Gross Anatomy Hepatic Lobes Biology Essay


Hepatic cells secrete bile that empties into bile canaliculus and then into tributary of bile duct.Small bile ducts are formed by union of tributaries of bile ducts from canaliculi of neighbouring lobules.Small bile ducts join together to form left and right hepatic ducts which emerge out of liver. And finally bile flows to main bile duct and gallbladder to be available for process of digestion in intestine.SINUSOIDS:

A blood space called Sinusoid is present in between neighbouring plates.sinusoids are approximately 8 - 10 micrometer in diameter.Sinusoids are oriented in radial direction in a lobule. Sinusoid is lined by endothelial cells and kupffer cells are presnt in between endothelial cells. When blood flows through sinusoids and space of disse towards central vein ,hepatocytes process and store the nutrients and worn out blood cells and bacteria are engulfed by kupffer cells.The direction of bile flow is opposite to direction of blood flow through sinusoids.


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Following types of ccells are present in liver

Hepatocytes,Kupffer cells,Sinusoidal endothelial cells,Bile duct epithelial cells and Hepatic stellate cells.


Hepatocytes constitutes 60 percent of liver s cells and 80 percent of liver s total cell mass (Heuman,et al,pg.159).Most of synthetic and metabolic functions of liver are performed by hepatocytes.Hepatocytes are arranged in plates which are single cell thick.Blood flowing towards hepatic vein passes through surface areas of hepatic plates and hepatocytes extract toxins and nutrients from blood.Bile production is one of important function of hepatocyte that averages about 15 mg/kg/day in humans(Jones and Spring- Mills ,1983).Normally 15 percent of cell volume is copmosed of smooth and rough endoplasmic reticulum and about 30 lysosomes and 500 peroxisomes are present per cell(Bloom and Fawcett,1975;Jones and Spring-Mills,1983;MacSween et al.,2002).


Kupffer cells are macrophages present in sinusoids.Kupffer cells constitute 15 percent of liver cells and produced from circulating monocytes(Jones and Spring-Mills,1983;MacSween et al.,2002;Bykov et al.,2004).kupffer cells clear out old red blood cells and bacteria.they also break down heme(iron containing pigment in heamoglobin) into bilirubin ,one of chief pigments of bile.The characteristic brown colour of faeces is due to later by product of bilirubin.


Sinusoidal endothelial cells are fenestrated(latin for windows) ,means they have large pores These cells are barrier between blood and hepatocytes and filter fluids, solutes and particles between blood and space of disse (Braet and Wisse,2002;Smedsrod,2004)SEC s can transfer particles by endocytosis due to fenestrae(Braet and Wisse,2002).Due to these pores proteins pass freely through sinusoidal endotheliun into space of disse and proteins then come in contact with hepatocytes.the pores are also bi directionl meaning protiens produced by liver and also other substances that are processed and stored by liver can also b passed back in blood. Fenestrae alterations play important role in diseases as atherosclerosis,cirrhosis and implantation of tumor metases(Braet and Wisse,2002;Smedsrod,2004)


These cells line interlobular bile ducts within portal triads. Biliary epithelium helps in conducting bile flow, it also modifies canalicular bile and concentrates bile in gallbladder.


These cells are present in space of Disse and constitute 5 percent of liver cells and were previously called Ito or fat storing cells. these cells play an important role in regeneration, hepatic fibrogenesis and cirrhosis(Ratziu and Friedman,19997;Fehrenbach et al.,2001;Albanis et al .,2003;Kawada,2004;mabuchi et al.,2004).HSC store and metabolise vitamin A and lipid and normally produce extracellular matrix.


METABOLIC FUNCTIONS: Liver cause metabolism of protiens,carbohydrates ,fats vitamins and hormones.


Liver stores many substances like glycogen,amino acids ,iron,folic acids and vitamind A,B 12 and D.


Liver produce glucose by gluconeogenesis.Plasma proteins and many other proteins (except immunoglobulins) as clotting factors,complement factors and hormone binding proteins are also synthesized by also synthesize steroids ,somatomedin and heparin.Liver can both synthesize cholestrol and remove it from body.Liver can also synthesize non essential amino acids when needed by body.


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Bile secretion is an imortant function of liver,and bile contains bile salts ,bile pigments,cholestrol,fatty acids and lecithin.Bile helps in digestion of fats in small intestine by breaking down fats in smaller components.Bile also helps in removing wastes including bilirubin,cholestrol and toxins.


Liver also excretes cholesterol, bile pigments, heavy metals (lead, arsenic), various toxins, bacteria and virus like yellow fever through bile


Due to various metabolic reactions, heat is also produced in liver.


Kupffer cells destroy senile RBECAUSEs after life span of 120 days.


Liver produces blood cells in foetus during hepatic stage.Liver also produces thromboprotein that is necessary for thrombocytes production.Liver stores vit B12 that is necessary for erythropoiesis and iron that synthesize haemoglobin.


Various types of hormones such as growth hormones,insulin,glucagon,cortisol Parathormone are catabolised by liver.Liver also inactivates drugs particularly Fat soluble drugs by converting them into water soluble substances which are excreted through bile or urine.



Five types of tests are commonly called liver function tests including Alanine aminotransferase(ALT or SGPT),Aspartate aminotransferase(AST or SGOT),Gammaglutamyl transferase(GGT),Alkaline phosphotase(ALP),Bilirubin.In majority cases LFTs indicates injury of liver cells(ALT and AST),or bile flow interruption or cholestasis (ALP or GGT),but dereased activity of liver cells is indicated by bilirubin.


Both Alanine aminotransferase(ALT) and Aspartate aminotransferase(AST) enzymes are present within cells of liver.These enzymes are released in circulation when hepatocytes die or are damaged,then they can be measured in circulation.Thus act as marker of liver injury.Both enzymes are differently distributed within hepatocytes.

The concentration of ALT is highest in hepatocytes but is also present in kidney,lung,pancreas,red blood cells and skeletal muscles.ALT is relatively specific indicator for dysfunctioning of hepatocytes.The cytoplasm of hepatocytes contains ALT.(Aranda-Michel J and Sherman KE,1998)

In addition to liver AST is also found in heart,brain,skeletal muscles and kidney.AST is not considered specific indicator for hepatocellular injury because its distribution is more than ALT.Both cytoplasm and mitochondria of hepatocytes contains AST.20 percent of total enzyme activity is cytosolic and 80 percent of total enzyme activity is mitochondrial.(Rejj R).

AST is highly concentrated in zone 3 of hepatic acinus,and AST level is highly altered ,if ischemic or toxic damage occur to this zone.Sinusoidal cells of liver carry out clearance of AST(Kamimoto y).

Plasma half life of AST is 16-18 hrs and ALT is 42-48 hrs,half life of mitochondrial AST is 87 hrs,.So upper reference limit for AST is 55U/L and ALT is 45 U /L.

