Week 6

Question 0

What does ADME represent?

Answer 0

Pharmacokinetics involves studying the absorption, distribution, metabolism and elimination of a drug.

Question 1

What’s the difference between pharmacokinetics and pharmacodynamics?

Answer 1

Pharmacokinetics is the study of the time course of drugs and their metabolites in the body
Pharmacodynamics is the effect that the drug has on the body, which depends on its free concentration and hence on its pharmacokinetics.

Question 2

Why can’t drugs be excreted in an unchanged form in the urine?

Answer 2

Many drugs are lipid soluble and are reabsorbed in the renal tubules - only 1% of a drug can be excreted unchanged.

Question 3

Name two drug which bypasses stage 1 metabolism and goes straight into stage 2

Answer 3

Morphine

Paracetamol

Question 4

What is the strategy of phase 1 of drug metabolism?

Answer 4

Add or expose a reactive group on the molecule to make it more reactive so it can be conjugated with a water soluble molecule in phase 2.

Question 5

What are the most common reactions in phase 1 of drug metabolism?

Answer 5

Hydrolysis, reduction and oxidation

Question 6

What is required for phase 1 drug metabolism?

Answer 6

Cytochrome P450 (CYP) system and NADPH as a cofactor.

Question 7

What is the ‘strategy’ of phase two of drug metabolism?

Answer 7

Conjugate the reactive intermediate from phase one with a polar molecule to make it water soluble.

Question 8

What is the most common conjugate in phase two of drug metabolism? Why?

Answer 8

Glucuronic acid - byproduct of metabolism.

Question 9

What substances can be used to conjugate reactive intermediates in stage two of drug metabolism?

Answer 9

Glucuronic acid, glutathione, sulphate ions

Question 10

What else is required for phase two of drug metabolism?

Answer 10

specific enzymes

UDPGA (uridine diphosphate glucuronic acid) - high energy cofactor

Question 11

Where does drug metabolism occur?

Answer 11

Mainly liver

Also lungs, kidneys, GI tract, plasma.

Question 12

What can cause variations in drug metabolism in the population?

Answer 12

Genetic differences - different levels of expression of enzymes
Environmental factors - other drugs or exposures that alter the activity of enzymes

Question 13

What is the most important enzyme in Cytochrome P450?

Answer 13

CYP3 A4 - accounts for 55% of drug metabolism

Question 14

What is a slow acetylator?

Answer 14

Someone who lacks the enzyme for acetylation in phase two, and can’t metabolise drugs that require this pathway.

Question 15

What is the consequence of low pseudocholinesterase?

Answer 15

Can’t metabolism drugs containing an ester bond such as suxamethonium (muscle relaxant used in anaesthesia)

Question 16

What is the first pass effect?

Answer 16

All substances absorbed into the blood from the ileum travel directly to the liver via the hepatic portal vein.
The liver is the main site of drug metabolism, so some drugs can be metabolised before reaching their target tissues, meaning large doses are required

Question 17

Why are large oral doses of paracetamol necessary?

Answer 17

90% of the drug is metabolised on the first pass through the liver and never reaches the target tissues.

Question 18

What is the fate of dietary alcohol?

Answer 18

10% excreted passively in urine or breath
90% metabolised - alcohol -> acetaldehyde (alcohol dehydrogenase) -> acetate (aldehyde dehydrogenase) -> Acetyl CoA (requires ATP)
Can be oxidised by CYP2E1 (inducible)

Question 19

What is the benefit of acetaldehyde dehydrogenase having a very low Km for acetaldehyde?

Answer 19

Acetaldehyde is toxic to cells, low km means it can be removed promptly even when present in low concentrations.

Question 20

What is the consequence of accumulation of acetaldehyde following excessive alcohol consumption?

Answer 20

Liver damage

Question 21

In what way is the NAD+/NADH ratio altered in excessive alcohol consumption and why?

Answer 21

Ratio is less as NAD+ is used to oxidise alcohol, and so it is present in the reduced form.

Question 22

How does alcohol metabolism lead to lactic acidosis?

