Basic Aspects

Inhibition of Cyclooxygenases

Inhibition of prostaglandin production through blockade of cyclooxygenases (COXs) was identified in the early 1970s as the major mechanism of action of aspirin/acetylsalicylic acid and the pharmacologically related non-steroidal anti-inflammatory drugs (NSAIDs) (Vane 1971). A variety of stimuli induce the formation of arachidonic acid from phospholipids of the cell membrane, mainly through cytosolic phospholipase A₂. Arachidonic acid then serves as the substrate for prostaglandin G/H synthases, colloquially also called COXs, which convert arachidonic acid into prostaglandin G₂ (PGG₂) and PGH₂ in a two-step process consisting of an initial COX reaction and a second hydroperoxidase reaction (Fig. 32-1). In the late 1980s and early 1990s, the first cDNA of COX enzymes from seminal vesicles was sequenced (Merlie et al 1988, DeWitt et al 1989). Molecular biologists subsequently discovered a second COX isoform whose expression was regulated by cytokines and glucocorticoids (Kujubu et al 1991, O’Banion et al 1991). Both isoforms were found to be encoded by separate genes and were called prostaglandin G/H synthase-1 and -2, or COX-1 and COX-2 (Fig. 32-2). They differ in their regional expression and temporal inducibility, which forms the basis of their different functions in health and disease (Vane et al 1994). COX-1 is constitutively expressed in most tissues and provides the tonic supply of prostanoids required for homeostasis in many organs, organ systems, and cells, including the upper gastrointestinal (GI) tract, platelets, and kidney. COX-2, on the other hand, is under the transcriptional control of pro- and anti-inflammatory cytokines. In many cells such as macrophages it becomes expressed only in response to inflammatory stimuli (Raz et al 1989, 1990), whereas immunosuppressants such as glucocorticoids reduce its expression (Masferrer et al 1992, Yamagata et al 1993). Such concepts fostered the idea of selective inhibition of COX-2 being sufficient for analgesic/anti-inflammatory effects but sparing unwanted effects in the GI tract and possibly in other organ systems. This dichotomous picture of constitutive COX-1 and inducible COX-2 is, however, not consistently followed in all organs. Constitutive or inflammation-independent expression of COX-2 has, for example, been observed in endothelial cells and in the kidney. Inhibition of constitutive COX-2 expression at these sites may contribute to the undesired actions of NSAIDs and coxibs, such as arterial hypertension (Forman et al 2005) and increased cardiovascular risk (Bombardier et al 2000, Bresalier et al 2005).

Cloning and subsequent heterologous expression of both enzymes allowed high-throughput screening of large compound libraries in the quest for selective inhibitors. Subsequent testing of established COX inhibitors on recombinant enzymes, as well as in isoform-specific ex vivo assays, revealed that most existing drugs were non-specific inhibitors of both enzymes (Patrignani et al 1994), but some experimental compounds proved to be selective (Masferrer et al 1994, Riendeau et al 1997).

Heterologous expression of both enzymes also paved the path for crystallographic analysis of both COXs. These studies provided important insight into the structural basis of their enzymatic activity (Picot et al 1994) and their interaction with inhibitors (Loll et al 1995, Kurumbail et al 1996). It was found that COX-1 and COX-2 insert as homodimers into lipid membranes (Smith and Dewitt 1996) and form a hydrophobic channel that allows arachidonic acid to reach the catalytic center of the enzymes (Picot et al 1994). Most known COX inhibitors inhibit the catalytic site or the channel in a competitive manner. Only aspirin/acetylsalicylic acid blocks this access irreversibly through covalent acetylation of a serine residue (S530) close to the catalytic center (Roth et al 1975). This irreversible action forms the basis for its unique long-lasting inhibitory action on platelet aggregation. The availability of structural information also permitted structure-based rational drug design approaches. It was discovered that differences in the structure of COX-1 and COX-2 were sufficiently large to enable selective inhibition of COX-2 (Kurumbail et al 1996). A side pocket present in the channel formed by the COX-2 enzyme but absent from COX-1 turned out to be particularly relevant for the design of subtype-selective blockers. A third COX isoform, called COX-3 (Chandrasekharan et al 2002), is not encoded by a separate gene but results from alternative splicing of the COX-1 gene and retention of intron 1. COX-3 mRNA has, however, been detected only in dogs and is apparently not present in humans (Dinchuk et al 2003).

