What Are the Different Types of COX Inhibitors?

Selective COX-2 inhibitors are a new class of NSAIDs, because they selectively inhibit the activity of COX-2 and have a small effect on COX-1. They are currently widely used in anti-inflammatory and analgesic effects of rheumatoid arthritis and osteoarthritis. treatment.

Selective COX-2 inhibitors are a new class of NSAIDs, because they selectively inhibit the activity of COX-2 and have a small effect on COX-1. They are currently widely used in anti-inflammatory and analgesic effects of rheumatoid arthritis and osteoarthritis. treatment.

Selective COX2 inhibitors

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used drugs for the treatment of acute and chronic pain. Their anti-inflammatory, analgesic, and antipyretic effects are achieved by inhibiting cyclooxygenase (COX). COX includes two isoenzymes, namely COX-1 and COX-2. COX-1 is an inherent housekeeping enzyme. It is mainly present in the stomach, kidneys and platelets. It catalyzes the production of prostaglandin E ₂ (PGE ₂ ) that is physiologically needed, regulates peripheral vascular resistance, maintains renal blood flow, and protects gastric mucosa. And regulate platelet aggregation. COX-2 is an enzyme that is rapidly expressed by monocytes and fibroblasts after being stimulated by inflammatory factors. It is called an inducing enzyme. It is one of the key enzymes that cause inflammatory reactions and can promote inflammation. Reaction, causing tissue damage. The analgesic and anti-inflammatory effects of traditional NSAIDs are the result of COX-2 inhibition. Selective COX-2 inhibitors are a new class of NSAIDs. Because they selectively inhibit the activity of COX-2, they have less effect on COX-1 and have fewer adverse reactions. They are currently widely used in rheumatoid arthritis and bone and joints. Anti-inflammatory and analgesic treatment of inflammation.

Selective COX2 inhibitors

Some functional groups of COX-2 inhibitor (coxib) can be inserted into the hydrophobic cavity formed by some amino acid residues of COX-2, making it allosteric and lose its catalytic function. Arachidonic acid cannot pass through the hydrophobic channel and cannot be used in COX- 2 under the catalysis of biological transformation, PGs synthesis is blocked, blocking the inflammatory process. At present, it has mainly developed bicyclic and tricyclic compounds. Tricyclic compounds mainly include heterocyclic compounds, cycloolefin series derivatives, and triphenyl series derivatives. Bicyclic compounds mainly include Xikang series derivatives, aniline derivatives, benzenesulfonamides and sulfonates, di-tert-butyl substituted phenols, and the like. Among the currently listed domestic COX-2 inhibitors, the tricyclic celecoxib is the first and only selective COX-2 inhibitor approved by the FDA. Its benzenesulfonamide structure has a significant effect on the COX-2 receptor. Higher selectivity without inhibition of COX-1. The serial nimesulide and meloxicam have a certain inhibitory effect on COX-1.

COX-2 Selective COX2 inhibitors 3. Several selective COX-2 inhibitors that have been marketed in China

1. Nimesulide

Nimesulide is the first selective COX-2 inhibitor on the market. The oral absorption of this drug is rapid and complete. It reaches the maximum blood concentration in 1-2 hours. The t _1/2 is 3 hours. It is metabolized by the liver and excreted by the kidneys. Analgesic and anti-inflammatory effects. IC ₅₀ (COX-2) / IC ₅₀ (COX-1) is 0.1, and its selectivity to COX-2 is 20 times stronger than that to COX-1.

2. Meloxicam

Meloxicam is a selective COX-2 inhibitor. Its selectivity to COX-2 is 100 times greater than that to COX-1, and its IC ₅₀ (COX-2) / IC ₅₀ (COX-1) is 0.33. In inflammatory tissues, meloxicam can selectively inhibit COX-2, and can maintain the synthesis of COX-1-dependent PGs in the stomach and kidneys, so it has strong anti-inflammatory and analgesic effects, fewer gastric and renal side effects, and does not affect platelets. Aggregation and synthesis of COX-1-dependent TXB ₂ in platelets are more beneficial for reducing gastrointestinal bleeding side effects.

The drug is completely absorbed orally, with a bioavailability of 84%, a strong first checkpoint effect, and the original drug excreted in urine <1%. About 50% of the drugs participate in enterohepatic circulation, so the time for absorption and distribution is significantly prolonged. Metabolized by the liver drug enzyme P ₄₅₀ system, metabolites can be excreted through urine and feces. It took effect at 1.5h after taking the drug, reached steady-state plasma concentration at 5-6h, and the plasma protein binding rate was 99.5%, which was mainly combined with albumin. Meloxicam's elimination t _1/2 is 20-22h, which is suitable for 1 time / d administration. No significant interaction with warfarin, cimetidine, aspirin, digoxin, etc. It is mainly used for osteoarthritis (OA) and rheumatoid arthritis (RA). It can also be used for low back pain and acute sciatica.

3. Celecoxib

The drug is a selective COX-2 inhibitor and is mainly used in OA and RA. Celecoxib selectively inhibits COX-2 without COX-1 inhibition. Pharmacokinetic studies found that peak plasma concentrations appeared 3 h after oral administration. Greasy food can slow its absorption. The peak drug concentration lags 1-2 hours, but the absorption rate can increase by 10% -20%. The plasma protein binding rate was 97%. It is metabolized by liver drug enzyme CYP2C9 into 3 kinds of inactive products, and excreted by urine and feces. The excretion of the original drug is <3%. Because the efficacy of the drug is maintained for 11 hours, this drug is suitable for 1-2 times / d administration. The drug is well tolerated and has few side effects, similar to placebo. The main side effects are headache, diarrhea, rhinitis, nausea, anorexia, and abdominal pain. Compared with traditional NSAIDs, the incidence of ulcers was significantly reduced (P <0.01), and the withdrawal rate was low due to gastrointestinal side effects.

