Pharmacokinetics Malarkey 2 & enzymes 3

Question 1

What is clearance of a drug?

Answer 1

Measure the efficiency of elimination for a particular drug

- apparent volume of plasma from which all the drug is irreversibly removed per unit time

Question 2

How can clearance across an organ be calcalated?

Answer 2

CL = Q x E

E is the extraction ratio
- fraction removed by the organ during one pass

Question 3

Which drugs have a large first pass effect?

Answer 3

Drugs with a high hepatic extraction ratio

E => 0.7 - 1

Question 4

What effect does the liver have on the concentration of drug in the plasma?

Answer 4

Less drug is available after passing through the liver to be delivered to the systemic circulation
- lower extent of bioavailability

F(oral) = 1 - E

Question 5

What is the total hepatic blood flow?

Answer 5

~ 80 L/hr

Question 6

What effect does a low extraction ratio have on clearance?

Answer 6

An increase in Fu or CL(intrinsic) increases CL

CL = Fu x Cl(intrinsic)

Question 7

What effect does a high extraction ratio have on clearance?

Answer 7

An increase in Fu or CL(intrinsic) does not change CL

CL = Q

Question 8

What is an irreversible inhibitor?

Answer 8

An inhibitor which forms a covalent bond with a residue (or residues) in the active site of the enzyme

• the enzyme is inactivated
• the inhibitor does not dissociate or dissociates very slowly

Question 9

What are the two types of irreversible inhibitors?

Answer 9

Affinity labelling agents
- reactive substrate analogues
Mechanism based inactivators
- suicide inhibitors

Question 10

How do affinity labelling agents work?

Answer 10

Reactive compounds which react directly with residues in the active site

Question 11

Give two examples of affinity labelling agents

Answer 11

Penicillins

Aspirin

Question 12

How do mechanism based inactivators work?

Answer 12

Compounds which are activated by the enzyme and then react with the enzyme
- bind in active site and combine with co-factor to a reactive group which then reacts to a residue in the active site

Question 13

Give two examples of mechanism based inactivators

Answer 13

Vigabatrin

5-fluorouracil

Question 14

What one of the effects of aspirin?

Answer 14

Inhibits biosynthesis of prostaglandins

Question 15

How are prostaglandins biosynthesised?

Answer 15

From arachidonic acid

Question 16

What are prostaglandins?

Answer 16

Small molecules which are involved in inflammation and fever

Question 17

Which enzyme is inhibited by aspirin?

Answer 17

Prostaglandin synthase

Question 18

How does aspirin inhibit prostaglandin synthase?

Answer 18

Acetylates a serine

- disables the enzyme

Question 19

How do penicillins and cephalosporins work?

Answer 19

Irreversibly inactive a transpeptidase found in bacterial cell wall biosynthesis
- acetylate a serine in the active site

Question 20

What is vital for the survival of bacteria?

Answer 20

Bacteria have a cell wall around the cell

- peptidoglycan made of a polymer of sugar units

Question 21

Which enzyme cross-links the peptidoglycan?

Answer 21

Transpeptidase

Question 22

How does penicillin work?

Answer 22

Penicillin is thought to mimic the shape of the D-ala-D-ala

Question 23

What effect does penicillin have on transpeptidase?

Answer 23

Transpeptidase mistakes penicillin for D-ala-D-ala and reacts with it

• forms intermediate by breaking the C-N bond
• the enzyme cannot undergo reaction with the natural substrate
• peptidoglycan-D-Ala-D-Ala
• cell wall biosynthesis is inhibited and the bacteria dies

Question 24

How is the inactivation of the transpeptidase made possible?

Answer 24

The reactivity of the B-lactam ring

Question 25

What is a beta-lactam ring?

Answer 25

The 4-membered ring is very strained and fairly reactive

- much more active than a normal amid bond

Question 26

Why doesn’t the beta-lactam ring acylate other proteins?

Answer 26

The beta-lactam ring is not so reactive that it reacts with every nucleophile

Question 27

When does the beta-lactam ring react?

Answer 27

It only reacts in the active site of the transpeptidase

- the enzyme holds the penicillin in the correct orientation for acylation

Question 28

What characteristics do active-site activated inhibitors have?

Answer 28

Unreactive compound
Metabolised by the target enzyme to a reactive intermediate
Activated species then inhibits the enzyme
- binding to residues in the enzyme active site by a covalent bond