GSK

GSK Uses, Dosage, Side Effects, Food Interaction and all others data.

GSK is a naphthylalkanone. Is is a non-selective prostaglandin G/H synthase (a.k.a. cyclooxygenase or COX) inhibitor that acts on both prostaglandin G/H synthase 1 and 2 (COX-1 and -2). Prostaglandin G/H synthase catalyzes the conversion of arachidonic acid to prostaglandin G2 and prostaglandin G2 to prostaglandin H2. Prostaglandin H2 is the precursor to a number of prostaglandins involved in fever, pain, swelling, inflammation, and platelet aggregation. The parent compound is a prodrug that undergoes hepatic biotransformation to the active compound, 6-methoxy-2-naphthylacetic acid (6MNA). The analgesic, antipyretic and anti-inflammatory effects of NSAIDs occur as a result of decreased prostaglandin synthesis.

The parent compound is a prodrug, which undergoes hepatic biotransformation to the active component, 6-methoxy-2-naphthylacetic acid (6MNA), that is a potent inhibitor of prostaglandin synthesis, most likely through binding to the COX-2 and COX-1 receptors.

NSAIDs, like nabumetone, are well established as analgesics. NSAIDs reduce both peripheral and central sensitization of nociceptive neurons due to inflammation which contribute to hyperalgesia and allodynia. This sensitization occurs through reducing the action potential threshold in peripheral neurons, reducing the intensity of painful stimuli needed to produce a painful sensation. Centrally, activation of dorsal horn neurons occurs along with increased release of glutamate, calcitonin gene-related peptide (CGRP), and substance P which increase the transmission of painful stimuli. Coupled with this is an inhibition glycinergic neurons which normally inhibit pain transmission, a phenomenon known as disinhibition. Increased activity ofn-methyl d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors leads to the establishment of central sensitization, allowing both mild painful and innocuous stimuli to produce action potentials in nociceptive projection neurons. NSAIDs are effective in reducing mild-moderate acute and chronic nociceptive pain, however, the usefulness of NSAIDs in neuropathic pain is limited.

The anti-inflammatory effect of NSAIDs is mediated by preventing vasodilation, increases in vascular permeability, and the release of cytokines from endothelial cells. These three effects together prevent immunocompetent cells from migrating to the site of injury thereby preventing additional damage and inflammation due to activation of the immune system at the site of damage. PGs also modulate T-helper cell activation and differentiation, an activity which is thought to be of importance in arthritic conditions.

The anti-pyretic effect of NSAIDs is mediated through preventing increases in temperature by prostaglandins (PGs) via the hypothalamus. Activation of this process by other inflammatory mediators relies upon subsequent action by PGs, therefore NSAIDs are able to reduce fever due to these mediators as well.

Trade Name GSK
Availability Prescription only
Generic Nabumetone
Nabumetone Other Names Nabumeton, Nabumetona, Nabumétone, Nabumetone, Nabumetonum
Related Drugs Humira, aspirin, prednisone, ibuprofen, meloxicam, naproxen, Cymbalta, hydroxychloroquine, Enbrel, Remicade
Type
Formula C15H16O2
Weight Average: 228.2863
Monoisotopic: 228.115029756
Protein binding

6-MNA is over 99% bound to plasma proteins, likely albumin. The unbound fraction is 0.1-0.2% and remains proportional in the dose range of 1000-2000mg

Groups Approved
Therapeutic Class Drugs for Osteoarthritis, Drugs used for Rheumatoid Arthritis
Manufacturer
Available Country
Last Updated: September 19, 2023 at 7:00 am
GSK
GSK

Uses

GSK is used for relief of signs and symptoms of osteoarthritis and rheumatoid arthritis. Carefully consider the potential benefits and risks of GSK and other treatment options before deciding to use GSK. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals

GSK is also used to associated treatment for these conditions: Osteoarthritis (OA), Rheumatoid Arthritis

How GSK works

GSK's active metabolite, 6-MNA, is an inhibitor of both COX-1 and COX-2 although it exhibits some COX-2 selectivity. Inhibition of COX-1 and COX-2 reduces conversion of arachidonic acid to PGs and thromboxane (TXA2). This reduction in prostanoid production is the common mechanism that mediates the effects of nambutone.

