Diflunisal

Last updated
Diflunisal
Diflunisal structure.svg
Diflunasil-3D-balls.png
Clinical data
Trade names Dolobid
AHFS/Drugs.com Monograph
MedlinePlus a684037
Pregnancy
category
  • AU:C
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: WARNING [1] Rx-only
Pharmacokinetic data
Bioavailability 80-90%
Protein binding >99%
Metabolism Hepatic
Elimination half-life 8 to 12 hours
Excretion Renal
Identifiers
  • 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.040.925 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C13H8F2O3
Molar mass 250.201 g·mol−1
3D model (JSmol)
  • O=C(O)c1cc(ccc1O)c2ccc(F)cc2F
  • InChI=1S/C13H8F2O3/c14-8-2-3-9(11(15)6-8)7-1-4-12(16)10(5-7)13(17)18/h1-6,16H,(H,17,18) Yes check.svgY
  • Key:HUPFGZXOMWLGNK-UHFFFAOYSA-N Yes check.svgY
   (verify)

Diflunisal is a salicylic acid derivative with analgesic and anti-inflammatory activity. [2] It was developed by Merck Sharp & Dohme in 1971, as MK647, after showing promise in a research project studying more potent chemical analogs of aspirin. [3] It was first sold under the brand name Dolobid, marketed by Merck & Co., but generic versions are now widely available. It is classed as a nonsteroidal anti-inflammatory drug (NSAID) and is available in 250 mg and 500 mg tablets.

Contents

Mechanism of action

Like all NSAIDs, diflunisal acts by inhibiting the production of prostaglandins, [4] hormones which are involved in inflammation and pain. Diflunisal also has an antipyretic effect, but this is not a recommended use of the drug. [5]

It has been found to inhibit p300 and CREB-binding protein (CBP), which are epigenetic regulators that control the levels of proteins that cause inflammation or are involved in cell growth. [6]

It has been reported that diflunisal has some antibacterial activity in vitro against Francisella tularensis live vaccine strain (LVS). [7]

Duration of effect

Though diflunisal has an onset time of 1 hour, and maximum analgesia at 2 to 3 hours, the plasma levels of diflunisal will not be steady until repeated doses are taken. [5] The long plasma half-life is a distinctive feature of diflunisal in comparison to similar drugs. To increase the rate at which the diflunisal plasma levels become steady, a loading dose is usually used. It is primarily used to treat symptoms of arthritis, [8] and for acute pain following oral surgery, especially removal of wisdom teeth. [9]

Effectiveness of diflunisal is similar to other NSAIDs, but the duration of action is twelve hours or more. This means fewer doses per day are required for chronic administration. In acute use, it is popular in dentistry when a single dose after oral surgery can maintain analgesia until the patient is asleep that night.

Medical uses

Amyloidosis

Both diflunisal [10] [11] and several of its analogues [12] have been shown to be inhibitors of transthyretin-related hereditary amyloidosis, a disease which currently has few treatment options. Phase I trials have shown the drug to be well tolerated, [13] with a small Phase II trial (double-blind, placebo-controlled, 130 patients for 2 years) in 2013 showing a reduced rate of disease progression and preserved quality of life. [14] However a significantly larger Phase III trial would be needed to prove the drugs effectiveness for treating this condition.

Side effects

In October 2020, the U.S. Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid. [15] [16] They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy. [15] [16]

Gastrointestinal

The inhibition of prostaglandins has the effect of decreasing the protection given to the stomach from its own acid. Like all NSAIDS, this leads to an increased risk of stomach ulcers, and their complications, with long-term use. Elderly users of diflunisal are at greater risk for serious GI events.

Cardiovascular

Ear, nose, throat, and eye

Central nervous system

Skin

Contraindications

Cautions

[ citation needed ]

Overdose

Deaths that have occurred from diflunisal usually involved mixed drugs and or extremely high dosage. The oral LD50 is 500 mg/kg. Symptoms of overdose include coma, tachycardia, stupor, and vomiting. The lowest dose without the presence of other medicines which caused death was 15 grams. Mixed with other medicines, a death at 7.5 grams has also occurred. Diflunisal usually comes in 250 or 500 mg, making it relatively hard to overdose by accident.

