Protein binding

Question 1

What bonds form between drugs and proteins

What bonds dont form and why

Answer 1

H bonds
Ionic bonds
Van der Waals forces

NOT covalent bonds (too strong + will denature protein)

Question 2

What is the formula for total drug concentration in the blood with respect to protein binding

Answer 2

Total = protein bound drug + free drug

Protein bound drug Free drug (in equilibrium)

Question 3

How does lipophilicity affect protein binding

Answer 3

In general (not always) highly lipophilic drugs are highly protein bound

Question 4

Describe the protein binding sites on albumin and which drugs bind to these sites

Answer 4

Sudlow site I –> Warfarin and phenylbutazone (NSAID)

Sudlow site II –> Benzos and ibuprofen (NSAID)

Question 5

What type of molecules does P-glycoprotein bind

Answer 5

One binging site only

• basic drugs
• steroid molecules

Question 6

What do lipoproteins bind

Answer 6

Lipid soluble drugs

E.g. Cannabinoids and cyclosporin

Not saturable (unlimited binding sites)

Question 7

What environmental factors alter protein-drug binding?

Answer 7

1. pH (alters unionized vs ionized)
2. Excess ligand (e.g. bilirubin)
3. Protein level (reduced total binding sites)
4. Temperature

Question 8

Which plasma protein binds bilirubin and fatty acids and why is this relevant

Answer 8

Albumin

If there is excessive bilrubin or fatty acid present then the receptor availability for drugs that also bind to albumin might be decreased increasing the free portion of drug –> altered effect / toxicity

Question 9

How does protein binding affect volume of distribution. Give an examples of two drugs that explain this

Answer 9

Ibuprofen has a volume of distribution of only 0.1 L/kg because it binds tightly to plasma albumin and is therefore confined to the circulating volume, as albumin generally is.

However, Amiodarone is also highly protein bound but prefers to distribute into the tissues. As such the fraction of plasma protein bound amiodarone is small

Question 10

how does protein binding effect metabolism and clearance.

What are two common exceptions to this?

Answer 10

If the drug is bound to proteins enzymes cannot access it for metabolism and the drug is not filter so clearance is reduced.

Only the free fraction of drug is susceptible to elimination

E.g. highly protein bound warfarin –> protein bound portion acts as a depot

Exceptions

1. Furosemide
   - -> Organic ion transport protein for furosemide in PCT in nephron strips furosemide off albumin so reduced protein will lead to reduced delivery to its site of active secretion in the kidney –> reduced pharmacological effect
2. Propranolol
   - -> Very high affinity hepatic enzyme system that its rate of clearance depends on its delivery (on protein) to the hepatocytes.

Question 11

How does protein binding affect measured drug levels

Answer 11

Blood sample mixed with high affinity reagent which strips drug of all proteins and measures total drug level. Clinically irrelevant as biologically active portion of drug is the free/unbound portion.

This is especially true for highly protein bound drugs.

Question 12

Why is phenytoin toxicity in ICU patients more common

Answer 12

Phenytoin is highly protein bound
Phenytoin has a narrow therapeutic index
ICU patient shave low protein
More free / unbound drug

—-> toxicity

Question 13

How does protein binding lead to drug interactions

Answer 13

Two drugs with different affinities to protein. Drug A affinity medium and Drug B affinity High.

Drug A already in body when Drug B is introduced.

Drug B displaces Drug A leading to increased unbound Drug A and potential for altered effect/ toxicity