Diclofenac

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Diclofenac
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200px
Systematic (IUPAC) name
2-(2-(2,6-dichlorophenylamino)phenyl)acetic acid
Clinical data
Pregnancy
category
  • AU: A
  • B (1st. and 2nd. trimenon), X (third trimenon)
Routes of
administration		 oral, rectal, im, iv (renal- and gallstones), topical
Legal status
Legal status
  • UK: Pharmacy medicines
  • Rx-only most preparations/countries. Limited OTC some countries. Manufacture and veterinary use is banned in India, Nepal and Pakistan due to imminent extinction of local vultures.
Pharmacokinetic data
Protein binding more than 99%
Metabolism hepatic, no active metabolites exist
Biological half-life 1.2-2 hr (35% of the drug enters enterohepatic recirculation)
Excretion biliary, only 1% in urine
Identifiers
CAS Number 15307-86-5
ATC code D11AX18 (WHO) M01AB05, M02AA15, S01BC03
PubChem CID 3033
DrugBank APRD00527
ChemSpider 2925
Chemical data
Formula C14H11Cl2NO2
Molar mass 296.148 g/mol[[Script error: No such module "String".]]
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Diclofenac (marketed under many names, see below: Trade names) is a non-steroidal anti-inflammatory drug (NSAID) taken to reduce inflammation and as an analgesic reducing pain in conditions such as arthritis or acute injury. It can also be used to reduce menstrual pain, dysmenorrhea. The name is derived from its chemical name: 2-(2,6-dichloranilino) phenylacetic acid.

In the United Kingdom, India, Brazil and the United States, it may be supplied as either the sodium or potassium salt, in China most often as the sodium salt, while in some other countries only as the potassium salt. Diclofenac is available as a generic drug in a number of formulations. Over the counter (OTC) use is approved in some countries for minor aches and pains and fever associated with common infections.

Meloxicam has been recommended to replace use of diclofenac, due to side effects in humans and toxicity in livestock eaten by vultures.[1]

History

Diclofenac originated from Ciba-Geigy (now Novartis) in 1973.[2] Diclofenac was first introduced in the UK in 1979.[3][4]

Mechanism of action[5]

The exact mechanism of action is not entirely known, but it is thought that the primary mechanism responsible for its anti-inflammatory, antipyretic, and analgesic action is inhibition of prostaglandin synthesis by inhibition of cyclooxygenase (COX), and it appears to inhibit DNA synthesis.[6]

Inhibition of COX also decreases prostaglandins in the epithelium of the stomach, making it more sensitive to corrosion by gastric acid.[citation needed] This is also the main side effect of diclofenac. Diclofenac has a low to moderate preference to block the COX2-isoenzyme (approximately 10-fold) and is said to have therefore a somewhat lower incidence of gastrointestinal complaints than noted with indomethacin and aspirin.[citation needed]

The action of one single dose is much longer (6 to 8 hours) than the very short half-life that the drug indicates.[citation needed] This could be due partly to a particular high concentration achieved in synovial fluids.

Diclofenac may also be a unique member of the NSAIDs. There is some evidence that diclofenac inhibits the lipoxygenase pathways,[citation needed] thus reducing formation of the leukotrienes (also pro-inflammatory autacoids). There is also speculation[by whom?] that diclofenac may inhibit phospholipase A2 as part of its mechanism of action. These additional actions may explain the high potency of diclofenac – it is the most potent NSAID on a broad basis.[citation needed]

There are marked differences among NSAIDs in their selective inhibition of the two subtypes of cyclo-oxygenase, COX-1 and COX-2.[citation needed] Much pharmaceutical drug design has attempted to focus on selective COX-2 inhibition as a way to minimize the gastrointestinal side effects of NSAIDs like aspirin. In practice, use of some COX-2 inhibitors with their adverse effects has led to massive numbers of patient family lawsuits alleging wrongful death by heart attack, yet other significantly COX-selective NSAIDs such as diclofenac have been well-tolerated by most of the population.[citation needed]

Besides the well-known and often-cited COX-inhibition, a number of other molecular targets of diclofenac have recently been identified which could contribute to its pain-relieving actions. These include:

  • Blockage of voltage-dependent sodium channels (after activation of the channel, diclofenac inhibits its reactivation also known as phase inhibition)[citation needed]
  • Positive allosteric modulation of KCNQ- and BK-potassium channels (diclofenac opens these channels, leading to hyperpolarization of the cell membrane)[citation needed]

Indications

File:Voltaren tablets.jpg
Voltaren enteric coated tablets (AU)
File:Arthrotec50.JPG
Combined Diclofenac sodium and misoprostol tablets

Diclofenac is used for musculoskeletal complaints, especially arthritis, rheumatoid arthritis, polymyositis, dermatomyositis, osteoarthritis, dental pain, TMJ, spondylarthritis, ankylosing spondylitis, gout attacks,[7] and pain management in cases of kidney stones and gallstones. An additional indication is the treatment of acute migraines.[citation needed] Diclofenac is used commonly to treat mild to moderate post-operative or post-traumatic pain, particularly when inflammation is also present,[7] and is effective against menstrual pain and endometriosis.

