INTRODUCTION 1 1 0 | C H A P T E R 1 INTRODUCTION | 1 1 The medicinal effect of the bark of the willow has been known for centuries. The active ingredient, a bitter glycoside called salacin, was first isolated in pure form in 1829 by Leroux. A series of simple chemical manipulations yielded sodium salicylate, which became widely used for the treatment of rheumatic fever and as an antipyretic in 1875. In 1899, acetylsalicylic acid was introduced into medicine under the name of aspirin. By the early 20th century, the chief therapeutic actions of aspirin (antipyretic, analgesic and anti-inflammatory activity) were known. This paved the way for the development of a host of new synthetic aspirin-like agents known as non-steroidal anti-inflammatory drugs (NSAIDs), beginning with indomethacin. [1] NSAIDs share similar therapeutic activity with aspirin (although important differences exist) and have superseded aspirin in the treatment of arthritic pain ever since clinical trials demonstrated equivalent efficacy of NSAIDs to salicylic acid. NSAIDs offer numerous significant clinical benefits, especially in the treatment of osteoarthritis (OA) and rheumatoid arthritis (RA). Due to the fact that they are multi- purpose, uptake is enormous. Population estimates suggest that 10-50% of people suffer from musculoskeletal disorders, of which a relatively large part is aged over 65 years. [2] In addition, approximately 70% of individuals aged over 65 years of age take at least one NSAID at least once a week, either prescribed or purchased over-the- counter (OTC). [3] NSAIDs also share side-effects with aspirin. They are amongst the highest contributors to adverse drug reactions (ADRs) including drug-related hospitalisations and deaths. This is due to the high frequency of NSAID use, their pharmacological mode of action and use in relation to patient risk factors. [4-6] The risks associated with use of OTC NSAIDs (including aspirin) are less well quantified, but since OTC use is prevalent, the contribution is likely to be significant. [7;8] Thus, NSAIDs offer benefit to many but the drawback is that ADRs to NSAIDs constitute a significant public health problem. ADRs to drugs can be categorised into different types: Type A, B, C and D (the latter two categories defined as ‘Chronic’ and ‘Delayed’ are less commonly used and not discussed here). [9;10] Type A reactions are the most common (approximately 80%) and are considered to be augmentations of a drug’s expected therapeutic action and/or rationalisable from known pharmacology. These reactions are more likely to be identified during pre-marketing clinical development and are often related to dose. Factors predisposing to Type A reactions include formulations, pharmacokinetic or pharmacodynamic abnormalities and drug-drug interactions. Thus, some patients 1 2 | C H A P T E R 1 INTRODUCTION | 1 3 are more likely to experience Type A reactions because of the presence of risk factors marked interindividual differences in patient responses with regard to efficacy and including extreme age (neonates or the elderly), co-morbidities and/or polypharmacy tolerability.[27] and pharmacogenetic factors involved in drug metabolism. Type B reactions are uncommon, idiosyncratic, unpredictable and often severe effects. The mechanisms of Mechanism of action Type B reactions are poorly understood, but may involve immunological mechanisms At the beginning of the 1970s, the Nobel prize winner Sir John Vane reported or rare pharmacogenetic factors. Such reactions can occur at any dose (even very that aspirin and related drugs exerted their therapeutic and toxic effects through a small quantities) and are often only identified through substantial clinical exposure, common mechanism: inhibition of prostaglandin synthesis via inhibition of the cyclo- postmarketing. oxygenase (COX) enzyme. [28] This was a major advance in the understanding of the Ever since the first demonstration of aspirin’s gastro-irritant effect was reported pharmacodynamics of these drugs. At that time, COX, which converts arachiodonic in 1938, [11] the principle focus of scientific literature with respect to the safety of acid to various prostaglandins, was believed to exist in one form. Whilst inhibition of NSAIDs has been on NSAID induced gastrointestinal (GI) problems (Type A reactions). COX explained many of the therapeutic similarities between NSAIDs and aspirin, it did Regardless of structural type, NSAID gastropathy is predominant, ranging from non- not account for differences in the adverse event profiles. In the 1990s, two forms of the specific dyspepsia (incidence 5% - 15%) to ulceration and upper GI bleeding which can COX enzyme were identified. [29] The COX-1 isoenzyme (COX-1) was reported to be result in hospital admission (incidence 