Diclofenac Na is a non steroidal anti-inflammatory drug, abbreviated as NSAID. It is a potent and one of the most widely used NSAIDs 1 ( D. Schapira 1986 ) . It is classified among the most powerful drug of this sort, while being one of the best tolerated NSAIDs2 ( Brunner and Krupp 1976 ) .
It is the most normally prescribed NSAID in the United Kingdom3 ( NG. Ryley ) . The figure of patients taking NSAID is & A ; gt ; 30 1000000s in the United States This figure besides indicates that a considerable figure of populations are exposed to its possible toxic effects4 ( David Bjorkman 1998 ) .
Diclofenac belongs to a chemical sub-group of NSAID that are an, arkylakanoic group of Phenylacetic acid5 ( Aydin G 2003 ) .
In the 18th century acetylsalicylic acid was isolated as the first analgetic drug of this group by Leroux who besides demonstrated its antipyretic consequence. By the terminal of 19th century other drugs were discovered that shared some or all of these actions6 ( Gillman 1996 ) .
The NSAIDs are classified on the footing of their chemical construction. They are either non-selective Cox inhibitor or selective Cox-2 inhibitor.
In non selective Cox inhibitor we have aspirine, actaminophene, Indocin, isobutylphenyl propionic acid, mefanamic acid, piroxcam and Diclofenac.
Selective COX-2 inhibitors are rofecoxib, Celebrex, endolac, nimesulide etc. Diclofenac is used as Na salt or K salt.
Mechanism of action
Major mechanism of action of NSAIDs is the suppression of Cox activity and hence the synthesis of prostaglandins7 ( John A 1991 ) . The Cox is the enzyme which converts arachidonic acid to prostaglandin ; arachidonic acid is a structural constituent of phospholipids into cell membrane and subcellular constructions of all tissues of the organic structure. Arachidonic acid is metabolized or released from the membrane phospholipids. Following mobilisation, arachidonic acid is oxygenated by four separate routes the Cox ( COX ) , lipooxygenase, p450 epoxygenase and isoprostane pathways8 ( Katzung 2007 ) .
In Cox tract prostaglandin H2 is synthesized this prostaglandin is converted into one of the three compounds, PGF2a or PGD2 or PGE2.
Two signifiers of Cox termed Cox-1 and Cox-2 have been identified. Cox -1 is expressed in most cells of the organic structure while Cox-2 is induced in redness and in malignant neoplastic diseases. However Cox-2 besides is constitutively expressed in certain countries of encephalon and kidney9 10 ( Breder et al. , 1995: Harris et al. , 1994 ) . Importantly Cox-1 but non Cox-2 is expressed in the tummy. This accounts for markedly reduced happening of stomachic toxicity with the usage of selective inhibitor of Cox-2 6 ( Gillman, 1996 ) .
Prostaglandins are released whenever cells are damaged, they appear in inflammatory exudations and about all NSAIDs suppress the biogenesis of prostaglandins in all cells11 ( Vane et al. , 1987 ) .
Inflammatory procedure is the organic structure ‘s defence mechanism against the infective agents, ischaemia, antigen-antibody interaction, physical hurt and other pathogens. Prostaglandins are released in response to all of the above mentioned stimulations. PGE2 and prostacyclin ( PGI2 ) cause erythema and increase in local blood flow due to vasodilatation and increase capillary permeableness. There is besides infiltration of leukocytes and Phagocytic cells12 ( Lippincott 2006 ) .
Pain is a phenomenon which consequences from stimulation of hurting fibres by chemical or mechanical stimulations. Bradykinin which is released from plasma kinenogen and cytokine elicit the hurting of redness. It liberates prostaglandins that promote hyperalgesia. Neuropeptides such as substance ‘P ‘ and calciterin, cistron related peptide besides may be involved in arousing hurting. Prostaglandin can do concern and vascular hurting when infused intravenously. Prostaglandin besides lowers the threshold of ‘C ‘ fibres.
Fever may ensue by infection, squealae of tissue harm, redness, malignance or other disease province. These conditions enhance the formation of cytokinase. The cytokinase in bend increases the synthesis of PGE2 in hypothalamus. PGE2 in hypothalamus increases the formation of cyclic AMP ; this triggers the hypothalamus to promote organic structure temperature by advancing addition in heat coevals and lessening in heat loss. Diclofenac suppresses this response by suppressing the synthesis of PGE2 ( Roberts et al. , 2001 ) 13.
