Drugs for inflammation and joint disease

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Chapter 16 Drugs for inflammation and joint disease

Clare Thornton, Justin C. Mason

Synopsis

A vast burden of human disease involves the process of inflammation and the engagement of an immune response, often entirely appropriately as in the case of defence against infection. By contrast, a number of organ-specific and multi-system rheumatic diseases are characterised by a primary abnormality within the immune response, requiring treatments that modify or suppress it. This chapter reviews the process of inflammation, drugs in current use and those in development that act to modify it, and the management of certain common inflammatory diseases. The chapter covers the following areas:

• Acute inflammation.

• Adaptive immune system.

• Glucocorticoids.

• NSAIDs/aspirin/paracetamol.

• Immunomodulatory drugs.

• Biologics.

• Management of common rheumatic diseases.

Introduction

The immune system is a complex of interrelated genetic, molecular and cellular components that provides defence against invading microorganisms and aberrant native cells, and repairs tissues once the pathogen is eradicated. The central process by which these are achieved is inflammation: the sequence of events by which a pathogen is detected, cells of the immune system are recruited, the pathogen is eliminated and resulting tissue damage repaired.

Inflammation is appropriate as a response to physical damage, microbial infection or malignancy. A number of illnesses result from abnormal activation or prolongation of the immune response. These include allergy (hay fever, asthma), autoimmunity (rheumatoid arthritis (RA), systemic lupus erythematosus (SLE)), and allograft rejection.

Anti-inflammatory drugs, by acting on and modifying the response of the innate immune system to a challenge, are useful in many settings to damp down an over-exuberant or pathologically prolonged inflammatory response. Immunomodulatory agents, which act on components of the adaptive immune response, are important for the treatment of complex autoimmune diseases and in preventing allograft rejection. Many drugs used in the treatment of these diseases have complex mechanisms of action, working on multiple arms of the immune response, and in some cases the principal way in which they exert their effects is not clear. Partly this is due to the complexity of the immune system itself; many components have overlapping functions, leading to redundancy, and many have several apparently unrelated actions.

Research over the last few decades has vastly improved our appreciation of the complexity of the immune system and of the pathogenesis of many autoimmune diseases. Although there does not appear to be one single factor that leads inexorably to the development or perpetuation of any inflammatory disease, certain mediators that play central roles in specific diseases have been identified. The advent of monoclonal antibodies, fusion proteins and other new drug development technology has allowed the manufacture of a rapidly expanding group of new agents (‘biologicals’) that target specific components of the immune response thought to be driving particular diseases. These drugs have dramatically changed treatment paradigms, and hopefully will lead to significant improvements in the future outlook for patients suffering rheumatic disease.

Inflammation

The process of acute inflammation is initiated when resident tissue leucocytes (macrophages or mast cells) detect a challenge, for example pathogenic bacteria, or monosodium urate crystals in the case of gout. This sets off a cascade of intracellular signalling that results in activation of the cell, release of soluble cytokines such as tumour necrosis factor-α (TNFα), interleukin-1 (IL-1) and interleukin-6 (IL-6) and other mediators such as histamine and prostaglandins. IL-1, IL-6 and TNFα stimulate endothelial cells at the site of injury to express cellular adhesion molecules, which attract and bind circulating leucocytes, principally neutrophils, and induce them to leave the circulation and migrate into the affected area. They also have systemic effects such as the development of fever and the production of acute phase proteins including C-reactive protein (CRP).

Neutrophils, along with macrophages, phagocytose the injurious stimulus and destroy it. Neutrophils and macrophages may also cause damage to the surrounding host tissue through the release of digesting enzymes such as matrix metalloproteinases and collagenases. The inflammatory process therefore needs to be halted rapidly once the invading organism has been cleared. This occurs partly because neutrophils have a very short lifespan and die quickly once they have left the circulation, and partly through the release of anti-inflammatory mediators.

