Making decisions about medicines
There's been a lot to learn in this tutorial, so this page is a summary to help you when choosing a medicine for a patient with liver dysfunction. It's the commonest problem you'll face. If you need to revert to first principles then, as we saw on the first page of this tutorial, you need to look at the way the drug is handled by the body:Absorption
✦ Is the drug lipophilic? Lipophilic drugs often need bile salts for absorption, so patients with cholestasis may experience a reduction in drug absorption.Distribution
✦ Is the drug highly plasma protein bound? For drugs that are highly protein bound, the risk of side effects might be increased in patients with low albumin levels. This is because there is less protein for the drug to bind to, leading to higher levels of free drug. Sometimes, highly protein bound drugs can be displaced from albumin in patients with high bilirubin levels which also gives higher levels of free drug.✦ Is the drug water-soluble? Larger doses of water-soluble drugs may be needed in patients with ascites as the drug distributes into the ascitic fluid resulting in lower blood concentrations.
Metabolism
✦ Is the drug metabolised (or activated) by the liver? In liver dysfunction, cytochrome p450 and other enzyme levels may be reduced. This means that some drugs might accumulate as they are not metabolised readily, or inactive pro-drugs are not changed into their active forms.✦ Note that oral medicines subject to high first-pass metabolism may be metabolised less if there is portal hypertension, which may divert blood supply away from the liver. This may make a medicine more bioavailable.
Elimination
✦ Is the drug excreted in bile? If the patient has cholestasis, biliary excretion may be impaired. This may particularly become an issue if the drug is excreted in an active form.✦ Does the drug undergo enterohepatic recirculation? If the patient has cholestasis then reabsorption via this route may be reduced, resulting in lower levels.
But it's not just pharmacokinetics. On the previous page, we also look at side effects that are of particular concern in patients with liver dysfunction. There are many of these, but three to always keep in mind are:
✦ Avoid hepatotoxic drugs where possible. Patients with existing hepatic disease have diminished reserve hepatic function and may suffer disproportionately if hepatotoxicity does occur. The advent of drug-induced hepatotoxicity on top of existing liver disease will also confuse the diagnostic picture.✦ Drugs that increase the risk of bleeding should be avoided or used with extreme caution, depending on the severity of liver disease.
✦ Avoid sedating drugs in patients at risk of encephalopathy. Many of these have long half-lives and are hepatically metabolised, so their duration and intensity of action may be prolonged in liver dysfunction. The brain also becomes more sensitive to sedating effects in liver disease. A sedative drug may precipitate or mask encephalopathy.
Finally here are some practical clinical tips to assist you when making decisions about choice of drug and dose in liver dysfunction:
✦ Drugs that are highly dependent on the liver for deactivation or clearance may need dose reduction in moderate to severe liver disease. Be alert to drug side effects: know what they are and monitor for them. Monitor drug levels where appropriate.✦ Continue to check LFTs regularly while liver dysfunction persists. A significant improvement or deterioration may require a review of drug choice or dose.
✦ Keep drug prescribing to a minimum – use the smallest effective doses at greatest interval, and titrate according to clinical response.
✦ In some circumstances non-systemic treatments or non-pharmacological options can be a helpful way to minimise drug handling by the liver.
✦ Renally excreted drugs are also preferred as long as renal function is normal. Monitor for any changes in renal function regularly.
✦ Look carefully at the side effect profile of the medicine you want to use and compare it to the patient's existing signs and symptoms, and their liver diagnosis.