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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.

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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

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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.,

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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.,

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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.,

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“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.

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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.

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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]
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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

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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

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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

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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

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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

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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

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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

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(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

(28)

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

(29)

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

(30)

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

(31)

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

(32)

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

(33)

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

(34)

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

(35)

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

(36)

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

(37)

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

(38)

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

(39)

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

(40)

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

(41)

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,

(42)

"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

(43)

ETHANOL

(44)

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

(45)

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

(46)

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

(47)

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

(48)

-cyclodextrin is much more soluble than silymarin itself. There have also been

prepared glycosides of silybin, which show better water solubility and even stronger

Figure

Fig No: 1
Table No:1
Fig No: 2
Fig No: 3
+7

References

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