Pharmacokinetics II Flashcards
Describe distribution
Drugs carried in plasma water, bulk flow of water/drug taken out by hydrostatic pressure
Barriers - Blood-Brain barrier, Placenta
Describe the factors affecting rate and extent of distribution
Regional blood flow
Lipid solubility
Plasma protein binding
Describe regional blood flow
Rate of entry into tissues depends on rate of blood flow through capillary beds
Well-perfused tissues: Kidneys, heart, lungs, brain
Moderate: Muscle, skin
Slowly: Fat
Negligibly: Bone
Describe the distribution of bodily fluids
Drug molecules in both free/bound solution forms
Weak acid/base exist in equilibrium or charged/non-charged depending on pH
What does distribution depend on?
Permeability across tissue barriers
Binding within areas
pH partition
Fat (water partition)
What is Kc dependent on?
Permeability of barriers
pH of areas
Binding capacity
Describe the distribution of bodily fluids in terms of body water
TBW of body weight varies from 50-70% Liquid in body: 60% of body weight ECF: Blood plasma 5%, ISF 16%, Lymph ICF: All cell content 35% Transcellular fluid 2%: Cerebrospinal, intraocular, peritoneal, pleural, synovial, digestive secretions Fat: 20%
What is the volume of distribution (Vd)?
Theoretical volume that would be needed to distribute a drug it found at same conc through body as measured in serum
Describe the link between binding of a drug and Vd
Binding of a drug outside plasma compartment or partitioning into body fat increases Vd beyond TBW
Describe a high Vd
Non-polar
High lipid solubility
Low ionisation rate
Low plasma protein binding
Describe a low Vd
Polar
Low lipid solubility
Ionised
Plasma bound
Describe the uses of Vd
Planning dose regimens
Interpreting drug interaction when protein binding displacement is weird
If poisoned, whether drug can be cleared by haemodialysis (if Vd low)
Describe Vd in obesity
Larger fraction of body weight in fat
TBW smaller % of BW
Plasma levels altered Adjust dose
Describe Vd in infants and pregnancy
Infant: TBW larger % BW
Vd appears larger
Pregnancy: Blood volume, extracellular water and subcutaneous fat increase
Vd may increase for drugs in TBW
Describe plasma protein binding
Free form - Active
Drug-protein complex - Inactive. Eg b-globulins, Albumin
Describe albumin
Most vital binding protein in plasma/ISF
Binds mainly acidic drugs
Overall negative charge at blood pH
Describe the binding to Albumin
Basic drugs: Bind high capacity but low affinity (many bound but readily released)
Acidic drugs: Bind low capacity but high affinity (saturation of binding site unlikely = Little bound, not readily released)
Describe the clinical problems with plasma protein binding
Competition between drug/endogenous ligand
Competition between drugs for same binding sites on albumin (leads to toxicity/bleeding)
Bound drug usually inactive
Can increase/decrease elimination by kidney/liver
Describe what happens if a drug has a large Vd
Amount of drug in plasma reflect small portion of that in entire body
Displacement from plasma proteins causes negligible effect on conc of free drug
Summarise the distribution of drugs within the body
Most drugs absorbed by first-order process.
Steady-state - Equilibrium point where amount of drug administered exactly replaces amount of drug excreted
