Metabolism

Question 1

What is metabolism and where does it occur?

Answer 1

-Metabolism is the enzymatic conversion of one chemical compound to another.
- mostly occurs in liver, small amount occurs in gut wall, lungs, plasma

Question 2

Why is metabolim necessary?

Answer 2

conversion of the drug from lipid soluble to water soluble by increasing its polarity is essential for excretion.

Question 3

What are the three different outcomes of drug metabolism?

Answer 3

1. conversion from toxic to non-toxic metabolite
2. conversion from pro-drug to active drug
3. conversion from active drug to inactive drug

Question 4

Which 4 factors influence metabolism?

Answer 4

1.Age - infants and elderely have decreased hepatocyte number and enzyme activity
2. Disease (diabetes)
3. Genetics (polymorphism)
4. Other drugs (CYP450 inhibition/induction)

Question 5

What is zero order / non-linear kinetics?

Answer 5

Saturation of eliminating enzymes at therapeutic conditions.
-small increas in dose can cause a dissproprotionately large increase in plasma concentration

This is when all the eliminating enzymes are occupied so and new increases in dose can produce large increases in plasma conc.

Question 6

Examples of drugs which display non-linear kinetics

Answer 6

Phenytoin
Salicylates
Ethanol

Question 7

What is cytochrome p450 and explain how the specific cytochromes have their names?

Answer 7

Large family of related enzymes housed in the smooth endoplasmic reticulum of the cell.

CYP2D6
CYP - cytochrome
2 - family
D - sub-family
6 - specific gene/isysome

Question 8

Explain the metabolic process of pro drugs in respect to the cyp450 inducers and inhibitors.

Question 9

What are the chemical reactions which occur in phase 1 metabolism and which is the most common?

Answer 9

Oxidation - most common
reduction
hydrolysis

Question 10

Why is the process of metabolism necessery?

Answer 10

For the drug to be excreted into the stool or urine, it must first be converted from a non-polar, lipid soluble substance to a polar, water soluble substances. (otherwise it will just be reabsorbed into the blood!!)

Question 11

Explain the process of phase 2 metabolism

Answer 11

May occur if the drug is still too polar after phase 1.
Involves conjugation.
Occurs in hepatocyte cytoplasm
Attachment of an ionised group (Methyl, sulfur, glutahtione) makes the metabolite more water soluble and less lipid soluble so that it may not be reabsorbed.
This fascilitates excretion and diminishes the pharmacological activity.

Question 12

Paracetamol produces toxic metabolites. Explain the process in which paracetamol is metabolised.

Answer 12

Paracetamol undergoes phase 1 metabolism, after which toxic metabolites are produced. It the must to through phase 2 conjugation to be converted into a non-toxic metabolite by the addition of a glutathione group.

Question 13

What happens in paracetamol overdoses?

Answer 13

There is not enough glutathione to detoxify the toxic metabolites.
Toxic metabolites accumulate which can cause hepatits.
Compounds need to be administrated to boost glutathione levels so phase 2 conjugation can take place.

Question 14

Explain CYP450 induction by example

Answer 14

Eg. Rifampicin can induce the effects of CYP450, increasing the rate of metabolism, This results in the plasma concentration of warafarin to fall below therapeutic levels causing an increasing in blood clotting.

Question 15

Explain CYP450 inhibition by example

Answer 15

Eg. Omeprazole can inhibit CYP450, decreasing the rate of metabolism, this results in larger concentrations of the active drug in plasma which can increase the therapeutic effect causing a risk of bleedingin patients taking warfarin

Question 16

Explain CYP450 induction in respect to warfarin and withdrawl of barbiturates.

Answer 16

Barbiturates can cause induction - warfarin clearence increases
Warfarin dose then increased, blood levels now normal
Barbiturates are withdrawn and replaced with valporate
Warfarin clearence falls - blood levels rise above normal
Patient dies.

Question 17

Explain the benificial use of CYP450 induction in new borns?

Answer 17

New borns have poorly devloped hepatic metabolic enzymes.
They conjugate Bilirubin inefficiently resulting in some infants to become jaundiced.
small doses of barbiturates can be used to induce the cyp450 and clear the bilirubin.

Question 18

What is first pass metabolism?

Answer 18

Drugs taken orally, need to pass through the liver to reach systematic circulation, but because the liver is the primary source of drug metabolism, some of the drug can be metabolised before even reaching systematic circulation. This decreases the bioavailability.

Question 19

If a drug has a heavy first pass effect, what arrangements can be made to achiveve the needed bioavailability?

Answer 19

The route of administration can be changed