Mechanisms of NSAID-induced hepatotoxicity: focus on nimesulide.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with idiosyncratic hepatotoxicity in susceptible patients. The molecular mechanisms underlying this toxicity have not yet been fully elucidated. However, experimental evidence suggests that they include increased concentration of the drugs in the hepatobiliary compartment, formation of reactive metabolites that covalently modify proteins and produce oxidative stress, and mitochondrial injury. Genetic and/or acquired patient factors can either augment the pathways leading to hepatic toxicity or impede the protective and detoxifying pathways. An example is nimesulide, a selective cyclo-oxygenase-2 inhibitor widely used for the treatment of inflammatory and pain conditions, which has been recently associated with rare but serious and unpredictable adverse reactions in the liver (increases in serum aminotransferase activities, hepatocellular necrosis, and/or intrahepatic cholestasis). Similar to other drugs causing idiosyncratic hepatotoxicity, both the molecule and the patient contribute to the hazard. Here, the weakly acidic sulfonanilide drug undergoes bioreductive metabolism of the nitroarene group to reactive intermediates that have been implicated in oxidative stress, covalent binding, and mitochondrial injury. It is only in a small number of susceptible patients, however, that genetic or nongenetic factors will cause this potential toxicity to become clinically manifest. In view of the very large recipient population, the incidence of nimesulide-induced liver injury has been low (approximately 0.1 per 100,000 patients treated). Although this estimation is based on spontaneous reporting data versus sales units and needs correction due to the classical bias of this system, the type and incidence of these rare but severe hepatic adverse reactions are comparable to that of other NSAIDs.     

Metabolic activation and drug‐induced liver injury: in vitro approaches for the safety risk assessment of new drugs

Drug‐induced liver injury (DILI) is a significant leading cause of hepatic dysfunction, drug failure during clinical trials and post‐market withdrawal of approved drugs. Many cases of DILI are unexpected reactions of an idiosyncratic nature that occur in a small group of susceptible individuals. Intensive research efforts have been made to understand better the idiosyncratic DILI and to identify potential risk factors. Metabolic bioactivation of drugs to form reactive metabolites is considered an initiation mechanism for idiosyncratic DILI. Reactive species may interact irreversibly with cell macromolecules (covalent binding, oxidative damage), and alter their structure and activity. This review focuses on proposed in vitro screening strategies to predict and reduce idiosyncratic hepatotoxicity associated with drug bioactivation. Compound incubation with metabolically competent biological systems (liver‐derived cells, subcellular fractions), in combination with methods to reveal the formation of reactive intermediates (e.g., formation of adducts with liver proteins, metabolite trapping or enzyme inhibition assays), are approaches commonly used to screen the reactivity of new molecules in early drug development. Several cell‐based assays have also been proposed for the safety risk assessment of bioactivable compounds. Copyright © 2015 John Wiley & Sons, Ltd.     

Is it possible to more accurately predict which drug candidates will cause idiosyncratic drug reactions?

The unexpected occurrence of idiosyncratic drug reactions during late clinical trials or after a drug has been released can lead to a severe restriction in its use or failure to release/withdrawal. This leads to considerable uncertainty in drug development and has led to attempts to try to predict a drug's potential to cause such reactions. It appears that most idiosyncratic drug reactions are due to reactive metabolites; however, many drugs that form reactive metabolites are associated with a very low incidence of idiosyncratic drug reactions. Therefore. screening drug for their ability to generate reactive metabolites is likely to cause the rejection of many good drug candidates. There is evidence to suggest that an idiosyncratic drug reaction is more likely if there is some "danger signal'. Thus drugs that cause some degree of cell stress or damage may be more likely to lead to a high incidence of idiosyncratic drug reactions. The exact nature of the putative danger signals is unknown. However, a screen of the effects of drugs known to be associated with a high incidence of idiosyncatic reactions using expression genomics and proteomics may reveal a pattern or patterns of mRNA and protein expression that predict which drugs will cause a high incidence of idiosyncratic drug reactions. Although idiosyncratic drug reactions are not usually detected in animal tests because they are just as idiosyncratic in animals as they are in humans, it is likely that drug reactive metabolites would also cause similar cell stress in animals. It is more likely that in most cases it is differences in the immune response to the reactive metabolites that determine which individuals will develop an idiosyncratic reaction. If the expression of certain proteins in animals treated with a drug candidate could be used as a screening method to predict a drug's potential to cause a high incidence of idiosyncratic drug reactions, it would greatly facilitate the development of safer drugs.     

