2021B03 a) Define “volume of distribution”. What factors influence the size of the volume of distribution? b) How may it be used in the calculation of a loading dose? What assumptions are made in this calculation?

 

List:

·     Theory

·     Determinants

·     Application

 

Theory:

Definition

·      The volume into which a substance appears to be dispersed based on relationship between dose and plasma concentration

·      Not a physical volume

·      Can be larger than total body volume

Subtypes

·      Body is not homogenous

·      Drugs given or absorbed into plasma, then distributed

·      Require multicompartmental modelling

·      Central VD: prior to distribution (e.g. propofol 0.3-0.6L/kg)

·      Steady state VD: after distribution (e.g. propofol 4L/kg)

Location

·      <40mL/kg: plasma (e.g. warfarin)

·      <200mL/kg: ECF (e.g. rocuronium)

·      <600mL/kg: TBW

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

 

Determinants:

Drug

↑VD:

·     Small (e.g. propofol)

·     Non-polar, lipophilic (e.g. fentanyl)

·     Tissue protein binding (e.g. amiodarone 70L/kg)

↓VD:

·     Large (e.g. suxamethonium)

·     Polar, hydrophilic (e.g. suxamethonium)

·     Plasma protein-bound (e.g. warfarin 0.1L/kg)

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

 

Application:

Measurement

·      Administer known amount of drug

·      Measure subsequent plasma concentration

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

Equations

·      VD = amount of drug / measured concentration
(loading dose = VD x desired concentration)

·      VD = clearance / rate constant

Assumptions

·      Single compartment

·      100% bioavailability

·      Equilibration complete

·      No metabolism or excretion prior to blood sampling

Use

·      Calculate loading dose (e.g. amiodarone)

·      Predict offset after drug infusion (e.g. propofol TCI models)

 

 

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