Although the role of COX inhibition and diminished prostanoid formation is generally accepted as the predominant mechanism of action of NSAIDs and coxibs, their role is much less clear in acetaminophen/paracetamol, dipyrone/metamizole, and related compounds. These drugs show only limited inhibition of COXs in vitro and largely lack anti-inflammatory action. They may, however, still inhibit COXs in vivo (e.g., through active metabolites). Recent evidence from ex vivo studies indeed suggests that acetaminophen/paracetamol possesses inhibitory actions on COX-2 in humans comparable even to those of coxibs (Hinz et al 2008). The combination of antipyretic and analgesic actions of acetaminophen/paracetamol is clearly consistent with an inhibitory effect of acetaminophen/paracetamol on prostaglandin formation. Its non-acidic (chemically neutral) nature may facilitate permeation of acetaminophen/paracetamol across the blood–brain barrier into the central nervous system (CNS), where an inhibitory action on COX-2–dependent production of prostaglandins would exert analgesic and antipyretic effects. The apparent lack of a clear anti-inflammatory action of acetaminophen/paracetamol may, on the other hand, be ascribed to the absence of their enrichment in inflamed tissue (see also below) and to the presence of higher arachidonic acid or peroxide concentrations in inflamed tissue, which would render competitive inhibition less effective.

Cyclooxygenase Products as Mediators of Hyperalgesia

Prostaglandins, in particular PGE₂ and PGI₂ (also called prostacyclin), increase the sensitivity of peripheral nociceptor endings to noxious stimuli (Fig. 32-3A). They facilitate activation of the receptors and ion channels involved in the nociceptive transduction process, such as the transient potential channel TRPV1 (Caterina et al 1997) and certain voltage-gated Na⁺ channels, in particular, Nav1.8 (Akopian et al 1996). These actions occur through G protein–coupled receptors specific for the different subtypes of prostaglandins and through the subsequent activation of different protein kinases.

Application of PGE₂ to isolated dorsal root ganglion (DRG) cells (Lopshire and Nicol 1997) or to HEK 293 cells transfected with TRPV1 (Rathee et al 2002) dramatically increases current responses to capsaicin and heat, two prototypical activators of TRPV1. This phenomenon is likely to underlie the thermal hyperalgesia in inflammatory disease states (Caterina et al 2000, Davis et al 2000). It is tempting to speculate that a leftward shift in TRPV1 activation by several degrees could render TRPV1 susceptible to activation by physiological temperatures. Such a process could contribute to the generation of spontaneous pain.

Tetrodotoxin-resistant Na⁺ channels, especially Na_v1.8, represent another potential substrate for peripheral nociceptive sensitization by prostaglandins. These channels become more readily activated in the presence of a number of inflammatory mediators, including PGE₂ (England et al 1996, Gold et al 1996). In particular, Na_v1.8 is selectively expressed in nociceptive small- and medium-sized DRG neurons (Akopian et al 1996). Modulation of these Na⁺ channels involves activation of adenylyl cyclase and increases in cyclic adenosine monophosphate, which possibly leads to protein kinase A–dependent phosphorylation of the channels. Via this mechanism, the prostaglandins produced during inflammatory responses may significantly increase the excitability of nociceptive nerve fibers and also contribute to the recruitment of nociceptors. A significant proportion of nociceptors in healthy (uninflamed and uninjured) tissue are mechanically insensitive and are not activated even by strong stimuli (Schaible and Schmidt 1988a, Kress et al 1992). Following tissue trauma and the release of prostaglandins, these silent nociceptors become excitable to pressure, changes in temperature, and tissue acidosis (Neugebauer et al 1995), which contributes to the generation and maintenance of hyperalgesia (Schaible and Schmidt 1988b).

