LIVER INJURY IN RATS”
A Dissertation Submitted to
THE TAMILNADU Dr. M.G.R. MEDICAL UNIVERSITY, CHENNAI- 600032
In partial fulfillment of the requirements for the award of the Degree of MASTER OF PHARMACY
IN
BRANCH-IV-PHARMACOLOGY
Submitted by K.THAMILARASAN REGISTER NO: 261425507
Under the guidance of MR. P. ROYAL FRANK, M. Pharm.,
Assistant Professor, Department of Pharmacology
THE ERODE COLLEGE OF PHARMACY & RESEARCH INSTITUTE, ERODE- 638112.
This is to certify that the dissertation work entitled “HEPATOPROTECTIVE ACTIVITY OF ETHANOLIC EXTRACT OF BARKS OF STERCULIA FOETIDA.L
AGAINST PARACETAMOL AND ETHANOL INDUCED LIVER INJURY IN RATS” submitted by Register No: 261425507 to The Tamilnadu Dr. M.G.R Medical University, Chennai, In partial fulfilment for The degree of MASTER OF PHARMACY in PHARMACOLOGY is the bonafide work carried out under the guidance and direct supervision of Mr. P. Royal Frank M.Pharm., Asst.Professor, Department of Pharmacology, THE ERODE COLLEGE OF PHARMACY AND RESEARCH INSTITUTE, ERODE-638112 during the academic year 2015-2016
1.INTERNAL EXAMINER 2.EXTERNAL EXAMINER
3. CONVENER OF EXAMINATION
EXAMINATION CENTRE
The Erode College of Pharmacy & Research Institute Place: Erode
Principal
Professor and Head, Department of Pharmaceutics, The Erode College of Pharmacy and Research Institute, Erode - 638112.
CERTIFICATE
This is to certify that the dissertation work entitled “HEPATOPROTECTIVE ACTIVITY OF ETHANOLIC EXTRACT OF BARKS OF STERCULIA FOETIDA.L
AGAINST PARACETAMOL AND ETHANOL INDUCED LIVER INJURY IN RATS” submitted by Register No: 261425507 to The Tamilnadu Dr. M.G.R Medical University, Chennai, In partial fulfilment for The degree of MASTER OF PHARMACY in PHARMACOLOGY is the bonafide work carried out under the guidance and direct supervision of Mr. P. Royal Frank M.Pharm., Asst.Professor, Department of Pharmacology, THE ERODE COLLEGE OF PHARMACY AND RESEARCH INSTITUTE, ERODE-638112 during the academic year 2015-2016.
Place: Erode Dr V.Ganesan, M.Pharm.,Ph.D.,
Professor and Head, Department of Pharmacology, The Erode College of Pharmacy and Research Institute, Erode - 638112.
CERTIFICATE
This is to certify that the dissertation work entitled “HEPATOPROTECTIVE ACTIVITY OF ETHANOLIC EXTRACT OF BARKS OF STERCULIA FOETIDA.L
AGAINST PARACETAMOL AND ETHANOL INDUCED LIVER INJURY IN RATS” submitted by Register No: 261425507 to The Tamilnadu Dr. M.G.R Medical University, Chennai, In partial fulfilment for The degree of MASTER OF PHARMACY in PHARMACOLOGY is the bonafide work carried out under the guidance and direct supervision of Mr. P. Royal Frank M.Pharm., Asst.Professor, Department of Pharmacology, THE ERODE COLLEGE OF PHARMACY AND RESEARCH INSTITUTE, ERODE-638112 during the academic year 2015-2016.
Place: Erode Dr. M .Periyasamy, M.Pharm.,Ph.D.,
Asst. Professor,
Department of Pharmacology,
The Erode College of Pharmacy and Research Institute, Erode - 638112.
CERTIFICATE
This is to certify that the dissertation work entitled “HEPATOPROTECTIVE ACTIVITY OF ETHANOLIC EXTRACT OF BARKS OF STERCULIA FOETIDA.L
AGAINST PARACETAMOL AND ETHANOL INDUCED LIVER INJURY IN RATS” submitted by Register No: 261425507 to The Tamilnadu Dr. M.G.R Medical University, Chennai, In partial fulfilment for The degree of MASTER OF PHARMACY in PHARMACOLOGY is the bonafide work carried out under the guidance and direct supervision of Mr. P. Royal Frank M.Pharm., Asst.Professor, Department of Pharmacology, THE ERODE COLLEGE OF PHARMACY AND RESEARCH INSTITUTE, ERODE-638112 during the academic year 2015-2016.
Place: Erode Mr. P. Royal Frank, M. Pharm.,
“HEPATOPROTECTIVE ACTIVITY OF ETHANOLIC EXTRACT OF BARKS OF
STERCULIA FOETIDA.L AGAINST PARACETAMOL AND ETHANOL INDUCED
LIVER INJURY IN RATS” was carried out by me in the department of pharmacology, The Erode College of Pharmacy and Research Institute, Erode 638112, under the guidance and direct supervision of Mr. P. Royal Frank M.Pharm., Asst.Professor, at the Department of Pharmacology, The dissertation is submitted to The Tamilnadu Dr. M.G.R Medical university, Chennai-32, as a partial fulfillment for the award of degree of Master Of Pharmacy in Pharmacology during the academic year 2015-2016. The work is original and has not been submitted in part or full for the award of any other or Diploma of this or other university.
complete my investigation studies successfully and I present this piece of work which is eternally indebted.
I would like to thank my family members who have always been a constant source of aspiration and encouragement. It is with their blessing that I embarked upon this project.
I thankful to my project guide Mr. P.Royal Frank, M.PHARM, Assistant Professor, Department of Pharcmacology for his inspiring nature, constant encouragement, valuable guidance and support to me throughout the course of this work.
I owe a debt of gratitude to my Principal, Dr.V.Ganesan, M.Pharm., Ph.D., Professor and HOD, Dept of Pharmaceutics, The Erode college of Pharmacy and Research Institute, Erode, for spending his valuable time on several occasions to impart me to gain his knowledge.
I express my sincere thanks to Mr. V.S. Saravanan, M.Pharm., Ph.D, Vice– Principal and Head of Pharmaceutical Analysis, The Erode College of Pharmacy, Erode.
I express my sincere thanks and respectful regard to my beloved President Dr.K.R.Paramasivam, Ph.D., and the Secretary and Correspondent of the Management, Mr. A. Natarajan, B.A., H.D.C., for all facilities that were provided to me at the institution for enabling me to do the work of his magnitude.
I express my sincere thanks to Dr.M.Periyasamy, M. Pharm., Ph.D., Dept. of Pharmacology for giving his valuable guidance and constant encouragement throughout the project work.
I also express my thanks to Mrs.Sumithra M.Pharm., for his supportive effect throughout this project work.
I also express my thanks to D.Akilan B.Pharm, and Gopalakrishnan M.Pharm., for his supportive effect throughout this project work.
