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| {{drugbox | | | {{Details|Diclofenac (ophthalmic)|'''ophthalmic'''}} |
| | IUPAC_name = 2-(2-(2,6-dichlorophenylamino)phenyl)acetic acid
| | {{Details|Diclofenac (patch)|'''patch'''}} |
| | image = Diclofenac.png
| | {{Details|Diclofenac (tablet)|'''tablet'''}} |
| | width= 180
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| | CAS_number = 15307-86-5
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| | ATC_prefix = M01
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| | ATC_suffix = AB05
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| | ATC_supplemental = {{ATC|M02|AA15}}, {{ATC|S01|BC03}}
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| | PubChem = 3033
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| | DrugBank = APRD00527
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| | C=14 |H=11 |Cl=2 |N=1 |O=2
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| | molecular_weight = 296.148 g/mol
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| | bioavailability = 100%
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| | protein_bound = more than 99%
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| | metabolism = hepatic, no active metabolites exist
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| | elimination_half-life = 1.2-2 hr (35% of the drug enters enterohepatic recirculation)
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| | excretion = biliary, only 1% in urine | |
| | pregnancy_AU = A
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| | pregnancy_US =
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| | pregnancy_category = B (1st. and 2nd. trimenon), X (third trimenon)
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| | legal_AU =
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| | legal_UK = POM
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| | legal_US =
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| | legal_status = Rx-only most preparations/countries. Limited OTC some countries
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| | routes_of_administration = oral, rectal, [[intramuscular|im]], [[intravenous|iv]] (renal- and gallstones), topical
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| }} | |
| {{CMG}} | |
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| {{Editor Help}}
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| '''Diclofenac''' (marketed as '''Voltaren''', '''Voltarol''', '''Diclon''', '''Dicloflex''' '''Difen''', '''Difene''', '''Cataflam''', '''Pennsaid''', '''Rhumalgan''', '''Modifenac''', '''Abitren''', '''[[Arthrotec]]''' and '''Zolterol''', with various drug dose combinations) is a [[non-steroidal anti-inflammatory drug]] (NSAID) taken to reduce [[inflammation]] and an [[analgesic]] reducing pain in conditions such as in [[arthritis]] or acute [[injury]]. It can also be used to reduce [[menstrual period|menstrual]] [[pain]], [[dysmenorrhea]]. The name is derived from its chemical name: 2-(2,6-'''dichlo'''ranilino)
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| '''phen'''yl'''ac'''etic acid
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| In the [[United Kingdom]], [[India]], and the [[United States]], it may be supplied as either the [[sodium]] or [[potassium]] [[salts|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 substance|Over the counter]] (OTC) use is approved in some countries for minor aches and pains and fever associated with common infections.
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| Diclofenac is well-tolerated after 30 years' experience by the general human population, but may unexpectedly become intolerated in some of the elderly population of long term users.
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| ==Mechanism of action==
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| The action of one single dose is much longer (6 to 8 hours) than the very short half-life that the drug indicates. This could partly be due to a particular high concentration achieved in [[synovial fluid|synovial fluids]].
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| The exact mechanism of action is not entirely known, but it is thought that the primary mechanism responsible for its anti-inflammatory/antipyretic/analgesic action is inhibition of [[prostaglandin]] synthesis by inhibition of [[cyclooxygenase]] (COX).
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| Inhibition of COX also decreases prostaglandins in the [[epithelium]] of the [[stomach]], making it more sensitive to corrosion by [[gastric acid]]. 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]].
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| Diclofenac may also be a unique member of the [[NSAID]]s. There is some evidence that diclofenac inhibits the [[lipooxygenase]] pathways, thus reducing formation of the [[leukotriene]]s (also pro-inflammatory autacoids). There is also speculation that diclofenac may inhibit [[phospholipase|phospholipase A<sub>2</sub>]] 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.
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| There are marked differences among NSAIDs in their selective inhibition of the two subtypes of cyclo-oxygenase, COX-1 and COX-2. 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_inhibitor|COX-2 inhibitors]] due to their [[Adverse_drug_reaction|adverse effects]] has led to massive numbers of patient family lawsuits alleging wrongful death by [[heart attack]], yet other significantly COX-selective NSAIDs like diclofenac have been well-tolerated by most of the population.
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| ==Indications==
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| [[Image:Arthrotec50.JPG|thumb|100px|Combined Diclofenac sodium and misoprostol tablets.]]
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| Diclofenac is used for musculoskeletal complaints, especially [[arthritis]] (rheumatoid arthritis, osteoarthritis, spondylarthritis, [[ankylosing spondylitis]]), [[gout]] attacks, and [[pain management]] in case of [[kidney stone]]s and [[gallstone]]s. An additional indication is the treatment of acute migraines. Diclofenac is used commonly to treat mild to moderate post-operative or post-traumatic pain, particular when inflammation is also present, and is effective against menstrual pain.