4. Refecoxib (listed in 1999 and withdrawn from the market in 2004)

The drug can selectively inhibit COX-2. The IC50 of a single dose of rofecoxib to inhibit COX-2 was 7.7 × 10 mol / L. After increasing the dosage to 1000 mg, there was still no inhibitory effect on COX-1. Compared to celecoxib, COX-2 has a higher selectivity for inhibition. Pharmacokinetic studies showed that peak plasma concentrations appeared 2-3 hours after administration, and reached steady state at 4 days. After oral administration of the drug at 12.5 mg, 25 mg, and 50 mg, the average bioavailability was about 93%. Absorption is not affected by food. When the plasma concentration was within 0.05-25 mg / L, about 87% bound to plasma proteins. After oral administration of 12.5 mg and 25 mg, the plasma clearance rates were 8.46 L / h and 7.2 L / h, respectively, and the steady-state apparent distribution volumes were 91 L and 86 L, respectively, and t _{1/2 at} steady state was about 17 h. Most of this product is metabolized by the liver, and the excretion of the prototype drug in the urine is <1%. This product is used for the treatment of OA, RA and dysmenorrhea and sharp pain in adults.

Rofecoxib is highly safe, with adverse reactions such as diarrhea, headache, insomnia, edema, and upper respiratory infections. The adverse reactions disappeared after discontinuation. Due to the selective inhibition of COX-2, the inhibition of COX-1 is very weak. Compared with traditional NSAIDs, the biggest advantage of this product is that the safety of the gastrointestinal tract is improved, and the incidence of serious gastrointestinal adverse reactions is significantly reduced.

Rofecoxib can antagonize the antihypertensive effect of angiotensin-converting enzyme inhibitors and diuretics; it can increase the blood concentration of lithium salts and methotrexate; rifampicin and non-specific drug enzyme inducers can make this product Accelerate metabolism. Combination with aspirin can increase the incidence of gastrointestinal adverse reactions; combined with warfarin, it may cause gastrointestinal bleeding and prolonged clotting time.

COX-2 Selective COX2 inhibitors 4. Advantages of clinical application of selective COX-2 inhibitors

Traditional NSAIDs gastrointestinal damage is quite common and includes complications such as gastrointestinal symptoms, ulcers, and bleeding. As the main development direction of reducing gastrointestinal adverse reactions of traditional NSAIDs, Coxib has been a research hotspot. In summary of all celecoxib clinical trials, it was found that only 2 cases of upper gastrointestinal bleeding occurred in all patients. It was 0.2%, and 7 patients with NSAIDs had upper gastrointestinal bleeding, and the annual incidence of ulcers was 1.7%. The results showed coxib's encouraging gastrointestinal safety. However, some studies have shown that COX-2 is also a native enzyme in some parts, and the PG produced plays a certain role in maintaining normal gastric mucosal physiological functions. Selective COX-2 inhibition does not cause toxic damage to the gastrointestinal mucosa of normal rats, but can aggravate existing gastrointestinal mucosal damage, which can cause gastric ulcer and small bowel necrosis. Multiple results suggest that the gastrointestinal safety of COX-2 inhibitors is significantly improved compared to traditional NSAIDs, but it is not yet complete.

COX-2 Selective COX2 inhibitors 5. Correct understanding of selective COX-2 inhibitors

1. Cardiovascular

On September 30, 2004, the withdrawal of coxib rofecoxib from the market raised academia's concerns about the cardiovascular safety of COX-2 inhibitors. However, judging from the large number of results before and after the listing of another coxib celecoxib, it does not suggest cardiovascular safety issues. Is it a common problem of coxib or the problem of individual drugs that affect cardiovascular safety? Unfavorable studies suggest that the mechanism by which rofecoxib increases the risk of thrombosis may be the structural COX-2 existing in endothelial cells, which catalyzes the production of PG ₂ I, and rofecoxib inhibits its production, causing PG ₂ I / TXA ₂ imbalance. , Which causes thrombosis and increased blood pressure. Favorable studies have confirmed that there is no significant difference in the cardiovascular safety of coxib celecoxib compared with the placebo group, the untreated group, or the traditional NSAIDs group. So far, there is no clear evidence that cardiovascular thrombotic events are a common effect of coxib. The different cardiovascular safety of different coxibs may be due to different molecular structures, pharmacokinetics and pharmacodynamic characteristics of the drug. Vascular safety remains the focus of debate, and more biological and clinical trials have yet to be proven.

2, kidney

Renal toxicity is the most common adverse reaction of traditional NSAIDs, and its incidence is 3-5%. There are comprehensive reports of kidney side effects of coxib. The data are from 114 randomized trials, including 116,094 participants, suggesting that coxib's renal toxicity is not significantly different from traditional NSAIDs.

3.Other

The adverse reaction of the liver is acute cholestatic hepatitis. Acute liver injury has also been reported and requires attention. It can also cause mental disorders, including neurological disorders, depression, hallucinations, anxiety, and abnormal thinking. There have also been reports of skin irritation and transient visual impairment.

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