Diclofenac

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Diclofenac
Systematic (IUPAC) name
2-(2-(2,6-dichlorophenylamino)phenyl)acetic acid
Clinical data
Trade namesAclonac, Cataflam, Voltaren
AHFS/Drugs.commonograph
MedlinePlusa689002
Pregnancy cat.C (AU) C (1st. and 2nd. trimenon), D (third trimenon)
Legal statusPrescription Only (S4) (AU) P (UK) Rx-only most preparations/countries, limited OTC in some countries, manufacture and veterinary use is banned in India, Nepal, and Pakistan due to imminent extinction of local vultures
Routesoral, rectal, intramuscular, intravenous (renal- and gallstones), topical
Pharmacokinetic data
Protein bindingmore than 99%
Metabolismhepatic, no active metabolites exist
Half-life1.2-2 hr (35% of the drug enters enterohepatic recirculation)
Excretion40% biliary 60% urine
Identifiers
CAS number15307-86-5 YesY
ATC codeD11AX18 M01AB05, M02AA15, S01BC03
PubChemCID 3033
IUPHAR ligand2714
DrugBankDB00586
ChemSpider2925 YesY
UNII144O8QL0L1 YesY
KEGGD07816 YesY
ChEBICHEBI:47381 YesY
ChEMBLCHEMBL139 YesY
Chemical data
FormulaC14H11Cl2NO2 
Mol. mass296.148 g/mol
 N (what is this?)  (verify)
 
  (Redirected from Voltaren)
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Diclofenac
Systematic (IUPAC) name
2-(2-(2,6-dichlorophenylamino)phenyl)acetic acid
Clinical data
Trade namesAclonac, Cataflam, Voltaren
AHFS/Drugs.commonograph
MedlinePlusa689002
Pregnancy cat.C (AU) C (1st. and 2nd. trimenon), D (third trimenon)
Legal statusPrescription Only (S4) (AU) P (UK) Rx-only most preparations/countries, limited OTC in some countries, manufacture and veterinary use is banned in India, Nepal, and Pakistan due to imminent extinction of local vultures
Routesoral, rectal, intramuscular, intravenous (renal- and gallstones), topical
Pharmacokinetic data
Protein bindingmore than 99%
Metabolismhepatic, no active metabolites exist
Half-life1.2-2 hr (35% of the drug enters enterohepatic recirculation)
Excretion40% biliary 60% urine
Identifiers
CAS number15307-86-5 YesY
ATC codeD11AX18 M01AB05, M02AA15, S01BC03
PubChemCID 3033
IUPHAR ligand2714
DrugBankDB00586
ChemSpider2925 YesY
UNII144O8QL0L1 YesY
KEGGD07816 YesY
ChEBICHEBI:47381 YesY
ChEMBLCHEMBL139 YesY
Chemical data
FormulaC14H11Cl2NO2 
Mol. mass296.148 g/mol
 N (what is this?)  (verify)

Diclofenac (cf. INN with trade names) is a nonsteroidal anti-inflammatory drug (NSAID) taken or applied to reduce inflammation and as an analgesic reducing pain in certain conditions, supplied as or contained in medications under a variety of trade names.

The name derives from its chemical name: 2-(2,6-dichloranilino) phenylacetic acid. Diclofenac originated from Ciba-Geigy (now Novartis) in 1973.[1] It was first introduced in the UK in 1979.[2][3]

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, including diclofenac diethylamine applied topically. Over-the-counter (OTC) use is approved in some countries for minor aches and pains and fever associated with common infections.

Medical uses[edit]

Diclofenac is used to treat pain, inflammatory disorders, and dysmenorrhea.[4]

Voltaren (diclofenac) 50 mg enteric coated tablets

Inflammatory disorders may include musculoskeletal complaints, especially arthritis, rheumatoid arthritis, polymyositis, dermatomyositis, osteoarthritis, dental pain, TMJ pain, spondylarthritis, ankylosing spondylitis, gout attacks,[5] and pain management in cases of kidney stones and gallstones. An additional indication is the treatment of acute migraines.[6] Diclofenac is used commonly to treat mild to moderate postoperative or post-traumatic pain, in particular when inflammation is also present,[5] and is effective against menstrual pain and endometriosis.

As long-term use of diclofenac and similar NSAIDs predisposes for peptic ulcer, many patients at risk for this complication are prescribed Arthrotec - a combination of diclofenac and misoprostol, a synthetic prostaglandin (PGE1) analogue, to protect the gastric mucosa.[citation needed]

Arthrotec (diclofenac and misoprostol) 50-mg tablets

Diclofenac is also available in topical forms under the brand names Flector, Pennsaid, Solaraze, and Voltaren for the treatment of conditions such as osteoarthritis, actinic keratosis, and acute pain caused by minor strains, sprains, and contusions (bruises).[7]

In many countries,[8] eye drops are sold to treat acute and chronic nonbacterial inflammations of the anterior part of the eyes (e.g., postoperative states).[citation needed] A common brand name is Voltaren-ophtha.

