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Paracetamol mechanism of action on slide share

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Paracetamol mechanism of action on slide share

  1. 1. Alf Claesson Awametox Consulting, Lilldalsvägen 17 A, SE-14461 Rönninge, Sweden. E-mail: alfeaclaesson@gmail.com Key words: paracetamol, acetaminophen, NAPQI, aspirin, diclofenac, indometacin, reactive metabolite, hepatotoxicity, liver injury, bioacti- vation, NSAID. Embed code <iframe src="//www.slideshare.net/slideshow/embed_code/39192733" width="476" height="400" framebor- der="0" marginwidth="0" marginheight="0" scrolling="no"></iframe> This paper might be cited as follows: Author and title of paper. Manuscript first published on SlideShare.net February 4, 2013. ABSTRACT: The analgesic mechanism of action of paracetamol (acetaminophen, also known as APAP) has been the object of considerable bewilderment but the hypotheses brought forward have not reached wide recognition. A novel hypothesis is presented here that APAP acts by covalently modifying several pain signaling proteins via the reactive metabolite N-acetyl-para-benzoquinoneimine (NAPQI). The most likely protein targets, it is suggested here, are cysteine proteases that take part in generation of pain signaling molecules, for example caspase-1 that acts on proIL-1beta. An extended hypothesis states that analgesic and anti-inflammatory effects of some NSAIDs that can form reactive me- tabolites might receive additional analgesic activity via analogous mechanisms. Testing the hypothesis in vivo is difficult since the proposed mechanism consists of a great number of concurrent targets. However, it should be possible to indicate some cysteine proteases as targets in vivo using radiolabeling and protein separation. Implications of the hypothesis are that the concept of exploiting reactive metabolites is a non- plausible route for design of new analgesics. Paracetamol (N-acetyl-p-aminophenol or APAP), also known as acetaminophen in the US, is a widely used non- prescription drug with antipyretic and analgesic actions but with very weak anti-inflammatory activity (review, [1]). It is an old drug, first synthesized in 1878, within the acetani- lides, a group that includes phenacetin and acetanilide (Fig. 1). It has an exceptionally simple structure with a molecular weight of only 151 Da that is less than most anesthetic gases have. Figure 1. Structures of and relationships between the acetanilide analgesics. All these structures can be metabolized to the reactive metabolite N-acetyl-para-benzoquinoneimine (NAPQI). There have been much bewilderment as to the mecha- nism(s) of action of this simple compound and a few sugges- tions involving the following unique mechanisms have been brought forward. A relatively modern hypothesis that gained wide publicity is based on the proven in vivo formation from APAP of N-(4- hydroxyphenyl)arachidonylamide (AM404) which has CB1 receptor-modulating properties, inhibit the enzyme fatty acid amide hydrolase-1, and also interferes with the uptake of anandamide [2]. Some authors even declared “mystery re- solved” [3]. There was also an observation that “the blockade of cannabinoid CB1 receptors has been shown to completely prevent the analgesic activity of paracetamol in rats” [3]. It was also suggested that AM404 would activate TRPV1 in the CNS thereby evoking an analgesic activity [4]. Other claims regarding the mechanism(s) of action of APAP involve inhibition of prostaglandin synthesis via COX inhibition, in particular COX-2 [5]. In 2002 the finding of a new cyclooxygenase (COX-3), which is synthesized from RNA splice variants in canines and mice was published [6]. It was suggested that a similar enzyme might be the thera- peutic target in humans since the canine COX-3 enzyme that was studied was particularly sensitive to APAP com- pared with standard NSAIDs. However, other researchers have argued that the COX-3 hypothesis lacks credibility be-
  2. 2. © 2013 Alf Claesson 2 cause of the unlikely existence of this enzyme in humans [7- 9]. The ion channel TRPA1 has also been suggested as the target via metabolites of APAP. In 2011 Andersson et al. published results that might indicate antinociceptive effects in mice of APAP, acting via its reactive metabolites NAPQI (Fig. 1) and benzoquinone that would activate spinal TRPA1 [10]. APAP was administered to trpa1-/- mice locally at the spinal cord (intrathecal injection) and also systemically; NAPQI was administered intrathecally. The report will be discussed below. A few other mechanisms have been men- tioned in reviews on APAP [1, 11]. So far, none of the mechanisms can be considered proven. The main purpose of the current paper is to present a novel hypothesis of mechanism of action that is not based on spe- cific receptors or enzymes but which fits with all the known pharmacology of APAP and analogues. The previous hy- potheses