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Diclofenac sodium 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 kind, while being one of the best tolerated NSAIDs2 (Brunner and Krupp 1976).
It is the most commonly prescribed NSAID in the United Kingdom3 (NG. Ryley). The number of patients taking NSAID is > 30 millions in the United States This number also indicates that a considerable number of populations are exposed to its potential 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 eighteenth century aspirin was isolated as the first analgesic drug of this group by Leroux who also demonstrated its antipyretic effect. By the end of nineteenth century other drugs were discovered that shared some or all of these actions6 (Gillman 1996).
The NSAIDs are classified on the basis of their chemical structure. They are either non-selective Cox inhibitor or selective Cox-2 inhibitor.
In non selective Cox inhibitor we have aspirine, actaminophene, indomethacin, ibuprofen, mefanamic acid, piroxcam and Diclofenac.
Selective COX-2 inhibitors are rofecoxib, celecoxib, endolac, nimesulide etc. Diclofenac is used as sodium salt or potassium salt.
Mechanism of action
Major mechanism of action of NSAIDs is the inhibition of cyclooxygenase activity and therefore the synthesis of prostaglandins7 (John A 1991). The cyclooxygenase is the enzyme which converts arachidonic acid to prostaglandin; arachidonic acid is a structural component of phospholipids into cell membrane and subcellular structures of all tissues of the body. Arachidonic acid is metabolized or released from the membrane phospholipids. Following mobilization, arachidonic acid is oxygenated by four separate routes the cyclooxygenase (COX), lipooxygenase, p450 epoxygenase and isoprostane pathways8 (Katzung 2007).
In cyclooxygenase pathway prostaglandin H2 is synthesized this prostaglandin is converted into one of the three compounds, PGF2a or PGD2 or PGE2.
Two forms of cyclooxygenase termed Cox-1 and Cox-2 have been identified. Cox -1 is expressed in most cells of the body while Cox-2 is induced in inflammation and in cancers. However Cox-2 also is constitutively expressed in certain areas of brain and kidney9 10 (Breder et al., 1995: Harris et al., 1994). Importantly Cox-1 but not Cox-2 is expressed in the stomach. This accounts for markedly reduced occurrence of gastric toxicity with the use of selective inhibitor of Cox-2 6(Gillman, 1996).
Prostaglandins are released whenever cells are damaged, they appear in inflammatory exudates and almost all NSAIDs inhibit the biosynthesis of prostaglandins in all cells11 (Vane et al., 1987).
Inflammatory process is the body's defense mechanism against the infectious agents, ischemia, antigen-antibody interaction, physical injury and other pathogens. Prostaglandins are released in response to all of the above mentioned stimuli. PGE2 and prostacyclin (PGI2) cause erythema and increase in local blood flow due to vasodilatation and increase capillary permeability. There is also infiltration of leucocytes and Phagocytic cells12 (Lippincott 2006).
Pain is a phenomenon which results from stimulation of pain fibers by chemical or mechanical stimuli. Bradykinin which is released from plasma kinenogen and cytokine elicit the pain of inflammation. It liberates prostaglandins that promote hyperalgesia. Neuropeptides such as substance 'P' and calciterin, gene related peptide also may be involved in eliciting pain. Prostaglandin can cause headache and vascular pain when infused intravenously. Prostaglandin also lowers the threshold of 'C' fibers.
Fever may result by infection, squealae of tissue damage, inflammation, malignancy or other disease state. These conditions enhance the formation of cytokinase. The cytokinase in turn increases the synthesis of PGE2 in hypothalamus. PGE2 in hypothalamus increases the formation of cyclic AMP; this triggers the hypothalamus to elevate body temperature by promoting increase in heat generation and decrease in heat loss. Diclofenac suppresses this response by inhibiting the synthesis of PGE2 (Roberts et al., 2001)13.
NSAIDs either inhibit Cox-1 or Cox-2 or both and the therapeutic effect of each of NSAIDs depends on its binding capacity with Cox-1 or Cox-2. These drugs covalently modify cyclooxygenase enzyme and prevent the binding of arachidonic acid to the active site of enzyme to make prostaglandin. Diclofenac sodium is the non selective Cox inhibitor. Platelets are especially susceptible to the action of Diclofenac as they have little or no capacity of protein biosynthesis and thus can not regenerate the cyclooxygenase enzyme.
