Pharmacokinetics Malarkey 2 & enzymes 3 Flashcards
What is clearance of a drug?
Measure the efficiency of elimination for a particular drug
- apparent volume of plasma from which all the drug is irreversibly removed per unit time
How can clearance across an organ be calcalated?
CL = Q x E
E is the extraction ratio
- fraction removed by the organ during one pass
Which drugs have a large first pass effect?
Drugs with a high hepatic extraction ratio
E => 0.7 - 1
What effect does the liver have on the concentration of drug in the plasma?
Less drug is available after passing through the liver to be delivered to the systemic circulation
- lower extent of bioavailability
F(oral) = 1 - E
What is the total hepatic blood flow?
~ 80 L/hr
What effect does a low extraction ratio have on clearance?
An increase in Fu or CL(intrinsic) increases CL
CL = Fu x Cl(intrinsic)
What effect does a high extraction ratio have on clearance?
An increase in Fu or CL(intrinsic) does not change CL
CL = Q
What is an irreversible inhibitor?
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
What are the two types of irreversible inhibitors?
Affinity labelling agents
- reactive substrate analogues
Mechanism based inactivators
- suicide inhibitors
How do affinity labelling agents work?
Reactive compounds which react directly with residues in the active site
Give two examples of affinity labelling agents
Penicillins
Aspirin
How do mechanism based inactivators work?
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
Give two examples of mechanism based inactivators
Vigabatrin
5-fluorouracil
What one of the effects of aspirin?
Inhibits biosynthesis of prostaglandins
How are prostaglandins biosynthesised?
From arachidonic acid
What are prostaglandins?
Small molecules which are involved in inflammation and fever
Which enzyme is inhibited by aspirin?
Prostaglandin synthase
How does aspirin inhibit prostaglandin synthase?
Acetylates a serine
- disables the enzyme
How do penicillins and cephalosporins work?
Irreversibly inactive a transpeptidase found in bacterial cell wall biosynthesis
- acetylate a serine in the active site
What is vital for the survival of bacteria?
Bacteria have a cell wall around the cell
- peptidoglycan made of a polymer of sugar units
Which enzyme cross-links the peptidoglycan?
Transpeptidase
How does penicillin work?
Penicillin is thought to mimic the shape of the D-ala-D-ala
What effect does penicillin have on transpeptidase?
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
How is the inactivation of the transpeptidase made possible?
The reactivity of the B-lactam ring
What is a beta-lactam ring?
The 4-membered ring is very strained and fairly reactive
- much more active than a normal amid bond
Why doesn’t the beta-lactam ring acylate other proteins?
The beta-lactam ring is not so reactive that it reacts with every nucleophile
When does the beta-lactam ring react?
It only reacts in the active site of the transpeptidase
- the enzyme holds the penicillin in the correct orientation for acylation
What characteristics do active-site activated inhibitors have?
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