will be discussed in this context. A novel hypothesis of mechanism of action The cited works present theories on narrow mechanisms of action of APAP. The novel hypothesis brought forward in the current paper is, like that of Andersson et al. [10], based on the formation of NAPQI and other reactive metabolites (RM), e.g. benzoquinone. These RMs were previously sug- gested [10] to elicit analgesia in mice through, somewhat surprising, specific activation of the noxious sensor TRPA1 (limited to local action at the spinal cord). The current paper suggests instead that the analgesic activity of APAP origi- nates from reactions of RMs with a larger number of pro- teins with many varied physiological roles in pain signaling. The good and the bad actions balance in slight favor toward the positive side. This idea puts the mechanism of action more in line with the now well recognized complexity of pain signaling than earlier hypotheses and does not limit the target of these RMs to a single protein. If there is some truth to this notion of “analgesic RMs” the hypothesis might be expanded also to connect the pharmacology of APAP to older reports of RMs from NSAIDs. For example, gentisic acid (Fig. 2), formed in vivo from aspirin, might be a pain relieving mediator via its easily formed benzoquinone-2-carboxylic acid. The hypotheses can be summarized in the following statements that will be en- larged in the following text.  APAP acts by covalently modifying pain signaling proteins via the reactive metabolite NAPQI.  The target proteins are mainly cysteine proteases. An extension of the hypothesis:  Analogous mechanisms might contribute to the analgesic and anti-inflammatory effects of some NSAIDs. NAPQI is a well-known liver and kidney toxin, which like similar quinoid RMs, is an indiscriminate electrophile and arylating species (and is also an oxidizing agent) that react preferentially with nucleophilic thiols in proteins or peptides [12], as happens in the irritant sensor TRPA1. Reactive me- tabolites (RMs) of drugs are notorious for causing severe side-effects such as drug-induced liver injury [13], and are thought to lie behind the hepatotoxicity of a great number of drugs, many of which have been withdrawn from the market, for example lumiracoxib in 2007-8 and sitaxentan in 2010. The largest group of RMs is the quinoids [14] to which also NAPQI belongs. Since these electrophilic com- pounds react preferentially with thiols they should be able to inhibit also the many (15+) human cysteine proteases by reacting with their active cysteine thiol, as demonstrated for NAPQI with papain [15]. Cysteine proteases are key players in a great number of cellular processes many of which in- volve formation of molecules that have been reported to take part in pain signalling [16-23] and in generation of neu- ropathies (possibly via initiation of apoptosis) [24]. In fact, such proteases have been explicitly referred to in the litera- ture as potential targets for new analgesics [22, 25]. The pro- teases that have been mentioned in connection with pain signalling include, for example caspase-1, caspase-3, cathep- sin B, K, L and S. It is of some interest that both oral inhibi- tors and an irreversible inhibitor of microglial cathepsin S were claimed to be active in neuropathic pain models [26, 27]. The implications of the latter finding are limited by the intrathecal route of administration. Figure 2. Aspirin is metabolized to the hydroquinone gentisic ac- id which can readily form a reactive benzoquinone metabolite. In the complex world of pain signaling, it would be pre- sumptuous to try to pinpoint one particular cysteine prote- ase whose systemic inhibition should entail particularly posi- tive effects. However, one might just speculate that the pro- teases that take part in the processing of procytokines, such as those generating IL-1beta and IL-6, could be key targets; they have also been mentioned as drug targets, mostly for therapies involving control of apoptosis [28]. The enzyme caspase-1, also called interleukin-1beta converting enzyme (ICE) is one of these, which has also been targeted in new
  3. 3. © 2013 Alf Claesson 3 drug research [29]. Patent applications also claim irreversible caspase-1 inhibitors as pain relieving agents[30]. It might be argued that NAPQI should not be available for enzyme inhibition throughout the human body since it is generated primarily in the liver by actions of cytochrome P- 450 enzymes and is quickly made harmless by reaction with glutathione. However, several other oxidizing enzymes are also able to generate NAPQI (and other RMs from APAP), including monophenol monooxygenase (tyrosinase), peroxi- dases and COX and there are reports of proteins in the periphery, including serum albumin [53], that form conju- gates with APAP in vivo [31-33]. See also comments in list of references at [51-52]. A fraction usually ranging from 5 to 15% of APAP is me- tabolized