CPT1: metabolism

Question 1

What is metabolism?

Answer 1

Enzymatic conversion of one chemical compound to another

Question 2

Where does metabolism occur?

Answer 2

• Mostly the liver
• some in the gut wall, lungs and blood

Question 3

What happens to a drug when it is metabolised? why is this required?

Answer 3

It can make it more water soluble which is essential from drugs being excreted in bodily fluids e.g. urine, bile

It usually results in dimished therapuetic effect

Question 4

What are factors effecting metabolism?

Answer 4

• Aging - decline in hepatocyte number and activity as age increases. Babies have poorly developed metabolising enzyme
• Disease - reduced hepatic blood flow - heart failure/ shock - (tissues/ organs less perfused so hepatic cells die and less metabolising enzymes)
• Genetic - drugs, diet, enviro factors - grape fruit juice and st johns worts. Cigretter smoke and brussle sprouts

Question 5

What do drugs which display ‘zero order’ or ‘non-linear’ kinetics do to eliminating enzyems?

Answer 5

They saturate elimination enxymes at therapeyutic concentrations. A small increase in dose leads to a disproportionaly large increase in plasma concentration.

Question 6

What are example of compounds which dispaly zero order kinetics?

Answer 6

• Salicylates
• Phenytoin
• ethanol

Question 7

Where are the enzymes essential for drug metabolism stored?

Answer 7

• Liver hepatocytes

Question 8

To what group do the maintain metabolising enzymes belong and where are these found?

Answer 8

CYP450s - held in the smooth endoplasmic recticulm of the cells

Question 9

What stages of metabolism occur and in what order?

Answer 9

• Phase 1 and 2
• Some drugs under go just 1 or just 2 but the majority under go 1 then 2

Question 10

What does phase 1 involve?

Answer 10

• Involves hydrolysis, but most commonly oxidation
• Oxidation catalysed by CYP450s (mainly CYP450 monoxygenase) (results in loss of electrons)
• Drug metabolite may still be active

Question 11

1. What does phase 2 metabolism involve?
2. Where does this normally occur?

Answer 11

1. involves conjugation - the addition of an ionised group to the drug e.g. glutathione, methyl or acetyl group
2. generally occur in hepatocyte cytoplasm

Question 12

What does phase 2 do to the drug

Answer 12

Makes it more water soluble which facilitates excretion and decreases pharmacological action

Question 13

1. What is the first pass effect?
2. What routes avoid this?

Answer 13

1. When the concentration of a drug is greatly reduced before reaching the systemic circulation.
2. Buccal and rectal

Question 14

Which blood vessel takes the drug to the liver when absorbed orally?

Answer 14

Hepatic portal vein

Question 15

What is the hepatic extraction ratio?

How is this calculated?

Answer 15

The fraction of the drug metabolised (and eliminated) by a single passage through the liver (E)

E= Cin - Cout / Cin

Question 16

What enzyme metabolizes drugs in the GUT wall?

Answer 16

CYP 3A4

Question 17

Discuss metabolism of paracetomal and how problems can be reversed

Answer 17

Paracetomal when metabolised produces a toxic metabolite. It can be detoxicifed with a phase 2 conjugation reaction with glutathione. However in over doses there is not enough glutathione to detoxify the metabolites. A compound which increases glutathione levels mjst be adminitstered to prevent hepatocytisis

Question 18

Describe induction

Answer 18

When one drug A increases the rate of metabolism of the drug B. Drug Bs concentration is reduced to below therapeutic levels and becomes ineffective

Question 19

Describe inhibition

Answer 19

When Drug A reduces the rate of metabolism of drug B and leads the concentration of drug B increasing above therapeutic levels to toxc levels

Question 20

What is onset?

Answer 20

An accumulation of inducing agemts and increase in enzyme production

Question 21

What is offset?

Answer 21

Elimination of inducing agents and decrease in efficacy of enzymes

Question 22

Describe the withdrawl of an inducer referring to specific examples

Answer 22

• PAteint takes warfarin and barbituates
• Barbituate causes induction so warfarin clearance is increased. To prevent this the dose is increased of warfarin.
• If barbituate is withdrawn them the levels of warfarin will increase above to toxic levels

Question 23

What are beneficail uses of inducers?

Answer 23

New borns have poorly developed metabolising enzymes.

If babies don’t conjugate bilirubin efficently iy will result in juandice. so small levels of barbituates can help induce liver enzymes to clear bilirubin

Question 24

What is induction and inhibitation in relation to CYP450s?

Answer 24

induction - increase in no. of enzymes in liver

Inhibitation - decrease in efficacy of enzymes

Question 25

Is alcohol a inhibitor or inducer?

Why?

Answer 25

It is normally an inducer however in acute intoxicatin it may not give enough time to synthesis new enzymes therefore leading to an inhibitory effect

Question 26

What is st johns wort

Answer 26

• Herbel remedy used to treat mental health problems
• Its an inducer
• may significantly reduce the effectvieness of the following by induction of hepatic CYP450s and intestinal p-GP:
• Anticonvulsants
• Cyclosporin
• Digoxin
• Protease inhibitors
• Oral contraceptives
• Theophylline
• Warfarin

Question 27

What effect do fruit juices have?

Answer 27

• Grape fruit juice contains antioxidants which inhibit CYP3A4 in the intestinal and GUT wall - leads to increased Ca2+ channel blockers
• Cranberry juice contains antioxidants which inhibit CYP450s - leads to rising levels of warfairn