Related Research Articles

<span class="mw-page-title-main">Aspirin</span> Medication

Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat include Kawasaki disease, pericarditis, and rheumatic fever.

<span class="mw-page-title-main">Nonsteroidal anti-inflammatory drug</span> Class of therapeutic drug for relieving pain and inflammation

Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of use, but largely include an increased risk of gastrointestinal ulcers and bleeds, heart attack, and kidney disease.

<span class="mw-page-title-main">Ibuprofen</span> Medication used for treating pain, fever, and inflammation

Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used to relieve pain, fever, and inflammation. This includes painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a patent ductus arteriosus in a premature baby. It can be used orally or intravenously. It typically begins working within an hour.

<span class="mw-page-title-main">Cyclooxygenase</span> Class of enzymes

Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme that is responsible for biosynthesis of prostanoids, including thromboxane and prostaglandins such as prostacyclin, from arachidonic acid. A member of the animal-type heme peroxidase family, it is also known as prostaglandin G/H synthase. The specific reaction catalyzed is the conversion from arachidonic acid to prostaglandin H2 via a short-living prostaglandin G2 intermediate.

<span class="mw-page-title-main">Diclofenac</span> Nonsteroidal anti-inflammatory drug

Diclofenac, sold under the brand name Voltaren, among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain and inflammatory diseases such as gout. It is taken by mouth or rectally in a suppository, used by injection, or applied to the skin. Improvements in pain last for as much as eight hours. It is also available in combination with misoprostol in an effort to decrease stomach problems.

<span class="mw-page-title-main">Naproxen</span> Nonsteroidal anti-inflammatory drug (NSAID) used to treat pain

Naproxen, sold under the brand name Aleve among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain, menstrual cramps, inflammatory diseases such as rheumatoid arthritis, gout and fever. It is taken orally. It is available in immediate and delayed release formulations. Onset of effects is within an hour and lasts for up to twelve hours.

<span class="mw-page-title-main">Rofecoxib</span> Nonsteroidal anti-inflammatory drug

Rofecoxib is a COX-2-selective nonsteroidal anti-inflammatory drug (NSAID). It was marketed by Merck & Co. to treat osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, acute pain conditions, migraine, and dysmenorrhea. Rofecoxib was approved in the US by the US Food and Drug Administration (FDA) in May 1999, and was marketed under the brand names Vioxx, Ceoxx, and Ceeoxx. Rofecoxib was available by prescription in both tablets and as an oral suspension.

Anti-inflammatory or antiphlogistic is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as opposed to opioids, which affect the central nervous system to block pain signaling to the brain.

COX-2 inhibitors (coxibs) are a type of nonsteroidal anti-inflammatory drug (NSAID) that directly target cyclooxygenase-2, COX-2, an enzyme responsible for inflammation and pain. Targeting selectivity for COX-2 reduces the risk of peptic ulceration and is the main feature of celecoxib, rofecoxib, and other members of this drug class.

<span class="mw-page-title-main">Transthyretin</span> Serum protein related to amyloid diseases

Transthyretin (TTR or TBPA) is a transport protein in the plasma and cerebrospinal fluid that transports the thyroid hormone thyroxine (T4) and retinol to the liver. This is how transthyretin gained its name: transports thyroxine and retinol. The liver secretes TTR into the blood, and the choroid plexus secretes TTR into the cerebrospinal fluid.

<span class="mw-page-title-main">Indometacin</span> Anti-inflammatory drug

Indometacin, also known as indomethacin, is a nonsteroidal anti-inflammatory drug (NSAID) commonly used as a prescription medication to reduce fever, pain, stiffness, and swelling from inflammation. It works by inhibiting the production of prostaglandins, endogenous signaling molecules known to cause these symptoms. It does this by inhibiting cyclooxygenase, an enzyme that catalyzes the production of prostaglandins.

<span class="mw-page-title-main">Meloxicam</span> Nonsteroidal anti-inflammatory drug (NSAID)

Meloxicam, sold under the brand name Mobic among others, is a nonsteroidal anti-inflammatory medication (NSAID) used to treat pain and inflammation in rheumatic diseases and osteoarthritis. It is used by mouth or by injection into a vein. It is recommended that it be used for as short a period as possible and at a low dose.