The alteration in aminotransferases can be "MILD",MODERATE"or 'MARKED'

'MILD' alteration indicates < 5 times the upper reference limit

'MODERATE' alteration indicates 5-10 times the upper reference limit

'MARKED' alteration indicates >10 times the upper reference limit.(1 24 25)

Normally ALT level is high in obese individuals.but in case of fatty liver,hepatitis particularly hepatitis C ALT level is also highly elevated.

AST level is not effected by obesity.In case of chronic hepatitis,alcoholic hepatitis,acute viral hepatitis,cirrhosis and toxic ischemic injury ,level of both ALT and AST can be increased.Marked alteration in aminotransferases is observed in acute hepatitis and paracetamol induced hepatitis.In case of alcoholic hepatitis ratio of ALT/AST is 2:1 and value of Gamma glutamyl transpeptidase(GGT) is twice than normal(Green RM, Flam S .AGA),

The different diseased condition can be differentiated by ALT/AST ratio ,in hepatitis C with cirrhosis,liver metases and HCV with cirrhosis high value of ALT /AST is observed ,but in acute inflammation and cholestasis low ALT /AST value is observed.(Hughes j,Jefferson A).


ALP is present in the liver, bone, kidney, intestine and placenta. Serum ALP comprises of various ALP isoenzymes . In normal serum, ALP from liver and bones are present. Bone ALP is heat labile. Liver ALP is rasied in any type of destruction , whether intrahepatic or extra hepatic. (Clementine YF Yap and Tar Choon Aw,2010)

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Alkaline phosphatases belongs to family of zinc metaloenzymes, with a serine group present at active center. In liver, alkaline phosphatase is pesent in the microvilli of bile canaliculi and on the sinusoidal surface of hepatocytes. Alkaline phosphatase from the liver, bone and kidney belongs to same gene but that from intestine and placenta belongs to different genes.( B.R. Thapa and Anuj Walia,2007).

Normal serum ALP is 30-120 UI/L.

.AlP transport lipids in intestine and cause calcification of bone.( M Adak and J N Shivapuri,2010)

In liver two distinct types of alkaline phosphatase are also present but their exact functions are unknown.

Average values of alkaline phosphatase vary with age and are relatively high in childhood and puberty and lower in middle age and higher again in old age. Males usually have higher values of ALP as compared to females.

Alkaline phosphatases reaches to highest value in cholestatic disorders.

The mechanism by which alkaline phosphatase enters the circulation is not confirmed; One hypothesis is that it may leak from the bile canaliculi into hepatic sinusoids through tight junctions. and the other hypothesis is that the in case of obstruction to liver,it does nt excrete alkaline phosphatase made in bone, intestine and liver.

Elevated serum levels of intestinal alkaline phosphatase have been found in patients with cirrhosis, particularly those with blood group type O,and In case of acute viral hepatitis, alkaline phosphatase is usually either normal or moderately increased.Marked elevation of ALP occur in case of Hepatitis

Metastasis in liver and bone can also cause raise levels of alkaline phosphatase. Other diseases like infiltrative liver diseases, abscesses, granulomatous liver disease and amyloidosis may also cause a elevation in alkaline phosphatase. Mildl rise in level of alkaline phosphatase may be seen in cirrhosis and hepatitis of congestive cardiac failure.

Low levels of alkaline phosphatase occur in hypothyroidism, pernicious anemia, zinc deficiency and congenital hypophosphatasia. Wilson's disease complicated by hemolysis and FHF may also have very low levels of alkaline phosphatase. This might be the result of replacement of cofactor zinc by copper and subsequent inactivation of alkaline phosphtase.

Drugs like cimetidine, frusemide, phenobarbitone and phenytoin usually raise levels of alkaline phosphtase.( B.R. Thapa and Anuj Walia,2007).

Serum ALP can also be raised in third trimester of pregnancy and half life of ALP in circulation is one week(Dufour DR et al.,2000)


Bilirubin is formed by enzymatic breakdown of haemoglobin in reticuloendothelial system.

Uncojugated and Conjugated bilirubin are two important types of bilirubin..Unconjugated bilirubin is then transported to liver,where it conjugates with glucuronic acid by UDP glucuronyl transferase to form conjugated bilirubin,which is excreted in bile.(  Edoardo G.Giannini et al.,2005)

Serum bilirubin is a mixture of alpha(unconjugated),beta(singly conjugated),gamma(doubly conjugated) and gamma fragments(covalently bound to albumin).

Direct and Indirect bilirubin are also two important types of bilirubin,Direct bilirubin is conjugated bilirubin but Indirect bilirubin is obtained from difference of total bilirubin and direct bilirubin.

Normal range of total bilirubin is (2-21micromoles/litres) and normal range of direct bilirubin is less than 8 micromoles/litres and indirect bilirubin is less than 12micromoles/litres.

During liver diseases srum bilirubin level is more than 17 micromoles/litres and abnormal Lab tests are observed when its level is above 24micromoles/litres..During jaundice bilirubin is visible in sclera ,mucous membrane and skin and blood level of bilirubin is 24 micromoles/litres.(Shivaraj Gowda et al.,2009)

The level of unconjugated bilirubin is increased due to increased production and impaired uptake but conjugated bilirubin is increased when its excretion is disturbed or conjugated and un conjugated bilirubin is regurgitated.( Thapa BR and Walia A,2007)

Serum bilirubin is helpful in differentiating different causes of jaundice.For example unconjugated bilirubin is increased in prehepatic jaundice but during post hepatic jaundice conjugated bilirubin is increased.unconjugated bilirubin is increased in hemolysis,gilbert s syndrome,hematoma reabsorption,ineffective erythropoiesis.Conjugated bilirubin is increased during bile duct obstruction,hepatitis,cirrhosis,autoimmune cholestatic disease.(Edoardo G.Giannini et al.,2005)

Unconjugated bilirubin is increased mostly during Gilbert s syndrome and hemolysis.The enzyme that conjugates bilirubin is partially altered during Gilbert s syndrome.

(Clifton P. Titcomb and Jr, MD,2003).

Salicylates,sulphonamides,free fatty acids usually displaces bilirubin from plasma albumin,so increases serum bilirubin level.(Thapa BR and Walia A,2007).

In normal asymptomatic pregnant women conjugated bilirubin is decreased during second and third trimester but total and free bilirubin level remain lowered during all three trimesters.A recent study has shown that neurologic damage due to stroke may be protected due to high level of serum total bilirubin(Shivaraj Gowda et al.,2009)


Lactate dehydrogenase (LDH) is a cyto plasmatic enzyme present in almost all important organs. . LDH present in extraceelullar tissue usually detect cell damage. LDH is released into the peripheral blood after cell death caused by various conditions as ischaemia, excess heat or cold, starvation, dehydration, injury.

Biochemistry and physiology OF LDH

Lactate dehydrogenase enzyme catalyses the oxidation of L-lactate to pyruvate and hydrogen is transferred to nicotinamide adenine dinucleotide (NAD)+ .the final step in the metabolic chain of anaerobic glycolysis. The reaction is reversible.

