CONTENTS

drug-drug interactions

• Medication stewardship
• P-glycoprotein
• Displacement from a carrier protein
• CYP enzymes
  • 1A2
  • 2B6
  • 2C9
  • 2C19
  • 2D6
  • 3A4
• Renal tubular secretion
• (Note: bolded medications are more relevant to critical care.)

pharmacokinetic issues

• Obesity
  • Body size descriptors
  • Absorption
  • Distribution
  • Hepatic metabolism
  • Renal clearance
• Pregnancy
  • Antibiotics ➡️
  • Anticoagulants
  • Antiemetics ➡️
  • Antiseizure medications ➡️
  • Cardiac medications
  • Sedation & analgesia
  • Steroid
• Hepatic drug clearance & hepatic dysfunction
• Oral bioavailability in critically ill patients
• Therapeutic plasma exchange (PLEX)
• Older adults

medication titration strategies

• Basic pharmacokinetic equations
• Loading dose for PO scheduled medications
• Conversion between loading bolus and continuous infusion rate
• Rapid titration of quasi-titratable infusions
  • Initiation of a quasi-titratable infusion
  • Weaning off a quasi-titratable infusion

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medication stewardship to limit drug-drug interactions

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• 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 incidence of adverse drug events in the ICU is twice as high as in the general ward. However, this rate is equivalent to the general ward rate when adjusted for the higher number of medications administered in the ICU. Although this does not prove causality, it does imply that using fewer medications would expose patients to a lower risk of adverse drug events (which is just common sense). (Erstad 2022)
• 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: 📖)

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p-glycoprotein

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substrates of P-glycoprotein

• Cardiac medications:
  • DOACs: Apixaban, rivaroxaban, edoxaban, dabigatran.
  • Digoxin.
  • Ticagrelor.
  • Colchicine.
  • Verapamil.
• Miscellaneous:
  • Linezolid.
  • Dexamethasone, hydrocortisone.
  • Ondansetron.
• Rare:
  • Cyclosporine.
  • Methotrexate.
  • Loperamide (P-glycoprotein inhibition may increase CNS penetration & sedative effects).
  • Protease inhibitors.
  • Antineoplastic agents.

inhibitors of P-glycoprotein

• ⚠️ Many drugs are handled by both P-glycoprotein and CYP3A4 (e.g., colchicine). Such drugs may have strong interactions with medications that are dual inhibitors of both P-glycoprotein and CYP3A4 (see purple text below). Commonly used medications that are dual inhibitors of P-glycoprotein and CYP3A4 include: amiodarone, diltiazem, ranolazine, ticagrelor, and azole antifungals.
• Cardiac medications:
  • [1] Amiodarone/Dronaderone group:
    • Amiodarone (weak P-gp-i, AUCR 1.4) – also inhibits CYP3A4, CYP2C9, CYP2D6, and OCT2.
    • Dronaderone (weak P-gp-i, AUCR 1.9) – also a moderate inhibitor at CYP3A4, CYP2D6.
  • [2] Nondihyropyridine CCBs and nicardipine:
    • Diltiazem (moderate P-gp-i) – also a moderate inhibitor of CYP3A4.
    • Verapamil (moderate P-gp-i) – also inhibits CYP3A4.
    • Nicardipine (strong P-gp-i) – also inhibits CYP3A4, CYP2D6, CYP2C8, CYP2C19
    • (Carvedilol causes minimal P-glycoprotein inhibition with AURC 1.2). (40349292)
  • [3] Other cardiac drugs including ticagrelor, ranolazine: 
    • Ticagrelor (minimal P-gp-i, AURC 1.3) – also inhibits CYP3A4, BCRP transporter. (40349292)
    • Ranolazine (moderate P-gp-i) – also weak CYP3A4i, moderate CYP2D6i, OCT2 inhibitor.
    • Quinidine (weak P-gp-i, AUCR 2) – also a potent inhibitor of CYP2D6.
    • Propafenone.
• Azole antifungals:
  • Voriconazole (strong P-gp-i) – also strong CYP3A4i, moderate CYP2C19i, weak CYP2C9i.
  • Posaconazole (mild-moderate P-gp-i) – also strong CYP3A4i.
  • Itraconazole (strong P-gp-i) – also strong CYP3A4i.
  • Isavuconazole (mild P-gp-i) – also moderate CYP3A4i, mild CYP2C9i, mild CYP2C19i.
• Immunosuppressives:
  • Cyclosporine (mild P-gp-i AUCR 1.8) – also inhibits CYP3A4, OATP1B1 transporters.
  • Tacrolimus (mild P-gp-i).
• Antivirals (often also inhibit CYP3A4):
  • Lopinavir (strong P-gp-i).
  • Ritonavir (strong P-gp-i, also inhibits OATP uptake).
• Antibiotics:
  • Azithromycin (weak P-gp-i with AURC 1.6; reversible).
  • Erythromycin (moderate P-gp-i; irreversible) – also CYP1A2i, moderate CYP3A4i. .

