Drug Metabolism

Question 1

What does half life depend on?

Answer 1

Directly on the volume of distribution and inversely on clearance

Question 2

Where are the sites of metabolism?

Answer 2

• Liver (main),
• Gut lumen,
• Gut wall,
• Plasma,
• Lungs,
• Kidneys,
• Nerves,

Question 3

What occurs in result of metabolism?

Answer 3

• Pharmacological deactivation,
• pharmacological activation,
• Type of pharmacological response,
• No change in the pharmacological activity,
• Change in drug uptake,
• Change in drug distribution

Question 4

Describe phase 1 metabolism in the liver

Answer 4

• Generally is oxidation, reduction or hydrolysis.
• Results in introduction/reveal a reactive chemical group so products are often more reactive.
• Predominately prepares drugs for phase 2 metabolism

Question 5

Describe phase 2 metabolism in the liver

Answer 5

• Conjugative reactions which results in hydrophobic inactive compounds being generated
• It causes detoxified, water-soluble easily secreted products

Question 6

What are some enzymes that cause the different reactions in phase 1 metabolism?

Answer 6

Oxidations - Mixed function oxidase system (Cytochrome P450), alcohol dehydrogenase.
Reductions - Anaerobic cytochrome P450 metabolism.
Hydrolysis - Ester hydrolysis eg, cholinesterases.

Question 7

Describe what the mixed-function oxidase system (CYP450s) consist of and require

Answer 7

Microsomal enzymes consisting of cytochrome P450, NAPDH-CYP450 reductase and lipids. They require molecular oxygen and NADPH.

Question 8

What are some factors that affect metabolism?

Answer 8

Age - Children (low level of activity) and elderly (starts to decline).
Genetic variation - Wide range of CYP phenotypes and race.
Disease - Can be dependant on proper liver function and amino acid supply.
Other medications - Induction/inhibition of metabolic enzymes

Question 9

Name an example of an impact of CYP variation on clinical outcomes

Answer 9

CYP2B6 deficient alleles are more common in African populations. So when taking efavirenz it increases risk of neurological symptoms

Question 10

What are some possible sources of drug excretion?

Answer 10

• Urine (kidneys are the most important organ involved in elimination of drugs),
• Breath,
• Saliva,
• Perspiration,
• Feces,
• Milk
• Bile,
• Hair

Question 11

Name some of the transporters that transfer drugs from the plasma to bile

Answer 11

• Organic cation transporters (OCTs),
• Organic anion transporters (OATs)
• P-glycoproteins (P-GP)

Question 12

Explain the enterohepatic circulation cycle

Answer 12

• Drugs in intestines then;
• Drugs in the blood (some renal excretion)
• The conjugate in liver then,
• Conjugate in bile,
• Then conjugate in the intestines (some excretion in feces) and stars from the beginning

Question 13

Explain the renal excretion of drugs

Answer 13

Glomerular filtration - filters drugs below 20 molecular weight and as long as they aren’t bound to albumin.
Tubular secretion - Cleared even if bound to albumin due to OATs and OCTs.
Diffusion across renal tubule - if tubule is freely permeable then 99% of drug reabsorbed

Question 14

Explain how the excretion of drugs changes with the pH of urine

Answer 14

• Weak acids are excreted more rapidly if urine is alkaline.

- Weak bases are more rapidly excreted if urine is acidic

Question 15

What is zero order metabolism?

Answer 15

This is where a constant amount is metabolised per unit time so does not vary with amount of drug present.
- Few drugs are metabolised this way but occurs with enzyme saturation

Question 16

What is first order metabolism?

Answer 16

Most drugs are metabolised this way. It is where a constant fraction of drug is metabolised per unit time therefore it increases proportionately to drug concentration (more drug then more metabolised)