LDH, pH 8.8-9.8

L-lactate + NAD+ ← Pyruvate + NADH + H+

pH 7.4-7.

There are five isoenzymes of LDH as LDH-1,LDH-2,LDH-3,LDH-4,LDH-5.

Tissue activities of LDH and its isoenzymes

LDH is present only in the cytoplasm of the cell . LDH is present in brain, kidney, liver, lung, lymph nodes, myocardium, skeletal muscle, spleen, erythrocytes, leucocytes, and also platelets . LDH level in tissues is high as compared to serum.Leakage of LDH from damaged tissue even smaller one raises serum level of LDH.

LDH- 1 and LDH-2 isoenzymes are high in myocardium,kidney and RBECAUSEs. In liver and skeletal muscle, level of LDH-4 AND LDH-5 isoenzymes is higher.( M. Drent et al.,1996)

LDH measures extent of tissue damage..


A typical range is 105 - 333 IU/L (international units per liter).


may indicate:


Cerebrovascular diseases as stroke,heart attack

Hemolytic Anemia

Infectious mononucleosis

Liver disease for example hepatitisLow B.P

Muscle injury

New abnormal tissue formation (usually cancer)


Drugs that can increase LDH levels include anesthetics, aspirin, clofibrate, fluorides, mithramycin, narcotics, and procainamide.

Other conditions that also increase LDH level include :

Anemia of vit B12 deficiency

Leukemia or lymphoma

Megaloblastic anemia




Autoimmune hepatitis is inflammation of liver with unknown cause.Histologically signs of hepatitis are present.,showing hypergammaglobulinemia and autoantibodies.It is nt a viral disease and is nt associated with any risk factor.






Antinuclear antibodies or smooth muscles antibodies are present in this type.Onset of this disease at all ages.The target autoantigen of this type is unknown.Antinuclear antibodies and smooth muscles antibodies are neither pathogenic nor disease specific,but their full characterization is important.Smooth muscles antibodies possess activity against actin and non actin components such as tubulin,desmin and skeleton.Antiactin antibodies are present in patients with smooth muscles antibodies ,in whom disease occur at early age and these patients show a poor response to corticosteroid therapy.Perinuclear anti neutrophil cytoplasmic antibodies and antibodies to asiaglycoprotein receptors are also present in this disease.


Anti LKM 1( antibodies to liver kidney microsome type 1) are present in this type.Anti LKM1 react with proximal tubules of murine kidney and cytoplasm of murine liver.Onset of this disease occur in children with 2-14 yrs age.Target autoantigen has been defined in this disease.this disease occur in those patients who already have high incidence of autoimmune diseases like type 1 diabetes mellitus and autoimmune thyroiditis and who have organ specific autoantibodies such as antibodies to parietal cells,islet of Langerhans and thyroid.


This is least developed form of autoimmune hepatitis.Anti SLA/LP (antibodies to soluble liver antigen or liver pancreas) are present in this type.Onset of this type occur at all ages.tRNP is autoantigen.Corticosteriods are used for its treatment.


Two mechansims have been proposed.Cell mediated cytotoxicity occur through differentiation of Activated CD4 helper T cells into cytotoxic T lymphocytes.Destruction of liver cells occur through release of lymphokines.

Cell mediated antibody dependent cytotoxicity also occur,plasma cells release IgG antibodies that form antigen antibodies complex on liver cell membrane surface.Fc receptors of natural killer cells target this antigen antibody complex and cytolysis occur.



Immunity play an important role in pathogenesis of viral hepatitis,because viral infection control,healing,transformation from acute to chronic infection and liver cirrhosis is also dependent on it.Acute or chronic hepatitis C is caused by HCV which is a non cytopathic hepatotrop virus.Interaction between HCV and host immune response effect the prognosis and evolution of infection.HCV RNA can

Be detected in serum after one to two weeks of exposure,then it replicates quickly reaching a serum level of 10 6 copies per ml.Initial peak of viral replication is followed by a period of 4 to 6 weeks ,during this period HCV RNA either slightly elevate or remain stable,HCV B and T lymphocytes liver inflammation does nt occur during this period.After 2 to 8 weeks of exposure serum aminotransferase level begin to rise ,reaching maximum level of 8 to 12 weeks,when maximum level is reached ,level of HCV RNA is diminished.Anti HCV antibodies are present either when aminotransferases level is maximum,later or nt at all.antibodies level fall down after viral clearance and it takes more time than serum clearance.this is nt confirmed at present whether HCV is completely eradicated.


Differentiation between acute and chronic infection is still problematic due to non specific diagnostic tests and currently used serum markers.


Core antigen determination is important test for diagnosing HCV infection.core antigen can be detected and quantified in serum using EIA test.Core antigen level in pg/ml is correlated with HCV RNA level and 1pg/ml core antigen is equal to 8000IU/ml HCV RNA with small variations among patients.


serum conversion is also important method for diagnosing HCV infection. In patients with impaired immunity detect able level of anti HCV antibodies is nt this case HCV infection is confirmed by RT-PCR (reverse transcriptase polymerase chain reaction).If anti HCV antibodies are nt present ,but infection is highly suspected then HCV-ARN assessment must be done.

Anti HCV serum conversion with positive HCV -RNA test and highly raised aminotransferase level are best indicators of HCV infection.Raised aminotransferase level and HCV -RNA is detectable in serum after 7-14 days of exposure and antibodies are present in serum after 4-10 weeks.


Monotherapy with pegylated interferon (1.5microgram/kg) for 24 weeks has similar effect as produced by standard interferon treatment.

High doses of interferon can produce better response as compared to therapeutic regimen in which interferon is used 3 times a week.Regimens used contain standard alpha2b interferon 5MU on daily basis for 4 weeks ,afterit is 5MU 3 times per week for 20 weeks.


Hepatitis B is also cause of chronic hepatitis ,cirrhosis,carcinoma of liver cells.Mostly Hepatitis B occur due to sexual activity,misuse of drugs.HBV is present in serum in concentration of 10 8 to 10 10 virions per milliliter.HBV is also present in saliva,cervical secretions,semen,leukocytes.

HBV belong to hepadnavirus family.HBV is partially double stranded circular DNA.The presence of HBV DNA in serum can be detected by hybridization method or polymerase chain reaction.Antibody to HbsAg can be detected in patients who recovered from acute hepatitis B or those immunized with HBV vaccine,but is nt detected in patients who recovered fully from infection.


Cirrhosis is the end stage of liver disease in which the liver becomes scarred with passage of time. It is diagnosed based on physical findings as well as a microscopic examination of liver tissue from a biopsy (tissue sample) or evidence from other diagnostic tests such as ultrasound. Under the microscope, cirrhosis appears as fibrous bands (made up of fibers) that divide the liver into nodules (small knots or collections of tissue). , Cirrhosis interferes with the function of the liver ,causing liver failure or liver cancer.


