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Drugs and The Liver
1.
2.
3.
4.
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.
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.
9.
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.
11.
12. • Mostly based on Child-Pugh Score
• But some based on
– Albumin level
Best method
– PT (Prothrombin time)
May be useful
– Bilirubin level
13.
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
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.
32.
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
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.
