Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 17) docx

15 Inflammation, arthritis and nonsteroidal anti-inflammatory drugs SYNOPSIS A third of all general practice consultations are for musculoskeletal complaints. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used, and their gastrointestinal effects account for an estimated 1200 deaths per year in the UK. A hitherto unsuspected inflammatory component is now known to accompany conditions such as atherosclerosis. As understanding of the complex mechanisms underlying the inflammatory process increases, new ways of influencing it are developed, as witness therapies directed against specific cytokines, and COX-2 specific NSAIDs (COXIBs). Inflammation Arthritis Nonsteroidal anti-inflammatory drugs Disease modifying antirheumatic drugs Drug treatment of arthritis Gout Inflammation The clinical features of inflammation have been recognised since ancient times as swelling, redness, pain and heat. The underlying mechanisms which produce these symptoms are complex, involving COX: cyclo-oxygenase COXIB: COX-2 specific NSAIDs DMARD: disease modifying antirheumatic drug FGF: fibroblast growth factor GM-CSF: granulocyte macrophage-colony stimulating factor M-CSF macrophage-colony stimulating factor HPETE: hydroperoxy-eicosatetraenoic acid IL: interleukin LT: leukotriene PG: prostaglandin TNF: tumour necrosis factor TX: thromboxane many different cells and cell products, and only a general account of the current understanding of the inflammatory process is provided here. A normal inflammatory response is essential to fight infections and is part of the repair mechanism and removal of debris following tissue damage. Inflammation can also cause disease, due to damage of healthy tissue. This may occur if the response is over- vigorous, or persists longer than is necessary. Additionally, we now know that some conditions have a previously unrecognised inflammatory com- ponent, e.g. atherosclerosis. THE INFLAMMATORY RESPONSE The inflammatory response occurs in vascularised tissues in response to injury; it is part of the innate (nonspecific) immune response. Inflammatory re- sponses require activation of leukocytes: neutrophils, 279 15 INFLAMNATION, ARTHRITIS AN D NSAIDS eosinophils, basophils, mast cells, monocytes and lymphocytes, although not all cell types need be involved in an inflammatory episode. The cells migrate to the area of tissue damage from the circulation and become activated. Inflammatory mediators Activated leukocytes at a site of inflammation release compounds which enhance the inflammatory res- ponse. The account below focuses on cytokines and eicosanoids (arachidonic acid metabolites) because of their therapeutic implications. Nevertheless, the complexity of the response, and its involvement of other systems, is indicated by the range of mediators, which include: Complement products, especially C3b and C5-9 (the membrane attack complex); kinins and the rela- ted proteins, bradykinin and the contact system (coagulation factors XI and XII, pre-kallikrein, high molecular weight kininogen); nitric oxide and vaso- active amines (histamine, serotonin and adenosine); activated forms of oxygen; platelet activating factor (PAF); proteinases (collagenses, gelatinases and proteoglycanase). Cytokines Cytokines are peptides that regulate cell growth, differentiation and activation, and some have thera- peutic value: • Interleukins produced by a variety of cells including T cells, monocytes and macrophages. Recombinant interleukin-2 (aldesleukin) is used to treat metastatic renal cell carcinoma and malignant melanoma. Interleukin-1 may play a part in conditions such as the sepsis syndrome and rheumatoid arthritis, and successful blockade of its receptor offers a therapeutic approach for these conditions. • Cytotoxic factors include tumour necrosis factor (TNF) which is similar to interleukin-1. Biological agents that block TNF, e.g. etanercept, infliximab are finding their place amongst drugs that modify the course of rheumatoid disease (and Crohn's disease, see p. 65). • Interferons are so named because they were found to interfere with replication of live virus in tissue culture. Interferon alfa is used for a variety of neoplastic conditions (see Table 30.3) and for chronic active hepatitis. • Colony-stimulating factors have been developed to treat neutropenic conditions, e.g.filgrastim (recombinant human granulocyte colony stimulating factor, G-CSF) and molgramostim (recombinant human granulocyte macrophage- colony stimulating