Nonsteroidal Antiinflammatory Drugs
Pain and painful events are the first complaints among the reasons for referring to a physician. Analgesic and non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed drugs after antibiotics. Arthritis and drug use, on the other hand, are a challenge for making mistakes and making choices despite all efforts and scientific steps, and modern approaches change frequently.
It may be useful to look at statistics around the world to identify the magnitude of the problem. The prevalence of osteoarthritis, which is a common arthritis, is 10-20%, and rheumatoid arthritis is 1-2% and at least half of these patients use NSAID. The prevalence of NSAID use in the population is 5%.
Analgesic drugs:
a. Opioids (narcotics)
b. Adjuvant analgesics
c. Nonopioid analgesics (non-narcotic analgesics):
I. Paracetamol and Aspirin
ii. We can summarize it as NSAI.
Classical NSAIDs are generally used because of analgesic, antipyretic, antiinflammatory and partly uricosuric effects. Reasons for use in arthritis are analgesic and anti-inflammatory effects. This group of drugs is classified as in Table 1.
Taking a look at the short history of NSAIDs, it is noteworthy that colchicine was first identified in 1820, salicylic acid was identified in 1860, and the first Aspirin tablet was synthesized in 1898. The NSAID name coincides with the synthesis of phenylbutazone, which was first used in 1949. This adventure in 1971 With John Wyane's work on the mechanisms of action and his description of the first cyclooxygenase absorption, John Wayne was given the title Sir and Nobel. In 1976, prostoglandin endoperoxide synthetase (cyclooxygenase = COX) enzyme, a new stop in the adventure, was obtained, thus accelerating the studies on the mechanisms of action, side effects and safety profile of NSAIDs. This is the latest development in the early 1990s, showing that COX is not a single molecule, and that multiple isomers have different functions, thus gaining a new dimension in clinical trials.
A. According to chemical structure
I. Carboxylic acids:
a. Salicylic acid and its esters
b. Anthranilic acid derivatives: Flufenamic acid, mefanamic acid
II. Acetic Acids:
a. Phenylacetic Acid: Diclofenac, phenclofenac
b. Carbo and heterocyclic acids: Infomethacin, etodolac, sulindac, tolmeltin
III. Propronic acids: Ebuprofen, ketoprofen, flurbiprofen, suprofen, naproxen, fenoprofen, thiaprofenic acid
IV. Phenamic Acids: flufenamic, mefenamic, meclofenamic
V. Enolic Acids:
a. Pyrazolones: phenylbutazene, oxyphenbutazone, azopropazone
b. Oxicams: piroxicam, pesoxicam, sudoxicam
VI. Nonaisidic Agents: proquazoma, traramide, pflunizole, naubmetan
B. By Half Life
I. Long half-life drugs (10-12 hours)
1. Azopropazone
2. Diflunocele
3. Perbufen
4. Nabumeton
5. Naproxen
6. Oxaprazocine
7. Phenylbutazone
8. Piroxicam
II. Short half-life medications (less than 6 hours)
1. Diclofenac
2. Etodolac
3. Phenoprofen
4. Flufenamic Acid
5. Flurbiprofen
6. Ibuprofen
7. Indomethacin
8. Ketoprafen
9. Pirprofen
10. Traprophenic acid
11. Tolmetin
NSAIDs whose general effects are listed above are effective in two ways:
1. Cyclooxygenase (COX)
2. Lipoxygenase.
The COX enzyme activity controls the pathway from membrane phospholipids to prostaglandin synthesis, which inhibits the synthesis of prostaglandin by inhibition of this enzyme by NSAID and the synthesis of leukotrienes by lipoxygenase. COX inhibition is the main pathway in the inhibition of inflammation by the classical NSAIDs.
General Impact Mechanisms of NSAIDs:
1. COX inhibition, suppression of prostoglandin synthesis
2. Lipoxygenase inhibition: Suppression of leukotriene synthesis
3. Suppression of superoxide production
4. Suppression of lysosomal enzyme release
5. Inhibition of hydrogen peroxide production
6. Inhibition of phospholipase-C activity in the cell membrane
7. Effect on cartilage metabolism, chondroprotective or chondrodestructive effect
8. Reduction of lymphoid transformation and DNA synthesis
9. Central analgesic effect
10. Suppression of bradycin-related inflammatory events
11. Production of antiinflammatory peptide from plasma proteins
12. Inhibition of signals required for neutrophil aggregation and activation
13. Inhibition of granulocyte-monocyte migration and phagocytosis
The pharmacokinetic properties of this group of drugs can be generalized as follows: Absorption in the gastrointestinal tract is good. The first pass mechanisms in the liver are low. They are highly bound to albumin and have low dispersion volumes. Some have synovium deposition properties. Excretion decreases in chronic renal failure.
Side effects are distributed over a wide spectrum and show a multicolored picture.
