Acetaminophen, Phenacetin and Dipyrone Do Not Modulate Pressor Responses to Arachidonic Acid or to Pressor Agents

Abstract

In contrast to nonsteroidal anti-inflammatory drugs (NSAIDs), the nonopioid analgesics phenacetin, acetaminophen and dipyrone exhibit weak anti-inflammatory properties. An explanation for this difference in pharmacologic activity was provided by the recent discovery of a new cyclooxygenase isoform, cyclooxygenase (COX)-3, that is reported to be inhibited by phenacetin, acetaminophen and dipyrone. However, COX-3 was found to be a spliced variant of COX-1 and renamed COX-1b. Although recent studies provide evidence for the existence of this new COX isoform, it is uncertain whether this COX-3 (COX-1b) isoform, or putative acetaminophen-sensitive pathway, plays a role in the generation of vasoactive prostaglandins. NSAIDs increase systemic blood pressure by inhibiting the formation of vasodilator prostanoids. Angiotensin II, norepinephrine and other vasoconstrictor agents have been reported to release prostaglandins. It is possible that this acetaminophen-sensitive pathway also modulates pressor responses to these vasoconstrictor agents. Therefore, the purpose of the present study was to determine whether this acetaminophen-sensitive pathway plays a role in the generation of vasoactive products of arachidonic acid or in the modulation of vasoconstrictor responses in the pulmonary and systemic vascular bed of the intact-chest rat. In the present study, the nonopioid analgesics did not attenuate changes in pulmonary or systemic arterial pressure in response to injections of the prostanoid precursor, arachidonic acid, to the thromboxane A₂ mimic, U46619, or to angiotensin II or norepinephrine. The results of the present study do not provide evidence in support of a role of a functional COX-3 (COX-1b) isoform, or an acetaminophen-sensitive pathway, in the generation of vasoactive prostanoids or in the modulation of responses to vasoconstrictor hormones in the intact-chest rat.

Acute Acetaminophen Overdose Is Associated with Dose‐Dependent Hypokalaemia: A Prospective Study of 331 Patients

“…In health, COX‐1 activity is critical for renal and systemic prostaglandin E2 production, while renal prostacyclin synthesis is COX‐2‐dependent [16]. Acetaminophen is capable of inhibiting COX isoenzymes 1a, 1b and 2; however, therapeutic doses are thought to confer only a weak inhibitory effect [17,18]. More potent COX inhibition is observed in the presence of acetaminophen concentrations between 500–3000 µmol/l (76–453 mg/l), and prostaglandin E2 synthesis is inhibited in a dose‐dependent manner within this range [19].…”

Relationship between Serum Acetaminophen Concentration and N‐Acetylcysteine‐Induced Adverse Drug Reactions

“…Acetaminophen is associated with inhibiting cyclooxygenase (COX) isoenzymes and thus might be expected to suppress inflammation [31]. Therapeutic acetaminophen concentrations weakly inhibit COX, while concentrations between 76 and 453 mg/l inhibit prostaglandin E2 synthesis [32,33]. Therefore, COX dose‐dependent mechanism might be important in cutaneous anaphylactoid reactions induced by N ‐acetylcysteine infusion.…”

Cyclooxygenases and the pathogenesis of chronic rhinosinusitis and nasal polyposis

“…A new COX isoform (COX-3) was discovered recently, and is reported to be inhibited by phenacetin, acetaminophen, and dipyrone. However, COX-3 was found to be a spliced variant of COX-1 and was renamed COX-1b [25]. One of the most important prostaglandins is PGE 2 , which can perform contrasting activities (eg, bronchodilatation and bronchoconstriction; anti-inflammatory and proinflammatory), depending partly on the diverse types of cell surface receptors that may be stimulated (EP1, EP2, EP3, and EP4) [26].…”