Lecture 6 - Drug distribution Flashcards
Describe drug distribution
Process by which drug reversibly leaves blood stream and enters the interstitium and/or cells of the tissues
what does the delivery os a drug from plasma to the interstitium primarily depend on?
- blood flow
- capillary permeability
- degree of binding of the drug to plasma and tissue proteins
- relative hydrophobicity of the drug
why does blood flow to tissue capillaries vary?
consequence of unequal cardiac output to various organs
what is capillary permeability dertermined by?
- capillary structure
- drug structure
give an example of drugs transported through emdothelial cells of capilaries of CNS
levodopa
what drugs can/cannot penetrate the CNS?
lipid soluble drugs readily penetrate the CNS
ionised or polar drugs unable to pass through the endothelial cells of the CNS
what do hydrophilic drugs go through ?
slit junctions
what sequesters drugs in non- diffusible form?
reversible binding to plasma proteins
is binding to plasma proteins selective or non?
non
what does a small Vd mean?
drug stays mostly in blood
how many litres of water are in the body parts?
total = 42
intracellular = 28
extra= 14
- interstitial = 10
- plasma = 4
what happens if Drug has a large MW or binds extensively to plasma proteins?
too large to move out through slit junctions of capillaries - drug trapped within the plasma
- limits to vascular compartment
what is the Vd for drugs confined to plasma vascular compartment ?
4 litres (6% of body weight in a 70kg person)
what happens if drugs have low molecular weight + hydrophillic properties ?
- can move into interstitial fluid but cannot enter cells
- distribute within extraceullular fluid
- moves through slit junctions into interstitial fluid
- unable to cross lipid membrane of cells + enter intracellular fluid
what is the Vd for extracellular fluid ?
20% body weight or 14 L in 70 kg person
what can ow MW and hydrophobic do?
move through capillary walls and cross cell membranes
what is VD for low mw and hydrophobic ?
60% bw
42 L in 70kg
By binding to ______ ____ (e.g. albumin) –
the drug is effectively ‘trapped’
plasma proteins
what does albumin have the strongest affinity for?
anionic (weak acids) and hydrophobic drugs
(most hydrophillic and neutral drugs do not bind to albumin)
what are the 2 classes of drugs with high affinity for albumin ?
- dependent on dose of the drug
- dependent on binding capacity of albumin
compare class 1 vs class 2 drugs in terms of ablunim binding dose/ cap ratio?
class 1 - low dose high cap
more binding sites
free active drug - low
class 2 - high dose low cap
limited binding sites
high active drug- high
explain administration of class 1 and 2 drug
Class II drugs displace Class I drugs from albumin, increasing the free (active) drug level. This can cause a sudden, stronger drug effect until a new balance is reached.
give an example of clinical displacement
interaction between
tolbutamide (class I
drug; 95% protein bound,
) and sulphonamide
antibiotic (class II drug, )
what does displacement impact largely depend on?
Vd
large - displaced drug moves into tissues, plasma levels change
small- drug stays in blood causing a bigger increase in plasma concentration - stronger effects or toxicity
