PHARM 19 Drugs and Liver Ds

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PHARM 19 Drugs and Liver Ds
2012-10-01 10:22:44
Pharmacology Liver

Drug therapy in Patients w Hepatic Ds
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  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)