Hepatic drug metabolism

Question 1

What are the four phases of pharmacokinetics?

Answer 1

Absorption
Distribution
Metabolism
Excretion

Question 2

What is first pass metabolism?

Answer 2

The extent of metabolism occurring before the drug enters the systemic circulation

Question 3

What is phase I of drug metabolism in the liver?

Answer 3

Oxidation
Reduction
Hydrolysis

[Addition of functional group e.g. OH or NH2 to increase polarity of drug and provide a site for phase 2 reactions]

Question 4

What are cytochrome P450 enzymes?

Answer 4

Haem proteins that require presence of oxygen, NADPH and NADPH cytochrome P450 reductase in order to function (mixed function oxidase system)

Question 5

What is the process of drug oxidation?

Answer 5

Cytochrome P450 catalyses the transfer of one oxygen atom to the drug (oxidation) and other oxygen atom reduced to water (reduction)

Question 6

What other phase 1 reactions can occur?

Answer 6

Reduction
Oxidation not involving P450 system
Hydrolysis

Question 7

What occurs during phase II of drug metabolism?

Answer 7

Drug must possess suitable site for phase II reaction (either present before or as a result of phase I reaction)
Conjugation reaction (attachment of large chemical group to functional group on drug molecule)
Almost always makes drug inactive and hydrophilic (and therefore more easily excreted)

Question 8

What does phase III involve in drug metabolism?

Answer 8

Transport into circulation or bile

Excretion via kidneys or faeces

Question 9

How does drug metabolism differ in neonates?

Answer 9

Immature metabolising enzymes
Inefficient renal clearance

= Lower drug doses required

Question 10

How does drug metabolism differ in children?

Answer 10

Mature CYPs and relative liver mass/ hepatic blood flow higher = quicker metabolic clearance than in adults
Doses dependent on age and body surface area

Question 11

How does drug metabolism differ in elderly patients?

Answer 11

Reduced capacity for drug metabolism (due to lower relative liver mass and hepatic blood flow)
Drug dose should be started with smallest effective dose

Question 12

What drug metabolism reactions are characterised by CYP3A?

Answer 12

Calcium channel blockers
Benzodiazepines 
HIV protease inhibitors
HMG-CoA-reductase inhibitors
Cyclosporine 
Non-sedating antihistamines
Oral contraceptives

Question 13

What are common examples of CYP3A inhibitors?

Answer 13

Antifungal drugs (-azole)
Macrolide antibiotics (.g. erythromycin)
Cimetidine (H2 receptor antagonist)
Grapefruit juice

Question 14

What can the presence of CYP3A inhibitors result in?

Answer 14

Reduced drug clearance = higher blood levels of primary drug = potentially toxic levels/ adverse effects

Question 15

What are common examples of CYP3A inducers result in?

Answer 15

Carbamazepine (anti-convulsant)
Rifampicin + Rifabutin (anti-bacterial)
Ritonavir (antiviral)
St. John’s Wort (herbal)

Question 16

What can the presence of CYP3A inducers result in?

Answer 16

Increased drug clearance = lower blood levels of primary drug = lack of therapeutic

Question 17

What effect does St. John’s Wort have on drug metabolism?

Answer 17

Induces activity of many P450 enzymes (e.g. CYP3A4, CYP2C9, CYP2E1, CYP1A2)
Increases metabolism and reduces plasma concentration of drugs such as warfarin, anti-epileptics and oral contraceptives

Question 18

What steps should be taken to avoid drug interactions?

Answer 18

1. Full medication history
2. Awareness of high risk patients (e.g. those on multiple medications, warfarin etc.)
3. Understanding of P450 enzymes
4. Use BNF

Question 19

How does codeine metabolism differ in poor metabolisers?

Answer 19

Cannot convert codeine to morphine = no pain relief + increased side effects (especially if dose is increased to relieve pain)

Question 20

How does codeine metabolism differ in ultra-rapid metabolisers?

Answer 20

Rapid conversion of codeine to morphine = opioid toxicity

Question 21

What are the common side effects of codeine?

Answer 21

Nausea/ vomiting
Light-headedness/ dizziness
Sweating
Constipation

Question 22

What are the common side effects of opioid toxicity?

Answer 22

Respiratory depression 
Skeletal muscle flaccidity 
Cold/ clammy skin 
Bradycardia 
Hypotension 
Constipation

Question 23

What are the effects of liver disease on drug action?

Answer 23

1. Impaired drug-metabolising capacity (especially first pass metabolism)
2. Porto-systemic shunting (directs drug away from liver)
3. Increased bioavailability (due to decreased first-pass metabolism)
4. Decreased protein binding

Question 24

What is the definition of bioavailability?

Answer 24

The proportion of administered drug which reaches the systemic circulation unchanged and is thus available for distribution to the site of action

Question 25

Where does first pass metabolism occur?

Answer 25

Liver (mainly)
Gut lumen (e.g. gastric acid and proteolytic enzymes)
Gut wall

Question 26

What drugs commonly have increased bioavailability due to cirrhosis?

Answer 26

Nicardipine (calcium channel antagonist)
Propanolol (beta-adrenoceptor antagonist)
Verapamil (calcium channel antagonist)