Plasm Protein Binding

Question 1

Describe the kinetics of drug binding?

Answer 1

Question 2

What are the 2 forms drugs exist as?

Answer 2

Unbound and bound

Question 3

Describe the rate of drug binding?

Answer 3

Very rapid and completely reversible

Question 4

What happens in the unbound drug concentration decreases?

Answer 4

Bond drug dissociates rapidly to restore equilibrium

Question 5

What are the characteristics of unbound concentration?

Answer 5

1. diffuses across membranes to the drug’s site of action.
2. interacts with the receptors to cause pharmacological and toxicological activities.
3. available for distribution and elimination.

Question 6

How can unbound drug be calculated?

Answer 6

Question 7

What is affinity?

Answer 7

The magnitude of the association constant that is expressed by k1/k2

Question 8

When would affinity increase?

Answer 8

K1&raquo_space;> k2, the ratio increases -> drug binding to plasma protein is favored -> drug binds to the plasma proteins extensively

Question 9

How does drug contention influence fu?

Answer 9

1. Plasma protein binding ↑ in proportion to ↑ in the drug concentrations:
2. fu remains constant over therapeutic plasma concentrations, with a few exception drugs.

Question 10

How does protein concentrations influence fu?

Answer 10

Quantity and quality of the available plasma protein for drug binding

↑ or ↓ plasma protein concentration  ↑ or ↓ drug binding  affect fu

Question 11

What factors influence protein concentrations?

Answer 11

1. ↓ Albumin concentrations  [liver disease, age, pregnancy, burns, other trauma.]
2. ↑ Albumin synthesis  [Thyroid hormone, corticosteroids, growth hormone, insulin].
3. ↑ AAG concentrations [physiological stress caused by myocardial infarction, cancer, surgery].
4. ↓ Lipoprotein concentrations  [dieting & therapy with statins].
5. ↑ Lipoprotein concentration  [Alcoholism & diabetes mellitus].

Question 12

How does renal disease influence fu?

Answer 12

1. In severe renal disease  drugs binding to albumin - ↓
2. ↓ Albumin levels & ↑ accumulation of compounds that compete for binding sites  alter the affinity of drugs for albumin

Question 13

How does hepatic diseases influence fu?

Answer 13

1. In chronic liver diseases  drugs binding to plasma protein – ↓.
2. ↓ Albumin and AAG concentrations.

Question 14

How does drug interactions at plasma protein-binding sites influence fu?

Answer 14

1. Binding of one drug may displace a second drug from its binding site  concentration-dependent displacement
2. Because of competition for a limited number of binding sites on the protein.
3. Alteration of the protein by a substance that modifies the affinity of the drug for the protein.

Question 15

What happens if binding decreases?

Answer 15

Increased pharmacological active unbound component causing increased toxicity

Question 16

How do you minimize the clinical consequences of changes in plasma protein binding?

Answer 16

1. Increased elimination
2. Little changes in drug concentrations outside the plasma

Question 17

What happens when you increase elimination?

Answer 17

1. Unbound drug is accessible to the elimination organs.
   When protein binding ↓ - unbound drug concentration 2. ↑ - proportional ↑ elimination – eventually the unbound drug concentration in the plasma ↓ to same value as that before the change in binding.
2. ↑ in the unbound concentration is canceled out by ↑ elimination

Question 18

What happens when you change drug concentration outside the plasma?

Answer 18

1. When plasma proteins binding is extensive, the fraction of the drug in the body located in the plasma is much less than that in the tissues
2. Because, the plasma comprises a relatively small physiological volume (3 L) by comparison to the rest of fluid volumes available for drug to distribute
3. When the fraction unbound ↑ in plasma, the extra drug that distributes to the tissues is very small by comparison to the fraction of the drug already present in the tissues, particularly for drugs with large Vd

Question 19

What is the most important application of Vd?

Answer 19

Calculating the LD

Question 20

When is LD best calculated?

Answer 20

Vd at steady-state because it is the most representative of PK properties at desired/targeted steady-state plasma drug concentration

Question 21

How do you calculate LD?

Answer 21

Question 22

What is the clinical significance of Vd between pediatric and adult dosing?

Answer 22

As body composition changes with aging, drug distribution will also change that loading doses between pediatrics and adults are different.

Question 23

What is the clinical significance of Vd between obese and non-obese?

Answer 23

The loading doses may be calculated based on different types of weights such as total body weight vs. ideal bodyweight depending on the pharmacokinetics of specific drugs such as high polarity or highly non-polarity to prevent over or under dosing.

Question 24

What is the clinical significance of Vd of conditions affecting plasma protein concentration?

Answer 24

The excess or deficiency of plasma proteins (e.g., albumin) may affect the amount of drug that remains in the plasma and therefore the apparent Vd.

Question 25

What is Vd unit?

Answer 25

L or L/kg