I express my deep gratitude to all other staff members for giving guidance and support, timely help and suggestions.
I would like to extend my sincere thanks to all our Lab Technicians and all the administrative staffs of The Erode College of Pharmacy and Research Institute, for their support in carrying out this project.
I would like extent my thanks to my classmates Muhamed Shabeer B.Pharm, Danish B.Pharm., especially with no words to express my heartiest and deepest gratitude to all my beloved family members and friends who always beloved in me and stood with me in good and bad times, and my special thanks to them for their friendship, adherent love, affection and encouragement they always showered on me. I thank my juniors who have contributed directly and indirectly in my dissertation.
A word of thanks to all those gentle people associated with this work directly or indirectly whose names have been unable to mention here.
WITH THANKS,
Reg.No:261425507
SL.NO CONTENTS PAGE.NO
1 INTRODUCTION 1
2 REVIEW OF LITERATURE 6
3 PLANT PROFILE 36
4 SCOPE OF THE PRESENT STUDY 43
5 AIM AND OBJECTIVES 44
6 PLAN OF WORK 45
7 MATERIALS AND METHODS 47
8 RESULTS AND DISCUSSION 70
9 SUMMARY AND CONCLUSION 89
10 FUTURE PROSPECTIVES 90
11 BIBLIOGRAPHY 91
SL.NO CONTENTS PAGE NUMBER
1. Chemical properties of ethanol 31
2. Results of the percentage yield of the ethanolic extract of
dried barks of Sterculia foetida.L 70
3. Data for ash values for powdered barks of
Sterculia
foetida.L 71
4. Data for extractive values and loss on drying of powdered
barks of Sterculia foetida.L 72
5. Results of the Phytochemical constituents of leaves of
Sterculia foetida.L 73
6.
Effect of ethanolic extract of barks of Sterculia foetida.L
on serum parameters against paracetamol intoxicated rats. 75
7.
Effect of ethanolic extract of Sterculia foetida.L on serum
SL.NO CONTENTS NUMBER PAGE
1. Anatomy of liver 6
2. Whole tree photo shot of Sterculia foetida.L 36
3. Photo shot of leaves of Sterculia foetida.L 37
4.
Diagrammatic representation of Effects of ethanolic
extract of Sterculia foetida.L on serum parameters against paracetamol intoxicated rats
76
5.
Diagrammatic representation of Effects of ethanolic extract of Sterculia foetida.L on total protein and total bilirubin against paracetamol intoxicated rats
77
6.
Diagrammatic representation of Effects of ethanolic extract of Sterculia foetida.L on serum parameters against Alcohol intoxicated rats
79
7.
Diagrammatic representation of Effects of ethanolic extract of Sterculia foetida.L on total protein and total bilirubin against Alcohol intoxicated rats
80
8. Histopathology of liver [Paracetamol model] 81
1. INTRODUCTION
Medicinal plants can be important sources of unknown chemical substances with
potential therapeutic effects. Besides, the World Health Organization has estimated
that over 75% of the world’s population still relies on plant-derived medicines, usually
obtained from traditional healers, for basic health-care needs.
The use of herbal medicines continues to expand rapidly across the world.
Many people now take herbal medicines or herbal products for their health care in
different national health-care settings. However, mass media reports of adverse
events tend to be sensational and give a negative impression regarding the use of
herbal medicines in general, rather than identifying the causes of these events,
which may relate to a variety of issues. Now-a-days, the safety of herbal medicines
has become a major concern to both national health authorities and the general
public. [1]
Herbal medicines form the basis of health care throughout the world. The earliest
days of mankind are still widely used, and have considerable importance in
international trade. Recognition of their clinical, pharmaceutical and economic value
is still growing, although it varies widely between countries [2].
Medicinal plants are important for pharmacological research and drug development,
not only for plant constituents which are used directly as therapeutic agents, but also
as starting materials for the synthesis of drugs or as models for pharmacologically
active compounds. Regulation of exploitation and exportation is therefore essential,
together with International cooperation and coordination for their conservation so as
to ensure their availability for the future [2]. The United Nations Convention on
Biological Diversity states that, ‘the conservation and sustainable use of biological
growing world population, for which purpose access to and sharing of both genetic
resources and technologies are essential’ [2].
‘Legislative controls’, in respect, of medicinal plants have not evolved around
a structured control model. There are different ways in which countries define
medicinal plants or herbs or products derived from them, and countries have
adopted various approaches to licensing, dispensing, manufacturing and trading to
ensure their safety, quality and
efficacy [2].
Despite the use of herbal medicines over many centuries, only a relatively
small number of plant species has been studied for possible medical applications.
Safety and efficacy data are available for an even smaller number of plants, their
extracts and active ingredients and preparations containing them [3].
Nature always stands as a golden mark to exemplify the outstanding
phenomenon of symbiosis. The biotic and abiotic elements of nature are all
interdependent. The plants are indispensable to man for his life. The three important
necessities of life –food, clothing, shelter- and a host of other useful products are
supplied to humans by the plant kingdom. Nature has provided a complete store–
house of remedies to cure all ailments of mankind .The knowledge of drugs has
accumulated over thousands of years as a result of man’s inquisitive nature so that,
today we possess many effective means of ensuring health care.[4].
Phytopharmaceuticals form an important part of herbal industry and so called
allopathic system of medicine has also recognized their importance. Many of the
drugs used their system eg. Sex and other hormones, anticancer and cardiovascular
THE ANCIENT INDIAN TRADITIONAL MEDICINES:
It mainly consist of three major systems namely
Ayurveda,
Siddha
Unani
Ayurveda:
Ayurveda is a system of healing from India. The origin of Ayurveda has been lost in
prehistoric antiquity, but their characteristic concepts appeared to have been
nurtured between 2500 and 500BC in India. Ayurveda is usually translated as “the
science of life”. In Indian system of traditional medicine, it is accepted as the oldest
written medical system that is also supposed to be more effective in certain cases
than modern therapies. Formulations and dosage forms have great importance in
Ayurveda. Generally Ayurvedic formulations are multi-component mixtures
containing plant and animal derived products, minerals and metals. During the
Samhita period (1000 BC), Ayurveda developed into eight branches of specialties.
Whereas, during the last 50 years it has developed into twenty-two specialties.
Despite the increasing popularity of herbal medicines and herbal cosmetics abroad,
it would seem that Ayurveda is yet to gain wider acceptance among medical
scientists internationally (Mukherjee et al., 2005a; Mukherjee, 2003b). Ayurveda is
effective in the hands of an experienced practitioner, and most of the herbs used are
fairly safe. Unfortunately, lack of regulation, quality issues in some products has led
Siddha:
Siddha System of Medicine Siddha system is one of the oldest systems of medicine
in India, which blends medicine and mysticism. The word Siddha was coined from
word ‘Siddhi’, which means attainment of perfection and the art was mastered,
practiced and teached by wise men known as ‘siddhars’. Although Siddha medicine
resembles the aspects of Ayurveda, they possess different origin. Siddha medicine
originated from the south of Indian subcontinent rather than the north. The diagnosis
of diseases involved identifying its causes. Identification of causative factors is
through the examination of pulse, urine, eyes, study of voice, colour of body, tongue
and the status of the digestive system. The Siddha system of medicine emphasizes
that medical treatment is oriented not merely to disease but has to take into account
the patient, environment, the meteorological consideration, age, sex, race, habits,
mental frame, habitat, diet, appetite, physical condition, physiological constitution
etc. This means the treatment has to be individualistic which ensures lesser chance
of committing mistakes in diagnosis or treatment.
