ASSIGNMENT #: 02
Title: “Bilirubin Metabolism”
Subject: Pharmacology and Therapeutics IIB
Submitted By: Zia Ul Islam
Reg: FA19-PHM-081
Submitted To: Dr. Khalid Rauf
Date of Submission: 26th, April, 2022
1 PHARMACY
DEPARTMENT OF
Table of Contents
1. Introduction: ................................................................................................ ……….3
2. Normal Bilirubin: ................................................................................................... 3
3. Normal Bilirubin Metabolism: ............................................................................... 3
3.1 Steps:…………………………………………………………………………………………………………………3
4. Drugs that can increase bilirubin: .......................................................................... 4
5. Drugs that can decrease bilirubin: ......................................................................... 4
6. DRUGS INTERFERING WITH BILIRUBINMETABOLISM .............................................. 5
6.1 Mechanism: ……………………………………………………………………………………………………5
6.1.1.Serum binding of bilirubin: ………………………………………………………………………………………………5
6.1.2.Haemolytic reactions: ………………………………………………………………………………………………………5
6.1.3.Interference with bilirubin uptake by the liver cell: ………………………………………………………5
6.1.4.DIRECT HEPATO-Toxicity: …………………………………………………………………………………………5
6.1.5.'MIXED' HYPERSENSITIVITY REACTIONS: ……………………………………………………………………5
6.1.6.Drugs disturbing bilirubin conjugation………………………………………………………………………5
6.6.7.Interference with canalicular excretion: …………………………………………………………………………5
7. Diseases Due To Drug Effect Metabolism OF Bilirubin ............................................ 6
7.1Increased indirect or total bilirubin may indicate: ……………………………………………6
7.2Increased direct bilirubin may indicate: ……………………………………………………………6
7. 3Additional conditions under which the test may be performed:………………………6
8. Conclusion: ..................................................................................................... 7
9. REFERENCES: ................................................................................................ 7
2
Introduction: Bilirubin is a yellowish pigment that is made during the normal breakdown of
red blood cells. Bilirubin is the catabolic product of heme metabolism. Within physiologic
range, bilirubin has cytoprotective and beneficial metabolic effects, but in high levels it is
potentially toxic.
Normal Bilirubin: A normal level is Direct (also called conjugated) bilirubin: less than 0.3
mg/dL (less than 5.1 µmol/L) Total bilirubin: 0.1 to 1.2 mg/dL (1.71 to 20.5 µmol/L).
Normal Bilirubin Metabolism: Bilirubin is generated from heme products, primarily
senescent red blood cells. A small portion is derived from myoglobin and maturing erythroid
cells. Within the reticuloendothelial system, heme is oxidized to biliverdin, which is then
converted to bilirubin.
Steps: Normal bilirubin metabolism can be summarized as a series of steps, including (1)
production, (2) uptake by the hepatocyte, (3) conjugation, (4) excretion into bile ducts, and
(5) delivery to the intestine. Jaundice can result from defects in any of these steps of
bilirubin metabolism.
Jaundice can result from defects in any of these steps of bilirubin metabolism.
3
Drugs that can increase bilirubin: Drugs that can increase bilirubin measurements include
 Allopurinol,
 Anabolic steroids,
 Some antibiotics,
 Antimalarials,
 Azathioprine,
 Chlorpropamide,
 Cholinergics,
 Codeine, morphine,
 Diuretics,
 epinephrine,
 Meperidine,
 Methotrexate,
 Methyldopa,
 MAO inhibitors, ,
 nicotinic acid,
 Oral contraceptives,
 Phenothiazines,
 Quinidine,
 Rifampin,
 Salicylates,
 Steroids,
 Sulfonamides.
Drugs that can decrease bilirubin: Drugs that can decrease bilirubin measurements include
 B arbiturates,
 Caffeine,
 Penicillin,
 And high-dose salicylates.
Within physiologic range, bilirubin has cytoprotective and beneficial metabolic effects, but
in high levels it is potentially toxic.
4
DRUGS INTERFERING WITH BILIRUBINMETABOLISM
Mechanism: Drugs disrupting bilirubin metabolism through following mechanism:
1. Serum binding of bilirubin: Unconjugated bilirubin is transported to the liver in the
plasma attached to albumin. Interference with this binding is particularly dangerous
in the neonate . Organic anions such as salicylate or sulphonamides compete with
the bilirubin for albumin and lead to its detachment, so causing kernicterus.
2. Haemolytic reactions: Drugs may disturb bilirubin metabolism by haemolytic action,
increasing bilirubin production from haem and so increasing the load on the liver
cell. This is rare as a single defect. In most instances, the haemolytic process is
combined with a hypersensitivity reaction which decreases hepato-cellular function.
Sulphonamides, for instance, can cause haemolysis but this is usually combined with
a generalised hypersensitivity effect.
3. Interference with bilirubin uptake by the liver cell: Certain drugs interfere with the
up take of bilirubin into the liver cell and its transport to the microsomes for
conjugation. Flavaspidic acid, theactive principle of male fern, is a good example of
this. This drug can be shown to constantly induce a mild unconjugated
hyperbilirubinaemia.
4. DIRECT HEPATO-Toxicity: Certain substances produce a predictable liver injury
when given to human subjects or to experimental animals
5. 'MIXED' HYPERSENSITIVITY REACTIONS: A number of other drugs cause jaundice of
mixed hepato-cellular and cholestatic types. The condition is therefore of
intermediate severity between the hepatic ('Iproniazid') and the cholestatic
('Chlorpromazine') types.
6. Drugs disturbing bilirubin conjugation: Two factors must be considered in discussing
the effect of drugs on the conjugating process. The drug might inhibit the
process(novobiocin) or it could increase (induce)the enzyme and so facilitate
conjugation(phenylbutazone orphenobarbitone).
7. Interference with canalicular excretion: There have been many reports of jaundice
inpatients
receiving
various
steroids
including
methyltestosterone,
norethandrolone,norethisterone, norethynodrel and ethinyloestranol.
5
Diseases Due To Drug Effect Metabolism OF Bilirubin
Jaundice is the discoloration of skin and sclera of the eye, which occurs when bilirubin
accumulates in the blood at a level greater than approximately 2.5 mg/dl. Jaundice occurs
because red blood cells are being broken down too fast for the liver to process, because of
disease in the liver, or because of bile duct blockage.
Increased indirect or total bilirubin may indicate:
 Erythroblastosis fetalis
 Gilbert's disease
 Hemolytic anemia
 Hemolytic disease of the newborn
 Physiological jaundice (normal in newborns)
 Sickle cell anemia
 Transfusion reaction
 Pernicious anemia
 Resolution of a large hematoma
Increased direct bilirubin may indicate:
 Gile duct obstruction

