Prescribing in Liver Disease Flashcards
3 major factors in liver cirrhosis?
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
Why does reduced plasma protein lead to ascites?
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
Why do men with liver cirrhosis end up with loss of their secondary sexual characteristics?
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
When does metabolism become saturated?
Switch from 1st order to 0 order, e.g: with alcohol, phenytoin, etc
Consequences of hormone release in liver cirrhosis, in terms of water and electrolytes?
Potassium loss
Sodium and water retention
This could progress to hepato-renal syndrome - development of renal failure in patients with advanced chronic liver disease
Function of renal prostaglandins?
Release is stimulated by various hormones released; it dilates renal arterioles
3 effects of moderated hepatic impairment?
Decreased renal clearance
Effect on unbound drug is masked by decreased protein binding
Renal function is reduced
4 signs of hepatic impairment?
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)
Why should NSAIDs not be used in people with ascites, for pain relief?
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
General consequences of NSAID use?
UGI ulcer complications CV toxicity Hypertension CHF Na+ retention Asthma Diarrhoea/colitis Renal failure
How should NSAIDs be prescribed?
Standard NSAID should be co-prescribed with a PPI
Main adverse effects of NSAIDs and the subsequent therapy required?
Increased BP and an anti-hypertensive
Main adverse effects of diuretic and the subsequent therapy required?
Gout and so drugs are required to treat this
Main adverse effects of metoclopramide (heartburn drug) and subsequent therapy required?
Parkinsonism and so L-DOPA is required
Why are opiates not used to treat ascites pain?
E.g: codeine - these are metabolised to morphine, which has a sedative effect
In COPD patients, it can cause respiratory depression
2 phases of drug metabolism?
Phase 1 - cytochrome p450; there is oxidation, reduction and hydrolysis; this phase is affected early
Phase 2 - conjugation (glucoronidation); this is affected late
?????????
How does paracetamol become toxic?
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
How does alcohol affect paracetamol metabolism?
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
Why does paracetamol toxicity occur in liver disease?
Reduced glutathione stores
Longer half-life
Increased P4502e1 in alcoholics
Toxicity with “normal” doses
So, what drug is given for pain in ascited?
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
Why does drug-induced liver disease occur?
Probably due to a genetic disposition
What is Hy’s rule?
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
Why are furosemide and thiazide diuretics not used for ascites?
Furosemide - reduced intravascular volume, hypokalaemia and hypomagnesaemia
Thiazide - hypokalaemia and hypomagnesaemia
Which drug is the best for ascites?
Spironolactone, with fluid restriction
Aim for a loss of 1kg/day weight loss
When sedation is sometimes needed, how should it be given?
Small doses and give phase II metabolised benzodiazepenes are used, e.g: lorazepam, oxazepam or lormetazapam
Safety with antibiotics in liver disease?
Mostly safe
Aminoglycosides are nephrotoxic
Quinolones are epileptogenic
Metronidazole reduces metabolism
Why is therapeutic drug monitoring important?
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
