Lec 7- Liver Flashcards
1
Q
Liver impairment
A
- Plasma proteins => alter unbound fraction, change distribution Changes metabolism
- Reduced blood flow => Reduce exposure of drugs to liver
- Reduced liver enzymes => Reduce metabolism of drugs
2
Q
Drug metabolism: phase 1 drug metabolism enzymes
A
- The major cause of drug metabolism is an enzyme in the liver (and small-intestine). This group of an enzyme is called
- Cytochrome P450 (CYP450) enzymes
- CYP450 is a superfamily of enzymes, with over 53 known enzymes divided into 3 main groups (CYP1, CYP2, CYP3) and each divided again into classes A-E
- CYP3A4 is the predominant enzyme
3
Q
Drug metabolism: What causes drug metabolism
A
- CYP3A metabolism over 50% of the 403 top drugs in the US/EU
- But just because CYP3A is the most abundant and metabolises many drugs, the abundance is not always important
- CYP2D6 = 2% total content BUT metabolises around 25% of all drugs and especially basic drugs
- the proportion of CYP isoenzymes that metabolise the top 403 drugs in the US/EU
4
Q
Drug metabolism: what causes drug metabolism
A
- Drug-drug interactions
- Digoxin (victim) + Verapamil (Perpetrator- that causes interaction)
- Reduced metabolism
- Increase plasma concentration
- AUC increases
- Elimination rate increases (longer to eliminate)
- Cmax increase = toxicity
5
Q
The process of drug metabolism- introduction
A
- Primary site: Liver (and intestines)
- Typically split into 2 phases
- Phase I- oxidation by CYP enzyme
- Phase II- Conjugation (glucuronidation)- add a sugar to make more polar therefore enter into the kidneys
6
Q
Drug metabolism: What causes drug metabolism
A
- Liver enzymes function according to Michaelis Menten kinetics
- We explored this in year 2 from a kinetics point of view
- From a PK point of view, this is very important
- V = (Vmax) x [S] / Km+ [S]
- Saturation is important with enzymes
7
Q
Drug metabolism: saturation of drug metabolism
A
- Most drugs show linear PK- Double dose = double concentration (e.g. Cmax or AUC)
- Some drugs show non-linearity:
- Double dose= double concentration
- Triple dose= 10x increase in concentration (i.e. NON-LINEAR)
- Therefore, when making dosage adjustments, the metabolism pathways should be considered as non-linear PK may show up when increase/changing the dose for a patient
- Clinical examples: antiepileptics (phenytoin, carbamazepine)
8
Q
Saturation of drug metabolims- Non-linear
What will happen to the half-life and AUC/Bioavailability
A
- Half-life tends to get longer, with a great excess of drug in the system
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9
Q
Clearance- definition
A
- The rate at which the liver eliminates a drug from the body may be described by the metabolic clearance
- The term reflects the LOSS of drug across the liver
- Clearance is often described as The volume of plasma that is cleared of drug per unit time
- Therebefore bear in mind that the PERFUSION of the organ is really important, with a maximum liver flow being around 1500mL/minute- therefore max clearance is 1.5L/min
- If you always use this method- Hepatic blood flow can change drastically between patients- CO etc
10
Q
Clearance- Hepatic extraction
A
- When we talk about drug metabolism we often refer to the drugs are being HIGH, MEDIUM or LOW extraction drugs
- If a drug is highly extracted it undergoes EXTENSIVE metabolism (metabolic clearance), hence the ability of the liver to metabolize the drug is very significant
- High extraction= significant breakdown
11
Q
Clearance- High extraction drugs
A
- E is a ratio (0-1) hence the maximum clearance for any drug is the liver blood flow
- Perfusion to the liver is now VERY important
- Clearance is very sensitive to changes in blood flow to the liver
- CL = Q x E
12
Q
Clearance-low extraction drugs
A
- CL = Q x E
- E is a ratio (0-1) hence the maximum clearance for any drug is the liver blood flow
- Perfusion to the liver is now NOT very important- clearance is not sensitive to change in Q
- Highly sensitive to change in plasma protein as only unbound drug gets in
- Clearance is very sensitive to changes in blood flow to the liver
- Minimally metabolised drugs- (poor permeability, little metabolism)
13
Q
Clearance- dependencies
A
14
Q
Clearance- relationships
A
- When thinking about drug clearance/metabolism/extraction, we are generally looking at how much drug is removed from the body
- To understand the clearance of a drug, we can use many different equations which are all inter-related
- The choice depends on the availability of different types of data
15
Q
A
17
Q
Clearance- special populations
Geiven IV (picking up hepatic elimination)
A
- We see change in elimination (reduced)
- Drug resides longer in the body
- How can you tell this from the graph
- Gradient is not as steep = less elimination
18
Q
Clearance- special population
Given Orally (+first pass effect)
A
- We see significant changes in absorption profile with an increased AUC (greater exposure and Increasing bioavailability
- Also the liver develop a ‘portal shunt’ where it transfers the blood supply away from the living liver cells (Bypassing the liver) and hence increasing bioavailability
- Higher AUC= reduced metabolism/clearance
19
Q
Clearance- special populations
clearance decreases
A
- Perhaps a change in blood flow or an elderly patient
- AUC Increase
- Half-life Increases
- More exposure for longer
- Toxicity
20
Q
Clearance- special population
Clearance increases
A
- Low extraction drug but with a change in protein binding (decreases)= increased potential for metabolism
- AUC decreases
- Half-life
- Less exposure
- Duration of action reduces
22
Q
Liver disease- progression of problems
A
23
Q
Liver disease- Testing
A
- There is no easy/simple way to test for liver function
- The child-pugh score is a commonly used approach which include 5 lab test checking
- Serum albumin; Total bilirubin; Prothrombin time; Ascites; Hepatic encephalopathy
- Based on the overall score (max 15) the initiation dosage is adjusted and titrated to a suitable level
