Lecture 11 Drugs and the Liver

Question 1

Give 7 functions of the liver

Answer 1

• Immunity against infection
• Produces proteins and cholesterol
• Excretes wastes via bile
• Excretes bile for fat digestion
• Regulates blood clotting -
• Clears blood of drugs, chemicals and alcohol
• Converts excess glucose into starch for storage.

Question 2

1. What do LFTs measure?

2. What other tests for liver function are carried out?

Answer 2

1. Serum levels of liver enzymes (test for inflammation/ blockage in the liver)
   - ALP/ GGT (elevated in obstructive jaundice)
   - AST/ ALT (Elevated in hepatic jaundice)
   - (bilirubin - which increases no matter what jaundice)
2. Prothrombin time (PT/ INR) - increases in liver failure
   - Albumin level - decreases
   Changes in these are a sign that there is serious liver impairment

Question 3

1. What phase of metabolism reactions are cytochrome P450 enzymes involved in?
2. Describe these enzymes

Answer 3

1. Phase 1 reactions.
2. e.g. CYP450 2D6 / CYP450 3A4.
   Large family (74) of harm protein isoenzymes. Have overlapping substrate specificities and large genetic/ species and environmental variation in activity.

Question 4

Explain Phase 1 metabolism reactions.

Answer 4

• Use oxidation/ reduction and hydrolysis
• Purpose is to form more chemically reactive products: may be pharmacologically active or toxic/ carcinogenic
• Enables the easy conjugation of a substituent group (phase 2 reaction) to make the molecule more water soluble (ready for excretion).

i.e. Phase 1 CYP450 monooxygenases create a more reactive (sticky) molecule

Question 5

1. What do enzyme inducers do?

2. List 8 enzyme inducers.

Answer 5

1. Increased synthesis or decreased breakdown of CYP isoenzymes (and so affect phase 1 reaction)
2. PC BRAGS
   Phenytoin
   Carbamazepine / Cigarettes
   Barbituates
   Rifampicin
   Alcohol
   Glucocorticoids
   St John’s Wort

Question 6

Give 5 examples of an enzyme inhibitor, the specific enzyme and then a substrate which will be affected.

Answer 6

Ciprofloxacin at 1A2 - theophylline (dangerous because narrow therapeutic range and fits at toxic conc)
Amiodarone at 2C9- S- Warfarin
Fluoxetine at 2D6 - Oxycodone
-azoles at 3A4 - Verapamil 
Erythromycin at 3A4 - Erythromycin

Question 7

Explain Phase 2 reactions.

Answer 7

• Conjugate almost always inactive
• Substitute groups: glucuronyl, sulfate, methyl. acetyl, glycyl.
• Make the molecule more polar (water soluble)
• Molecule ready for excretion in the urine or bile.

i.e. Conjugation - sticking a polar moiety onto the molecule to enable excretion in the urine or bile.

Question 8

1. Describe the different spectrum of liver damage.

2. List 8 drugs which are hepatotoxic

Answer 8

1. Raised AST -> Hepatitis –> Liver failure
2. (1) Alcohol
   (2) Excessive paracetamol
   (3) Isoniazid
   (4) Statins
   (5) Methotrexate
   (6) Amiodarone
   (7) Chlorpromazine (Obstructive jaundice)
   (8) Halothane (Immune mediated)

Question 9

Describe what occurs in paracetamol overdose.

Answer 9

In excessive doses the usual conjugation pathways become overwhelmed and the remaining paracetamol is oxidised to the toxic intermediate metabolite NABQI - N-Acetyl-p-benzoquinoneuimine. (Needs to be conjugated with glutathione)

Question 10

How do the symptoms of paracetamol poisoning change with time?

Answer 10

0-24 hours may be nothing, sometimes vomiting and sweating
24-36 hours may be nothing, sometimes upper abdominal pain
36-72 hours - onset of liver or renal failure
72-120 hours - Jaundice, bleeding, liver failure and renal failure.

Question 11

How do you track the levels of paracetamol in the blood?

Answer 11

Paracetamol treatment line.