Investigational uses[edit]

Diclofenac is often used to treat chronic pain associated with cancer, in particular if inflammation is also present (Step I of the World Health Organization (WHO) scheme for treatment of chronic pain).[9] Good results (sometimes better than those with opioids) have been seen in the pain associated with bony metastases.[citation needed]

Dyloject (diclofenac) 2 ml for IV and IM administration

Diclofenac can be combined with opioids if needed. Under trade names such as Combaren and Voltaren Plus, a fixed combination of diclofenac and codeine (50 mg each) is available in Europe. 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.

Sintofarm (diclofenac) for suppository administration

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 effective against all strains of multidrug-resistant E. coli, with a MIC of 25 micrograms/ml. Therefore, it may have the capacity to treat uncomplicated urinary tract infections caused by E. coli.[10] It has also shown effectiveness in treating Salmonella infections in mice,[11] and is under investigation for the treatment of tuberculosis.[12]

Diclofenac is an antiuricosuric.[13]

This drug is dangerous to take within five days of having an EGD or a colonoscopy[citation needed]


Contraindications[edit]

Side effects[edit]

Cardiac[edit]

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 nonusers.[14] 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 found no additional cardiovascular risk from diclofenac use.[15] A very large study of 1,028,437 Danish users of various NSAIDs or coxibs found the "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."[16] In Britain the Medicines and Healthcare Products Regulatory Agency (MHRA) said in June 2013 that the drug should not be used by people with serious underlying heart conditions—people who had suffered heart failure, heart disease or a stroke were advised to stop using it completely.[17]

Diclofenac has similar COX-2 selectivity to celecoxib.[18] A review by FDA Medical Officer David Graham concluded diclofenac does increase the risk of myocardial infarction.[19]

Gastrointestinal[edit]

Hepatic[edit]

Renal[edit]

Mental health[edit]

Other[edit]

Mechanism of action[edit]

The exact mechanism of action is not entirely known, but the primary mechanism responsible for its anti-inflammatory, antipyretic, and analgesic action is thought to be inhibition of prostaglandin synthesis by inhibition of cyclooxygenase (COX). It also appears to exhibit bacteriostatic activity by inhibiting bacterial DNA synthesis.[25]

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 hr) than the very short half-life of the drug indicates.[citation needed] This could be partly because it persists for over 11 hours in synovial fluids.[26]

Diclofenac may also be a unique member of the NSAIDs. Some evidence indicates it inhibits the lipoxygenase pathways,[citation needed] thus reducing formation of the leukotrienes (also pro-inflammatory autacoids). It also may inhibit phospholipase A2 as part of its mechanism of action. These additional actions may explain its high potency - it is the most potent NSAID on a broad basis.[27]

Marked differences exist among NSAIDs in their selective inhibition of the two subtypes of cyclooxygenase, 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 such as 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 possibly contributing to its pain-relieving actions have recently been identified. These include:

Ecological effects[edit]

Use of diclofenac in animals has been reported to have led to a sharp decline in the vulture population in the Indian Subcontinent, a 95% decline in 2003,[28] 99.9% decline as of 2008. The mechanism is, it is presumed, renal failure, a known side effect of diclofenac. Vultures eat the carcasses of livestock that have been administered veterinary diclofenac, and are poisoned by the accumulated chemical,[29] as vultures do not have a particular enzyme to break down diclofenac. At a meeting of the National Wildlife Board in March 2005, the Government of India announced it intended to phase out the veterinary use of diclofenac.[30] Meloxicam is a safer candidate to replace use of diclofenac.[31] It is more expensive than diclofenac, but the price is coming down as more drug companies begin to manufacture it.[32]

"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"[31] and casualties of almost 50,000 people.[33] The Government of India cites this as one of those major consequences of a vulture species extinction.[30] 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; whereas vultures' digestive systems safely destroy many species of such pathogens.

The resulting multiplication of feral dogs in India and Pakistan has caused a multiplication of leopards feeding on those dogs and invading urban areas looking for dogs as prey, resulting in occasional attacks on human children.[34]

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 alternative methods of disposal.[31]

Diclofenac has been shown also to harm freshwater fish species such as rainbow trout.[35][36][37][38]

Formulations[edit]

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, a minimally systemic topical patch formulation of diclofenac, is indicated for acute pain due to minor sprains, strains, and contusions. The patch has been approved in many other countries outside the US 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 the potassium salt, while Cataflam in some other countries is the potassium salt only. However, Voltarol Emulgel contains it as dichlofenac diethylammonium where 1.16% is equivalent to 1% of the sodium variety.