NSAID Side Effects
1. In GIS; dyspepsia, gastric erosion, peptic ulcer, upper GIS bleeding, intestinal inflammation
2. In GOS; reduction in glomerular filtration, acute renal failure; papillary necrosis
3. Pulmonary; bronchospasm asthma provocation, pneumonitis
4. Neuropsychiatric; headache, dizziness, disturbances, provocation of epilepsy, aseptic meningitis
5. Dermatological; urticaria, leukocytoclastic vasculitis, erythema multiforme, drug eroption
6. Hematological; tendency to bleeding, aplastic anemia, thrombocytopenia, agranulocytosis
7. Hepatic; toxic hepatitis, cholestatic jaundice, liver failure
Interactions of NSAIDs with Other Drugs:
1. Increase the effect of oral anticoagulants
2. Reduce the excretion of lithium
3. Increase the effect of oral hypoglycemics
4. Increase phenytoin levels
5. Increase digoxin levels
6. Increase the level of aminoglycosides
7. Antacids slow their absorption
8. Probenecid slows the excretion of these drugs
9. Barbiturates increase metabolic clearance of these drugs
10. Caffeine increases absorption rates
11. Cholestyramine slows absorption.
In many studies, error rates in choosing the appropriate drug exceed 20%. It has been estimated that more than 13 million people use NSAIDs in the US every day and their annual worth is over $ 1 billion, while it is estimated at $ 5.7 billion worldwide in 1995. The cost of gastrointestinal complications is 0.8-1.6 billion dollars and the number of hospitalized patients varies between 200-400 thousand every year. In the USA, GIS complication and mortality rate due to NSAID use is the third most common cause after death from smoking and cancer and is reported as 0.2%.
It is also reported that most of the patients were asymptomatic in the period before drug-induced GIS side effects (Singh et al .: 81%, Amustrens, Blower: 58%). In the literature, GIS intolerance is reported as 30% and endoscopic ulcer prevalence is reported as 10-30%. In Europe, bleeding / perforation is directly attributed to NSAIDs in 400 out of 1000 people hospitalized daily for upper GI bleeding. All these figures emphasize the importance of public health issues and the extent to which the problem of pharmaco-economic approaches (direct and indirect) is thought-provoking.
Solution:
Especially classical drugs are as therapeutically effective as opposed to finding new options with a higher safety profile (significantly less frequent side effects).
Drugs produced as examples of these options, known as COXIBs, induce inducible COX inhibition in the inflammatory area of the above-mentioned side effect without inhibiting COX1 that is located in the tissue and known as structural. That is, COX1 is found mostly in the stomach, intestine, kidney and platelets, whereas COX2 is made by macrophages, synoviocytes and endothelial cells. While classic NSAIDs inhibit both enzymes, COX2 inhibitors inhibit inducible COX2 and suppress inflammation without structural side effects.
With this approach, COX inhibitors are classified as follows:
1. COX1 Specific Agents: COX1 inhibition without inhibition of COX2, such as low-dose Aspirin
2. COX Nonspecific Agents: Conventional NSAIDs that inhibit both enzymes
3. COX2 Selective Agents: Ourlar (meloxicam, nabumetane, nimesulide) cause COX1 inhibition, which is evident at increasing doses, while inhibiting CO2 in humans and animals at clinical therapeutic doses.
4. COX2 Specific Agents: Agents that do not cause inhibition of clinically significant COX, even at maximum therapeutic dose (celecoxib, rofecoxib)
The results of clinical trials with COX2-specific agents can be summarized as follows:
- Even above therapeutic doses, it leads to lower symptomatic ulcers and ulcer complications than conventional NSAIDs.
- GIS side-effect profile remains unchanged (celecoxib) despite use with low-dose Aspirin.
- Since they do not interact with drugs such as methotrexate and warfarin, they can be used safely in patients requiring RA and anticoagulant therapy.
- They do not affect platelet aggregation.
- Clinically they are as effective as conventional NSAIDs on pain and inflammation.
- Hemoglobin and hemetocrit levels do not decrease despite long term use.
- There is enough experience in the use of advanced age, they are reliable.
- There is an increase in peripheral edema compared to placebo, but they do not differ from conventional NSAIDs.
- They can be used safely in Agrave hypertension and hypertension and do not cause a significant increase in blood pressure.
- They should not be used in people with excessive sulfonamide sensitivity.
- There is no evidence of significant allergic reactions or bronchospasm in patients with asthma.
- Celecoxib has no negative effect on renal function and does not affect renal function even in patients with low glomenular filtration rate. They do not lead to an increase in creatine level.
- It does not cause clinically significant liver function test disorders and does not cause changes in enzyme levels even in patients with borderline and laboratory values up to three times higher.
- An increase in the incidence of cardiovascular and cerebrovascular events, especially for celecoxib, did not show an increase compared to conventional NSAIDs.
* Although this group of drugs is not perfect, it is as effective as conventional drugs, but it is more reliable in terms of side effects and safety profile and appears to be able to open new horizons for clinical and laboratory (reducing cancer risk, controlling Alzheimer's, etc.).
* There is not enough information about the use of this group of drugs in children, pregnant and lactating motherhood. This issue should be investigated in detail.
39AXX
Berkley Jensen Extra Strength Non-Aspirin Pm Caplets, 500 Count
