Pharm - Drugs and the Liver Flashcards
Describe the ways drugs are metabolised in the liver
Predominantly to convert lipophillic drugs to polar drugs which can be excreted by the kidneys. May also convert pro-drugs to drugs and detoxify substances
Phase I and Phase II reactions:
Phase 1: oxidation, reduction, hydrolysis
- adds or unmasks polar bodies
- Cytochrome p450 system is important in oxidation reactions. These enzymes show genetic variability and are affected by the presence of other drugs. (Important consideration for drugs with a narrow therapeutic window where inhibition of CYP450 causes toxicity and induction renders the drug ineffective)
- Drugs that undergo phase I reactions: paracetamol, steroids
Phase II: conjugation by sulphation, glucuronidation, acetylation, methylation
- Add groups to substance to increase water solubility
Which drugs can cause damage to the liver?
The most commonly encountered drug causing direct hepatocellular damage is ethanol. Chronic alcohol abuse in genetically susceptible individuals causes progressive inflammatory liver damage->result in fatty liver and cirrhosis through three main mechanisms:
- Damage to cell and mitochondrial membranes by ethanol and its metabolite acetaldehyde
- Damage from free radicals, superoxides and hydroperoxides generated during ethanol
metabolism
- Alcoholic hepatitis stimulates the immune system, which generates
autoantibodies
Halothane induced hepatitis has a mortality rate of 50%
- reversible transaminitis from hepatic hypoxia
- can lead to centrilobular liver necrosis in what appears to be
an immune-mediated process.
- Halothane is oxidised, producing trifluroacetyl metabolites, which bind
to liver proteins. In genetically susceptible individuals this causes an
autoimmune response and antibodies are generated against the complex.
- Risk factors include repeated exposure, female sex, obesity and middle age.
The volatile agents enflurane and isoflurane are also metabolised to
acetylated metabolites, but this only involves 2 and 0.2% of the total dose
respectively, compared to 20% of halothane.
How does chronic liver disease affect the drugs used in anaesthesia?
Mechanisms:
- Portocaval shunts - reduced first pass metabolism
- Low albumin - more unbound drug
- Ascites - increased Vd
- Reduced metabolism for Phase I and II reactions
- Impaired coagulation may prevent use of neuraxial anaesthesia
Drugs:
- Benzodiazepines: avoid - metabolism impaired, effects enhanced
- Opiates: reduced doses - metabolism impaired, effects enhanced
- Barbituates: metabolism impaired but effects terminated by redistribution
- Suxamethonium: acquired apnoea due to reduced plasma cholinesterases
- Non-depolarising relaxants: effects enhanced as usually highly protein bound. In severe chronic liver disease, there is an acidaemia which may reduce Hoffmann degredation for atracurium
- Fluids: use with caution, fluid overload likely, lactate metabolism impaired so avoid Hartmann’s
What is the hepatic extraction ratio?
Hepatic extraction ratio is the fraction of drug removed from the blood by the liver. It depends on:
- hepatic blood flow
- hepatocellular uptake
- hepatocellular enxyme metabolic capacity (enzyme activity is described by the Michaelis constant which is the concentration of substrate at which the enzyme is working at 50% maximum rate. If the Michaelis constant is higher than clinical concentrations the metabolic capacity will be high)
Different patterns can be seen:
- Rapid uptake, high metabolic capacity
- e.g. propofol. Rapid drug metabolism maintains a concentration gradient between hepatocyte and plasma, therefore metabolism is dependent on blood flow - High protein binding, low metabolic capacity
- e.g. phenytoin. Drug metabolism is dependent on metabolic capacity not blood flow. Changes to protein binding may cause drug levels to rise significantly because there is enzyme saturation at low concentrations - Low protein binding, low metabolic capacity. Metabolism is unaffected by blood flow or protein binding.