Mechanism of idiosyncratic drug reactions: reactive metabolite formation,protein binding and the regulation of the immune system

Drug-induced adverse reactions, especially type B reactions, represent a major clinical problem. They also impart a significant degree of uncertainty into drug development because they are often not detected until the drug has been released onto the market. Type B reactions are also termed idiosyncratic drug reactions by many investigators due to their unpredictable nature and our lack of understanding of the mechanisms involved. It is currently believed that the majority of these reactions are immune-mediated and are caused by immunogenic conjugates formed from the reaction of a reactive metabolite of a drug with cellular proteins. It has been shown that most drugs associated with idiosyncratic reactions form reactive metabolites to some degree. Covalent binding of reactive metabolites to cellular proteins has also been shown in many cases. However, studies to reveal the role of reactive metabolites and their protein-adducts in the mechanism of drug-induced idiosyncratic reactions are lacking. This review will focus on our current understanding and speculative views on how a reactive metabolite of a drug might ultimately lead to immune-mediated toxicity.     

Idiosyncratic drug-induced liver injury: an overview

Drug-induced liver injury (DILI) encompasses a spectrum of clinical disease ranging from mild biochemical abnormalities to acute liver failure. The majority of adverse liver reactions are idiosyncratic, occurring in most instances 5 – 90 days after the causative medication was last taken. The diagnosis of DILI is clinical, based on history, probability of the suspect medication as a cause of liver injury and exclusion of other hepatic disease. DILI can be hepatocellular (predominant rise in alanine transaminase), cholestatic (predominant rise in alkaline phosphatase) or mixed liver injury. An elevated bilirubin level more than twice the upper limit of normal in patients with hepatocellular liver injury implies severe DILI, with a mortality of ～ 10% and with an incidence rate of 0.7 – 1.3 per 100,000. Although acute liver failure is rare, 13 – 17% of all acute liver failure cases are attributed to idiosyncratic drug reactions. Response to drug withdrawal may be delayed up to 1 year with cholestatic liver injury with occasional subsequent progressive cholestasis known as the vanishing bile duct syndrome. Overall, chronic disease may occur in up to 6% even if the offending drug is withdrawn. Antibiotics and NSAIDs are the most common cause of DILI. Statins rarely cause significant liver injury whereas antiretroviral therapy is associated with hepatotoxicity in 10% of treated patients. Multiple mechanisms of DILI have been implicated, including TNF-α-activated apoptosis, inhibition of mitochondrial function and neoantigen formation. Risk factors for DILI include age, sex and genetic polymorphisms of drug-metabolising enzymes such as cytochrome P450. In patients with human immunodeficiency virus, the presence of chronic viral hepatitis increases the risk of antiretroviral therapy hepatotoxicity. Over the next decade, the combination of accurate case ascertainment of DILI via clinical networks and the application of genomics and proteomics will hopefully lead to accurate prediction of risk of DILI, so that pharmacotherapy can be optimised with avoidance of adverse hepatic events.     