PGE2 is the primary PG involved in modulation of nociception. It mediates peripheral sensitization through a variety of effects. PGE2 activates the Gq-coupled EP1 receptor leading to increased activity of the inositol trisphosphate/phospholipase C pathway. Activation of this pathway releases intracellular stores of calcium which directly reduces action potential threshold and activates protein kinase C (PKC) which contributes to several indirect mechanisms. PGE2 also activates the EP4 receptor, coupled to Gs, which activates the adenylyl cyclase/protein kinase A (AC/PKA) signaling pathway. PKA and PKC both contribute to the potentiation of transient receptor potential cation channel subfamily V member 1 (TRPV1) potentiation, which increases sensitivity to heat stimuli. They also activate tetrodotoxin-resistant sodium channels and inhibit inward potassium currents. PKA further contributes to the activation of the P2X3 purine receptor and sensitization of T-type calcium channels. The activation and sensitization of depolarizing ion channels and inhibition of inward potassium currents serve to reduce the intensity of stimulus necessary to generate action potentials in nociceptive sensory afferents. PGE2 act via EP3 to increase sensitivity to bradykinin and via EP2 to further increase heat sensitivity. Central sensitization occurs in the dorsal horn of the spinal cord and is mediated by the EP2 receptor which couples to Gs. Pre-synaptically, this receptor increases the release of pro-nociceptive neurotransmitters glutamate, CGRP, and substance P. Post-synaptically it increases the activity of AMPA and NMDA receptors and produces inhibition of inhibitory glycinergic neurons. Together these lead to a reduced threshold of activating, allowing low intensity stimuli to generate pain signals. PGI2 is known to play a role via its Gs-coupled IP receptor although the magnitude of its contribution varies. It has been proposed to be of greater importance in painful inflammatory conditions such as arthritis. By limiting sensitization, both peripheral and central, via these pathways NSAIDs can effectively reduce inflammatory pain.

PGI2 and PGE2 contribute to acute inflammation via their IP and EP2 receptors. Similarly to β adrenergic receptors these are Gs-coupled and mediate vasodilation through the AC/PKA pathway. PGE2 also contributes by increasing leukocyte adhesion to the endothelium and attracts the cells to the site of injury. PGD2 plays a role in the activation of endothelial cell release of cytokines through its DP1 receptor. PGI2 and PGE2 modulate T-helper cell activation and differentiation through IP, EP2, and EP4 receptors which is believed to be an important activity in the pathology of arthritic conditions. By limiting the production of these PGs at the site of injury, NSAIDs can reduce inflammation.

PGE2 can cross the blood-brain barrier and act on excitatory Gq EP3 receptors on thermoregulatory neurons in the hypothalamus. This activation triggers an increase in heat-generation and a reduction in heat-loss to produce a fever. NSAIDs prevent the generation of PGE2 thereby reducing the activity of these neurons.

The adverse effects of NSAIDs stem from the protective and regulatory roles of prostanoids which have been well-characterized. PGI2 and PGE2 regulate blood flow to the kidney by similar mechanisms to the vasodilation they produce in inflammation. Prevention of this regulation by NSAIDs produces vasoconstriction which limits renal function by reducing blood flow and the hydrostatic pressure which drives filtration. PGE2 also regulates gastric protection via EP3 receptors which are, in this location, coupled to Gi which inhibits the AC/PKA pathway. This reduces the secretion of protons by H+

Dosage

GSK dosage

Osteoarthritis and Rheumatoid Arthritis: The recommended starting dose is 1,000 mg taken as a single dose with or without food. Some patients may obtain more symptomatic relief from 1,500 mg to 2,000 mg per day. GSK can be given in either a single or twice-daily dose. Dosages greater than 2,000 mg per day have not been studied. The lowest effective dose should be used for chronic treatment. Patients weighing under 50 kg may be less likely to require dosages beyond 1,000 mg; therefore, after observing the response to initial therapy, the dose should be adjusted to meet individual patients’ requirements.

Side Effects

Gastrointestinal: Diarrhea (14%), dyspepsia (13%), abdominal pain (12%), constipation, flatulence, nausea, positive stool guaiac, dry mouth, gastritis, stomatitis, vomiting.

Central Nervous System: Dizziness, headache, fatigue, increased sweating, insomnia, nervousness, somnolence.

Dermatologic: Pruritus, rash

Special Senses: Tinnitus

Miscellaneous: Edema

Toxicity

LD50 Values

Mouse: 4290 mg/kg (Oral), 2380 mg/kg (IP)

Rat: 3880 mg/kg (Oral), 1520 mg/kg (IP), >10 g/kg (SC)

Monkey: 3200 mg/kg (Oral)

Overdose

Signs and symptoms of nabumetone overdose include lethargy, drowsiness, nausea, vomiting, and epigastric pain. These are considered reversible with supportive care. GI bleeding, hypertension, acute kidney injury, respiratory depression, and coma are rare but can occur. No antidote exists for nabumetone overdose although administration of activated charcoal and/or induction of emesis can reduce absorption if the nabumetone dose was taken less than 4 hours prior. 6-MNA is cannot be cleared by dialysis.