Hepatitis B or C infection

• Autoimmune liver diseases, like autoimmune hepatitis,primary biliary cirrhosis

• Nonalcoholic fatty liver disease, often observed in obese individuals who do not intake alcohol. .

• Hereditary metabolic liver diseases, such as hemochromatosis (iron overload), Wilson disease (copper overload), and 1-antitrypsin deficiency (inability to make a type of protein)

• Long-term intake of alcohol can also cause cirrhosis.


Jaundice or yellowing of skin occur because of disruption in bile and bilirubin processing.

• Palmar erythema (redness of the palms), spider angiomas (blood vessels that spread out in a spider shape), gynecomastia (breast enlargement in men), decreased body hair, and shrinking of the testicles may occur.

•Spontaneous bleeding can also occur because liver can not produce clotting factors.

• With progression of disease ,blood can not pass through vessels of liver easily ,resulting in portal hypertension,so the formation of esophageal varices (enlarged veins in the esophagus) that can bleed easily.

• Portal hypertension and low albumin levels cause ascites (accumulation of fluid in the abdominal space) and edema (water retention leading to swelling in dependent areas).

• As the liver fails, toxins are not removed from body,so hepatic encephalopathy develop. (Ann R.Punnose et al.,2012).


AST and ALT Often normal or moderately elevated

ALP Elevated <3-fold

Bilirubin Elevated later than GGT and ALP

Albumin Decreased in advanced cirrhosis Prothrombin time Decreased in advanced cirrhosis Thrombocytes and leukocytes Thrombocytopenia (Leukopenia) (. (Detlef Schuppan and Nezam H. Afdhal ,2008)

Pathogenesis and Pathophysiology of Cirrhosis

Liver fibrosis results from the prolongation of the normal wound healing response resulting in abnormal connective tissue production. Cirrhosis is an advanced stage of liver fibrosis ,with disruption of hepatic vessels,so blood flow in liver is disturbed ana also exchange between hepatic sinusoids and the adjacent liver parenchyma, i.e., hepatocytes. In cirrhosis the space of Disse is filled with scar tissue and endothelial fenestrations are lost, a process termed sinusoidal capillarization . In Cirrhosis liver function is disturbed with occurrence of portal hypertension and hepatocellular carcinoma.Portal hypertension occur due to circulatory abnormalities.Regression of cirrhosis and its reversal is possible. (Detlef Schuppan and Nezam H. Afdhal ,2008)


• If possible, treat the conditions that cause cirrhosis.

• Supply nutrition,transfuse clotting factors,and use medication for alleviation of ascites ,edema and toxins production.

• Avoid alcohol and any medications that may damage the liver.

• Liver transplantation. (Ann R.Punnose et al.,2012).


Cholangitis is pathologic condition associated with inflammation and infection of bile duct.Two important factors causing cholangitis are obstruction of bile duct and infection of bile duct by parasites.Mirizzi syndrome and lemmel syndrome are also important causes of cholangitis.

Cholangitis occur due to bacterial infection in bile duct,this raises pressure of bile duct,due to which bacteria and other endotoxins enters vascular system of body,causing severe infections like sepsis and hepatic abscess.

Acute and Chronic cholangitis are two important types of cholangitis.

Acute cholangitis is further divided into following types

1) Acute cholangitis developing from acute cholecystitis

2) Acute non-suppurative cholangitis

3) Acute suppurative cholangitis

4) Acute obstructive suppurative cholangitis

5) Acute suppurative cholangitis accompanied by hepatic abscess.( Yasutoshi Kimura et al.,2007)





Paracetamol(recommended international nonproprietary name) (acetaminophen) was synthesized by Morse in 1878 by the reduction of para-nitrophenol to para- aminophenol followed by acetylation of the product and first used clinically by von Mering in 1887. . But it was quickly discarded in favor of phenacetin.But later on phenacetin was discarded due to its nephrotoxic effects.(A Bertolini et al.,2006)

In 1940s, paracetamol was rediscovered as the most important metabolite of acetanilide and phenacetin in humans .In 1950 ,first time paracetamol was marketed in the USA and subsequently in the UK in 1956.Since 1950 paracetamol is considered highly efficacious drug in reducing fever and relieving pain caused by cancer , dental surgery or arthritis.(Regina Botting,2004).


Paracetamol is 4-acetaminophen and may be represented by the following formula:

In some publications, it is described as 4-hydroxyacetanilide or N-acetyl-p-aminophenol and in the US Pharmacopoeia it is known as paracetamol.Paracetamol is aniline derivative.


Paracetamol is a white, odourless crystalline powder with a bitter taste,


Paracetamol is soluble in 70 parts of water (1 in 20 boiling water), 7 parts of alcohol (95%), 13 parts of acetone, 40 parts of glycerol, 9 parts of propylene glycol, 50 parts of chloroform, or 10 parts of methyl alcohol. It is also soluble in solutions of alkali hydroxides. It is insoluble in benzene and ether. A saturated aqueous solution has a pH of about 6 and is stable (half-life over 20 years) but stability decreases in acid or alkaline conditions, the paracetamol being slowly broken down into acetic acid and p-aminophenol.


Paracetamol also called( N acetyl p - aminophenol ,4 hydroxy acetanilide) or acetaminophen is commonly used analgesic and antipyretic drug throughout the world.In therapeutic range it is safe and effective drug,but toxic response due to paracetamol occur when high dose of drug is taken accidentally or for suicidal attempt.Toxic doses of paracetamol causes centrilobular necrosis in liver,liver failure and finally death occur due to toxic effect.(Yilmaz Cigremis,2009)

Paracetamol is slightly water soluble and also lipid soluble weak acid.pka value of paracetamol is 9.5 and is unionized over physiological ph.(L F Prescott,1980)



Absorption of paracetamol taken orally is negligible from the stomach but occur at high rate from the small intestine . Absorption rate of paracetamol depends on the gastric emptying rate .

Absorption of paracetamol is slowed, if gastric emptying is delayed due to any condition as by food, posture, disease , but the total amount of drug absorbed is not decreased.In fasting conditions paracetamol absorptions occur at high rate and peak plasma concentration is reached within 15 to 30 mins.


Volume of distribution of paracetamol in human is 0.9l/kg.

Paracetamol is rapidly and uniformly distributed in all tissues.Binding of paracetamol to plasma proteins is insignificant.


Basically biotransformation of paracetamol occur in liver but a bit one metabolism also occur in gut and kidney.Paracetamol is rapidly metabolized in liver and only 2-5% of drug is excreted unchanged in urine.Metabolism of paracetamol is dependent on age and dose.Plasma half life of paracetamol is 1.5-2.5h.(L F Prescott,1980)

Two major pathways are involved in metabolism of paracetamol,major one is glucuronyl transferase and minor one is through cytochrome mixed function oxidase system.The proportion of metabolites of paracetamol occuring in urine are paracetamol glucuronide(55%),paracetamol sulphate(30%),unchanged paracetamol(4%),cysteine and mercapturic acid conjugates of paracetamol(each 4%).Toxic intermediate of paracetamol (N acetyl p benzoquinoneimine) is also produced by cyp 450 mixed function oxidase system.But this metabolite is inactivated by glutathione of liver and cysteine and mercapturic acid conjugates are formed ,which are excreted through kidney.(C. Harold Jackson et al.,1984)

High doses of paracetamol causes necrosis of liver due to depletion of glutathione and binding of toxic intermediate to vital constituents of cell.Acute necrosis of renal tubule by paracetamol also occur by same mechanism,but renal toxicity is dependent on activity of microsomal enzymes and availibilty of glutathione.