Idiosyncratic drug-induced liver injury: an overview

Drug-induced liver injury (DILI) encompasses a spectrum of clinical disease ranging from mild biochemical abnormalities to acute liver failure. The majority of adverse liver reactions are idiosyncratic, occurring in most instances 5-90 days after the causative medication was last taken. The diagnosis of DILI is clinical, based on history, probability of the suspect medication as a cause of liver injury and exclusion of other hepatic disease. DILI can be hepatocellular (predominant rise in alanine transaminase), cholestatic (predominant rise in alkaline phosphatase) or mixed liver injury. An elevated bilirubin level more than twice the upper limit of normal in patients with hepatocellular liver injury implies severe DILI, with a mortality of approximately 10% and with an incidence rate of 0.7-1.3 per 100,000. Although acute liver failure is rare, 13-17% of all acute liver failure cases are attributed to idiosyncratic drug reactions. Response to drug withdrawal may be delayed up to 1 year with cholestatic liver injury with occasional subsequent progressive cholestasis known as the vanishing bile duct syndrome. Overall, chronic disease may occur in up to 6% even if the offending drug is withdrawn. Antibiotics and NSAIDs are the most common cause of DILI. Statins rarely cause significant liver injury whereas antiretroviral therapy is associated with hepatotoxicity in 10% of treated patients. Multiple mechanisms of DILI have been implicated, including TNF-alpha-activated apoptosis, inhibition of mitochondrial function and neoantigen formation. Risk factors for DILI include age, sex and genetic polymorphisms of drug-metabolising enzymes such as cytochrome P450. In patients with human immunodeficiency virus, the presence of chronic viral hepatitis increases the risk of antiretroviral therapy hepatotoxicity. Over the next decade, the combination of accurate case ascertainment of DILI via clinical networks and the application of genomics and proteomics will hopefully lead to accurate prediction of risk of DILI, so that pharmacotherapy can be optimised with avoidance of adverse hepatic events.     

Idiosyncratic drug hepatotoxicity: a 2008 update

Pharmaceutical preparations, and also herbal products and dietary supplements, are emerging contributors to severe forms of liver disease. Although acetaminophen intoxication is still the reason for many cases of drug-induced liver injury (DILI) in Western countries, the bulk of hepatic reactions to drugs are idiosyncratic. Only a small fraction of individuals exposed to a drug associated with liver injury will develop hepatotoxicity. Indeed, the rarity of this serious adverse event prevents its detection in clinical trials. The pathogenesis of idiosyncratic DILI is not well known because of a lack of reliable animal models, although it probably involves the metabolism of the drug and/or activation of the immune system. Different databases have described antibiotics, NSAIDs and anticonvulsants as the main group of drugs incriminated in DILI. Clinical presentation of DILI includes predominantly a hepatocellular type of damage, yet cholestatic and mixed types are also common; the determinants of the type of damage induced by a given drug are poorly understood. Analysis of pooled data has recently underlined the influence of older age in the cholestatic/mixed expression of liver injury, as well as the independent association of female gender, older age, aspartate aminotransferase levels with hepatocellular type of damage and high bilirubin levels with the risk of fulminant liver failure/death. In the long term (providing the patient survives the initial episode), persistent damage may occur in at least 6% of patients, with the cholestatic mixed type of damage more prone to becoming chronic, while in the hepatocellular pattern the severity is greater, with further likelihood of evolution to cirrhosis. Cardiovascular and CNS drugs are the main groups leading to chronic liver damage. The diagnosis of hepatotoxicity remains a difficult task owing to the lack of reliable markers for use in general clinical practice. Diagnostic algorithms may add consistency to clinical judgment by translating a suspicion into a quantitative score. Currently, the Council for International Organizations of Medical Sciences/Roussel Uclaf Causality Assessment Method instrument is considered the gold standard in causality assessment of hepatotoxicity, although there is probably room for improvement. Current efforts in collecting bona fide cases will make refinements of existing scales feasible. Efforts should also be directed towards the development of an abridged instrument for use in evaluating suspected drug-induced hepatotoxicity at the very beginning of the diagnosis and treatment process when clinical decisions need to be taken. The treatment of idiosyncratic DILI is largely supportive. Early suspicion and withdrawal of the offending agent is the most important therapeutic measure.     

