Metabolism S6 - Drug Metabolism

Question 1

Define Pharmacodynamics and Pharmacokinetics

Answer 1

Pharmacodynamics is the action of the drug on the body

Pharmacokinetics is the action of the body on the drug

Question 2

What processes are covered by pharmacokinetics?

Answer 2

Absorption

Distribution

Metabolism

Elimination

(ADME)

Question 3

What can be said about the activity of drug metabolites?

Give some exceptions to this rule

Answer 3

Normally less active

Examples of more active metabolites include:

Primidone –> Phenobarbitone

Pethidine —> Norpethidine

Codeine —> Morphine

Question 4

What is Phase 1 of drug metabolism?

Answer 4

As most drugs are relatively stable and unreactive a reactive group must be first exposed or added to generate a reactive intermediate.

Question 5

What are the common chemical reactions of Phase 1 of drug metabolism?

Answer 5

Oxidation

Reduction

Hydrolysis

Question 6

What enzyme system is utilised in drug metabolism?

What co-factor is normally used by these enzymes in phase 1 of drug metabolism?

Answer 6

Cytochrome P450

NADPH

Question 7

Why do some drugs totally bypass phase 1 of drug metabolism?

Give an example of a drug that bypasses phase 1

Answer 7

Already have a reactive group

Morphine

Question 8

What is Phase 2 of drug metabolism?

Answer 8

The reactive intermediate from phase 1 is conjugated with a polar molecule (conjugate) to form a water soluble complex. This process is know as conjugation.

Question 9

What is the most common conjugate

Give 2 examples of other conjugates

Answer 9

Glucoronic acid

Sulphate ions, Glutathione

Question 10

What is required by phase 2 of drug metabolism?

Answer 10

Specific enzymes

High energy cofactor (uridine diphosphate glucuronic acid) - UDPGA

Question 11

What is the first pass effect?

Answer 11

Substances absorped through the ileum enter venous blood which drains directly into the hepatic portal vein and is transported directly to the liver

The liver is the main site of drug metabolism and contains most of the necessary enzyme systems.

Therefore any drug absorped from the ileum may be extensively metabolised by the liver during its first pass through

Question 12

Give an example of the effect of first pass metabolism on a common drug

Answer 12

90% of paracteamol is metabolised by first pass metabolism

Question 13

Describe the enzymes of the Cytochrome P450 system

Hint: Number of enzymes? Important enzymes? Variations?

Answer 13

Around 50 haem containing enzymes

There are polymorphisms in the human population

The isoform CYP A4 accounts for 55% of drug metabolism

The CYP cofactor is NADPH

Question 14

How do genetic factors affect drug metabolism?

Answer 14

We all differ slightly on expression of CYP enzymes therefore drug effects vary from person to person.

Some individuals may lack a crucial CYP enzyme (EG. CYP A4) and this will have a large effect on drug metabolism.

Question 15

Give 2 examples of how genetic factors may influence drug metabolism.

Answer 15

Some people may be slow acetylators because they lack the main enzyme for the acetylation reaction in phase 2.

This has a large effect on rate of metabolism of drugs requiring this pathway.

Some people have a low level of pseudocholinesterase enzymes in the plasma which affects their ability to metabolise drugs containing an ester group such as suxamethonium

Question 16

How do environmental factors affect drug metabolism?

Answer 16

If two drugs are given at once then the metabolism of one drug may affect the other

Enzyme inhibition or induction can occur

Question 17

Give 3 examples of enzyme inducing drugs

Answer 17

Nicotine

Barbituates

Ethanol

Question 18

What class of drugs does paracetamol belong to?

Answer 18

Antipyretics

Question 19

Describe the metabolism of Parcetamol at a therapeutic dose

Answer 19

Paractamol conjugates with glucuronide or sulphate in phase 2

Question 20

Describe what might happen if a toxic dose of paracetamol is taken

Answer 20

The normal glucuronide and sulphate conjugation pathways become saturated.

Paracetamol undergoes phase 1 metabolism instead of bypassing it as normal.

This produces a toxic metabolite

This metabolite is called:

N-acetyl-p-benzo-quinone-imine (NAPQI)

NAPQI is toxic to hepatocytes and also conjugates with glutathione, an important liver anti-oxidant

Liver failure occurs over the course of a few days.

Question 21

Where is the major site of alcohol metabolism?(C’mon freshers, this is essential knowledge right here)

Answer 21

Liver

Question 22

Give the major pathway for alcohol metabolism and give the enzyme(s) and anything else required

Make sure to include equation(s)

Answer 22

Alcohol —> Acetaldehyde —> Acetate

Step 1: Alcohol dehydrogenase

Step 2: Aldehyde dehydrogenase

Complete oxidation forms NADH from NAD+

Acetate is converted to AcetlyCoA with ATP

ATP —> AMP + 2Pi

Question 23

What are the 3 major effects of prolonged alcohol comsumption?

