Antipyretic Analgesics: Nonsteroidal Antiinflammatory Drugs,
Selective COX-2 Inhibitors, Paracetamol and Pyrazolinones B. Hinz (✉)• K. Brune
Department of Experimental and Clinical Pharmacology and Toxicology, Friedrich Alexander University Erlangen-Nuremberg, Fahrstrasse 17, 91054 Erlangen, Germany firstname.lastname@example.org
Abstract Antipyretic analgesics are a group of heterogeneous substances including acidic (nonsteroidal antiinﬂammatory drugs, NSAIDs) and nonacidic (paracetamol, pyrazoli- nones) drugs. Moreover, various selective cyclooxygenase-2 (COX-2) inhibitors with im- proved gastrointestinal tolerability as compared with conventional NSAIDs have been estab- lished for symptomatic pain treatment in recent years. The present review summarizes the pharmacology of all of these drugs with particular emphasis on their rational use based on the diverse pharmacokinetic characteristics and adverse drug reaction proﬁles. Referring to
the current debate, potential mechanisms underlying cardiovascular side effects associated with long-term use of COX inhibitors are discussed.
Keywords Nonsteroidal antiinﬂammatory drugs · Selective cyclooxygenase-2 inhibitors · Paracetamol · Pyrazolinones · Pharmacokinetics · Mechanisms of hyperalgesia
Mode of Action of Antipyretic Analgesics
Inhibition of Cyclooxygenase Enzymes
In 1971, Vane showed that the antiinﬂammatory action of nonsteroidal antiin- ﬂammatory drugs (NSAIDs) rests in their ability to inhibit the activity of the cy- clooxygenase (COX) enzyme, which in turn results in a diminished synthesis of proinﬂammatory prostaglandins (Vane 1971). This action is considered not the sole but a major factor of the mode of action of NSAIDs. The pathway leading to the generation of prostaglandins has been elucidated in detail. Within this pro- cess, the COX enzyme (also referred to as prostaglandin H synthase) catalyzes the ﬁrst step of the synthesis of prostanoids by converting arachidonic acid into prostaglandin H2, which is the common substrate for speciﬁc prostaglandin synthases. The enzyme is bifunctional, with fatty-acid COX activity (catalyz- ing the conversion of arachidonic acid to prostaglandin G2) and prostaglandin hydroperoxidase activity (catalyzing the conversion of prostaglandin G2 to prostaglandin H2; Fig. 1).
In the early 1990s, COX was demonstrated to exist as two distinct iso-
forms (Masferrer et al. 1990; Xie et al. 1991). COX-1 is constitutively ex- pressed as a “housekeeping” enzyme in nearly all tissues, and mediates physi- ological responses (e.g., cytoprotection of the stomach, platelet aggregation). COX-2 expressed by cells that are involved in inﬂammation (e.g., macrophages, monocytes, synoviocytes) has emerged as the isoform that is primarily re- sponsible for the synthesis of prostanoids involved in pathological processes, such as acute and chronic inﬂammatory states. The expression of the COX-2 enzyme is regulated by a broad spectrum of other mediators involved in inﬂammation. Accordingly, glucocorticoids and antiinﬂammatory cytokines (interleukin-4, -10, -13) have been reported to inhibit the expression of the COX-2 isoenzyme (Masferrer et al. 1990; Onoe et al. 1996; Niiro et al. 1997). On the other hand, products of the COX-2 pathway [e.g., prostaglandin 2 by virtue of its second messenger cyclic AMP (cAMP)] may exert a positive feedback action on the expression of its biosynthesizing enzyme in the inﬂamed tissue (Nantel et al. 1999) as well as in numerous cell types (Hinz et al. 2000a, b,
2005b; Maldve et al. 2000). Likewise, the arachidonic acid derivative and endo- cannabinoid anandamide has recently been shown to elicit COX-2 expression via de novo synthesis of ceramide (Ramer et al. 2003; Hinz et al. 2004).
