Non steroidal anti-inflammatory drugs

Substances that inhibit inflammatory processes in the organism by inhibiting prostaglandin synthesis. This reduces the stimulation of nociceptors and achieves an analgesic effect. Non-steroidal anti-inflammatory drugs - NSAID - are used in pain therapy and in the treatment of rheumatic complaints.

Depending on which cyclooxygenase (COX) isoform is inhibited, antipyretic analgesics can be divided into 2 groups:

Non-selective COX inhib itors (inhibit both COX isoforms - COX1/COX2) at therapeutic doses. Non-selective COX inhibitors can be further divided into:

• Pharmaceuticals with antiphlogistic activity (also called acid analgesics, since their chemical structure classifies them as acids).
• Salicylates (acetylsalicylic acid/aspirin)
• Arylpropionic acid derivatives (ibuprofen, flurbiprofen, naproxen, ketoprofen, tiaprofenic acid)
• Arylacetic acid derivatives (diclofenac)
• Indoleacetic acid derivatives (indometacin)
• Anthranilic acid derivatives (flufenamic, mefenamic acid),
• Enolacetic acid derivatives
• Oxicams (piroxicam, tenoxicam, meloxicam)
• Pharmaceuticals without antiphlogistic effect (no acids)
• Aminophenols (paracetamol - mechanism of action not exactly known; COX3 inhibitors?)
• Pyrazolones (metamizole, COX3 inhibitors?)

Selective COX2 inhibitors (coxibe; no acid structure, antiphlogistic activity)

• Celecoxib, parecoxib, etoricoxib
• Rofecoxib, Lumiracoxib, Valdecoxib (these preparations have had their marketing authorisation withdrawn because of serious side effects).

Note: COX3 is another COX isoform, and the product of a splice variant of the COX-1 gene. This enzyme is expressed in the CNS. It is apparently inhibited particularly effectively by paracetamol and metamizole. So far, it is unclear whether COX-3 inhibition contributes to the analgesic effect of these drugs.

Antipyretic action: Inflammation and tissue damage stimulate the production of interleukin-6 (IL-6), which travels by blood to the CNS.In the hypothalamus, it induces the expression of COX-2, where this enzyme mediates the formation of PGE2, which increases the body temperature set point in the hypothalamic thermoregulatory centre via EP3 receptors. COX inhibitors cause the set point to be reset, thereby lowering body temperature. Selective and nonselective COX inhibitors have comparable antipyretic effects.

Superiorly, nonopioid analgesics interfere with the nociceptive conduction system at the posterior horn of the spinal cord. Non-acidic antipyretic analgesics can additionally interfere with pain conduction in the spinal cord via the TRPA1 channel. This enhances their otherwise comparably small analgesic effect via the COX.

Effect on blood coagulation: In addition to their antiphlogistic and antipyretic effects, non-opioid analgesics interfere with blood coagulation. By inhibiting cyclooxygenases, thromboxane A2, an activator of platelet aggregation, can no longer be formed - blood clotting is disrupted. The effect of these non-opioid analgesics on coagulation depends on the part of the COX molecule they attack:

• Acetylsalicylic acid acetylates the COX enzyme at a serine residue near the catalytic center. It irreversibly inhibits the COX enzyme with this step. Other acid non-opioid analgesics act as competitive-reversible or non-competitive-reversible inhibitors of the COX. This is of great importance for the long-term effect, because acetylsalicylic acid permanently decreases thromobxane synthesis, whereasibuprofen , for example, only contributes to short-term anticoagulation.

Analgesics without antipyretic-antiphlogistic effect: These include paracetamol and metamizole. This small group of non-opioid analgesics have analgesic effects only. They act directly on receptors or channels depending on the active ingredient. These include voltage-dependent potassium channels, NMDA receptors, vanilloid receptors (see below TRP channels), N-type calcium channels and cannabinoid receptors.

• Cardio-vascular complications: Both selective COX2 inhibitors and traditional NSAIDs (with the exception of naproxen) lead to a significantly increased risk of cardio-vascular and cerebro-vascular complications (increase of 20-30%). Regarding the selective COX-2 inhibitors, see there. Increase in arterial blood pressure (inhibition of COX-2-mediated endothelial PGI2 synthesis).

  The gastrointestinal and vascular side effects of nonsteroidal anti-inflammatory drugs (NSAID) were reexamined in a meta-analysis of 639 randomized clinical trials involving 353 389 participants. The trials examined coxibe vs placebo or vs NSAID (including ibuprofen, diclofenac, and naproxen), but also compared different NSAIDs with each other and coxibe with each other. The rate of serious vascular events (nonfatal myocardial infarction or stroke or cardiovascular-related death) was increased by 37% with coxibs and 41% with diclofenac. The risk of serious coronary events (nonfatal myocardial infarction or cardiac death) was increased by a factor of 2.0 with ibuprofen. The exception was naproxen. Naproxen could potentially have a similar protective effect as ASA and was the only NSAID studied for which no significantly increased rate of vascular death was found. However, the substance, like all other NSAIDs, increases the risk of heart failure. In addition, naproxen was found to be the riskiest NSAID for gastrointestinal complications, including the dreaded bleeding. For every 1 000 patients with an intermediate baseline cardiac risk treated with a high-dose NSAID (other than naproxen) for 1 year, 3 serious, possibly lethal, cardiovascular events should be expected.

• Ulcer complaints (gastric ulcers, ulcer perforations, ulcer bleeding are potentially life-threatening complications. For every 1 000 patients at intermediate baseline risk for gastrointestinal complications, 4 to 16 gastrointestinal complications occur during one year, depending on the NSAID, the majority under naproxen (Meyer R 2013).

• Kidney: nephrotoxic effects (see with the individual substances); analgesic nephropathy(acute tubulointerstitial nephritis).
• NSAID cystitis
• Analgesic headache (with regular overuse of antipyretic analgesics)
• Allergic and pseudoallergic reactions (NSAID-exacerbated respiratory disease = NERD; NSAID-exacerbated cutaeous disease = NECD; NSAID-induced urticaria (angioedema = NIUA; true type I or type IV drug allergies = SNIUAA ). See below NSAID hypersensitivity. Anaphylactic reactions have been observed after parenteral administration.

1. Meyer R (2013) Nonsteroidal anti-inflammatory drugs: increased risk of myocardial infarction with long-term use. Dtsch Arztebl 110: A-1563 / B-1378 / C-1361