The sensitizing actions of prostaglandins are not restricted to peripheral nociceptor endings but also occur at spinal sites (Fig. 32-3B). Intrathecal injection of PGE₂ causes sensitization to thermal and mechanical stimuli. Expression of COX-2 (Beiche et al 1996, Samad et al 2001) and inducible prostaglandin E synthase (mPGES1) (Claveau et al 2003, Guay et al 2004) increases in the CNS in response to peripheral inflammation. In rodents, hyperalgesia can be partially prevented or reversed by intrathecally injected NSAIDs (Malmberg and Yaksh 1992a, 1992b) or coxibs (Reinold et al 2005), an action that is accompanied by a decrease in spinal PGE₂ concentrations (Malmberg and Yaksh 1995). Different cellular mechanisms of action have been proposed for the pro-nociceptive effects of PGE₂ in the spinal cord. Baba and colleagues (2001) have shown that PGE₂ can directly depolarize deep dorsal horn neurons, and Ahmadi and associates (2002) demonstrated that PGE₂ reduces inhibitory glycinergic neurotransmission through a post-synaptic mechanism. This latter action is triggered by activation of PGE₂ receptors of the EP2 subtype (Reinold et al 2005). Activation of these receptors leads to the protein kinase A–dependent phosphorylation and inhibition of a certain isoform of glycine receptors that contain the α3 subunit (GlyRα3) (Harvey et al 2004). This subunit is expressed in the superficial layers of the spinal dorsal horn, where nociceptive afferents terminate and where glycinergic neurotransmission is inhibited by PGE₂. Evidence of the in vivo relevance of this centrally mediated form of inflammatory pain sensitization comes from several studies using mice carrying targeted mutations in genes critically involved in these pathways. Mice lacking neuronal protein kinase A showed less thermal hyperalgesia after injection of PGE₂ into the spinal canal (Malmberg et al 1997). Specific disruption of COX-2 in neural cells (through the use of nestin-driven cre expression) protects mice from mechanical hyperalgesia after peripheral inflammation (Vardeh et al 2007). Mice deficient in either GlyRα3 or the EP2 receptor not only lack PGE₂-mediated inhibition of glycinergic neurotransmission in the spinal cord dorsal horn but also largely lack the pro-nociceptive effects of spinal PGE₂ (Harvey et al 2004, Reinold et al 2005). Subsequent work has studied the phenotypes of GlyRα3-deficient mice in more detail. These studies showed that disruption of the GlyRα3 gene did not affect nociceptive responses in the formalin test and after peripheral nerve lesions (Hosl et al 2006), which is consistent with the specific involvement of prostaglandins in inflammatory pain. Similar unchanged nociceptive responses were also reported for carrageenan-induced cutaneous inflammation and kaolin/carrageenan-induced arthritis or iodoacetate osteoarthritis (Harvey et al 2009).

The contribution of a spinal site of action of COX inhibitors in humans has recently been addressed in two studies that tested the action of intrathecally injected ketorolac against experimental pain in human volunteers (Eisenach et al 2010b) and postoperative and chronic pain in patients (Eisenach et al 2010a). Intrathecal ketorolac was well tolerated, but its analgesic effects were much less than expected based on preclinical data from animal experiments. It showed some efficacy against sunburn-induced hyperalgesia in volunteers but did not induce significant analgesia against postoperative pain. Only in a subset of chronic pain patients whose spinal prostaglandin levels were increased most significantly did intrathecal ketorolac reduce spinal PGE₂ levels and show analgesic efficacy.

Diminished Prostaglandin Production As a Source of Other Desired Effects of Cyclooxygenase Inhibitors

Diminished formation of prostanoids can also explain most of the anti-inflammatory and antipyretic actions of antipyretic analgesics. Edema formation and plasma extravasation are promoted in particular by PGI₂ (Murata et al 1997). Antipyresis originates from reduced activation of EP3 receptors in the hypothalamus (Ushikubi et al 1998). There is good evidence that the pro-pyretic PGE₂ does not originate from neural sources as the pro-nociceptive PGE₂ does but instead originates from endothelial cells that reside in the walls of cerebral blood vessels and produce PGE₂ through COX-2 (Vardeh et al 2007). Inhibition of platelet aggregation may also be considered a desired effect of antipyretic analgesics. It occurs through reduced formation of COX-1–dependent thromboxane in platelets. Inhibition of platelet aggregation to a degree relevant for the prevention of arterial thrombosis is primarily seen with low doses of aspirin/acetylsalicylic acid. Inhibition by other reversible COX inhibitors is probably too transient to exert clinically relevant therapeutic effects (Patrono and Baigent 2009). With respect to cardiovascular risks, increases in blood pressure and the reduced anti-aggregatory and vasodilating effects of PGI₂ probably counteract the transient beneficial effects from transient thromboxane inhibition by classic NSAIDs (Grosser et al 2006). The transient nature of inhibition of platelet aggregation does, however, not exclude increased bleeding risk in predisposed patients receiving NSAIDs or dipyrone/metamizole.

