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• Rofecoxib, Lumiracoxib, Valdecoxib (these preparations have had their marketing authorisation withdrawn because of serious side effects).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 effect: Inflammation and tissue damage stimulate the formation of interleukin-6 (IL-6), which enters the CNS via the bloodstream. In the hypothalamus, it induces the expression of COX-2, an enzyme that mediates the formation of PGE2, which increases the body temperature set point in the hypothalamic thermoregulation center via EP3 receptors. COX inhibitors cause the set point to be reset and thus lower the body temperature. Selective and non-selective COX inhibitors have a comparable antipyretic effect.

Non-opioid analgesics intervene in the nociceptive conduction system at the posterior horn of the spinal cord. Non-acidic antipyretic analgesics can also interfere with pain conduction in the spinal cord via the TRPA1 channel. This enhances their otherwise comparably low analgesic effect via COX.

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

• Acetylsalicylic acid acetylates the COX enzyme at a serine residue near the catalytic center. With this step, it irreversibly inhibits the COX enzyme. Other acidic non-opioid analgesics act as competitive-reversible or non-competitive-reversible inhibitors of COX. This is of great importance for the long-term effect, as acetylsalicylic acid permanently reduces thromobxan synthesis, whereasibuprofen , for example, only contributes to short-term coagulation inhibition.

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

Cardiovascular complications: Both selective COX2 inhibitors and traditional NSAIDs (with the exception of naproxen) lead to a significantly increased risk of cardiovascular and cerebrovascular complications (increase of 20-30%). With regard to selective COX-2 inhibitors, see above. Increase in arterial blood pressure (inhibition of COX-2-mediated endothelial PGI2 synthesis).

The gastrointestinal and vascular side effects of non-steroidal anti-inflammatory drugs (NSAIDs) were newly investigated in a meta-analysis of 639 randomized clinical trials with 353,389 participants. The studies investigated Coxibe vs. placebo or vs. NSAID (including ibuprofen, diclofenac and naproxen), but also compared different NSAIDs with each other and Coxibe. The rate of serious vascular events (non-fatal heart attacks or strokes or cardiovascular-related death) was 37% higher with coxibs and 41% higher with diclofenac. The risk of serious coronary events (non-fatal myocardial infarction or cardiac death) was increased by a factor of 2.0 with ibuprofen. The exception was naproxen. Naproxen could possibly have a similar protective effect as ASA and was the only NSAID examined for which no significantly increased rate of vascular deaths was found. However, the substance, like all other NSAIDs, increases the risk of heart failure. In addition, naproxen proved to be the riskiest NSAID in terms of 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 one year, 3 serious and possibly fatal cardiovascular events can be expected.

Ulcer complaints (gastric ulcers, ulcer perforations, ulcer bleeding are potentially life-threatening complications. Depending on the NSAID, 4 to 16 gastrointestinal complications occur per 1,000 patients with an average initial risk of gastrointestinal complications during a year, most of them with naproxen (Meyer R 2013).

Kidney: Nephrotoxic effects (see individual substances); analgesic nephropathy(acute tubulointerstitial nephritis)

NSAID cystitis

Analgesics Headache (with regular overuse of antipyretic analgesics)

Allergic and pseudo-allergic 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. Angeletti F et al. (2020) Hypersensitivity reactions to non-steroidal anti-inflammatory drugs (NSAIDs) - a retrospective study. J Dtsch Dermatol Ges 18:1405-1416.

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