Pharmacokinetics 2

Question 1

What are the stages of drug disposition ?

Answer 1

Absorption
Distribution
Metabolism
Excretion

Question 2

What is drug elimination ? how many processes are there ?

Answer 2

Irreversible loss of drug from body
2

Question 3

What are the processes of drug elimination ?

Answer 3

Metabolism
Excretion

Question 4

Where does drug metabolism occur ?

Answer 4

Predominantly liver

Question 5

What happens in drug metabolism ?

Answer 5

Drugs altered chemically in less active form for easier excretion

Phases decrease lipid solubility, increasing renal elimination

Question 6

How many phases are in drug metabolism ?

Answer 6

2

Question 7

What is first pass metabolism ?

Answer 7

Some drugs are extracted so well by the gut wall/ liver circulation that little reaches the circulation

Question 8

What is a problem with first pass metabolism and how can it be solved ?

Answer 8

• reduces bioavailability (drug in circ.) lose drug conc in stomach, intestines and liver
• increase dose or new route of administration

Question 9

What reactions involve phase one metabolism ?

Answer 9

• reactions involve oxidation, reduction and hydrolysis
• usually pharmacologically active, toxic or carcinogenic

Question 10

What reactions involve phase 2 metabolism ?

Answer 10

• conjugation of a reactive group
• usually lead to an inactive state

Question 11

What serves as a target for phase 2 ?

Answer 11

Catabolic introduction of functional group into molecule to increase polarity

Question 12

What is a CYP ?

Answer 12

Cytochrome P450- haem protein

Question 13

What is biotransformation ?

Answer 13

Irreversible transformation of parent compounds to daughter compounds

Question 14

What’s a pharmacologically active metabolite ?

Answer 14

Prodrug
- eg Levodopa —> dopamine

Question 15

What is enterohepatic ?

Answer 15

Molecules released into bile get reabsorbed again in small intestine and returned to liver

• increased toxicity and half life

Question 16

Give an example of enterohepatic circulation ?

Answer 16

NSAID- indomethacin

Half life = 10 h

90% plasma bound

Question 17

What has to happen to prodrugs ?

Answer 17

Must be made pharmacologically active

Question 18

What is the first step of drug metabolism (oxidation) ?

Answer 18

• cytochrome P450 containing ferric iron combines with drug substrate (binary complex)

Question 19

What is the second step of drug metabolism (oxidation) ?

Answer 19

• NADPH donates electron to P450 reductase, this reduces Fe3+ to Fe2+

Question 20

What is the third step of drug metabolism (oxidation) ?

Answer 20

NADPH-P450 reductase introduces a second electron

Reduces oxygen

Forms activated O2 p450 frug complex

Question 21

What is the last step of drug metabolism (oxidation) ?

Answer 21

Hydrogen atom extracted from complex leading to an oxidised drug and water

Question 22

What processes are involved in phase 2 (conjugation) ?

Answer 22

Glucuronidation, glutathione, sulphation, methylation, acetylation, fatty acid and amino acid conjugation, condensation

Question 23

What is required for phase 2 ?

Answer 23

• suitable group to attach from phase 1
• high energy intermediates
• specific enzymes
• conjugates polar molecules, readily excreted and usually active

Question 24

Draw the flow chart of glucoronidation ?

Answer 24

Question 25

What is the toxic metabolite of paracetamol ? When is it produced ?

Answer 25

NAPQI N-acetylbenzoquinoimine - CYP addition

Question 26

What are the steps of paracetamol overdose ?

Answer 26

- mainly undergoes phase 2 - toxicity-saturation of phase 2 pathways - depletion of sulphate and glucuronic acid conjugation - depletion of glutathione below 30% - more metabolism via phase 1 CYPs Therefore more NAPQI (toxic)

Question 27

How do we detoxify from paracetamol overdose ?

Answer 27

intravenous N-acetylcysteine (NAC)

Question 28

Which CYP is important for paracetamol toxicity ?

Answer 28

CYP2E1

Question 29

What is the effect on resistant and sensitive individuals ?

Answer 29

Resistant - minimal Sensitive - maximal

Question 30

What does a young age do to metabolism

Answer 30

Changes in absorption patterns, undeveloped enzyme systems

Question 31

What does old age do to metabolism of drugs ?

Answer 31

Low plasma proteins, poor renal function, may be on ‘drug cocktail’

Question 32

How does gender affect drug metabolism ?

Answer 32

Women metabolite drugs slower - liver metabolism reduced and higher body fat % so drugs accumulate

Question 33

What does environmental factors do ?

Answer 33

Influence activity and level of CYP enzymes - nutrition, smoking, alcohol, drugs, environment, genetic polymorphism

Question 34

What side effect could a reduction in metabolism lead to ?

Answer 34

Arrhythmia

Question 35

What factors affect renal excretion of a drug ?

Answer 35

- Age and disease- glomerulnephritis- dec excretion - high drug lipid solubility- inc. Vd so poor renal excretion -Water soluble- low Vd- poor reabsorbtion - re absorption increases half life of drug

Question 36

What are the features of first order kinetics ?

Answer 36

- mainly in elimination - increase in concentration equal to increase in rate of metabolism - half life constant

Question 37

What are the features of zero order kinetics ?

Answer 37

Question 38

What are the features of zero order kinetics ?

Answer 38