Naproxen

Absorption

Naproxen is available as a free acid and sodium salt. At comparable doses, (naproxen 500 mg = naproxen sodium 550 mg) they differ slightly in their rates of absorption, but otherwise they are therapeutically and pharmacologically equivalent. Naproxen sodium achieves a peak plasma concentration after 1 hour, while peak plasma concentration is observed after 2 hours with naproxen (free acid). There are no differences between the 2 forms in the post-absorption phase pharmacokinetics. The difference in initial absorption should be considered when treating acute pain, since naproxen sodium may offer a quicker onset of action.
The mean Cmax for the various formulations (immediate release, enteric coated, controlled release etc.) of naproxen are comparable and range from 94 mcg/mL to 97.4 mcg/mL. In one pharmacokinetic study, the mean Tmax of naproxen 500 mg (immediate release) given every 12 hours over 5 days was 3 hours, compared to a mean Tmax of 5 hours for Naprelan 1000 mg (controlled release) given every 24 hours over 5 days. In this same study, the AUC0-24hr was 1446mcgxhr/mL for naproxen immediate release and 1448 mcgxhr/mL for the controlled release formulation. A separate study comparing the pharmacokinetics of Naprosyn tablets and EC-Naprosyn observed the following values: Tmax and AUC0-12hrs of EC-Naprosyn were 4 hours and 845 mcgxhr/mL respectively, and Tmax and AUC0-12hrs values of Naprosyn were 1.9 hours and 767 mcgxhr/mL respectively.
When given in combination with sumatriptan the Cmax of naproxen is roughly 36% lower compared to naproxen sodium 550 mg tablets, and the median Tmax is 5 hours.
Based on the AUC and Cmax of naproxen, Vimovo (naproxen/esomeprazole combination product) and enteric-coated naproxen may be considered bioequivalent.
Overall, naproxen is rapidly and completely absorbed when administered orally and rectally. Food may contribute to a delay in the absorption of orally administered naproxen, but will not affect the extent of absorption.

Toxicity

Although the over-the-counter (OTC) availability of naproxen provides convenience to patients, it also increases the likelihood of overdose. Thankfully, the extent of overdose is typically mild with adverse effects normally limited to drowsiness, lethargy, epigastric pain, nausea and vomiting. Although there is no antidote for naproxen overdose, symptoms will typically subside with appropriate supportive care.
Naproxen is classified as Category B during the first 2 trimesters of pregnancy, and as Category D during the third trimester. Naproxen is contraindicated in the 3rd trimester since it increases the risk of premature closure of the fetal ductus arteriosus and should be avoided in pregnant women starting at 30 weeks gestation.

Description

Naproxen is synthesized from 2-methoxynaphthalene and the (+)-isomer obtained by resolution with cinchonidine (61). It was introduced in the United States in 1976 and, as a generic drug, has consistently been among the more popular NSAIDs. It is marketed as the S-(+)-enantiomer, but interestingly, the sodium salt of the (–)-isomer also is on the market as Anaprox. As an inhibitor of prostaglandin biosynthesis, it is 12 times more potent than aspirin, 10 times more potent than phenylbutazone, three to four times more potent than ibuprofen, and four times times more potent than fenoprofen, but it is approximately 300 times less potent than indomethacin.

Description

Naproxen is a naphthalenepropionic acid derivative that is widely sold as its sodium salt. It is a nonsteroidal anti-inflammatory drug that is used to reduce pain, fever, and inflammation in muscles and joints. Its preparation in racemic form was first reported in 1968 in a patent awarded to Syntex.

Chemical properties

white to light yellow crystal powde

Originator

Naprosyn,Syntex,UK,1973

The Uses of Naproxen

Being analogous to other drugs of this series, naproxene exhibits analgesic, fever-reducing, and long-lasting anti-inflammatory action. It causes reduction and removal of painful symptoms including joint pain, stiffness, and swelling in the joints. It is used in the same indications as ibuprofen.

The Uses of Naproxen

An anti-inflammatory, analgesic, antipyretic. A non-steroidal anti-inflammatory

The Uses of Naproxen

(S)-(+)-2-(6-Methoxy-2-naphthyl)propionic acid is a non-selective cyclooxygenase (COX-1 and COX-2) inhibitor.