Diclofenac is available in stomach acid-resistant formulations (25 and 50 mg), fast-disintegrating oral formulations (25 and 50 mg), powder for oral solution (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 in some countries: 12.5 mg diclofenac as potassium salt in Switzerland (Voltaren dolo), the Netherlands (Voltaren K), United Kingdom (since October 2008 as Voltarol Pain-eze), and preparations containing 25 mg diclofenac as the potassium salt in Germany (various trade names), 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). Solaraze (3% diclofenac sodium gel) is topically applied, twice a day for three months, to manage the skin condition known as actinic or solar keratosis. Parazone-DP is combination of diclofenac potassium and paracetamol, manufactured and supplied by Ozone Pharmaceuticals and Chemicals, Gujarat,India

Trade names[edit]

Trade names include:

  • Aclonac Emulsi Gel
  • A-fenac (Bangladesh)
  • Abitren
  • Acteric (Costa Rica)
  • Almiral
  • Anaflex (Argentina)
  • Anuva
  • Arthrotec (combination with misoprostol)
  • Artifen (Pakistan Abbott Laboratories LTD)
  • Befol
  • Berifen
  • Betaren
  • Bufenac Forte
  • Cambia
  • Cataflam
  • Catafast
  • Caflam (Pakistan)
  • Clafen
  • Clofast
  • Clonac
  • Dedolor
  • Deflamat
  • Deflox
  • Diclac
  • Diclo M (India & Myanmar) V.I.P Pharma
  • Dicloberl
  • Diclobene
  • Diclo-Denk (Germany)
  • Diclofenac
  • Diclofenac-Asteria (USA and Korea)
  • Diclofenaco Normon (Spain)
  • Diclofenacum
  • Dicloflam (South Africa)
  • Dicloflex
  • Diclogem
  • Diclogesic (Jordan and Romania)
  • Diclohexal
  • Diclon
  • Diclomex (Finland)
  • Dicloran (Malaysia)
  • Diclowin Plus (India)
  • Diclon
  • Diclopar (Tanzania)
  • Diclotab (Laos)
  • Diklofenak T Actavis (Sweden)
  • Difen
  • Difenac (Venezuela)
  • Difene
  • Dinac (Nepal)
  • Dioxaflex (Latin America, Central America)
  • Disflam K (diclofenac potassium, Central America)
  • Dolex
  • Dolphin (Egypt)
  • Dolmina (Czech Republic)
  • Dyloject
  • Feloran
  • Fenac (diclofenac potassium, Australia)
  • Flamrase
  • Flector Patch
  • Flogozan (Mexico)
  • Idinac (India)
  • Immunagel (India)
  • Kemoren (Indonesia)
  • Klodifen
  • Modifenac
  • Morbidic (India)
  • Motifene
  • Naklofen
  • Neofenac (Bangladesh)
  • Neopyrazon (United Laboratories, ASIA)
  • Oflam
  • Olfen
  • Ortofen
  • Phlogin - Diclofenac Sodium (Pakistan)
  • Panamor
  • Parazone-DP (combination of Paracetamol & Diclofenac potassium)
  • Pennsaid
  • Pritaren
  • Rapidus
  • Rapten-K
  • Reactin (India)
  • Rhumalgan
  • Rofenac (Middle East)
  • Rufenal
  • Safeguard (combination with misoprostol)
  • Sandoz (diclofenac sodium, Australia)
  • Solaraze
  • Seradic (India)
  • Topac
  • Trabona
  • Tratul (Austria, Romania, Moldova)
  • Uno
  • Veltex CR (South Africa)
  • Vetagesic
  • Voldic
  • Volini (India)
  • Volfenac (Thailand)
  • Voltaflam (India)
  • Voltaren (Argentina, Australia, Belgium, France, Germany, Norway, Portugal, Russia, South Africa, Turkey)
  • Voltaren Emulgel (Australia, Canada, UK)
  • Voltaren Gel (US)
  • Voltarol
  • Voltarol Emulgel
  • Voltarol Pain-eze
  • Voltfast
  • Voren (Taiwan)
  • Voltral (UK, Pakistan)
  • Votrex
  • Vostar
  • Votalin (China)
  • Voveran
  • Vurdon
  • Zipsor
  • Zolterol
  • Zengesic (combination of Paracetamol & Diclofenac sodium)
  • Hitflam (Ambee Pharmaceuticals Ltd. Bangladesh)

References[edit]

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  2. ^ http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1434053
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  29. ^ "Vet drug 'killing Asian vultures'". BBC News. 2004-02-28. 
  30. ^ a b "Saving the Vultures from Extinction" (Press release). Press Information Bureau, Government of India. 2005-05-16. Retrieved 2006-05-12. 
  31. ^ a b c 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. PMID 16435886. 
  32. ^ Gill, V. New drug threat to Asian vultures BBC News December 9, 2009.
  33. ^ Rabies follows disruption in food cycle
  34. ^ Nature Shock, UK Channel 5 television, Tuesday 7 Sept 2010,8 to 9 pm.
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External links[edit]