In neonates and young children glucuronide conjugation is deficient ,so half life of paracetamol is prolonged,and major metabolism occur through sulphate conjugation.(L F Prescott,1980)

With hepatotoxic doses metabolism of paracetamol is impaired and its half life is prolonged.Major portion of drug is then excreted as cysteine and mercapturic acid conjugates and saturation of sulphate conjugation occur.(L F Prescott,1980)



The renal clearance of paracetamol is dependent on flow rate of urine but not on ph of urine.In patients with impaired renal function plasma half life of paracetmol is not increased,but accumulation and retention of conjugates occur.(L F Prescott,1980)


Paracetamol (acetaminophen) inhibits synthesis of prostaglandins (PGs) ,when arachidonic acid level is low (less than about 5 mumol/L). Because at low concentration of arachidonic acid, PGs are synthesized largely by COX-2 in cells that contain both COX-1 and COX-2. Thus, the apparent selectivity of paracetamol may be due to inhibition of COX-2-dependent pathways that are proceeding at low rates. This hypothesis is consistent with the similar pharmacological effects of paracetamol and the selective COX-2 inhibitors. COX-3, a splice variant of COX-1, has also been proposed to be inhibited by paracetamol.

Another proposed antinociceptive action of paracetamol is due to activation of descending serotonergic pathways, but its main role is to inhibit PG synthesis.

At molecular level, action of paracetamol is not obvious, but it has been suggested that it might be due to synthesis of reactive metabolites by the peroxidase function of COX-2, which then cause depletion of glutathione, a cofactor of enzymes such as PGE synthase (Graham G G and Scott K F ,2005).

Paracetamol also acts on Endogenous cannaboid system for analgesic actions.(Ottani A et al.,2006). Paracetamol is metabolized to AM404, which inhibits the reuptake of the endogenous cannabinoid/vanilloid anandamide by neurons.Because due to reuptake of anandamide,its amount 'll be less in synaptic space and the TRPV1 (older name: vanilloid receptor)(main pain receptor of body) 'll be activated to a lesser extent . Because paracetamol inhibits anandamide uptake,its concentration in synaptic apace 'll remain high and it 'll cause desensitization of TRPV1 receptor.

Furthermore, AM404 also inhibits sodium channels, like anesthetics.  Either of these actions reduce pain, and are a possible mechanism of action for paracetamol.

However, it has been observed that, if cannabinoid receptors are blocked by synthetic antagonists analgesic effects of paracetamol are also prevented,this proves that endogenous cannabinoid system is also site of action of paracetamol .(David A Anderson et al.,2011)


Following are different routes of administration of paracetamol. Absorption of paracetamol and time to reach maximum plasma concentration is different from each route.Peak plasma concentration from Intravenous route is achieved in shortest time.

1.Oral route

2.Rectal route

3.Intravenous route


With oral route , Paracetamol is easily absorbed from the gastrointestinal tract and first pass metabolism is also low from liver.Bioavailability with oral route of administration is 63-89%.


Paracetamol is most unpredictably absorbed from rectal route.Bioavailability from rectal route is 24-98%.The absorption rate of suppositories is variable due to various factors, Higher bioavailibilty of suppositories is achieved if lipophilic bases are used more.Suppository size,their quantity and particle size of paracetamol effect the absorption through rectal route. Rectal pH effect absorption of paracetamol through rectal membrane by influencing its dissociation rate. In children, range of rectal pH is 7.8-11.4, and rate of dissociation of paracetamol in this range is 2-99%.(Chris Oscier et al.,2007).


Previously propacetamol a pro drug of paracetamol has been available for intravenous use and suitable well for analgesic effects. 'Propacetamol' is the N-acetylparaminophenol diethyl aminoacetic ester of paracetamol (Barney Ward et al .,2012).

Since 1985, In France propacetamol, provided as a reconstituted powder.But propacetamol causes contact dermatitis and pain at injection site .So Intravenous paracetamol (Perfalgan, Bristol-Myers Squibb) is formulated as aqueous solution in glass vial for infusion. Unlike propacetamol, intravenous paracetamol is available in a preformed solution, and does 'nt cause pain on injection or contact dermatitis. (Chris Oscier et al.,2007).


The predominant mechanisms of analgesic effects of APAP's are in the central nervous system (CNS). Although, central effects are basically responsible for APAP's effects on pain remain uncertain. Perhaps, the most accepted theory is positive effects of APAP's on the serotonergic descending inhibitory pathways. However, effects on opioidergic systems, eicosanoid systems, and/or nitric oxide containing pathways may also be involved.


Prostaglandin H2 synthetase (PGHS) enzyme causes metabolism of arachidonic acid to the unstable PGH2.

There are 2 major forms of PGHS, as the constitutive PGHS-1 and the inducible PGHS-2. These 2 enzymes are commonly called as COX-1 and COX-2.The COX enzyme should be in oxidized form for being active and APAP reduces oxidised form of this enzyme by acting on POX site. A PGHS variant (COX-3) exists in the central nervous system (CNS), and COX3 is also sensitive to APAP .It has been proposed that analgesic mechanism of APAP is due to inhibition of central cyclo-oxygenases (COX-1, COX-2, and COX-3). Basically Arachidonic acid is converted to PGG2 in presence of the tyrosine-385 radical (Tyr385*) at the COX site ,and this radical is produced by ferryl protoporphyrin IX radical cation (Fe4+ =OPP*+) at the POX site. APAP interferes with PGG2 synthesis from arachidonic acid,by reducing availability of Fe4+ = OPP*+, by acting as a reducing cosubstrate . Consequently, less Tyr385* is available for converting aracdonic acid to PGG2. APAP is more active in environments that has low peroxide concentration and low arachidonic acid levels, suc in the CNS . Grahh asam and Scott have suggested that the peroxidase function of the COX-1 and COX-2 produces following results. First, local depletion of the glutathione,that finally causes decreased production of PGE2. Secondly the 2 reactive metabolites of paracetamol combine with enzymes that are involved in PG synthesis and inhibit these enzymes . Furthermore,paracetamol also competitively inhibit cyclo oxygenases. .( Howard S. Smith ,2009)


Ruggieri et al determined role of the opioidergic system for analgesic effects of APAP metabolite AM404, because μ and κ receptors are strongly involved in supraspinal and spinal opioid induced analgesia. A functional relationship has been suggested between the opioidergic and serotonergic systems for analgesia.

