Hepatic Drug Metabolism

Question 1

What are the effects the liver can have on drugs in metabolism?

Answer 1

1. Conversion to drugs to inactive compounds (most common fate of active drugs) - this can promote excretion by the kidneys
2. Inactive prodrugs converted to active drugs with altered absorption kinetics, preventing adverse effects and improving distribution E.G. codeine -> morphine

Question 2

What is first pass metabolism?

Answer 2

Where a drug is taken in via the GI tract wall, into the blood and metabolised in the liver BEFORE it reaches the systemic circulation and therefore, its targets (reduces bioavailability) E.G. oral drugs

Question 3

How can you avoid first pass metabolism?

Answer 3

By giving a drug IV as it goes straight into the systemic circulation (will still go through liver at some point still)

Question 4

Do drugs only pass through the liver once?

Answer 4

No, this can happen continually if they are in the circulation, metabolising the drug each time to an extent

Question 5

Provide an overview of drug metabolism in the liver.

Answer 5

Phase 1: Adds a functional group to increase polarity of drug, less pharmacologically active and make it more susceptible to phase 2 reactions
Phase 2: Conjugation reaction which add a group that makes the drug less pharmacologically active, more soluble and thus, more easily excretable (some drugs can go straight to phase 2 if they have a group already suitable for conjugation)

Phase 3: Conjugated metabolite gets out of hepatocyte and into excretion system e.g. kidneys(urine) or biliary system (faeces)

Question 6

What reactions are involved in Phase I metabolism?

Answer 6

Oxidation
Reduction
Hydrolysis
- provide OH or NH2 group for e.g.

Question 7

What is the relevance of cytochrome P450 enzymes having various isoforms?

Answer 7

A whole variety of drugs can be metabolised by the isoforms that have low specificity

Question 8

What are cytochrome P450 enzymes and what do they do?

Answer 8

Haem proteins
Require presence of oxygen, NADPH and NADPH cytochrome P450 reductase to function = mixed function oxidase system
They catalyse the transfer of 1 oxygen atom to the drug whilst the other oxygen atom is reduced to water

Question 9

What is the oxidation reaction involving cytochrome P450s?

Answer 9

DH + O2 + NADPH + H+  DOH + H2O + NADP+

Question 10

What is the most abundant cytochrome P450 isoform?

Answer 10

CYP3A

Question 11

What are examples of other Phase I reactions?

Answer 11

Reductions
Oxidations
Hydrolytic reactions

Question 12

Example of oxidations NOT involving the P450 system?

Answer 12

Ethanol being metabolized by alcohol dehydrogenase which is a cytosolic enzyme

Question 13

What does Phase 2 conjugation reactions involve?

Answer 13

Mainly in liver but also lung and kidney
Chemical groups involved include glucuronyl, acetyl, methyl, sulphate and glutathione
Conjugating enzyme UDP-glucuronyl transferase exist in many isoforms

Question 14

What happens in Phase 3 transport?

Answer 14

Removed from hepatocyte by a multi-purpose membrane-bound transport carrier system into circulation then either:
Renal elimination (most common)
Into bile for elimination in faeces (principal route for larger molecules)

Question 15

Where in the liver to drugs go to be excreted?

Answer 15

EITHER
the sinusoid so they can flow into the central vein, leave the liver and be emptied into the systemic circulation
OR
across canaliculi membrane to be emptied into the bile system

Question 16

What types of transporters are on the hepatocyte relevant to this process?

Answer 16

Uptake transporters on the sinusoid take the drug up before metabolism
Efflux transporters either take them into vascular space or the bile canaliculi after metabolism

Question 17

What is the problem with phase I metabolism and paracetamol?

Answer 17

Toxic metabolite that is more chemically reactive is produced

Question 18

What are the effects of age on drug metabolism?