Several drugs in current use act on the various stages of this inflammatory process. Antagonists of TNFα, IL-1 and IL-6 are available (see Biologic agents, p. 253). Colchicine, used in the treatment of gout, interferes with neutrophil chemotaxis, thus inhibiting their recruitment to the site of inflammation.

Many leucocytes, including mast cells and macrophages, as well as endothelial cells, synthesise pro-inflammatory eicosanoids and platelet-activating factor (PAF) (Fig. 16.1). These are 20-carbon unsaturated fatty acids derived from phospholipid substrates in the plasma membrane by the enzymes phospholipase A2, cyclo-oxygenase (COX) and lipo-oxygenase (which are induced by IL-1). The prostaglandins, thromboxanes and leukotrienes have diverse pro-inflammatory roles. Leukotrienes promote the activation and accumulation of leucocytes at sites of inflammation. Prostaglandins induce vasodilatation of the microcirculation and are important in pain signalling from locally inflamed tissue. Platelet-activating factor and thromboxane A2 affect the coagulation and fibrinolytic cascades. Non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, inhibit COX and hence prostaglandin and thromboxane synthesis. Glucocorticoids act by inducing the synthesis of lipocortin-1, a polypeptide that inhibits phospholipase A2, and thereby exert a broad anti-inflammatory effect. The leukotriene receptor antagonists montelukast and zafirlukast cause bronchodilatation and are used to treat asthma.

image

Fig. 16.1 Synthesis of eicosanoids and platelet-activating factor, and drugs acting on this pathway. The enzymes phospholipase A2, cyclo-oxygenase and lipo-oxygenase are involved in the synthesis of prostaglandins, thromboxanes, leukotrienes and platelet-activating factor, all of which are derived from phospholipid substrates in plasma membranes. Glucocorticoids induce lipocortin 1, which inhibits phospholipase A2. NSAIDs inhibit cyclo-oxygenases 1 and 2, preventing formation of prostaglandins and thromboxanes.

The adaptive immune response

The adaptive immune response, although integrated into the process of inflammation, becomes active at later stages. Its key properties are (1) specificity: each B and T lymphocyte recognises a single specific peptide sequence; and (2) memory: when an invading pathogen has been recognised once, a small number of specific cells remain dormant within the lymph tissue for many years. If that pathogen is detected again, a very rapid response is mounted to eradicate it before the development of clinical symptoms.

An adaptive immune response is initiated when a helper T cell recognises a peptide antigen presented on the surface of an antigen-presenting cell (APC) and is activated (Fig. 16.2). The activated helper T cell is then able to activate other types of T cell and B cells. This results in the proliferation of adaptive cellular effectors, the generation and release of antibodies by plasma cells and the production of a range of cytokines by the participating leucocytes. On occasion, amplification loops may become self-perpetuating, leading to chronic autoimmune disease.

image

Fig. 16.2 Three general mechanisms of action of glucocorticoids and the glucocorticoid receptor in the inhibition of inflammation. TNFα, tumour necrosis factor α; HSP, heat-shock protein; mRNA, messenger RNA; P, phosphate. The three mechanisms are non-genomic activation, DNA-dependent regulation, and protein interference mechanisms (e.g. NF-KB elements). Black arrows denote activation, the red line inhibition, the red dashed arrow repression, and the red X lack of product (i.e. no mRNA).

Many immunomodulatory drugs, such as the calcineurin inhibitors, seek to break these loops by inhibiting lymphocyte proliferation. Other newer approaches target specific components of the immune system. For example, rituximab binds CD20, a cell surface molecule found only on B lymphocytes and not memory cells. It is used to treat diseases in which pathogenic autoantibody production is prominent, such as rheumatoid arthritis and SLE. Abatacept blocks co-stimulatory signals, which are required when a helper T cell is activated, by recognising bound antigen presented by an APC. This is a central process in the pathogenesis of rheumatoid arthritis, and abatacept is licensed to treat this.