Human biology-based drug safety evaluation: scientific rationale,current status and future challenges

Introduction: Animal toxicity studies used to assess the safety of new candidate pharmaceuticals prior to their progression into human clinical trials are unable to assess the risk of non-pharmacologically mediated idiosyncratic adverse drug reactions (ADRs), the most frequent of which are drug-induced liver injury and cardiotoxicity. Idiosyncratic ADRs occur only infrequently and in certain susceptible humans, but are caused by many hundreds of different drugs and may lead to serious illness.

Areas covered: Idiosyncratic ADRs are initiated by drug-related chemical insults, which cause toxicity due to susceptibility factors that manifest only in certain patients. The chemical insults can be detected using in vitro assays. These enable useful discrimination between drugs that cause high versus low levels of idiosyncratic ADR concern. Especially promising assays, which have been described recently in peer-reviewed scientific literature, are highlighted.

Expert opinion: Effective interpretation of in vitro toxicity data requires integration of endpoints from multiple assays, which each address different mechanisms, and must also take account of human systemic and tissue drug exposure in vivo. Widespread acceptance and use of such assays has been hampered by the lack of correlation between idiosyncratic human ADR risk and toxicities observed in vivo in animals.     

Involvement of the immune system in idiosyncratic drug reactions

There is strong evidence that most idiosyncratic drug reactions (IDRs) are immune-mediated and are caused by reactive metabolites of a drug rather than by the drug itself. Several hypotheses have been proposed by which a drug could induce an immune response. The major hypotheses are the hapten hypothesis and the danger hypothesis; however, the characteristics and spectrum of IDRs are different with different drugs, and this likely reflects mechanistic differences; therefore, no one hypothesis is likely to explain all IDRs. Some IDRs appear to involve epigenetic effects, direct activation of antigen-presenting cells, or disturbing the normal balance of the immune system. It has been suggested that many cases of idiosyncratic liver injury are not immune-mediated, and other mechanisms such as mitochondrial injury may be involved. It is essential that any hypothesis be consistent with the clinical characteristics of the IDR. Although the characteristics of most idiosyncratic liver injury do not suggest that mitochondria are the major target, it is quite possible that milder mitochondrial injury could stimulate an immune-mediated reaction. The observation that IDRs can vary widely among different drugs and different patients is most easily explained by an immune mechanism in which the target of the immune response is different.     

Clinical pharmacokinetics of non-steroidal anti-inflammatory drugs

The number of non-steroidal anti-inflammatory drugs (NSAIDs) available for clinical use has dramatically increased during the last decade. As a general rule, NSAIDs are well absorbed from the gastrointestinal tract, with the exception of aspirin (and possibly diclofenac, tolfenamic acid and fenbufen) which undergoes presystemic hydrolysis to form salicylic acid. Concomitant administration of NSAIDs with food or antacids may in some cases lead to delayed or even reduced absorption. The NSAIDs are highly bound to plasma proteins (mainly albumin), which limits their body distribution to the extracellular spaces. Apparent volumes of distribution of NSAIDs are, therefore, very low and usually less than 0.2 L/kg. The elimination of these drugs depends largely on hepatic biotransformation; renal excretion of unchanged drugs is usually small (less than 5% of the dose). Total body clearance is low and for most NSAIDs is less than 200 ml/min. The effect of age and disease on the disposition of NSAIDs has not been extensively studied. Due to the central role of the liver in the overall elimination of the majority of these compounds, hepatic disease will most likely lead to a significant alteration in their pharmacokinetic behaviour. NSAIDs have been reported to be involved in numerous pharmacokinetic drug interactions. Aspirin decreases the plasma concentrations of many other NSAIDs, although the clinical significance of this is uncertain. Due to the extremely high plasma protein binding of NSAIDs (around 99% in many cases), competition for the same binding sites on plasma proteins may be at least partly responsible for some interactions of NSAIDs with other highly bound drugs; however, another mechanism such as decreased metabolism or decreased urinary elimination is usually involved as well. The most important interactions with NSAIDs are those involving the oral anticoagulants and oral hypoglycaemic agents, though not all NSAIDs have been found to interact with these drugs. In clinical practice, there appear to be no clear-cut guidelines to assist the clinician in the selection of the most appropriate drug for an individual patient. The selection of an anti-inflammatory drug should be based on clinical experience, patient convenience (e.g. once or twice daily dosage schedule), side effects and cost. Since a marked interindividual variability exists in the clinical response to a given NSAID, clinicians prescribing these agents may try several of them sequentially until an adequate response is obtained.     