0.25 – 1.25%). [3] Of these, approximately 20% constitutively expressed in many tissues, including the stomach, intestines, kidneys and of patients die. [12;13] Estimates suggest one-third of patients taking NSAIDs long-term in platelets and involved in the physiological production of prostaglandins; conversely have gastric or duodenal ulcers, but not all progress to having serious GI complications. the COX-2 isoenzyme (COX-2) was inducible at sites of inflammation and injury. [30] [14] Lower GI complications are less commonly reported. [15] Other examples of Type Thus, the therapeutic activity of traditional non-selective (ns)NSAIDs was proposed to A reactions to NSAIDS include adverse effects on cardio-renal function. [16] These are depend on inhibition of COX-2, with GI and other adverse effects, to varying degrees, particularly important in patients with diminished renal function or cardiovascular (CV) being related to inhibition of COX-1. [31] co-morbidity such as heart failure. [17;18] There are complications arising from alteration The pharmacological basis of inhibition of COX-2 by NSAIDs was demonstrated of renal haemodynamics such as (worsening of) congestive heart failure, oedema and subsequent to the molecular structure of COX-1 and COX-2 being defined. [32-34] increased blood pressure,[19;20] as well as possible aggravation of myocardial ischaemia. In common to both isotypes is a long hydrophobic substrate binding channel which is [21] Central nervous system toxicity includes aseptic meningitis, psychotic reactions, and larger and more accessible in COX-2. Almost all the traditional nsNSAIDs, including cognitive dysfunction, the latter occurring especially among elderly patients. [22] Serious aspirin, bind to and inhibit both. nsNSAIDs can be further divided into groups, based Type B reactions (hypersensitivity reactions, blood dyscrasias, erythema multiforme and on their mode of inhibition; rapidly reversible, competitive inhibitors which compete hepatitis) are rare or very rare. [23;24] Allergic reactions are uncommon and may affect with substrates for occupation of the hydrophic active site (e.g ibuprofen), or slow, time- patients with underlying immunological problems. [25;26] dependent irreversible inhibition (from formation of ionic bonds with the carboxylic group of these drugs) (e.g indomethacin). Aspirin is unique in that it irreversibly acetylates a serine residue in the hydrophobic active site. [35] This strong inhibition of COX-1, The search for safer NSAIDs also demonstrated for indomethacin and piroxicam, is associated with the highest risk In the 1960s, there was a proliferation in the development and introduction of GI damage. [35] of numerous, structurally variable NSAIDs, all aimed at providing more effective The discovery of the two COX isoenzymes triggered the development of other, and safer therapy. Indomethacin, phenylbutazone and newer proprionic acid drugs ‘pharmacologically cleaner’ NSAIDs, through targeted drug design. This led to the became established by the end of the 1960s. Clinical experience demonstrated development of highly selective COX-2 inhibitors (hereafter referred to as ‘coxibs’), and further exploration of the COX-2 selectivity of traditional NSAIDs. [36-38] The first 1 4 | C H A P T E R 1 INTRODUCTION | 1 5 generation coxibs, rofecoxib (Vioxx®) and celecoxib (Celebrex®) were specifically designed The ability of coxibs to inhibit COX-2 enzyme activity is related to structural with the COX-2 hypothesis in mind (Figure 1). [39] The COX-2 hypothesis proposed differences in the substrate binding channels of COX-1 and COX-2. The side pocket that these (and similar) drugs should have fewer unwanted side effects, especially GI within the COX-2 binding channel enables access of the bulky coxib molecule to complications, than traditional nsNSAIDs by virtue of their COX-1 sparing effects, but prevent substrate access to the active site deep within the COX-2 binding channel, with equivalent therapeutic potential. [40] whilst the structure of the COX-1 binding channel does not permit access of these drugs (Figure 2). [41] As a group, the coxibs are heterogeneous in structure [sulphonamides Figure 1. Differential effects of non-selective (ns) NSAIDs, and coxibs on production of prostanoids. (celecoxib and valdecoxib), methylsulphones (etoricoxib and rofecoxib) and arylacetic Membrane phospholipids acids (lumiracoxib)] and pharmacokinetics. However, it is unclear whether these structural Diverse stimuli differences are related to COX-2 selectivity, [42] and whether these differences offer clinically significant advantages in vivo in terms of efficacy or safety under conditions of Phospholipase A 2 routine clinical practice, whereupon selectivity may vary at target site. [43-50] nsNSAIDs