via the oxidation pathway. Since the bioavailability of APAP is high, 60-89%, a normal therapeutic dose of 700- 1000 mg gives rise to high plasma concentrations, in the range 33-132 µM, e.g. [34]. APAP is uniformly distributed throughout most body fluids, freely crosses the placenta and penetrates the blood-brain barrier. This means that a num- ber of extrahepatic oxidative enzymes have the possibility to generate RMs from APAP in the system, usually with nega- tive consequences (for example, proposed to occur in the lungs [35]) but maybe, for a limited set of proteins, with a slightly positive, pain relieving outcome. Also, APAP forms p-aminophenol by hydrolysis and this can also be oxidized to RMs. An extrapolation of the hypothesis to certain NSAIDs Here, it is relevant to point to the often made observations that NSAIDs have many effects that do not primarily involve prostaglandins. The point and hypothesis, related to NAPQI as the presumed explanation for the analgesic activity of APAP, is that some NSAIDs might receive extra analgesic activity from similar quinoid metabolites (Fig. 2 and Fig. 4) that react with a number of proteins, other than COX, rele- vant in pain signaling. The time-dependent irreversible inhibition of “the fatty ac- id oxygenase”, i.e. COX, by aspirin and indometacin was first reported in 1971 [36]. Some structural requirements for time-dependent inhibition of prostaglandin biosynthesis by anti-inflammatory drugs were published in 1975 [37] and in 1994 [38]. It was noted that the compounds ibuprofen and flurbiprofen (Fig. 3) which have Ki values of 3 and 1 µM, respectively, behave differently in that only flurbiprofen gives time-dependent inhibition. The inhibition of prosta- glandin cyclooxygenase by gentisic acid (metabolite of salicyl- ic acid, Fig. 2) was further studied [39]. Since effective NSAIDs have been shown to form RMs it is not far-fetched to think that certain compounds of this class, for example indometacin and diclofenac, might provide additional analgesic activity from quinoid metabolites (Fig. 4), similar to NAPQI, that react with a number of proteins relevant in pain signalling, including COX [37, 38]. As stat- ed, this might be considered an extended hypothesis from that of APAP forming analgesic NAPQI. Obviously, this is a bold speculation but it is not unreasonable based on evi- dence of non-prostaglandin effects of NSAIDs. For example, diclofenac showed a dose-dependent anti-apoptotic effect that, it was hypothesized, went via a non-prostaglandin “suppression of the activation of caspases” [40]. Also, the first hydroxylated metabolite from analgesic sali- cylic acid is gentisic acid and this hydroquinone is only one easy step from the reactive benzoquinone-2-carboxylic acid (Fig. 2) which should quickly react with available protein thiols. Figure 3. Structures of flurbiprofen (left), which has an irreversi- ble component as inhibitor of COX-1, and ibuprofen which is a purely competitive inhibitor. This might provide a mechanistic explanation for the anal- gesic/anti-inflammatory activity of salicylic acid which is a weak COX inhibitor but yet has analgesic activity compara- ble with aspirin [41]. Other authors have also sought expla- nations in this direction to try to explain the discrepancy [42]. Other NSAIDs than the ones mentioned also form para-hydroxylated drug metabolites, en route to quinoid species, when they are so predisposed. In principle, to verify this hypothesis it should be possible to differentiate the common NSAIDs based on their analge- sic activity (in relation to free plasma concentration in hu- mans) plotted against COX inhibition constants. This plot might reveal whether there is any correlation with propensi- ty to form RMs (of the quinoid class). A further point is that every reactive metabolite generated, be it from APAP or an NSAID, has a unique structure and therefore should have its own spectrum of pain-relevant tar- get proteins which might confer a certain pharmacology. It might not be a coincidence that the the carboxylic acid gen- tisic acid (via its reactive metabolite, benzoquinone-2- carboxylic acid, Fig. 2) inhibits COX, possibly preferentially. The hypothesis in relation to earlier ones Regarding the proposal that APAP works via an arachidon- ic amide metabolite there is no doubt that APAP forms AM404 in vivo in rats but the hypothesis of a resolved mech- anism of action cannot be considered strong; as the authors
