Drug Metabolism

Question 1

What is the aim of pharmacotherapy?

Answer 1

To achieve an effective concentration of drug at its target

It depends on getting the drug into the body and to its site of action

Question 2

What is the difference between pharmacokinetics and pharmacodynamics?

Answer 2

Pharmacokinetics is what the body does to the drug

Pharmacodynamics is what the drug does to the body

Question 3

What is bioavailability?

Answer 3

The proportion of a an administered drug that is available in the body, this is significantly different for an orally administered drug vs a drug administered intravenously

Question 4

Why is the bioavailability of a drug administered orally less?

Answer 4

It has to be absorbed across the GI tract and then distributed in the blood
It is vulnerable to metabolism and excretion before it reaches the site of action

Question 5

What does ADME stand for?

Answer 5

Absorption, distribution, metabolism and excretion

Question 6

Why is bioavailability for intravenous drugs higher?

Answer 6

They are immediately distributed, they are still vulnerable to metabolism and excretion before reaching the site of action

Question 7

Define drug absorption

Answer 7

The passage of a drug from the site of administration into the plasma

Question 8

What type of administration delivers drug directly into the plasma?

Answer 8

Intravenous

Question 9

What is the most common way of drugs crossing cellular membranes?

Answer 9

Passive diffusion

Question 10

What is the less common mode of transport for drugs and when does this happen?

Answer 10

Carrier mediated transfer, it happens when a drug is similar in structure to an endogenous molecule that has a specialised transport process, i.e uses another molecules transporter

Question 11

Give an example of a drug that is transported using carrier mediated transport

Answer 11

L-DOPA, anti-Parkinsonian drug, it resembles the amino acid phenylalanine and so can use the amino acids transporter to cross the blood brain barrier

Question 12

What is the main factor that determines the rate of passive diffusion of a drug across a membrane?

Answer 12

The drugs ability to dissolve in lipids

Question 13

What are the 4 factors that affect the drugs distribution?

Answer 13

Cardiac output and regional blood flow
Permeability f membranes
Disease
Binding of drugs to plasma proteins

Question 14

What is the main protein found in plasma?

Answer 14

Albumin

Question 15

What type of bonding occurs between drugs and albumin?

Answer 15

Non-covalent forces

Question 16

Give some types of molecules that binds to albumin

Answer 16

Fatty acids, hormones, ions and drugs

Question 17

What does pharmacodynamics of a drug mainly depend on?

Answer 17

Their concentration at their targets

Question 18

What is the plasma concentration of a drug dependent on?

Answer 18

ADME

Question 19

What is the main factor that controls the duration of action of lipid soluble drugs?

Answer 19

Rate of metabolism

Question 20

Why does metabolism not apply as much to polar drugs?

Answer 20

They are excreted largely unchanged

Question 21

During metabolism, what are lipid soluble drugs converted to?

Answer 21

Water soluble metabolites

Question 22

Where are drug metabolising enzymes found?

Answer 22

Mainly in the liver but also in the gut wall, lungs and kidney

Question 23

What does the extent of metabolisation of a drug depend on?

Answer 23

The enzyme specificity and the similarity of a drug to the normal substrate of the enzyme

Question 24

What are microsomes?

Answer 24

The small vesicles of endoplasmic reticulum that are formed when the liver is homogenised

Question 25

What type of reactions do microsomes do when metabolising drugs?

Answer 25

Oxidisation, reduction, hydrolysis and conjugation (combining)

Question 26

Where in the liver cells are metabolising enzymes found?

Answer 26

In the endoplasmic reticulum

Question 27

Describe the structure of the liver

Answer 27

2 major lobes each consisting of many lobules

Question 28

Describe the structure of a lobule

Answer 28

They are hexagonal structures made up of hepatocytes arranged around interconnected channels around a central vein

Question 29

What are the 2 major vessels that supply the liver with blood?

Answer 29

Hepatic artery: oxygenated blood | Hepatic portal vein: deoxygenated blood and nutrients from the GI tract

Question 30

What are sinusoids?

Answer 30

The spaces between hepatocytes where the vessels flow through before draining into the hepatic vein

Question 31

What is the vessel that blood in the liver drains out from?

Answer 31

Hepatic vein

Question 32

What happens in drug metabolism?

Answer 32

The centre of a drug molecule is made reactive so that it attaches to other polar groups making them readily excreted

Question 33

What is the most important system in the endoplasmic reticulum?

Answer 33

The hydroxylation system

Question 34

What is the outcome of hydroxylation of a drug molecule?

Answer 34

An OH group is added to the drug | NADPH + H+ + O2 + drug forms NADP + Drug-OH + H2O

Question 35

What enzymes carry out hydroxylation

Answer 35

Cytochrome P450 enzymes with A P450 reductase to supply energy from NADPH

Question 36

What is the cofactor in cytochrome P450 that allows hydroxylation to occur?

Answer 36

A haem molecule that contains an iron atom

Question 37

When is Phase 2 metabolism able to happen without Phase 1?

Answer 37

If the drug already has a reactive centre

Question 38

What is the outcome of Phase 2 metabolism?

Answer 38

The drug molecule undergoes a conjugation reaction using the OH added from Phase 1 to make the a more polar molecule

Question 39

When does Phase 2 metabolism not occur?

Answer 39

If the metabolite from Phase 1 is sufficiently polar to be excreted

Question 40

What is the role of the coenzyme and the enzyme in Phase 2 metabolism?

Answer 40

Coenzyme adds on the reactive group | Enzyme is the molecule that carries out this process

Question 41

Give 2 examples of conjugation reactions that are part of Phase 2 metabolism

Answer 41

Sulphation | Acetylation

Question 42

Where does glucuronic acid gets its energy to allow it to conjugate with a drug molecule in Phase 2 metabolism?

