This document discusses drug dose adjustment for liver diseases. It explains that the liver is important for drug elimination and abnormalities can affect drug clearance and metabolism. Diseases like hepatitis, carcinoma, necrosis and cirrhosis impact drug elimination by decreasing hepatic clearance and increasing half-life. The hepatic extraction ratio determines if a drug is highly, intermediately or poorly extracted by the liver, affecting how liver disease impacts dosing. Drugs with low hepatic extraction are more dependent on liver function, so doses may need adjustment for liver disease. Antipyrine, which is only eliminated by the liver, is used to assess hepatic abnormalities.

1. DRUG DOSE ADJUSTMENT
FOR LIVER DISEASES
DIPTI S
B PHARMACY
Viii SEMESTER
RNO :8

2.  Liver is one of the common organ via which
drugs are eliminated .
 A few abnormalities in the liver might affect
the clearance and metabolism of drugs .
 Some of the diseases include hepatitis
carcinoma ,necrosis ,cirrhosis and obstructive
jaundice

3. EFFECT OF HEPATIC DISEASES ON DRUG
ELIMINATION AND METABOLISM
 Hepatic clearance of drug decreases
 Half life increases
There may be a few exceptions as some drugs have
other factors influencing the clearance and half life
like plasma protein binding
Volume of distribution is also a factor altering the
clearance

4. DOSE ADJUSTMENT IN HEPATIC
ABNORMALITIES
ANTIPYRINE : Antipyrine is an NSAID drug belonging
to the pyrazolidine di -one derevative
This is uses as a standard for determining Hepatic
abnormalities due to the following reasons
i) As it is negligibly protein bound
ii) And it is excreted via hepatic route
only .This is an example of a drug
exhibiting low hepatic ratio

5. Hepatic Extraction Ratio
 Hepatic Clearance: Cl(h) = Q [(f x Clint)/(Q+ f x
Clint)]
 Q = hepatic blood flow
 f = fraction of free drug (not bound)
 Clint = intrinsic capacity of the hepatocytes to
metabolize a drug

6. High extraction ratio
 .These drugs are rapidly and extensively
cleared from the blood by the liver (e.g. in a
single pass).
 Their clearance depends primarily on
hepatic blood flow, and binding to blood
components is not an obstacle for extraction;
the extraction is said to be non-restrictive or
blood flow dependent.When this is the case
in Rowlands equation: f x Clint is »Q and the
equation can be simplified to Cl(h) = Q

7. LOW HEPATIC RATIO DRUGS
These drugs are not efficiently cleared by the liver and
are extracted less avidly and incompletely from
hepatic blood.
 Their clearance is relatively independent of
hepatic blood flow, and is primarily determined by
the intrinsic metabolizing capacity of the liver and
by the free drug fraction.
 The extraction is said to be restrictive or capacity
limited. When this is the case f x Clint is «Q and
Rowland's equation can be simplified to Cl(h) = f x
Clint. An increase in the fraction of unbound drug (f)
will increase clearance, and a decrease in unbound
drug will decrease clearance

8. INTERMEDIATE HEPATIC RATIO
DRUGS
 Intermediate extraction ratio. Hepatic
clearance of these drugs is dependent on
both hepatic blood flow, intrinsic
metabolising capacity of the liver and the free
drug fraction.

9. SNO HIGH INTERMEDIATE LOW
1 morphine aspirin phenytoin
2 lidocaine nortriptyline warfarin
3 verapamil codeine Diazepam
4 propranolol quinidine Cimitidine

10. REFERENCES
 i) Biopharmaceutics and clinical
pharmacokinetics by MILO GIBALDI
 ii)Text book of Biopharmaceutics and
pharmacokinetics by CVS Subramanyam
 Woosley RL (1987): Pharmacokinetics and
pharmacodynamics