Undesired Effects of Cyclooxygenase Inhibitors

Classic side effects of COX inhibitors include ulcers of the upper GI tract, asthma, increases in blood pressure, kidney damage, and bleeding. Inhibition of constitutive prostaglandin formation in the GI tract and in the kidneys is a major cause of the undesired effects of the classic NSAIDs, in particular, GI tract toxicity and renal impairment. PGE₂ protects the gastric mucosa by reducing acid and promoting mucous secretion via activation of EP1 and EP3 receptors (Takeuchi et al 1999, Suzuki et al 2001, Kato et al 2005). The GI tract toxicity of NSAIDs is probably aggravated by accumulation of these acidic compounds in mucosal cells through a process called ion trapping (see also below), and part of the mucosal damage evoked by orally administered NSAIDs may also be derived from COX-independent toxicity, which is supported by the observation that gastric ulcers still develop in COX-1–deficient mice after oral administration of indomethacin (Langenbach et al 1995). Asthma attacks induced by aspirin/acetylsalicylic acid and by NSAIDs have for a long time been attributed to the so-called leukotriene shift—a shift of arachidonic acid metabolism from COX-mediated production of prostaglandins to increased lipoxygenase-dependent leukotriene production. More recent evidence suggests that under conditions of airway inflammation, certain prostaglandins, in particular, PGD₂ and PGE₂, exert a protective function by down-modulating the immune responses (Hammad et al 2007) or by dilating the airways (Tilley et al 2003). Blockade of their formation would then cause acute bronchoconstriction. In the kidney, prostaglandins regulate perfusion, filtration, and salt reuptake, actions that contribute to the significant increases in arterial blood pressure that are already seen after short-term use of classic NSAIDs. Long-term use or abuse of NSAIDs has been the leading cause of terminal renal failure for several decades.

In addition to these classic side effects, the potential cardiovascular toxicity of coxibs and NSAIDs has gained significant attention after the withdrawal of rofecoxib from the market because of its association with increased cardiovascular risk (Bombardier et al 2000, Bresalier et al 2005). Initially, it was thought that the increased cardiovascular toxicity would be a problem specific to coxibs, most likely caused by a coxib-induced imbalance of protective (PGI₂) and potentially harmful (thromboxane) mediators. There is now widespread consensus that the increase in cardiovascular risk results from inhibition of PGI₂ formation and occurs independent of the presence or absence of additional blockade of thromboxane formation (Grosser et al 2006).

Interactions of Antipyretic Analgesics with Non-prostanoid Mediators

Although diminished prostanoid formation provides a plausible explanation for many of the desired and undesired actions of NSAIDs and coxibs and possibly at least for part of the analgesic and antipyretic effects of classic non-acidic antipyretic analgesics, these drugs also interfere with the production of other mediators such as endocannabinoids, which potentially also contribute to their in vivo actions (Fig. 32-4). Several reports suggest that COXs serve other enzymatic functions in addition to the formation of prostanoids. COX-2, but not COX-1, metabolizes the two endocannabinoids arachidonoyl ethanol amide (AEA or anandamide) (Yu et al 1997) and 2-arachidonoyl glycerol (2-AG) to generate prostaglandin ethanolamides (prostamides) and prostaglandin glyceryl ester (Kozak et al 2002). Blockade of COX-2 might thus not only reduce tissue concentrations of prostanoids but also increase levels of endocannabinoids. Increases in spinal endocannabinoid tone might indeed contribute to the spinal analgesic action of indomethacin and flurbiprofen (Guhring et al 2002, Ates et al 2003). Furthermore, there is evidence of biological activity of prostamides (Woodward et al 2008) and possibly also prostaglandin glyceryl esters (Nirodi et al 2004, Sang et al 2007). Inhibition of COX-2 could thus interfere with nociception not only through diminished formation of prostanoids but also through reduced degradation of endocannabinoids or reduced formation of prostamides or prostaglandin glyceryl esters.