Answer 22

Insufficient NAD+ to oxidise lactate to pyruvate.
Decreased utilisation of lactate by lifer cells - lactate accumulates in blood.
Can cause lactic acidosis.

Question 23

How can alcohol metabolism cause gout?

Answer 23

Low levels of NAD+ means lactate is not utilised in the liver as it cannot be converted to pyruvate.
Lactate accumulates in the blood.
This decreases the kidneys ability to excrete uric acid.
Crystals of urate appear in the tissues - gout.

Question 24

Why do alcoholics get fasting hypoglycaemia?

Answer 24

Poor diet = low liver glycogen
Low NAD+ means lactate cannot be converted to pyruvate for gluconeogenesis. Gluconeogenesis from pyruvate also requires NADH. Therefore cannot synthesise glucose - fasting hypoglycaemia

Question 25

What causes a fatty liver in alcoholics?

Answer 25

Increased acetyl CoA from alcohol metabolism, cannot be oxidised due to low NAD+. Therefore rate of fatty acid synthesis and ketone body synthesis increases.
Fatty acids are converted to TAGs
Can’t synthesise lipoproteins therefore remain in liver

Question 26

Why can alcoholics get ketoacidosis?

Answer 26

Low NAD+ means high levels of acetyl CoA can’t be oxidised for energy release, so fatty acid synthesis and ketone body synthesis is favoured.
Levels of ketone body synthesis can be high enough to cause ketoacidosis.

Question 27

What is used to treat alcohol dependence and how does it work?

Answer 27

Disulfiram inhibits acetaldehyde dehydrogenase. This causes accumulation of acetaldehyde in the tissues. This causes the symptoms of a hangover.
Must be accompanied by support.

Question 28

How can liver damage be diagnosed?

Answer 28

Presence of enzymes such as AST and ALT, and gamma glutamyl transpeptidase in the blood indicates leaky plasma membranes of damaged liver cells

Question 29

Why might alcoholics get jaundice?

Answer 29

Liver cells damaged by acetaldehyde means cells can’t take up and conjugate bilirubin leads to hyperbilirubinaemia and jaundice

Question 30

What’s the consequence of a reduction of the capacity of the liver to produce urea in an alcoholic?

Answer 30

Hyperammonaemia and high levels of glutamine (from alphaketoglutarate - inhibits Krebs)

Question 31

What is the consequence of reduced protein synthesis in the liver in an alcoholic?

Answer 31

Reduced synthesis of lipoproteins means lipids synthesised in the liver accumulate and cause fatty liver.
Reduced synthesis of albumins can lead to oedema due to reduced oncotic pressure
Reduced synthesis of clotting factors leads to an increase in clotting time

Question 32

What are the indirect effects of excessive alcohol consumption?

Answer 32

Poor dietary habits including vitamin and mineral deficiency and carbohydrate and protein deficiency.

Question 33

What is the consequence of excessive alcohol consumption on the GI tract?

Answer 33

Damages cells- causes poor absorption of nutrients such as thiamine, vitamin K folic acid and pyridoxine.
Also diarrhoea and poor appetite.

Question 34

What is Wernicke-Korsakoffs syndrome?

Answer 34

Mental confusion and unsteady gait ?ataxia? Due to thiamine deficiency -poor absorption

Question 35

Why might alcoholics be anaemic?

Answer 35

Damaged gut lining = poor absorption of folic acid = B12 deficiency anaemia.

Question 36

What is used to treat paracetamol overdose and what does it do?

Answer 36

n-Acetyl cysteine (antioxidant, counters the effect of depleted glutathione)
Liver transplant

Question 37

How is paracetamol metabolised at therapeutic dosages?

Answer 37

Straight to phase 2 - conjugation with glucuronide or sulphate

Question 38

What happens if a toxic dose of paracetamol is ingested?

Answer 38

Phase 2 pathway quickly saturated.
Undergoes phase 1 produces NAPQI (N-Acetyl p-benzo quinone imine) which is toxic
Then phase two conjugation with glutathione - depletes glutathione - destruction of liver cells and liver failure occurs over several days.