Unani:
Unani System of Medicine Unani Tibb (Unani means Greek [Ionnian] and Tibb, from
the Arabic, means medicine) is a system of medicine practiced today in the South
Asian countries of India, Pakistan, and Bangladesh. Its origins lie in ancient Greek,
Arabic, and Persian medicine. In India, Arabs introduced the Unani system of
medicine, which was developed by the Mughal emperors who invaded India. Here
diseases are considered as a natural process and its symptoms are the reaction of
the body to the diseases. Unani, with its humoral philosophy, views nature and
mankind as ideally coexisting in a balanced manner. Specifications for a range of
behaviours and events that could lead to sickness and disease are outlined in the
emphasizes the use of flavors and tastes to adjust the imbalances which contribute
to disease. The choices of foods and the manner in which they are prepared are
considered to be among the most important issues to consider when choosing a diet
to improve or maintain health. Skilful use of warming and cooling spices and herbs
contribute heavily to the appropriateness of the meal to correct the root causes of
imbalances.
With the emerging interest in the world to adopt and study the traditional system and
to exploit their potentials based on different healthcare systems, Government of India
is exploring several possibilities for the evaluation of these systems to bring out
therapeutic approaches available in original system of medicine as well as to help in
generating data to put these products on national health care program. The Indian
herbal products including Ayurveda, Unani, Siddha and Homeopathy are regulated
under the Drugs & Cosmetics Act and licensing of such products remains a state
subject. Provision relating to the regulatory aspects of natural products manufacture
2. REVIEW OF LITERATURE
ANATOMY OF LIVER:
Fig No: 1
The liver is the heaviest gland of the body, weighing about 1.4 kg (about 3 lb) in an
average adult. Among all the organs of the body, it is second only to the skin in size.
The liver is inferior to the diaphragm and occupies most of the right hypochondriac
and part of the epigastric regions of the abdominopelvic cavity
The gallbladder (gall- bile) is a pear-shaped sac that is located in a depression of
the posterior surface of the liver. It is 7–10 cm (3–4 inch) long and typically hangs
from the anterior inferior margin of the liver.
The liver is almost completely covered by visceral peritoneum and is completely
covered by a dense irregular connective tissue layer that lies deep to the
peritoneum. The liver is divided into two principal lobes—a large right lobe and a
[image:19.595.72.527.149.455.2]right lobe is considered by many anatomists to include an inferior quadrate lobe and a posterior caudate lobe, based on internal morphology (primarily the distribution of
blood vessels), the quadrate and caudate lobes more appropriately belong to the left
lobe. The falciform ligament extends from the undersurface of the diaphragm
between the two principal lobes of the liver to the superior surface of the liver,
helping to suspend the liver in the abdominal cavity. In the
free border of the falciform ligament is the ligamentum teres (round ligament), a
remnant of the umbilical vein of the fetus; this fibrous cord extends from the liver to
the umbilicus. The right and left coronary ligaments are narrow extensions of the
parietal peritoneum that
suspend the liver from the diaphragm. The parts of the gallbladder include the broad
fundus, which projects inferiorly beyond the inferior border of the liver; the body, the
central portion; and the neck, the tapered portion. The body and neck project
superiorly.
Histology of the Liver and Gallbladder
Histologically, the liver is composed of several components
1. Hepatocytes (hepat- liver; -cytes - cell). Hepatocytes are the major functional
cells of the liver and perform a wide array of metabolic, secretory, and endocrine
functions. These are specialized epithelial cells with 5 to 12 sides that make up
about 80% of the volume of the liver. Hepatocytes form complex three-dimensional
arrangements called hepatic laminae. The hepatic laminae are plates of
hepatocytes one cell thick bordered on either side by the endothelial-lined vascular
spaces called hepatic sinusoids. The hepatic laminae are highly branched, irregular
structures. Grooves in the cell membranes between neighboring hepatocytes provide
spaces for canaliculi (described next) into which the hepatocytes secrete bile. Bile, a
yellow, brownish, or olive-green liquid secreted by hepatocytes, serves as both an
2. Bile canaliculi (kan-a-LIK-u- -li _ small canals). These are small ducts between
hepatocytes that collect bile produced by the hepatocytes. From bile canaliculi, bile
passes into bile ductules and then bile ducts. The bile ducts merge and eventually
form the larger right and left hepatic ducts, which unite and exit the liver as the
common hepatic duct.The common hepatic duct joins the cystic duct (cystic _
bladder) from the gallbladder to form the common bile duct. From here, bile enters
the small intestine to participate in digestion.
3. Hepatic sinusoids. These are highly permeable blood capillaries between rows
of hepatocytes that receive oxygenated blood from branches of the hepatic artery
and nutrient-rich deoxygenated blood from branches of the hepatic portal vein.
Recall that the hepatic portal vein brings venous blood from the gastrointestinal
organs and spleen into the liver. Hepatic sinusoids converge and deliver blood into a
central vein. From central veins the blood flows into the hepatic veins, which drain
into the inferior vena cava. In contrast to blood which flows toward a central vein, bile
flows in the opposite direction. Also present in the hepatic sinusoids are fixed
phagocytes called stellate reticuloendothelial (Kupffer) cells, which destroy
worn-out white and red blood cells, bacteria, and other foreign matter in the venous blood
draining from the gastrointestinal tract. Together, a bile duct, branch of the hepatic
artery, and branch of the hepatic vein are referred to as a portal triad (tri _ three).
The hepatocytes, bile duct system, and hepatic sinusoids can be organized into
anatomical and functional units in three different ways:
1. Hepatic lobule. For years, anatomists described the hepatic lobule as the
functional unit of the liver. According to this model, each hepatic lobule is shaped like
a hexagon (six-sided structure). Figure 24.15e, left at its centre is the central vein,
and radiating out from it are rows of hepatocytes and hepatic sinusoids. Located at
the liver of adult pigs. In the human liver, it is difficult to find such well-defined
hepatic lobules surrounded by thick layers of connective tissue.
2. Portal lobule. This model emphasized the exocrine function of the liver, that is,
bile secretion. Accordingly, the bile duct of aportal triad is taken as the centre of the
portal lobule. The portal lobule is triangular in shape and is defined by three
imaginary straight lines that connect three central veins that are closest to the portal
triad. This model has not gained widespread acceptance.