factor, GM-CSF) (see Ch. 30). Eicosanoids Eicosanoids (prostaglandins, thromboxanes, leuko- trienes, lipoxins) is the name given to a group of 20- carbon 1 unsaturated fatty acids derived principally from arachidonic acid in cell walls. They are short- lived, extremely potent and formed in almost every tissue in the body. Eicosanoids are involved in most types of inflammation and it is on mani- pulation of their biosynthesis that most present anti-inflammatory therapy is based. Their bio- synthetic paths appear in Figure 15.1 and are amplified by the following account. • Arachidonic acid is stored mainly in phospholipids of cell walls, from which it is mobilised largely by the action of phospholipase. Glucocorticoids prevent the formation of arachidonic acid by inducing the synthesis of an inhibitory polypeptide called lipocortin-1; the capacity to inhibit the subsequent formation of both prostaglandins and leukotrienes, explains part of the powerful anti-inflammatory effect of glucocorticoids (for other actions, see p. 664). • Arachidonic acid is further metabolised by cyclo- oxygenase (COX, also called PGH synthase), which changes the linear fatty acids into the cyclical structures of the prostaglandins. Nonsteroidal anti-inflammatory drugs (NSAIDs) act exert their anti-inflammatory effects by inhibiting COX. • COX exists as two different types, COX-1 and COX-2. The isoform COX-1 is predominantly constitutive 2 (although activity is increased 2^1-fold by inflammatory stimuli); it is present in 1 The Greek word for 20 is eicosa, hence the term eisocanoid. 2 Constantly produced by the cell regardless of growth conditions. 280 15 Phospholipase A 2 (inhibited by lipocortin-l produced in response to glucorticoids) ARACHIDONICACID t Prostaglandin G/H synthase (cyclo-oxygenase) (inhibited by NSAIDs) ARACHIDONICACID t Lipoxygenase ARACHIDONICACID PROSTACYCLIN THROMBOXANE OTHER Pgs LEUKOTRIENES (platelets) (endothelium) e.g PGE PGF 2 Fig. 15.1 Biosynthetic path of eicosanoids (see text for description). Prostaglandins are found in virtually all tissues of the body. most tissues, especially stomach, platelets and kidneys. COX-2 is inducible (10-20-fold) by inflammatory stimuli in many cells including macrophages, synoviocytes, chondrocytes, fibroblasts and endothelial cells, and only in low concentration in the gastrointestinal mucosa. Crucially, NSAIDs differ in their relative inhibition of the two isoforms of COX, recognition of which has lead to the development of selective COX-2 inhibitors. Such drugs have less adverse effects, especially on the gastrointestinal tract (see below). • Arachidonic acid is also metabolised by lipoxygenase to straight-chain hydroperoxy acids and then to leukotrienes which cause increased vascular permeability, vasoconstriction, bronchoconstriction, as well as chemotactic activity for leucocytes (whence their name). Inhibitors of lipoxygenase, e.g. zileuton, and leukotriene receptor antagonists, e.g. montelukast, zafirlukast, have found a place in the therapy of asthma (see p. 559). • Lipoxins are lipoxygenase-derived eicosanoids that probably down-regulate inflammation in the INFLAMNATION gastrointestinal tract and other organs by antagonising effects of TNF-oc. In health, PCs have a number of important physiological roles, namely: • protection of the gastrointestinal tract (PGE 2 and PGI 2 ) • renal homeostasis (PGE 2 and PGI 2 ) • vascular homeostasis (PGI 2 and TXA 2 ) • uterine function, embryo implantation and labour (PGF 2 ) • regulation of the sleep-wake cycle (PGD 2 ) • body temperature (PGE 2 ). Synthetic analogues of prostaglandins are being used in medicine, namely: • PGI 2 : epoprostenol (inhibits platelet aggregation, used for extracorporeal circulation and primary pulmonary hypertension). • PGE r - alprostadil (used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects, and for erectile dysfunction by injection into the corpus cavernosum of the penis); misoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs); gemeprost (used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for termination of pregnancy). • PGE 2 : dinoprostone (used as cervical and vaginal gel to induce labour and for late therapeutic abortion). • PGF 2a : dinoprost (termination of pregnancy). CHRONIC INFLAMMATORY DISEASE In many diseases, the pathological process is chronic inflammation; some of these are shown in Table 15.1, together with the predominant inflammatory cell infiltrates. The factors which allow development of a chronic inflammatory state, while not fully known, are thought to include a genetic predisposition and an environmental trigger, perhaps a virus or other infective agent. An imbalance of the inflammatory response occurs in many of these conditions, because proinflammatory mediators are present in excess. This is a feature of rheumatoid arthritis, inflammatory lung disease (fibrosing alveolitis) and inflammatory bowel disease (Crohn's disease). The 281 Plasminogen (in cell wall) 15 INFLAMNATION, ARTHRITIS AND NSAIDS dominant cell types and some of the key pro- inflammatory cytokines are illustrated in Figure 15.2. Once activated, macrophages may further be upregulated by the cytokines they release (IL8, GM- TABLE 1 5. 