Pharmacological manipulation of inflammatory mediators

Glucocorticoids

Glucocorticoids (GCs) are among the most widely prescribed anti-inflammatory drugs, due to their profound efficacy, long history of use and familiarity. Besides their anti-inflammatory actions they exert effects on carbohydrate, protein and lipid metabolism, some of which contribute to their substantial adverse effect profile.

GCs are used in acute and chronic settings to treat inflammatory conditions ranging from asthma and allergy, to prevention of allograft rejection, to rheumatoid arthritis and systemic vasculitis. Because of their rapid onset of action (less than 24 h) and potency, they remain the preferred acute treatment for severe inflammatory disease in a wide variety of settings despite their adverse effects. In chronic disease the aim now is to minimise cumulative exposure by using other immunomodulatory ‘steroid-sparing’ drugs, and proactively to manage potential long-term side-effects such as osteoporosis.

Mode of action

GCs, being lipophilic, diffuse across the cell membrane and bind the cytosolic glucocorticoid receptor (GR) (Fig. 16.3). Receptor polymorphisms influence the strength of the receptor interaction, and represent one source of variation in sensitivity to exogenous steroids. Once bound, the GC-GR complex translocates to the nucleus where it acts in at least two ways to alter gene transcription:

1. The GC-GR complex binds to the glucocorticoid response element within target gene promoters, increasing transcription of various anti-inflammatory genes. These include I-κB, which inhibits the activation of nuclear factor (NF)-κB, and the cytokines IL-4, IL-10, IL-13 and transforming growth factor (TGF)β, which have immunosuppressive and anti-inflammatory activity.

2. The GC-GR complex interferes with the binding of the transcription factors activating protein (AP)-1 and NF-κB to their response elements. This action decreases the transcription of a range of pro-inflammatory mediators. These include IL-1β and TNFα; IL-2, which stimulates T-cell proliferation; a range of chemokines and cellular adhesion molecules; metalloproteinases; COX-2; and inducible nitric oxide synthase.

3. GCs increase synthesis of the polypeptide lipocortin-1, which inhibits phospholipase A2 and thereby the synthesis of prostaglandins, thromboxane A2 and PAF (see Fig. 16.1).

image

Fig. 16.3 Mechanisms of glucocorticoid anti-inflammatory effects. Glucocorticoids exert pleiotropic effects on cellular metabolism. They increase transcription of a number of genes encoding anti-inflammatory proteins and decrease transcription of pro-inflammatory genes. AP-1, activating protein-1; COX, cyclo-oxygenase; GR, glucocorticoid receptor; GRE, glucocorticoid response element; IL, interleukin; iNOS, inducible nitric oxide synthase; NF, nuclear factor; TGF, transforming growth factor.

At the cellular level, GCs reduce the numbers of circulating lymphocytes, eosinophils and monocytes. This is maximal 4–6 hours after administration and is achieved by a combination of apoptosis induction and inhibition of proliferation. Chronic administration of GC is associated with a neutrophilia caused by release of neutrophils from the bone marrow and reduced adherence to vascular walls.

In inflammatory disease, the choice of GC preparation will reflect the site and the extent of inflamed tissue, e.g. oral or parenteral for systemic disease, inhaled in asthma, topical in cutaneous, ocular, oral or rectal disease. Different corticosteroid preparations, their pharmacokinetics, modes of delivery and adverse effects are discussed elsewhere, except for the management of steroid-induced osteoporosis, which is found in the section on management of rheumatoid arthritis at the end of this chapter.

Non-steroidal anti-inflammatory drugs (NSAIDs)

NSAIDs are an extremely widely prescribed group of drugs that are mainly used for their analgesic effects. They possess a single common mode of action: inhibition of cyclo-oxygenase, thereby reducing prostaglandin synthesis. This is also the mode of action of paracetamol (acetaminophen) and aspirin.

