How the Liver Processes (Metabolises) Drugs and Toxins Flashcards
What are the two reasons why drug metabolism occurs
To de-activate any pharmacological activity and to create a water soluble metabolite primed for extraction
How many drug molecules can the enzyme metabolise before saturating
Maximum of 4 drug molecules
Explain what is happening at 25% rate of enzyme reaction
The amount of drug present is a rate-limiting factor for substrate conversion (drug metabolism)
Explain what is happening at 50% rate of enzyme reaction
Although the drug concentration as increased, the amount of enzyme present is still not the rate-limiting factor for substrate conversion
Explain what is happening at 75% rate of enzyme reaction
The concentration of drug is approaching the maximum the enzyme can handle, but it’s not quite there
Explain what is happening at 100% rate of enzyme reaction
The enzyme is now working at full capacity converting as much drug as possible
What happens if you add more drug to the system at 100% rate of enzyme reaction
The system is over-saturated. The enzyme cannot work any faster to metabolise the excess drug present. The drug may build up to toxic levels because of this
What is the Michaelis-Menten equation
v = Vmax x [drug] / Km + [drug]
What does Vmax represent
A drug concentration causing the fastest turnover an enzyme can achieve. Any higher a drug concentration may cause toxic saturation effects
What does the Km of an enzyme represent
The concentration of drug (substrate) that makes the enzyme turnover at half the maximum rate (Vmax/2)
What is another name for phase I metabolism
Functional metabolism
What is the role of phase I metabolism
To expose/ create a mechanically reactive group on the drug to facilitate further metabolism processing in phase II
What do phase I mediated enzyme reactions include
Oxidation, reduction, de-esterification, isomerisation plus many more
What can phase I do
Activate the therapeutic activity of ‘pro-drugs’ but it can have very unwanted toxic effects too
Describe phase II metabolism
The drug (or intermediate metabolite generated from phase I) can now be a) deactivated and b) made water soluble by phase I enzymes in advance of either renal or hepatobiliary excretion
How are drugs made water soluble during phase II metabolism
Typically by replacing the drug’s pharmacophoric regions with a sugar or sulphate group
What is the most significant family of Phase I enzymes
Cytosome P450 (CYP
What are CYP responsible for
Oxidative modification usually in advance of Phase II
What enter CYP
Oxygen ans a drug molecule
What leaves CYP
An oxidised intermediate metabolite and water
What does CYP contain
A haem group
What does the fact that CYP are ‘on demand’ enzymes mean
They are induced only when the drug/ toxin they metabolise is detected
What are UTGs
UDP-glucuronsyl tranferase are phase II enzymes
What do UTGs do
Conjugate a water soluble glucuronide to the drug/ metabolite (that also de-activates pharmacological activity)
Describe how unconjugated bilirubin interacts with UGT
Uncojugated bilirubin and UDP glucuronic acid enter UGT, water soluble conjugated bilirubin leaves
What happens in Gilbert’s and Crigler-najjar syndromes
There is mutated or deleted UDT1A1 which results in build-up of unconjugated bilirubin and hence jaundice in the patient
What is the evolutionary advantage of multiple isoforms
There is ‘overlap’ in what drugs can be metabolised in the event of enzyme dysfucntion/ deletion
Why do multiple isoforms of CYPs and UGTs exist
As a function of substrate/ drug specificity
What does CYP3A4 do
Responsible for approximately half of all Phase I drug metabolism
What does CYP1A1 do
Prefers to metabolise theophylline
What does CYP1A2 do
Metabolises caffeine and theophylline
What does CYP2E1
Metabolises ethanol (alcohol) and the list goes on
Describe pharmacogenetics in relation to CYP and UGT
Subtle mutations in genes coding for CYP and UGT lead to significant differences in how individuals process drugs
What is the function of genetic screening in relation to CYP and UGT
Genetic screening allows certain drugs to be avoided to reduce ADRs
What can a point mutation result in
Changes in a haem group causing ADRs
What does each drug have the potential to influence
The pharmacodynamics of another drug by altering its pharmacokinetics, particularly its metabolism
What is pharmacokinetics
What the body does to the drug
What is pharmacodynamics
What the drug does to the body
What are drug interactions
A drug influencing the pharmacodynamics of another drug by altering its pharmacokinetics
What drug-drug interactions may manifest in the liver
Drug interactions (drugs affecting drugs), enzyme induction effects, enzyme inhibition effects, pre-systemic elimination
Describe how enzyme induction effects occur
Drug A may lower the circulating concentration of Drug B by inducing an enzyme that metabolises drug B
How can St John’s Wort cause enzyme induction
St John’s Wort (containing hyperforin) can induce CYP3A4 which then also metabolises the combined oral contraceptive pill containing eithinylestradiol, reducing it to sub-therapeutic levels
Describe enzyme inhibition
Drug A may increase the circulating concentration of drug B by inhibiting the enzyme that normally metabolises drug B
Describe how the antibiotic erthromycin exerts enzyme inhibition effects
Erythromycin occupies CYP3A4 preventing metabolism of the combined oral contraceptive pill containing ethinylestradiol which increases the potential for ethinylestradiol ADRs
Describe pre-systemic elimination
Some orally administered drugs are extensively metabolised by gut and liver enzymes before reaching the systemic circulation.