<span class="mw-page-title-main">Ketorolac</span> Nonsteroidal anti-inflammatory drug (NSAID; analgesic)

Ketorolac, sold under the brand names Toradol, and Biorolac among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain. Specifically it is recommended for moderate to severe pain. Recommended duration of treatment is less than six days, and in Switzerland not more than two days. It is used by mouth, by nose, by injection into a vein or muscle, and as eye drops. Effects begin within an hour and last for up to eight hours.

<span class="mw-page-title-main">Etodolac</span> Nonsteroidal anti-inflammatory drug

Etodolac is a nonsteroidal anti-inflammatory drug (NSAID).

<span class="mw-page-title-main">Carprofen</span> Non-steroidal anti-inflammatory drug

Carprofen is a nonsteroidal anti-inflammatory drug (NSAID) of the carbazole and propionic acid class that was previously for use in humans and animals but is now only available to veterinarians for prescribing as a supportive treatment for various conditions in animals. Carprofen reduces inflammation by inhibition of COX-1 and COX-2; its specificity for COX-2 varies from species to species. Marketed under many brand names worldwide, carprofen is used as a treatment for inflammation and pain, including joint pain and postoperative pain.

<span class="mw-page-title-main">Fenoprofen</span> NSAID analgesic and anti-inflammatory drug

Fenoprofen, sold under the brand name Nalfon among others, is a nonsteroidal anti-inflammatory drug (NSAID). Fenoprofen calcium is used for symptomatic relief for rheumatoid arthritis, osteoarthritis, and mild to moderate pain. It has also been used to treat postoperative pain. It is available as a generic medication.

<span class="mw-page-title-main">Tenoxicam</span> Non-steroidal anti-inflammatory drug

Tenoxicam, sold under the brand name Mobiflex among others, is a nonsteroidal anti-inflammatory drug (NSAID). It is used to relieve inflammation, swelling, stiffness, and pain associated with rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, tendinitis, bursitis, and periarthritis of the shoulders or hips.

Naproxcinod (nitronaproxen) is a nonsteroidal anti-inflammatory drug (NSAID) developed by the French pharmaceutical company NicOx. It is a derivative of naproxen with a nitroxybutyl ester to allow it to also act as a nitric oxide (NO) donor. This second mechanism of action makes naproxcinod the first in a new class of drugs, the cyclooxygenase inhibiting nitric oxide donators (CINODs), that are hoped to produce similar analgesic efficacy to traditional NSAIDs, but with less gastrointestinal and cardiovascular side effects.

<span class="mw-page-title-main">Grapiprant</span> NSAID anti-inflammatory veterinary drug

Grapiprant is a small molecule drug that belongs in the piprant class. This analgesic and anti-inflammatory drug is primarily used as a pain relief for mild to moderate inflammation related to osteoarthritis in dogs. Grapiprant has been approved by the FDA's Center for Veterinary Medicine and was categorized as a non-cyclooxygenase inhibiting non-steroidal anti-inflammatory drug (NSAID) in March 2016.

Prostaglandin inhibitors are drugs that inhibit the synthesis of prostaglandin in human body. There are various types of prostaglandins responsible for different physiological reactions such as maintaining the blood flow in stomach and kidney, regulating the contraction of involuntary muscles and blood vessels, and act as a mediator of inflammation and pain. Cyclooxygenase (COX) and Phospholipase A2 are the major enzymes involved in prostaglandin production, and they are the drug targets for prostaglandin inhibitors. There are mainly 2 classes of prostaglandin inhibitors, namely non- steroidal anti- inflammatory drugs (NSAIDs) and glucocorticoids. In the following sections, the medical uses, side effects, contraindications, toxicity and the pharmacology of these prostaglandin inhibitors will be discussed.

