The pharmacokinetics of many drugs are altered in patients with hepatic disease. The extent of alteration depends on the drug's elimination pathway and the severity of the liver disease. Drugs primarily metabolized by the liver will have their clearance reduced in patients with liver dysfunction. The bioavailability of drugs undergoing first-pass metabolism may increase due to reduced first-pass effect. Child-Pugh score is commonly used to assess liver disease severity and predict changes in drug pharmacokinetics. Dosage adjustments are usually required for drugs eliminated hepatically when treating patients with hepatic impairment.

5. • Pharmacokinetics of many drugs are altered in hepatic
diseases
• The extent of alteration depends on
– The elimination pathway of the drug &
– The severity of the hepatic disease
• Awareness on the disease is very important.

6. Relationship ?
Clinical application?

8. • If AST ↑
→
• If ALT ↑
→ indicates liver damage
• If plasma protein (albumin) ↓ → indicates ↓
synthetic capacity of the liver.
• but none of the tests directly measure the
reflection of the disease severity.

10. • Yes .. It depends on the type of the hepatic disease as
well
• for example
– Acute viral hepatitis – has very little effect on drug clearance
.. But
– Chronic hepatitis – effects on drug pharmacokinetics
depending on degree of disease severity (eg. degree of
cirrhosis)
• It also depends on the extraction ratio of the drug by
the liver.

12. • Mostly based on Child-Pugh Score
• But some based on
– Albumin level
Best method
– PT (Prothrombin time)
May be useful
– Bilirubin level

14. Child-Pugh classification of prognosis in cirrhosis
Score
1
2
3
Encephalopathy
None
Mild
Marked
PBC/sclerosing
cholangitis
< 68
68-170
> 170
Other causes of cirrhosis
< 34
34-50
> 50
Albumin (g/L)
> 35
28-35
< 28
Prothrombin time
(seconds prolonged)
<4
4-6
>6
Ascites
None
Mild
Marked
Bilirubin (μmoL/L)
Add the individual scores: < 7 = Child's A, 7-9 = Child's B, > 9 = Child's C

15. Survival in cirrhosis
Survival %
Child-Pugh
Grade
1 year
5 years
10 years
Hepatic death
(%)
A
82
45
25
43
B
62
20
7
72
C
42
20
0
85

17. Changes in bioavailability

18. • Bioavailabilty 20% means that
– 100 mg (oral) of drug A = 20 mg (IV) of the same drug
• One of the reasons of low bioavailability is “high
first pass extraction”.

19. 1. Oral dose need to be ↓ severe hepatic disease
because
– There will be ↓ in 1st pass extraction →↑ bioavailability
2. In cholestasis –
– Bioavailability of lipophilic drugs will be ↓
(eg. ciclosporin)

20. • Mostly concerned with the individual drug’s –
– Plasma protein binding
– Tissue binding
– Lipid solubility

21. • In hepatic diseases,
• Plasma protein (albumin) can be ↓
• Plasma protein binding of drugs can be ↓
• Free fraction of the drug can be ↑
• There can be increased drug action and effect.

22. • Actually, elimination of drugs mainly depend on
renal excretion, therefore renal function mainly
determines.
• But for drugs which are mainly matabolised by
liver, hepatic function is important for their
clearance.

23. • Define as the product of blood flow (delivery of the drug to the
organ of removal) and the extraction ratio.
ER
=
Cin-Cout
Cin
100-20
= 80 %
=
100

24. • For High ER (i.e. ER > 70%) drugs,
• Eg. Morphine (ER is 0.7 or 70%)
• It is a drug mainly eliminated by liver, when it is given
orally, it delivers 1st to liver, can face with first pass
effect.
• Its Bioavailability will be 1-ER = 0.3 or 30%

25. • In severe cirrhosis –
– There is reduction in the ability of the liver to metabolize
– Presence of porto systemic shunts
– Bioavailability can become – 100%
– Which can lead to adverse effects…
• Liver diseases can change ER ratio &
• There will be clinically significant changes on
bioavailability of high ER drugs.

26. • In cholestasis → bile flow ↓ → accumulation of bile in liver →
injury to hepatocytes +
• In advanced cases of biliary cirrhosis → there is reduction in
intrinsic clearance activity of liver
• If bile flow is disturbed → there will be disturbance of
Enterohepatic circulation (which is useful for action of some
drugs)

27. • 2 phases of drug metabolism
– Phase I – functionalization phase
– Phase II – conjugation reactions
• Phase II is a true detoxification pathway,
– resulting water soluble products that are easily excreted.
• Process of phase II reactions
– glucoronidation, sulphation, methylation, acetylation,
glutathione conjugation.

28. CYP
• The enzyme used – CYP superfamily
• Around 500 enzymes
CYP
Cytochrome P450
3
A
4
Individual
gene/enzyme
subfamily
family

29. Clinical significance
• CYP 3A4 – most important CYP involved in 50% of currently used
drugs
• There is strong correlation between CYP score and extent of hepatic
metabolisms
• In cirrhosis – CYP level can be ↓

30. • formation of porto-systemic anastomoses (Presence of shunts) +
reduced hepatic metabolism
→ greatly increase the oral bioavailability of drugs undergo extensive
1st pass metabolism.
• For eg. 2 fold increase in bioavailability of propranolol in cirrhosis
compared to normal.

31. • It is difficult to come up with definite dosage guidelines
• Routine liver function tests are not a good complete guide
• CP score is a useful guide for determining prognosis in COL
cases.
– But its usefulness in predicting drug doses is less clear
• Precise dose determination in liver diseases is to be based
on drug to drug basis and back ground disease state.

33. • Interference with bilirubin metabolism and excretion
– Steroids, androgens, estrogens, oral contraceptives
– Rifampicin
• Centrilobular necrosis
– Paracetamol, carbon tetrachloride
• Hepatocellular necrosis
– Salicyclates
• Fatty change in liver cells and hepatic failure
– tetracycline

34. • Acute hepatocellular necrosis
– Halothane (GA)
– Carbamazepine, phenytoin, sodium valproate, phenobarbital
(antiepileptics)
– MAOI (antidepressants)
– Ibuprofen (anti-inflammatory)
– Isoniazid, sulphonamides, (anti infectives)
– Methyldopa, hydralazine (CVS drugs)
• Cholestatic hepatitis
– Phenothiazine neuroleptics (Chlorpromazine)

35. • Benign liver tumor
– Anabolic steroids
– Oral contraceptives
• Chronic active hepatitis
– Isoniazid
– Dantrolene
• Hepatic fibrosis or cirrhosis
– Methotrexate
– Amiodarone

36. References
• Penny North-Lewis (2008). Drugs and the Liver. 1 Lambeth High
Street, London: Royal Pharmaceutical Society of Great Britain . 23135.
• Palmer, KR and Penman ID. (2010). Alimentary tract and pancreatic
disease. In: Colledge, NR, Walker, BR and Ralston SH Davidson's
Principle and Practice of Medicine. 21st ed. London : Churchill
Livingstone. 835-918.
• Tripathi, KD. 2008. Essentials of Medical Pharmacology. 6th Edition.
India: Jaypee Brothers Medical Publishers (P) Ltd.