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ESA 1 - Metabolism > Drug and Alcohol Metabolism > Flashcards

Drug and Alcohol Metabolism Flashcards

(54 cards)

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1
Q

Define pharmacodynamics

A

What a drug does to the body

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2
Q

Define pharmacokinetics

A

What the body does to a drug

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3
Q

How do the metabolites of a drug usually compare to the original form?

A

They are usually less pharmacologically active, with a few exceptions

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4
Q

Give three exceptions to the rule that metabolites of drugs are less pharmacologically active than the original

A
  • Primidone to phenobarbitone
  • Pethidine for norpethidine
  • Codeine to morphine
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5
Q

Describe the characteristics of a pro-drug

A

Stable and relatively unreactive

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6
Q

What happens to pro-drugs in phase 1 metabolism?

A

A reactive group is exposed on the parent molecule, or added to the molecule

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7
Q

What is the result of the exposure of a reactive group in phase I metabolism?

A

It generates a reactive intermediate that can be conjuated in phase II with a water-soluble molecule to form a water soluble complex

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8
Q

What are the most common chemical reactions that occur in phase I metabolism?

A
  • Oxidation
  • Reduction
  • Hydrolysis
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9
Q

What to the chemical reactions in phase I metabolism require?

A

A complex enzyme system called the cytochrome P450 (CYP) system, and a high energy cofactor, NADPH

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10
Q

What happens to the reactive intermediate from phase I in phase II metabolism?

A

It is conjugated with a polar molecule to form a water soluble complex in a process called conjugation

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11
Q

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

A

Glucoronic acid

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12
Q

Why is glucaronic acid the most common conjugate used in phase II metabolism?

A

Becasue it’s an available by-product of cell metabolism

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13
Q

Other than glucoronic acid, what else can drugs be conjugated with in phase II metabolism?

A
  • Sulphate ions
  • Glutathione
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14
Q

What does phase II metabolism require?

A

Specific enzymes and a high-energy cofactor- uridine diphosphate glucuronic acid

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15
Q

What happens to substances absorbed from the lumen of the ileum?

A

The enter the venous blood

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16
Q

Where does the venous blood from the ileum drain?

A

Into the hepatic portal vein, which is then transported directly to the liver

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17
Q

What is the problem with venous blood from the ileum being transported directly to the liver?

A

The liver is the main site of drug metabolism, as it contains all the necessary enzyme systems, and so any drug absorbed from the ileum may be extensively metabolised during the first pass through the liver - the first pass effect

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18
Q

What % of an oral dose of paracetamol is metabolised by the first pass effect?

A

90%

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19
Q

What do the enzymes in the cytochrome P450 system contain?

A

Haem

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20
Q

How many different haem-containg enzymes are the in the cytochrome P450 system?

A

About 50, and polymorphisms in the human population

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21
Q

What is the most important isoform in the cytochrome P450 system?

A

CYP3 A4

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22
Q

What % of drug metabolism is CYP3 A4 responsible for?

23
Q

What is the CYP co-factor?

24
Q

What accounts for variation in drug metabolism in the population?

