Drug handling in liver impairment

Question 1

In relation to drug handling, what parameters are affected by LD?

Answer 1

Drug clearance, especially if a drug has higher hepatic clearance

Biotransformation is the process by which substances that enter the body are changed from hydrophobic to hydrophilic molecules to facilitate elimination from the body

Pharmacokinetics

Question 2

What are some of the factors that are responsible for the alteration in parameters? What is the overall effect?

Answer 2

Intestinal absorption
Plasma protein binding due to reduce synthesis of the proteins. If a drug is highly plasma bound, this means in LD there will be an increase in the ‘free’ drug
Hepatic extraction ratio
Liver blood flow
Portal systemic shunting due to portal hypertension, meaning that the liver can be bypassed
Biliary excretion
Enterohepatic circulation
Reduced renal clearance due to reduced renal blood flow

Essential all of these factors can contribute to an increased bioavailability, meaning that usual doses can become toxic

Question 3

Are the effects on drug handling predictable in a patient with liver disease?

Answer 3

Unlike dose adjustments in renal function, both the severity and type of liver disease does not always correlate to elevations in liver function tests and increase in bioavailability.
There are no specific dose reductions that are required.

Question 4

What is phase I metabolism?

Answer 4

Phase I biotransformation reactions introduce or expose functional groups on the drug with the goal of increasing the polarity of the compound. As most small molecule drugs are lipophilic in nature, drug metabolism converts these hydrophobic compounds into more water soluble compounds that can be excreted.

Question 5

What are some examples of processes that occur in phase I metabolism?

Answer 5

Oxidation (e.g. Azathioprine)
Reduction (e.g. Halothane)
Hydrolysis (e.g. Atropine)

Question 6

What is phase II metabolism?

Answer 6

Phase 2 metabolism involves conjugation - that is, the attachment of an ionised group to the drug. The attachment of an ionised group makes the metabolite more more water soluble ready for excretion out of the body.

Question 7

What are some examples of processes that occur in phase II metabolism?

Answer 7

Glucuronidation (e.g. Paracetamol)
Sulphonation (e.g. Steroids)
Acetylation (e.g. Hydralazine)
Methylation (e.g. Nicotine)

Question 8

What is the rate of hepatic clearance dependent on?

Answer 8

Both the metabolism capacity but also the blood flow through the liver

Question 9

What does having a high extraction ratio mean?

Answer 9

That the clearance of the drugs in this categories is highly dependent on hepatic blood flow.

Question 10

What does having a low extraction ratio mean?

Answer 10

That the clearance of the drugs in this category is not dependent on hepatic blood flow but instead relies more heavily on metabolism.

Question 11

What are examples of drugs within the high extraction ratio?

Answer 11

Chlormethiazole,
Lignocaine,
Morphine,
Propranolol,
Verapamil,
Metoprolol,
Pethidine

Question 12

What are examples of drugs within the low extraction ratio?

Answer 12

Chlorpropamide,
Phenytoin,
Diazepam,
Warfarin
Atenolol,
Frusemide,
Prednisolone,
Lorazepam

Question 13

What do drugs with a high extraction ratio undergo?

Answer 13

Extensive first pass metabolism by the liver

Question 14

How do the extraction ratios differ between low and high?

Answer 14

Drugs with a high extraction ratio will have this value as close to 1 and those with a low extraction ratio this will be close to 0.

Question 15

Which type of drug require a greater reduction in dose?

Answer 15

Drugs with a high extraction ratio although unlike renal impairment there are no set requirements.

Question 16

How is dose reduction managed in LD?

Answer 16

Intensive monitoring for therapeutic and toxic effects and titrating the dose accordingly.

Question 17

What are the additional issues associated with use of CYP450 inhibitors and inducers in LD?

Answer 17

LD causes a reduction in the magnitude of interactions due to enzyme inhibition and induction.

Therefore Monitor effects of drug and plasma concentrations if appropriate

Question 18

What are examples of CYP 450 inhibitors, increasing the effects of the drugs?

Answer 18

Sodium valproate
Isoniazid
Cimetidine
Ketoconazole
Fluconazole
Alcohol & Grapefruit juice
Chloramphenicol
Erythromycin
Sulfonamides
Ciprofloxacin
Omeprazole
Metronidazole

And viral infections
Chronic cardiac failure
Cirrhosis

Question 19

What are examples of CYP 450 inducers, decreasing the effects of the drugs?

Answer 19

Carbemazepines
Rifampicin
Alcohol
Phenytoin
Griseofulvin
Phenobarbitone
Sulphonylureas

And smokers a
Heavy drinkers

Question 20

What is an additional effect of enzyme inducers?

Answer 20

Causes an increase in GGT levels

Question 21

What are some of the pharmacodynamic changes in patients with LD?

Answer 21

They have an increased sensitivity to certain drugs which:
Affects clotting/bleeding due to the inability of the liver in LD to synthesise clotting factors

Exerts effects or has side effects on the CNS due to the increased risk of hepatic encephalopathy

Diuretics due to their ability to cause hypovolemia and hypokalaemia both of which are risk factors for hepatic encephalopathy

Cause constipation this is also a risk factor for hepatic encephalopathy as reduced gut motility, increased exposure of nitrous products in the gut leading to increased absorption