Introduction
When we say an organ is impaired we are actually saying that for some reasons that organ is unable to perform its normal function(s) optimally or not at all. This can be due to trauma, disease or effect of drugs. Therefore, prescribing drugs for patients with liver diseases should be when it is absolutely necessary and it must be carefully monitored during therapy. Liver impaired patients at greatest risk are those with Ascitis (the accumulation of fluid in the peritoneal cavity, causing abdominal swelling. Causes include infections e.g tuberculosis, heart failure, portal hypertension, cirrhosis and various cancers particularly ovary and liver), jaundice (especially hepatocellular jaundice) or evidence of encephalopathy (i.e. any of the diseases that affect the functioning of the brain).
Pharmacokinetics Changes in Hepatic Impairment
A look at the pharmacokinetic changes that can occur with liver diseases ranges from;
- Drug metabolizing capacity is reduced where liver cells are either sick or, they are functioning normally but in reduced numbers.
- Liver cells responsible for drug metabolism are bypassed when the portal – systemic shunts develop as in cirrhosis.
- Liver disease may cause hypoproteinaemia leading to reduced plasma protein ̴drug binding capacity, thus allowing more unbound and pharmacologically active drug in circulation.
The normal healthy liver can metabolize and extract a significant proportion of a drug rapidly in a single pass through the liver (i.e. the hepatic first pass effect) or slowly metabolize and extract same in a single pass through the liver.
In the first scenario (hepatic first pass effect), poor liver cells functioning means less drug will be extracted from blood as it passes through the liver and the portal-system shunts means a portion of the blood bypasses the liver altogether. Therefore the predominant change in kinetic of drug administered orally is increase in systemic availability of that drug. That is the amount that reaches the circulation is greater with corresponding pharmacologic/toxic effects. The biological half-life (t1/2) is also increased. Examples drugs like Labetalol, propranolol, pethidine, pentazocine. For this group of patients, the initial dose of their medication must be adjusted downwards whilst being assessed to individualize their dose regimen.
In the second scenario (slow metabolism and poor extraction), these drugs do not exhibit significant first-pass extraction after oral administration. The major change caused by liver disease is again the prolongation of t1/2. Consequently the dosage interval for these patients may need to be lengthened and the time to reach steady-state concentration n the plasma (5 x t1/2) is increased. Examples drugs like Diazepam, Lorazepam, phenobarbitone, theophylline and clindamycin.
Drugs with Significant First Pass Effect
Examples of some drugs with significant first pass effect includes;
- Imipramine
- Morphine
- Propranolol
- Diazepam
- Midazolam
- Cimetidine and
- Lidocaine.
To avoid this first pass effect for some of these drugs we now have them formulated for use by alternative routes e.g. Suppository, Intravenous, Intramuscular, Sublingual, Aerosol and Trans-dermal. If the oral route must still be used, the medication is formulated as the Pro-drug
Examples:
Pro-drug Active moiety
Codeine ———–> Morphine
Fosphenytoin ——-> Phenytoin