1. Clinical Pharmacokinetics
University of Nizwa
College of Pharmacy and Nursing
School of Pharmacy
Clinical Pharmacokinetics
PHCY 350
Lecture-14 Drug Dosing in Special Populations- Hepatic & Cardiovascular Disorders Dr. Sabin Thomas, M. Pharm. Ph. D. Assistant Professor in Pharmacy Practice School of Pharmacy University of Nizwa

2. Outcome Upon completion of this lecture the students will be able to
differentiate the type of hepatic disorders and its influence in pharmacokinetics of drugs,
measure the ability of liver to metabolize the drugs and to
explain the alterations in pharmacokinetics of drugs during cardiovascular disorders

3. Hepatic Disorders
Most lipid soluble drugs are metabolized to some degree by the liver, the mechanism:
Phase I : oxidation, hydrolysis and reduction; mediated by the cytochrome P-450 enzyme system, occur in hepatocytes
Phase II: conjugation to form glucuronides, acetates, or sulfates; mediated by cytosolic enzymes in hepatocytes
Phase I and II drug metabolism results in metabolites that are more water soluble and prone to elimination by kidneys.

4. Equation for Hepatic drug metabolism
LBF = liver blood flow
fB = the fraction of unbound drug in the blood
Clint = intrinsic clearance
The free intrinsic clearance may be thought of as the clearance of drug from liver plasma water, devoid of the influence of blood flow or binding.

5. Two major types of liver disease
Hepatitis
- Patients with hepatitis inflammation of the liver decreased ability of hepatocytes or die.
- Acute hepatitis: mild, transient decreases in drug metabolism required no or minor changes in drug dosing
- Chronic hepatitis: irreversible hepatocytes damage required drug dosage changes.
Patients with long term hepatocytes damage can progress to hepatic cirrhosis
2. Cirrhosis; a permanent loss of functional hepatocytes. Drug dosage schedules usually need to be modified

6. Altered pharmacokinetic parameters
When hepatocytes are damaged Clint decreases hepatic clearance reduces
If the drug has a hepatic first-pass effect BA will increases
A simultaneous effect of (1) and (2) results in extremely large increases in Css for orally administered drugs

7. Altered pharmacokinetic parameters
4. LBF decreases depresses hepatic drug clearance even further.
5. The liver produces albumin and a-1-acid glycoprotein in the blood. The production of these proteins decline in patient with cirrhosis free fraction of drugs in the blood.
6. Since clearance decreases and VD usually increases the t½ almost always increases.

8. Measurement of liver function
No single laboratory test to assess the liver function (not like CLCrest to measure renal function)
The most common way to estimate the ability of the liver to metabolize the drug is to determine the Child-Pugh score for a patient

9. The Child-Pugh score
Consists of 5 laboratory test or clinical symptoms, ie:
- serum albumin
- total bilirubin
- prothrombin time
- ascites
- hepatic encephalopathy

10. Table: Child-Pugh scores for patients with liver disease
Test/symptom
Score 1 point
Score 2 points
Score 3 points
Total bilirubin (mg/dl)
< 2.0
2.0 – 3.0
>3.0
Serum albumin (g/dl)
> 3.5
2.8 – 3.5
< 2.8
Prothrombin time (seconds prolonged over control)
< 4
4 – 6
> 6
Ascites
Absent
Slight
Moderate
Hepatic encephalopathy
None
Severe

11. Each of the symptom is given a score of 1 (normal) to 3 (severely abnormal), and the scores for the five areas are summed.
The Child-Pugh score for a patient with normal liver function is 5, whereas for abnormal (hepatic damage) is 15

12. Dosage Adjustment
A Child-Pugh score of 8 – 9 : a moderate decrease (+ 25%) in initial daily drug dose for agents that are primarily (> 60%) metabolized hepatically
A Child-Pugh score of > 10 : a significant decrease in initial daily dose (+ 50%) is required for drugs that are mostly liver metabolized
It is possible to decrease the dose while retaining the normal dosage interval, retain the usual dose and prolong the dosage interval, or modify both the dose and dosage interval
(+ 25%) Why? Plus or minus? It is 26 or 23%

13. Heart Failure
Is accompanied by a decrease in cardiac output results in lower liver and renal blood flow
Decreased drug bioavailability has been reported, due to collection of edema fluid in the GI tract difficult absorption and decreased blood flow to GI tract
VD of some drugs decreases, the alteration in t½ is difficult to predict in patients with heart failure

14. How can CVD affect pharmacokinetic of drugs?
Cardiac output
Hepatic blood flow
Renal blood flow
Absorption
Elimination
Diminished perfusion of absorption site.
e.g. *GIT & muscle
Distribution
Due to reduced cardiac output ,hepatic and renal blood few decreased, lead to reduced clearance
Diminished perfusion to many organs
*GIT > Gastrointestinal tract