  4. 4. © 2013 Alf Claesson 4 themselves state: “.. it can only be hypothesized that AM404 is formed in man and contributes to the pharmacological effects of acetaminophen.” [2]. Also, it should be noted that the high dose of 300 mg/kg of APAP to rats only led to formation of tiny amounts (< 11 pg/g) of AM404 in the brains. One might add as a side-note that the whole concept of cannabinoids as analgesics, although having been a topic for decades, so far has failed to mature beyond the limited applications of some compounds as adjunct pain relievers [43]. The most recent efforts in the field have focused on fatty acid amide hydrolase-1 (FAAH) as a target; here, PF- 04457845 failed to show analgesic activity in patients with pain due to osteoarthritis of the knee [44]. Figure 4. Reactive quinoid metabolites of diclofenac (left) and indometacin. There have been much interest in the COX enzymes as a target of APAP. Hinz [5] has pointed to COX-2 inhibition at therapeutic plasma concentrations but the evidence was based on lowered PGE2 excretion from thrombocytes and not on direct enzyme inhibition. There is, however, clear indications that APAP, acting as a reducing agent, can influ- ence the oxidation state of COX and thereby decrease the output of prostaglandins, especially from intact cells [45, 46]. The earlier mentioned hypothesis [10] that is closest to the current one proposes to see antinociceptive effects in mice of APAP given systemically and locally at the spinal cord (intrathecal injection) to trpa1-/- mice; the reactive metabo- lites NAPQI and benzoquinone were only administered intrathecally. The authors relied on the hot-plate, cold-plate and writhing tests to measure what they declare are antino- ceptive effects in wildtype (trpa1+/+ ) mice. The trpa1-/- mice, on the other hand, did not show an antinociceptive re- sponse under any of these conditions. The observations pro- vided the basis for an audacious conclusion: “Our study provides a molecular mechanism for the antinociceptive effect of acetaminophen and discloses spinal TRPA1 activa- tion as a potential pharmacological strategy to alleviate pain.” The far-reaching implication of the experiments is that the antinociceptive effects of APAP seen in mice should be ascribed to activation of the noxious sensor TRPA1 in the spinal cord (by inhibition of pain signals thereby overrid- ing the noxious effects of TRPA1 activation in the periph- ery). This would seem a rather specific action of a com- pound that generates indiscriminate reactive metabolites and the conclusions should be further scrutinized. As men- tioned, the authors also rely on rodent models of pain that are notoriously problematic to translate into analgesia in man [47]. Testing the hypothesis The mechanism proposed consists of concurrent attacks on a great number of targets the sum of which balances in favour of an overall (weak) analgesic activity. Testing of this polypharmacology in vivo is therefore difficult. However, it might be possible to test the effect of scavengers of NAPQI (and of benzoquinone), such as the ones, e.g. N- acetylcysteine, used in APAP intoxications, to antagonize the analgesic effects of APAP in animal models or even in hu- man. Obviously, it should be possible to study the NAPQI inhibition of a few selected caspases or cathepsins in vitro as was already done with papain [15]. It should also be possi- ble to assess ex vivo whether a few selected cysteine proteases become inhibited by conjugation with administered APAP. In contrast to the vast number of liver proteins that be- come covalently bound to RMs from APAP [48] fewer stud- ies have dealt with the extent of binding to peripheral pro- teins [31-33]. Whole body autoradiography using radioac- tively labeled APAP does not seem to have been reported in a way meaningful for the current discussion although APAP distribution in the CNS has been studied [49]. These au- thors used [3 H]-APAP, which is not ideal, and they did not see any specific binding. Using an immunochemical assay Ware et al. found protein adducts in rat enterocytes with APAP that had not passed the liver [33]. It might be of value to run whole body autoradiography using stably labeled [14 C]-APAP, possibly in combination with microautoradiog- raphy, to find out just how diffuse or localized the covalent binding to peripheral proteins is. Conclusions The quest for the mechanism of action of APAP might have gone too far toward seeking narrow and elaborate ex- planations. The hypothesis brought forward here, even if difficult to test and far from detailed, obeys the principle of Occam's razor since it provides the simplest imaginable an- swer in agreement with all known data. At the same time as reactive metabolites might provide some analgesic effects, according to the current hypothesis, their covalent binding to proteins is problematic. In most cases these nonspecific reactions should cause negative ef- fects, which means drug side-effects. The devastating harm- ful effects of overdoses of APAP worldwide is a grim re- minder of how we value pain relief in relation to drug safety [50]. Thinking about new drugs based on general reactivity or affinity labeling, there is a delicate cost/benefit balance to observe. The concept of exploiting reactive metabolites does not seem a plausible route for design of new analgesics.
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