Nonsteroidals, Selective COX-2 Inhibitors, Paracetamol and Pyrazolinones
All conventional NSAIDs interferewith the enzymatic activity of both COX-1 and COX-2 at therapeutic doses (Patrignani et al. 1997). Whereas many of the side effects of NSAIDs (e.g., gastrointestinal ulceration and bleeding, platelet dysfunctions) are due to a suppression of COX-1-derived prostanoids, inhibi- tion of COX-2-derived prostanoids facilitates the antiinﬂammatory, analgesic, and antipyretic effects of NSAIDs. Consequently, the hypothesis that selec- tive inhibition of COX-2 might have therapeutic actions similar to those of NSAIDs, but without causing the unwanted side effects, was the rationale for the development of selective COX-2 inhibitors. However, the simple concept of COX-2 being an exclusively proinﬂammatory and inducible enzyme cannot be sustained in the light of more recent experimental and clinical ﬁndings. Ac- cordingly, COX-2 has also been shown to be expressed under basal conditions in organs including the ovary, uterus, brain, spinal cord, kidney, cartilage, bone and even the gut, suggesting that this isozyme may play a more complex physiological role than previously recognized (for review see Hinz and Brune
2002; Fig. 1). Moreover, during the past few years, evidence has increased to suggest that a constitutively expressed COX-2 may play a role in renal and
cardiovascular functions which will be discussed later in detail (see Sect. 4.4).
Fig. 1 Physiological and pathophysiological roles of COX-1 and COX-2. The COX-1 isozyme is expressed constitutively in most tissues and mediates housekeeping functions by producing prostaglandins. The COX-2 isoform is an inducible enzyme, which becomes expressed in inﬂammatory cells (e.g., macrophages, synoviocytes) after exposure to endotoxin, mitogens, or proinﬂammatory cytokines. COX-2 has been implicated in the pathophysiology of various inﬂammatory and mitogenic disorders. However, in some tissues (e.g., genital tract, bone, kidney, endothelial cells) COX-2 is already signiﬁcantly expressed even in the absence of inﬂammation and appears to fulﬁll various physiological functions
Impact of Biodistribution on Pharmacological Effects of Antipyretic Analgesics
Following the discovery that aspirin-like drugs exert their pharmacological action by suppressing the synthesis of prostaglandins, the question was asked why aspirin and its pharmacological relatives, the (acidic) NSAIDs, exerted antiinﬂammatory activity and analgesic effects, whereas the nonacidic drugs phenazone and paracetamol were analgesic only (Brune et al. 1974). It was speculated that all acidic antiinﬂammatory analgesics, which are highly bound to plasma proteins and show a similar degree of acidity (pKa values between 3.5 and 5.5), should lead to a speciﬁc drug distribution within the body of man or animals (Fig. 2). In fact, high concentrations of these compounds are reached in blood stream, liver, spleen, and bone marrow (due to high protein binding and an open endothelial layer of the vasculature), but also in body compart- ments with acidic extracellular pH values (Brune et al. 1976). The latter type of compartments includes the inﬂamed tissue, the wall of the upper gastrointesti- nal tract and the collecting ducts of the kidneys. By contrast, paracetamol and phenazone, compounds with almost neutral pKa values and a scarce binding to plasma proteins, are distributed homogeneously and quickly throughout the body due to their ability to penetrate barriers such as the blood–brain barrier easily (Brune et al. 1980). It is evident that the degree of prostaglandin synthesis inhibition depends on the potency of the drug and its local concentration.
On the other hand, the differential distribution of acidic and nonacidic antipyretic analgesics may explain why only the acidic compounds (NSAIDs) are antiinﬂammatory and cause acute side effects in the gastrointestinal tract (ulcerations), the blood stream (inhibition of platelet aggregation), and the kidney (ﬂuid and sodium retention), whereas the nonacidic drugs are devoid of both antiinﬂammatory activity and gastric and (acute) renal toxicity. Fi- nally, chronic inﬂammation of the upper respiratory tract (e.g., asthma, nasal polyps) leads to the accumulation of inﬂammatory prostaglandin-producing cells in the respiratory mucosa. Inhibition of COX appears to shift part of the metabolism of the prostaglandin precursor arachidonic acid to the produc- tion of leukotrienes which may induce pseudoallergic reactions (i.e., aspirin- induced asthma).