A possible contribution of the endocannabinoid system to the analgesic activity of antipyretic analgesics has been studied particularly extensively for acetaminophen/paracetamol. At least in the rodent brain and spinal cord, acetaminophen/paracetamol is converted to N-arachidonoyl phenolamine (AM404) through metabolism by fatty acid amide hydrolase (FAAH) and conjugation with arachidonic acid (Hogestatt et al 2005). AM404 interferes with a variety of enzymes and ion channels. It is a known inhibitor of anandamide reuptake (Beltramo et al 1997) and degradation by FAAH (Glaser et al 2003). It binds CB1 receptors, activates TRPV1 channels (Yue et al 2004), and inhibits COX-1 and COX-2 (Hogestatt et al 2005). Interestingly, recent data indicate that the analgesic actions of acetaminophen/paracetamol are in fact lost in mice lacking CB1 receptors and are antagonized by pharmacological blockade of CB1 receptors (Mallet et al 2008). Whether this CB1 receptor–dependent analgesia by acetaminophen/paracetamol is due to reduced endocannabinoid metabolism by COX-2, inhibition of cannabinoid transport or degradation, or other still unidentified processes is not known at present. Other intriguing aspects of acetaminophen/paracetamol pharmacology include the contribution of TRPV1 activation to its analgesic antipyretic actions (Gavva et al 2007, Mallet et al 2010). An alternative explanation for its efficacy was recently published, namely, that nociceptive input to the spinal cord is blocked by metabolites of paracetamol/acetaminophen acting on transient receptor potential ankyrin 1 (TRPA1) (Andersson et al 2011).

Aspirin/acetylsalicylic acid not only blocks the formation of prostanoids from arachidonic acids but also redirects the metabolic activity of COX-2 to the formation of so-called aspirin-triggered lipoxins (ATLs), which exert anti-inflammatory effects (Chiang et al 2005). One of these ATLs reduces inflammatory hyperalgesia both after systemic and after intrathecal injection. Possible cellular mechanisms of the spinal anti-hyperalgesia include a reduction in the activation of spinal astrocytes (Svensson et al 2007).

Biodistribution of Antipyretic Analgesics

The desired and undesired actions of antipyretic analgesics are not only determined by their molecular actions on COXs and possibly other enzymes but also strongly influenced by their pharmacokinetic properties, in particular, by their biodistribution (Brune et al 2010). Most non-selective COX inhibitors (classic NSAIDs) are weak acids with pK_a values between 3.5 and 5.5. This physicochemical property predisposes NSAIDs to become enriched (“trapped”) inside cells neighboring an acidic environment, such as cells in the stomach wall, the urinary tract, and inflamed tissues (Fig. 32-5). Since this pattern of biodistribution also reflects the major sites of action of NSAIDs, it is tempting to speculate that the acidic nature of NSAIDs contributes to the distinct actions and side effects of NSAIDs and non-acidic antipyretic COX inhibitors and coxibs. The higher lipophilicity of the non-acidic compounds, such as acetaminophen/paracetamol, dipyrone/metamizole, and most coxibs, may facilitate their penetration into the CNS.

NSAIDs

Classic (non-selective) COX inhibitors differ in their potency, that is, the dose necessary to achieve a certain effect, which ranges from a few milligrams (lornoxicam) to about 1 g (e.g., salicylic acid). They also differ in their pharmacokinetic characteristics: speed of absorption (time to peak, t_max, which may also depend on the galenic formulation used), maximal plasma concentrations (c_max), elimination half-life (t_½), and oral bioavailability (AUC_rel). Based on these characteristics we propose here that NSAIDs be classified as (1) NSAIDs with a short elimination half-life and low potency, (2) NSAIDs with a short elimination half-life and high potency, and (3) NSAIDs with a long elimination half-life.