Vast majority of NSAIDs are organic acids and act as reversible competitive inhibitor of cyclooxygenase activity.
These compounds are generally well absorbed orally. They are highly bound to plasma proteins and excreted either by glomerular filtration or by tubular secretion. Experiments showed that the main route of drug elimination is different in various species; renal excretion is being the most important in man and rhesus monkey1 (D. Schapira 1986).
Duration of action of all NSAIDs (except aspirin) is primarily related to the pharmacokinetic clearance of the from the body, they are roughly 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 inflammation, which is an attractive pharmacokinetic property of drugs intended as anti inflammatory agents.
All NSAIDs including Cox-2 inhibitors are antipyretic, analgesic and anti-inflammatory except acetaminophen, which is devoid of anti-inflammatory activity14 15(Morrison et al., 1999; Malmstrome et al., 1999).
When employed as analgesics these drugs usually are effective only against pain of low-to-moderate intensity such as dental pain. Pain arising from inflammation is particularly well controlled by NSAIDs, where pain arising from the hollow viscera usually not relieved.
As antipyretic Diclofenac sodium reduces the body temperature in febrile states.
Chief clinical application of Diclofenac sodium is as anti-inflammatory agent in the treatment of musculoskeletal disorders such as rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. Chronic treatment of patients with Cox-2 inhibitors has shown to be effective in suppressing inflammation without gastric toxicity16 17 18 (Benson et al., 1999; Emery et al., 1999; Hawkey et al., 2000). In general Diclofenac sodium provides only symptomatic relief from pain and inflammation associated with the disease and does not arrest the progression of pathological injury to the tissue.
Diclofenac sodium has been found effective in the control of postoperative pain when used pre-operatively19 (Wuolijoki et al., 1987). Other uses of Diclofenac sodium also depend upon their capacity to block prostaglandin biosynthesis. Prostaglandins have been implicated in the maintenance of patency of ductus arteriosus, and the Diclofenac have been used in neonates to close the ductus arteriosus when it has remained patent20 (Clyman et al., 1999).
Prostaglandins are released from endometrium during menstruation, thus causing cramps and dysmenorrhoea. Treatment of this condition with Diclofenac met with considerable success21 (Shapiro, 1988).
In systemic mastocytosis PGD2 is released from the mast cells and antihistamine are ineffective in this condition while Diclofenac sodium usually leads to effective prevention of episodes22 (Roberts and Oates 1991).
In the treatment of Bartler' syndrome Diclofenac sodium has been found a useful agent. In a study carried by Thu et al23 (1991) and Giovannucci et al 24(1995), it was found that there is about 50% reduction in the incidence of colon cancer by the frequent use of Diclofenac sodium.
Incidences of drug associated adverse effects are 12%:
The most frequently reported adverse effects are gastrointestinal, reported in 7.6% of patients25 (Martindale, 1994).
Renal papillary necrosis and nephrotic syndrome have been reported in patients taking Diclofenac and other NSAIDs26 (Scott et al., 1986).
Diclofenac at a dosage of 150mg/d appear to impair renal blood flow and glomerular filtration rate8 (Katzung 2007).
Other effects are elevation of serum aminotransferase activity and clinical hepatitis. Reports of hepatic injury range from insignificant and transient liver enzyme elevation, to sever and fulminent hepatitis27.(AV Manoukian 1996)
Self limiting skin reactions such as rash or pruritis may occur in patients given Diclofenac sodium.
There are also reports of haematological abnormalities including haemolytic anaemia thrombocytopenia and agranulocytosis occurring in patients given Diclofenac28 (Kramer 1986).
Localized spontaneous bleeding, bruising, inhibition of platelet, aggregation and prolonged bleeding time have been reported. Most of these effects are as results from blockage of synthesis of endogenous prostaglandin and thromboxane A2.
Prolongation of gestation and or spontaneous labour and premature closure of patent ductus have been observed.
Absorption and fate
Diclofenac is rapidly and completely absorbed after oral administration, intramuscular injection and rectal suppositories. It is absorbed slowly if given with food, and absorbed more slowly when given as an enteric coated tablets25 (Martindale, 1994).
