Drugs And The Liver

Question 1

What is the perivenal region of the liver?

Answer 1

Consists of the central vein which drains into the IVC. It is an oxygen-poor region where glycolysis occurs instead. Glucorinidation of drug metabolites occur here, and glutamine synthesis.

Question 2

What is the periportal region of the liver?

Answer 2

Region where blood supply enters the liver, consisting of the hepatic portal vein and hepatic artery. It is an oxygen rich region where gluconeogenesis and oxidative phosphorylation can occur. Ammonia uptake and urea formation is present here.

Sulphation conjugation is the main form that occurs.

Question 3

What does the hepatic portal vein transport?

Answer 3

Absorbed drugs from enterocytes.

Question 4

What does the hepatic artery transport?

Answer 4

Circulating drugs in the bloodstream.

Question 5

What do bile salts transport?

Answer 5

Drug metabolites.

Question 6

What does the hepatic vein transport?

Answer 6

Drug metabolites.

Question 7

What affects hepatic clearance of oral drugs?

Answer 7

Protein transport of the drugs in the bloodstream
Liver blood flow
Intrinsic clearance

Question 8

What is intrinsic clearance?

Answer 8

Ability of the liver to metabolise a drug when there is normal blood flow and the oral drug is bound to proteins.

Question 9

What is the equation for the hepatic clearance?

Answer 9

Hepatic blood flow/
(Free drug x Intrinsic clearance) / (Flow + Free drug x clearance)

Question 10

What is a high extraction ratio?

Answer 10

Drugs are rapidly cleared from the body by the single pass effect, with clearance depending on hepatic blood flow.

Question 11

What is the intermediate extraction ratio?

Answer 11

Hepatic clearance of the drug transported from the hepatic portal vein relies on both hepatic blood flow and the intrinsic clearance capacity of the liver.

Question 12

What is low extraction ratio?

Answer 12

Elimination of the drug from blood flow is independent on hepatic blood flow, and relies on the intrinsic metabolising capacity of the liver.

Question 13

Which drugs have a high extraction ratio?

Answer 13

Verapamil
Morphine
Propanolol

Question 14

Which drugs have an intermediate extraction ratio?

Answer 14

Aspirin
Codeine

Question 15

Which drugs have a low extraction ratio?

Answer 15

Warfarin
Phenytoin

Question 16

What occurs in phase 1 drug metabolism?

Answer 16

Functionalisation reaction out by Cytochrome P450 to make drugs more polar active metabolites via:
Reduction
Oxidation
Hydrolysis

CYP40 is important for processing other compounds like foods and microorganisms. The gene expression is not proportional to its action in the body, and levels of this enzyme vary between individuals

Question 17

What occurs in phase 2 drug metabolism?

Answer 17

Cytochrome P450 conjugates the drugs to increase their polarisation, therefore making it more water soluble for greater excretion in the urine. Glucoronidation and sulphation are the most common forms.n

Question 18

What is the most common phase II conjugation reaction?

Answer 18

Glucoronidation to allow for more efficient kidney and bile excretion.

Question 19

What is Phase III drug elimination?

Answer 19

The 2 excretion pathways for drugs which include:
Biliary excretion, which is more common for polar and lipopohilic drugs, especially after glucoronic acid conjugation
Active transport, which is energy dependent and can be saturated.

Question 20

What are the features of amino acid conjugation?

Answer 20

Typically conjugation occurs with glutamine or glycine, and are more readily excreted in urine than bile. In neonates, this type of conjugation with glucoronic acid is slower with chloramphenicol antibiotic and can cause greater side effects.

Question 21

What are the features of aspirin metabolism?

Answer 21

In Phase 1 drug metabolism, aspirin is converted -> Salicylic acid.
In Phase 2 drug metabolism, salicylic acid undergoes conjugation to be excreted in urine.

Question 22

How does aspirin metabolism occur?

Answer 22

In Phase 1 drug metabolism, aspirin is converted -> salicylic acid.
In Phase 2 drug metabolism, saliciyclic acid is conjugated and excreted in the urine.

Question 23

How does hepatocellular failure affect drug metabolism?

Answer 23

Decreased hepatocellular blood flow, enzyme function and lower production of plasma proteins so there is more free drug in the bloodstream. Bile production is also lower.

Question 24

Which other factors affect liver drug metabolism?

Answer 24

Liver disease affects the kidneys and reduces renal clearance of drugs. There is a risk of malnutrition with lower drug metabolism.

Question 25

What is drug induced liver disease?

Answer 25

Reversible damage to the liver due to overdosage of drug intake which can cause an elevation in liver enzymes or liver failure.

Question 26

What is idiosyncranatic drug induced liver disease?

Answer 26

Liver damage despite taking the recommended dose of liver, which occurs after a period of latency for weeks or months, and results in jaundice. This is due to an immune response driven by T cells activation, with risk factors including post-infection, age and HLA type.

Question 27

What are the risk factors for drug-induced liver disease?

Answer 27

Excess alcohol intake
Obesity
Use of methotrexate

-> It is important to monitor ALT elevations, and serum markers for fibrosis and perform liver biopsy.

Question 28

How does paracetamol cause hepatotoxicity?

Answer 28

Overdose over 10g can cause hepatic necrosis, which causes progressive liver failure after 48 hrs. A prolongation of prothrombin time and prescence of acidosis indicates poor survival. Chronic use of alcohol will act as an inducer and cause hepatotoxicity, with a lower risk in plasma with vomiting.

Question 29

How is paracetamol metabolised?

Answer 29

By Cytochrome p45, paracetamol is -> NAPQ1.
NAPQ1 will then be conjugated with glutathione to be excreted in urine.
If there is hepatotoxicity when levels accumulate, then NAPQ1 willl rise and damage hepatic cells and cause liver failure.