What are the applications of Application

Naproxen is a Cox-1 and Cox-2 inhibitor

Indications

Naproxen is indicated for the management of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, polyarticular juvenile idiopathic arthritis, tendinitis, bursitis, acute gout, primary dysmenorrhea, and for the relief of mild to moderate pain. Further, it is first-line therapy for osteoarthritis, acute gouty arthritis, dysmenorrhea, and musculoskeletal inflammation and pain.

Background

Naproxen is classified as a nonsteroidal anti-inflammatory dug (NSAID) and was initially approved for prescription use in 1976 and then for over-the-counter (OTC) use in 1994. It can effectively manage acute pain as well as pain related to rheumatic diseases, and has a well studied adverse effect profile. Given its overall tolerability and effectiveness, naproxen can be considered a first line treatment for a variety of clinical situations requiring analgesia. Naproxen is available in both immediate and delayed release formulations, in combination with sumatriptan to treat migraines, and in combination with esomeprazole to lower the risk of developing gastric ulcers.

Definition

ChEBI: A methoxynaphthalene that is 2-methoxynaphthalene substituted by a carboxy ethyl group at position 6. Naproxen is a non-steroidal anti-inflammatory drug commonly used for the reduction of pain, fever, inflammation and stiffness caused by conditions such a osteoarthritis, kidney stones, rheumatoid arthritis, psoriatic arthritis, gout, ankylosing spondylitis, menstrual cramps, tendinitis, bursitis, and for the treatment of primary dysmenorrhea. It works by inhibiting both the COX-1 and COX-2 enzymes.

Indications

Naproxen (Naprosyn) also has pharmacological properties and clinical uses similar to those of ibuprofen. It exhibits approximately equal selectivity for COX-1 and COX-2 and is better tolerated than certain NSAIDs, such as indomethacin. Adverse reactions related to the GI tract occur in about 14% of all patients, and severe GI bleeding has been reported. CNS complaints (headache, dizziness, drowsiness), dermatological effects (pruritus, skin eruptions, echinoses), tinnitus, edema, and dyspnea also occur.

Manufacturing Process

According to US Patent 3,658,858, a solution of 24 grams of 2-bromo-6- methoxynaphthalene in 300 ml of tetrahydrofuran is slowly added to 2.5 grams of magnesium turnings and 100 ml of tetrahydrofuran at reflux temperature. After the addition is complete, 20 grams of cadium chloride is added, and the resultant mixture is refluxed for 10 minutes to yield a solution of di-(6-methoxy-2-naphthyl)cadmium (which can be separated by conventional chromatography, although separation is unnecessary).
A solution of 18 grams of ethyl 2-bromopropionate in 20 ml of tetrahydrofuran is then added to the cooled reaction mixture. After 24 hours at 20°C, the product is hydrolyzed by adding 200 ml of 5 weight percent methanolic sodium hydroxide followed by heating to reflux for 1 hour. The reaction mixture is then diluted with excess 1 N sulfuric acid and extracted with ether. The ether phase is separated, evaporated to dryness and the residue is recrystallized from acetone-hexane to yield 2-(6-methoxy-2- naphthyl)propionic acid.

brand name

Naprosyn (Roche), Anaprox (Syntex, Canada, USA), Apranax (Roche, France), Bonyl (Ercopharm, Denmark), Miranax (Syntex, Finland), Novo-Naprox (Novorpharm, Canada), Proxen (Hoffmann La Roche, Germany).

Therapeutic Function

Antiinflammatory

Synthesis Reference(s)

Tetrahedron, 49, p. 8433, 1993 DOI: 10.1016/S0040-4020(01)81926-8

General Description

Naproxen (Naprosyn, Anaprox), marketed as the (S)-enantiomer,is well absorbed after oral administration, givingpeak plasma levels in 2 to 4 hours and a half-life of 13 hours.Naproxen is highly protein bound and displaces most protein-bound drugs. It is recommended for use in RA, OA, acute gouty inflammation, and in primary dysmenorrhea. Itshows good analgesic activity (i.e., 400 mg is comparable to75–150 mg of oral meperidine and superior to 65 mg ofpropoxyphene and 325 mg of aspirin plus 30 mg of codeine).It is also available OTC as 200-mg tablets (Aleve).

