PHARM 19 Drugs and Liver Ds

  1. Altered drug respone in Liver Disease
    Pharmacokinetics (concs of drug in tissue)

    Pharmacodynamics (tissue response to drug)
  2. Pharmacokinetic changes
    • - bioavailabilty
    • - protein binding... and therefore distrubtn
    • - hepatic drug clearance - Phase 1 (cyt P450 etc)
    •                                         Phase 2 (gulcuronidation etc)
  3. Flow dependent v Enz Dependent Drugs
    Hepatic blood flow ~ 1500mL/min

    "Flow dependnt " clearance > 800ml/min

    Enz-dependnt clearance < 300mL/min
  4. Flow dependent drugs
    • 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


    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).
  5. Enzyme-dependent” drugs.
    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.
  6. Altered volume of distribution.
    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.
  7. Pharmacodynamic changes.
    Increased sensitivity to drugs - important egs
    • - Anticoagulants
    • - Sedatives
    • - Diuretics
  8. Anticoagulants
    - Contraindicated w liver disease because:
    • Decreased clotting factor synthesis
    • Increased effectiveness of warfarin and heparin
    • Increased bleeding risk
  9. Sedatives – take care when administering to person w liver Ds because:
    - Increased sensitivity to sedatives such as benzodiazepines and opiates

    Increased risk of over-sedation and hepatic encephalopathy
  10. Diuretics – avoid K+-depleting diuretics w liver Ds because...
    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.
    • --->  Naand H2O retention, and K+ loss.
  11. Guidelines.
    • 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)
Card Set
PHARM 19 Drugs and Liver Ds
Drug therapy in Patients w Hepatic Ds