Outline how pre-systemic elimination may occur
Drug is metabolised by GI tract enzymes, drug is also transported via hepatic portal vein to the liver where CYP and UGT continue to metabolise the drug, sub-therapeutic levels of the active drug reach the systemic circulation
How can you compensate for pre-systemic circulation
Altering the drug dose an/or route of administration
What can drugs cause
Hepatitis and cholestatis
What does any pathology that affects the liver have the potential to do
Uncouple normal drug metabolism
What are the implications of cholestatis
Implications for drug metabolite excretion in the faeces
What is cholestatis
Impaired bile flow from liver to duodenum
What do liver function tests do
Blood tests for levels of key biochemicals, give an indication of the general state of the liver
What does the standard LFT battery include
Prothrombin time (INR), gamma glutamyl transpeptidase, albumin, total conjugated bilirubin, alanine- asparate transaminases, alkaline phosphatase
What does a long prothrombin time suggest
A deficiency of clotting factors made by the liver or a deficiency of vitamin K which is needed for the factors to work
What does gamma glutamyl transpeptidase detect
Liver damage from the drugs and alcohol and for early detection of rejection after liver transplantation
What does raised GGT and ALP mean
Biliary tract disease
What causes decreased albumin
Extensive loss of liver tissue in long-standing liver disease, malnutrition, kidney disease due to loss of protein in urine and inflammatory conditions in body
What does raised total conjugates bilirubin mean
Liver disease or a blockage of passage of bile to gut e.g. by gall stones
What does raised alanine asparate transaminases indicate
Leakage from cells due to inflammation or cell death
When does AAT rise more than ALP
In acute liver damage such as hepatitis
What causes an increase in ALP
Liver blockage and blockage of ducts due to increased bile duct pressure causing the liver to make more ALP
What does any hepatic dysfunction have the potential to do
Impede normal drug metabolism
What may you have to consider in hepatic dysfunction
Alternative non-pharmacological options or reduce the frequency and/or dose of the drug given
What is a toxic dose of paracetamol
4-6g
In the UK what do paracetamol tablets come as
0.5g doses
What is a lethal dose of paracetamol
> 12g in one go
What is the normal metabolism of paracetamol
1g paracetamol- majority of this dose is directly glucuronidated by UGT (bit of sulphation), water soluble inactivated paracetamol-glucuronide is easily excreted. 1g paracetamol generates small amount of Phase I toxic species (via CYP1A2 and CYP2E1) n-acetyl-p-benxoquinone imine (NAPBQI). NAPBQI very rapidly de-activated to conjugated glutathione (anit-oxidant). No net damage to hepatocytes
Describe overdose metabolic pathway
Toxic dose of paracetamol means no UGT as the glucuronidation pathway is overwhelmed with the paracetamol concentration. Excess paracetamol forced down CYP pathway. CYP1A2 & CYP2E1 generate large amounts of phase I toxic species NAPBQI. Glutathione reserves are rapidly depleted from the liver. Significant damage to hepatocytes
Describe paracetamol overdose pathway
Rapidly replenishing hepatic glutathione is achieved with IV infusions of n-acetyl cysteine (NAC) which limits hepatotoxicity of NAPBQI
What do you do on admission of a person with paracetamol overdose
Measure plasma levels on admission. If levels on or above treatment line begin infusions of NAC, consult BNF for NAC dosing
What is the liver the principle organ for metabolising
Xenobiotic and endobiotic compounds
What two phases is drug metabolism split into
Phase I (functionalism) and Phase I (conjugative)
What can Phase I metabolism generate
Chemically reactive intermediates which can be good or bad
What does liver dysfunction have the potential to seriously alter
Rates of drug metabolism in the patient
What is the hepatotoxix species generated in significant quantities following paracetamol overdose
n-acetly-p-benzoquinone imine) NAPBI
Which enzyme is likely to dysfunctional in Gilbert’s syndrome leading to jaundice
UDP-glucuronosyl tranferase 1A1 (UGT1A1)
