Drug metabolism

Question 0

What is pharmacokinetics?

Answer 0

• The time course of drugs and its metabolites in the body, i.e. what the body does to the drug
• ADME -> absorption, distribution, metabolism, elimination

Question 1

What is pharmacodymanics?

Answer 1

-How the drug works, i.e. what the drug does to the body

Question 2

What is the overall aim of the body’s drug metabolism?

Answer 2

-To deactivate and eliminate

Question 3

Why is elimination a problem in drug metabolism?

Answer 3

-Majority of drugs are lipid-soluble so they are not readily excreted in the urine (always reabsorbed in the tubules) so need to be made water-soluble

Question 4

What is the aim of the first phase of drug metabolism?

Answer 4

-To expose/add a reactive group on the parent molecule in order to produce a reactive metabolite

Question 5

What are the three main types phase 1 reactions?

Answer 5

• Oxidation
• Reduction
• Hydroxylation

Question 6

What is required in phase 1 of drug metabolism?

Answer 6

• Cytochrome P450 enzyme system

- NADPH

Question 7

Give an example of phase I metabolism

Answer 7

-Diamorphine-> hydroxylation breaks ester bonds producing morphine

Question 8

What is the main location of phase I drug metabolism?

Answer 8

-Hepatocytes in the liver (contain microsomes)

Question 9

What are the other locations of phase I drug metabolism besides the liver?

Answer 9

• GI tract
• Kidneys
• Lungs
• Plasma

Question 10

When giving drugs metabolised in the GI tract, what needs to be altered?

Answer 10

-Increase the dosage

Question 11

What metabolic reaction occurs in the plasma for phase 1 drug metabolism?

Answer 11

-Hydrolysis of ester bonds through cholinesterases

Question 12

What is the ultimate aim of phase II metabolism?

Answer 12

-Elimination of the drug

Question 13

What happens in phase II drug metabolism?

Answer 13

-Conjugation: The reactive derivative is conjugated with a polar molecule to form a water-soluble complex which can be excreted in urine

Question 14

What is the most common conjugate used in phase II metabolism and why?

Answer 14

-Glucaronic acid because it is a very polar molecule which is freely available due it being a by-product of metabolism

Question 15

What other conjugates, apart from glucaronic acid, can be used in phase II metabolism?

Answer 15

• Suplhate ions

- Glutathione

Question 16

What is conjugation with glucaronic acid in phase II drug metabolism known as?

Answer 16

-Glucaronidation

Question 17

What is required in order for conjugation to occur in phase II metabolism?

Answer 17

• Specific enzymes

- High energy co-factor, typically UDP

Question 18

Why is UDP required in phase II drug metabolism?

Answer 18

-To provide energy to transfer glucaronic acid onto reactive metabolite

Question 19

Which cyp enzyme is responsible for 55% of drug metabolism?

Answer 19

-CYP3 A4

Question 20

What is meant by the CYP P450 enzymes being inducible?

Answer 20

-Certain drugs will increase the synthesis of certain enzymes and certain drugs will inhibit the production of certain enzymes

Question 21

What are gene polymorphisms a problem in drug metabolism?

Answer 21

• Certain people with a certain gene polymorphisms may metabolise a drug more slowly/quickly
• eg, gene polymorphisms for acetylation may mean that the patient will be slow acetylators and therefore metabolise the drug slower

Question 22

When can gene polymorphisms of drug metabolism become a problem in surgery?

Answer 22

• Patient may have polymorphism which produces low amount of plasma cholinesterases
• Suxamethonium is a muscle relaxant given in anaesthetic
• normally lasts 15 mins but can last hours in these patients

Question 23

Why can some drugs enter phase II metabolism immediately?

Answer 23

-Already have reactive group

Question 24

What environmental factors can involve with drug metabolism?

Answer 24

- Enzyme levels are not fixed, influenced by lifestyle - Some CYP enzymes can be induced through drinking/smoking/barbituates resulting in quicker drug metabolism -> problem for surgery - Some CYP enzymes can be inhibited through food and drink -> cranberry/grapefruit juice interferes with metabolism of cimetidine (gastric ulcer treatment)

Question 25

What is enzyme inhibition in drug metabolism?

Answer 25

-One drug inhibits the metabolism of another drug

Question 26

What is enzyme induction in drug metabolism?