Serotonergic neurons are involved in pathways that interact with opioid mediated antinociceptive circuit. Opioid and serotonin systems interacts for producing antinociceptive effects through regulation of central μ and κ receptors . Therefore, involvement of both serotonergic and opioidergic systems in the activity of APAP could occur through a mechanism in which the activation of one pathway will effect the other (Ruggieri V et al.,2008)

There also exsists a physiological interaction between 5-HT2 and μ-opioid receptors in some cortical areas. Thus, APAP may act through both opioidergic and serotonergic systems in a synergistic manner.(Marek G J,2003)


The analgesic mechanism of action of paracetamol also involve 5HT (Pini LA et al.,1996)( Pelissier T et al.,1995). Both AM404 and APAP act on the serotonergic system for producing analgesia.Paracetamol induced analgesia also involve serotonergic (5-HT1A, 5-HT2, and 5-HT3) receptor subtypes . It has been postulated that APAP-induced stimulation of 5-HT1A receptor may enhancing activity of bulbospinal 5-HT descending inhibitory pathways at the supraspinal level. However, analgesic mechanisms of APAP depend on effect of APAP upon both COX activities and the 5-HT system. APAP stimulates spinal 5-HT1A receptors, by enhancing activity of 5-HT descending pathways, and thus modulates pain transmission in a complex manner.At cellular level APAP upregulating the expression of GH and IGF- 1 receptors,producing analgesia.(Bonnefont J et al.,2007)


APAP is converted to N-arachidonoyl-phenolamine (AM404) in brain, which is an agonist of transient receptor potential vanilloid type 1, a ligand at selective cannabinoid subtype 1 (CB1) receptors and an inhibitor of cellular anandamide uptake, because its inhibition will increase the level of endogenous cannabinoids . Cannabinoids produce analgesic effects through CB1 receptors . Cannabinoid- induced analgesic effect is also dependant on the release of opioid peptides into the brain . APAP can be metabolized in the brain into AM404, and then inhibit the reuptake of anandamide , with subsequent stimulation of CB1 receptors via FAAH . Thus, the antinociceptive activity of APAP may also comprise involvement of endocannabinoid system .( Hogestatt ED et al.,2005)

The interaction of APAP with the endocannabinoid system may be due to reinforcement of the serotonergic system. ( Mallet C et al.,2008)


Paracetamol has little or no anti inflammatory activity ,because paracetamol can inhibit COX 1 and COX 2 enzymes ,in an environment which contains low concentration of arachidonic acid and peroxides.But as in inflammatory conditions such as rheumatoid arthritis extracellular concentration of both of these chemicals is high,so paracetamol shows little or no anti inflammatory activity.(Graham G et al.,2005).

Paracetamol basically acts on prostaglandin endoperoxide H2 synthase(PGHS) enzyme. Currently it is known inhibitory effect of paracetamol on PGHS activity is directly connected with the elimination of "peroxide tone". At site of inflammation high concentrations of reactive chemicals like peroxy nitrate and endoperoxides are present,these compounds decrease effect of paracetamol on PGHS activity.

So weak anti inflammatory activity of paracetamol is due to its free radical scavenger activity.(Chodorowski Z et al.,2009).


Fever occurs when level of PGE rises in certain areas of brain(David m.Aronoff et al.,2001) .

In response to infectious stimuli ,leukocyte release endogenous pyrogens ,that increase level of PGE in cerebrospinal fluid.Body temperature is elevated due to disturbance in thermoregulatory control of hypothalamus.Paracetamol shows its antipyretic activity by inhibiting synthesis and release of prostaglandins in hypothalamus.Activation of arginine vasopressin V-1 receptor is not required for antipyresis and also inhibition of arachidonic acid metabolism is not required for antipyretic activity of paracetamol.(www.tylenol

In febrile children or HIV-infected patients , paracetamol produces an unexpected antipyretic activity when the body temperature can fall as low as 35C.(Regina Botting,2004)



Paracetamol is a safe and effective analgesic for the relief of mild to moderate pain associated with oral surgery, episiotomy, postpartum pain, cancer, osteoarthritis, dysmenorrhea, and headache.


Paracetamol doesn't inhibit PG synthesis in platelets; because concentration of peroxides is low in platelets, so platelets aggregation is not inhibited. Since it has no effect on hemostasis, and no risks of increased bleeding, so can be used safely in children. (Regina M.Botting,2000)


Paracetamol increases concentration of PGE2 and PGI2 in stomach, thus providing protective effects. Paracetamol protects the gastric mucosa from damage not only by increasing synthesis of mucosal PGs but possibly also by other mechanisms, such as scavenging of free hydroxyl radicals (Regina M.Botting,2000).



In addition to necrosis of liver, paracetamol also cause nephrotoxicity.Chronic renal disease,gender and conditions that effect Cyp 450 enzyme system usually increases renal toxicity.In case of acute toxicity glomerular filtration rate is reduced and injury of proximal tubular cells occur.(Roland C.Blantz,1996).

Possible mechanisms of nephrotoxicity include the cytochrome P-450 pathway, as well as prostaglandin synthetase, and N deacetylase enzymes.(Bessem JG et al.,2001).


In addition to liver necrosis, paracetamol also cause nephrotoxicity,In therapeutic doses paracetamol is metabolised by glucuronidation and sulfation with excretion of water soluble metabolites.Less than 5% drug is oxidised by Cyp450 enzyme system releasing NAPQI,as reactive metabolite ,wich is reduced by glutathione to mercapturic acid.With large doses of paracetamol ,extensive depletion of glutathione occur,with excessive production of NAPQI,which form adducts with sulfhydryl and glutathione moieties on cellular proteins. This causes apoptosis ,necrosis and ultimately organ dysfunction.Cyp 450 depend process occur in cortex of kidney. The mechanism of paracetamol induced toxicity is properly explained for the liver, but is less clearly described in the kidney. Glutathione conjugates are involved in formation of nephrotoxic compounds. Animal models have demonstrated that APAP-induced nephrotoxicity can be alleviated by inhibition of the metabolism or transport of these conjugates. It is not sure whether the renal injury is due directly to the paracetamol-glutathione conjugate or due to its metabolites.

Another possibility is that the formation of these conjugates may cause glutathione depletion, and detoxification of metabolites is inhibited. This may be a selective mechanism for paracetamol-induced nephrorotoxicity.


PGES is an enzyme present in the kidney and converts paracetamol to toxic metabolites as NAPQI,and finally this metabolite bind to cellular protein causing necrosis.This method occurs basically in medulla of kidney.


N deacetylase enzyme is also involved in paracetamol-induced nephrotoxicity, but its role is

uncertain. N deacetylase enzyme acts on APAP or NAPQI,deacetylating its substrate to p-aminophenol, which is then converted to a free radical and then bind with cellular proteins. This process can also occur in combination with the actions of the CYP-450 enzyme system. (Maryann Mazer and Jeanmarie Perrone,2008)


In adolescent children paracetamol is responsible for occurance and/or maintenance of asthma, rhinoconjunctivitis, and eczema .