inducers of P-glycoprotein

• Carbamazepine (strong) – also induces CYP1A2 (strong), CYP2B6 (moderate), CYP2C9 (moderate), CYP2C19, CYP3A4 (strong).
• Dexamethasone (strong; this may limit dexamethasone's own efficacy over time) – also induces CYP2C9, CYP2C19, CYP3A4.
• Phenytoin (strong) – also induces CYP2C9, CYP2C19, CYP3A4.
• Rifampin (strong P-gp inducer and also a transient P-gp-inhibitor following each dose) – also induces CYP1A2, CYP2B6 (moderate), CYP2C9 (moderate), CYP2C19 (moderate), CYP3A4 (strong), and inhibits the OATP1B1 transporter.
• 💡 CYP3A4 induction is a predictor of P-glycoprotein induction (these are regulated by transcriptional activation through the same nuclear receptor). (40349292)

P-glycoprotein 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 drugs away from the fetus.
  • Lymphocyte: P-glycoprotein pumpsthe  drug out of the cell.
• P-glycoprotein inducers primarily act to reduce bioavailability.
• P-glycoprotein inhibitors may increase bioavailability and/or reduce clearance.

how important is P-glycoprotein inhibition?

• Isolated P-glycoprotein induction or inhibition:
  • Usually has a limited impact.
  • Exceptions: digoxin, dabigatran. (Erstad 2022)
•  Combined effect on P-glycoprotein PLUS CYP enzyme system: may have a bigger impact (especially when CYP inhibition is strong).
• FDA guidelines indicate that a P-glycoprotein inhibitor is defined as a drug that causes in vitro inhibition of P-glycoprotein and causes >1.5-fold increase in the area under the curve for dabigatran, digoxin, or edoxaban. (40349292)
  • Digoxin is the reference probe for renal P-glycoprotein activity.
  • Dabigatran and fexofenidine are the reference probes for intestinal P-glycoprotein activity.

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displacement from a carrier protein

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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)

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CYP enzymes

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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.

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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 a 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 (LUVOX) (strong).
• 🛑 Ethinyl estradiol.
• 🛑 Mexilitine (moderate).
• 🛑 Moderate to severe inflammation may increase drug levels twofold. (Erstad 2022)

inducer for CYP 1A2

• 🔥 Carbamazepine (strong).
• 🔥 Rifampin (moderate).
• 🔥 Phenobarbital.
• 🔥 Tobacco smoking.

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CYP 2B6

substrate for CYP 2B6

• Bupropion (major).
• Efavirenz (major).
• Methadone.
• Prasugrel.
• Propofol (weak).
• Ketamine (minor, more pronounced at high doses).

inhibitor for CYP 2B6

• 🛑 Voriconazole (moderate).

inducer for CYP 2B6

• 🔥 Carbamazepine (moderate).
• 🔥 Rifampin (moderate).
• 🔥 Pregnancy.

comment

• CYP 2B6 often works in conjunction with other CYPs.

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CYP 2C9 

substrate for CYP 2C9

• Antiseizure medications:
  • Ketamine (minor, clinically insignificant).
  • Phenobarbital (primary).
  • Phenytoin (major; ~90%).
  • Valproic acid (weak).
• NSAIDs:
  • Celecoxib (major).
  • Diclofenac (major).
  • Ibuprofen (major).
  • Indomethacin (major).
  • Ketorolac (minor).
  • Meloxicam (major).
• Rosuvastatin.
• Ruxolitinib (moderate).
• S-warfarin (moderate; interaction with amiodarone may cause significant elevation in plasma levels). (Peck 2021)
• 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).

other comments for CYP 2C9

• Genetic polymorphisms exist, including CYP2C9*3, which has reduced activity.

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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).
  • Pantoprazole (strong).
  • Lansoprazole (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

• Similar to CYP2D6, there is substantial genetic variation. ~25% of the Asian population may be poor metabolizers. (Levenson 2023)

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CYP 2D6 

substrate for CYP2D6

• [1] Antipsychotics & antiemetics:
  • Haloperidol (minor).
  • Metoclopramide (moderate).
  • Ondansetron (strong).
  • Quetiapine (minor).
• [2] Beta-blockers:
  • Carvedilol (major; strong inhibition increases level by 2-3x).
  • Metoprolol (major; strong inhibition increases level by 2-5x).
  • Propranolol (less important).
• [3] Opioids:
  • Codeine.
  • Oxycodone (strong).
  • Tramadol (major).
• [4] SSRIs et al:
  • Escitalopram (moderate).
  • Paroxetine.
  • Venlafaxine (major).
• Other:
  • Mexilitine (moderate).

inhibitor for CYP2D6

• 🛑 Amiodarone (weak).
• 🛑 Celecoxib (moderate).
• 🛑 Metoclopramide.
• Psych/neuro:
  • 🛑 Bupropion (strong).
  • 🛑 Citalopram (weak).
  • 🛑 Clobazam (moderate).
  • 🛑 Diphenhydramine (moderate).
  • 🛑 Doxepin (moderate).
  • 🛑 Duloxetine (moderate).
  • 🛑 Escitalopram (weak).
  • 🛑 Fluoxetine (strong).
  • 🛑 Haloperidol.
  • 🛑 Hydroxyzine (moderate; Ki of 4-6 uM).
  • 🛑 Paroxetine (strong).
  • 🛑 Sertraline (moderate).
• 🛑 Qunidine (strong).
• 🛑 Ranolazine (moderate)
• 🛑 Ritonavir (weak).

inducer for CYP2D6

• 🔥 None.

other comments

• Genetic variation:
  • Poor metabolizers (no functional alleles) are most common among Caucasians (~10%), followed by African Americans (~5%), Hispanics (~4%), and Asians (~1%). (32115202)
  • Intermediate metabolizers (one functional allele).
  • Extensive metabolizers (two functional alleles).
  • Ultrarapid metabolizers (multiple copies of a functional allele) are more common in African and Mediterranean populations.