File:Diclofenac sodium IV 75mg.jpg
A vial of Diclofenac sodium intended for IV/IM use
File:Diclofenac sodium 100mg.jpg
Diclofenac suppositories

As long-term use of diclofenac and similar NSAIDs predisposes for peptic ulcer, many patients at risk for this complication are prescribed a combination (Arthrotec) of diclofenac and misoprostol, a synthetic prostaglandin analogue, to protect the gastric mucosa.[citation needed]

An external, gel-based formulation containing 3% of diclofenac (Solaraze) is available for the treatment of facial actinic keratosis which is caused by over-exposure to sunlight. Some countries have also approved the external use of diclofenac 1% gel to treat musculoskeletal conditions.

Over-the-counter use against minor aches and pains and fever associated with common infections is also licensed in some countries, such as Australia and New Zealand.[citation needed]

In many countries[where?] eye-drops are sold to treat acute and chronic non-bacterial inflammations of the anterior part of the eyes (e.g. postoperative states).[citation needed] A common brand name is Voltaren-ophta.


Off label/investigational uses

Diclofenac is often used to treat chronic pain associated with cancer, particularly if inflammation is also present (Step I of the World Health Organization (WHO) Scheme for treatment of chronic pain). Good results (sometimes better than those with opioids) have been seen in female breast cancer and in the pain associated with bony metastases.[citation needed] Diclofenac can be combined with opioids if needed. Combaren, a fixed combination of diclofenac and codeine (50 mg each), is available for cancer treatment in Europe.[citation needed] Combinations with psychoactive drugs such as chlorprothixene and/or amitriptyline have also been investigated and found useful in a number of cancer patients.[citation needed]

Fever due to malignant lymphogranulomatosis (Hodgkin's lymphoma) often responds to diclofenac.[citation needed] Treatment can be terminated as soon as the usual treatment with radiation and/or chemotherapy causes remission of fever.

Diclofenac may prevent the development of Alzheimer's disease if given daily in small doses during many years.[citation needed] All investigations were stopped after it was found that some of the other investigated NSAIDs (naproxen, rofecoxib) caused a higher incidence of death cases due to cardiovascular events and stroke compared to placebo.[citation needed]

Diclofenac has been found to increase the blood pressure in patients with Shy-Drager syndrome and Diabetes Mellitus. Currently, this use is highly investigative and cannot be recommended as routine treatment.

Diclofenac has been found to be effective against all strains of multi drug resistant E. coli, with a MIC of 25 micrograms/mL. Therefore, it may be suggested that diclofenac has the capacity to treat uncomplicated urinary tract infections (UTI) caused by E. coli.[8] It has also been shown to be effective in treating Salmonella infections in mice[9] and is under investigation for the treatment of tuberculosis.[10]

Diclofenac is an antiuricosuric.[11]

Contraindications

  • Hypersensitivity against diclofenac
  • History of allergic reactions (bronchospasm, shock, rhinitis, urticaria) following the use of Aspirin or another NSAID
  • Third-trimester pregnancy
  • Active stomach and/or duodenal ulceration or gastrointestinal bleeding
  • Inflammative intestinal disorders such as Crohn's disease or ulcerative colitis
  • Severe insufficiency of the heart (NYHA III/IV)
  • Recently, a warning has been issued by FDA not to use to treat patients recovering from heart surgery
  • Severe liver insufficiency (Child-Pugh Class C)
  • Severe renal insufficiency (creatinine clearance <30 ml/min)
  • Caution in patients with preexisting hepatic porphyria, as diclofenac may trigger attacks
  • Caution in patients with severe, active bleeding such as cerebral hemorrhage
  • NSAIDs in general should be avoided during dengue fever.

Side effects

  • Diclofenac is among the better tolerated NSAIDs. Though 20% of patients on long-term treatment experience side effects, only 2% have to discontinue the drug, mostly due to gastrointestinal complaints.

