Lecture 3 Distribution

Question 1

What are the two examples that disrupt pH-partition Hypothesis?

Answer 1

1) Weakly acidic drugs generally exist in their unionised forms in the acidic environment of the stomach but are not mainly absorbed there
2) Drugs injected via IM or SC all still fully absorbed regardless of charge and size due to fenestration of capillaries

Question 2

pH-Partition Hypothesis holds up under what circumstances?

Answer 2

1) When the membrane is tight
2) When there is a difference in pH on the sides of the barriers

Question 3

What are the 4 membrane characteristics?

Answer 3

1) Tightness of junctions (BBB Vs Glomerulus)
2) Membrane thickness
3) Sink condition
4) Transporters present

Question 4

What is going on when you see a bi-exponential decline in plasma drug concentrations?

Answer 4

1) Distribution kinetics (Drug goes from plasma to distribution with elimination also present)
2) Elimination kinetics (Distribution equilibrium is achieved and just elimination is present)

Question 5

What is the difference between passive diffusion and mediated-carrier transport?

Answer 5

Relationship between passive diffusion and drug concentration is linear (First order).

Relationship between mediated-carrier transport and drug concentration plateaus due to the transporters becoming saturated at a certain concentration level.

Question 6

What drives BBB permeability?

Answer 6

1) Partition Coefficient (LogP)
2) Substrate of Efflux/ Uptake transporter
3) Size/ Molecular weight

Question 7

How do you know when the rate of distribution is perfusion rate limited?

Answer 7

When the membrane presents no barrier to distribution
1) Drug is very lipophilic
2) Drug is very small

Question 8

What are the units for perfusion rate?

Answer 8

Volume of blood per minute per gram of tissue
Volume of blood per minute per volume of tissue

Question 9

What are the important parameters and equations to calculate rate of distribution to a particular tissue?

Answer 9

1) Rate of presentation of drug to tissue = Blood flow x Concentration at artery (Q x Ca) mg/min
2) Rate of uptake = Blood flow x Concentration at artery minus vein [Q x (Ca-Cv)] mg/min
3) Max uptake = Q x Ca mg/min; When drug just enters the body
4) Min uptake = 0 mg/min; After distribution equilibrium
5) Amount of drug in tissue at distri eqm = Volume of Tissue x Concentration of Tissue (Vt x Ct)/ (Vt x Kpb x Ca)/ (Vt x Kpb x Cv)
6) Tissue-to-blood eqm ratio (Kpb) = Concentration in tissue/ Concentration in blood (Ct/Cb)
7) After stopping infusion, rate of drug leaving tissue = Distribution rate constant x Amt of drug in tissue (Kt x Vt x Kpb x Cv) = (Q x Cv)
8) Distribution rate constant (Kt) = Perfusion / Tissue ratio [(Q/ Vt)/ Kpb]
9) Distribution half life = ln2/ Kt

Question 10

How is distribution half life affected by perfusion?

Answer 10

Greater perfusion decreases half life [(ln2 x Kpb)/ (Q/ Vt)]

Question 11

What is the effect of Kpb?

Answer 11

Different tissues have different Kpb values for different drugs, higher Kpb increases half life as the drug has a greater tendency to bind to the tissues

Question 12

When is the rate of distribution permeability rate limited?

Answer 12

When the drug has trouble crossing the membrane
1) Same drug but different membrane (Diff physiological properties)
2) Same membrane but different drug (Diff physiochemical properties)

Question 13

Factors affecting permeability

Answer 13

1) Log P (Larger value better)
2) pKa (Important to determine fraction unionised)

Question 14

A patient is overdosed with phenobarbital (log P = 1.5; pKa 7.3 (weak acid); Half life = 2-7 days) what can you do to treat this patient?

Answer 14

Change the pH of the urine, making it more basic such that phenobarbital has a higher fraction in the ionised form for greater excretion in urine

Question 15

Is there a difference between Kpb and Kp?

Answer 15

Yes
Kpb = Ct/ Cb
Kp = Ct/ C
They are numerically different but mean the same thing

Question 16

If Kpb or Kb is equal to 1 does that mean there is no barrier to distribution?

Answer 16

No it does not

Question 17

What are the physiological volumes in a 70kg man?

Answer 17

Plasma water = 3L
Intracellular water = 27L
Interstitial Fluid = 12L
Total Body Water = 42L (60% body weight)

Question 18

What is apparent volume of distribution?

