Prescribing in Hepatic disease

Question 1

What is the cycle of prescribing in hepatic/renal disease?

Answer 1

Pts with renal (or hepatic) impairment are less able to metabolise or excrete drugs
&
Drugs commonly cause hepatic (or renal) impairment

Question 2

In what 3 ways are drugs metabolised by the liver?

Answer 2

To INACTIVE metabolites
To ACTIVE metabolites
To TOXIC metabolites

Question 3

What kind of metabolite does the liver convert paracetamol to?

Answer 3

To toxic

Question 4

What kind of metabolite does the liver convert methotrexate, carbamazepine & codeine to?

Answer 4

to active metabolites

Question 5

What kind of metabolite does the liver convert ramipril and simvastatin to?

Answer 5

they are pro-drugs so they get –> their active metabolites

Question 6

How can you prevent drug-induced liver disease?

Answer 6

anticipate it when starting a drug –> warn patients to be vigilant
monitor patient 1) clinically 2) LFTs
check plasma drug levels if appropriate
stop drug early if liver abnormalities develop
(2nd drug may reduce hepatotoxicity of first)

Question 7

What drugs cause abnormal LFTs?

Answer 7

The anti’s:
Anti-epileptics (phenytoin, valproate)
Anti-TB (except ethambutol)
Anti-psychotics (TYPICAL)

Statins, amiodarone, spironolactone, methotrexate
COCP
Alcohol

Question 8

What drugs may have idiosyncratic reactions? (& cause abnormal LFTs)

Answer 8

NB: idiosyncratic drug reactions, = type B reactions = drug reactions that occur rarely and unpredictably amongst the population.

Antibiotics: Flucloxacillin, Erythromycin
DM drugs: Sulphonyureas, Glitazones

Question 9

Which drugs increase risk of hepatic encephalopathy (so be cautious of/avoid in pts with established liver disease)?

Answer 9

Opiates

Diuretics

Question 10

Why should you be wary of/avoid use of oral hypoglycaemics in pts with established liver disease?

Answer 10

oral hypoglycaemics = loss of glucose homeostasis & increase risk of lactic acidosis

Question 11

Why should you be wary of/avoid use of WARFARIN in pts with established liver disease?

Answer 11

the effects are enhanced

blocks Vit K epoxide Reductase [VKORC1] in liver

Question 12

How do you minimise harm in prescribing for patients with established liver disease?

Answer 12

Use minimum number of drugs...
BUT Where prescribing is unavoidable:
use the BNF 
use safest possible drug 
minimise dose 
monitor carefully (clinical, biochemistry, drug levels) 
alter dose of drug (or stop) accordingly 
PLAN STOP DATE

Question 13

Why is the liver so vulnerable?

Answer 13

most drugs are taken orally which goes from the GI tract –> portal circulation (SMV + IMV + SV –> PV)
20% cardiac output passes through liver
liver metabolism may produce toxic metabolites

Question 14

What is phase 1 in the hepatic metabolism of drugs?

Answer 14

Phase 1 metabolism makes:
1) drugs more polar
2) and may create a reactive site for conjugation (thats phase 2 metabolism)
This metabolism may activate a pro drug, inactivate a drug or create a toxic metabolite

Question 15

What are the ways of making a drug more polar (phase 1 of hepatic drug metabolism)?

Answer 15

oxidation = loss of electon(s), (CYP450)
reduction = gain of electron(s)
hydrolysis = insertion of H2O into drug (esterases, proteases)

Question 16

How do proteases and esterases work on drugs?

Answer 16

they hydrolyse e.g. insert H2O into drugs

Question 17

How do cytochrome P450 enzymes work?

Answer 17

they oxidise drugs e.g. cause loss of electrons

Question 18

What is phase 2 in the hepatic metabolism of drugs?

Answer 18

the COUPLING of a drug / polar metabolite TO A SUBSTRATE catalysed by an enzyme
–> conjugated drugs are INERT and WATER-SOLUBLE

Question 19

What are examples of substrates made by phase 2 hepatic metabolism (e.g. coupling –> substrate by enzyme)

Answer 19

• Glucuronate (glucuronyl transferase)
• Acetate (N acetyl transferases)
• Sulphate
• Amino acids
• Glutathione