Paracetamol enhance allergic inflammation by increasing oxygen stress due to depletion ofglutathione-dependent enzymes, which also increase allergic immune response.Allergic reaction results in development or worsening of preexisting asthma, rhinoconjunctivitis, or eczema.

Furthermore, paracetamol inhibit the immune response , and prolong the symptomatic illness from, rhinovirus infections , which potentiate asthma in childhood and adult life and in infancy paracetamol is associated with an increased risk of asthma .( Richard W. Beasley et al.,2011)


High doses of paracetamol is associated with increased risk of haematological malignancies including non Hodgkin's lymphoma,myeloid neoplasm and plasma cell disorders,and also increase the risk of mononuclear cell leukemia and have carcinogenic effects on liver and bladder, but not associated with chronic lymphocytic leukemia or small lymphocytic lymphoma.

Paracetamol inhibits replicative DNA synthesis and DNA repair synthesis and increases the frequency of chromosomal damage in cell by inhibiting ribonucleotide reductase.

N-acetyl-p-benzoquinone imine(NAPQI) cause breakage in DNA single-strand and enhance DNA cleavage by topoisomerase II in vitro. Similarly, p-aminophenol, another metabolite of paracetamol,is mutagenic and caus single-strand breaks and chromosome aberrations.( Roland B. Walter et al.,2011)




At therapeutic doses paracetamol is considered safe ,but toxic doses of paracetamol cause centrilobular hepatic necrosis(L.F. Prescott 1980).Necrosis but not apoptosis, is cause of cell death.(Gujral et al.,2002).

Toxic doses of paracetamol causes hepatotoxicity leading to increased level of liver enzymes(ALT,AST,ALP,LDH,BILIRUBIN), with decreased level of GSH and increased level of MDA and NO in liver.(Yilmaz Cigremis et al.,2008)

Following factors are considered to be involved in paracetamol induced hepatotoxicity,

Oxidative stress,nitrotyrosine formation,inflammatory cytokines,mitochondrial permeability transition.


Paracetamol is metabolically activated by Cyp 450 to reactive metabolite N acetyl p benzoquinoneimine (NAPQI).GSH cause detoxification of paracetamol to paracetamol -GSH conjugate. At toxic doses ,as GSH is depleted so toxic metabolite covalently bound with cysteine gp of proteins and paracetamol-protein adducts are formed. Following is its schematic representation


After formation of paracetamol protein adducts,finally cellular death occur.Different mechanisms 've been proposed for this toxicity.

One mechanism is that due to covalent binding of metabolite with cellular protein,its functional activity is lost,leading to cell death and lysis.Different types of mitochondrial and cytosolic proteins are involved in formation of adducts(Laura p. james et al.,2003)).Primary targets are mitochondrial proteins and proteins that control ions of cell.(Nelson 1990).

Paracetamol induced cell death can also occur due to loss of mitochondrial or nuclear ion balance,the reason is that because of this loss Ca 2+ concentration of cytosol is increased,cycling of mitochondrial Ca2+ occur and proteases and endonucleases become activated anf finally DNA strand breaks,causing cellular lysis.(Salas and Corcoran 1997).

It has been investigated that paracetamol toxicity can also occur due to inhibition of mitochondrial respiration(Donnelly et al.,1994.)


Oxidative stress also plays an important role in paracetamol induced liver toxicity.Iron mediated oxidative stress or Fenton mechanism is usually considered to be involved.This process causes increased production of superoxide,whose dismutation leads to increased hydrogen peroxide production.Superoxide formation may involve variety of mechanisms like uncoupling of cytochrome P-4502E1 or other enzymes and mitochondria or activation of NADPH oxidase. CYP2E1 is involved in the metabolism of paracetamol to NAPQI; however, other CYPs including CYP1A2 and CYP3A4 also causes paracetamol metabolism . Catalytic property of CYP2E1 along with uncoupling may be a reason of increased oxidative stress in the liver cells. Uncoupling of oxygen consumption with NADPH oxidation produces superoxide leading to other reactive oxygen species such as hydrogen peroxide or peroxynitrite (Gonzalez 2007).

NADPH oxidase is the major respiratory burst enzyme that generates superoxide formation in activated Kupffer cells. (James et al. 2003c).

Due to formation of NAPQI metabolite in acetaminophen induced hepatotoxicity ,glutathione(GSH) is depleted,resulting in compromised detoxification process of peroxides(due to depletion of glutathione peroxidase). Thus, glutathione depletion causes increased oxidative stress via Fenton mechanism. This mechanism involves that ferrous ions causes reduction of peroxides with production of hydroxyl radical,which oxidizes lipids,proteins and nucleic acids.Data supporting Fenton mechanism-mediated oxidative stress indicates that deferoxamine decreases acetaminophen induced hepatotoxicity whereas addition of iron makes liver cells susceptible to paracetamol induced hepatotoxicity.( Ito et al., 1994)


Nitric oxide in addition to Fenton mediated mechanism is also involved in oxidative stress.Nitric oxide(NO) reacts with superoxide to form peroxynitrite. Peroxynitrite(ONOO) is not only an oxidizing agent but also a nitrating agent. Peroxynitrite is detoxified by glutathione ,whose depletion occurs by NAPQI,so detoxification mechanism is disturbed.Nitrotyrosine formed by reaction of peroxynitrite with tyrosine ,nitrates hepatic proteins in centrilobular regions.Nitrated proteins causes necrosis of liver cells.In paracetamol induced hepatotoxicity serum level of nitrate and nitrite is increased.(Hinson et al.,1998)

In paracetamol induced hepatotoxicity, inducible nitric oxide synthase(iNOS) is also increased in the centrilobular hepatocytes.(Gardner et al.,1998).


Macrophages are also involved in paracetamol induced hepatotoxicity. Kupffer cells are phagocytic macrophages of liver and upon activation release different types of signaling molecules like hydrolytic enzymes, eicosanoids, nitric oxide and super oxide. Inflammatory cytokines like I L-1,IL-6 are also released by kupffer cells(Laskin et al.,1995).

In paracetamol induced hepatotoxicity various types of cytokines are released (Bourdi et al.,2002 a ,b).

Kupffer cells are involved in toxicity induced by paracetamol and finally concluded that kupffer cells release various cytokines during this mechanism and cause toxicity. (Laskin et al.,1995.)


Various types of inflammatory mediators and cytokines are increased in paracetamol induced hepatotoxicity, commonly TNF and IL-1. (Blazka et al.,1996).

Macrophage migration inhibitory factor (MIF) ,an important cytokine ,whose level is also increased in this toxicity.(Bourdi et al.,2002b).

MIF basically increases concentration of other pro-inflammatory cytokines, adhesion molecules, matrix metalloproteinase-2 expression, NO release, and cyclooxygenase-2(Baugh and Bucala,2002).