3. Hepatic acinus. In recent years, the preferred structural and functional unit of the
liver is the hepatic acinus. Each hepatic acinus is an approximately oval mass that
includes portions of two neighboring hepatic lobules. The short axis of the hepatic
acinus is defined by branches of the portal triad—branches of the hepatic artery,
vein, and bile ducts—that run along the border of the hepatic lobules. The long axis
of the acinus is defined by two imaginary curved lines, which connect the two central
veins closest to the short axis center. Hepatocytes in the hepatic acinus are
arranged in three zones around the short axis, with no sharp boundaries between
them Cells in zone 1 are closest to the branches of the portal triad and the first to
receive incoming oxygen, nutrients, and toxins from incoming blood. These cells are
the first one to take up glucose and store it as glycogen after a meal and break down
glycogen to glucose during fasting. They are also the first to show morphological
changes following bile duct obstruction or exposure to toxic substances. Zone 1 cells
are the last one to die if circulation is impaired and the first ones to regenerate. Cells
in zone 3 are farthest from branches of the portal triad and are the last to show the
effects of bile obstruction or exposure to toxins, the first one to show the effects of
impaired circulation, and the last one to regenerate. Zone 3 cells also are the first to
show evidence of fat accumulation. Cells in zone 2 have structural and functional
characteristics intermediate between the cells in zones 1 and 3. The hepatic acinus
based on the fact that it provides a logical description and interpretation of (1)
patterns of glycogen storage and release and (2) toxic effects, degeneration, and
regeneration in the three zones of the hepatic acinus relative to the proximity of the
zones to branches of the portal triad. The mucosa of the gallbladder consists of
simple columnar epithelium arranged in rugae resembling those of the stomach. The
wall of the gallbladder lacks a submucosa. The middle, muscular coat of the wall
consists of smooth muscle fibers. Contraction of the smooth muscle fibers ejects the
contents of the gallbladder into the cystic duct. The gallbladder’s outer coat is the
visceral peritoneum. The functions of the gallbladder are to store and concentrate
the bile produced by the liver (up to tenfold) until it is needed in the small intestine. In
the concentration process, water and ions are absorbed by the gallbladder mucos a.
Blood supply to the liver:
The liver receives blood from two sources. From the hepatic artery it obtains
oxygenated blood, and from the hepatic portal vein it receives deoxygenated blood
containing newly absorbed nutrients, drugs, and possibly microbes and toxins from
the gastrointestinal tract. Branches of both the hepatic artery and the hepatic portal
vein carry blood into liver sinusoids, where oxygen, most of the nutrients, and certain
toxic substances are taken up by the hepatocytes. Products manufactured by the
hepatocytes and nutrients needed by other cells are secreted back into the blood,
which then drains into the central vein and eventually passes into a hepatic vein.
Because blood from the gastrointestinal tract passes through the liver as part of the
hepatic portal circulation, the liver is often a site for metastasis of cancer that
Functions of liver:
In addition to secreting bile, which is needed for absorption of dietary fats, the liver
performs many other vital functions:
• Carbohydrate metabolism. The liver is especially important in maintaining a
normal blood glucose level. When blood glucose is low, the liver can break down
glycogen to glucose and release the glucose into the bloodstream. The liver can also
convert certain amino acids and lactic acid to glucose, and it can convert other
sugars, such as fructose and galactose, into glucose. When blood glucose is high,
as occurs just after eating a meal, the liver converts glucose to glycogen and
triglycerides for storage.
• Lipid metabolism. Hepatocytes store some triglycerides; break down fatty acids to
generate ATP; synthesize lipoproteins, which transport fatty acids, triglycerides, and
cholesterol to and from body cells; synthesize cholesterol; and use cholesterol to
make bile salts.
• Protein metabolism. Hepatocytes deaminate (remove the amino group, NH2,
from) amino acids so that the amino acids can be used for ATP production or
converted to carbohydrates or fats. The resulting toxic ammonia (NH3) is then
converted into the much less toxic urea, which is excreted in urine. Hepatocytes also
synthesize most plasma proteins, such as alpha and beta globulins, albumin,
prothrombin, and fibrinogen.
• Processing of drugs and hormones. The liver can detoxify substances such as
alcohol and excrete drugs such as penicillin, erythromycin, and sulfonamides into
bile. It can also chemically alter or excrete thyroid hormones and steroid hormones
such as estrogens and aldosterone.
• Excretion of bilirubin. As previously noted bilirubin, derived from the heme of
Most of the bilirubin in bile is metabolized in the small intestine by bacteria and
eliminated in motion.
• Synthesis of bile salts. Bile salts are used in the small intestine for the
emulsification and absorption of lipids.
• Storage. In addition to glycogen, the liver is a prime storage site for certain
vitamins (A, B12, D, E, and K) and minerals (iron and copper), which are released
from the liver when needed elsewhere in the body.
• Phagocytosis. The stellate reticuloendothelial (Kupffer) cells of the liver
phagocytize aged red blood cells, white blood cells, and some bacteria.
• Activation of vitamin D. The skin, liver, and kidneys participate in synthesizing the
active form of vitamin D.[7]
EXPERIMENTAL MODELS FOR HEPATOTOXICITY:
Animal models represent a major tool for the study of mechanisms in virtually all of
biomedical research [8]. They involve the complexity of the whole animal thus
making the monitoring of in vivo systems quite difficult. An in vivo system fully
reflects the exposing profile and the cellular function as the compounds are exposed
in the successive manner through absorption from the first exposed site followed by
metabolism, distribution, and elimination. However, it should involve basically the
same mechanism as the reactions in humans and the adverse effect must be
clinically sufficiently high. Both small animals like rats, mice, rabbits and guinea pigs,
as well as large animals like pigs, cattle, sheep and monkeys, are useful and reliable
for studying the hepato-toxic effects, distribution and clearance. They may be used
to elucidate the basic mechanism of xenobiotic activities, which will be useful in
understanding their impact on human health. However, the experimental model is a
roadmap for discovery of new molecular, noble signaling pathways for the
Paracetamol induced hepatotoxicity :
Paracetamol, a widely used analgesic and antipyretic drug, produces acute liver
damage in high doses. Paracetamol administration causes necrosis of the
centrilobular hepatocytes characterized by nuclear pyknosis and eosinophilic
cytoplasm, followed by large excessive hepatic lesion. The covalent binding of
N-acetyl-P-benzoquinoneimine, an oxidative product of paracetamol to sulfydryl groups
of protein, result in lipid peroxidative degradation of glutathione (GSH) level and
thereby, produces cell necrosis in the liver [11]. Hepatotoxicity was noted after
administration of paracetamol (500 mg/kg, orally) for 2 weeks in rats [12]
Galactosamine induced hepatotoxicity
Galactosamine produces diffuse type of liver injury simulating viral hepatitis. It
presumably disrupts the synthesis of essential uridylate nucleotides resulting in
organelle injury and ultimately cell death. Depletion of those nucleotides would
impede the normal synthesis of RNA and consequently would produce a decline in
protein synthesis. This mechanism of toxicity brings about an increase in the cell
membrane permeability leading to enzyme leakage and eventually cell death. The
cholestasis caused by galactosamine may be from its damaging effects on bile ducts
or ductules or canalicular membrane of hepatocytes galactosamine decrease the bile
flow and its content i.e. bile salts, cholic acid and deoxycholic acid. Galactosamine
reduces the number of viable hepatocytes as well as rate of oxygen consumption.
