultaneous inhibition or induction of the CYP3A4 enzyme. (Erstad 2022)
substrates of P-glycoprotein
- DOACs:
- Apixaban.
- Riveroxiban.
- Edoxaban.
- Dabigatran.
- Ticagrelor.
- Linezolid.
- Digoxin.
- Colchicine.
- Dexamethasone, hydrocortisone.
- Cyclosporine.
- Methotrexate.
- Loperamide (P-glycoprotein inhibition may increase CNS penetration & sedative effects).
- Ondansetron.
- Verapamil.
- Protease inhibitors.
- Antineoplastic agents.
inhibitors of P-glycoprotein
- Cardiac medications:
- Amiodarone (moderate).
- Dronaderone (moderate).
- Diltiazem (moderate).
- Verapamil (moderate).
- Ticagrelor (moderate).
- Quinidine (moderate).
- Azole antifungals:
- Voriconazole (strong).
- Posaconazole (mild-moderate).
- Itraconazole (strong).
- Isavuconazole (mild).
- Immunosuppressives:
- Cyclosporine (moderate).
- Tacrolimus (mild).
- Antivirals:
- Lopinavir (strong).
- Ritonavir strong).
- Erythromycin (moderate; irreversible).
inducers of P-glycoprotein
- Carbamazepine (strong).
- Dexamethasone (strong; this may limit dexamethasone's own efficacy over time).
- Phenobarbital (strong).
- Phenytoin (strong).
- Rifampin (strong).
- Tenofovir.
basics
- Usually, displacement only causes minor changes in the free drug level (elevated free levels may increase drug metabolism and tissue distribution, leading to a relatively stable concentration of free drug). However, rapid IV administration might have more substantial changes on the free drug level.
- Drugs most likely to be affected have the following properties:
- [1] Small volume of distribution (for drugs with larger Vd, an increase in free level may increase tissue penetration with maintenance of similar drug levels).
- [2] >80% protein binding.
- [3] Narrow therapeutic index.
- [4] The free versus bound fraction does not affect drug metabolism. This may occur in the following situations:
- [i] High hepatic extraction ratio (all the drug in the blood is cleared; examples may include lidocaine, verapamil, propafenone). (Levenson 2023)
- [ii] Phenytoin metabolism is readily saturated, so phenytoin is cleared via zero-order pharmacokinetics. The rate of phenytoin clearance remains constant regardless of the concentration of the drug. (Erstad 2022, Peck 2021)
- Displacement may cause errors when titrating drugs against the total drug level (rather than the free drug level).
- Most so-called “protein-binding” interactions actually reflect variations in drug metabolism. (Peck 2021)
albumin
- May bind to acidic drugs, e.g.:
- Anti-epileptics.
- Benzodiazepines.
- Negative acute-phase reactant (levels decrease in sepsis or acute stress).
- Phenytoin may be affected; discussed here:
alpha-1-acid glycoprotein
- May bind basic drugs, e.g.:
- Lidocaine.
- Synthetic opioids.
- Tricyclic antidepressants.
- Factors that affect levels of alpha-1-acid glycoprotein:
- Decreased in:
- Pregnancy.
- Uremia.
- Hepatitis, cirrhosis.
- Malnutrition.
- Hyperthyroidism.
- Nephrotic syndrome.
- Increased in:
- Stress response.
- Inflammatory bowel disease, RA, SLE.
- Acute MI.
- Trauma.
- Epilepsy.
- Stroke.
- Surgery.
- Burns.
- Most cancers (except pancreatic).
- Acute glomerulonephritis.
- Organ transplantation.
- Obesity. (Levenson 2023)
- Decreased in:
basics of CYP enzymes
- CYP enzymes perform Phase I metabolism (oxidation, hydrolysis, reduction), rendering drugs more hydrophilic.
- CYP enzymes are primarily located in the liver, but also located in the small intestine, lungs, and kidneys.
susceptibility to drug-drug interaction by CYP inhibitor
- CYP inhibition may cause substrate drug accumulation.
- Clinically significant accumulation may occur if:
- Narrow therapeutic index.
- The drug isn't metabolized by alternative pathways.
susceptibility to drug-drug interaction by CYP inducer
- CYP induction may cause substrate drug elimination.
- Clinically significant elimination may occur if:
- Narrow therapeutic index.
- CYP enzyme causes a substantial clearance of the drug.
- 💡 Note that if several metabolic pathways metabolize a drug, this may protect from a CYP inhibitor but not necessarily from a CYP inducer.
CYP 1A2
substrate for CYP 1A2
- Acetaminophen.
- Cloazpine (major).
- Duloxetine (major).
- Lidocaine (moderate).
- Melatonin (major).
- Olanzapine (moderate).
- Theophylline (moderate).
