Drugs And The Liver

Question 1

Define:

1. Metabolism
2. intrinsic clearance
3. conjugation
4. hydrolysis
5. reduction
6. oxidation

Answer 1

1. all chemical reactions involved in maintaining the living state of the cells and the organisms
2. theoretical unrestricted maximum clearance of unbound drug by an eliminating organ, in absence of blood flow or plasma protein binding limitations
3. addition of chemical group to drugs during metabolism
4. the chemical breakdown of a compound due to reaction with water
5. the loss of oxygen (gain of electrons) within a chemical reaction
6. the gain of oxygen (loss of electrons) within a chemical reaction

Question 2

What are the functions of the liver?

Answer 2

Nutrient metabolism (carbohydrate, protein, lipids)

Protein synthesis (albumin, coagulation factors, complement factors, haproglobin, ceruloplasmin, transferrin, protease inhibitors)

Excretion (bile salts and bilirubin)

Storage (iron, copper, vitamins A, D, B12)

Question 3

What causes hepatocytes to have different characteristics?

Answer 3

Due to differences in oxygen concentration (high O2 at periportal end, low O2 at perivenous end) and signalling molecules along the acinus, the hepatocytes have different characteristics

Question 4

What are periportal hepatocytes?

Answer 4

zone 1
perfused with blood rich in oxygen, nutrients and hormones since it is closest to the hepatic artery and portal vein. Hepatocytes in this region are specialized for oxidative phosphorylation, gluconeogenesis etc.

Question 5

What are perivenous hepatocytes?

Answer 5

zone 3
perfused with blood depleted in oxygen, nutrients and hormones but enriched in CO2 and other products of metabolism (e.g. VLDLs, glucose, ketones, urea, glutamine etc.) depending on fed or fasting state. Hepatocytes in this zone are specialised to a glycolytic phenotype due to low oxygen environment

Question 6

Where do phase 1 and 2 drug metabolism reactions occur?

Answer 6

periportal and perivenous zones
however majority occurs within perivenal region. You also get different conjugation reactions depending on where you are.

Question 7

Describe the entry of drugs into hepatocytes?

Answer 7

Given IV or orally and enters the blood, it can either
o Remain in an unbound
o Taken up by blood cells (may have an action on the blood cell, may not)
o Taken up by proteins within the blood e.g. albumin (affects availability to do its
action)
o Taken up by hepatocytes

Within the hepatocytes it can either be o Put back into blood
o Metabolised
-Phase 1 reaction = may form a more or less active metabolite
-Conjugation then secretion (into bile or back into blood for excretion in urine)

Question 8

What is the hepatic clearance of oral drugs dependent on?

Answer 8

Efficacy of metabolizing enzymes
Liver blood flow
Intrinsic clearance (linked to efficiency of metabolising enzymes)
Protein binding

Question 9

How do you calculate hepatic clearance?

Answer 9

Clh = Q [ (f x Clint) / (Q + f x Clint) ]
• Q = hepatic blood flow
• f = fraction of free drug (not bound)
• Clint = intrinsic capacity of the hepatocytes to metabolize a drug (intrinsic clearance
capability)
• Clh = hepatic clearance

Question 10

What does a high extraction ratio indicate?

Answer 10

Drugs rapidly cleared from the blood by the liver (e.g. in a single pass)
Clearance depends primarily on hepatic blood flow (i.e. ability to get the drug to the
liver will limit clearance, the drug is easily taken up by hepatocytes) o Therefore, clearance is non-restrictive
e.g. verapamil, morphine, propranolol

Question 11

What does a low Extraction ratio indicate?

Answer 11

Drugs not efficiently cleared by the liver and extracted incompletely from hepatic
blood
o Clearance is
o Relatively independent of hepatic blood flow
——Determined by the intrinsic metabolizing capacity of the liver (i.e.ability of liver to process the drugs) and by the free drug fraction
——The extraction is said to be restrictive or capacity limited o e.g. warfarin, phenytoin

Question 12

What does intermediate extraction ratio?

Answer 12

Hepatic clearance of these drugs is dependent on both hepatic blood flow, intrinsic
metabolising capacity of the liver and the free drug fraction e.g. aspirin, codeine

Question 13

What toxins does the liver detoxifies?

Answer 13

Metabolic end products
Microorganisms
Contaminants
Pollutants
Insecticides
Pesticides
Food additives
Drugs
Alcohol

Question 14

Describe phase 1 of drug metabolism?

Answer 14

First pass effect
Consists of oxidation, hydrolysis, hydroxylation, deamination
Make drugs more polar
Cytochrome P450 enzymes
o Most versatile biocatalyst known
o Many CYP families of P450 enzymes
o On each liver pass a fraction of the drug is converted to inactive metabolites
Microsomal drug-oxidizing system: oxidation of metabolite using P450 enzyme

Question 15

Describe phase 2 drug metabolism?

Answer 15

Detoxification or conjugation pathway
Conjugation - addition of another substance (e.g. cysteine, glycine or sulphur) to a toxic chemical or drug to render it less harmful
This makes the toxin or drug water-soluble (because the added substance is ionic/charged), hence it can be excreted from the body via bile or urine

Question 16

Describe phase 3 drug metabolism?

Answer 16

Pathways of elimination 
Urine excretion
Biliary excretion
o Directly into bile if highly polar
o After conjugation
Active transport mechanisms
o Energy dependent and can be saturated
o Biliary pole of hepatocyte
Biliary excretion important if molecular weight > 200kDa
As molecular weight decreases the urinary route becomes more important

Question 17

Describe P450?