Recently concern has arisen over the effect of traditional NSAIDs and COX-2 inhibitors on the cardiovascular system, with analysis of the VIGOR1 study showing that rofecoxib in particular increases the risk of myocardial infarction (rofecoxib has since been withdrawn from use). While they retain an important role in the treatment of acute gout, inflammatory arthritis, ankylosing spondylitis and dysmenorrhea, long-term prescription should only be undertaken following a full discussion with the patient regarding the balance of risks and benefits.

Mode of action

NSAIDs inhibit cyclo-oxygenase (COX), which catalyses the synthesis of prostaglandins and thromboxane from arachidonic acid (see Fig. 16.1). There are two isoforms of COX:

• COX-1 is constitutively2 expressed in most cell types.

• COX-2 is induced when inflammatory cells (fibroblasts, endothelial cells and macrophages) are activated by cytokines such as IL-1β and TNFα. It is also often upregulated in cancer cells, and is constitutively expressed in the kidney and brain.

Both isoforms generate prostaglandins during an inflammatory response, while COX-1 activity is required for prostaglandin synthesis for tissue homeostasis. Thus, many NSAID adverse effects are due to reductions in beneficial prostaglandin production, for example in the gastric mucosa (PGI2 and PGE2) and renal medulla. Recognition of this led to the development of COX-2 selective drugs.

NSAIDs can be categorised according to their COX specificity as:

• COX-2-selective compounds (coxibs), which inhibit COX-2 with at least five times greater potency than COX-1. The group includes celecoxib, etoricoxib, lumiracoxib, meloxicam and etodolac.

• Non-COX-2-selective compounds, which comprise all other NSAIDs. These drugs inhibit COX-1 as well as COX-2.

Pharmacokinetics

NSAIDs are absorbed almost completely from the gastrointestinal tract, tend not to undergo first-pass elimination (see p. 87), are highly protein bound and have small volumes of distribution. Their t½ values in plasma tend to group into short (1–5 h) or long (10–60 h). Differences in t½ are not necessarily reflected proportionately in duration of effect, as peak and trough drug concentrations at their intended site of action following steady-state dosing are much less than those in plasma. The vast majority of NSAIDs are weak organic acids and localise preferentially in the synovial tissue of inflamed joints (see pH partition hypothesis, p. 80).

Uses

Analgesia

All NSAIDs are analgesics and are particularly effective for disorders with an inflammatory component, as the analgesic action is due to COX inhibition, both in the brain and at the site of inflammation. The non-selective and COX-2-selective agents have generally comparable analgesic efficacies.

Anti-inflammatory action

The majority of NSAIDs are anti-inflammatory because they inhibit COX in the periphery. COX inhibition in most chronic inflammatory conditions, while useful for symptomatic relief, does not modify the course of disease.

Antipyretic action

Paracetamol and all other NSAIDs reduce cytokine-induced prostaglandin synthesis in the hypothalamus, thus reducing fever.

Antiplatelet action

Aspirin irreversibly acetylates a serine residue in COX-1. In platelets the main result is inhibition of thromboxane A2 (which promotes platelet adhesion, coagulation and vasoconstriction) production for the life of the platelet (7 days). This is the basis for the use of aspirin to prevent and treat arterial thromboses secondary to atherosclerosis and other predisposing illnesses such as the antiphospholipid syndrome.

Other non-selective NSAIDs bind reversibly to COX-1 and produce a variable antiplatelet action. Ibuprofen may block access of aspirin to the active site on platelets and interfere with its cardioprotective effect when taken regularly (but not intermittently, and aspirin taken 2 h before ibuprofen may avoid the problem). Other NSAIDs do not appear to have this interaction.

It has been suggested that inhibition of COX-2 reduces synthesis of endothelial PGI2 (prostacyclin – which acts to prevent platelet aggregation and causes vasodilatation), while allowing the continued production of COX-1-derived thromboxane A2. In theory this could alter the balance within the vasculature in favour of thromboxane A2, and increase the risk of cardiovascular events, although the relative contributions of COX-1 and COX-2 in endothelial prostacyclin synthesis remain to be determined.