Role of Metabolism in Drug-Induced Idiosyncratic Hepatotoxicity

Rare adverse reactions to drugs that are of unknown etiology, or idiosyncratic reactions, can produce severe medical complications or even death in patients. Current hypotheses suggest that metabolic activation of a drug to a reactive intermediate is a necessary, yet insufficient, step in the generation of an idiosyncratic reaction. We review evidence for this hypothesis with drugs that are associated with hepatotoxicity, one of the most common types of idiosyncratic reactions in humans. We identified 21 drugs that have either been withdrawn from the U.S. market due to hepatotoxicity or have a black box warning for hepatotoxicity. Evidence for the formation of reactive metabolites was found for 5 out of 6 drugs that were withdrawn, and 8 out of 15 drugs that have black box warnings. For the other drugs, either evidence was not available or suitable studies have not been carried out. We also review evidence for reactive intermediate formation from a number of additional drugs that have been associated with idiosyncratic hepatotoxicity but do not have black box warnings. Finally, we consider the potential role that high dosages may play in these adverse reactions.     

Role of metabolism in drug-induced idiosyncratic hepatotoxicity

Rare adverse reactions to drugs that are of unknown etiology, or idiosyncratic reactions, can produce severe medical complications or even death in patients. Current hypotheses suggest that metabolic activation of a drug to a reactive intermediate is a necessary, yet insufficient, step in the generation of an idiosyncratic reaction. We review evidence for this hypothesis with drugs that are associated with hepatotoxicity, one of the most common types of idiosyncratic reactions in humans. We identified 21 drugs that have either been withdrawn from the U.S. market due to hepatotoxicity or have a black box warning for hepatotoxicity. Evidence for the formation of reactive metabolites was found for 5 out of 6 drugs that were withdrawn, and 8 out of 15 drugs that have black box warnings. For the other drugs, either evidence was not available or suitable studies have not been carried out. We also review evidence for reactive intermediate formation from a number of additional drugs that have been associated with idiosyncratic hepatotoxicity but do not have black box warnings. Finally, we consider the potential role that high dosages may play in these adverse reactions.     

Cell based approaches for evaluation of drug-induced liver injury

An improved understanding of mechanisms that underlie drug-induced liver injury (DILI) is required to enable design of drugs that have minimal potential to cause this adverse reaction in man. Available evidence suggests DILI arises in susceptible patients because of an imbalance between chemical insults (which are an inherent property of certain drugs and/or their metabolites) and the ability of the liver to mount compensatory/adaptive responses. In vivo safety testing in pre-clinical species ensures that drugs which enter clinical trials do not cause reproducible and dose-dependent liver injury in man, but is of limited value for exploration of underlying mechanisms and does not assess potential to cause rare idiosyncratic DILI. This review highlights the value that can be gained from in vitro studies using cultured hepatocytes and also hepatocyte-derived cell lines transfected with individual human cytochrome P450 (CYP450) isoforms. We have evaluated a range of mechanisms and endpoints (cell necrosis, mitochondrial injury, inhibition of biliary transporters and metabolite-mediated toxicity) using these model systems. Our data indicate that multiple mechanisms are likely to be involved in development of idiosyncratic DILI in man caused by numerous drugs, e.g. the anticonvulsant chlorpromazine.     