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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 CYP3A4

• 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.
    • Nicardipine (moderate).
    • Nimodopine (major).
    • Diltiazem.
    • Verapamil.
  • Prasugrel, ticargrelor.
• Antibiotics:
  • Clarithromycin, erythromycin.
• Anticoagulants
  • Rivaroxaban (50%; increased bleeding risk with verapamil/diltiazem; note also that verapamil/diltiazem inhibit P-glycoprotein, so there are numerous routes whereby they will increase levels of rivaroxaban). (37259844)
  • Apixaban (20%). (37259844)
  • R-warfarin.
• 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:
    • Buprenorphine. (major)
    • Fentanyl.**
    • Methadone** (major).
    • Oxycodone** (major).
  • Antipsychotics:
    • Haloperidol (major; 65%).
    • Quetiapine (major).
  • Ketamine (primary).
  • Buspirone.
  • Carbamazepine (major).**
  • Ondansetron** (moderate).
  • Trazodone** (major).
  • Venlafaxine** (moderate).
• PPIs:
  • Esomeprazole (major).
  • Lansoprazole (moderate).
  • Omeprazole (major).
  • Pantoprazole (moderate).
• Miscellaneous:
  • Bosentan (major).
  • Colchicine.
  • Oral contraceptives.
• **Indicate medications that may promote serotonin syndrome.

inhibitor for CYP3A4

• Antibiotics:
  • 🛑 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 the levels of isavuconazole.
  • 🛑 PAXLOVID (nirmatrelvir/ritonavir; strong, irreversible).
• Azoles (vori > posa > fluc)
  • 🛑 Voriconazole (strong).
  • 🛑 Posaconazole (strong).
  • 🛑 Ketoconazole (strong).
  • 🛑 Itraconazole (strong).
  • 🛑 Fluconazole ~ Isavuconazole (moderate).
• Cardiac:
  • 🛑 Amiodarone; dronaderone (moderate).
  • 🛑 Amlodipine (moderate), nifedipine, nicardipine.
  • 🛑 Diltiazem (moderate); verapamil (moderate).
  • 🛑 Ranolazine (weak; only relevant for sensitive substrates with narrow therapeutic range).
• PPIs:
  • 🛑 Esomeprazole (mild).
  • 🛑 Omeprazole (mild).
  • (Not pantoprazole or lansoprazole.)
• SSRIs:
  • 🛑 Fluvoxamine (strong).
  • 🛑 Nefazodone (strong).
• (Valproic acid is a weak inhibitor, not clinically significant). (11736863)

inducer for CYP3A4

• Antiseizure:
  • 🔥 Carbamazepine (strong).
  • 🔥 Oxcarbazepine (moderate).
  • 🔥 Phenobarbital & primidone (moderate).
  • 🔥 Phenytoin (moderate).
• Antivirals & CF:
  • 🔥 Efavirenz (moderate).
  • 🔥 Lumacaftor, lumacaftor-ivacaftor.
  • 🔥 Nevirapine.
• Antimicrobials:
  • 🔥 Nafcillin (moderate).
  • 🔥 Rifampin (strong; may reduce some drug levels by 90%); rifabutin.
• 🔥 Dexamethasone (mild).
• Non-medication inducers:
  • 🔥 Traumatic brain injury may double activity over days.
  • 🔥 Saint John's Wort.
  • 🔥 Pregnancy.

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renal tubular secretion

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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.
  • Levofloxacin.
  • Metformin.
  • Lamivudine
• Inhibitors:
  • Cobicistat.
  • Dolutegravir.
  • Quinolones.
  • Rilpiririne
  • Ritonavir.
  • Trimethoprim.

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drug dosing in obesity

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body size descriptors

obesity & BMI

• Obesity = BMI >30 (~1/3 of the US population)
• Class I = BMI 30-35 (usual dosing is often adequate)
• Class II = BMI 35-40
• Class III = BMI >40 (~10% of the US population; patients often excluded or under-represented in usual studies, which complicates dosing). (Erstad 2022)

lean body weight (LBW, aka fat-free mass)

• Best index of fat-free mass.
• Lean body weight may correlate best with drug clearance & renal function.
• Formulae (Janmahastian method):
  • ♂ (9270 x wt in kg)/(6680+216*BMI)
  • ♀(9270 x wt in kg)/(8780+244*BMI)
• Online calculator here

adjusted body weight

Adjusted wt = Ideal wt + 0.4(Actual – Ideal)

• Used for aminoglycoside dosing.
• 0.4 is the most commonly used coefficient.