Aspirin/Acetylsalicylic Acid

Aspirin/acetylsalicylic acid deserves special discussion. Aspirin/acetylsalicylic acid is about 100 times more potent as a COX inhibitor than its metabolite salicylic acid is. As outlined above, the parent compound acetylates a serin residue in the active center of COX-1 and COX-2 and inactivates both COXs permanently. Most cells, however, compensate for this inactivation by de novo synthesis of the enzyme, with the exception of thrombocytes, in which a single dose of aspirin/acetylsalicylic acid blocks COX-1 activity irreversibly and hence the body’s thromboxane synthesis for several days (the turnover time of thrombocytes). When low doses are given, aspirin/acetylsalicylic acid acetylates COX-1 and blocks thromboxane synthesis in all platelets passing through the capillary bed of the GI tract but does not interfere with prostacyclin synthesis in endothelial cells outside the gut. This selectivity is due to the rapid cleavage of aspirin/acetylsalicylic acid, which leaves little if any intact aspirin/acetylsalicylic acid in the post-hepatic systemic circulation. The endothelial cells thus continue to release prostacyclin and maintain their antithrombotic activity. The dominant indication for aspirin/acetylsalicylic acid is for the prevention of thromboembolic events. Even at these low doses, acetylsalicylic acid may still cause bleeding from existing ulcers as a result of its long-lasting platelet inhibitory effect, as well as topical irritation of the gastric mucosa. Because of the high risk for bleeding, use of aspirin/acetylsalicylic acid for analgesia has largely been abandoned and only a few very specific indications in pediatrics (Kawasaki’s syndrome and acute rheumatic fever) have remained in addition to antithrombotic therapy. Furthermore, aspirin/acetylsalicylic acid should not be used by pregnant women (premature bleeding, closure of the ductus arteriosus) or by children before puberty (Reye’s syndrome with severe liver and brain damage).

Preferential and Selective Cyclooxygenase-2 Inhibitors

Following the discovery that the prostaglandins responsible for inflammation and the accompanying pain and hyperalgesia are predominantly produced by COX-2, selective COX-2 inhibitors were developed (Flower 2003). At present, two classes are on the market. They are both non-acidic and show relatively homogeneous distribution throughout the body. The characteristics of COX-2–selective compounds are detailed in Table 32-3.

Depending on the speed of absorption, bioavailability, and terminal elimination half-life, these drugs are useful for acute and prolonged pain states. Both compounds have been shown to be associated with reduced GI toxicity in comparison to the classic non-selective (and acidic) compounds (FitzGerald and Patrono 2001, Flower 2003). On the other hand, some patients experience less analgesic and anti-inflammatory activity than with non-selective acidic compounds. All these compounds interfere with prostanoid production in the kidney and blood vessels and thereby cause increases in blood pressure and water retention. They may also interfere with blood pressure control in hypertensive patients (White and Campbell 2010). Celecoxib inhibits CYP2D6, which causes interactions with cardiovascular (e.g., metoprolol) and psychotropic drugs (Werner et al 2003). The methyl sulfone etoricoxib is metabolized by drug-oxidizing enzymes and consequently has only few drug interactions (e.g., with methotrexate).

Etoricoxib is absorbed quickly and eliminated slowly, which may make it particularly suitable for fast but long-lasting pain relief; however, long persistence in the body may also have disadvantages (see Brune et al 2009). Finally, it should be borne in mind that blockade of COX-2 may be problematic in patients at risk for cardiovascular thromboembolic reactions. It could be shown that endothelium-derived PGI₂ is partly produced by COX-2 (for review see FitzGerald and Patrono 2001). Recent evidence indicates that all inhibitors of COX-2—selective and non-selective—may increase the risk for myocardial infarction and stroke (Bombardier et al 2000, Bresalier et al 2005, Solomon et al 2005, Warner and Mitchell 2008). As a consequence, COX inhibitors should be given at the lowest dose and for the shortest period necessary.