Study These Flashcards
A
  • Genetic factors
  • Environmental factors
25
In terms of genetics, why can drug effects vary from person to person?
We all differ slightly in the level of expression of metabolic enzymes
26
Give three examples of a genetic difference that might have a big effect on drug metabolism?
* Some individuals may lack the gene that codes for a crucial enzyme such as CYP3 A4 * Some people are described as slow acetylators, as they lack the main enzyme responsible for the acetylation reaction in phase II * Some people have relatively low levels of pseudocholinesterase enzymes in the plasma, which affects their ability to metabolise drugs containg an ester bone
27
Give an example of a drug containing an ester bond, and what it does?
Suxamethonium, which is a muscle relaxant used during anasthesia
28
How can the environment effect drug metabolism?
If two drugs are given together, the metaboilsm of one drug may affect the metabolism of another
29
How can the metabolism of one drug affect the metabolism of another?
Enzyme induction or inhibition can occur
30
Give three examples of enzyme inducers
* Ethanol * Nicotine * Barbituates
31
What is paracetamol?
A widely available anti-pyretic drug
32
What happens to paracetamol at therapeutic levels?
It conjugates with glucuronide or sulphate in phase II
33
What happens to paracetamol at toxic doses?
The gluronide and sulphate pathways become quickly saturated, and paracetamol undergoes phase I metabolism to produce the toxic metabolite NAPQI
34
What are the toxic effects of NAPQI?
* It is toxic to hepatocytes, causing liver failure over a period of several days * It undergoes conjugation with glutathione, which is an important anti-oxidant
35
Where is the major site of alcohol metabolism?
The liver
36
Give the stages in the metabolism of alcohol
1. Alcohol to acetaldehyde, *by the action of the enzyme alcohol dehydrogenase* 2. Acetaldehyde to acetate, *by the action of the enzyme aldehyde dehydrogenase* 3. ATP forms AMP and 2Pi, and converts acetate to acetyl-CoA
37
What molecule does the complete oxidation of alcohol require?
NAD+, *forming reduced NADH*
38
What allows toxic acetaldehyde levels to be kept to a minimum?
Aldehyde dehydrogenase has a low Km
39
What can happen with prolonged alcohol consumption?
* Acetaldehyde can accumulate, causing liver damage * The decreased NAD+/NADH ratio, and increased acetyl-CoA affect liver metabolism
40
What is CYP2E1?
An inducible enzyme that also metabolises alcohol via oxidation
41
What is NAD+ used for?
* Fatty acid oxidation * Conversion of lactate to pyruvate * Metabolism of glycerol
42
What are the potential consequences of the decreased NAD+/NADH ratio that results from prolonged alcohol consumption?
* Accumulation of lactate in the blood might cause lactic acidosis * Will reduce the kidneys ability to excrete uric acid, and so crystals of urate may accumulate in the tissues, causing gout * Gluconeogenesis cannot be activated, and so fasting hypoglycaemia may be a problem
43
Why can't gluconeogenesis be activated when there is a low NAD+/NADH ratio?
Because decreased NAD+ results in decreased lactate use, and so decreased glycerol use
44
What causes the high acetyl-CoA in prolonged alcohol consumption?
Acetyl-CoA cannot be oxidised due to the decreased NAD+/NADH ratio
45
What is increased as a result of the high acetyl-CoA in chronic alcohol consumption?
There is increased synthesis of fatty acids and ketone bodies
46
What happens to the fatty acids produced due to prolonged alcohol consumption?
They are converted to triacylglycerols, but cannot be transported because there is a lack of lipoproteins, therefore fatty liver develops
47
What can be used as an indicator of liver damage?
The levels of enzymes such as transaminases and gamma glutamyl transpeptiase
48
Why is the presence of transaminases and gamma glutamyl transpeptidase in the blood an indicator of liver damage?
Because damaged liver cells have leaky plasma membranes and so these enzymes can be lsost to the blood
49
What can reduced liver function result in?
* Decreased uptake of conjugated bilirubin, leading to hyperbilirubinaemia and jaundice * Decreased urea production, leading to hyperammonaemia and increased glutamine * Decreased protein synthesis, leading to decreased albumin, clotting factors, and lipoproteins * Decreased serum albumin may produce oedema * Decreased clotting factors increases blood-clotting time * Decreased lipoproteins can cause lipid build up in the liver
50
What are the nutritional indirect effects of alcohol?
* Likely to be vitamin and mineral deficiencys * May be inadequate protein and carbohydrate uptake
51
What are the direct effects of alcohol on the GI tract?
There is often loss of appetite, diarrhoea, and impaired absorption of nutrients (vitamin K, folic acid, pyridoxine and thiamine)
52
What can thiamine deficiency lead to?
Wernicke-Korsakoff syndrome, *with mental confusion and unsteady gait*
53
What drug is used to treat alcohol deficiency?
Disulfiram
54
How does disulfiram work?
It is an inhibitor of the aldehyde dehydrogenase enzyme, whereby if the patient drinks alcohol, acetaldehyde accumulates in the blood, giving hangover symptoms

ESA 1 - Metabolism (6 decks)

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