Lecture 3 Distribution Flashcards
What are the two examples that disrupt pH-partition Hypothesis?
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
pH-Partition Hypothesis holds up under what circumstances?
1) When the membrane is tight
2) When there is a difference in pH on the sides of the barriers
What are the 4 membrane characteristics?
1) Tightness of junctions (BBB Vs Glomerulus)
2) Membrane thickness
3) Sink condition
4) Transporters present
What is going on when you see a bi-exponential decline in plasma drug concentrations?
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)
What is the difference between passive diffusion and mediated-carrier transport?
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.
What drives BBB permeability?
1) Partition Coefficient (LogP)
2) Substrate of Efflux/ Uptake transporter
3) Size/ Molecular weight
How do you know when the rate of distribution is perfusion rate limited?
When the membrane presents no barrier to distribution
1) Drug is very lipophilic
2) Drug is very small
What are the units for perfusion rate?
Volume of blood per minute per gram of tissue
Volume of blood per minute per volume of tissue
What are the important parameters and equations to calculate rate of distribution to a particular tissue?
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
How is distribution half life affected by perfusion?
Greater perfusion decreases half life [(ln2 x Kpb)/ (Q/ Vt)]
What is the effect of Kpb?
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
When is the rate of distribution permeability rate limited?
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)
Factors affecting permeability
1) Log P (Larger value better)
2) pKa (Important to determine fraction unionised)
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?
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
Is there a difference between Kpb and Kp?
Yes
Kpb = Ct/ Cb
Kp = Ct/ C
They are numerically different but mean the same thing
If Kpb or Kb is equal to 1 does that mean there is no barrier to distribution?
No it does not
What are the physiological volumes in a 70kg man?
Plasma water = 3L
Intracellular water = 27L
Interstitial Fluid = 12L
Total Body Water = 42L (60% body weight)
What is apparent volume of distribution?
It is the fluid volume in which a drug seems to be distributed to account for its plasma concentration
How is apparent volume of distribution determined?
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
What is the Free Drug Hypothesis?
It is that therapeutic effect is based on unbound concentrations of a drug (free drug)
What happens to free drug fraction? (Fu)
1) Distributed into tissues
2) Active at target
3) Metabolised
4) Eliminated
What are the plasma proteins available?
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
What plasma protein do acidic drugs tend to bind to?
Albumin
What plasma protein do basic drugs tend to bind to?
Alpha 1 acid glycoprotein
What are the 3 different inter-individual variations for plasma protein binding?
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)
What is Fu,p?
Fraction of unbound plasma proteins = Free proteins/ Total proteins
What is the relationship between fu and fup?
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)
What is the effect of fu on V?
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)
What is Gibaldi and McNamara Model and when is it used?
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)
What is Oie and Tozer Model and when is it used?
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
What does V, Fu, and FuT tell you?
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)
Is Cu dependent on Fu?
NO, Cu is insensitive to plasma protein binding
What happens to Cu/C when fu changes?
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
What is the difference between Gibaldi&McNamara Model and Oie&Tozer Model?
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