Pharmacokinetics

Naproxen is an established non-selective NSAID and is useful as an analgesic, anti-inflammatory and antipyretic. Similar to other NSAIDs, the pharmacological activity of naproxen can be attributed to the inhibition of cyclo-oxygenase, which in turn reduces prostaglandin synthesis in various tissues and fluids including the synovial fluid, gastric mucosa, and the blood.
Although naproxen is an effective analgesic, it can have unintended deleterious effects in the patient. For instance, naproxen can adversely affect blood pressure control. A study found that use of naproxen induced an increase in blood pressure, although the increase was not as significant as that found with ibuprofen use.
Further, studies have found that the risk of upper gastrointestinal bleeding is on average four-fold higher for individuals taking NSAIDs. Other factors that increase the risk of upper gastrointestinal bleeding include concurrent use of corticosteroids or anticoagulants, and a history of gastrointestinal ulcers.

Pharmacokinetics

Naproxen is almost completely absorbed following oral administration. Peak plasma levels are achieved within 2 to 4 hours following administration. Like most of the acidic NSAIDs (pKa = 4.2), it is highly bound (99.6%) to plasma proteins. Approximately 70% of an administered dose is eliminated as either unchanged drug (60%) or as conjugates of unchanged drug (10%). The remainder is converted to the 6-O-desmethyl metabolite by both CYP3A4 and CYP1A2 and, further, to the glucuronide conjugate of the demethylated metabolite. The 6-O-desmethyl metabolite lacks anti-inflammatory activity. Like most of the arylalkanoic acids, the most common side effect associated with the use of naproxen is irritation to the GI tract. The most common other adverse reactions are associated with CNS disturbances (e.g., nausea and dizziness).

Clinical Use

Naproxen is indicated for the treatment of rheumatoid arthritis, osteoarthritis, juvenile arthritis, ankylosing spondylitis, tendinitis, bursitis, acute gout, and primary dysmenorrhea and for the relief of mild to moderate pain.

Side Effects

Common side effects of Naproxen may include indigestion, heartburn, stomach pain, nausea, headache, dizziness, drowsiness, bruising, itching, rash, swelling, or ringing in the ears. Seek immediate medical attention if you have any of the following serious drug reactions. For example: shortness of breath, swelling or rapid weight gain, rash, signs of stomach bleeding (bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds), liver problems (nausea, upper stomach pain, itching, feeling tired, flu-like symptoms, loss of appetite, dark urine, clay-coloured stools, jaundice), kidney problems (little or no urination, pain or difficulty in urinating, swelling of the feet or ankles, feeling tired or shortness of breath), low red blood cells (anaemia), etc. In addition, in rare cases, a severe allergic reaction to naproxen may occur. You may also suffer from stomach ulcers and other adverse reactions when taking it for a long time.

Synthesis

Synthesis of Naproxene: Friedel - Crafts acylation (aluminum chloride - nitrobenzene) of β-naphthol methyl ether affords 2-acetyl-6- methoxynaphthalene, which, when treated with either dimethylsulfonium or dimethylsulfoxonium methylide, gives 2-(6-methoxynaphthalen-2-yl)propylene oxide. Treatment of the latter with boron trifluoride etherate in tetrahydrofuran gives 2-(6-methoxynaphthalen- 2-yl)propionaldehyde, which is oxidized using Jones reagent (4 M chromic acid) to yield the racemic 2-(6-methoxynaphthalen-2- yl)propionic acid. Resolution and isolation of the dextrorotatory enantiomer is accomplished via its cinchonidine salt.
2-(6-methoxy-2-naphthyl)-propionic acid (3.2.15) can be synthesized by the methods of synthesis described for ibuprofen as well as by the methods of fenoprofen (3.2.21) and ketoprofen (3.2.27) synthesis that will be described below from 2-acetyl or 2-chloromethyl-6-methoxynaphthaline [99–101].