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| [[Image:Diclofenac_sodium_100mg.jpg|thumb|100px|Diclofenac suppositories]]
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| 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.
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| An external, gel-based form of diclofenac (Solareze®) 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 gel to treat muskoskeletal conditions.
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| Over-the-counter use against minor aches and pains and fever associated with common infections is also licensed in some countries.
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| In many countries eye-drops are sold to treat acute and chronic non-bacterial inflammations of the anterior part of the eyes (e.g. postoperative states). A common brand name is Voltaren-ophta.
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| ===Off label/investigational uses===
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| Diclofenac is often used to treat chronic pain associated with [[cancer]], particularly if inflammation is also present (Step I of the [[World Health Organisation]] (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. Diclofenac can be combined with opioids if needed. In Europe Combaren® exists, a fixed combination of diclofenac and codeine (50 mg each) for cancer treatment. Combinations with psychoactive drugs such as [[chlorprothixene]] and/or [[amitriptyline]] have also been investigated and found useful in a number of cancer patients.
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| Fever due to malignant lymphogranulomatosis ([[Hodgkin's lymphoma]]) often responds to diclofenac. Treatment can be terminated as soon as the usual treatment with radiation and/or chemotherapy causes remission of fever.
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| Diclofenac may prevent the development of [[Alzheimer's disease]] if given daily in small doses during many years. 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.
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| Diclofenac has been found to increase the blood pressure in patients with [[Shy-Drager syndrome]] (autonomous [[hypotension]]) often seen in diabetic patients. Currently, this use is highly investigational and cannot be recommended as routine treatment.
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| Diclofenac has been found to be effective against all strains of multi drug resistant e coli, with a MIC of 25 microg/mL. Therefore, it may be suggested that diclofenac has the capacity to treat UTI (uncomplicated urinary tract infections) caused by E. coli.<ref name="pmid17091768">{{cite journal |author=Mazumdar K, Dutta NK, Dastidar SG, Motohashi N, Shirataki Y |title=Diclofenac in the management of E. coli urinary tract infections |journal=In Vivo |volume=20 |issue=5 |pages=613–9 |year=2006 |pmid=17091768 |doi=}}</ref>
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| ==Contraindications==
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| * Hypersensitivity against diclofenac
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| * History of allergic reactions (bronchospasm, shock, rhinitis, urticaria) following the use of Aspirin or another NSAID
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| * Third-trimester pregnancy
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| * Active stomach and/or duodenal ulceration or gastrointestinal bleeding
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| * Inflammative intestinal disorders such as Crohn's disease or ulcerative colitis
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| * Severe insufficiency of the heart (NYHA III/IV)
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| * Recently, a warning has been issued by FDA not to treat patients recovering from heart surgery
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| * Severe liver insufficiency (Child-Pugh Class C)
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| * Severe renal insufficiency (creatinine clearance <30 ml/min)
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| * Caution in patients with preexisting hepatic porphyria, as diclofenac may trigger attacks
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| * Caution in patients with severe, active bleeding such as cerebral hemorrhage
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| ==Side effects==
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| * 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.
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| ===Cardiac===
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| * 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.<!--
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| --><ref name="BMJ2006-Kearney">{{cite journal | author=Kearney P, Baigent C, Godwin J, Halls H, Emberson J, Patrono C | title=Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. | journal=BMJ | volume=332 | issue=7553 | pages=1302-8 | year=2006 | id=PMID 16740558}}</ref><!--
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| --> 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.<br> A subsequent large study of 74,838 users of NSAIDs or coxibs, published in May 2006 found no additional cardiovascular risk from Diclofenac use.<!--
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| --><ref name="ArthritisRheum2006-Solomon">{{cite journal | author=Solomon D, Avorn J, Stürmer T, Glynn R, Mogun H, Schneeweiss S | title=Cardiovascular outcomes in new users of coxibs and nonsteroidal antiinflammatory drugs: high-risk subgroups and time course of risk. | journal=Arthritis Rheum | volume=54 | issue=5 | pages=1378-89 | year=2006 | id=PMID 16645966}}</ref>
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| * Diclonefac has similar COX-2 selectivity to celecoxib <ref name="pmid11496855">{{cite journal |author=FitzGerald G, Patrono C |title=The coxibs, selective inhibitors of cyclooxygenase-2 |journal=N Engl J Med |volume=345 |issue=6 |pages=433-42 |year=2001 |pmid=11496855}}</ref>. 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]] <ref name="pmid16968830">{{cite journal |author=Graham D |title=COX-2 inhibitors, other NSAIDs, and cardiovascular risk: the seduction of common sense |journal=JAMA |volume=296 |issue=13 |pages=1653-6 |year=2006 |pmid=16968830 | doi=10.1001/jama.296.13.jed60058 | url=http://jama.ama-assn.org/cgi/content/full/296/13/1653}}</ref>.
