Elimination (metabolism and excretion)

Question 1

What is elimination?

Answer 1

Elimination is the removal of drug from the body.

Question 2

What is the process of elimination?

Answer 2

Metabolism - transformation of the drug molecule into a different molecule
and / or
Excretion - expulsion of the drug molecule in the body’s liquid, solid or gaseous ‘waste’.

Question 3

What is the main site of drug metabolism?

Answer 3

The liver

Oher tissues that display considerable activity include;
GIT, skin, lungs, kidneys, neurones, blood.

Question 4

What are the two main effects of metabolism?

Answer 4

• increase water solubility (hydrophilicity)

- reduces pharmacological activity

Question 5

What is the main purpose of metabolism?

Answer 5

To make drugs more hydrophilic (water soluble) so that they can be excreted without being reabsorbed into the system.

Question 6

What happens at phase 1 metabolism?

Answer 6

Produces a modified chemical which can then (in phase 2) be linked to another molecule that makes it more water-soluble.
The main reaction involved is oxidation catalysed by CYP450 enzyme.

Question 7

What is cytochrome P450?

Answer 7

A generic term for a large number of related oxidative enzymes responsible for metabolism of thousands of endogenous and exogenous substances, found mainly in the hepatocytes in the membranes of the smooth endoplasmic reticulum.

Question 8

What is the drug oxidation by CYP450?

Answer 8

The oxidation mechanism involves a complex cycle. The addition of one atom of oxygen to the drug to form a hydroxyl group (OH) to form the product, ‘Drug-OH’.

Question 9

What happens at phase 2 metabolism?

Answer 9

Conjugation reactions produce Polar metabolites which are water soluble and can thus be excreted into the urine.
Catalysed by specific transferases, found in the ER and cytoplasm of hepatocytes.
Phase 2 metabolites usually have lower pharmacological activity or toxicity.

Question 10

What are toxic metabolites?

Answer 10

e.g. paracetamol.
At normal therapeutic doses, most paracetamol is conjugated as glucuronide or sulphate via phase 2 metabolism in the liver.

Question 11

What happens when an overdose of paracetamol is taken?

Answer 11

The levels of glutathione are rapidly depleted, leaving reactive intermediates to damage liver cells.

Question 12

List the route of excretions

Answer 12

• Urine: Main route for low molecular weight substances
• Bile: Large, high molecular weight substances - often conjugates
• Faeces: compounds excreted through bile and materials or not absorbed in gut.
• Sweat: water soluble drug products.
• Breath - volatile substances, gases, aerosols and solvents.
• Saliva - low molecular weight compounds
• Milk - lipid soluble and water soluble products
• Hair - very slow - not significant for elimination.

Question 13

What is the rate of elimination?

Answer 13

Rate of elimination (metabolism and excretion) is proportional to the amount of drug in the body. 
high conc (shortly after administration) -> High rate of elimination.
Low conc (after some time in body) -> low rate of elimination.

Question 14

What is first order kinetics?

Answer 14

• Rate of elimination is directly proportional to drug conc.
  constant fraction eliminated per unit of time.
• most drugs

Question 15

What is zero order kinetics?

Answer 15

• independent of drug conc, e.g. rate unaffected by increases in drug conc.
• constant amount eliminated per unit of time
• can occur when enzyme system responsible for a drug’s metabolism becomes saturated e.g. alcohol (-10ml/hr) phenytoin.