STEPTRACKERPHARMACOLOGY | PHARMACOKINETICS | HIGH-YIELD REVIEW

Absorption, Distribution & Volume of Distribution

How much of a dose reaches the blood, and where it goes once there — the numbers behind loading doses, dialysis decisions and drug interactions.

FOCUS ON

Bioavailability (F) = fraction of an oral dose reaching systemic circulation unchanged (IV = 100%); ↓ by poor absorption and first-pass hepatic metabolism (nitroglycerin, morphine, propranolol, lidocaine). Volume of distribution: Vd = amount in body ÷ plasma concentration. Low Vd (≈ 3–5 L) → drug stays in plasma (large, charged, highly protein-bound: heparin, warfarin); medium (≈ 14–40 L) → extracellular/total body water (aminoglycosides, ethanol); high (> 40 L, up to hundreds) → tissues and fat (amiodarone, digoxin, TCAs, chloroquine). High-Vd drugs are not removed by dialysis. ↑ Vd in liver/kidney disease (↓ albumin, edema) and in obesity for lipophilic drugs. Protein binding: only free drug acts; displacement (sulfonamides, valproate) raises free levels of warfarin, phenytoin and bilirubin.

CONCEPT

DEFINITION · FORMULA

WHAT CHANGES IT

CLINICAL EXAMPLE

Absorption

Movement from the site of administration into blood; mostly passive diffusion of the non-ionized (lipid-soluble) form

pH and pKa, surface area, gut motility, food, chelation

Tetracyclines and fluoroquinolones bind Ca²⁺, Mg²⁺, Fe²⁺

Ionization & trapping

Weak acids are non-ionized in acid; weak bases in base · ionized drug is trapped in the opposite pH

Urine pH

Alkalinize urine for weak acids (aspirin, phenobarbital, methotrexate) · acidify for weak bases (amphetamines — rarely done)

Bioavailability (F)

AUC oral ÷ AUC IV × 100%

First-pass metabolism, incomplete absorption, efflux pumps (P-gp)

Oral morphine dose ≈ 3× IV dose

First-pass effect

Portal blood → liver metabolizes drug before systemic circulation

Bypassed by sublingual, IV, transdermal, rectal (partly) routes

Sublingual nitroglycerin · cirrhosis/portosystemic shunts ↑ bioavailability

Volume of distribution

Vd = dose (amount in body) ÷ plasma concentration

Lipophilicity, protein binding, tissue binding, body composition

Apparent volume — can exceed body size

Low Vd (plasma)

≈ 3–5 L

Large, charged or highly albumin-bound molecules

Heparin, warfarin, large proteins

Medium Vd (ECF / TBW)

≈ 14–40 L

Small hydrophilic molecules

Aminoglycosides (ECF), ethanol (TBW)

High Vd (tissues)

> 40 L

Lipophilic or tissue-bound

Amiodarone, digoxin, TCAs, chloroquine · poorly dialyzable

Plasma protein binding

Albumin binds acids; α1-acid glycoprotein binds bases

Hypoalbuminemia (nephrotic, cirrhosis, malnutrition), displacement

↑ free phenytoin with low albumin · sulfonamides displace bilirubin → kernicterus

Barriers

Blood-brain barrier, placenta

Lipid solubility, P-glycoprotein efflux, inflammation

Meningitis ↑ penicillin entry · lipophilic drugs cross the placenta

Dialyzable drugs

Low Vd, low protein binding, small, water-soluble

—

Lithium, salicylates, methanol, ethylene glycol, metformin, theophylline

Mechanism — why Vd decides the loading dose

Target plasma level (Cp)

→

Loading dose = Cp × Vd ÷ F

→

Large Vd → large loading doseDigoxin, amiodarone

The loading dose depends on Vd only; it is unchanged in renal failure. The maintenance dose depends on clearance.

Vd categories

COMPARTMENT

EXAMPLES

Low

Plasma

Heparin, warfarin

Medium

Extracellular / total water

Aminoglycosides, ethanol

High

Tissues, fat

Amiodarone, digoxin, TCAs

How it's tested

COMMON CONFUSIONWeak acid overdose (aspirin) → alkalinize urine with bicarbonate to trap the ionized form; the drug's pKa tells you which way.

THE TRAPA drug with a huge Vd (TCAs, digoxin) is not cleared by hemodialysis, however toxic the patient — use antidotes or binding agents.

YOUR APPROACHRoute → bioavailability → Vd category → protein binding → what a disease state or second drug changes.

If you see… think…

Oral dose much larger than IV dose → first-pass metabolism

Nitroglycerin given under the tongue → bypass first pass

Vd ≈ 4 L → drug confined to plasma

Vd ≈ 500 L → extensive tissue binding (not dialyzable)

Loading dose formula → Cp × Vd ÷ F

Treatment that speeds aspirin excretion → urine alkalinization

Toxic phenytoin effects with normal total level, low albumin → ↑ free fraction

Kernicterus after a sulfa drug in a newborn → bilirubin displaced from albumin

Antacid with ciprofloxacin → chelation, poor absorption

Overdoses cleared by hemodialysis → lithium, salicylates, toxic alcohols, metformin