Hepatic injury is induced by intraperitoneal single dose injection of D-galactosamine
(800 mg/kg) [13]
Thioacetamide induced hepatotoxicity
Thioacetamide interferes with the movement of RNA from the nucleus to the
(perhaps s-oxide) is responsible for hepatic injury. Thioacetamide reduce the number
of viable hepatocytes as well as rate of oxygen consumption. It als o decreases the
volume of bile and its content, i.e. bile salts, cholic acid and deoxycholic acid.
Thioacetamide is oxidized to a reactive metabolite S-oxide which is responsible for
the amendment in cell permeability and the concentration of Ca2+ increases
intracellular in nuclear volume and also obstructs mitochondrial activity which clues
to cell death [14]. Administration of thioacetamide (200 mg/kg, i.p) thrice in a weekly
for 8 weeks to induced hepatotoxicity [13].
Carbon tetrachloride (CCl4) induced hepatotoxicity
CCl4 is metabolized by CYPs in endoplasmic reticulum and mitochondria with the
formation of CCl3O-, a reactive oxidative free radical, which initiates lipid
peroxidation. Administration of a single dose of CCl4 to a rat produces, within 24 hrs,
a centrilobular necrosis, and fatty changes. The poison reaches its maximum
concentration in the liver within 3 hrs of administration. Thereafter, the level falls and
by 24 hrs there is no CCl4 left in the liver. The development of necrosis is associated
with leakage of hepatic enzymes into serum [15]. It has been noted that
administration of dose (2 ml/kg, S.C.) of CCl4 for 2 days in rats showed significant
increase in serum glutamic pyruvic transaminase (SGPT), serum glutamic oxalacetic
transaminase (SGOT) levels which leads to hepatotoxicity [16].
Lead induced hepatotoxicity
Many metals play important roles in the functioning of the enzyme, cell-signaling
processes and gene regulation. Lead is a blue-gray and highly toxic divalent metal
that occurs naturally in the earth’s crust and is spread throughout the environment by
various human activities. Lead induced hepatic damage is mostly rooted in LPO and
species (ROS) [17]. Lead toxicity lead to free radical damage by two separate
pathway: (1) Generation of ROS, including hydro-peroxides, singlet oxygen, and
hydrogen peroxide and, (2) the direct depletion of antioxidant reserves. The cell
membrane is the main target of the oxidative damage produced by heavy metals.
This is mainly due to changes in polyunsaturated fatty acids having double bonds,
largely present in the phospholipids of membranes. Lead is known to produce
oxidative damage by enhancing per oxidation of membrane lipids, and LPO is a
deleterious process carried out by free radicals. LPO is an outcome of the chain of
events involving initiation, propagation, and termination reactions. GSH depletion is
another important mechanism of lead toxicity. GSH is a tri-peptide containing
cysteine with a reactive –SH group and reductive potency. It can act as a
nonenzymatic antioxidant by direct interaction of the –SH group with ROS, or it can
be involved in the enzymatic detoxification reaction for ROS as a cofactor. Lead bind
exclusively to the –SH group, which decreases the GSH level and can interfere with
the antioxidant activity of GSH [18]. Rats administered a single dose (20 mg/kg, i.p.)
of lead acetate revealed significant elevations of serum aspartate aminotransferase
(AST), alanine aminotransferase (ALT), acid phosphatase (ACP), lactate
dehydrogenase, cholesterol, triglyceride and bilirubin which caused hepatotoxicity
[19].
Alcohol-induced hepatotoxicity
Liver is among the organs most susceptible to the toxic effects of ethanol. Alcohol
consumption is known to cause fatty infiltration, hepatitis, and cirrhosis. Fat
infiltration is a reversible phenomenon that occurs when alcohol replaces fatty acids
in the mitochondria. Hepatitis and cirrhosis may occur because of enhanced lipid
peroxidative reaction during the microsomal metabolism of ethanol. Alcohol can
of an increase in hepatic lipid peroxidation, which may eventually affect cellular
functions results in loss of membrane structure and integrity. The effects of ethanol
can enhance the generation of free radicals during its oxidation in liver. These results
in elevated levels of glutamyl transpeptidase, a membrane bound enzyme in serum.
Ethanol inhibits GSH peroxidase, decrease the activity of catalase, superoxide
dismutase, along with an increase in levels of GSH in liver. The decrease in activity
of antioxidant enzymes superoxide dismutase, GSH peroxidase are speculated to be
due to the damaging effects of free radicals produced following ethanol exposure or
alternatively could be due to a direct effect of acetaldehyde, formed by oxidation of
ethanol [20]. It has been observed that the dose of alcohol (5 ml/kg, orally) for a
period of 4 weeks and increase in serum levels of ALT, and AST which leads to liver
damage in rats [5].
Anti-tubercular drugs induced hepatotoxicity
Drug-induced hepatotoxicity is a potentially serious adverse effect of the currently
used anti-tubercular therapeutic regimens containing isoniazid (INH), rifampicin and
pyrazinamide. Adverse effects of anti-tubercular therapy are sometimes potentiated
by multiple drug regimens. Thus, though INH, rifampicin and pyrazinamide each in
itself are potentially hepatotoxic, when given in combination, their toxic effect is
enhanced. INH is metabolized to monoacetyl hydrazine, which is further metabolized
to a toxic product by CYP450 leading to hepatotoxicity. Patients on concurrent
rifampicin therapy have an increased incidence of hepatitis. This has been
postulated due to rifampicin-induced CYP450 enzyme-induction, causing an
increased production of the toxic metabolites from acetyl hydrazine (AcHz).
Rifampicin also increases the metabolism of INH to isonicotinic acid and hydrazine,
both of which are hepatotoxic. The plasma half-life of AcHz (metabolite of INH) is
increasing the oxidative elimination rate of AcHz, which is related to the higher
incidence of liver necrosis caused by INH and rifampicin in combination. Rifampicin
induces hydrolysis pathway of INH metabolism into the hepatotoxic metabolite
hydrazine. Pharmacokinetic interactions exist between rifampicin and pyrazinamide
in tuberculosis patients, when these drugs are administered concomitantly.
Pyrazinamide decreases the blood level of rifampicin by decreasing its bioavailability
and increasing its clearance. Pyrazinamide, in combination with INH and rifampicin,
appears to be associated with an increased incidence of hepatotoxicity[21]. The
combined administration of the INH and rifampicin at the dose (50 mg/kg, orally) for
28 days caused hepatotoxicity in rats [22].