Answer 23

Low NAD+/NADH ratio

High acetylCoA

Decreased liver function

Question 24

What is the alternative method of alcohol metabolism?

Answer 24

CYP 2E1 is an inducible enzyme that can metabolise alcohol through oxidation

Question 25

What is the effect of a low NAD+/NADH ratio?

Answer 25

Accumulation of lactate in the blood possibly causing lactic acidosis This in turn will reduce the kidney's ability to excrete uric acid, crystals of urate may accumulate in tissues causing gout. Gluconeogenesis cannot be activated and this may cause fasting hypoglycaemia

Question 26

What is the effect of high AcetylCoA levels caused by alcohol consumption?

Answer 26

AcetylCoA cannot be oxidised due to low NAD+ therefore more ketone bodies and fatty acids are synthesised Production of ketones may cause ketoacidosis TAGS are produced from fatty acids and due to lack of lipoproteins cannot be transported, therefore a fatty liver develops.

Question 27

What tests can be done to look for liver damage? Explain the biochemical basis behind this.

Answer 27

Test blood for transaminase enzymes and gamma glutamyl transpeptidase (Liver function tests) Damaged liver cells have a leaky cell membrane allowing these enzymes to diffuse into blood.

Question 28

What is the result of reduced liver function? Hint: 3 main points, be sure to elaborate on consequences of metabolic disfunction

Answer 28

Decreased uptake of bilirubin causing hyperbilirubinaemia (resulting in jaundiced appearance) Decreased urea production causing hyperammonaemia and increased glutamine Decreased protein synthesis (Such as albumin, clotting factors and lipoproteins) - Decreased serum albumin may cause Oedema - Decreased clotting factors increase blood clotting time - Decreased lipoproteins cause lipid build up leading to fatty liver.

Question 29

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

Answer 29

Loss of appetite Diarrhoea Impaired absorption of nutrients (Vit K, Folic acid, Pyridoxine, thiamine). Vitamin and Thiamine deficiency results

Question 30

How is alcohol dependency commonly treated?

Answer 30

Disulfuram is used, this is an aldehyde dehydrogenase inhibitor If the patient drinks alcohol, acetaldehyde accumulates in blood giving 'hangover' effects very quickly.

Question 31

How is blood glucose concentration controlled?

Answer 31

By the endocrine system Insulin/Glucagon

Question 32

Describe the use of glucose by the CNS

Answer 32

140g per 24hrs Glucose dependant Glucose uptake relates to blood glucose concentration Therefore blood concentration must be kept in a certain range to adequately supply CNS (4-6mM)

Question 33

What is hypoglycaemia and some of the common symptoms? Hint: Don't worry about all the symptoms, just list like, 3 of 'em or something. Or whatever, I'm a flashcard, not your supervisor.

Answer 33

Blood glucose below 3mM Acute effects include: Trembling Sweating Weakness Tiredness Headache Sweating Sickness Palpitations Slurred speech/staggering walk

Question 34

Compare the effects of Insulin and Glucagon on nutrient storage.

Answer 34

Insulin: Increase glucose uptake and utilisation by muscle and adipose tissue Promotes glucose storage in the liver and muscle as glycogen Promotes lipogenesis and storage of fatty acids as TAGS in adipose tissues Promotes amino acid uptake and protein synthesis in the liver and muscle Glucagon: Stimulates gluconeogensis to maintain glucose supply to brain Stimulates glycogenolysis in the liver to maintain blood glucose Stimulates lipolysis in adipose tissues to provide fatty acids for use in tissues

Question 35

How do feeding and fasting effect hormonal control of glucose?

Answer 35

Feeding stimulates release of insulin Fasting promotes release of glucagon and insulin release is depressed

Question 36

How is gluconeogenesis initiated?

Answer 36

Blood glucose falls This stimulates ACTH release by pituitary This in turn stimulates cortisol release Cortisol directly stimulates gluconeogenesis and makes gluconeogenic substrates such as glycerol and amino acids avaliable by stimulating the breakdown of proteins and fats. Glucagon also stimulates gluconeogensis

Question 37

What is the effect of Thyamine defieciency?

Answer 37

Can lead to Wernicke-Korsakoff syndrome - mental confusion and unsteady gait

Question 38

What is significant about the action of aldehyde dehydrogenase?

Answer 38

Low Km which helps keep the level of toxic acetaldehyde to a minimum