Lecture 6.1: Drug Metabolism

Question 1

What is Pharmacology?

Answer 1

It is the study of drug interaction with the body

Question 2

What is a Drug?

Answer 2

A chemical substance which produces a biological effect following its administration to the body

Question 3

What is Medication or Medicine?

Answer 3

A drug administered to the body to cure or improve a medical condition

Question 4

What is Pharmacokinetics?

Answer 4

What the body does to the drug
The study of the movement of drugs and their metabolites through the body

Question 5

What is Pharmacodynamics?

Answer 5

What the drug does to the body

Question 6

Pharmacokinetic Stages: ADME

Answer 6

Absorption
Distribution
Metabolism
Elimination

Question 7

Drug Metabolism

Answer 7

• As soon as a drug enters the body it will start to be metabolised
• Drugs are foreign to the body & are potentially toxic
• So they need to be deactivated and eliminated
• Most drugs are lipid soluble rather than water soluble
• They need to be made more water soluble
• Thus they can be excreted directly by the kidneys

Question 8

Pro-Drugs

Answer 8

Some drugs are made active during their metabolism

Question 9

Pro-Drugs Examples: Where metabolites more pharmacologically active than the parent drug molecule

Answer 9

pethidine —> norpethidine
codeine —> morphine

Question 10

Phase I of Drug Metabolism

Answer 10

Reactions that convert the parent drug to a more polar/ reactive product by unmasking or inserting a polar functional group such as ´OH, ´SH, or ´NH2

Occurs mostly in liver (most enzymes in the ER of cells), may also occur in the GI tract, kidney, lung and plasma

Converts lipophilic drugs into more polar molecules

Involves oxidation (most common), reduction and hydrolysis reactions

Question 11

CYP450 Enzymes

Answer 11

• There are around 60 CYP enzymes (many isoforms)
• CYP 1-3 families are involved in drug metabolism

Isoforms:
• CYP3A4 accounts for ~55% of drug metabolism
• CYP2D6 accounts for ~25% of drug metabolism

Question 12

Variation in CYP450 Activity: Genetic

Answer 12

There is a huge genetic variability in P450 enzymes amongst individuals and races, which can affect drug efficacy and the risk of side effects
• mutation in CYP2D6, involved in metabolic conversion of codeine to morphine

Question 13

Variation in CYP450 Activity: Environmental

Answer 13

Environmental factors (diet, pesticides, other drugs etc.) may also alter P450 enzyme activity
• e.g. grapefruit juice and cimetidine act as inhibitors
• e.g. nicotine act as inducers

Question 14

Phase II of Drug Metabolism

Answer 14

• Occurs in liver (cytosolic and endoplasmic reticulum enzymes)
• Drugs with –OH, -NH2 , -COOH groups will directly go to Phase II
• Many phase I metabolites are still too lipophilic
• Involves conjugation reactions (addition of a water soluble group to drug)
• Leads to production of inactive metabolites

Question 15

Phase II of Drug Metabolism: What groups are added?

Answer 15

• (Glucuronate) Glucuronic acid conjugation (glucuronidation)
• Sulphate or (acetate) acetyl group conjugation
• Glutathione conjugation
• Glycine
• Methyl group

Question 16

Glucuronidation

Answer 16

Glucuronic acid is transferred from uridine diphosphate-glucuronic acid (UDPGA) to substrate (e.g. morphine)

Question 17

Metabolism of Paracetamol in normal levels

Answer 17

A therapeutic dose of paracetamol is metabolised in Phase II by conjugation with glucuronic acid or sulphate

Acetaminophen is conjugated to harmless glucuronide and sulphate metabolites when it is taken in recommended doses by patients with
normal liver function

Question 18

Metabolism of Paracetamol during overdose

Answer 18

A toxic dose of paracetamol is metabolised in Phase I and Phase II

In Phase II Glutathione conjugation and sulphation

Question 19

Metabolism of Paracetamol during overdose if Phase II is saturated

Answer 19

If glutathione stores are exhausted, however, the reactive intermediate combines with sulfhydryl groups on essential hepatic cell proteins, resulting in cell death

Prompt administration of other sulfhydryl donors (eg, acetylcysteine) may be life-saving after an overdose

Question 20

What makes you more susceptible to paracetamol overdose?

Answer 20

In severe liver disease, stores of glucuronide, sulphate, and glutathione may be depleted

Making the patient more susceptible to hepatic toxicity with near-normal doses of acetaminophen

Question 21

N-Acetylcysteine

Answer 21

N-Acetylcysteine is the drug of choice for the treatment of an acetaminophen overdose

It is thought to provide cysteine for glutathione synthesis

Possibly to form an adduct directly with the toxic metabolite of acetaminophen, Nacetyl-p-benzoquinoneimine

Question 22

Metabolism of Alcohol

Answer 22

> 90% alcohol is metabolised and < 10% is excreted passively via urine and breath

The main route of its metabolism is via alcohol dehydrogenase

However its small amounts are also metabolised by P4502E1 enzymes in liver or by catalase in brain

Alcohol dehydrogenase oxidises alcohol to acetaldehyde and then oxidises acetaldehyde to acetate (acetic acid)

The acetate is converted to acetyl CoA by acetyl CoA- synthase

Question 23

Consequences of Prolonged/ Excessive Alcohol Consumption

Answer 23

Liver toxicity due to acetaldehyde accumulation which leads to liver damage and dysfunction

Altered liver metabolism due to decrease in NAD+/NADH ratio and increased availability of acetyl CoA

Question 24

Dysfunction of Liver

Answer 24

• Escape of liver enzymes such as AST (aspartate transaminase) and ALT (alanine transaminase) to blood
• Reduced taking up & conjugation of bilirubin leading to hyperbilirubinaemia
• Reduced production of urea leading to hyperammonaemia
• Reduced synthesis of proteins (albumin, clotting factors and lipoproteins)

Question 25

Why Alcoholics May Have a Fatty Liver?

Answer 25

• Reduced levels of NAD+ in liver for fatty acid oxidation
• Increased levels of acetyl CoA will not be oxidised due to reduced levels of
NAD+
• Increased fatty acid synthesis and ketone synthesis (may lead to
ketoacidosis) from acetyl CoA
• Increased synthesis of triacylglycerols, which cannot be transported from
the liver due to reduced synthesis of lipoproteins, leads to a fatty liver

Question 26

Why Alcoholics May Have Gout?

Answer 26

Increased blood lactate leads to lactic acidosis and reduces the kidney’s ability to excrete uric acid

As uric acid levels increase, crystals of urate accumulate in tissues leading to gout

Question 27

Treatment of Alcoholism

Answer 27

• Disulfiram inhibits aldehyde dehydrogenase
• This increases conc of acetalderhyde
• Which in increased concs causes nasuea, vomiting, blurred vision,
palpitations…etc
• Produces acute sensitivity to alcohol