Carcinogenicity & Mutagenicity

GSK was not significantly carcinogenic in rats or mice studied over 2 years. Neither the Ames test nor mouse micronucleus test showed nabumetone or it's active metabolite, 6-MNA, to be mutagenic. Chromosomal abberation has been observed in cultured lymphocytes exposed to concentrations of 80 mcg/mL and higher of nabumetone or 6-MNA equivalent to the maximum recommended human dose.

Reproductive Toxicity

No adverse effects on fertility have been observed in male and female rats at doses of 320 mg/kg/day.] No teratogenicity has been observed in pregnant rabbits or rats. Dystocia and delayed parturition have been noted in rats resulting in reduced survival of offspring. This has been attributed to the role of prostaglandins in uterine contraction. NSAIDs can also cause premature closure of the ductus ateriosus.

Lactation

6-MNA has been detected in the milk of lactating rats. While no data is available in humans, 6-MNA is both highly protein bound and exists in its anionic form in circulation. For these reasons partitioning into breast milk is expected to be limited.

Precaution

GSK cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of GSK in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions

Interaction

Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.

Food Interaction

  • Avoid alcohol. Alcohol use may aggravate the gastrointestinal irritation caused by this drug.
  • Take with food. Food increases the rate of absorption.

GSK Alcohol interaction

[Moderate] GENERALLY AVOID:

The concurrent use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) and ethanol may lead to gastrointestinal (GI) blood loss.

The mechanism may be due to a combined local effect as well as inhibition of prostaglandins leading to decreased integrity of the GI lining.



Patients should be counseled on this potential interaction and advised to refrain from alcohol consumption while taking aspirin or NSAIDs.

GSK Hypertension interaction

[Major] Fluid retention and edema have been reported in association with the use of nonsteroidal anti-inflammatory drugs (NSAIDs).

Therapy with NSAIDs should be administered cautiously in patients with preexisting fluid retention, hypertension, or a history of heart failure.

Blood pressure and cardiovascular status should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.

Hypertension interaction

[Moderate] Nonsteroidal anti-inflammatory drugs (NSAIDs), including topicals, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which can contribute to the increased incidence of cardiovascular events.

NSAIDs should be used with caution in patients with hypertension.

Blood pressure should be monitored closely during the initiation of NSAID therapy and throughout the course of therapy.

Volume of Distribution

The Vd of 6-MNA reported after administration of a single dose is 0.1-0.2 L/kg or approximately 5-10 L. Vdss reported in official product labeling is approximately 53 L.

Elimination Route

GSK is well-absorbed from the GI tract and undergoes significant first pass metabolism resulting in approximately 35% being converted to the active metabolite, 6-MNA. Tmax for 6-MNA varies widely with a mean values of 3 and 11 hours reported in official product monographs, and described as 9-12 hours in published literature Administration with food increases Cmax by 33% and increases absorption rate. If formulated as a suspension the Cmax increases and the Tmax is reduced by 0.8 hours while the all other pharmacokinetic parameters remain unchanged.

Half Life

6-MNA has a mean half-life of 24 hours with a range of 19-36 hours.

Clearance

6-MNA has an apparent steady-state clearance of 20 - 30 mL/min.

Elimination Route

Most drug is eliminated via hepatic metabolism with minimal to no parent drug detectable in the plasma. 80% of the dose is then excreted by the kidneys and 10% in the feces. It does not appear to undergo enterohepatic recirculation.

Pregnancy & Breastfeeding use

Pregnancy Category C. Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate, well-controlled studies in pregnant women. GSK should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers: It is not known whether this drug is excreted in human milk, however 6MNA is excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from GSK, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Labor and Delivery: In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of GSK on labor and delivery in pregnant women are unknown.

Contraindication

GSK is contraindicated in patients with known hypersensitivity to nabumetone or its excipients. GSK should not be given to patients who have experienced asthma, urticaria, or allergictype reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients. GSK is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery

Special Warning

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).

Acute Overdose

Symptoms following acute NSAIDs overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression, and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.

Patients should be managed by symptomatic and supportive care following a NSAIDs overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 g/kg in children), and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

There have been overdoses of up to 25 grams of GSK reported with no long-term sequelae following standard emergency treatment (i.e., activated charcoal, gastric lavage, IV H2-blockers, etc.).

Storage Condition

Store at 25°C; excursions permitted to 15-30°C in well-closed container; dispense in light-resistant container.

Innovators Monograph

You find simplified version here GSK

GSK contains Nabumetone see full prescribing information from innovator GSK Monograph, GSK MSDS, GSK FDA label

*** Taking medicines without doctor's advice can cause long-term problems.
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