Although orally administered Diclofenac is almost completely absorbed, it is subject to first pass metabolism so that only 50-60 % of the drug reaches the systemic circulation in the unchanged form. Diclofenac is also absorbed percutaneously.
Peak concentrations in plasma are reached within 2-3 hours. Diclofenac penetrates synovial fluid and has been detected in breast milk29 (fowler et al., 1983). It has been detected in synovial fluids two hours after dose and remained constant for nine hours.
Diclofenac is metabolized to 4-hydroxydiclofenac, 5-hydroxydiclofenac, 3-hydroxydiclofenac and 4', 5-dihydroxy Diclofenac. It is then excreted in the form of glucoronoid and sulphate conjugate mainly in the urine (65%) but also in the bile (35%).
Bioavailability following oral administration is only 50% due to first pass effect, i.e. 50% of the drug is metabolized by liver as it first passes through it.
The usual dose by mouth is 75 to 150 mg of Diclofenac sodium daily in divided doses. It may also be given as rectal suppositories in a usual dose 100mg each evening. By injection is 75 mg once daily or twice daily in sever conditions. In children the recommended dose is 1-3mg /kg body weight daily in divided doses for juvenile arthritis25 (Martindale, 1994).
A 0.1%opthalamic preparation is recommended for prevention of postoperative ophthalmic inflammation and can be used after intraocular lens implantation and strabismus surgery.
Gross anatomy- It is the 2nd largest organ and the largest gland of the body.
It is a wedge shaped organ in the right hypochondrium and epigastrium. Surfaces are diaphragmatic and visceral. For the purpose of description the diaphragmatic surface is further divided into anterior, superior right and posterior.
Hepatic veins emerge from the posterior surface while all the other structures enter or leave the liver at porta hepatic. Ligamentum teres lies at the lower free margin of falciform ligament while right and left triangular ligament lie on the posterior surface of respective lobes which are actually folds of peritoneum from the lobes to the abdominal wall.
An H-shaped pattern of structures is seen on posterior and visceral surfaces when viewed from below. Porta hepatis forms the central line of H, while the right limb is formed by inferior vena cava and gall bladder. The left limb is formed by the fissures of ligamentum venosum and ligamentum teres. To the right of inferior vena cava bare area of liver. At porta hepatis the three structures lie as vein artery and duct from behind forward so the duct is more accessible during surgery30 (Sinnatamby 2003)
Gall bladder lies in the fossa on visceral surface with cystic duct close to the right end of porta hepatis. Quadrate lobe lies between the gall bladder and the fissure for ligamentum teres.
The bare area is in contact with right surface and diaphragm. The visceral surface is in relation with stomach, duodenum hepatic flexure of colon and right kidney. Esophageal impression 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 using the attachment of falciform ligament and fissure for ligamentum teres and venosum as the line of demarcation. The caudate and quadrate lobes lie on the posterior and visceral surfaces respectively. They were considered as the part of right lobe.
The branching pattern of blood supply and biliary drainage in the liver creates a system of lobes and further subdivisions (sectors or segments). This also reflects the early development. The common hepatic artery, portal vein and bile duct divide and subdivide with a common pattern31 (William et al., 1995). On the basis of blood supply and biliary drainage there are four hepatic sectors, left lateral and left medial sectors and the right anterior and right posterior hepatic sectors. These four sectors are further subdivided into eight segments which are numbered using roman numerals. Caudate lobe is assigned as segment no I, it lies in left functional plane. It is an autonomous segment receiving blood from right and left branches of hepatic artery and portal vein. It drains the bile into right and left hepatic ducts.
Segment II and III lie in left lateral sector. Quadrate lobe is the segment IV. Inferior segment of right anterior sector is segment V and the right posterior is segment VI. Segments VII and VIII are the superior segments of right posterior and right anterior sectors respectively. These segments are arranged in approximately anticlockwise direction around the porta hepatis.
Liver receives both arterial and venous blood. Arterial blood is brought about through hepatic artery which divides into right and left branches in the porta hepatis. The right branch divides into anterior and posterior sectoral branches.
The left branch divides into medial and lateral sectoral branches.
Venous blood is carried to the liver by portal vein. Portal vein in turn divides into right and left branches which give sectoral branches like the arteries. There is no communication between the right and left halves of the liver, even within each half the arteries are end arteries.