Colorectal cancer

Long-term administration of NSAID reduces the incidence of colonic cancer by approximately 50%. This appears to be related to the inhibition of COX-2, which is up-regulated in colon tumours.

Adverse effects

Gastrointestinal

Dyspepsia is one of the commonest side-effects of NSAIDs. The propensity to gastrointestinal (GI) ulceration may result in occult or overt blood loss. Use of NSAIDs is associated with an approximately four-fold increased incidence of severe gastrointestinal haemorrhage, and such complications account for between 700 and 2000 deaths in the UK each year. In addition, ulceration and stricture of the small intestine can result in anaemia, diarrhoea and malabsorption, similar to Crohn’s disease. The risk of NSAID-induced GI haemorrhage is associated with high doses and prolonged use, age over 65 years, previous history of peptic ulceration, concomitant use of glucocorticoids, anticoagulants or other NSAIDs, heavy smoking and alcohol use, and the presence of Helicobacter pylori infection.

NSAID-associated gastrointestinal disease appears to result from the inhibition of COX–1-mediated production of cytoprotective mucosal prostaglandins, especially PGI2 and PGE2, which inhibit acid secretion in the stomach, promote mucus production and enhance mucosal perfusion. Several large randomised controlled trials have investigated the incidence of gastrointestinal adverse effects in traditional NSAIDs compared with coxibs. The VIGOR (rofecoxib versus naproxen), CLASS3 (celecoxib versus ibuprofen and diclofenac) and TARGET4 (lumiracoxib versus ibuprofen and naproxen) studies all indicate that coxib use leads to an approximately 50% reduction of upper gastrointestinal adverse events.

The gastrointestinal toxicity of traditional NSAIDs may be reduced by co-prescription of a proton pump inhibitor, e.g. omeprazole, an H2-receptor blocker, e.g. ranitidine, or the prostaglandin analogue misoprostol. Proton pump inhibitors are more effective than the other classes of gastroprotective agent and should be considered in all patients with at least one of the above risk factors. In fact, it is now recommended by the UK National Institute for Health and Clinical Effectiveness (NICE) that all patients over 45 years prescribed an NSAID, whether COX-2 selective or not, also receive a proton pump inhibitor.

Cardiovascular

The VIGOR and APPROVE5 trials reported increased thrombotic cardiovascular events in patients treated with rofecoxib, leading to concerns about a class effect of the coxibs. It was suggested that COX-2 selectivity resulted in an imbalance between prostacyclin and thromboxane production, an effect which would not be seen with traditional NSAIDs which inhibited the synthesis of both equally. Subsequent data from the prospective MEDAL6 and TARGET trials have not supported a class effect based on COX-2 selectivity. These studies suggest that treatment with either a coxib or an NSAID results in a small increase in cardiovascular risk. The risk is dose-related and rofecoxib, particularly at doses exceeding 50 mg per day, confers the highest cardiovascular risk in the majority of studies. A recent study of more than 1 million patients quantified cardiovascular risk as a composite of coronary death, non-fatal myocardial infarction and fatal and non-fatal stroke, and reported that diclofenac and rofecoxib were associated with the highest cardiovascular risk, while naproxen and perhaps celecoxib at doses ≤ 200 mg per day were the least likely to cause a cardiovascular event.7 NICE guidelines recommend that patients with pro-thrombotic risk, coronary artery or cerebrovascular disease should not be prescribed NSAIDs or a coxib. For other patients, treatment decisions should be made on an individual patient basis taking into account both cardiovascular and gastrointestinal risk factors. The medication should be prescribed for the shortest possible time and regularly reviewed.