• Measure plasma paracetamol conc over four hours after they have taken the overdose
• Measure at intervals to observe id levels are going up or done
• Will be gone by 24 hours after OD so no point in doing plasma conc then but can still give treatment for the damage

Question 12

Who are the high risk patients in paracetamol overdose?

Answer 12

• Malnourished (deficient in glucathione)
• Alcoholics
• Known liver disease
• On anticonvulsants

Question 13

1. What is the antidote to paracetamol overdose?
2. What is the mechanism of action?
3. When should treatment be commenced?
4. How much should be given?

Answer 13

1. N-acetylcysteine IV infusion
2. Glutathione donor, allowing safe metabolism of NABQI
3. Ideally within 12 hours of ingestion
4. Interpret paracetamol levels and need for antidote according to nomogram. Can make mistakes with N-acetylcysteine because it needs to be given at different concentrations and speeds. If you give to much too soon 10% develop an anaphylactoid reaction

Question 14

Give 4 signs of liver disease

Answer 14

(1) Distended veins around the umbilicus
(2) Hepatosplenomegaly
(3) Anaemia
(4) Jaundiced

Question 15

How does cirrhosis manifest itself in the body?

Answer 15

• Ascites (fluid in the peritoneal cavity)
• Encephalopathy (loss of higher mental functioning due to long-term damage to neurones. Confusion and agitation)
• Coagulopathy (bleeding due to lack of clotting factors)
• Hepatorenal syndrome (kidneys fail because the pressure is built up)
• Varices/ Portal hypertension

Question 16

1. What is the name of the scoring system for cirrhosis?

2. What are the classes of liver disease and what action do you take?

Answer 16

1. Child-Turcotte-Pugh scoring system for cirrhosis. Based on clinical variables.
2. Child class:
   A = 5-6 points
   B = 7-9 points and can start to consider transplant
   C = 10-15 points and risk of transplant is too high.

Question 17

1. List 4 non-pharmacological ways to relieve ascites

2. Describe the pharmacological measures taken to relieve ascites.

Answer 17

1. (1) Sodium restriction
   (2) Paracentesis (drained off)
   (3) Banano catheter
   (4) Transjugular intrahepatic portosystemic shunt (TIPS) - bypass the portal system because the liver is blocking it. High risk of encephalopathy.
2. Diuretics:
   Spironolactone - potassium sparing diuretic that blocks the aldosterone receptor in the distal tubule.
   Furosemide - Loop diuretic which inhibits the Na+/K+/Cl- carrier in the luminal membrane of the Loop of Henle.

Question 18

1. Why does liver failure cause Hepatic Encephalopathy?

2. How is it treated?

Answer 18

1. ?? Due to excess ammonia from bacteria in the GIT, not being converted to urea and therefore making it to the systemic circulation

?? Due to excess GABA (neuroinhibitory substance) or neurosteroids building up in the brain

2. Lactulose 30mls 2-3 times a day.
   - Nonabsorbable disaccharide that stimulates the passage of ammonia from tissues into the gut lumen and inhibits intestinal ammonia production.

Treat malnutrition with Pabrinex Thiamine, riboflavin, pyridoxine and ascorbic acid

• 2 paired vials given as slow IVI 8 hourly for a few days
• Change to oral thiamine supplements

Antibiotics - rifaximin for GIT bacteria/ blocks RNA transcriptase. Limited effective evidence in the absence of spontaneous bacterial peritonitis

Herpa merz (L-ornithine L-aspartate)

• Important substrates in the formation of urea from ammonia
• Theoretical benefit
• Unliscenced.

Question 19

1. What characterises coagulopathy in hepatic failure?

2. How is it treated?

Answer 19

1. Increased prothrombin time.
2. Treated with Vitamin K which is often unsuccessful due to poor absorption and poor remnant synthetic function. Replace factors if acutely bleeding.

Question 20

1. What causes hepatorenal syndrome?

2. How is it treated?

Answer 20

1. Multifactorial but one issue is splanchnic vasodilation - increased vascular resistance
2. Limited successful treatments due to difficult fluid balance
   Some success with vasopressin (ADH) analogies
   - Terlipressin
   - V1 (ADH receptor) - selective vasoconstriction
   - Also used in variceal bleeding.