Cardiac

  • Following the identification of increased risks of heart attacks with the selective COX-2 inhibitor rofecoxib in 2004, attention has focused on all the other members of the NSAIDs group, including diclofenac. Research results are mixed with a meta-analysis of papers and reports up to April 2006 suggesting a relative increased rate of heart disease of 1.63 compared to non-users.[12] Professor Peter Weissberg, Medical Director of the British Heart Foundation said, "However, the increased risk is small, and many patients with chronic debilitating pain may well feel that this small risk is worth taking to relieve their symptoms". Only Aspirin was found not to increase the risk of heart disease; however, this is known to have a higher rate of gastric ulceration than diclofenac.

A subsequent large study of 74,838 users of NSAIDs or coxibs, published in May 2006, found no additional cardiovascular risk from diclofenac use.[13] A very large study of 1,028,437 Danish users of various NSAIDs or coxibs, published online on June 8, 2010, found that "Use of the nonselective NSAID diclofenac and the selective cyclooxygenase-2 inhibitor rofecoxib was associated with an increased risk of cardiovascular death (odds ratio, 1.91; 95% confidence interval, 1.62 to 2.42; and odds ratio, 1.66; 95% confidence interval, 1.06 to 2.59, respectively), with a dose-dependent increase in risk." .[14]

  • Diclofenac has similar COX-2 selectivity to celecoxib.[15] Perhaps related to this selectivity, a review of this constantly-changing topic by FDA Medical Officer David Graham concluded in September, 2006 that diclofenac does increase the risk of myocardial infarction.[16]

Gastrointestinal

  • Gastrointestinal complaints are most often noted (see above). The development of ulceration and/or bleeding requires immediate termination of treatment with diclofenac. Most patients receive an ulcer-protective drug as prophylaxis during long-term treatment (misoprostol, ranitidine 150 mg at bedtime or omeprazole 20 mg at bedtime).

Hepatic

  • Liver damage occurs infrequently, and is usually reversible. Hepatitis may occur rarely without any warning symptoms and may be fatal. Patients with osteoarthritis more often develop symptomatic liver disease than patients with rheumatoid arthritis. Liver function should be monitored regularly during long-term treatment. If used for the short term treatment of pain or fever, diclofenac has not been found to be more hepatotoxic than other NSAIDs.
  • As of 12/2009 Endo, Novartis and FDA notified healthcare professionals to add new warnings and precautions about the potential for elevation in liver function tests during treatment with all products containing diclofenac sodium.[17]
  • Cases of drug-induced hepatotoxicity have been reported in the first month, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation.
  • Physicians should measure transaminases periodically in patients receiving long-term therapy with diclofenac. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac.

Renal

  • Studies in Pakistan showed that diclofenac caused acute kidney failure in vultures when they ate the carcasses of animals that had recently been treated with it (see below at Ecological problems). Species and individual humans that are drug sensitive are initially assumed to lack genes expressing specific drug detoxification enzymes.
  • NSAIDs "are associated with adverse renal [kidney] effects caused by the reduction in synthesis of renal prostaglandins"[18] in sensitive persons or animal species, and potentially during long term use in non-sensitive persons if resistance to side effects decreases with age. Unfortunately this side effect can't be avoided merely by using a COX-2 selective inhibitor because, "Both isoforms of COX, COX-1 and COX-2, are expressed in the kidney... Consequently, the same precautions regarding renal risk that are followed for nonselective NSAIDs should be used when selective COX-2 inhibitors are administered."[18] However, diclofenac appears to have a different mechanism of renal toxicity.[11]

Other

  • Bone marrow depression is noted infrequently (leukopenia, agranulocytosis, thrombopenia with/without purpura, aplastic anemia). These conditions may be life-threatening and/or irreversible, if detected too late. All patients should be monitored closely. Diclofenac is a weak and reversible inhibitor of thrombocytic aggregation needed for normal coagulation.
  • Induces warm antibody hemolytic anemia by inducing antibodies to Rh antigens, Ibuprofen also does this.[19]
  • Diclofenac may disrupt the normal menstrual cycle.