- Tizanidine (major; severe toxicity can occur when combined with strong inhibitor such as ciprofloxacin).
inhibitor for CYP 1A2
- 🛑 Ciprofloxacin (strong; levofloxacin or moxifloxacin have little/no inhibition and may be used as a substitute). (Muller 2016)
- 🛑 Erythromycin (irreversible).
- 🛑 Fluvoxamine (strong).
- 🛑 Ethinyl estradiol.
- 🛑 Moderate to severe inflammation may increase drug levels two-fold. (Erstad 2022)
inducer for CYP 1A2
- 🔥 Carbamazepine (strong).
- 🔥 Rifampin (moderate).
- 🔥 Phenobarbital.
- 🔥 Tobacco smoking.
CYP 2B6
substrate for CYP 2B6
- Bupropion (major).
- Efavirenz (major).
- Prasugrel.
- Propofol (weak).
- Ketamine (minor, more pronounced at high doses).
inhibitor for CYP 2B6
- 🛑 Voriconazole (moderate).
inducer for CYP 2B6
- 🔥 Carbamazepine (moderate).
- 🔥 Rifampin (moderate).
CYP 2C9
substrate for CYP 2C9
- Ketamine (minor, clinically insignificant).
- Phenobarbital (primary).
- Phenytoin (major; ~90%).
- Rosuvastatin.
- Ruxolitinib (moderate).
- S-warfarin (moderate; interaction with amiodarone may cause significant elevation in plasma levels). (Peck 2021)
- Valproic acid (weak).
- Voriconazole (weak).
inhibitor for CYP 2C9
- 🛑 Amiodarone (moderate).
- 🛑 Azoles:
- Fluconazole (moderate).
- Voriconazole (weak).
- Isavuconazole (weak).
- 🛑 Isoniazid (weak).
- 🛑 Metronidazole (moderate).
- 🛑 Sulfamethoxazole (mild).
- 🛑 Valproic acid.
- 🛑 Moderate to severe inflammation may increase drug levels twofold. (Erstad 2022)
inducer for CYP 2C9
- 🔥 Carbamazepine (moderate).
- 🔥 Dexamethasone.
- 🔥 Phenobarbital (mild; induces its own metabolism).
- 🔥 Phenytoin.
- 🔥 Rifampin (moderate).
CYP 2C19
substrate for CYP 2C19
- Citalopram.
- Clobazam (strong).
- Clopidogrel activation (strong)
- 2C19 is required to convert clopidogrel (a prodrug) into its active metabolite.
- Omeprazole or esomeprazole may theoretically inhibit the activation of clopidogrel, thereby reducing its antiplatelet activity.
- Diazepam (moderate).
- Labetalol (moderate).
- Lacosamide.
- Phenytoin (minor; ~10%).
- Proton pump inhibitors:
- Esomeprazole (strong).
- R-warfarin.
- Venlafaxine (moderate).
- Voriconazole (strong).
inhibitor for CYP 2C19
- 🛑 Armodafinil (weak).
- 🛑 Azoles
- Fluconazole (strong).
- Voriconazole (moderate).
- Isavuconazole (weak; minimal clinical impact).
- 🛑 Fluoxetine (moderate).
- 🛑 Isoniazid (weak)
- 🛑 Ketoconazole (moderate)
- 🛑 Modafinil (moderate)
- 🛑 Oxcarbazepine.
- PPIs
- 🛑 Esomeprazole (moderate).
- 🛑 Lansoprazole.
- 🛑 Omeprazole (weak).
- (Not pantoprazole.)
- 🛑 Grapefruit juice.
inducer for CYP 2C19
- 🔥 Carbamazepine.
- 🔥 Dexamethasone.
- 🔥 Phenobarbital.
- 🔥 Phenytoin.
- 🔥 Rifampin (moderate).
other comments
- ~25% of Asian populations may be poor metabolizers. (Levenson 2023)
CYP 2D6
substrate for CYP 2D6
- Codeine.
- Beta-blockers:
- Carvedilol (major).
- Metoprolol.
- Propranolol.
- Escitalopram (moderate).
- Haloperidol (minor).
- Metoclopramide (moderate).
- Mexilitine (moderate).
- Ondansetron (strong).
- Oxycodone (strong).
- Paroxetine.
- Quetiapine (minor).
- Tramadol (major).
- Venlafaxine (major).
inhibitor for CYP 2D6
- 🛑 Amiodarone (weak).
- 🛑 Clobazam (moderate).
- 🛑 Diphenhydramine (weak).
- 🛑 Doxepin (moderate).
- Psych:
- 🛑 Bupropion (strong).
- 🛑 Citalopram (weak).
- 🛑 Duloxetine (moderate).
- 🛑 Escitalopram (weak).
- 🛑 Fluoxetine (strong).
- 🛑 Paroxetine (strong).