NSAIDs either suppress Cox-1 or Cox-2 or both and the curative consequence of each of NSAIDs depends on its binding capacity with Cox-1 or Cox-2. These drugs covalently modify Cox enzyme and forestall the binding of arachidonic acid to the active site of enzyme to do prostaglandin. Diclofenac Na is the non selective Cox inhibitor. Platelets are particularly susceptible to the action of Diclofenac as they have small or no capacity of protein biogenesis and therefore can non renew the Cox enzyme.
Huge bulk of NSAIDs are organic acids and act as reversible competitory inhibitor of Cox activity.
These compounds are by and large good absorbed orally. They are extremely bound to plasma proteins and excreted either by glomerular filtration or by cannular secernment. Experiments showed that the chief path of drug riddance is different in assorted species ; nephritic elimination is being the most of import in adult male and Macaca mulatta monkey1 ( D. Schapira 1986 ) .
Duration of action of all NSAIDs ( except acetylsalicylic acid ) is chiefly related to the pharmacokinetic clearance of the from the organic structure, they are approximately divided into two groups ; those with short half life less than 6 hours and long half life more than 10 hours. These drugs accumulate at the site of redness, which is an attractive pharmacokinetic belongings of drugs intended as anti inflammatory agents.
All NSAIDs including Cox-2 inhibitors are antipyretic, analgetic and anti-inflammatory except Datril, which is devoid of anti-inflammatory activity14 15 ( Morrison et al. , 1999 ; Malmstrome et al. , 1999 ) .
When employed as anodynes these drugs normally are effectual merely against hurting of low-to-moderate strength such as dental hurting. Trouble originating from redness is peculiarly good controlled by NSAIDs, where hurting originating from the hollow entrails normally non relieved.
As antipyretic Diclofenac Na reduces the organic structure temperature in feverish provinces.
Chief clinical application of Diclofenac Na is as anti-inflammatory agent in the intervention of musculoskeletal upsets such as arthritic arthritis, degenerative arthritis and ancylosing spondylitis. Chronic intervention of patients with Cox-2 inhibitors has shown to be effectual in stamp downing redness without stomachic toxicity16 17 18 ( Benson et al. , 1999 ; Emery et al. , 1999 ; Hawkey et al. , 2000 ) . In general Diclofenac Na provides merely diagnostic alleviation from hurting and redness associated with the disease and does non collar the patterned advance of pathological hurt to the tissue.
Diclofenac Na has been found effectual in the control of postoperative hurting when used pre-operatively19 ( Wuolijoki et al. , 1987 ) . Other utilizations of Diclofenac Na besides depend upon their capacity to barricade prostaglandin biogenesis. Prostaglandins have been implicated in the care of patency of ductus arteriosus, and the Diclofenac have been used in newborns to shut the ductus arteriosus when it has remained patent20 ( Clyman et al. , 1999 ) .
Prostaglandins are released from endometrium during menses, therefore doing spasms and dysmenorrhoea. Treatment of this status with Diclofenac met with considerable success21 ( Shapiro, 1988 ) .
In systemic mastocytosis PGD2 is released from the mast cells and antihistamine are uneffective in this status while Diclofenac Na normally leads to effectual bar of episodes22 ( Roberts and Oates 1991 ) .
In the intervention of Bartler ‘ syndrome Diclofenac Na has been found a utile agent. In a survey carried by Thu et al23 ( 1991 ) and Giovannucci et al 24 ( 1995 ) , it was found that there is about 50 % decrease in the incidence of colon malignant neoplastic disease by the frequent usage of Diclofenac Na.
Incidences of drug associated inauspicious effects are 12 % :
The most often reported inauspicious effects are GI, reported in 7.6 % of patients25 ( Martindale, 1994 ) .
Nephritic papillose mortification and nephrotic syndrome have been reported in patients taking Diclofenac and other NSAIDs26 ( Scott et al. , 1986 ) .
Diclofenac at a dose of 150mg/d appear to impair nephritic blood flow and glomerular filtration rate8 ( Katzung 2007 ) .
Other effects are lift of serum transaminase activity and clinical hepatitis. Reports of hepatic hurt scope from undistinguished and transeunt liver enzyme lift, to break up and fulminent hepatitis27. ( AV Manoukian 1996 )
Self restricting skin reactions such as roseola or pruritis may happen in patients given Diclofenac Na.
There are besides studies of hematologic abnormalcies including hemolytic anemia thrombopenia and agranulosis happening in patients given Diclofenac28 ( Kramer 1986 ) .
Localized self-generated hemorrhage, bruising, suppression of thrombocyte, collection and prolonged hemorrhage clip have been reported. Most of these effects are as consequences from obstruction of synthesis of endogenous prostaglandin and thromboxane A2.
Prolongation of gestation and or self-generated labor and premature closing of patent ductus have been observed.