1 Diseases with a chronic inflammatory component Inflammatory disease Acute respiratory distress syndrome Asthma Atherosclerosis Glomerulonephritis Inflammatory bowel disease Osteoarthritis Psoriasis Rheumatoid arthritis Sarcoidosis Inflammatory cell infiltrate Neutrophil Eosinophil.T cell, monocyte, basophil T cell, monocyte Monocyte.T cell, neutrophil Monocyte, neutrophil.T cell, eosinophil Monocyte, neutrophil T cell, neutrophil Monocyte, neutrophil T cell, monocyte CSF, M-CSF, called the autocrine loop). TNF-oc and IL-1 are potent upregulators of several cell types including fibroblasts and T cells. TNF-a may act earlier in the hierarchy than other cytokines and has proven to be an important target for anticytokine therapy in rheumatoid arthritis and Crohn's disease (see later, anti-TNF therapy). Some small amounts of anti-inflammatory cytokines may also be present (such as IL-10 and interferon-y), but because the system is not in balance, the end result is inflammation. Arthritis The most common types of arthritis in the UK are osteoarthritis (UK prevalence 23%) and rheumatoid arthritis (1%). The less common types of inflamma- tory arthritis include: juvenile idiopathic arthritis; spondylarthritis (ankylosing spondylitis, Reiter's syndrome, psoriatic arthritis, arthritis associated with inflammatory bowel disease) and reactive arthritis associated with infection. Joint pains (arthralgia) are common in many other diseases, for example the connective tissue diseases (systemic lupus erythema- tosus, scleroderma), endocrine conditions (hypo- and hyperthyroidism) and malignancies, but in these, joint inflammation and damage do not usually occur. The crystal associated conditions, gout and pseudo- gout, are considered later in this chapter. Drugs have an important place in the therapy of all forms of arthritis, to alleviate symptoms, to modifying the course of the disease and, in the case of septic arthritis, to cure. There follows an account of these drugs. Nonsteroidal anti- inflammatory drugs (NSAIDs) Fig. 15.2 The main cells and inflammatory cytokines in chronic inflammatory disease. MODE OF ACTION The members of this class of drug, although struc- turally heterogeneous, possess a single common mode of action which is to block prostaglandin synthesis. Various NSAIDs have other actions that may con- tribute to differences between the drugs and these 282 NON STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) 15 include: the inhibition of lipoxygenases (diclofenac, indomethacin); superoxide radical production and superoxide scavenging; effects on neutrophil agg- regation and adhesion, cytokine production and cartilage metabolism. Nevertheless, their key action of inhibiting prostaglandin formation is reflected in the range of effects, beneficial and adverse, which the members exhibit. NSAIDs may be categorised according to their COX specificity as: • COX-2 selective compounds, whose selectivity for inhibiting COX-2 is at least 5 times that for COX- 1. The group includes rofecoxib, celecoxib, meloxicam, etodolac and nabumetone. • Non-COX-2 selective compounds, which comprise all other NSAIDs. These drugs inhibit COX-1 as much as, or even more than, COX-2. PHARMACOKINETICS In general, NSAIDs are absorbed almost completely from the gastrointestinal tract, tend not to undergo first-pass (presystemic) elimination, are highly bound to plasma albumin and have small volumes of distribution. Their t 1 /, values in plasma tend to group into those that are short (1-5 h) or long (10-60 h). Differences in t 1 /^ are not necessarily reflected pro- portionately in duration of effect, for peak and trough drug concentrations at their intended site of action in synovial (joint) fluid at steady-state dosing, are much less than those in plasma. The vast majority of NSAIDs are weakly acidic drugs that localise preferentially in the synovial