Allyl alcohol-induced hepatotoxicity
The toxicity of allyl alcohol is considered to be mediated via acrolein, which is
generated from allyl alcohol by the enzyme alcohol dehydrogenase. Acrolein is a
powerful electrophile and reacts with nucleophiles such as sulfydryl groups. The
reaction is accelerated by the activity of cytosolic GST to form an aldehyde-GSH
adducts, which are metabolized to acrylic acid. GSH is primarily involved in the
reaction, which result in a depletion of cellular GSH stores, followed by
hepatocellular necrosis. Allyl alcohol induces increase in SGOT, SGPT and total
bilirubin, whereas decrease in total protein. The rats treated with allyl alcohol shows
necrosis around branches of the central hepatic vein and presence of a large amount
of nuclear debris. It has been noted that the administration of a single dose (35
mg/kg, i.p.) of allyl alcohol in rats leads to increased liver weight associated with
Halothane induced hepatotoxicity
Halothane is chemically 2-bromo-2-chloro-1-1-trifluoroethane. It has been used
widely as an inhaled anesthetic and as liver toxicant in animal models. It is well
established that halothane is metabolized in the liver as a lipophilic xenobiotic to
hepatotoxic intermediates by monooxygenases through the CYP450-2E1 system.
Thus, halothane anesthesia causes hepatocellular necrosis, destruction of the
lipid-protein interactions in human erythrocyte membranes, decrease in activities of
membrane enzymes and alteration of cerebral glucose-6-phosphate dehydrogenase
activities. Halothane treated rat liver shows extensive centrilobular necrosis and
denaturation. Administration of halothane at dose (30 mmol/kg, i.p.) dissolved in 2 ml
of olive oil to female, and male rats lead to hepatotoxicity at 12 hrs after the
administration of drug [24].
Ranitidine induced hepatotoxicity
Liver injury induced by ranitidine is due to its metabolite which may lead to hepatic
oxidative damage, and one of its metabolite is generating the immunoallergic
reaction. It also produces a reaction as reflected by infiltration of hepatocytes.
Severe inflammatory changes with collagenous septa beginning to form after
pronounced centrilobular and bridging necrosis. In the parenchyma, there was focal
liver cell necrosis with some accumulation of histocytic elements and slight steatosis
and cholestasis. Portal tract shows fibrosis, bile duct proliferation and infiltrate
consisting of lymphocytes, plasma cells, polymorphs, and eosinophils. Liver injury is
manifested in terms of increase in levels of serum amino transferases, modest
hepatic infiltration by both lymphocytes and eosinophils and slight focal
hepatocellular necrosis also causes liver cholestasis associated with increased
dose (30 mg/kg, i.v.) leads to hepatotoxicity in rats increases in serum ALT and
serum AST activity. These changes reflect hepatotoxicity in rats [26].
Mercury induced hepatotoxicity
Human activities play a major role in polluting the environment by toxic and
carcinogenic metal compounds. These are evidences that these metals by
accumulating contaminates water sources and food chain with their compounds.
Mercury and its compounds are widely used in industries, and their hazards to
animals have been documented. Mercury is a transition metal, and it promotes the
formation of ROS such as hydrogen peroxides. These ROS enhance the peroxides
and hydroxyl radicals. These lipid peroxides and hydroxyl radical may cause cell
membrane damage and thus destroy the cell. Mercury also inhibits the activities of
the free radical quenching enzyme such as catalase, superoxide dismutase, and
GSH peroxidase. Mercury causes cell membrane damage like lipid per-oxidation,
which leads to the imbalance between synthesis and degradation of enzyme protein.
The excess production of ROS by mercury may be explained by its ability to produce
alteration in mitochondria by blocking the permeability transition pore. It has been
noted that after the administration of mercuric chloride (5 mg/kg, i.p.) for 20 days and
(2 mg/kg, orally) for 30 days induced hepatotoxicity in rats [27].
Liver Function Tests (LFTs)
Liver Function Tests (LFTs) are one of the most commonly-requested screening
blood tests. Whether for the investigation of suspected liver disease, monitoring of
disease activity, or simply as ‘routine’ blood analysis, these tests can provide a host
of information on a range of disease processes. The title ‘liver function tests’ is,
however, somewhat of a misnomer; only the bilirubin and albumin given in this panel
evaluation of liver enzymes simply gives information as to whether a patient’s
primary disorder is hepatitic or cholestatic in origin. However, much more may be
interpreted from these assays with knowledge of enzyme ratios and pattern
recognition. This paper offers an insight to generalists of how to yield greater
information from this simple test.[28]
Uses of liver functional tests:
The various uses of Liver function tests include:
Screening : They are a non-invasive yet sensitive screening modality for liver
dysfunction.
Pattern of disease : They are helpful to recognize the pattern of liver disease. Like
being helpful in differentiating between acute viral hepatitis and various cholestatic
disorders and chronic liver disease. (CLD).
Assess severity : They are helpful to assess the severity and predict the outcome
of certain diseases like primary biliary cirrhosis.
Follow up : They are helpful in the follow up of certain liver diseases and also helpful
in evaluating response to therapy like autoimmune hepatitis[29]
1. SERUM BILIRUBIN
Bilirubin is an endogenous anion derived from hemoglobin degradation from the
RBC. The classification of bilirubin into direct and indirect bilirubin are based on
the original van der Bergh method of measuring bilirubin. Bilirubin is altered by
exposure to light so serum and plasma samples must be kept in dark before
measurements are made. When the liver function tests are abnormal and the
Types of bilirubin
i. Total bilirubin: This is measured as the amount, which reacts in 30 minutes
after addition of alcohol. Normal range is 0.2-0.9 mg/dl (2-15µmol/L). It is
slightly higher by 3-4 µmol/L in males as compared to females. It is this
factor, which helps to diagnose Gilbert syndrome in males easily.