Answer 18

It is the fluid volume in which a drug seems to be distributed to account for its plasma concentration

Question 19

How is apparent volume of distribution determined?

Answer 19

Dose (mg)/ Initial Plasma Conc. (mg/ L)

Assuming,
One compartment model due to cardiac output of 6 L/min

OR

Amt = Vol of plasma (3L) x Conc in plasma + Vol of tissue (39L) x Kp x Conc in plasma

As Amt = Vol x Conc

Vol = Vol of plasma + Kp x Vol of tissue

Question 20

What is the Free Drug Hypothesis?

Answer 20

It is that therapeutic effect is based on unbound concentrations of a drug (free drug)

Question 21

What happens to free drug fraction? (Fu)

Answer 21

1) Distributed into tissues
2) Active at target
3) Metabolised
4) Eliminated

Question 22

What are the plasma proteins available?

Answer 22

1) Albumin (Highest conc.) => Most drugs => Low affinity
2) alpha 1 acid glycoprotein => Lipophilic amines => Low affinity
3) Lipoproteins => Lipophilic drugs => Low affinity
4) Transcortin => Corticosteroids => High affinity

Apart from albumin other 3 are easily saturated

Question 23

What plasma protein do acidic drugs tend to bind to?

Answer 23

Albumin

Question 24

What plasma protein do basic drugs tend to bind to?

Answer 24

Alpha 1 acid glycoprotein

Question 25

What are the 3 different inter-individual variations for plasma protein binding?

Answer 25

1) Variation in drug-protein affinity (Mutation in binding site)
2) Variation in circulating level of proteins (Liver disease lowers albumin synthesis; Albumin leaked from renal disease; Inflammation increases alpha 1 AGP production)
3) Drug-drug interactions (Inducer of plasma proteins; Chemical changes to proteins during synthesis)

Question 26

What is Fu,p?

Answer 26

Fraction of unbound plasma proteins = Free proteins/ Total proteins

Question 27

What is the relationship between fu and fup?

Answer 27

Fu = 1/ (1 + Ka x fup x Pt)
Fraction drug unbound = 1/ (1 + Association constant x Fraction protein unbound x Total protein)
Assume Ka x fup x Pt is very large

Approx.
Fu = 1/(Ka x Fup x Pt)

Question 28

What is the effect of fu on V?

Answer 28

For drugs with high V, changes in fu is significant (>1, 1 x 70kg = 70L)
For drugs with low V, changes in fu is minimal (<0.2, 0.2 X 70kg = 14L)

Question 29

What is Gibaldi and McNamara Model and when is it used?

Answer 29

V = Vp + Vt x (fu/ fuT)
Volume of distr = Vol of plasma + Vol of tissues x (Unbound in plasma/ Unbound in tissues)
Vol of plasma = 3L
Vol of tissues = Up to 39L

Assumes that albumin only exists in plasma but albumin also exists in interstitial space

This is more suitable to calculate for drugs with large V (>15)

Question 30

What is Oie and Tozer Model and when is it used?

Answer 30

V = 7.5 + (7.5 + Vr/ Fur) x Fu

Vr = Intracellular water volume
Fur = Fraction unbound in cell

Assume drug does not permeate into the cells therefore Vr = 0
Scenario 1: Fu = 1, V = 15L = Plasma Vol (3L) + Interstitial Fluid (12L)

Scenario 2: Fu = 0, V = 7.5L = Volume of plasma albumin

Question 31

What does V, Fu, and FuT tell you?

Answer 31

Fu tells us about the affinity of the drug to plasma proteins
FuT tells us about the affinity of the drug to tissue proteins
V tells us whether the drug is found more in tissue (>42L) or in the plasma (<42L)

Question 32

Is Cu dependent on Fu?

Answer 32

NO, Cu is insensitive to plasma protein binding

Question 33

What happens to Cu/C when fu changes?

Answer 33

Cu remains constant but C changes accordingly

This is because any extra unbound drug will go into the tissue instead only for drugs with high V

Question 34

What is the difference between Gibaldi&McNamara Model and Oie&Tozer Model?

Answer 34

G&M: Only considers 2 compartments Plasma (3L) and Others (≤39L because sometimes BBB is inaccessible so CNS fluid not included) = More suitable for drugs with a large V

O&T: Considers 3 compartments plasma (3L), interstitial (12L) and intracellular (≤27L), suitable for drugs that have high affinity to albumin regardless of V

V of Albumin = 7.5L