The venous return differs that it shows mixing of right and left halves of liver. There are three main hepatic veins. A large central vein receives the blood from each half of the liver. Further laterally are right and left veins all the veins have no extrahepatic course31. (William et al., 1995)
Hepatic lymph vessels are divisible into superficial and deep systems. They run in subserosal areolar tissue over the whole surface of the organ draining in four directions.
The hepatic nerves arise from the hepatic plexus containing sympathetic and parasympathetic fibers. They enter the porta hepatis and largely accompany blood vessels and bile ducts. Their lamination is uncertain (William et al., 1995)
The liver parenchymal cells, the hepatocytes are arranged into polyhedral lobules, which appear hexagonal in cross section. Terminal branches of hepatic artery and hepatic portal vein are located at the angels of lobule boundaries in portal tracts supplying more than one lobule. In the centre of each lobule lies cenrtrilobular Venule. In human there are no interlobular septa.
Another approach is to consider the functional unit of the liver to be the territory supplied by each terminal branch of the hepatic artery and hepatic porta vein. It is called a hepatic acinus. It is also polyhedral in shape with portal tract forming its central axis.
The hepatocytes form flat anastomosing plates usually only one cell thick. Sinusoids are present on both sides of these plates. These sinusoids are lined by discontinuous layer of cells which do not rest on basement membrane and which are separated from the hepatocytes by a narrow space the space of Disse. This space drains into the lymphatics of the portal tracts.
Hepatocytes themselves are large polyhedral cells with large round nuclei, with peripherally dispersed chromatin and prominent nucleoli. Occasional binuclear cells are also seen. Irregular unstained areas are visible within cytoplasm this is due to the fact that significant quantities of glycogen and lipid are stored in the hepatocytes, which are dissolved during tissue processing leaving unstained areas. Cytoplasm is eosinophilic with extensive ribosomes and RER.
The sinusoidal lining cells include endothelial cells, kupffer cells and fibroblasts. The endothelial cells have flattened nucleus and attenuated cytoplasm. Kupffer cells are large cells with ovoid nucleus. These cells form part of the monocyte-macrophage defense system and with the spleen participate in the removal of spent erythrocytes and other particulate debris from circulation.
Another cell type known as Ito cells or stellate cells can not be easily distinguished by light microscopy. These cell types have lipid droplets containing vitamin A in their cytoplasm. These cells have the dual function of vitamin A storage and production of extracellular matrix and collagen. During liver injury these cells are thought to produce greatly increased amount of collagen, causing the liver cirrhosis.
Supporting framework of the liver is formed by a fine meshwork of reticular fibers which radiate from the central vein to merge with the supporting tissue of portal tracts and lobule boundaries. External surface of the liver is covered by a capsule called Glisson's capsule. It is made up of collagen fibers.
Bile canaliculi are fine channels formed by the plasma membrane of adjacent hepatocytes. The canaliculi of adjacent hepatocytes plates merge to form canals of Herring. Finally they drain into bile ductules of the portal tracts32
The liver arises as a ventral outgrowth from the caudal part of the foregut early in the fourth week. At sufficient level, fibroblast growth factor (FGFs) secreted by the developing heart interacts with the bipotent endothelial cell and induce formation of the hepatic diverticulum. The hepatic diverticulum extends into the septum transversum, enlarges rapidly and divides into two parts. The large cranial part of hepatic diverticulum is primordium of the liver. The proliferating endodermal cells give rise to interlacing cords of hepatic cells and to the epithelial lining of the intrahepatic part of biliary apparatus33(Moor2003).
The hepatic cords anastomose around endothelium lined spaces, the primordium of the hepatic sinusoids. The fibrous 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 soon becomes larger.
Gross anatomy of Rabbit liver
The liver is attached to the diaphragm by a fold of peritoneum, its substance imperfectly divided by a series of fissures into five lobes. From each lobe arises a tiny hepatic duct and theses unite mutually and with the cystic duct from the thin walled gall bladder , situate in a depression on the right posterior surface of the liver. The common bile duct formed by the union of the cystic and hepatic ducts, opens into the dorsal aspect of duodenum near the pylorus34 (Parker T. J.1962)