Answer 26

-One drug induces the enzymes needed for metabolism of another drug

Question 27

When can enzyme inhibition/induction be a problem in drug metabolism?

Answer 27

-Polytherapy

Question 28

Where does phase II drug metabolism occur?

Answer 28

-Liver

Question 29

Describe paracetamol metabolism at therapeutic levels

Answer 29

- Metabolised by phase II | - Conjugation with glucaronic acid/sulphate

Question 30

Describe paracetamol metabolism at toxic levels

Answer 30

- Glucaronidation/sulphation becomes saturated - Paracetamol enters phase I metabolism - Metabolised to NAPQI which is toxic to hepatocytes - Undergoes conjugation with glutathione

Question 31

Why is paracetamol conjugation with glutathione a problem?

Answer 31

- Depletes glutathione stores - Cells become vulnerable to ROS - Leads to destruction of liver cells - Leads to liver failure (can take 1 week)

Question 32

What is the treatment for paracetamol overdose?

Answer 32

- N-acetyl-cysteine to provide protection against ROS - Must be injected intravenously within a time window before the liver becomes too necrosed - If too necrosed transplant is only option

Question 33

How can alcohol be excreted other than metabolised?

Answer 33

-Breathed out

Question 34

What is phase I of alcohol metabolism?

Answer 34

-Alcohol is oxidised to acetoaldehyde by alcohol dehydrogenase and CYP2 E1

Question 35

What is phase II of alcohol metabolism?

Answer 35

-Acetoaldehyde oxidised to acetate by aldehyde dehydrogenase

Question 36

What happens to acetate produced from alcohol metabolism?

Answer 36

-Converted to acetyl CoA

Question 37

Why is alcohol metabolised quicker the more a person drinks?

Answer 37

-CYP2 E1 is inducible

Question 38

Where is alcohol metabolised?

Answer 38

-Liver

Question 39

Why is acetoaldehyde removed so quickly?

Answer 39

-Aldehyde dehydrogenase has very high affinity

Question 40

What are the product results of prolonged drinking?

Answer 40

- Increased AcetylCoA - Increased acetoaldehyde - Decreased NAD+/NADH ratio

Question 41

Why is NAD+ dercreased from long term drinking?

Answer 41

-Used as a cofactor in alcohol metabolism

Question 42

What effects does decreased NAD+ have on the body, in releation to the liver?

Answer 42

- Inadequate levels for b-oxidation - inadequate levels for lactate conversion to pyruvate - Inadequate levels for glycerol metabolism

Question 43

How does increased drinking lead to fatty liver?

Answer 43

-Increased acetyl coA produced which are converted to TAGs and not transported due to insufficient lipoprotein synthesis so are stored in the liver

Question 44

How does gout occur in alcoholics?

Answer 44

- Increased lactate due to decreased conversion to pyruvate due to lack of NAD+ - Reduces kidneys ability to excrete uric acid - Crystal deposition in the kidneys leads to gout

Question 45

Why can lactic acidosis occur in alcoholics?

Answer 45

- Decreased NAD+ due to use in alcohol metabolism | - Lactic acid builds up leading to acidosis

Question 46

Why can fasting hypoglycaemia occur in alcoholics?

Answer 46

- Decreased gluconeogenesis from glycerol due to insuffcient NAD+ - Poor diet so low glycogen store

Question 47

What are the toxic effects of acetoaldehyde?

Answer 47

- Damaged hepatocytes-> leaky pm-> loss of enzymes (transaminases and gamma glutamyl transpeptidases)-> defective N metabolism resulting in hyperammonia - Hyperbilirubinaemia/jaudice-> decreased ability to conjugate and clear bilirubin - Low serum albumin potentially causing oedema - Reduced clotting factor production increasing clotting time

Question 48

What is the rate of alcohol metabolism?

Answer 48

-7g/hr (8g pure ethanol in one unit)

Question 49

What are the direct effects of acetaldehyde on the GI tract?

Answer 49

- loss of appetite - Diarrhoea - Impaired absorption of nutrients

Question 50

What nutrient deficiences are associated with alcoholics?

Answer 50

- Wernickle-Korsakoffe syndrome-> malabsorption of thiamine | - Anaemia-> malabsorption of folic acid

Question 51

What are the treatments for alcoholism?

Answer 51

- Mental heath councilling and support | - Disulfram -> aldehyde dehydrogenase inhibitor-> build up produces a direct toxic effects on GI that last for a week