Pharmacokinetics I - Lecture 3

Question 1

Factors that Determine Rate and Extent of Drug Distribution

Answer 1

Blood flow and tissue mass/volume
Capillary permeability
Lipid solubility of the drug
Extent of drug ionization and tissue pH
Transport mechanisms available
Extent of drug binding to plasma and tissue proteins

Question 2

Significance of Blood Flow and Tissue Mass/Volume

Answer 2

Larger mass of muscle —> accumulates more drug, but lower CO/mass slows time to reach pharmaceutical effect

Question 3

What is necessary to produce a pharmacological effect?

Answer 3

Critical drug concentration

Question 4

Capillary permeability

Answer 4

Peripheral capillaries are porous - liver and kidney extremely porous

Capillaries in brain are non-porous - tight junctions and astrocyte foot form BBB to preclude bulk flow, so drugs MUST enter via passive diffusion or transporters

Question 5

Lipid solubility of drug vs lipid content of tissue

Answer 5

Highly lipophilic drugs tend to accumulate in fatty tissues, therefore slower to leave fat and body

Question 6

Extent of ionization of drug in the different body fluids

Answer 6

pH in cell is usually lower (more acidic) than plasma (basic media)

Question 7

For drugs transported by passive diffusion…

Answer 7

WA: [drug] higher in plasma (higher pH, basic)

WB: [drug] higher inside the cell (lower pH, acidic)

Question 8

Weak Acid Drugs

Answer 8

Higher concentration in plasma

Question 9

Weak Basic Drugs

Answer 9

Higher concentration inside the cell

Question 10

Ion Trapping

Answer 10

Concentration of charged species is higher in tissue than in plasma and the drug accumulates in tissue

Acidic drugs trapped in basic environments and vise Versa

Question 11

Compounds charged at all physiological pHs…

Answer 11

Diffuse poorly across lipid membrane and rely on carrier-mediated transport to cross the membrane

Question 12

Nicotinic cholinergic receptor antagonist

Answer 12

Blocks ACh binding

Question 13

Skeletal muscle relaxant targets…

Answer 13

Diaphragm

Question 14

Apparent Volume Distribution (Vd)

Answer 14

Relationship between the amount of drug in the body via IV (X0) and the concentration of drug in the plasma (Cp) immediately after admin

Question 15

How is the immediate concentration determined?

Answer 15

Non-linear regression and extrapolate regression back to T=0

Question 16

Inverse Relationship of Cp and Vd

Answer 16

For a constant drug (X0):
Decreased Cp = increased Vd
Increased Cp = decreased Vd

Question 17

What does Vd represent?

Answer 17

When a drug is injected into the bloodstream and allowed to distribute to the different tissues of the body, a certain plasma concentration (Cp) is obtained

Vd equals the volume that X0 occupiers in body to yield a Cp

Question 18

Volume of Fluid for a 70kg Male

Answer 18

Plasma - 7L
Extracellular fluid outside the blood - 12L
Total body water - 42L

Question 19

What does it mean if the volume of distribution is 13L?

Answer 19

3L < Vd < 15L

Drug is bound to plasma proteins and increases the Cp

Decreased Vd, increased Cp

Question 20

If the drug gets into total body fluid (42L) and is bound to albumin, what would be the Vd?

Answer 20

15L < Vd < 42L

Drugs that enter the total body water but bind plasma proteins

Decreased Vd, increased Cp

Question 21

What does it mean if the Vd is 100L? Is the pt 100L in volume?

Answer 21

Drug occupies total body water and bonds to tissue proteins and/or stored in fat. More drug is in the tissues than expected.

Vd > 42L

Increased Vd, decreased Cp

Question 22

What would the volume of distribution be if the drug entered the total body water and was stored in fat tissue?

Answer 22

Vd > 100c considered stored in fat

Drastic increase in Vd, drastic decreased in Cp

Question 23

Clinical relevance of volume of distribution

Answer 23

Estimation of the amount of drug in the body tissues or blood

Proportion available for therapeutic effect or excretion

Utilized in the calculation of doses and dose rates

Where the drug goes within the body

Question 24

Drugs with larger Vd

Answer 24

More lipophilic
Easier to cross BBB
Accumulate in tissues or fat
Maintained longer in body 
Requires hepatic metabolism for elimination

Question 25

Drugs with smaller Vd

Answer 25

More hydrophobic
Remains in blood with little accumulation in fat, tissue, or brain
Large MW or bind to plasma proteins
Eliminated primarily by kidney

Question 26

Distribution Within Blood Plasma Protein Binding

Answer 26

Drug in blood can be free and bound to plasma proteins

Free/bound equilibrium based on affinity for proteins

Free and bound percentages are characteristic for each drug at therapeutic levels (% bound remains relatively constant, binding is saturable, drugs/xenobiotics with similar affinities can displace drug)

Albumin binds mainly acidic drugs

Alpha-1 acidic glycoprotein bonds mainly basic drugs

Question 27

Only free drug can…

Answer 27

Be transported

Enter tissues

Bind receptors

Deliver a pharmacological effect or be eliminated via kidney

Question 28

Distribution Within Tissues - Tissue Binding

Answer 28

Some drugs bind tissue/cellular constituents (proteins - bind to receptors (functional) or non specific (non-functional), (lipids - highly lipophilic drugs prone to accumulation in adipose tissue)

Liver - drugs with “high extraction ratios” can be taken up by liver rapidly with the flow of blood

Lung - basic with large lipophilic groups and pKa > 8

Bone - complexes calcium and incorporated into bone lattice