- 🛑 Sertraline (moderate).
- 🛑 Haloperidol.
- 🛑 Qunidine (strong).
- 🛑 Ritonavir (weak).
inducer for CYP 2D6
- 🔥 None.
other comments
- ~10% of Caucasians are poor metabolizers. (Levenson 2023)
CYP3A4
general comments
- CYP3A4 is located in the gut wall, which may increase the first-pass metabolism of orally administered medications. (Levenson 2023)
substrate for CYP 3A4
- Cardiac:
- Amiodarone.
- Atorvastatin, simvastatin (risk of rhabdomyolysis when combined with CYP3A4 inhibitors). (Muller 2016) Statins that are less affected include pravastatin and rosuvastatin.
- Calcium channel blockers:
- Amlodipine.
- Nifedipine.
- Felodipine.
- Nimodopine (major).
- Diltiazem.
- Verapamil.
- Prasugrel, ticargrelor.
- Antibiotics:
- Clarithromycin, erythromycin.
- Anticoagulants
- Antivirals:
- Nelfinavir, ritonavir, saquinavir.
- Boceprevir, Telaprevir.
- Immunosuppressives:
- Calcineurin inhibitors (cyclosporine, tacrolimus).
- Sirolimus (major).
- Cyclophosphamide.
- Dexamethasone > methylprednisolone, prednisolone > hydrocortisone. (Erstad 2022)
- Neurologics
- Benzodiazepines:
- Diazepam (moderate).
- Midazolam (major).
- Opioids:
- Fentanyl.**
- Methadone** (major).
- Oxycodone** (major).
- Antipsychotics:
- Haloperidol (major; 65%).
- Quetiapine (major).
- Ketamine (primary).
- Buspirone.
- Carbamazepine (major).**
- Ondansetron** (moderate).
- Trazodone** (major).
- Venlafaxine** (moderate).
- Benzodiazepines:
- PPIs:
- Esomeprazole (major).
- Lansoprazole (moderate).
- Omeprazole (major).
- Pantoprazole (moderate).
- Miscellaneous:
- Bosentan (major).
- Colchicine.
- Oral contraceptives.
- **Indicate medications that may promote serotonin syndrome.
inhibitor for CYP 3A4
- Antibitoics:
- 🛑 Ciprofloxacin (moderate).
- 🛑 Clarithromycin (strong).
- 🛑 Erythromycin (moderate, irreversible).
- Antivirals, e.g.:
- 🛑 Ritonavir, Indinavir (strong, irreversible).
- This may be intentionally used to boost the level of protease inhibitors.
- May double isavuconazole levels.
- 🛑 PAXLOVID (nirmatrelvir/ritonavir; strong, irreversible).
- 🛑 Ritonavir, Indinavir (strong, irreversible).
- Azoles (vori > posa > fluc)
- 🛑 Voriconazole (strong).
- 🛑 Posaconazole (strong).
- 🛑 Ketoconazole (strong).
- 🛑 Itraconazole (strong).
- 🛑 Fluconazole ~ Isavuconazole (moderate).
- Cardiac:
- 🛑 Amiodarone.
- 🛑 Amlodipine (modeate), nifedipine.
- 🛑 Diltiazem (moderate).
- 🛑 Verapamil (moderate).
- PPIs:
- 🛑 Esomeprazole (mild).
- 🛑 Omeprazole (mild).
- (Not pantoprazole or lansoprazole.)
- 🛑 Valproic acid (weak inhibitor, not clinically significant). (11736863)
- 🛑 Moderate to severe inflammation may increase drug levels twofold. (Erstad 2022)
inducer for CYP 3A4
- 🔥 Carbamazepine (strong).
- 🔥 Dexamethasone, methylprednisolone, prednisolone, prednisone (all mild).
- 🔥 Efavirenz (moderate).
- 🔥 Nevirapine.
- 🔥 Oxcarbazepine (moderate).
- 🔥 Nafcillin (moderate).
- 🔥 Phenobarbital (moderate).
- 🔥 Phenytoin (moderate).
- 🔥 Rifabutin.
- 🔥 Rifampin (strong; may reduce some drug levels by 90%).
- Non-medication inducers:
- 🔥 Traumatic brain injury may double activity over days.
- 🔥 Saint John's Wort.
These interactions aren't generally a significant issue. The only well-established inhibitor of the OAT system is probenecid (which results in a 30-90% reduction in renal clearance). The clinical relevance of these interactions may be greater in renal insufficiency, and for drugs with very narrow therapeutic indices (e.g., procainamide, methotrexate). (Erstad 2022)
OAT1 (organic anion transporter 1)
- Substrates:
- Acyclovir.
- Adefovir, cidofovir.
- Methotrexate.
- Oseltamavir.
- Pravastatin.
- Raltegravir.