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| ===Gastrointestinal===
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| * 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 150mg at bedtime or omeprazole 20 mg at bedtime).
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| ===Hepatic===
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| * Liver damage occurs infrequently, but 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.
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| ===Renal===
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| * 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 [[Diclofenac#Ecological problems|Ecological problems]]). Species and individual humans that are drug sensitive are initially assumed to lack genes expressing specific drug detoxification enzymes. Because elderly humans have reduced expression levels of all enzymes, elderly human metabolisms may gradually approach those of vultures, thus unexpectedly becoming more diclofenac intolerant.
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| * NSAIDs "are associated with adverse renal [kidney] effects caused by the reduction in synthesis of renal prostaglandins"<!--
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| --><ref name="Brater2002">{{cite journal | author=Brater DC | title=Renal effects of cyclooxygyenase-2-selective inhibitors | journal=J Pain Symptom Manage | year=2002 | pages=S15-20; discussion S21-3 | volume=23 | issue=4 Suppl | id=PMID 11992745}}</ref><!--
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| --> 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."<ref name="Brater2002"/>
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| ===Other===
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| * 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.
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| ==Formulations==
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| [[Image:Dicloflexec50.JPG|thumb|100px|[[Enteric_coating|Enteric Coated]] Diclofenac Sodium tablets by Dexel-Pharma Ltd.]]
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| 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.
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| Diclofenac is available in stomach acid resistant formulations (25 and 50 [[milligram|mg]]), fast disintegrating oral formulations (50 mg), slow- and controlled-release forms (75, 100 or 150 mg), suppositories (50 and 100 mg), and injectable forms (50 and 75 mg).
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| Diclofenac is also available [[Over-the-counter substance|over the counter]] (OTC) in some countries: Voltaren dolo (12.5 mg diclofenac as potassium salt) in [[Switzerland]] and [[Germany]], and preparations containing 25 mg diclofenac in [[New Zealand]].
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| ==Ecological problems==
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| Use of diclofenac in animals has been reported to have led to a sharp decline in the [[vulture]] population in the Indian subcontinent, up to 95% in some areas.<!--
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| --><ref name="Oaks2004>{{cite journal | author=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 | title=Diclofenac residues as the cause of vulture population decline in Pakistan | journal=Nature | year=2004 | pages=630-3 | volume=427 | issue=6975 | id=PMID 14745453}}</ref><!--
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| --> The mechanism is probably [[renal failure]], a known side-effect of diclofenac. Vultures eat the carcasses of domesticated animals that have been administered veterinary diclofenac, and are poisoned by the accumulated chemical. 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.<ref name="PIB2005">{{cite press release | publisher=Press Information Bureau, Government of India | date=[[2005-05-16]] | url=http://pib.nic.in/release/release.asp?relid=9303 | title=Saving the Vultures from Extiction | accessdate=2006-05-12}}</ref> Meloxicam is a safer (though more expensive) candidate to replace use of diclofenac.<ref name="Swan2006">{{cite journal | author=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 | title=Removing the threat of diclofenac to critically endangered Asian vultures | journal=PLoS Biol | year=2006 | pages=e66 | volume=4 | issue=3 | id=PMID 16435886}}</ref>
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| "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 benefited from the disappearance of [[Griffon_Vulture|Gyps vultures]] as the main scavenger of wild and domestic ungulate carcasses. Associated with the rise in dog numbers is an increased risk of human cases of rabies."<ref name="Swan2006"/>
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| The Government of India cites one of those major consequences as a vulture species extinction.<ref name="PIB2005"/> 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.
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| The loss of vultures has had a social impact on the Indian [[Zoroastrianism|Zoroastrian]] Parsi community, who traditionally use vultures to dispose of human corpses in "sky burials", and are now having to seek alternative disposal methods.<ref name="Swan2006"/>
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| In [[Punjab (India)|Punjab]] it appears that vulture numbers are slowly rising after use of the drug was discontinued.
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| ==References==
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| {{reflist|2}}
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| ==External links==
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| <!-- * [http://novartis.com/special/voltaren.shtml 30 years of Voltaren] - Anniversary press release, published by Novartis in 2004 -->
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| {{NSAIDs}}
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| {{Anti-inflammatory and antirheumatic products}}
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| {{Topical products for joint and muscular pain}}
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| [[de:Diclofenac]]
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| [[th:ไดโคลฟีแนค]]
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| [[Category:Carboxylic acids]]
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| [[Category:Non-steroidal anti-inflammatory drugs]]
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| [[Category:Organochlorides]]
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