Mitochondrial dysfunction also play an important role in paracetamol-induced hepatotoxicity. Mitochondrial permeability transition (MPT) causes formation of superoxide, and then peroxynitrite formation,oxidative stress and tyrosine nitration also occur.Oxidation of thiol groups in mitochondria by NAPQI causes MPT.Due to MPT ,increase in permeability of mitochondrial membrane occur due to change in permeability of mitochondria ,depolarization of membrane occur, uncoupling of oxidative phosphorylation, mitochondrial membrane ions and metabolic intermediates are increased, so mitochondrial dysfunction occur leading to reactive oxygen and nitrogen species. (Laura P.James et al.,2003)



Paracetamol potentiates the anticoagulant effects of warfarin, with increased risk of bleeding. Paracetamol at 4 g day−1 , increasing the risk of bleeding associated with warfarin.Warfarin is the drug of choice for prevention and treatment of venous thromboembolic disease and atrial fibrillation . Paracetamol is recommended as a first-line analgesic therapy in patients receiving oral anticoagulation, as other nonsteroidal anti-inflammatory drugs (NSAIDS) enhance the risk of oral anticoagulation-associated bleeding by inhibiting platelet function and can also produce gastric erosions .

In fact, the mechanism by which the anticoagulant effect of warfarin (and other oral anticoagulants) may be enhanced by paracetamol is unclear .

The proposed mechanism is through action on cytochrome P450 enzyme system,increasing plasma concentrationof warfarin, when paracetamol is coadministered. Warfarin is a racemic mixture of R- and S-enantiomers. S-warfarin is the most potent enantiomer of warfarin and is metabolized to 7-hydroxywarfarin by CYP2C9, while R-warfarin is metabolized by CYP1A2 and CYP2C19. At therapeutic dosages, the majority of paracetamol is eliminated by conjugation and the last part is metabolized by CYP1A2, CYP2E1. Since paracetamol is neither a substrate nor an inhibitor of CYP2C9, the predominant pathway of warfarin metabolism, the findings of an increase of anticoagulant effect by paracetamol in this way is subject to caution

The effect can be nonpharmacokinetic, that factor vii concentration is decreased.

Paracetamol is still much safer than aspirin and other NSAIDs in patients taking warfarin. Due to the lack of a safer alternative, if a patient on oral anticoagulation requires an analgesic or antipyretic drug, paracetamol should still be chosen, but the dose and duration of therapy should be as low as possible. In any case, it is recommended that the anticoagulant effect be closely monitored when regular paracetamol is either started or stopped when the patient is on warfarin.( I Mahé et al.,2005)


Carbamazepine increases the risk of paracetamol hepatotoxicity by inducing the Cyp450 enzymes and thus increasing the formation of toxic metabolites

In addition, paracetamol has been shown to have lower bioavailability in epilectic patients receiving enzyme inducing anticonvulsants , including phenytoin and fosphenytoin. On the other hand, paracetamol enhances the urinary elimination of lamotri gine .


Sulfinpyrazone, like carbamazepine, increases the risk of paracetamol toxicity by in creasing the formation of hepatotoxic metabolites .


Coadministration of paracetamol with zidovudine may result in neutropenia or hepatotoxicity (Alfio Bertolini et al.,2006).


Of major concern is the interaction with alcohol. Alcohol - paracetamol syndrome is defined as the development of acute toxic hepatic symptoms in long-term alcoholics who take paracetamol, in doses generally considered non-toxic. Patients wih alcohol-paracetamol syndrome have a worse prognosis than non-alcoholic patients overdosed with paracetamol. Con- current use of alcohol and paracetamol may increase the CYP2E1-mediated metabolism of paracetamol to the highly hepatotoxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). In non-alcoholics, NAPQI is detoxified by conjugation with glutathione. In alcoholics, the combination of CYP2E1 induction and glutathione depletion results in NAPQI accumulation . In these subjects, the highest risk of paracetamol toxicity occurs after a brief (12 h) abstinence of alcohol, since CYP2E1 is still induced, but alcohol is not present to compete for CYP2E1 metabolism ( Draganov P et al.,2000)


Global's SGOT kit is used for the determination of SGOT (ASAT) activity in serum.


SGOT (ASAT) catalyzes the conversion of amino group between L-Aspartate and α Ketoglutarate to form Oxaloacetate and glutamate. The Oxaloacetate formed reacts with NADH in the presence of Malate Dehydrogenase to form NAD. The rate of oxidation of NADH to NAD is measured as a decrease in absorbance which is proportional to the SGOT (ASAT) activity in the serum.


L-Aspartate + α Ketoglutarate → Oxaloacetate + L- Glutamate


Oxaloacetate + NADH +H+ → Malate + NAD+


L1: Enzyme Reagent

L2: Starter Reagent


Wavelength/ filter : 340 nm

Temperature : 370C

Light path : 1 cm


Pipette into a clean dry test tube labeled as Test (T):

(T) 370C

Addition of Reagent

0.8 ml

0.1 ml

Enzyme Reagent (L1)


Incubate at the assay temperature for 1 minute and add

0.2 ml

Starter Reagent(L2)

Mix well and read the initial absorbance A0 and repeat the absorbance reading after every 1, 2, 3 minutes. Calculate the mean absorbance change per minute (∆A/min).


SGOT (ASAT) Activity in U/L 37oC = ∆A/ min Ã- 1746


Serum (males) : 37 U/L 370C

(Females): 31 U/L 370C

It is recommended that each laboratory establish its own normal range representing its patient population.


IFCC methods for measurement 0f catalytic concentrations of enzymes, J. Clin. Chem. Clin Biochem (1986) 24:497.

Analytical Method for the Quantitative Determination Of SGPT

Global's SGPT Kit is used for the determination of SGPT (ALAT) activity in serum.

Principal of Test

SGPT (ALAT) catalyzes the transfer of amino group between L-Alanine and α Ketoglutarate to form Pyruvate and Glutamate. The Pyruvate formed reacts with NADH in the presence of Lactate Dehydrogenase to form NAD. The rate of oxidation of NADH to NAD is measured as a decrease in absorbance which is proportional to the SGPT (ALAT) activity in the sample.

L- Alanine + α Ketoglutarate → Pyruvate + L- Glutamate

Pyruvate + NADH + H+ → Lactate + NAD+


L1: Enzyme Reagent

L2: Starter Reagent

Storage/ Stability Of KIT

The contents of the Global's SGPT (ALAT) Kit are stable at 2- 80C till the expiry date mentioned on Vial/bottle labels.


Wavelength/ Filter : 340 nm

Temperature : 370C

Light path : 1 cm


Pipette into a clean dry test tube labeled as Test (T):

(T)37 0C

Addition of Reagent


0.1 ml

Enzyme Reagent(L1)


Incubate at the assay temperature for 1 minute and add

0.2 ml

Starter Reagent(L2)

Mix well and read the initial absorbance A0 after 1 minute and repeat the absorbance reading after every 1, 2, 3 minutes. Calculate the