- Tenofovir.
- Inhibitors:
- Furosemide.
- Probenecid.
OAT2 (organic anion transporter 2)
- Substrates:
- Cidofovir.
- Famotidine, ranitidine.
- Oseltamavir.
- Pravastatin.
- Valacyclovir.
- Tenofovir.
- Meropenem.
- Inhibitors:
- Bumetanide.
- Furosemide.
- Probenecid.
OCT2 (organic cation transporter 2)
- Substrate:
- Amiodarone, dofetilide, procainamide.
- Cisplatin.
- Digoxin.
- Diltiazem, verapamil.
- Levlfolxacin.
- Metformin.
- Lamivudine
- Inhibitors:
- Cobicistat.
- Dolutegravir.
- Quinolones.
- Rilpiririne
- Ritonavir.
- Trimethoprim.
The following are some basic pharmacokinetic equations, reproduced from a website by the University of Florida College of Pharmacy (here). The abbreviations and terminology in these equations will be used throughout the following chapter.
For oral medications, a loading dose can be calculated with the following formula: 🌊
The best way to understand this is to look at the graph below, which shows how the loading dose relates to a ratio of the dosing interval and the half-life:
- If (dosing interval)/(half life) is high, then individual doses don't overlap much (instead, each dose of medication is mostly eliminated before the next dose is given). In this situation, the loading dose is close to the maintenance dose, so there is no need to use a distinct loading dose.
- If (dosing interval)/(half life) is low, a loading dose is needed. If the drug is started without a loading dose, doses will overlap considerably, leading to accumulation over time. Thus, it would take many doses to reach a steady state.
The loading dose pharmacokinetics for various antibiotics are shown below. This explains why doxycycline should be started with a 200 mg loading dose for serious infections. (8225622, 28819873) 🌊
Suppose you are giving an IV loading dose of a drug followed by a maintenance infusion (let's say, for example, IV diltiazem). You've given a few IV doses of the drug to determine a safe and effective loading dose. How should this loading dose estimate a rational continuous infusion rate?
The following equation relates a loading dose with a maintenance infusion rate that will achieve the same serum drug level: 🌊
Quasi-titratable medication infusions are drugs with an intermediate half-life, which makes titration challenging (e.g., diltiazem, labetalol, milrinone, nicardipine). Although the medication is given by a continuous infusion, it's not easy or straightforward to simply adjust the infusion rate and immediately observe what happens (since effects will often be seen several hours later).
One approach is to start with loading boluses to determine the required dose. The loading bolus dose can then be converted to a continuous infusion rate, as described above ⚡️. However, for some medications (e.g., milrinone), giving multiple loading boluses may be dangerous or laborious.
A mathematically valid approach to rapidly adjust these medications is shown below.
initiation of a quasi-titratable infusion
- [1] The infusion is started at the upper end of the dosing range (e.g., 0.75 ug/kg/min for milrinone). This will cause the drug level to rise in a steady and controlled fashion (as shown in the graph above). Although the infusion is continued at a fixed rate, drug levels will accumulate, causing the drug to auto-titrate itself.
- [2] Hemodynamics are meticulously monitored to determine when a therapeutic effect is achieved.
- [3] As soon as a satisfactory effect is seen, the infusion rate is dropped down to a maintenance infusion. The rate of the maintenance infusion can be calculated based on how long it takes to reach a therapeutic effect, as follows: 🌊
weaning off a quasi-titratable infusion
This is essentially the above process in reverse:
- [1] We start out with a patient on a baseline infusion rate.
- [2] The infusion is shut off completely.
- [3] Hemodynamics are meticulously monitored to evaluate for any deterioration.
- [4] If deterioration occurs, the medication may be resumed at a reduced dose corresponding to the latest time point when hemodynamics were adequate. This reduced infusion rate may be calculated using the following equation: 🌊
To keep this page small and fast, questions & discussion about this post can be found on another page here.
Guide to emoji hyperlinks 
= Link to online calculator.
= Link to Medscape monograph about a drug.
= Link to IBCC section about a drug.
= Link to IBCC section covering that topic.
= Link to FOAMed site with related information.- 📄 = Link to open-access journal article.
= Link to supplemental media.
References
- U. Florida College of Pharmacy collection of pharmacokinetic equations
- Muller M, 2016. Clinical pharmacology: Current topics and case studies. Springer International Publishing Switzerland.
- Peck T and Harris B, 2021. Pharmacology for Anaesthesia and Intensive Care 5th Edition. Cambridge University Press.
- Erstad BL, 2022. Critical Care Pharmacotherapy, second edition. American College of Clinical Pharmacy.
- Levenson JL and Ferrando SJ, 2023. Clinical Manual of Psychopharmacology in the Medically Ill, Third Edition. American Psychiatric Publishing.
