Prescribing in Liver Disease

Question 1

3 major factors in liver cirrhosis?

Answer 1

Reduced liver blood flow due to portal hypertension; this leads to shunting of blood so it bypasses liver, e.g: via an anastamosis leading to varices

Liver has reduced metabolic capacity

High portal pressure and low albumin (plasma protein) leads to ascites

Question 2

Why does reduced plasma protein lead to ascites?

Answer 2

There is low plasma volume, so RAAS activity increases and there is Na+ and water retention

The hormones also cause vasoconstriction and this squeezes the renal arterioles, causing fluid to lead out

Question 3

Why do men with liver cirrhosis end up with loss of their secondary sexual characteristics?

Answer 3

Aldosterone is not metabolised and they can get secondary aldosteronism, leading to gynecomastia and testicular atrophy

Also, oestrogen and endothelin are no longer metabolised by the liver

Question 4

When does metabolism become saturated?

Answer 4

Switch from 1st order to 0 order, e.g: with alcohol, phenytoin, etc

Question 5

Consequences of hormone release in liver cirrhosis, in terms of water and electrolytes?

Answer 5

Potassium loss
Sodium and water retention

This could progress to hepato-renal syndrome - development of renal failure in patients with advanced chronic liver disease

Question 6

Function of renal prostaglandins?

Answer 6

Release is stimulated by various hormones released; it dilates renal arterioles

Question 7

3 effects of moderated hepatic impairment?

Answer 7

Decreased renal clearance

Effect on unbound drug is masked by decreased protein binding

Renal function is reduced

Question 8

4 signs of hepatic impairment?

Answer 8

Gut oedema leads to absorption

Liver and kidney congestion leads to reduced function

Gross oedema and ascited

Congestive Heart Failure (can get liver cirrhosis secondary to this)

Question 9

Why should NSAIDs not be used in people with ascites, for pain relief?

Answer 9

Decrease renal PGE synthesis; this:
Worsens renal impairment
Increases Na+ retention
Increases risk of hepato-renal syndrome 
Worsen any CHF 

Increases cirrhotic peptic ulcers and so there is a risk of GI bleed or perforation

Question 10

General consequences of NSAID use?

Answer 10

UGI ulcer complications
CV toxicity
Hypertension
CHF
Na+ retention
Asthma
Diarrhoea/colitis
Renal failure

Question 11

How should NSAIDs be prescribed?

Answer 11

Standard NSAID should be co-prescribed with a PPI

Question 12

Main adverse effects of NSAIDs and the subsequent therapy required?

Answer 12

Increased BP and an anti-hypertensive

Question 13

Main adverse effects of diuretic and the subsequent therapy required?

Answer 13

Gout and so drugs are required to treat this

Question 14

Main adverse effects of metoclopramide (heartburn drug) and subsequent therapy required?

Answer 14

Parkinsonism and so L-DOPA is required

Question 15

Why are opiates not used to treat ascites pain?

Answer 15

E.g: codeine - these are metabolised to morphine, which has a sedative effect

In COPD patients, it can cause respiratory depression

Question 16

2 phases of drug metabolism?

Answer 16

Phase 1 - cytochrome p450; there is oxidation, reduction and hydrolysis; this phase is affected early
Phase 2 - conjugation (glucoronidation); this is affected late

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Question 17

How does paracetamol become toxic?

Answer 17

Paracetamol is metabolised to sulphates and glucoronides as well as a highly reactive intermediate, N-acetyl-p-benzoquinonimine

Glutathione inactivates this intermediate to produce cysteine and mercapturic acid conjugates

Eventually though, glutathione runs out and paracetamol becomes toxic

Question 18

How does alcohol affect paracetamol metabolism?

Answer 18

Paracetamol is metabolised by CYP2E1 but alcohol blocks this and so prevents paracetamol toxicity initially

But alcohol induces CYP2E1 into proliferating and then paracetamol is oxidised, so there is late toxicity

Question 19

Why does paracetamol toxicity occur in liver disease?

Answer 19

Reduced glutathione stores
Longer half-life
Increased P4502e1 in alcoholics
Toxicity with “normal” doses

Question 20

So, what drug is given for pain in ascited?

Answer 20

Paracetamol 1g twice daily; do not exceed 3g daily and avoid prolonged use

OR

Could use codeine 30 mg three times daily but be aware of sedation

Avoid NSAIDs

Question 21

Why does drug-induced liver disease occur?

Answer 21

Probably due to a genetic disposition

Question 22

What is Hy’s rule?

Answer 22

Rule of thumb that a drug is at high risk of causing a fatal drug-induced liver injury when given to a large population, if it caused cases of liver injury that satisfied certain criteria when given to a smaller population

ALT/AST (alanine transaminase / aspartate transaminase) > 5 x ULN (upper limits of normal)

and if

Bilirubin is > 3 mg/dl

Question 23

Why are furosemide and thiazide diuretics not used for ascites?

Answer 23

Furosemide - reduced intravascular volume, hypokalaemia and hypomagnesaemia

Thiazide - hypokalaemia and hypomagnesaemia

Question 24

Which drug is the best for ascites?

Answer 24

Spironolactone, with fluid restriction

Aim for a loss of 1kg/day weight loss

Question 25

When sedation is sometimes needed, how should it be given?

Answer 25

Small doses and give phase II metabolised benzodiazepenes are used, e.g: lorazepam, oxazepam or lormetazapam

Question 26

Safety with antibiotics in liver disease?

Answer 26

Mostly safe
Aminoglycosides are nephrotoxic
Quinolones are epileptogenic
Metronidazole reduces metabolism

Question 27

Why is therapeutic drug monitoring important?

Answer 27

Drug can combine to the protein but so will the endogenous ligand so there will be less protein

Dose reduction is the general rule regardless of the route of elimination of the drug/metabolite