Plasm Protein Binding Flashcards
Describe the kinetics of drug binding?
What are the 2 forms drugs exist as?
Unbound and bound
Describe the rate of drug binding?
Very rapid and completely reversible
What happens in the unbound drug concentration decreases?
Bond drug dissociates rapidly to restore equilibrium
What are the characteristics of unbound concentration?
- diffuses across membranes to the drug’s site of action.
- interacts with the receptors to cause pharmacological and toxicological activities.
- available for distribution and elimination.
How can unbound drug be calculated?
What is affinity?
The magnitude of the association constant that is expressed by k1/k2
When would affinity increase?
K1»_space;> k2, the ratio increases -> drug binding to plasma protein is favored -> drug binds to the plasma proteins extensively
How does drug contention influence fu?
- Plasma protein binding ↑ in proportion to ↑ in the drug concentrations:
- fu remains constant over therapeutic plasma concentrations, with a few exception drugs.
How does protein concentrations influence fu?
Quantity and quality of the available plasma protein for drug binding
↑ or ↓ plasma protein concentration ↑ or ↓ drug binding affect fu
What factors influence protein concentrations?
- ↓ Albumin concentrations [liver disease, age, pregnancy, burns, other trauma.]
- ↑ Albumin synthesis [Thyroid hormone, corticosteroids, growth hormone, insulin].
- ↑ AAG concentrations [physiological stress caused by myocardial infarction, cancer, surgery].
- ↓ Lipoprotein concentrations [dieting & therapy with statins].
- ↑ Lipoprotein concentration [Alcoholism & diabetes mellitus].
How does renal disease influence fu?
- In severe renal disease drugs binding to albumin - ↓
- ↓ Albumin levels & ↑ accumulation of compounds that compete for binding sites alter the affinity of drugs for albumin
How does hepatic diseases influence fu?
- In chronic liver diseases drugs binding to plasma protein – ↓.
- ↓ Albumin and AAG concentrations.
How does drug interactions at plasma protein-binding sites influence fu?
- Binding of one drug may displace a second drug from its binding site concentration-dependent displacement
- Because of competition for a limited number of binding sites on the protein.
- Alteration of the protein by a substance that modifies the affinity of the drug for the protein.
What happens if binding decreases?
Increased pharmacological active unbound component causing increased toxicity
How do you minimize the clinical consequences of changes in plasma protein binding?
- Increased elimination
- Little changes in drug concentrations outside the plasma
What happens when you increase elimination?
- 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. - ↑ in the unbound concentration is canceled out by ↑ elimination
What happens when you change drug concentration outside the plasma?
- 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
- Because, the plasma comprises a relatively small physiological volume (3 L) by comparison to the rest of fluid volumes available for drug to distribute
- 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
What is the most important application of Vd?
Calculating the LD
When is LD best calculated?
Vd at steady-state because it is the most representative of PK properties at desired/targeted steady-state plasma drug concentration
How do you calculate LD?
What is the clinical significance of Vd between pediatric and adult dosing?
As body composition changes with aging, drug distribution will also change that loading doses between pediatrics and adults are different.
What is the clinical significance of Vd between obese and non-obese?
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.
What is the clinical significance of Vd of conditions affecting plasma protein concentration?
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.