ii. Direct Bilirubin : This is the water-soluble fraction. This is measured by the
reaction with diazotized sulfanilic acid in 1 minute and this gives estimation
of conjugated bilirubin. Normal range 0.3mg/dl( 5.1µmol/ L)
iii. Indirect bilirubin: This fraction is calculated by the difference of the total
and direct bilirubin and is a measure of unconjugated fraction of
bilirubin.1,5 The diazo method of bilirubin estimation is not very accurate
especially in detecting low levels of bilirubin. Direct bilirubin over estimates
bilirubin esters at low bilirubin levels and under estimates them at high
concentration. Thus slight elevation of unconjugated bilirubin not detected,
which is of value in detecting conditions like Gilbert syndrome[31]
Alanine amino transferase (ALT)
ALT is found in kidney, heart, muscle and greater concentration in liver compared
with other tissues of the body. ALT is purely cytoplasmic catalysing the
transamination reaction. Normal serum ALT is 7–56 U/ L. Any type of liver cell injury
can reasonably increases ALT levels. Elevated values up to 300 U/L are considered
nonspecific. Marked elevations of ALT levels greater than 500 U/L observed most
often in persons with diseases that affect primarily hepatocytes such as viral
hepatitis, ischemic liver injury (shock liver) and toxin-induced liver damage. Despite
the association between greatly elevated ALT levels and its specificity to
with the extent of liver cell damage. Viral hepatitis like A, B, C, D and E may be
responsible for a marked increase in aminotransferase levels. The increase in ALT
associated with hepatitis C infection tends to be more than that associated with
hepatitis A or B. Moreover in patients with acute hepatitis C serum ALT is measured
periodically for about 1 to 2 years. Persistence of elevated ALT for more than six
months after an occurrence of acute hepatitis is used in the diagnosis of chronic
hepatitis. Elevation in ALT levels are greater in persons with non-alcoholic
steatohepatitis than in those with uncomplicated hepatic steatosis. In a recent study
the hepatic fat accumulation in childhood obesity and nonalcoholic fatty liver disease
causes serum ALT elevation. Moreover increased ALT level was ass ociated with
reduced insulin sensitivity, adiponectin and glucose tolerance as well as increased
free fatty acids and triglycerides. Presence of Bright liver and elevated plasma ALT
level was independently associated with increased risk of the metabolic syndrome in
adults. ALT level is normally elevated during 2nd trimester in asymptomatic normal
pregnancy. In one of the study, serum ALT levels in symptomatic pregnant patients
such as in hyperemesis gravidarum was 103.5U/L, in pre-eclampsia patients was
115U/L and in haemolysis with low platelet count patients showed 149U/L. However
in the same study ALT rapidly drops more than 50% of the elevated values within 3
days indicating the improvement during postpartum. One of the recent study has
shown that coffee and caffeine consumption reduces the risk of elevated serum ALT
activity in excessive alcohol consumption, viral hepatitis, iron overload, overweight,
and impaired glucose metabolism[32]
Aspartate amino transferase (AST)
AST catalyse transamination reaction. AST exist two different isoenzyme forms
which are genetically distinct, the mitochondrial and cytoplasmic form. AST is found
liver, skeletal muscle and kidney. Normal serum AST is 0 to 35U/L. Elevated
mitochondrial AST seen in extensive tissue necrosis during myocardial infarction and
also in chronic liver diseases like liver tissue degeneration and necrosis. About 80%
of AST activity of the liver is contributed by the mitochondrial isoenzyme, whereas
most of the circulating AST activity in normal people is derived from the cytosolic
isoenzyme. However the ratio of mitochondrial AST to total AST activity has
diagnostic importance in identifying the liver cell necrotic type condition and alcoholic
hepatitis. AST elevations often predominate in patients with cirrhosis and even in
liver diseases that typically have an increased ALT. AST levels in symptomatic
pregnant patient in hyperemesis gravidarum were 73U/L, in pre-eclampsia 66U/L,
and 81U/L was observed in hemolysis with low platelet count and elevated liver
enzymes[32]
Alkaline phosphatase (ALP)
ALP is present in mucosal epithelia of small intestine, proximal convoluted tubule of
kidney, bone, liver and placenta. It performs lipid transportation in the intestine and
calcification in bone. The serum ALP activity is mainly from the liver with 50%
contributed by bone. Normal serum ALP is 41 to 133U/L. In acute viral hepatitis, ALP
usually remains normal or moderately increased. Elevation of ALP with prolonged
itching is related with Hepatitis A presenting cholestasis. Tumours secrete ALP into
plasma and there are tumour specific isoenzymes such as Regan, Nagao and
Kasahara. Hepatic and bony metastasis can also cause elevated levels of ALP.
Other diseases like infiltrative liver diseases, abscesses, granulomatous liver
disease and amyloidosis may cause a rise in ALP. Mildly elevated levels of ALP may
be seen in cirrhosis, hepatitis and congestive cardiac failure. Low levels of ALP
occur in hypothyroidism, pernicious anaemia, zinc deficiency and congenital
asymptomatic normal pregnancy showing extra production from placental tissue.
ALP levels in hyperemesis gravidarum were 21.5U/L, in pre-eclampsia 14U/L, and
15U/L in haemolysis with low platelet count was seen during symptomatic
pregnancy. Transient hyperphosphataemia in infancy is a benign condition
characterized by elevated ALP levels of several folds without evidence of liver or
bone disease and it returns to normal level by 4 months. ALP has been found
elevated in peripheral arterial disease, independent of other traditional
cardiovascular risk factors. Often clinicians are more confused in differentiating liver
diseases and bony disorders when they see elevated ALP levels and in such
situations measurement of gamma glutamyl transferase assists as it is raised only in
DRUG PROFILE
PARACETAMOL
PARACETAMOL
Paracetamol, also known as acetaminophen or APAP, is a medication used to
treat pain and fever. It is typically used for mild to moderate pain. There is poor
evidence for fever relief in children. It is often sold in combination with other
ingredients such as in many cold medications. In combination with opioid pain
medication, paracetamol is used for more severe pain such as cancer pain and after
surgery. It is typically used either by mouth or rectally but is also
available intravenously. Effects last between two and four hours.
Paracetamol is generally safe at recommended doses. Serious skin rashes may
rarely occur. Too high a dose can result in liver failure. It appears to be safe
during pregnancy and when breastfeeding. In those with liver disease, it may still be
mild analgesic. It does not have significant anti-inflammatory activity and how it
works is not entirely clear.
Paracetamol was discovered in 1877. It is the most commonly used medication for
pain and fever in both the United States and Europe. It is on the WHO Model List of
Essential Medicines, the most important medications needed in a basic health
system. Paracetamol is available as a generic medication with trade names
including Tylenol and Panadol among others. The wholesale price is less than 0.01
USD per dose. In the United States it costs about 0.04 USD per dose.
Medicinal uses
Fever
Paracetamol is used for reducing fever in people of all ages The World Health
Organization (WHO) recommends that paracetamol be used to treat fever in children
only if their temperature is greater than 38.5 °C (101.3 °F). The efficacy of
paracetamol by itself in children with fevers has been questioned and a
meta-analysis showed that it is less effective than ibuprofen.
Pain
Paracetamol is used for the relief of mild to moderate pain. The use of the
intravenous form for pain of sudden onset in people in the emergency department is
supported by limited evidence.
Osteoarthritis
The American College of Rheumatology recommends paracetamol as one of several
treatment options for people with arthritis pain of the hip, hand, or knee that does not
improve with exercise and weight loss. A 2015 review, however, found it provided
Paracetamol has relatively little anti-inflammatory activity, unlike other common
analgesics such as the NSAIDs aspirin and ibuprofen, but ibuprofen and
paracetamol have similar effects in the treatment of headache. Paracetamol can
relieve pain in mild arthritis, but has no effect on the underlying inflammation,
redness, and swelling of the joint. It has analgesic properties comparable to those of
aspirin, while its anti-inflammatory effects are weaker. It is better tolerated than
aspirin due to concerns with bleeding with aspirin.