Answer 42

By binding to UDP

Question 43

In Phase 2 metabolism, where on a Glutathione molecule is the drug added?

Answer 43

On the S atom

Question 44

In Phase 2 metabolism, acetylation does not make the molecule more polar, what does it do instead?

Answer 44

Creates functional groups on drugs which can then undergo conjugation reaction

Question 45

In Phase 2 metabolism, methylation does not make the molecule more polar, what does it do instead?

Answer 45

It inactivates parts of the drug molecule using conjugation reactions so that receptor binding is inhibited and the drug is made inactive, the metabolite also becomes more water soluble

Question 46

What type of medicine is aspirin?

Answer 46

Analgesic, anti-inflammatory and anti-pyretic

Question 47

Where is aspirin metabolised to salicylate?

Answer 47

Mainly in the liver, stomach, intestinal mucosa and blood

Question 48

Which metabolite of aspirin is responsible for the anti-inflammatory, anti-pyretic and analgesic effects?

Answer 48

Salicylate

Question 49

Which metabolite of aspirin is responsible for the antiplatelet-aggregating effect?

Answer 49

Acetylsalicylate

Question 50

Which protein do aspirin and salicylate bind to in the plasma?

Answer 50

Albumin

Question 51

Which phase metabolism is the most common for metabolism of salicylate?

Answer 51

Phase 2

Question 52

What is the half life of salicylate?

Answer 52

2 hours

Question 53

What are the indications for paracetamol?

Answer 53

Mild to moderate pain | Fever

Question 54

Why is bioavailability of paracetamol increased so much with higher doses?

Answer 54

The capacity for metabolism in the liver is overwhelmed with higher doses of paracetamol, increasing the bioavailability

Question 55

What is the type of conjugation reaction that paracetamol undergoes when it is metabolised?

Answer 55

Glucuronidation

Question 56

How are hepatoxic metabolites of paracetamol synthesised?

Answer 56

By Cyp450

Question 57

How are the hepatoxic metabolites of paracetamol neutralised?

Answer 57

By conjugation with glutathione using glutathione transferase

Question 58

When do hepatoxic metabolites of paracetamol become harmful to the body?

Answer 58

If he concentration of them outweighs the amount of available glutathione which is what normally neutralises it

Question 59

What are the 3 treatments of intoxication?

Answer 59

Gastric emptying and administration of active charcoal to absorb metabolite Administration of N-acetylcysteine to add glutathione Haemodialysis

Question 60

How many families of CYP enzymes are there?

Answer 60

18

Question 61

How are CYP enzymes named?

Answer 61

CYP followed by a number which represents the family, followed by a letter to show the sub family and then another number for each specific enzymes

Question 62

What is the role of CYP enzymes?

Answer 62

To metabolise chemicals and substrates

Question 63

Where are Cyp P450 enzymes found?

Answer 63

In most tissues in the body

Question 64

What are CYP450 enzymes important for?

Answer 64

Steroid hormone synthesis and breakdown, cholesterol synthesis and vitamin D metabolism

Question 65

Where are CUP450 enzymes mostly found?

Answer 65

In the liver

Question 66

Which families of CYPs are responsible for metabolising 70-80% of drugs?

Answer 66

families 1-3

Question 67

What is the most important factor in determining the duration of action of a drug?

Answer 67

The rate and extent of metabolism

Question 68

What does drug metabolism potential represent?

Answer 68

The spectrum of cytochrome P450 activity present

Question 69

What are some factors that affect drug metabolism?

Answer 69

Age, sex, hormones, health, genetics, drug interactions,

Question 70

How does age affect drug metabolism?

Answer 70

Adults have higher levels of P450s than children. Less glucuronidation occurs in infants due to their lower levels of EDGT, CYP450 levels can also go down in elderly

Question 71

How does sex affect drug metabolism?

Answer 71

Rats showed a difference in drug metabolism between males and females, the rate is usually higher in males but there is no marked difference in humans

Question 72

How does health affect drug metabolism rate?

Answer 72

Diseases that affect the liver and kidney have profound effects

Question 73

What is the difference between a mutation and polymorphism?

Answer 73

Mutations occur in less than 1% of the population whereas polymorphism is more frequent than 1% of the population

Question 74

What are microsatellite repeats?

Answer 74

Regions of repeated base sequences in the promoter region of DNA

Question 75

What is copy number variation?

Answer 75

When on of the chromosomes in a pair has more than one copy of a gene

Question 76

What are the 4 major phenotypes that polymorphisms in CYP genes can lead to?

Answer 76

``` Poor metabolisers (PMs) Intermediate metabolisers (IMs) Efficient metabolisers (EMs) Ultra-rapid metabolisers (UMs) ```

Question 77

Describe PMs

Answer 77

Removed enzyme activity due to lack of functional gene, patients have 2 defective alleles of the particular CYP450 gene

Question 78

Describe IMs

Answer 78

Reduced enzyme activity, one defective allele

Question 79

Describe EMs

Answer 79

Normal enzyme activity, 2 functional gene copies

Question 80

Describe UMs

Answer 80

Increased enzyme activity, more than 2 functional copies of CYP450 gene`

Question 81

What is metabolic ratio (MR)?

Answer 81

The ratio of parent drug : metabolite

Question 82

What can the patient experience if they have a poor metaboliser?

Answer 82

Adverse Drug Reactions resulting in higher concentrations of the drug in the blood compared to a normal patient

Question 83

What is enzyme induction?

Answer 83

When the enzyme activity increases due to newly synthesised enzymes for example from other drug interactions

Question 84

How do drug and food interactions affect metabolism?

Answer 84

Drug and foods can inhibit or induce CYP enzymes resulting in a change in metabolism rate, this leads to changes in drug that enters the blood