It has been claimed that nabumetone, etodolac, and meloxicam are particularly well tolerated in the GI tract because they inhibit predominantly COX-2. These results are not fully accepted. The active metabolite of nabumetone shows no selectivity for COX-2, and the selectivity of etodolac and meloxicam is not superior to that of diclofenac when tested ex vivo in humans (Patrignani et al 1994, Riendeau et al 1997).

Aniline Derivatives

Acetaminophen/paracetamol is representative of the members of this group remaining on the market. Its typical desired and undesired effects are summarized in Table 32-4, and its pharmacokinetic and pharmacodynamic data are presented in Table 32-5. In vitro, acetaminophen/paracetamol is a very weak, possibly indirect inhibitor of COXs, but evidence that it is indeed working through COX inhibition comes from ex vivo experiments showing that acetaminophen/paracetamol is a preferential COX-2 inhibitor in vivo. In doses of up to 4 g/day it reduces PGE₂ production in humans to below 80% (Hinz et al 2008). The weak COX inhibition by acetaminophen/paracetamol appears to result from its low efficacy, which limits its use to mild pain. Increasing the dose above 4 g/day will cause serious liver damage (Bridger et al 1998). Moreover, it is now well documented that use of acetaminophen/paracetamol is associated with increased blood pressure (Sudano et al 2010) and an increase in cardiovascular events (Chan et al 2006). In addition, acetaminophen/paracetamol given during pregnancy has been linked with cryptorchidism (reduced fertility of the male offspring; Kristensen et al 2011) and with asthma (Etminan et al 2009, Scialli et al 2010). Finally, acetaminophen/paracetamol increases the risk for GI tract ulcers when given together with aspirin/acetylsalicylic acid (Rahme et al 2008, Shaheen et al 2010).

After overdosage, acetaminophen/paracetamol is metabolized to highly toxic nucleophilic benzoquinones, which bind covalently to DNA and structural proteins in parenchymal cells (e.g., in the liver and kidney), where these reactive intermediates are produced (Fig. 32-6) (for review, see Seeff et al 1986). In the absence of early proper treatment, the consequence is potentially fatal liver damage. If detected early (within the first 12 hours after intake), intoxication can be treated with N-acetylcysteine, which regenerates the detoxifying mechanisms. Acetaminophen/paracetamol should not be taken by patients with seriously impaired liver function. The remaining indications for acetaminophen/paracetamol are fever and mild forms of pain, such as in the context of viral respiratory infections. Acetaminophen/paracetamol is still used in children, but despite its somewhat lower toxicity in juvenile patients, lethal cases of (involuntary) overdosage have occurred.

Phenazone and Its Derivatives

Following the discovery of phenazone some 130 years ago, drug companies tried to improve two aspects of this compound to produce a more potent drug and to develop a water-soluble derivative that can be given intravenously. The best-known results of these attempts are dipyrone/metamizole and propyphenazone (see Tables 32-4 and 32-5). The two compounds differ from phenazone in their potency, elimination half-life (Levy et al 1995), and water solubility (dipyrone is a water-soluble prodrug of methyl aminophenazone).

Phenazone, propyphenazone, and dipyrone/metamizole are used in many countries as the prevailing antipyretic analgesics (Latin America, many countries in Asia, Eastern and Central Europe). Dipyrone/metamizole has been accused of causing agranulocytosis. The incidence, however, is generally very low (one case per million treatment periods) (Levy 1986, Kaufman et al 1991).

All antipyretic analgesics have been claimed to cause Stevens–Johnson syndrome and Lyell’s syndrome, as well as shock reactions. New data indicate that the incidence of these events is on the same order of magnitude as, for example, penicillins (Roujeau et al 1995, Mockenhaupt et al 1996, Kaufman 2003). All non-acidic phenazone derivatives lack anti-inflammatory activity; they are devoid of GI tract and (acute) renal toxicity. Dipyrone/metamizole is safe at overdosage, which is in contrast to acetaminophen/paracetamol (Wolhoff et al 1983). If one compares aspirin/acetylsalicylic acid, acetaminophen/paracetamol, and propyphenazone for the same indication (e.g., occasional headache), it is obvious that aspirin/acetylsalicylic acid is more dangerous than either propyphenazone or acetaminophen/paracetamol.

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