558 - 2: Volume of Distribution (VD)
Weight of water
1 kg/L
Calculate VD in a one compartment model given dose & C at some time other than Co
1) Co = C/e^-(kt) 2) VD = D/Co
Variability (Drugs)
1) DDI --> PB changes 2) Changes in hydration status
A drug in a human body is either in the?
1) Plasma 2) Periphery
Factors which influence VD
1) Plasma protein binding (fu) 2) Tissue binding (fut) 3) Volume of plasma (Vp) 4) Volume of the tissue (Vt)
Variability (Diseases)
1) Volume shifts 2) PB changes 3) Tissue Binding changes 4) Protein concentration changes
Variability
1) Weight 2) Hydration status 3) Diseases 4) Genetics 5) Age 6) Drugs 7) Gender/pregnancy
Drugs concentration that decrease VD tend to reside where?
Plasma
Inter-Drug Variability - Different Drugs
Protein binding Lipophilicity pKa Affinity for tissue (ex. receptors) Ability to cross membranes
Intra-Patient
Same Drug Same Patient
Intra-Drug Variability
Same Drug/Different Patients The same drug will exhibit a range of VD in different patients
When is Vp considered in terms of VD?
Small (<20L) VD
Calculate VD in a one compartment model given the dose & Co
VD = D/Co
Large, polar drugs that do not enter cells (AGS)
Vt = ECF - plasma
Small, non-polar drugs which can gain entry into cells (Caffeine & EtOH)
Vt = TBW - plasma
Can a change in VD result in a change in half-life?
Yes Cl = KV Increase VD / increase half-life
Total Body Water (TBW)
60%
Human Volume (L) is Close to Weight (kg)
70 kg is about 70L
Volume of Distribution (VD)
A proportionality constant that relates the amount of drug in the body to serum concentration It is the volume of fluid that the drug would occupy if it was evenly distributed through that volume at the concentration measured in the serum
Serum Volume
Approximately 3L Remove clotting factors from plasma
Volume of plasma (Vp)
Approximately 3L Very narrow range
Blood Volume
Approximately 5.5L
What happens if Vp decreases?
Dehydration & death
What happens if Vp increases?
High BP & leak everywhere
Would drugs that can gain entry into cells have a high or low VD than drugs that cannot?
High VD
Plasma Volume
Increase Vp / increase VD Approximately 3L Extract formed elements: WBCs, RBCs, and plates from blood
Volume of the tissue (Vt)
Increase Vt / increase VD 1) Weight proportional to VD/related to Vt 2) Does the molecule pass through cell membranes?
Fraction unbound in the plasma (fu)
Increase fu / increase VD Decrease fu / decrease VD
Fraction unbound in the tissue (fut)
Increase fut / decrease VD / decrease tissue binding Decrease fut / increase VD / increase tissue binding
Drugs concentration that increase VD tend to reside where?
Outside of plasma (periphery)
Extracellular Fluid (ECF)
25% Interstitial fluid - 21% Plasma - 4%
Intracellular Fluid
35%
AGS
4 kg - 0.25 L for 70 kg - 17.5
Theophylline
4 kg - 0.5 L for 70 kg - 34
Diphenylhydantoin or Phenytoin (DPH)
4 kg - 0.65 L for 70 kg - 45.5
Li, Vanco, Phenobarbital
4 kg - 0.7 L for 70 kg - 49
Quinidine
4 kg - 2.7 L for 70 kg - 189
Digoxin
4 kg - 7.3 L for 70 kg - 511
Non-H2O
40%
