PK Foundations — Vd, Clearance, Compartments, CSHT, Protein Binding

It's a proportionality constant relating dose to measured plasma level — NOT an anatomic volume.

Small Vd (<0.4 L/kg ≈ ECF): drug stays in plasma/interstitium → muscle relaxants (rocuronium 0.3 L/kg), heparin, mannitol.

Moderate Vd (0.4-1 L/kg ≈ TBW): drug distributes through body water → propofol 0.5 L/kg (initial), midazolam 1-2 L/kg.

Large Vd (>1 L/kg): drug sequesters in tissue (fat, protein, intracellular) → fentanyl 3-5 L/kg, amiodarone 60 L/kg, digoxin 7 L/kg.

Vd determines LOADING dose (loading dose = Vd × target plasma concentration); clearance determines maintenance dose.

Hepatic extraction ratio (ER) = fraction of drug removed in one pass through the liver.

HIGH-ER drugs (ER >0.7): propofol, fentanyl, lidocaine, morphine, naloxone — clearance is FLOW-LIMITED; reduce dose in any state that decreases hepatic blood flow (CHF, beta-blockade, halothane, hypovolemia).

LOW-ER drugs (ER <0.3): methadone, diazepam, warfarin, phenytoin — clearance is CAPACITY-LIMITED (enzyme-dependent); reduce dose in hepatic enzyme failure, cirrhosis, P450 inhibition.

INTERMEDIATE-ER drugs (alfentanil, midazolam ER ~0.4-0.6) are affected by both.

One-compartment model: single first-order decay with elimination half-life t1/2 = 0.693 × Vd / CL — applies to small-Vd, slowly-distributing drugs (heparin, NMBs).

Two-compartment: initial rapid distribution phase (alpha t1/2) reflects movement from central compartment (plasma + well-perfused organs) into peripheral (muscle, skin); then slower elimination phase (beta t1/2) — applies to most anesthetic IVs (propofol, midazolam, opioids).

Three-compartment: adds a deep peripheral compartment (fat) — applies to highly lipophilic drugs (fentanyl, sufentanil, thiopental).

The deep compartment is why fentanyl has a long terminal half-life (~4 hr) but rapid offset after a single bolus — offset is by redistribution, not elimination.

Context-sensitive half-time (CSHT) = time for plasma concentration to fall by 50% AFTER stopping an infusion of given duration.

At infusion durations >4 hr: remifentanil CSHT ~4 min (constant — extrahepatic esterase metabolism, no compartmental accumulation), alfentanil ~50-60 min, sufentanil ~30 min (paradoxically shorter than alfentanil at long durations because of higher CL despite higher Vd), fentanyl >250 min, propofol ~50 min, midazolam ~80 min.

Clinical implication: for long cases or ICU sedation where rapid wake-up is desired, remifentanil + propofol minimize accumulation; fentanyl by infusion (>4 hr) leads to prolonged emergence.

Acidic drugs (warfarin, phenytoin, NSAIDs, barbiturates, diazepam) bind albumin.

Basic drugs (lidocaine, bupivacaine, fentanyl, alfentanil, propranolol, antidepressants) bind alpha-1-acid glycoprotein (AAG).

Highly protein-bound drugs (>90%): warfarin 99%, diazepam 98%, propofol 98%, bupivacaine 95%, fentanyl 84%.

Hypoalbuminemia (cirrhosis, nephrosis, malnutrition, sepsis, burns) increases free fraction of acid drugs — reduce loading dose of phenytoin, warfarin; check FREE phenytoin level in cirrhosis.

AAG is an acute-phase reactant — RISES in surgery, MI, RA, cancer → DECREASES free fraction of basic drugs (lidocaine apparent toxicity threshold rises).

Pregnancy: ↓albumin + ↓AAG → modestly increased free fraction.

Pregnancy: ↑plasma volume + ↑CO + ↓protein binding + ↑hepatic enzyme activity + ↑GFR — net effect is drug-specific.

Moderate-duration case (1-3 hr): fentanyl bolus then small redoses, or sufentanil infusion 0.5-1.5 mcg/kg/hr.

Long case where rapid emergence is critical (obese, OSA, neuro): remifentanil 0.1-0.3 mcg/kg/min — flat CSHT means stopping the infusion 5 min before extubation predictably restores ventilation.

ICU sedation requiring breakthrough analgesia later: avoid fentanyl infusion >4-6 hr; use intermittent boluses or transition to hydromorphone/methadone for chronic pain control.

The CSHT chart is the single most useful PK tool in the anesthetic workspace.