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absorption

oral bioavailability

• Bioavailability generally seems to be unchanged in obesity.
• The bioavailability of midazolam may be increased due to increased gut perfusion or decreased expression of gut CYP3A4 enzymes. (29431542)

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distribution (Vd determines the loading dose)

hydrophilic drugs (small Vd/wt)

• Examples: aminoglycosides, lithium, acyclovir, beta-lactams, low-molecular-weight heparins.
• Vd often correlates with lean body weight.
• However, vancomycin Vd appears to vary linearly with total body weight (despite a LogP of -3). (29431542)

lipophilic drugs

• Examples: phenytoin, midazolam, voriconazole.
• Vd correlates with total body weight.
• Careful: Vd only applies after distribution of the drug throughout the body. For medications with multi-compartment physiology and slow distribution, a loading dose may need to be given slowly to avoid high peak serum levels.
• Increased Vd may also increase the half-life (as shown in the equation below).

t_1/2 = [0.693V_D]/CL

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hepatic metabolism

• This may be complicated by MAFLD (metabolic dysfunction-associated fatty liver disease).
• Hepatic blood flow may increase, increasing the metabolism of high-extraction (E_H) drugs.
• CYP activity may be altered (but this primarily affects low-E_H drugs):
  • CYP3A4 may be reduced by 10-35%.
  • CYP2D6 may increase.
  • CYP2C9 may be increased.
  • CYP2C19 may decrease (potentially impairing clopidogrel activation).
  • CYP2E1 may increase (potentially increasing the toxic NAPQI metabolite of acetaminophen).
  • CYP1A2 may be stable. (29431542)
• Phase II reactions may be increased (especially glucurono-conjugation). (29431542)

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renal clearance 

• CKD-EPI needs to be scaled up based on body surface area. An alternative is to use a Cockcroft-Gault calculation based on lean body weight. (29431542)
• (Further discussion of GFR estimation in obesity is here.)

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pregnancy

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subsections on pregnancy-related pharmacology

• Antibiotics ➡️
• Anticoagulants
• Antiemetics ➡️
• Antiseizure medications ➡️
• Cardiac medications
• Sedation & analgesia
• Steroid

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pharmacologic changes in pregnancy

Absorption

• Bowel motility is reduced, with delayed gastric emptying and prolonged small bowel transit time. (Hameed 2020)
• Gastric pH increases in pregnancy:
  • Reduced absorption of weak acids (e.g., aspirin).
  • Increased absorption of weak bases (e.g., caffeine). (32115202)
• However, studies on sotalol and propranolol haven't shown different bioavailability. (30704579)
• Nausea and vomiting may be increased, especially during the first trimester. (40221297)

Distribution

• Blood volume increases substantially (up to 50%).  This increases V_d for hydrophilic medications.
• Fat mass increases, increasing the Vd for lipophilic drugs. However, the average increase in fat mass is not substantial (4 kg), so this probably doesn't cause a significant difference of Vd. (36938691)
• Albumin levels decrease by ~75%, and alpha1-acid-glycoprotein decreases by ~50%. (32115202)
  • Ideally, free drug concentrations should be measured in pregnancy.
  • Highly protein-bound drugs may have greater volume of distribution, higher free levels, and lower half-life (since higher free drug levels may accelerate clearance).

Metabolism

• Drugs with a high hepatic extraction ratio (ER) are cleared based on hepatic perfusion, which may increase during pregnancy (e.g., propranolol, verapamil, nitroglycerine). (30704579)
• Clearance of low extraction ratio (ER) drugs is less affected. However, if low albumin causes an increased free fraction of the drug, hepatic metabolism may increase.
• CYP enzymes are often altered in pregnancy
  • Upregulated: CYP3A4, CYP2B6, CYP2C9.
  • Downregulated: CYP1A2, CYP2C19.
  • CYP2D6 may increase among rapid metabolizers, but decrease among poor metabolizers. (32115202)
• UGT1A1 and UGT1A4 increase. This may increase the metabolism of some medications (e.g., labetalol, lamotrigine).

Elimination

• GFR often increases by 50% by the end of the first trimester and may continue to rise as high as 85% above baseline toward the end of the third trimester. (Hameed 2020)
• Renal transporters are upregulated. This includes P-glycoprotein, some organic cation transporters (OCTs), and organic anion transporters (OATs). (32115202) 
• PEPT1 (peptide transporter 1), which pumps substrate out of the urine and back into the renal tubule cell, is downregulated. This may contribute to lower serum ampicillin levels. (32115202) 

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anticoagulation & antiplatelets in pregnancy 

Warfarin or DOACs (direct-acting oral anticoagulants) are contraindicated prior to delivery. Consequently, treatment generally involves either unfractionated heparin or low molecular-weight heparin. Following delivery, therapeutic options are broader (e.g., heparin, low molecular-weight heparin, or warfarin are all safe during lactation).