References

  1. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 Oct 2023.
  2. ↑ Boullard O, Leblanc H, Besson B (2012). "Salicylic Acid". Ullmann's Encyclopedia of Industrial Chemistry . Weinheim: Wiley-VCH. doi:10.1002/14356007.a23_477.
  3. ↑ Adams SS (1999). "Ibuprofen, the propionics and NSAIDs: personal reflections over four decades". Inflammopharmacology. 7 (3): 191–7. doi:10.1007/s10787-999-0002-3. PMID   17638090. S2CID   11074565.
  4. ↑ Wallace JL (October 2008). "Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn't the stomach digest itself?". Physiological Reviews. 88 (4): 1547–65. doi:10.1152/physrev.00004.2008. PMID   18923189. S2CID   448875.
  5. 1 2 Tempero KF, Cirillo VJ, Steelman SL (February 1977). "Diflunisal: a review of pharmacokinetic and pharmacodynamic properties, drug interactions, and special tolerability studies in humans". British Journal of Clinical Pharmacology. 4 (Suppl 1): 31S–36S. doi:10.1111/j.1365-2125.1977.tb04511.x. PMC   1428837 . PMID   328032.
  6. ↑ "New Metabolic Pathway Reveals Aspirin-Like Compound's Anti-Cancer Properties. June 2016". Archived from the original on 2016-06-04. Retrieved 2016-06-09.
  7. ↑ Jayamani E, Tharmalingam N, Rajamuthiah R, Coleman JJ, Kim W, Okoli I, et al. (September 2017). "Characterization of a Francisella tularensis-Caenorhabditis elegans Pathosystem for the Evaluation of Therapeutic Compounds". Antimicrobial Agents and Chemotherapy. 61 (9). doi:10.1128/AAC.00310-17. PMC   5571314 . PMID   28652232.
  8. ↑ Brogden RN, Heel RC, Pakes GE, Speight TM, Avery GS (February 1980). "Diflunisal: a review of its pharmacological properties and therapeutic use in pain and musculoskeletal strains and sprains and pain in osteoarthritis". Drugs. 19 (2): 84–106. doi:10.2165/00003495-198019020-00002. PMID   6988202. S2CID   24191409.
  9. ↑ Lawton GM, Chapman PJ (August 1993). "Diflunisal--a long-acting non-steroidal anti-inflammatory drug. A review of its pharmacology and effectiveness in management of postoperative dental pain". Australian Dental Journal. 38 (4): 265–71. doi:10.1111/j.1834-7819.1993.tb05494.x. PMID   8216032.
  10. ↑ Tojo K, Sekijima Y, Kelly JW, Ikeda S (December 2006). "Diflunisal stabilizes familial amyloid polyneuropathy-associated transthyretin variant tetramers in serum against dissociation required for amyloidogenesis". Neuroscience Research. 56 (4): 441–9. doi:10.1016/j.neures.2006.08.014. PMID   17028027. S2CID   42504073.
  11. ↑ Kingsbury JS, Laue TM, Klimtchuk ES, Théberge R, Costello CE, Connors LH (May 2008). "The modulation of transthyretin tetramer stability by cysteine 10 adducts and the drug diflunisal. Direct analysis by fluorescence-detected analytical ultracentrifugation". The Journal of Biological Chemistry. 283 (18): 11887–96. doi: 10.1074/jbc.M709638200 . PMC   2335343 . PMID   18326041.
  12. ↑ Adamski-Werner SL, Palaninathan SK, Sacchettini JC, Kelly JW (January 2004). "Diflunisal analogues stabilize the native state of transthyretin. Potent inhibition of amyloidogenesis". Journal of Medicinal Chemistry. 47 (2): 355–74. doi:10.1021/jm030347n. PMID   14711308.
  13. ↑ Berk JL, Suhr OB, Sekijima Y, Yamashita T, Heneghan M, Zeldenrust SR, et al. (June 2012). "The Diflunisal Trial: study accrual and drug tolerance". Amyloid. 19 (Suppl 1): 37–8. doi:10.3109/13506129.2012.678509. PMID   22551208. S2CID   40303434.
  14. ↑ Berk JL, Suhr OB, Obici L, Sekijima Y, Zeldenrust SR, Yamashita T, et al. (December 2013). "Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial". JAMA. 310 (24): 2658–67. doi:10.1001/jama.2013.283815. PMC   4139164 . PMID   24368466.
  15. 1 2 "FDA Warns that Using a Type of Pain and Fever Medication in Second Half of Pregnancy Could Lead to Complications". U.S. Food and Drug Administration (FDA) (Press release). 15 October 2020. Retrieved 15 October 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  16. 1 2 "NSAIDs may cause rare kidney problems in unborn babies". U.S. Food and Drug Administration. 21 July 2017. Retrieved 15 October 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
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