Answer 17

Each P450 has a degree of specificity

One P450 isoenzyme may be involved in the metabolism of one or more drugs, and a single drug may be acted on by multiple enzymes

The binding affinity between certain drugs and P450 may vary so that a single P450 may be
largely responsible for the metabolism of some drugs e.g.
o Drug A and drug B are metabolised individually by P450I and P450II respectively,
there drugs will not bind with the other P450s
o However some P450 can metabolism 2 drugs at once as shown by the ability of a single P450III to bind to drugs C and D

Question 18

Describe drug-drug interactions

Answer 18

Affects clearance and production of toxic metabolites

Drugs bind at different affinities to P450 than others, hence some will be processed quicker than other drugs

Alternatively, if the patient suffers from chronic alcohol consumption it can affect P450
activity, and hence affects drug metabolism

Depending on the drugs given, there may be a build-up of toxic metabolites depending on the drugs that are interacting

Administration of one drug may influence the metabolism and elimination of another depending on whether the drug-metabolising enzyme system is induced or inhibited

Question 19

Name drugs that induce p450 activity

Answer 19

Ethanol
Barbiturates 
Oral contraceptive 
Cigarette 
Marijuana 
Phenytoin 
Rifampin 
Isoniazid

Question 20

What drugs are p450 inhibitors?

Answer 20

Ethanol (acute)
Cimetidine 
Ketoconazole 
Allopurinol 
Amiodarone 
Isoniazid

Question 21

What are the risk factors for impaired metabolism?

Answer 21

Hepatocellular failure

Decreased hepatic blood flow – decreased delivery to drug to hepatocytes

Decreased enzyme function – ability of P450 to work is reduced

Decreased plasma protein binding – increases volume of drug distribution

Reduced renal clearance in association with reduced renal function seen with liver disease

Malnutrition – reduced availability of micronutrients important in metabolism

Question 22

Describe the primary mechanism of impaired drug metabolism in liver disease?

Answer 22

Reduced cell mass/function - diminished complement of enzymes available for metabolism, also may be functionally impaired because of poor perfusion (intact hepatocyte hypothesis)

Reduced drug delivery – due to formation of collaterals, attendant extrahepatic portocaval shunting, intrahepatic shunting, capillarisation (and resulting hypoxia)

Reduced bile flow (from intrahepatic inflammation or extrahepatic obstruction) – applies to drugs that are primarily excreted in bile without undergoing biochemical changes (e.g. nafcillin, piperacillin, apalcillin)

Question 23

What are the consequences of drug biotransformation?

Answer 23

Drugs that are administered in their inactive forms (prodrugs) are metabolised into active compounds by the liver

Drugs which are active when administered are metabolised in the liver into active or inactive metabolites

Another important outcome of drug biotransformation is the generation of toxic metabolites

Oxidation of nitrosamines by cytochrome P450 plays an important role in carcinogenesis,
conjugation reactions may also generate carcinogens

Question 24

Describe the mechanisms of drug induced hepatic necrosis?

Answer 24

Drug when metabolised can produce free radicals/electrophiles which can damage cells

Immune reactions can occur as a result of cell damage leading to necrosis

Question 25

What is halothane hepatitis?

Answer 25

Type 1 hepatitis response = reasonably mild immune response Type 2 hepatitis response = strong immune response which can easily lead to fatal consequences

Question 26

Describe idiosyncratic drug liver disease?

Answer 26

When you load a patient with drugs, it should lead to adaptive type response Adaptive process, increases signalling pathways to cope with reactive metabolite = no liver injury However in a certain percentage of patients this process does not occur, the same reactive metabolites are produced but the signalling pathways aren't activated causing haptenization (immune system recognises the reactive metabolites as foreign and undergoes immune response causing hepatocyte injury) and sensitization = leads to necrosis and apoptosis causing liver disease – significant problem with many drugs

Question 27

Give an example of drug induced liver disease?

Answer 27

fibrosis due methotrexate Methotrexate – widely used Significant damage rare – 1 in 300 patient years Associated with cumulative doses of >2g Excess alcohol, obesity, age increase risk Monitoring – LFTS, serum markers of fibrosis Liver biopsy

Question 28

What is paracetamol hepatotoxicity?

Answer 28

Used as suicidal agent 10g produces hepatic necrosis Plasma levels affected by vomiting Alcohol – you need to be very proactive in patients who have taken both alcohol and paracetamol because: —Chronic use induces enzymes and increases hepatotoxicity —Acute use inhibits enzymes

Question 29

What is progress after paracetamol overdose?

Answer 29

No signs of toxicity for 48hrs Then progressive liver failure Severe prolongation of prothrombin time (because liver not working properly, and coagulation factors aren't being produced) and presence of acidosis predicts poor survival Liver transplantation

Question 30

What is the therapy for patients who have overdosed on paracetamol?

Answer 30

Administration of cysteine donors - glutathione = used to conjugate paracetamol metabolites Intravenous N-acetyl cysteine (Parvolex) Level of treatment is dependent on the point of ingestion

Question 31

What are the best ways to avoid paracetamol overdose?

Answer 31

Blister packs Bulk buying not allowed Addition of methionine to tablets

Question 32

How do you make a diagnosis of drug induced hepatotoxicity?

Answer 32

High index of suspicion o History of drug-related disorder o Clinical/laboratory pattern consistent with known pattern of drug injury (Hepatocellular, Cholestatic, Others) o Short duration of drug use by patient o Use of drug combinations (i.e. isoniazid/rifampin, alcohol/acetaminophen) known to predispose to drug toxicity o Systemic manifestations (i.e. fever, rash, eosinophilia, multisystem involvements) o Liver biopsy consistent with drug-induced injury (not always necessary)- Exclusion of other causes o Improvement (clinical/laboratory) after cessation of drug use o Rechallange (almost never indicated)