LMWH (low molecular weight heparin)

• DVT prophylactic dose:
  • Initially 40 mg/day s.q. for patients weighing 50-90 kg.
  • As the patient's weight increases during pregnancy, the dose should be increased (e.g., 0.25 mg/kg enoxaparin q12 hours; see the table below).
• Therapeutic dose:
  • Enoxaparin 1 mg/kg q12 hours should be used initially. (Fishman 2023)
  • The precise dosing weight is unclear. The weight utilized to dose enoxaparin might ideally be a weight obtained during the 1st-2nd trimesters. (Lapinsky 2020)
  • The pharmacokinetics of LMWH in pregnancy may be altered. Thus, monitoring of anti-Xa levels is prudent, four hours after the third dose (especially in the context of obesity plus pregnancy). 📖
• LMWH should be held for at least 24 hours before delivery or procedures. Occasionally, an unfractionated heparin infusion may be utilized as bridging therapy.

unfractionated heparin

• DVT prophylactic dose:
  • First trimester: 5000 units subcutaneously every 12 hours.
  • Second trimester: 7500 units subcutaneously every 12 hours.
  • Third trimester: 10,000 units subcutaneously every 12 hours. (32360109, Erstad 2022)
  • Consider checking an anti-factor Xa level (e.g., with  ≥10,000 units).
• Therapeutic heparin infusion:
  • Patients may be switched from enoxaparin to a heparin drip as they approach delivery.
  • Heparin doses may need to be up-titrated to about twice the typical doses due to increased circulating heparin-binding proteins, elevated plasma volume, and increased placental heparin degradation. (36938691)
  • Heparin drip may be stopped 4-6 hours before epidural anesthesia. (Hameed 2020)

other anticoagulants 

• Fondaparinux doesn't cross the placenta, so it might be the preferred agent for patients who cannot receive heparin (e.g., due to heparin-induced thrombocytopenia). It is class B in pregnancy. (34405872)
• Argatroban may penetrate the placenta, but it also seems reasonably safe.

antiplatelet agents

• Aspirin:
  • Low-dose aspirin is generally safe (e.g., 81 mg/day). It is commonly used in the prevention of preeclampsia. (30704579)
  • High-dose aspirin should be avoided due to the risk of premature closure of the ductus arteriosus. (30704579)
• Clopidogrel is the preferred P2Y12 inhibitor in pregnancy (Class B). However, it should be used for the shortest duration possible. Clopidogrel should be held for a week before epidural anesthesia. (30704579)

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cardiac medications in pregnancy

diuretics

• Furosemide is the mainstay of therapy in pregnancy.
• Thiazides may be utilized if needed. Hydrochlorothiazide is class B in pregnancy and may be supported by the most experience. There is some concern regarding the possibility of inducing electrolyte imbalance within the fetus, so caution is required. Randomized trials involving hydrochlorothiazide for the treatment of hypertension in pregnancy detected a reduced risk of preeclampsia and no evidence of harms. (3917318) 
• 🚫 Mineralocorticoid receptor antagonists aren't well investigated in pregnancy, so they aren't generally used.

antiarrhythmics

• Adenosine: Generally safe.
• Amiodarone:
  • Class D; may cause congenital goiter, bradycardia, and QT prolongation. (33832606) Fetal thyroid abnormalities may impair neurocognitive development. (30704579)
  • Amiodarone can be utilized, but only if truly necessary.
• Atropine is generally safe. (Hameed 2020)
• Beta-blockers are generally safe:
  • Beta-1 selective agents are often preferred (e.g., metoprolol – which has a track record for efficacy and safety). (Hameed 2020) Selectivity for the beta-1 receptor may avoid fetal hypoglycemia and also avoid alteration of beta-2 mediated uterine relaxation and peripheral vasodilation. (30704579)
  • Labetalol is safe. Unfortunately, upregulation of UGT1A1 may increase labetalol metabolism, decreasing its half-life from 6-8 hours to 2 hours. (32115202)
  • Propranolol is generally considered safe.
  • 🚫 Esmolol may cause fetal bradycardia so it's not ideal.
  • 🚫 Atenolol is contraindicated (it's an undesirable drug regardless, due to renal clearance with a tendency to accumulate).
• Calcium channel blockers: Diltiazem is generally preferred over verapamil in atrial fibrillation (based on greater hemodynamic stability). However, verapamil may be preferred for treatment of SVT (supraventricular tachycardia). (30704579) Calcium channel blockers may have a tocolytic effect. (Griffin 2022)
• Digoxin is generally safe, but requires close monitoring of levels. Accelerated drug metabolism and higher circulating volume in pregnancy may require the use of higher doses than usual.
• Dofetilide: Class C in pregnancy; arguably preferable to amiodarone.
• Ibutilide.
• Lidocaine is generally safe (Class B). There may be a risk of neonatal CNS depression. (Griffin 2022)
• Magnesium.
• Sotalol is Class B (potential risks of fetal bradycardia or intrauterine growth restriction). (Griffin 2022)

vasodilators & other antihypertensives

• Hydralazine is commonly utilized for afterload reduction (but avoid IV hydralazine if possible).
• IV nitroglycerine or oral isosorbide dinitrate are safe.
• Calcium channel blockers are safe: amlodipine, nifedipine.
  • CYP3A4 metabolizes Nifedipine. Due to CYP3A4 induction, more frequent doses might be needed. (32115202)
• Clonidine seems safe, but may require shorter dosage intervals. (30704579) There is a rare risk of neonatal hypertension. (Griffin 2022)
• 🚫 ACE inhibitors / ARBs / renin inhibitors are contraindicated due to teratogenicity.
• 🚫 Nitroprusside can cause fetal cyanide poisoning.
• Further discussion of antihypertensives in the chapter on preeclampsia: 📖

