Influence of Hepatic Insufficiency on Drug Elimination and Response

Question 1

What are the pharmacokinetic changes that are influenced by the liver?

Answer 1

Bioavailability

Protein binding, and therefore distribution

Hepatic drug clearance (phase 1 = cytochrome P450, etc. Phase 2 = glucuronidation and sulphation)

Question 2

What are the 2 sources of drug to the liver?

Answer 2

The portal vein (first pass hepatic clearance)

The hepatic artery (Systemic clearance)

thus liver failure or poor liver function would result in more bioavailable drugs

Question 3

What is “flow-dependent” clearance?

Answer 3

For some drugs, clearance is so rapid that it is effectively dependent only on the rate of hepatic blood flow, thus, it is flow dependent. These drugs all have high first pass clearance and thus have low oral bioavailability. drugs that do this have a hepatic clearance >800ml/min (hepatic blood flow = 1500 ml/min)

Question 4

What is “enzyme-dependent clearance”?

Answer 4

Drugs with hepatic clearance of < 300ml/min have that limitation because enzyme activity only allows that much making them enzyme-dependent and open to enzyme induction or inhibition.

Question 5

What causes caput medusa?

Answer 5

Reopening of umbilical veins in the anterior abdomen caused by increased pressure in the portal vein pressure due to hepatic scarring/cirrhosis obstructing hepatic blood flow.

Question 6

What happens to drugs that are cleared by the liver if the liver is damaged/scarred?

Answer 6

They are unable to be cleared as rapidly and end up moving through venous anastomoses (umbilical veins for example) making them more potent and bioavailable. In addition to this is a drop in systemic clearance from arterial blood.

Question 7

Can flow-dependent drugs be given orally?

Answer 7

Some can be, however, it isn’t ideal because they are flow-dependent drugs and are cleared really fast.

Question 8

What common drugs are flow dependent?

Answer 8

Lignocaine

Calcium channel blockers

Opioids

Question 9

What common drugs are enzyme-dependent?

Answer 9

Most anti-convulsants

Warfarin

Benzodiazepines

Theophylline

Most NSAIDs

Amiodarone

Question 10

What factors influence the effects of hepatic disease?

Answer 10

Depends on the degree of hepatic damage (impaired clearance common in severe liver failure but unpredictable in less severe failure)

Not predictable from hepatic function tests

Alcohol induces some P450 isoenzymes (increased clearance initially)

Question 11

What happens to albumin levels in liver failure?

Answer 11

They drop. This makes bound fraction of highly albumin-bound drugs much lower increasing the bioavailability of these drugs.

Question 12

How does liver failure increase bioavailability of drugs?

Answer 12

Scarring leads to decreased first pass and systemic clearance of drugs.

Hypoalbuminaemia results in more unbound drugs.

Hypoalbulinaemia leads to Increased extravascular water volume and decreased intravascular water volume results in altered distribution volume for highly water soluble drugs.

Question 13

With albumin binding drugs what must be taken into account with people that have liver damage/failure?

Answer 13

The free drug concentration is most important for effect.

Question 14

Why is volume different in hypoalbulinaemic patients?

Answer 14

Plasma albulin is important to maintain plasma osmotic pressure. thus less fluid is retained in blood vessels

Question 15

Why is drug cleared more slowly in patients with altered volume of distribution caused by hypoalbulinaemia? Which drugs are particularly affected by this?

Answer 15

Drop in plasma concentration means less plasma is cleared each our which means less drug passes through the liver making it take much longer to clear.

Aminoglycosides result in renal damage and deafness

Methotrexate results in bone marrow and gut toxicity.

Question 16

What are some important examples of drugs affected by pharmacodynamic changes seen in hepatic clearance?

Answer 16

Anticoagulants (Less clotting factors synthesized, effectiveness of drugs becomes more pronounced thus increasing bleeding risk)

Sedatives

Diuretics

Question 17

What are some important examples of drugs affected by pharmacodynamic changes seen in hepatic clearance?

Answer 17

Anticoagulants (Less clotting factors synthesized, effectiveness of drugs becomes more pronounced thus increasing bleeding risk)

Sedatives (increasing sensitivity to sedatives such as opiates and benzos as well as an increased risk of oversedation and hepatic encephalopathy)

Diuretics (Drop in blood volume due to drop in albumin leads to aldosterone production which leads to potassium excretion, meaning diuretics will increase amount of potassium being excreted making patients more potassium depleted. This can be addressed with aldosterone antagonists (spironolactone) and potassium sparing diuretics.)

Question 18

What are the main guidelines for drug reactions in hepatic failure?

Answer 18

Avoid high risk drugs like anticoagulants or minimise the dose.

Reduce doses of flow-dependent drugs (as low as 10% for oral dosing)

For enzyme-dependent drugs, start with lower doses and titrate up while watching clinical response and drug concentration.