Hepatic Failure

Question 1

Drugs in liver

Answer 1

_ High concentrations of drugs in the liver
 Significant portion of a drug taken orally passes through the liver
 20% of the cardiac output passes through the liver  Liver metabolism may produce toxic metabolites

Question 2

Phase 1 metabolism

Answer 2

Catabolic ‘’
 Oxidation, reduction or hydrolysis

Metabolism may
 Activate a pro-drug
 Inactivate a drug
 Create a toxic metabolite

Question 3

Phase 2 metabolism

Answer 3

Anabolic
Produces inactive or excretable metabolite by conjugation

Question 4

METABOLISM OF PARACETAMOL AT NORMAL DOSE

Answer 4

’- Sulfate derivative
- Glucuronide derivative ——> urine elimination
- NAPQI——> Glutathione derivative
GSH

Question 5

‘AT THE NORMAL DOSE

Answer 5

 Paracetamol conjugated with glucuronide or
sulfate to non-toxic metabolites
 Excreted in urine
 Small amount metabolized by CYP450 enzyme
to potentially toxic NAPQI
 However this is safely conjugated with
glutathione to be excreted

Question 6

AFTER OVERDOSE

Answer 6

 Conjugation with glucoronide/sulfate becomes
saturated
 Shift to CYP450 enzyme
 Glutathione rescue becomes depleted
 Subsequent hepatotoxicity

Question 7

PARACETAMOL OVERDOSE
24h
24-48h
48-72h
72-96h

Answer 7

1. 24 Hours :Nausea, pallor, abdominal pain
   OR Asymptomatic
2. 24-48 Hours: Liver dysfunction
3. 48-72 Hours: Fulminant hepatic failure
4. 72-96 Hours: Complete recovery
   OR Death

Question 8

PARACETAMOL ANTIDOTE
+ MoA

Answer 8

Antidote: N acetyl cysteine

MOA: replenishes glutathione
stores

Question 9

PARACETAMOL ANTIDOTE
Maximum protective effects + within one hour

Answer 9

Maximum protective effects: up to 8 hours post-ingestion
- can be administered even over 8h

Within one hour: activated charcoal

Question 10

-LIVER FAILURE

Common causes

,

Answer 10

 Alcohol abuse
 Viral hepatitis
 Non-alcoholic fatty liver disease

Once chronic decompensated liver failure ensues, not much treatment, you can only treat complications

Question 11

LIVER FAILURE
, Complications

Answer 11

1. . Hepatic encephalopathy
2. Ascites
3. Variceal bleeding
4. Spontaneous bacterial peritonitis
5. Hepatocellular carcinoma

Question 12

MANAGEMENT
Ascites + Spontaneous bacterial peritonitis

Answer 12

Management is symptomatic
Definitive treatment: liver transplant

-treat Ascites w/
 Salt restriction
 Diuretics (Spironolactone and Furosemide)
 Paracentesis

-treat Spontaneous bacterial peritonitis w/
 Antibiotics

Question 13

Hepatic encephalopathy
Management

Answer 13

Toxic compounds generated by gut bacteria
e.g. ammonia

Question 14

HEPATIC ENCEPHALOPATHY

Treatment

Answer 14

1. Lactulose
    Non-absorbable disaccharide
    Entrapment of ammonia in the gut lumen
   •Lactulose metabolism by gut bacteria to lactic acid
   • Ammonia becomes ammonium
    Alters ammonia metabolism by microbial flora
2. Rifaximin
    Non-adsorbable antibiotic

Question 15

ESOPHAGEAL VARICES
Occurs why

Answer 15

B/c of portal HTN I’m haptic failure and there’s increase in portal blood flow b/c there’s splachnic vasodilation. There’s increased resistance which leads to variceal formation

Question 16

ESOPHAGEAL VARICES

Prophylaxis

Answer 16

• Non-selective beta-blockers (e.g. propranolol)
  • Reduction in splanchnic blood flow and portal
  pressure
  - Β1-adrenergic receptor blockade: reduced CO —. -Β2-adrenergic receptor blockade: splanchnic
  vasoconstriction

Question 17

‘Acute variceal bleeding tx

Answer 17

Fluids
Terlipressin: vasopressin agonist
Somatostatin or analogue (octreotide)
-Constrict splanchnic blood vessels

Variceal ligation once stable

Question 18

’. PRESCRIBING FOR PATIENTS WITH LIVER DISEASE

Answer 18

 Use minimum number of drugs

 Where prescribing is unavoidable
- Use safest possible drug
- Minimise dose
- Plan stop date
-Monitor carefully (clinical, biochemistry, drug
levels)
- Alter dose of drug accordingly

Question 19

DRUGS TO AVOID IN LIVER FAILURE

Answer 19

 Opiates ex. Codeine (increase risk of hepatic encephalopathy)
 Diuretics (increase risk of hepatic encephalopathy)
 Oral hypoglycemics (loss of glucose homeostasis)
 Warfarin (effects enhanced)

Question 20

PREVENTION OF DRUG INDUCED LIVER DAMAGE

Answer 20

– Anticipate possibility when starting drug
 Warn patients to be vigilant
 Monitor patient
- Clinically
- Liver function tests and enzymes
- Plasma drug levels if appropriate
 Stop drug early if liver abnormalities develop
 2nd drug may increase hepatotoxicity of first
Ex. Hepatotoxic drugs: rifampicin (CYP450 inducer), isoniazid , pyrazinamide

Question 21

-DRUGS THAT CAUSE ABNORMAL LFTs
(Liver fxn tests)

Answer 21

 Paracetamol - in overdose  Statins  Fibrates  Amiodarone  Combined oral contraceptive pill  Spironolactone  NSAIDs  Valproic acid