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sedation, analgesia, neuromuscular paralysis

This is largely the same as for non-pregnant patients.  

sedation

• Propofol is commonly utilized.
• Dexmedetomidine is generally considered safe. There may be a potential for fetal bradycardia, but available data are reassuring. (36938691)
• Benzodiazepines appear safe, although high-dose lorazepam may be associated with an increased risk of propylene glycol toxicity in the neonate. Maternal use may carry a risk of neonatal respiratory depression, floppy baby syndrome, and neonatal withdrawal syndrome. (36938691)

analgesia

• Acetaminophen is generally considered safe and a front-line therapy for pain.
• Opioids are generally safe. Morphine, fentanyl, and hydromorphone were class C.
• Ketamine is generally safe (class B). However, it may increase uterine tone, especially at higher doses. There is some data that it may affect fetal neurological development, so limiting exposure might be prudent. (36938691)

paralysis

• This is largely the same as for other patients.
• Rocuronium may be used for intubation.
• Cisatracurium has been suggested as the preferred agent if a paralytic infusion is needed (as in other patients). (36938691)

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systemic steroid

• Risk?
  • Systemic steroid use in the first trimester was previously thought to associate with a very small risk (~0.2%) of cleft palate in the fetus. However, newer studies have found that there is actually no risk. (24777675, 21482652, 23011170)
  • Steroid does increase the risk of gestational diabetes mellitus and preeclampsia.
  • If genuinely indicated (e.g., uncontrolled asthma), the benefit of steroid outweighs the risks.
• Different steroids carry varying risk:
  • 🏆 Prednisone, prednisolone, and methylprednisolone have limited fetal uptake due to active retrograde transport by P-glycoprotein and metabolism to inactive metabolites by placental 11-beta-hydroxysteroid dehydrogenase. (26590298) By using these agents, benefits may be achieved while minimizing effects on the fetus.
  • Dexamethasone and betamethasone cross the placenta.
• Steroid to induce lung maturity:
  • This is often utilized in preterm gestation, if there is a risk of early delivery (with a goal of reducing neonatal respiratory distress syndrome).
  • The dose is 6 mg dexamethasone twice daily for 48 hours.
• ⚠️ Patients on prolonged courses of systemic steroids should consider stress-dose steroids during labor. (Fishman 2023)

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uterotonic medications: cardiopulmonary consequences

• 1st line agent: Oxytocin
  • Causes reduced blood pressure with a slight elevation in pulmonary pressures.
  • Most effective uterotonic agent.
  • Avoid bolus administration in patients with cardiac disease.
  • Vasodilation may need to be counteracted with the use of a vasopressor agent.
• 2nd line agent in unstable patients: misoprostol
  • This is the least effective agent but seems to be hemodynamically stable.
• Methylergonovine
  • Can cause profound elevation of systemic vascular resistance, pulmonary vascular resistance, and coronary vasospasm.
  • Generally avoided in cardiac patients. (Hameed 2020)
• Carboprost
  • Causes profound elevation in pulmonary artery pressure.
  • May cause bronchospasm with ventilation/perfusion mismatch.
  • Avoid in patients with asthma or patients unable to tolerate increased pulmonary pressure. (Hameed 2020)

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hepatic drug clearance

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high E_H vs low E_H drugs

• Drugs with high hepatic extraction ratio (E_H):
  • [1] Drugs have high intrinsic hepatic clearance (CL_int), indicating that the liver can metabolize them very efficiently. Rapid metabolism generates a steep concentration gradient, allowing the liver to efficiently extract the drugs from the blood.
  • [2] Metabolism is limited by hepatic blood flow (while being relatively insensitive to changes in plasma protein binding and the activity of drug-metabolizing enzymes).
  • [3] There is a high first-pass metabolism. Hepatic dysfunction may result in much higher serum levels following oral administration. In hepatic failure, IV administration might be preferred (to avoid variations in first-pass metabolism).
  • [4] Drug levels are reduced in heart failure or cirrhosis (conditions that reduce hepatic blood flow). Drug-drug interactions may be caused by alterations in hepatic blood flow (e.g., reduced by beta-blockers; increased by nitrates).
• Drugs with low hepatic extraction ratio (E_H):
  • [1] Drugs have low intrinsic hepatic clearance (CL_int), indicating that the liver can metabolize them less efficiently.
  • [2] Metabolism is limited by alterations in hepatic enzyme function and plasma protein binding (with less dependence on hepatic blood flow).
  • [3] There is low first-pass metabolism. Hepatic dysfunction should have less impact on oral bioavailability.  (Erstad 2022)
  • [4] Drug levels are reduced by changes in liver enzyme activity and changes in protein binding. This may increase susceptibility to drug-drug interactions.