Low back pain
Based on a systematic review, paracetamol is recommended by the American
College of Physicians and the American Pain Society as a first-line treatment for low
back pain. However other systematic reviews concluded that evidence for its efficacy
is lacking.
Headaches
A joint statement of the German, Austrian, and Swiss headache societies and the
German Society of Neurology recommends the use of paracetamol in combination
with caffeine as one of several first line therapies for treatment of tension or migraine
headache. In the treatment of acute migraine, it is superior to placebo, with 39% of
people experiencing pain relief at 1 hour compared to 20% in the control group.
Postoperative pain
Paracetamol, when combined with NSAIDs, may be more effective for treating
postoperative pain than either paracetamol alone or NSAIDs alone.
Other
The efficacy of paracetamol when used in combination with weak opioids (such
number experiencing side effects. Combination drugs of paracetamol and strong
opioids like morphine improve analgesic effect.
The combination of paracetamol with caffeine is superior to paracetamol alone for
the treatment of common pain conditions including dental pain, postpartum pain, and
headache.
Adverse Effects:
Healthy adults taking regular doses of up to 4,000 mg a day show little evidence of
toxicity (although some researchers disagree). They are more likely to have
abnormal liver function tests, but the significance of this is uncertain.
Liver damage
Acute overdoses of paracetamol can cause potentially fatal liver damage. In 2011
the US Food and Drug Administration launched a public education program to help
consumers avoid overdose, warning: "Acetaminophen can cause serious liver
damage if more than directed is used. In a 2011 Safety Warning the FDA
immediately required manufacturers to update labels of all prescription combination
acetaminophen products to warn of the potential risk for severe liver injury and
required such combinations contain no more than 325 mg of acetaminophen (within
3 years). FDA has likewise requested prescribers limit combination opioids to
325 mg of acetaminophen. Such overdoses are frequently related to high
dose recreational use of prescription opioids as these opioids are most often
combined with acetaminophen. The overdose risk may be heightened by frequent
consumption of alcohol.
Paracetamol toxicity is the foremost cause of acute liver failure in the Western world,
and accounts for most drug overdoses in the United States, the United Kingdom,
"56,000 emergency room visits, 26,000 hospitalizations, and 458 deaths per year
related to acetaminophen-associated overdoses during the 1990s. Within these
estimates, unintentional acetaminophen overdose accounted for nearly 25 percent of
the emergency department visits, 10 percent of the hospitalizations, and 25 percent
of the deaths.
Paracetamol is metabolised by the liver and is hepatotoxic; side effects are multiplied
when combined with alcoholic drinks, and are very likely in chronic alcoholics or
patients with liver damage. Some studies have suggested the possibility of a
moderately increased risk of upper gastrointestinal complications such as stomach
bleeding when high doses are taken chronically. Kidney damage is seen in rare
ETHANOL
Properties
Chemical formula
C2H6O
Molar mass 46.07 g/mol
Appearance Colorless liquid
Density 0.789 g/cm3 (at 20°C)
Melting point −114 °C (−173 °F; 159 K)
Boiling point 78.37 °C (173.07 °F;
351.52 K)
Solubility in water
miscible
log P −0.18
Vapor pressure 5.95 kPa (at 20 °C)
Acidity (pKa) 15.9 (H2O), 29.8 (DMSO)[2][3]
Basicity (pKb) −1.9
Refractive index(nD)
1.361
Viscosity 1.2 mPa·s (at 20 °C), 1.074
mPa·s (at 25 °C)[4]
[image:44.595.78.350.65.555.2]Dipole moment 1.69 D[5]
Table No:1
Ethanol also commonly called alcohol, ethyl alcohol, and drinking alcohol, is the
principal type of alcohol found in alcoholic beverages, produced by
the fermentation of sugars by yeasts. It is a neurotoxic, psychoactive drug, and one
of the oldest recreational drugs. It can cause alcohol intoxication when consumed in
sufficient quantity.
Ethanol is a volatile, flammable, colorless liquid with a slight chemical odor. It is used
as an antiseptic, a solvent, a fuel, and due to its low freezing point, the active fluid in
group linked to ahydroxyl group. Its structural formula, CH3CH2OH, is often
abbreviated as C2H5OH, C2H6O or EtOH.
The stem word "eth-" used in many related compounds originates with the German
word for ethanol (äthyl).
Medical uses
Antiseptic
Ethanol is used in medical wipes and in most common antibacterial hand
sanitizer gels at a concentration of about 62% v/v as an antiseptic. Ethanol kills
organisms by denaturing their proteins and dissolving their lipids and is effective
against most bacteria and fungi, and many viruses. Ethanol is ineffective against
bacterial spores.
Antitussive
Ethanol is widely used, clinically and over the counter, as an antitussive agent.
Antidote
Ethanol may be administered as an antidote to methanol and ethylene
glycol poisoning.
Medicinal solvent
Ethanol, often in high concentrations, is used to dissolve many water-insoluble
medications and related compounds. Proprietary liquid preparations of cough and
cold remedies, analgesics, and mouth washes may be dissolved in 1 to 25%
concentrations of ethanol and may need to be avoided in individuals with adverse
Recreational
Ethanol is a central nervous system depressant and has significant psychoactive
effects in sublethal doses. Based on its abilities to alter human consciousness,
ethanol is considered a psychoactive drug.
The amount of ethanol in the body is typically quantified by blood alcohol
content (BAC), which is here taken as weight of ethanol per unit volume of blood.
Small doses of ethanol, in general, produce euphoria and relaxation; people
experiencing these symptoms tend to become talkative and less inhibited, and may
exhibit poor judgment. At higher dosages (BAC > 1 g/L), ethanol acts as a central
nervous system depressant, producing at progressively higher dosages, impaired
sensory and motor function, slowed cognition, stupefaction, unconsciousness, and
possible death. Ethanol is commonly consumed as a recreational drug, especially
SILYMARIN:
Silibinin (INN), also known as silybin (both from Silybum, the generic name of
the plant from which it is extracted), is the major active constituent of silymarin, a
standardized extract of the milk thistle seeds, containing a mixture
of flavonolignans consisting of silibinin, isosilibinin, silicristin, silidianin, and others.
Silibinin itself is mixture of two diastereomers, silybin A and silybin B, in
approximately equimolar ratio.[1] The mixture exhibits a number of pharmacological
effects, particularly in the liver, and there is some clinical evidence for the use of
silibinin as a supportive element in alcoholic and child grade 'A' liver cirrhosis.
Formula- C25H22O10
Molar mass-482.44 g/mol
Pharmacology:
Poor water solubility and bioavailability of silymarin led to the development of
enhanced formulations. Silipide (trade name Siliphos), a complex of silymarin
and phosphatidylcholine (lecithin), is about 10 times more bioavailable than
silymarin. An earlierstudy had concluded Siliphos to have 4.6 fold higher
-cyclodextrin is much more soluble than silymarin itself. There have also been
prepared glycosides of silybin, which show better water solubility and even stronger