Answer 18

Neonates (1st 30 days of life) - hepatic drug metabolizing enzymes e.g. conjugating enzymes are absent or present in low amounts
Children (1-12yrs) - metabolic clearance can be quicker after 30 days of life so metabolic clearance can be greater than adults - obtain dosage from paediatric dosage handbook using age and body surface area
Elderly - hepatic drug metabolism, particularly phase I reduced and simultaneous use of several drugs is common so usually start drug treatment with lowest dose

Question 19

Why is drug interaction a problem for hepatic metabolism?

Answer 19

Drugs compete for same metabolising enzyme and thus, the effect they have on the metabolism of others e.g. cytochrome P450s

Question 20

What are examples of CYP3A inhibitors and what do they do?

Answer 20

Azole antifungal drugs
Macrolife antibiotics
H2 receptor antagonist
Grapefruit juice
-> reduced clearance and higher blood levels of primary drug (potentially toxic levels and adverse effects)

Question 21

What are CYP3A inducers and what do they do?

Answer 21

Anti-convulsant
Antibacterial
Antiviral
St Johns Wort 
-> increased clearance and lower blood levels of primary drug = lack of therapeutic efficacy

Question 22

What is St. Johns Wort?

Answer 22

Herbal OTC remedy for depression that induces activity of many P450 enzymes increasing metabolism and reducing concentration of drugs such as warfarin, antiepileptics and oral contraceptives

Question 23

How can we avoid drug interactions?

Answer 23

Full medication history
Remember high risk patients (4 or > medications & medications like warfarin, anticonvulsant and antibiotics et.)
Understanding of P450 metabolism
Consult BNF

Question 24

What is the effect of genetic polymorphisms on drug metabolism?

Answer 24

Mutations in CYPP540 enzymes means variation in expression and activity of that particular type meaning drugs are metabolized at different rates

Question 25

If a genetic polymorphism means a CYP is a poor metaboliser, what does this mean?

Answer 25

If the active drug is inactivated usually by CYP metabolism, the active drug may accumulate to toxic levels so may require decrease in dose e.g. CYP2C19 mutation and omeprazole (usually converted from active proton pump inhibitor to inactive form)
If the pro-drug is activated by CYP metabolism, there is decreased efficacy as pro-drug may accumulate to toxic levels so may require alternative drug

Question 26

If a CYP has a mutation that makes it a rapid metaboliser, what does this mean?

Answer 26

If the pro-drug is normally activated by the CYP, there is increased efficacy, rapid onset of effect so may need decrease in dose to prevent accumulation of active metabolite e.g. CYP2D6 converting the weak analgesic codeine to the strong analgesic morphine
If the active drug is inactivated by CYP, there is decreased efficacy as active drug rapidly inactivated so may need increase in dose

Question 27

How to poor metabolisers and ultra-rapid metabolisers respond to codeine?

Answer 27

Not well
Poor metabolizers cannot convert codeine to morphine so no pain relief but codeine side effects
Ultra-rapid metabolisers rapidly convert codeine to morphine so toxic levels of morphine causes opioid toxicity symptoms

Question 28

What are codeine’s side effects?

Answer 28

Nausea/vomiting
Light-headedness
Dizziness
Sweating
Constipation

Question 29

Symptoms of opioid toxicity:

Answer 29

Respiratory depression, skeletal muscle flaccidity, cold/clammy skin, bradycardia, hypotension and constipation

Question 30

What is the effect of liver disease on drug action?

Answer 30

In cirrhosis, there is impaired liver function including decreased drug-metabolising capacity and porto-systemic shunting directs drug away from liver

Question 31

How can liver disease influence drug action?

Answer 31

Increased bioavailability due to decreased 1st pass metabolism e.g. nicardipine, propranolol and verapamil (1st pass activation of pro-drugs decreased too e.g. ACE inhibitors)
Decreased protein binding because liver disease causes hypoproteinaemia leading to reduced drug-binding capacity = more unbound pharmacologically active drug to circulate -> enhanced response

Question 32

What are the precautions that should be taken when prescribing in liver disease?

Answer 32

Carry out with care
Drugs extensively metabolised by liver should be given in smaller doses
Patients more susceptible to hepatotoxic effects of ANY drug