Renal

NSAIDs decrease renal perfusion in individuals with congestive cardiac failure, chronic renal disease and cirrhosis with ascites: states in which renal perfusion is dependent upon prostaglandin-mediated vasodilatation. NSAIDs may also promote sodium and water retention, causing oedema and hypertension in some individuals. Papillary necrosis and interstitial nephritis are rare complications, often in the context of chronic and excessive NSAID use.

Worsening of asthma

NSAID intolerance in asthmatics probably reflects diversion of arachidonic acid metabolism towards excessive products of the lipo-oxygenase pathway. It is not immune-mediated but clinically may resemble hypersensitivity, with manifestations including vasomotor rhinitis, urticaria, bronchoconstriction, flushing, hypotension and shock.

Other unwanted effects

include headache, confusion, photosensitivity, erythema multiforme, toxic epidermal necrolysis, deranged liver function, cytopenias, haemolytic anaemia and inhibition of ovulation.

Principal interactions

NSAID interactions include:

• Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers: there is a risk of renal impairment and hyperkalaemia.

• Quinolone antimicrobials: convulsions may occur if NSAIDs are co-administered.

• Anticoagulant (warfarin) and antiplatelet agents (dypiridamole, clopidogrel): increased risk of gastrointestinal bleeding with NSAIDs.

• Antihypertensives: their effect is lessened due to sodium retention by inhibition of renal prostaglandin formation.

• Ciclosporin and tacrolimus: nephrotoxic effect is exacerbated by NSAIDs.

• Cytotoxics: renal tubular excretion of methotrexate is reduced by competition with NSAIDs, with risk of methotrexate toxicity (low-dose methotrexate given weekly avoids this hazard).

• Diuretics: NSAIDs cause sodium retention and reduce diuretic efficacy and there is a risk of hyperkalaemia with potassium-sparing diuretics.

• Lithium: NSAIDs delay the excretion of lithium by the kidney and may cause lithium toxicity.

Paracetamol (acetaminophen)

Mode of action and uses

Paracetamol is an effective treatment for mild-moderate pain and for relieving fever. It does not affect platelet function or disrupt the GI mucosal barrier. Paracetamol has analgesic efficacy equivalent to aspirin, but in therapeutic doses it has only weak anti-inflammatory effects, a functional separation that reflects its differential inhibition of enzymes responsible for prostaglandin synthesis.8 For this reason, some would not class paracetamol as an NSAID.

Pharmacokinetics

Paracetamol (t½ 2 h) is well absorbed from the GI tract. It is inactivated in the liver, principally by conjugation as glucuronide and sulphate. Minor metabolites of paracetamol are also formed, of which one oxidation product, N-acetyl-p-benzoquinone imine (NAPQI), is highly reactive chemically. This substance is normally rendered harmless by conjugation with glutathione. The supply of hepatic glutathione is limited and, if the amount of NAPQI formed is greater than the amount of glutathione available, the excess metabolite oxidises thiol (SH-) groups on key enzymes, causing cell death. This is the mechanism of hepatic necrosis in paracetamol overdose.

Dose

The oral dose is 0.5–1 g every 4–6 h; maximum daily dose 4 g.

Adverse effects

Paracetamol is usually well tolerated. Allergic reactions and rash sometimes occur. Maximal, long-term, daily dosing may predispose to chronic renal disease.

Acute overdose

Severe hepatocellular damage and renal tubular necrosis can result from taking 150 mg/kg body-weight (about 10 or 20 tablets) in one dose.9 Patients at particular risk include:

• Those whose enzymes are induced as a result of taking drugs or alcohol; their liver and kidneys form more NAPQI.

• Those who are malnourished (chronic alcohol abuse, eating disorders, HIV infection) to the extent that the liver and kidneys are depleted of glutathione to conjugate with NAPQI.

Clinical signs of hepatic damage (jaundice, abdominal pain, hepatic tenderness) and increased liver enzymes do not become apparent for 24–48 h after the overdose. Hepatic failure may ensue 2–7 days later; and is best monitored using prothrombin time.