tissue of inflamed joints (see pH partition hypothesis, p. 97). USES The wide range of recognised uses is expressed below. Some NSAIDs are available 'over the counter' in the UK (without a prescription), an acknowledgement of their general level of safety. Analgesia: NSAIDs are effective for pain of mild to moderate intensity including musculoskeletal and postoperative pain, and osteo- and inflammatory arthritis; they have the advantage of not causing dependence, unlike opioids (but see analgesic nephropathy, below). Anti-inflammatory action: this is utilised in all types of arthritis, musculoskeletal conditions and pericarditis. Antipyretic action: cytokine-induced PG synthesis in the hypothalamus is blocked, thus reducing fever. Antiplatelet function: aspirin is indicated for the treatment and/or prevention of myocardial infarc- tion, transient ischaemic attacks and embolic strokes. Prolongation of gestation and labour: inhibition of PG synthesis by the uterus during labour by indomethacin will prolong labour. Patency of the ductus arteriosus: as PGs maintain the patency, indomethacin given to a new-born child with a patent ductus can result in closure, avoiding the alternative of surgical ligation. Primary dysmenorrhoea: mefanamic acid is used to reduce the production of PGs by the uterus which cause uterine hypercontractility and pain. Further areas of potential benefit from NSAIDs are being explored, including the prevention of Alzheimer's dementia and colorectal carcinoma. ADVERSE REACTIONS Gastrointestinal effects Gastric and intestinal mucosal damage is the com- monest adverse effect of NSAIDs. The physiological function of mucosal prostaglandins is cytoprotective, by inhibiting acid secretion, by promoting the secretion of mucus and by strengthening resistance of the mucosal barrier to back-diffusion of acid from the gastric lumen into the submucosal tissues where it causes damage. Inhibition of prostaglandin biosynthesis removes this protection. Indigestion, gastro-oesophageal reflux, erosions, peptic ulcer, gastrointestinal haemorrhage and perforation, and small and large bowel ulceration occur. In the UK an estimated 12 000 peptic ulcer complications and 1200 deaths per year are attributable to NSAID use. 3 Toxicity relates to anti- 3 Hawkey C J 1996 Scandinavian Journal of Gastroenterology (Suppl.) 220: 124-127,221: 23-24. 283 15 INFLAMMATION, ARTHRITIS AND NSAIDS inflammatory efficacy. A meta-analysis of 12 con- trolled epidemiological studies ranked common NSAIDs according to their propensity for causing gastrointestinal complications. 4 Azapropazone, pir- oxicam, ketoprofen and indomethacin were asso- ciated with high risk (and azapropazone was 9.2 times more likely than low-dose ibuprofen to cause such adverse effects). Clinical trial evidence in general appears to support the theory that COX-2 selective inhibitors are as effective as, but have fewer adverse effects than, non-COX-2 selective compounds; for example meloxicam is better tolerated than diclofenac or piroxicam. 5 ' 6 The relative risk of serious gastro- intestinal effects (bleeding peptic ulcers) due to rofecoxib (COX-2 selective) was 0.51 compared with conventional NSAIDs. 7 COX-2 selective drugs are yet associated with significant dyspeptic symptoms (indigestion, heartburn), and these effects may result from inhibition of the (protective) constitutively expressed COX-2 in the stomach. In practice, a minority of patients are intolerant of all NSAIDs. They may benefit from the co- administration of a proton pump inhibitor, a H 2 - receptor blocker or the prostaglandin analogue, misoprostol. To address this problem, some NSAIDs are presented in combination with misoprostol, e.g. diclofenac with misoprostol (Arthrotec) and nap- roxen with misoprostol (Napratec). Some patients experience abdominal pain and diarrhoea from the misoprostol component. Ulceration and stricture of the small bowel may also be caused by NSAIDs, and in some patients there is occult blood loss, diarrhoea and malabsorption, i.e. a clinical syndrome indistinguishable from Crohn's disease. Renal effects Renal blood flow is reduced because the synthesis of vasodilator renal prostaglandins is inhibited; the 4 Henry D et al 1996 British Medical Journal 312:1563. 5 Hawkey C J et al 1998 British Journal of Rheumatology 37: 937. 6 Dequeker J et al 1998 British Journal of Rheumatology 37: 946. 