Antipyretic Analgesics: Nonsteroidal Antiinflammatory Drugs

16 May

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 hinz@pharmakologie.uni-erlangen.de

References

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).

Antipyretic Analgesics

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).


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