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

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

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.

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.

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

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

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.

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

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

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

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

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%

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

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