Evaluation of felbamate and other antiepileptic drug toxicity potential based on hepatic protein covalent binding and gene expression

Felbamate is an antiepileptic drug that is associated with minimal toxicity in preclinical species such as rat and dog but has an unacceptable incidence of serious idiosyncratic reactions in man. Idiosyncratic reactions account for over half of toxicity-related drug failures in the marketplace, and improving the preclinical detection of idiosyncratic toxicities is thus of paramount importance to the pharmaceutical industry. The formation of reactive metabolites is common among most drugs associated with idiosyncratic drug reactions and may cause deleterious effects through covalent binding and/or oxidative stress. In the present study, felbamate was compared to several other antiepileptic drugs (valproic acid, carbamazepine, phenobarbital, and phenytoin), using covalent binding of radiolabeled drugs and hepatic gene expression responses to evaluate oxidative stress/reactive metabolite potential. Despite causing only very mild effects on covalent binding parameters, felbamate produced robust effects on a previously established oxidative stress/reactive metabolite gene expression signature. The other antiepileptic drugs and acetaminophen are known hepatotoxicants at high doses in the rat, and all increased covalent binding to liver proteins in vivo and/or to liver microsomes from human and rat. With the exception of acetaminophen, valproic acid exhibited the highest covalent binding in vivo, whereas carbamazepine exhibited the highest levels in vitro. Pronounced effects on oxidative stress/reactive metabolite-responsive gene expression were observed after carbamazepine, phenobarbital, and phenytoin administration. Valproic acid had only minor effects on the oxidative stress/reactive metabolite indicator genes. The relative ease of detection of felbamate based on gene expression results in rat liver as having potential oxidative stressor/reactive metabolites indicates that this approach may be useful in screening for potential idiosyncratic toxicity. Together, measurements of gene expression along with covalent binding should improve the safety assessment of candidate drugs.     

Highly active antiretroviral therapy-induced liver injury

With the advent of highly active antiretroviral therapy (HAART), the reduction in overall mortality and morbidity in HIV patients has been accompanied by the emergence of liver disease as a leading cause of death. Elevated liver enzymes may be due to HAART or to other risk factors, including hepatitis co-infection and alcohol use. The different components of HAART are each associated with different risks of liver toxicity. Most drugs are metabolized by cytochrome P450 enzymes in the liver, and this may be affected by liver disease. The mechanisms for drug-induced liver injury include dose-dependent toxicity, hypersensitivity reactions, idiosyncratic reactions, mitochondrial toxicity, and immune reconstitution. The diagnosis of drug-induced liver injury is exclusionary. Once diagnosed, management generally involves discontinuation of the offending drug(s). A number of studies in progress are investigating whether treatment of hepatitis co-infection can improve the tolerability of HAART.     

NSAID induced gastrointestinal damage and designing GI-sparing NSAIDs

ABSTRACT

NSAIDs are widely used to treat pain and rheumatic conditions, but they induce adverse events in different body systems, although the major, most frequent events occur in the upper and lower gastrointestinal (GI) tracts.

Areas covered: This review is focused on damage caused by NSAIDs in the upper and lower GI tracts, the different mechanisms of damage and the GI-sparing NSAIDs designed to minimize adverse events based on understanding of these mechanisms.

Expert commentary: Among the new NSAIDs, COX-2 selective inhibitors have been extensively investigated, and some were approved for human use. Celecoxib demonstrated its safety for the entire GI tract, compared to traditional NSAIDs. However, coxibs, like traditional NSAIDs, are toxic to the cardiovascular (CV) system. Other GI-sparing agents include nitric oxide-NSAIDs and phosphatidylcholine-associated NSAIDs. Testing in animal models and humans they showed GI advantages over the parent NSAID compounds, but none obtained regulatory approval or were further investigated. Hydrogen sulfide-releasing NSAIDs are currently under clinical development, and more data are needed before clinical use. Alternative therapies, such as modulating gut microbiota, are being explored. Currently, clinicians must continue prescribing traditional NSAIDs or coxibs, associated with/without proton pump inhibitor therapy, based on the presence of GI/CV risk factors.     