Cirrhosis

Crigler-Najjar syndrome (very rare)

Dubin-Johnson syndrome (very rare)

Hepatitis
Additional conditions under which the test may be performed:
Biliary stricture
Cholangiocarcinoma
Cholangitis
Choledocholithiasis
Hemolytic anemia due to G6PD deficiency
Hepatic Encephalopathy
6
Conclusion:
Untoward hepatic reactions to drugs are classified according to the possible mechanism.
Interference with bilirubin metabolism, direct hepatotoxicity, hepatic and cholestatic
hypersensitivity reactions are recognised. The role of hepatic enzyme induction in drug
metabolism and in therapy is discussed. Individual variation in the hepatic reactions to a
drug are illustrated by the neonate, the pregnant, the state of hepato-cellular function and
by the response to some oral contraceptives.
REFERENCES:
 https://www.hsc.wvu.edu/media/5107/bilirubin-summary.pdf
 https://journals.sagepub.com/doi/pdf/10.1177/00045632700070040
 https://ascpt.onlinelibrary.wiley.com/doi/pdf/10.1002/cpt.619
 https://www.malacards.org/card/bilirubin_metabolic_disorder?showAll=True
 https://accessmedicine.mhmedical.com/content.aspx?bookid=1130&sectionid=7974
8447
 https://pmj.bmj.com/content/postgradmedj/39/450/176.full.pdf
 https://slideplayer.com/slide/12174190/
7