classification of commonly used ICU drugs

• High E_H (>60%)
  • Buspirone.
  • Chlorpromazine.
  • Cyclosporine.
  • Doxepin.
  • Fluvastatin.
  • Imipramine.
  • Isosorbide dinitrate.
  • Labetalol.
  • Lovastatin.
  • Metoprolol.
  • Midazolam.
  • Morphine.
  • Nicardipine.
  • Nitroglycerine.
  • Perphenazine.
  • Propranolol.
  • Quetiapine.
  • Sertaline.
  • Sirolimus.
  • Tacrolimus.
  • Venlafaxine.
  • Verapamil.
• Intermediate E_H (30-60%)
  • Amiodarone.
  • Amitriptyline.
  • Atorvastatin.
  • Azathioprine.
  • Carvedilol.
  • Ciprofloxacin.
  • Clomipramine.
  • Clozapine.
  • Codeine.
  • Diltiazem.
  • Erythromycin.
  • Felodipine.
  • Fluphenazine.
  • Haloperidol.
  • Itraconazole.
  • Lidocaine.
  • Nifedipine.
  • Nortriptyline.
  • Olanzapine.
  • Omeprazole.
  • Pareoxetine.
  • Pravastatin.
  • Ranitidine.
  • Simvastatin.
• Low E_H (<30%)
  • Acetaminophen.
  • Alprazolam.
  • Carbamazepine.
  • Ceftriaxone.
  • Chlordiazepoxide.
  • Clarithromycin.
  • Clindamycin.
  • Diazepam.
  • Diphenhydramine.
  • Glipizide.
  • Isoniazid.
  • Lamotrigine.
  • Lansoprazole.
  • Levetiracetam.
  • Lorazepam.
  • Methadone.
  • Methylprednisolone.
  • Metoclopramide.
  • Metronidazole.
  • Mycophenolate mofetil.
  • Oxazepam.
  • Phenobarbital.
  • Phenytoin.
  • Prednisolone.
  • Prednisone.
  • Rifampin.
  • Risperidone.
  • Temazepam.
  • Theophylline.
  • Topiramate.
  • Trazodone.
  • Valproic acid.
  • Zolpidem. (Erstad 2022)

susceptibility of various enzymes to hepatic dysfunction

• Cytochrome P450 enzymes (phase I) is more affected than phase II.
  • CYP3A4, CYP1A2, and CYP2C19 may be more susceptible to this effect.
  • CYP2D6 and CYP2C9 may be less affected.
• Phase II is less affected. Sulfonation reactions are more affected than glucuronidation. (Erstad 2022)

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oral bioavailability in critically ill patients

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Several factors may affect oral bioavailability. This is often most affected early on, when patients are most ill. Drugs with lower oral bioavailability at baseline are subject to greater inter-individual variation.  

[1] issues regarding tube feeding

• Drugs may bind to the feeding tube: for example, carbamazepine, clonazepam, diazepam, hydralazine, and phenytoin. (36942898)
• Crushing tablets: This may alter how the drug is released from excipients within the tablet.
• Postpyloric location of feeding tube:
  • Little data are available for most medications to support postpyloric administration. (36942898)
  • For some drugs, postpyloric administration limits first-pass metabolism and may cause toxicity (e.g., azathioprine, morphine) or therapeutic failure (prodrugs that require hepatic activation). (36942898)
  • Bypassing the stomach decreases the efficacy of aspirin, cyclosporine, sucralfate, rivaroxaban, and valproic acid. (36942898)
• Interaction with enteral nutrition: Increased viscosity may reduce the dispersion of drugs with high solubility.

[2] gastrointestinal dysmotility

• This may occur in about half of critically ill patients. (36942898)
• Dysmotility usually reduces absorption.
• Slow passage reduces the time to peak drug levels (which may be problematic for antibiotics that depend on a high peak/MIC ratio).

[3] elevated gastric pH

• This may decrease absorption of drugs that are weak bases (E.g., azole antifungals, defpodoxime, dipyridamole).
• This may enhance absorption of weak acids (e.g., some beta-blockers) and drugs that undergo less degradation due to avoiding an acidic environment (e.g., digoxin, erythromycin, Penicillin G). (36942898)

[4] intestinal mucosal atrophy and/or hypoperfusion

• Atrophy may result from prolonged lack of enteral nutrition. This may reduce absorption by decreasing the absorptive surface area.

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therapeutic plasma exchange (PLEX)

