PHARM 19 Drugs and Liver Ds

Pharmacokinetics (concs of drug in tissue)

Pharmacodynamics (tissue response to drug)

• - bioavailabilty
• - protein binding... and therefore distrubtn
• - hepatic drug clearance - Phase 1 (cyt P450 etc)
•                                         Phase 2 (gulcuronidation etc)

Hepatic blood flow ~ 1500mL/min

"Flow dependnt " clearance > 800ml/min

Enz-dependnt clearance < 300mL/min

• Flow-dependent drugs are cleared so rapidly that it is effectively dependent only on the rate of hepatic
• blood flow.

• This high first pass hepatic clearance means that there
• is low oral bioavailability.

In chronic hepatic disease, scarring can lead to obstructed blood vessels and shunting via anastomoses.

• Drugs then end up in the portal and arterial blood, bypassing the hepatocytes, decreasing hepatic clearance and increasing
• bioavailability.

• Examples:
• Nitrates
• Opiates
• Beta-adrenoceptor blockers (not
• atenolol)
• Calcium channel blockers
• Lignocaine

Verapamil

When given parenterally, systemic clearance is decreased to 50% and therefore blood concentrations increase by 2x.

• However oral administration increases bioavailability from 0.2 to 0.5, which effectively increases blood
• concentrations by 5x (with the same level of clearance).

Enzyme-dependent drugs cleared less rapidly... clearance is ltd by amount of enz (usu P450) available --> clearance is subject to changes by enzyme induction/inhibition.

• egs- 
• Most anti-convulsants
• Warfarin
• Benzodiazepines (except oxazepam)
• Theophylline
• Most non-steroidal anti-inflammatory drugs
• Amiodarone

• Effects of age and hepatic disease:
• Depends on the degree of hepatic damage – impaired clearance is common in severe liver failure (cirrhosis or acute liver failure), but is unpredictable with less severe failure.
• Not predictable from hepatic function tests

Alcohol induces some P450 isoenzymes – which leads to increased clearance initially (e.g.phenytoin)

Hepatic clearance of unbound (i.e.“free”) drug generally falls by around 30% with advanced age,and this only seems to make a difference for drugs that are largely unbound, that is, have low plasma protein binding.

Liver failure ---> leads to decreased albumin, and a decreased bound fraction of highly protein-bound drugs

So take care in applying drug assay results for highly protein bound drugs.

Decreased plasma albumin --> decreased plasma osmotic pressure, and increased tissue fluid (maybe> 10L), which increases the Vd for highly H2O-soluble drugs.

This increased in Vd increases the half-life, if the rate of clearance is unchanged.

eg if Vd increases by 20%, plasma concentration will decrease by 20%, so clearing 10 L ofplasma/hour removes 20% less drug, so it takes longer for half thedrug in the body to be removed.

This means prolonged exposure to the toxic effects of the drugs-

• Aminoglycosides – renal damage and deafness
• Methotrexate: decreased DNA synth – bone marrow and gut toxicity.

• - Anticoagulants
• - Sedatives
• - Diuretics

• Decreased clotting factor synthesis
• Increased effectiveness of warfarin and heparin
• Increased bleeding risk

- Increased sensitivity to sedatives such as benzodiazepines and opiates

Increased risk of over-sedation and hepatic encephalopathy

Decreased plasma albumin --> decreased plasma osmotic pressure

• Increased tissue fluid & decreased plasma volume leads --> decrease in renal blood flow
• ---> results in activation of Renin system
• ---> increased levels of renin, angiotensin II andaldosterone.
• --->  Na⁺ and H₂O retention, and K⁺ loss.

• Avoid high-risk drugs (anticoagulants)
• or minimise dose (opiates)

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

For enz-dependent drugs, start w lower doses (around half in clinically moderate liver failure), titrate up, watching clinical response and drug concentration (if available)