Absorption and destiny
Diclofenac is quickly and wholly absorbed after unwritten disposal, intramuscular injection and rectal suppositories. It is absorbed easy if given with nutrient, and absorbed more easy when given as an enteral coated tablets25 ( Martindale, 1994 ) .
Although orally administered Diclofenac is about wholly captive, it is capable to first base on balls metamorphosis so that merely 50-60 % of the drug reaches the systemic circulation in the unchanged signifier. Diclofenac is besides absorbed percutaneously.
Peak concentrations in plasma are reached within 2-3 hours. Diclofenac penetrates synovial fluid and has been detected in chest milk29 ( fowler et al. , 1983 ) . It has been detected in synovial fluids two hours after dosage and remained changeless for nine hours.
Diclofenac is metabolized to 4-hydroxydiclofenac, 5-hydroxydiclofenac, 3-hydroxydiclofenac and 4 ‘ , 5-dihydroxy Diclofenac. It is so excreted in the signifier of glucoronoid and sulphate conjugate chiefly in the piss ( 65 % ) but besides in the gall ( 35 % ) .
Bioavailability following unwritten disposal is merely 50 % due to first base on balls consequence, i.e. 50 % of the drug is metabolized by liver as it first passes through it.
The usual dosage by oral cavity is 75 to 150 milligram of Diclofenac sodium daily in divided doses. It may besides be given as rectal suppositories in a usual dosage 100mg each eventide. By injection is 75 milligram one time day-to-day or twice daily in sever conditions. In kids the recommended dosage is 1-3mg /kg organic structure weight daily in divided doses for juvenile arthritis25 ( Martindale, 1994 ) .
A 0.1 % opthalamic readying is recommended for bar of postoperative ophthalmic redness and can be used after intraocular lens nidation and squint surgery.
Gross anatomy- It is the 2nd largest organ and the largest secretory organ of the organic structure.
It is a cuneus shaped organ in the right hypochondrium and epigastrium. Surfaces are diaphragmatic and splanchnic. For the intent of description the diaphragmatic surface is farther divided into anterior, superior right and buttocks.
Hepatic venas emerge from the posterior surface while all the other constructions enter or leave the liver at porta hepatic. Ligamentum teres lies at the lower free border of falcate ligament while right and left triangular ligament prevarication on the posterior surface of several lobes which are really creases of peritoneum from the lobes to the abdominal wall.
An H-shaped form of constructions is seen on posterior and splanchnic surfaces when viewed from below. Porta hepatis forms the cardinal line of H, while the right limb is formed by inferior veins cava and saddle sore vesica. The left limb is formed by the crevices of ligamentum venosum and ligamentum teres. To the right of inferior vena cava au naturel country of liver. At porta hepatis the three constructions lie as vena arteria and canal from behind forward so the canal is more accessible during surgery30 ( Sinnatamby 2003 )
Gall vesica lies in the pit on splanchnic surface with cystic canal near to the right terminal of orifice hepatis. Quadrate lobe lies between the saddle sore vesica and the crevice for ligamentum teres.
The au naturel country is in contact with right surface and stop. The splanchnic surface is in relation with tummy, duodenum hepatic flection of colon and right kidney. Esophageal feeling lies on the posterior surface of left lobe of liver.
In classical division of liver in lobes, it was divided in right and left lobes utilizing the fond regard of falciform ligament and crevice for ligamentum teres and venosum as the line of limit. The caudate and quadrate lobes lie on the buttocks and splanchnic surfaces severally. They were considered as the portion of right lobe.
The ramification form of blood supply and bilious drainage in the liver creates a system of lobes and farther subdivisions ( sectors or sections ) . This besides reflects the early development. The common hepatic arteria, portal vena and bile canal divide and subdivide with a common pattern31 ( William et al. , 1995 ) . On the footing of blood supply and bilious drainage there are four hepatic sectors, left sidelong and left median sectors and the right front tooth and right buttocks hepatic sectors. These four sectors are farther subdivided into eight sections which are numbered utilizing Roman numbers. Caudate lobe is assigned as section no I, it lies in left functional plane. It is an independent section having blood from right and left subdivisions of hepatic arteria and portal vena. It drains the gall into right and left hepatic canals.
Segment II and III prevarication in left sidelong sector. Quadrate lobe is the section IV. Inferior section of right front tooth sector is section V and the right buttocks is section VI. Sections VII and VIII are the superior sections of right buttocks and right front tooth sectors severally. These sections are arranged in about counterclockwise way around the orifice hepatis.
Liver receives both arterial and venous blood. Arterial blood is brought about through hepatic arteria which divides into right and left subdivisions in the orifice hepatis. The right subdivision divides into anterior and posterior sectoral subdivisions.
The left subdivision divides into median and sidelong sectoral subdivisions.
