2013C05 Discuss the concept of volume of distribution.
How may it be used in the calculation of a loading dose?
What assumptions are made in this calculation?

 

List:

·      Definition and key features

·      Determinants

 

Volume of distribution: key aspects

Definition

·  The volume into which a substance appears to be dispersed

·  Not a physical volume

·  Can be larger than total body volume

Units

·  L/kg body weight

Equations

·  VD = amount of drug / measured concentration

·  VD = clearance / rate constant

Measurement

·  Administer known amount of drug

·  Measure subsequent plasma concentration

·  VD = n / C (where ‘n’ is the total bioavailable amount)

Assumptions

·  Single compartment

·  100% bioavailability

·  Equilibration complete

·  No metabolism or excretion prior to blood sampling

Location

·  <40mL/kg: plasma (e.g. warfarin)

·  <200mL/kg: ECF (e.g. rocuronium)

·  <600mL/kg: TBW (e.g. ?)

·  >600mL/kg: fat (e.g. propofol) or tissue protein-bound (e.g. amiodarone)

Subtypes

·  Body is not homogenous

·  Drugs given or absorbed into plasma, then distributed

·  Require multicompartmental modelling

·  VDC (central): prior to distribution (e.g. propofol 0.3-0.6L/kg, predicts usual dose)

·  VDSS (steady state): after distribution (e.g. propofol 4L/kg, predicts lethal dose)

Use

·  Allows calculation of loading dose to expedite steady state (e.g. amiodarone infusion then tablets)

 

Volume of distribution: determinants

Drug factors (most important)

↑VD:

·   Small (e.g. propofol)

·   Non-polar, ↑lipid solubility (e.g. fentanyl)

·   Low % plasma protein binding (e.g. ketamine)

·   ICF sequestration (e.g. amiodarone 70L/kg)

↓VD:

·   Large (e.g. suxamethonium)

·   Polar, ↓ lipid solubility (e.g. suxamethonium)

·   ↑Plasma protein binding (e.g. warfarin 0.1L/kg)

Special physiology

·  Neonate: ↑total body water, ↑VD water soluble drugs

·  Pregnant: ↑muscle, ↑adipose, ↑water; ↑VD most drugs

·  Elderly: ↓muscle, ↓water, ↑%adipose: ↓VD water soluble drugs

Pathology

·  Fluid overload (heart/liver/kidney failure): ↑VD water soluble drugs

·  ↓Plasma proteins (e.g. liver failure): ↑VD highly plasma protein bound drugs

·  If low hepatic extraction ratio: ↑↑Free drug -> ↑↑effect (e.g. phenytoin)

·  Dehydration: ↓VDC most drugs (e.g. propofol), ↓VDSS water-soluble drugs

 

 

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