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physiology

• Drugs most likely to be affected, in order of decreasing importance:
  • [1] Low volume of distribution (<0.2-0.3 L/kg). This is probably the most crucial parameter. If the drug is distributed outside the plasma, then plasma exchange can't remove it.
  • [2] PLEX occurs within <2-3 times the distribution half-life. PLEX will remove more drug if it is performed right after the drug is administered (before it has time to distribute into the tissues).
  • [3] Elimination half-life >>2 hours. If a drug has a short elimination half-life (e.g., vasopressor infusion), then PLEX will only have a temporary effect, which is less likely to be significant. (32445106)
  • [4] High degree of protein binding (>80%). High protein-binding is traditionally cited as an important factor affecting drug clearance by PLEX. Still, it's unclear how much information protein binding provides independent of the Vd (noting that high protein-binding will often cause a reduction in Vd). PLEX clears any drug out of the plasma (regardless of whether it is bound or unbound). Perhaps the best illustration of these principles is that PLEX strongly affects enoxaparin despite enoxaparin's having minimal protein binding (thereby illustrating that Vd is the key parameter here, not protein binding).
• Percent removal of solutes within the plasma:
  • 1 plasma volume exchange (~60 ml/kg): 63% removal.
  • 1.5 plasma volume exchange (~90 ml/kg): 78% removal.
  • 2 plasma volumes exchanged (~120 ml/kg): 86% removal. (Erstad 2022, 32445106)
• Where the drug is removed from:
  • After plasma exchange, serum drug levels may be low. This may be important for drugs that act within the bloodstream (e.g., antibiotics for endocarditis).
  • After plasma exchange, tissue drug levels may remain therapeutic.

examples

• Enoxaparin: Vd ~0.05 L/kg; not protein bound. Serum levels may drop 100% after PLEX. (32445106)
  • Dosing may depend on the clinical scenario.
  • Scheduling enoxaparin to be given immediately after PLEX might mitigate this.
  • Measurement of anti-Xa levels may be utilized to guide therapy.
  • Transitioning to an unfractionated heparin infusion might be easier to monitor and titrate.
• Heparin: Vd ~0.07 L/kg; binds to antithrombin III.  Serum levels may drop by ~50% after PLEX.
  • Affected by replacement with FFP vs. albumin.
  • Removal of antithrombin-III may cause heparin resistance (which might favor replacement with FFP).
  • One study maintained adequate anti-Xa levels by increasing the heparin infusion by 65% during PLEX. (32445106) However, if heparin levels are low for a few hours, that might not matter (depending on the clinical context).
• Amphotericin B liposomal: Vd ~0.13 L/kg; 95% protein binding. Concentrations drop by ~40% after PLEX; supplementation after PLEX may be required.
• Ceftriaxone: Vd ~0.15 L/kg; ~90% protein binding;
  • Up to 23% of the drug may be removed if PLEX is done right after administration.
  • Ceftriaxone should ideally be given >15 hrs before PLEX.
  • Consider utilizing a 2-gram dose rather than a 1-gram dose.
• Aspirin: Vd ~0.15 L/kg; 80-90% protein binding; possibly affected.
• Ampicillin, Cefepime, Ceftaz, Piptazo: Vd ~0.25 L/kg; ~20% protein binding.
  • PLEX generally doesn't affect drug levels very much.
  • Avoid giving within <2 hrs before PLEX (or especially during PLEX).
• Aminoglycoside: Vd ~0.3 L/kg; 30% protein binding.
  • Only ~5-10% of the total body aminoglycoside stores are removed.
  • Probably not an issue if aminoglycosides can be given well before PLEX.
• Phenytoin: Vd ~0.65 L/kg; 90% protein binding. PLEX only removes 3-5% of the total body phenytoin stores. (Erstad 2022)
• Vancomycin: Vd ~0.7 L/kg; 40% protein binding. Data is conflicting, but there is probably minimal interference from PLEX as long as it isn't performed shortly after giving vancomycin. PLEX likely removes only ~5-10% of the total body vancomycin stores.
• Digoxin: Vd 5-8 L/kg.  PLEX removes only 1-2% of the total body digoxin stores.

strategies for dosing medications

• [1] Avoid giving medications right before PLEX or (especially) during PLEX.
  • The best time to give medications is right after PLEX.
  • The second-best time to give medications is >2-3 distribution half-lives before PLEX (often equivalent to >2 hours before PLEX).
• [2] Consider using therapeutic drug monitoring. However, this may be challenging:
  • [i] Avoid checking drug levels right after PLEX because the serum levels may be artificially low. A period of re-equilibration must be allowed before obtaining a meaningful value.
  • [ii] When possible, check a free drug level. If a free level isn't possible, consider following the albumin level. Shifts in protein levels may cause a dissociation between total drug levels and free drug levels.
  • In general practice, this is probably only truly needed for anticoagulants (e.g., enoxaparin).

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older adults

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It's unclear precisely how to define older adults, especially in the context of critical care (wherein most of our patients are relatively old).  

pharmacokinetic changes

• Absorption:
  • Delayed gastric emptying and motility may delay drug onset.
  • Increased gastric pH.
• Distribution:
  • Fat content may increase, increasing the Vd for lipophilic drugs.
  • Total body water decreases by ~10-15%, decreasing Vd for hydrophilic drugs.
• Metabolism:
  • Hepatic blood flow is reduced, which decreases clearance by high E_H drugs.
  • Phase I metabolism may decrease (i.e., CYP enzymes).
  • Phase II metabolism is generally normal.
• Elimination:
  • Renal function is reduced.
  • Be wary of drugs with active metabolites that may be prone to accumulate.

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basic pharmacokinetic equations

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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.

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loading dose for PO scheduled medications

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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) 🌊

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conversion between loading bolus and continuous infusion rate

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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: 🌊

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rapid titration of quasi-titratable medication infusions

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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.

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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: 🌊

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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: 🌊

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questions & discussion

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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 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.