Venous blood is carried to the liver by portal vena. Portal vena in bend divides into right and left subdivisions which give sectoral subdivisions like the arterias. There is no communicating between the right and left halves of the liver, even within each half the arterias are end arterias.
The venous return differs that it shows commixture of right and left halves of liver. There are three chief hepatic venas. A big cardinal vena receives the blood from each half of the liver. Further laterally are right and left venas all the venas have no extrahepatic course31. ( William et al. , 1995 )
Hepatic lymph vass are divisible into superficial and deep systems. They run in subserosal areolate tissue over the whole surface of the organ run outing in four waies.
The hepatic nervousnesss arise from the hepatic rete incorporating sympathetic and parasympathetic fibres. They enter the orifice hepatis and mostly accompany blood vass and bile canals. Their lamination is unsure ( William et al. , 1995 )
The liver parenchymal cells, the hepatocytes are arranged into polyhedral lobules, which appear hexagonal in cross subdivision. Terminal subdivisions of hepatic arteria and hepatic portal vena are located at the angels of lobule boundaries in portal piece of lands providing more than one lobule. In the Centre of each lobule lies cenrtrilobular Venule. In human there are no interlobular septa.
Another attack is to see the functional unit of the liver to be the district supplied by each terminal subdivision of the hepatic arteria and hepatic orifice vena. It is called a hepatic acinus. It is besides polyhedral in form with portal piece of land organizing its cardinal axis.
The hepatocytes form level inosculating home bases normally merely one cell midst. Sinusoids are present on both sides of these home bases. These sinusoids are lined by discontinuous bed of cells which do non rest on cellar membrane and which are separated from the hepatocytes by a narrow infinite the infinite of Disse. This infinite drains into the lymphatics of the portal piece of lands.
Hepatocytes themselves are big polyhedral cells with big unit of ammunition karyon, with peripherally dispersed chromatin and outstanding nucleole. Occasional binucleate cells are besides seen. Irregular unstained countries are seeable within cytol this is due to the fact that important measures of animal starch and lipoid are stored in the hepatocytes, which are dissolved during tissue treating go forthing unstained countries. Cytoplasm is eosinophilic with extended ribosomes and RER.
The sinusoidal liner cells include endothelial cells, kupffer cells and fibroblasts. The endothelial cells have flattened karyons and attenuated cytol. Kupffer cells are big cells with egg-shaped karyon. These cells form portion of the monocyte-macrophage defence system and with the spleen participate in the remotion of spent red blood cells and other particulate dust from circulation.
Another cell type known as Ito cells or stellate cells can non be easy distinguished by light microscopy. These cell types have lipid droplets incorporating vitamin A in their cytol. These cells have the double map of vitamin A storage and production of extracellular matrix and collagen. During liver hurt these cells are thought to bring forth greatly increased sum of collagen, doing the liver cirrhosis.
Supporting model of the liver is formed by a all right net of reticular fibres which radiate from the cardinal vena to unify with the back uping tissue of portal piece of lands and lobule boundaries. External surface of the liver is covered by a capsule called Glisson ‘s capsule. It is made up of collagen fibres.
Bile canaliculi are all right channels formed by the plasma membrane of next hepatocytes. The canaliculi of next hepatocytes home bases merge to organize canals of Herring. Finally they drain into bile ductuluss of the portal tracts32
The liver arises as a ventral branch from the caudal portion of the foregut early in the 4th hebdomad. At sufficient degree, fibroblast growing factor ( FGFs ) secreted by the developing bosom interacts with the bipotent endothelial cell and bring on formation of the hepatic diverticulum. The hepatic diverticulum extends into the septum transversum, enlarges quickly and divides into two parts. The big cranial portion of hepatic diverticulum is anlage of the liver. The proliferating endodermal cells give rise to intertwining cords of hepatic cells and to the epithelial liner of the intrahepatic portion of bilious apparatus33 ( Moor2003 ) .
The hepatic cords anastomose around endothelium lined infinites, the anlage of the hepatic sinusoids. The hempen and hemopoiteic tissue and kupffer cells of liver are derived from mesenchyme in the septum. Initially the right and left lobes are about the same size but the right lobe shortly becomes larger.
Gross anatomy of Rabbit liver
The liver is attached to the stop by a crease of peritoneum, its substance amiss divided by a series of crevices into five lobes. From each lobe arises a bantam hepatic canal and theses unite reciprocally and with the cystic canal from the thin walled gall vesica, situate in a depression on the right posterior surface of the liver. The common gall canal formed by the brotherhood of the cystic and hepatic canals, opens into the dorsal facet of duodenum near the pylorus34 ( Parker T. J.1962 )