Drug distribution in special compartments Flashcards
Define special compartments
- breast milk
- CNS
- foetus
- bone and teeth
Define distribution and describe the factors that modify distribution
How drug is spread throughout the body
Distribution will depend on:
1. Permeability across tissue barriers
2. Binding within the compartments
3. pH partitioning
4. Fat:Water partitioning
Describe passage across blood capillaries
Capillaries in different organs display wide variation in drug permeability
However, most small to intermediate drugs gain access to interstitial fluid
(not the case for the brain, see later)
Via junctions, fenestrae, endocytosis/exocytosis, diffusion
Rate at which drugs leave the blood will depend on :
1. Lipid solubility
2. Molecular weight
3. Degree of protein binding
Describe the effect of capillary type on drug passage
- continuous: Many capillaries are continuous capillaries
Only allow diffusion of water and small solutes through intercellular clefts
e.g. skeletal and smooth muscle, connective tissues, lungs - fenestrated:
More permeable than continuous capillaries
Allow rapid exchange of fluid and solutes as large as small peptides
e.g. kidneys, villi of small intestine, choroid plexus - sinusoids:
Wider and more winding than other capillaries
Incomplete basement membrane, large fenestrations, very large clefts
Allow large proteins to pass through
e.g. liver, spleen
Describe mechanisms of passage of drug across cell membranes
- diffusion: dependent on molecular size, oil/water partition coefficient, ionisation state
- transport: isially, a str analogue of natural substrate of transporter
Describe the effect of permeability partition coefficient and size
permeability icnreasess as partiion coeff increases
partition coeffience relates oil to water
greater coeffcient means increased oil solubility
note:
not all drugs obey this, eg can be highly permeable with midrange partitional coefficeint
Describe effect of lipophilicity on membrane permeation
Lipid soluble drugs diffuse faster
Greater permeability
steeper concentration gradient
Describe effect of pH on drug permeation and steady state distribution
Many drugs are acids (A) or bases (B)
The ionised species is usually impermeable
(i.e. A- or BH +)
pH, therefore, determines:
(1) Rate at which drugs permeate membranes
(2) The steady state distribution of drug in aqueous compartments
Describe how pH contributes to weak acid/base partitioning
- a weak acid will be more greatly ionised in alkaline solution eg urine vs plasma or gastric juice - so it is largely found here
- a weak base eg pethidien, opioid analgesic, similar to morphone, will be partitioned to gastric juice e.f acid pH, as ionisation will be greatest here
Not realistic for two reason:
(1) There will be some diffusion of the charged species.
(2) Equilibrium is only rarely reached.
Important with respect to
renal excretion and
penetration through the
blood brain barrier
The stomach (and therefore gastric pH) is not a
key player in determining drug absorption from GIT
(mostly a surface area issue)
What happens to weak acids/bases when urine pH is altered?
What happens to CNS drugs that are weak acids/bases when plasma pH is altered?
Describe the four compartment model of drug distribution
Fur compartments: blood/vrg, muscle, fat, vrp is fourth
Order of drug distribution follows the degree
of perfusion of the different “groups”
1st
2nd
3rd
Capacity to accumulate
drug follows reverse order i.e. most in fat, then muscle, then VRGs
Then what could explain
the ‘Fat’ peak being
lower than that of
muscle?*
Describe the make up of the various comparmentse
VR: brain heart liver kid endo glands
muscl: and skin
fat
vessel poor: bone, ligament, cartilage
Describe drug distribution to different body compartments
TBW - small water sol eg etoh
EC eater - larger water sol e.g. manntirol
plasma- stongly bound plasma prote, Vlarge, or highly chareged eg heparin
Fat: highly lipid sol eg diazepam
bon- certian ions eg F-
Passage of drugs into CNS and brain:
Transcelluar water 2% of body fluid compartements
Blood flow to brain is very high
10 X greater than that to resting muscle
You might therefore expect that drugs would
equilibrate quickly between blood and brain.
Blood-Brain Barrier
Blood-CSF Barrier
True for some drugs
Very slow for many drugs
Practically not at all for others
Blood brain barrier:
Tight endothelial junctions
Absence of fenestrations
Diminished trans-endothelial vesicle movement
Forms a very good barrier for polar compounds
excluding >98% of small molecule drugs
Criteria to cross:
* Lipid soluble
* Molecular weight < 400 Daltons
* Not a substrate for an active transport process
(e.g. P-glycoprotein, Organic Anion-Transporting Polypeptide)
n.b. encepalities, mennigitis can inc perm –> IV vs Intrathecal
Distributiin into bone and teeth
eg tetracycline
Children on short or long term therapy with
tertracycline may develop permanent
discolouration of the teeth.
Risk highest in neonates and babies,
but up to the age of 8 years
Treatment of pregnant patients can
discolour teeth of their children
May depress bone growth in premature infants
(reversible if exposure is short)
Distribution of certain drugs into bone can have
therapeutic use - investigate
bisphosphonates
Distribution into breast milk
Almost all drugs pass into breast milk
Generally via passive diffusion
[Drug] in the milk is related to the maternal plasma [drug]
The M ilk to Plasma ratio can be used to describe this relationship (M/P ratio)
M/P ratio is affected by chemical properties of the drug and is different for different drugs
Can be used to estimate dose to the infant:
Infant Dose = [Maternal plasma] x M/P x Volume of milk
Milk contains more lipid, less protein and is slightly more acidic than plasma.
Therefore, drugs which tend to concentrate in milk:
* are weak bases
* have low plasma protein binding
* are highly lipid soluble
Distribution to foetus
Foetus can be considered as a special type of
compartment into which drugs can distribute
Drugs cross the placenta by:
* Simple diffusion
* Active transport
* Pinocytosis
* Filtration
Active transport can also prevent some drugs from crossing placenta
Passive diffusion of drugs across the placenta is determined by the drugs:
* molecular weight
* pKa
* lipid solubility
* protein binding
Drugs with molecular weight > 500 Da do not cross the placenta well