Ecological problems

Use of diclofenac in animals has been reported to have led to a sharp decline in the vulture population in the Indian subcontinent, 95% decline in 2003,[20] 99.9% decline as of 2008. The mechanism is probably renal failure, a known side-effect of diclofenac. Vultures eat the carcasses of livestock which have been administered veterinary diclofenac, and are poisoned by the accumulated chemical.[1] At a meeting of the National Wildlife Board in March 2005, the Government of India announced that it intended to phase out the veterinary use of diclofenac.[21] Meloxicam is a safer candidate to replace use of diclofenac.[22] It is more expensive than diclofenac, but the price is coming down as more drug companies begin to manufacture it.[23]

"The loss of tens of millions of vultures over the last decade has had major ecological consequences across the Indian subcontinent that pose a potential threat to human health. In many places, populations of feral dogs (Canis familiaris) have increased sharply from the disappearance of Gyps vultures as the main scavenger of wild and domestic ungulate carcasses. Associated with the rise in dog numbers is an increased risk of rabies"[22] and casualties of almost 50,000 people.[24] The Government of India cites one of those major consequences as a vulture species extinction.[21] A major shift in transfer of corpse pathogens from vultures to feral dogs and rats can lead to a disease pandemic causing millions of deaths in a crowded country like India. The resulting multiplication of feral dogs in India and Pakistan has also caused a multiplication of leopards feeding on those dogs and invading urban areas looking for dogs to prey on, resulting in occasional attacks on human children.[25]

The loss of vultures has had a social impact on the Indian Zoroastrian Parsi community, who traditionally use vultures to dispose of human corpses in Towers of Silence, but are now compelled to seek alternate methods of disposal.[22]

Diclofenac has been shown also to harm freshwater fish species such as rainbow trout.[26][27][28][29]

Formulations

File:Dicloflexec50.JPG
Enteric Coated Diclofenac Sodium tablets by Dexcel-Pharma Ltd.

Pennsaid is a minimally systemic prescription topical lotion formulation of 1.5% w/w diclofenac sodium which is approved in the US, Canada and other countries for osteoarthritis of the knee.

Flector Patch is a minimally systemic topical patch formulation of diclofenac. It is indicated for acute pain due to minor sprains, strains, and contusions. The patch has been approved in many other countries outside the U.S.A under different brand names..

Voltaren and Voltarol contain the sodium salt of diclofenac. In the United Kingdom Voltarol can be supplied with either the sodium salt or potassium salt, while Cataflam in some other countries is the potassium salt only.

Diclofenac is available in stomach acid resistant formulations (25 and 50 mg), fast disintegrating oral formulations (25 and 50 mg), slow- and controlled-release forms (75, 100 or 150 mg), suppositories (50 and 100 mg), and injectable forms (50 and 75 mg).

Diclofenac is also available over the counter (OTC) in some countries: 12.5 mg diclofenac as potassium salt in Switzerland, Germany ("Voltaren dolo"), United Kingdom (since October 2008 as "Voltarol Pain-eze"), and preparations containing 25 mg diclofenac as the potassium salt in New Zealand, Australia, Japan, ("Voltaren Rapid"), and Sweden ("Voltaren T" and "Diclofenac T"). Diclofenac as potassium salt can be found throughout the Middle East in 25 mg and 50 mg doses ("Cataflam").

Trade names

Trade names include:

Safeguard ( Diclofenac and misoprostol for Arthritis Condition)

