influence of hepatic insufficiency on drug elimination

Question 1

flow dependant drug

Answer 1

drug clearance is so rapid that it is effectively dependant only on the rate of hepatic blood flow

Question 2

enzyme dependant drug

Answer 2

drugs with hepatic clearance <300ml/min have that limitation because that is what the hepatic enzyme activity allows
open to enzyme induction or inhibition of CYP450

Question 3

shunting

Answer 3

occurs in advance cirrhotic liver disease
caput meducae
dilated veins because the patient has developed portal obstruction and tries to drain portal circulation through other pathways
will only partly encounter the liver and not make full contact with hepatocytes

Question 4

flow-dependant drugs

Answer 4

nitrates 
opiates 
b-adrenoceptor blockers (not atenolol) 
calcium channel blockers 
lignocaine

Question 5

enzyme dependant drug examples

Answer 5

• most anti-convulsants
• warfarin
• benxodiazepines
• theophylline
• most non steroidal anti inflammatory drugs
• amiodarone

Question 6

effects of hepatic disease on enzyme dependant. drugs

Answer 6

• depends on the degree of hepatic damage
• not predictable from hepatic function tests
• alcohol induces some P450 enzymes

Question 7

hypoalbuminaemia

Answer 7

liver failure causes decreased albumin
decreased bound fraction of highly albumin bound drugs
increased extravascular water volume and decreased intravascular water volume causing altered distribution volume for highly water soluble drugs

Question 8

reduced plasma albumin binding

Answer 8

only free drug has access to target and elimination

Question 9

reduced plasma albumin concentration causes

Answer 9

reduced plasma osmotic pressure
and increased tissue fluid
increased volume of distribution for highly H2O soluble drugs
increased volume of distribution leads to increased half life and prolonged exposure to toxic effects of the drugs

Question 10

anticoagulants in liver disease

Answer 10

liver disease causes decreased clotting factor synthesis, and increased effectiveness of warfarin, heparin, dabigatran, factor IX inhibitors and increased bleeding risks

Question 11

sedatives in liver disease

Answer 11

increases sensitivity too sedatives
eg. benzodiazepines, opiates
increased risk of over sedation and hepatic encephalopathy

Question 12

diuretics in liver disease

Answer 12

decreased plasma albumin causes decreased osmotic pressure
increased tissue fluid and decreased plasma volume
decreased rnal blood flow
increased renin causes increased angiotensin causing increased aldosterone
potassium is depleted causing arrhythmia risk

Question 13

aldosterone

Answer 13

responsible for the inducible production of sodium potassium exchange

Question 14

rough guidelines for drug rx in hepatic failure

Answer 14

avoid high-risk drugs (anticoagulants) or minimise dose (opiates)
reduce doses of flow-dependant drugs (sometimes as low as 10% for oral dosing)
- for enzyme-dependant drugs, start with lower doses (around half in clinically moderate liver failure), titrate up, watching clinical response and drug concentration (if available)