Drug Distribution

Question 0

Blood flow perfusion

Answer 0

Highly perfused lean tissue group-> blood cells, heart, lung, liver, kidney, glands, brain
Poorly perfused lean tissue group-> muscle, skin
Fat group-> adipose! bone marrow
Negligible perfusion-> teeth, hair, bone, tendon, cartilage

Question 1

Distribution

Answer 1

Movement of drug from circulating blood to sites of action, binding and elimination
Rate and extent depends on
-> relative arterial blood perfusion rate of different organs
-> permeability characteristics of barrier
-> binding in blood or tissues

Question 2

Thiopental

Answer 2

Highly lipid soluble IV induction anaesthetic
Unconscious in 20 secs, lasts 5-10 mins
Elimination half life is 10 hours
Crosses BBB quickly -> rapid induction
Redistribution pulls thiopental from the brain-> muscle and fat

Question 3

1 compartment model

Answer 3

Often the behaviour of oral dosing
Drug stays in one compartment
Or is so slowly redistributed that elimination happens first
Straight line graph

Question 4

2 compartment model

Answer 4

Distributed in to the periphery then back in to blood for elimination
a phase-> curve-> drug is distributing,elimination also starts
b phase-> straight line-> at point of change the drug has redistributed-> elimination phase
Can extrapolate elimination phase back to get Ct0

Question 5

3 compartment model

Answer 5

Distributed in to periphery and deep (binding sites on fats and muscle)

Question 6

Permeability factors

Answer 6

Most capillary endothelial have large intracellular pores-> passage by bulk flow -> virtually all drugs gain access to intersitial fluid
Ability to enter cells is determined by lipid solubility
Kidney-> diffusion and filtration dependent on molecule size
Liver-> sinusoid all endothelium incomplete-> drugs have easy access

Question 7

BBB

Answer 7

Few intracellular pores
Numerous tight junctions
Surrounded by glial cells
Lipid soluble drugs can cross
Water soluble/ionised can't 
Less effective in meningitis-> can give antibiotics that wouldn't get through 
Some drugs taken up by active transport 
Exit from brain by reversal of conc gradient or CSF

Question 8

Placenta

Answer 8

Lipid soluble drugs can cross -> risk of teratogenic effects and neonatal toxicity
Water soluble drugs much slower
Highly ionised cross at high doses
Elimination from fetus is by diffusion back across
Replace warfarin with heparin
Don’t use sodium valproate

Question 9

Tissue localisation

Answer 9

Reversible:
PH differences 
Protien binding 
Solution in fat
-> may cause side effects
Irreversible:
Chelation (tetracycline)-> covalent binding of drug/metabolite-> binds Ca-> discolours teeth

Question 10

Plasma protein binding

Answer 10

Readily reversible, rapid, pH dependent, transport system
Many acidic drugs bind a common site on albumin -> drug interactions-> displacement-> increased elimination of unbound drug country’s this
Some basic drugs bind a acid glycoprotein
Some drugs get saturation of binding-> marked free conc increase
Only unbound drugs transferred across membranes, pharmacologically active and metabolised or excreted

Question 11

Volume of distribution

Answer 11

Apparent volume of fluid in which the total dose of the drug is distributed at the same conc as in plasma
Measure before elimination

Question 12

Using Vd to work out where drug is

Answer 12

Vd-> 3l-> drug distributed only in plasma
12-> plasma and intersitial fluid
40-> total body wat
>40 -> drug bound to tissues
Drugs which remain in plasma -> heparin! plasma expanded, monoclonal antibodies
Drugs with limited distribution->
-> lipid soluble, bound tightly to plasma protiens-> warfarin, ibroprofen
-> polar water soluble drugs-> nm blockers, penicillins, aminoglycosides, cephalosporins
Drugs which are extensively distributed->
-> highly lipid soluble-> anaesthetics, opiods, beta blockers,
-> drugs with marked tissue localisation -> griseofulvin, amidarone