5. Drugs and the liver Flashcards
In which ways are drugs
metabolised by the liver?
What are the majority reaction for
Rate drug metab im
What are prodrugs - examples
The metabolism of drugs in the liver is defined
modification or degradation of drugs
in order to activate, deactivate, toxify or detoxify drugs
in the body.
The majority of metabolic reactions serve to
de-activate and aid the excretion of the drugs,
often by turning a lipophilic compound to a readily excreted polar one
Some drugs are given as pro-drugs that need to be metabolised in order to become active, e.g. enalapril, which must be converted to enalaprilat for its
action.
Others may have active substrates, such as morphine, or substrates with completely different actions.
How are drugs metabolised by the liver?
Types of reaction?
where mostly take place?
specifically
What is inovolved in one type
Why
What doe this do?
Which mainly occur in liver
which can occur elsewhere
What enzymes are involved in 1
what’s the importance of these
Examples of first type of reaction
can drugs be elim like this?
The types of reaction that occur can be classified into phase I or phase II reactions.
While they may occur in other parts of the body, the majority take place in the smooth endoplasmic reticulum of liver.
Phase I reactions:
> These normally precede phase II reactions and involve oxidation,
reduction or
hydrolysis
to activate or deactivate it.
> adds or unmasks polar bodies in the chemical.
> Oxidation and reduction are mainly hepatic,
hydrolysis is more widespread throughout the body, e.g. by plasma cholinesterase.
> For oxidation reactions the cytochrome P450 system of enzymes is particularly important.
These enzymes show genetic variability and their
activity can be induced or inhibited by the presence of certain other drugs or chemicals (see Table 5.1).
Important if induction/ inhibition raises/reduces levels
> Drugs undergoing phase 1 reactions include phenothiazines, paracetamol and steroids.
> For some drugs, this reaction will be sufficient to allow excretion, but others will require further modification and undergo phase II reactions.
Enzyme inhibitors
Metronidazole Ciprofloxacin Fluconazole ( Erythromycin Ethanol (Chronic use) Dextroproxyphene (co-proxamol) Cimetidine I Amiodarone Ketoconazole Etomidate Grapefruit
Enzyme inducers
Carbamazepine
Rifampicin
Alcohol Acute intake)
Phenytoin
Griseofulvin
Primidone
nhalational agents (enflurane, halothane)
Smoking
Barbiturates
Glucocorticoids
Phase II reactions:
adding groups to the drugs
referred to as conjugation or synthetic reactions.
These groups increase the water solubility of the drugs and allow excretion in the bile or urine.
often follow Phase I reactions they may be the only step in the metabolism of drugs.
> Phase II reactions include glucuronidation, sulphation, acetylation and methylation.
Which drugs can cause damage
to the liver?
alcohol
type of damage/
how?
Volatiles
mortality?
how
affect?
what is produced
whats the affect of this
RF
what else can cause but to less degree
acute or chronic drug exposure.
most commonly = direct hepatocellular damage
is ethanol.
Chronic alcohol abuse in susceptible individuals can
progressive inflammatory liver damage,
can result in fatty liver and cirrhosis.
1 Ethanol and its metabolite acetaldehyde damage the liver cell and mitochondrial membranes.
2 antibodies
The volatile anaesthetic agent halothane is also known to cause hepatitis, with a mortality rate of 50% in those affected.
> Halothane can cause a reversible transaminitis as a result of hepatic hypoxia.
> It can cause significant 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?
1.
Porto-caval shunts occurring in cirrhosis reduce
hepatic blood flow and hence the extraction ratio of the drug.
This results in an increased drug bioavailability.
2.
> Impaired production of albumin results in reduced drug plasma protein binding. This leads to an increase in the free, active component of the drug.
3.
> Ascites and the overall increase in total body water leads to an increase in the volume of distribution of drugs.
4.
> Reduced metabolic function (phase I and II reactions) leads to prolonged action of hepatically metabolised drugs.
5.
> Impaired coagulation (the liver synthesises many of the clotting factors) and liver-induced thrombocytopenia may contraindicate the use of central neuroaxial blocks.
Specific drugs in liver diz
BZD
Opiates
Barbiturates
Suxamethonium
Muscle relaxanat
Fluid
Benzodiazepines:
Metabolism impaired and effects enhanced. These drugs should be avoided.
Opiates: Metabolism impaired and effects enhanced. Use with caution in reduced doses.
Barbiturates: Metabolism impaired, though their effects are terminated by redistribution.
Suxamethonium: Duration of action prolonged as decreased plasma cholinesterases.
Muscle relaxants: Effects enhanced as usually highly protein bound.
Hoffmann degradation of atracurium may be reduced in the lower pH associated with severe disease.
Fluid: Extreme care should be used in administering intravenous fluids as oedema and fluid overload are
likely. Also avoid lactate-containing fluids, e.g. Hartmann’s as lactate metabolism will be impaired.