N-acetyltransferases: Pharmacogenetics and clinical consequences of polymorphic drug metabolism

Since the discovery of polymorphicN-acetylation of drugs nearly 40 years ago, great progress has been made in understanding the molecular genetics of acetylation as well as the clinical consequences of being a rapid or slow acetylator. Inborn errors (several different alleles) at the NAT2 locus are responsible for the traditional acetylator polymorphism. Studies have revealed variant alleles at the NAT1 locus as well. The consequences of pharmacogenetic variation in these enzymes include (i) altered kinetics of specific drug substrates; (ii) drug-drug interactions resulting from altered kinetics; (iii) idiosyncratic adverse drug reactions. The latter have been extensively investigated for the arylamine-containing sulfonamide antimicrobial drugs. Individual differences in multiple metabolic pathways can increase the likelihood of covalent binding of reactive metabolites of the drugs to cell macromolecules with resultant cytotoxicity and immune response to neoantigens. This can result clinically in an idiosyncratic hypersensitivity reaction, manifested by fever, skin rash, and variable toxicity to organs including liver, bone marrow, kidney, lung, heart, and thyroid. Slow acetylation by NAT2 is a risk factor for such reactions to sulfonamides. Given the incidence of these severe adverse drug reactions (much less than 1/1000), slow acetylation cannot be the sole mechanism of predisposition in the population. Differences in rates of production of hydroxylamine metabolites of the drugs by cytochrome P450 (CYP2C9), myeloperoxidase, and thyroid, roxidase, along with an inherited abnormality in detoxification of the hydroxylamines are critically important in determining individual differences in adverse reaction risk. Both NATs, particularly NAT1, also can further metabolize hydroxylamine metabolites toN-acetoxy derivatives. Intensive investigation of patients with these rare adverse reactions using a variety of tools fromin vitro cell toxicity assays through molecular genetic analysis will help elucidate mechanisms of predisposition and ultimately lead to diagnostic tools to characterize individual risk and prevent idiosyncratic drug toxicity.     

Possible Optic Nerve Side Effeects Associated with Nonsteroidal Anti-Inflammatory Drugs

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the largest-selling groups of drugs in the world. We evaluated 144 cases of possible optic nerve abnormalities associated with the use of these agents, which were reported to the National Registry of Drug-Induced Ocular Side Effects. The findings include papillitis, retrobulbar optic neuritis, and papilledema. Although several NSAIDs have been reported to cause papilledema associated with or without pseudotumor cerebri, our data suggest the possibility that on rare occasions most NSAIDs are suspect. Although 120 cases of papillitis or retrobulbar optic neuritis associated with NSAID use have been reported to the Registry, a cause-and-effect relationship cannot be established. In general, visual complaints from patients taking NSAIDs were most commonly reported by those taking indomethacin, but only at a rate of 1.14 ± 0.46 incidents per 100 patient years. Patients with significant visual complaints who are taking NSAIDs may need to be evaluated for possible optic nerve abnormalities.     

Patient Outcomes and Drug Usefulness

Abstract

Many of the therapeutic agents for the treatment of chronic adult diseases are marketed as a racemic mixture. It is of concern from a clinical perspective because most of the patients in whom the drugs are used have compromised metabolic functions and/or are receiving co-medications. The less active component of the racemate may contribute to adverse consequences through stereoselective metabolism or drug-drug interactions. Therefore, this article discusses the potential problems associated with using racemic drugs, especially, the 2-arylpropionic acid NSAIDs.