Veterinary Drugs and Treatments

The manufacturer lists the following indications: “…for the relief of inflammation and associated pain and lameness exhibited with myositis and other soft tissue diseases of the musculoskeletal system of the horse.” (Package Insert; Equiproxen?—Syntex). It has also been used as an antiinflammatory/analgesic in dogs for the treatment of osteoarthritis and other musculoskeletal inflammatory diseases (see adverse reactions below).

Drug interactions

Potentially hazardous interactions with other drugs
ACE inhibitors and angiotensin-II antagonists: antagonism of hypotensive effect; increased risk of nephrotoxicity and hyperkalaemia
. Analgesics: avoid concomitant use of 2 or more NSAIDs, including aspirin (increased side effects); avoid with ketorolac (increased risk of side effects and haemorrhage).
Antibacterials: possibly increased risk of convulsions with quinolones.
Anticoagulants: effects of coumarins and phenindione enhanced; possibly increased risk of bleeding with heparins, dabigatran and edoxaban - avoid long term use with edoxaban.
Antidepressants: increased risk of bleeding with SSRIs and venlaflaxine.
Antidiabetic agents: effects of sulphonylureas enhanced.
Antiepileptics: possibly increased phenytoin concentration.
Antivirals: increased risk of haematological toxicity with zidovudine; concentration possibly increased by ritonavir.
Ciclosporin: may potentiate nephrotoxicity
Cytotoxics: reduced excretion of methotrexate; increased risk of bleeding with erlotinib.
Diuretics: increased risk of nephrotoxicity; antagonism of diuretic effect; hyperkalaemia with potassium-sparing diuretics.
Lithium: excretion decreased.
Pentoxifylline: increased risk of bleeding.
Probenecid: excretion reduced by probenecid.
Tacrolimus: increased risk of nephrotoxicity.

Metabolism

Naproxen is heavily metabolized in the liver and undergoes both Phase I and Phase II metabolism. The first step involves demethylation of naproxen via CYP 1A2, 2C8, and 2C9. Both naproxen and desmethylnaproxen proceed to Phase II metabolism; however, desmethylnaproxen can form both acyl and phenolic glucoronide products, while naproxen only produces the acyl glucuronide. The acyl glucuronidation process involves UGT 1A1, 1A3, 1A6, 1A7, 1A9, 1A10 and 2B7, while phenolic glucuronidation is catalyzed by UGT 1A1, 1A7,1A9, and 1A10. Desmethylnaproxen also undergoes sulphation which is mediated by SULT 1A1, 1B1 and 1E1.

Metabolism

Naproxen is extensively metabolised in the liver to 6-0-desmethyl naproxen. Both naproxen and 6-0-desmethyl naproxen are further metabolised to their respective acylglucuronide conjugated metabolites. About 95% of a dose is excreted in urine as naproxen and 6-O-desmethylnaproxen and their conjugates. Less than 5% of a dose appears in the faeces.

References

[1] barnett j, chow j, ives d, et al. purification, characterization and selective inhibition of human prostaglandin g/h synthase 1 and 2 expressed in the baculovirus system[j]. biochimica et biophysica acta (bba)-protein structure and molecular enzymology, 1994, 1209(1): 130-139.
[2] laneuville o, breuer d k, dewitt d l, et al. differential inhibition of human prostaglandin endoperoxide h synthases-1 and-2 by nonsteroidal anti-inflammatory drugs[j]. journal of pharmacology and experimental therapeutics, 1994, 271(2): 927-934.
[3] dubois r n, abramson s b, crofford l, et al. cyclooxygenase in biology and disease[j]. the faseb journal, 1998, 12(12): 1063-1073.
[4] agdeppa e d, kepe v, petri a, et al. in vitro detection of (s)-naproxen and ibuprofen binding to plaques in the alzheimer’s brain using the positron emission tomography molecular imaging probe 2-(1-{6-[(2-[18 f] fluoroethyl)(methyl) amino]-2-naphthyl} ethylidene) malononitrile[j]. neuroscience, 2003, 117(3): 723-730.