References

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External links

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  1. ↑ 1.0 1.1 "Vet drug 'killing Asian vultures'", BBC News, 28 January 2004, webpage: BBC583.
  2. ↑ http://www.novartis.com/about-novartis/company-history/index.shtml
  3. ↑ http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1434053
  4. ↑ Salmann, AR (1986) The history of diclofenac. Am. J. Med. 80(4B): 29-33
  5. ↑ "Data Sheet: Voltaren Rapid 25". Information for Health Professionals. Medsafe - New Zealand Medicines and Medical Devices Safety Authority. 2007-07-10. Retrieved 2009-03-17. 
  6. ↑ Dutta NK, Annadurai S, Mazumdar K, Dastidar SG, Kristiansen JE, Molnar J, Martins M, Amaral L (2000). "The anti-bacterial action of diclofenac shown by inhibition of DNA synthesis". Int. J. Antimicrob. Agents. 14 (3): 249–51. doi:10.1016/S0924-8579(99)00159-4. PMID 10773497. 
  7. ↑ 7.0 7.1 "RUFENAL", Birzeit Pharmaceutical Company, BPC.ps, web: [3].
  8. ↑ Mazumdar K, Dutta NK, Dastidar SG, Motohashi N, Shirataki Y (2006). "Diclofenac in the management of E. coli urinary tract infections". In Vivo. 20 (5): 613–619. PMID 17091768. 
  9. ↑ Dutta NK, Annadurai S, Mazumdar K, Dastidar SG, Kristiansen JE, Molnar J, Martins M, Amaral L. (2007). "Potential management of resistant microbial infections with a novel non-antibiotic: the anti-inflammatory drug diclofenac sodium". Int. J. Antimicrob. Agents. 30 (3): 242–249. doi:10.1016/j.ijantimicag.2007.04.018. PMID 17644318. 
  10. ↑ Dutta NK, Mazumdar K, Dastidar SG, Park JH (2007). "Activity of diclofenac used alone and in combination with streptomycin against Mycobacterium tuberculosis in mice". Int. J. Antimicrob. Agents. 30 (4): 336–340. doi:10.1016/j.ijantimicag.2007.04.016. PMID 17644321. 
  11. ↑ 11.0 11.1 Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  12. ↑ Kearney P, Baigent C, Godwin J, Halls H, Emberson J, Patrono C (2006). "Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials". BMJ. 332 (7553): 1302–8. doi:10.1136/bmj.332.7553.1302. PMC 1473048 Freely accessible. PMID 16740558. 
  13. ↑ Solomon D, Avorn J, Stürmer T, Glynn R, Mogun H, Schneeweiss S (2006). "Cardiovascular outcomes in new users of coxibs and nonsteroidal antiinflammatory drugs: high-risk subgroups and time course of risk". Arthritis Rheum. 54 (5): 1378–89. doi:10.1002/art.21887. PMID 16645966. 
  14. ↑ Fosbøl EL, Folke F, Jacobsen S, Rasmussen JN, Sørensen R, Schramm TK, Andersen SS, Rasmussen S, Poulsen HE, Køber L, Torp-Pedersen C, Gislason GH (2010). "Cause-Specific Cardiovascular Risk Associated With Nonsteroidal Antiinflammatory Drugs Among Healthy Individuals". Circ Cardiovasc Qual Outcomes. 3 (4): 395–405. doi:10.1161/CIRCOUTCOMES.109.861104. PMID 20530789. 
  15. ↑ FitzGerald G, Patrono C (2001). "The coxibs, selective inhibitors of cyclooxygenase-2". N Engl J Med. 345 (6): 433–42. doi:10.1056/NEJM200108093450607. PMID 11496855. 
  16. ↑ Graham D (2006). "COX-2 inhibitors, other NSAIDs, and cardiovascular risk: the seduction of common sense". JAMA. 296 (13): 1653–6. doi:10.1001/jama.296.13.jed60058. PMID 16968830. 
  17. ↑ http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm193047.htm
  18. ↑ 18.0 18.1 Brater DC (2002). "Renal effects of cyclooxygyenase-2-selective inhibitors". J Pain Symptom Manage. 23 (4 Suppl): S15–20; discussion S21–3. doi:10.1016/S0885-3924(02)00370-6. PMID 11992745. 
  19. ↑ www.merck.com/mmpe/sec11/ch131/ch131b.html?qt=diclofenac&alt=sh#sec11-ch131-ch131b-174
  20. ↑ Oaks JL, Gilbert M, Virani MZ, Watson RT, Meteyer CU, Rideout BA, Shivaprasad HL, Ahmed S, Chaudhry MJ, Arshad M, Mahmood S, Ali A, Khan AA (2004). "Diclofenac residues as the cause of vulture population decline in Pakistan". Nature. 427 (6975): 630–3. doi:10.1038/nature02317. PMID 14745453. 
  21. ↑ 21.0 21.1 "Saving the Vultures from Extinction" (Press release). Press Information Bureau, Government of India. 2005-05-16. http://pib.nic.in/release/release.asp?relid=9303. Retrieved 2006-05-12. 
  22. ↑ 22.0 22.1 22.2 Swan G, Naidoo V, Cuthbert R, Green RE, Pain DJ, Swarup D, Prakash V, Taggart M, Bekker L, Das D, Diekmann J, Diekmann M, Killian E, Meharg A, Patra RC, Saini M, Wolter K (2006). "Removing the threat of diclofenac to critically endangered Asian vultures". PLoS Biol. 4 (3): e66. doi:10.1371/journal.pbio.0040066. PMC 1351921 Freely accessible. PMID 16435886. 
  23. ↑ Gill, V. New drug threat to Asian vultures BBC News December 9, 2009.
  24. ↑ Rabies follows disruption in food cycle
  25. ↑ Nature Shock, UK Channel 5 television, Tuesday 7 Sept 2010,8 to 9 pm,
  26. ↑ Schwaiger et al. (2004). Aquat. Toxicol. 68(2): 141-150
  27. ↑ Triebskorn et al. (2004). Aquat. Toxicol. 68(2): 151-166
  28. ↑ Schwaiger & Triebskorn (2005). UBA-Berichte 29/05: 217-226
  29. ↑ Triebskorn et al. (2007). Analyt. Bioanalyt. Chem. 387(4):1405–1416
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