The plasma concentration of paracetamol is of predictive value; if it lies above a semi-logarithmic graph joining points between 200 mg/L (1.32 mmol/L) at 4 h after ingestion to 50 mg/L (0.33 mmol/L) at 12 h, then serious hepatic damage is likely (plasma concentrations measured earlier than 4 h are unreliable because of incomplete absorption). Patients who are malnourished are regarded as being at risk at 50% of these plasma concentrations.

The general principles for limiting drug absorption apply if the patient is seen within 4 h. Activated charcoal by mouth is effective and should be considered if paracetamol in excess of 150 mg/kg body-weight or 12 g, whichever is the smaller, is thought to have been ingested within the previous hour. The decision to use activated charcoal must take into account its capacity to bind the oral antidote methionine.

Specific therapy involves replenishing stores of liver glutathione, which conjugates NAPQI and so diminishes the amount available to do harm. Glutathione itself cannot be used as it penetrates cells poorly, but N-acetylcysteine (NAC) and methionine are effective as they are precursors for the synthesis of glutathione. NAC is administered intravenously – an advantage if the patient is vomiting. The regimen is: 150 mg/kg in 200 mL 5% dextrose over 15 min; then 50 mg/kg in 500 mL 5% dextrose over 4 h; then 100 mg/kg in 1000 mL 5% dextrose over 16 h. While it is most effective if administered within 8 h of the overdose, evidence shows that continuing treatment for up to 72 h still provides benefit. Methionine alone may be used to initiate treatment when facilities for infusing NAC are not immediately available. The earlier such therapy is instituted the better, and it should be started if:

• a patient is estimated to have taken more than 150 mg/kg body-weight, without waiting for the measurement of the plasma concentration

• plasma concentration indicates the likelihood of liver damage (above), or

• there is uncertainty about the amount taken, or its timing.

Aspirin (acetylsalicylic acid)

In the 18th century, the Reverend Edmund Stone wrote about the value of an extract of bark from the willow tree (of the family Salix) for alleviating pain and fever. The active ingredient was salicin, which is metabolised to salicylic acid in vivo. Sodium salicylate manufactured from salicin proved highly successful in the treatment of rheumatic fever and gout, but it was a gastric irritant. In 1897, Felix Hoffman, a chemist at the Bayer Company, whose father developed abdominal pain with sodium salicylate, succeeded in producing acetylsalicylic acid in a form that was chemically stable. The new preparation proved acceptable to his father and paved the way for the production of aspirin.

Mode of action

The anti-inflammatory, analgesic and antipyretic actions of aspirin are those of NSAIDs in general (see above). The following additional actions are relevant:

• An antiplatelet effect due to permanent inactivation, by acetylation, of COX-1 in platelets, preventing synthesis of thromboxane A2. Platelets cannot regenerate the enzyme and the resumption of thromboxane A2 production is dependent on the entry of new platelets into the circulation (platelet lifespan is 7 days). Thus a continuous antiplatelet effect is achieved with low doses.

• Respiratory stimulation is a characteristic of aspirin intoxication and occurs both directly by stimulation of the respiratory centre and indirectly through increased carbon dioxide production.

• Although aspirin in high dose reduces renal tubular reabsorption of uric acid so increasing its elimination, other treatments for hyperuricaemia are preferred. Indeed aspirin should be avoided in gout as low doses inhibit uric acid secretion and on balance its effects on uric acid elimination are adverse.

Uses

The main use of aspirin is as an antiplatelet agent to prevent arterial thrombotic events due to atherosclerosis. It has largely been overtaken by NSAIDs and paracetamol as an analgesic. In high doses it is used to treat inflammation in Kawasaki disease, in combination with intravenous immunoglobulin, but in other inflammatory illnesses it has now been superseded by other, more effective agents with fewer side-effects.

Pharmacokinetics

Aspirin (t½

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