7 Langman M J et al 1999 Journal of the American Medical Association 282: 1929. result is sodium and fluid retention and arterial blood pressure may rise. Renal failure may occur when glomerular filtration is dependent on the vasodilator action of prostaglandins, e.g. in the elderly, those with pre-existing renal disease, hepatic cirrhosis, cardiac failure, or on diuretic therapy sufficient to reduce intravascular volume. Analgesic nephropathy. Mixtures of NSAIDs (rather than single agents) taken repeatedly cause grave and often irreversible renal damage, notably chronic interstitial nephritis, renal papillary necrosis and acute renal failure; these effects appear to be due at least in part to ischaemia through inhibition of formation of locally produced vasodilator pro- staglandins. The condition is most common in people who take high doses over years, e.g. for severe chronic rheumatism and patients with personality disorder. Whilst analgesic nephropathy appears to be associated with long-term abuse of NSAID mixtures, the strong evidence that phenacetin was particularly responsible has rendered this drug obsolete. 8 Cutaneous effects Urticaria, severe rhinitis and asthma occur in susceptible individuals, e.g. with nasal polyposis, who are exposed to NSAIDs, notably aspirin; the 8 During the influenza pandemic of 1918 a physician to a big factory in a Swedish town prescribed an antipyretic powder containing phenacetin, phenazone (both NSAIDs) and caffeine. Survivors of the epidemic thought they felt fitter and reinvigorated during convalescence if they took the powder and they continued to take it after recovery. Consumption increased and many families 'could not think of beginning the day without a powder. Attractively wrapped packages of powder were often given as birthday presents'. Deaths from renal insufficiency rose in the 'phenacetin town', but not in a similar Swedish town, and in the decade of 1952-61 they were more than 3 times as many. An investigation was resisted by the factory workers to the extent that there was an organised burning of a questionnaire on powder-taking. It was eventually discovered that most of those who used the powders did so, not for pain, but to maintain a high working pace, from 'habit', or to counter fatigue (an effect probably due to the caffeine). Eventually the rising death rate brought home to the consumers the gravity of the matter, something that has yet to be achieved for tobacco smoking or alcohol drinking (Grimlund K 1964 Acta Medica Scandinavica 174: suppl. 405). 284 15 mechanism may involve inhibition of synthesis of bronchodilator prostaglandins, notably PGE2 (see Pseudoallergic reactions, p. 146). Other effects on the skin include photosensitivity, erythema multiforme, urticaria, and toxic epidermal necrolysis. Other general effects include cholestasis, hepato- cellular toxicity, thrombocytopenia, neutropenia, red cell aplasia, and haemolytic anaemia. Ovulation may be reduced or delayed (reversibly). An account of adverse reactions that probably relate to individual chemical classes of NSAID is given later. INTERACTIONS NSAIDs give scope for interaction, by differing pharmacodynamic and pharmacokinetic mecha- nisms, with: • ACE inhibitors and angiotensin II antagonists: there is risk of renal impairment and hyper- kalaemia. • Quinolone antimicrobials: convulsions may occur if NSAIDs are co-administered. • Anticoagulant (warfarin) and antiplatelet agents (ticlopidine, clopidogrel): reduced platelet adhesiveness and GI tract damage by NSAIDs increase risk of alimentary bleeding (notably with azapropazone). Phenylbutazone, and probably azapropazone, inhibit the metabolism of warfarin, increasing its effect. • Antidiabetics: azapropazone and phenylbutazone inhibit the metabolism of sulphonylurea hypoglycaemics, increasing their intensity and duration of action. • Antiepileptics: azapropazone and phenylbutazone inhibit the metabolism of phenytoin and sodium valproate, increasing their risk of toxicity. • Antifungal: fluconazole raises the plasma concentration of, and thus risk of toxicity from, celecoxib. • Antihypertensives: their effect is lessened due to sodium retention by inhibition of renal prostaglandin formation. • Antivirals: ritonavir may raise plasma concentration of piroxicam; NSAIDs may increase haematological toxicity from zidovudine. I N Dl VI DUAL NSAIDS • Ciclosporin: nephrotoxic effect is aggravated 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 and antihypertensive efficacy; risk of hyperkalaemia with potassium-sparing diuretics; increased nephrotoxicity risk (with indomethacin, ketorolac). • Lithium: NSAIDs delay the excretion of lithium by the kidney and may cause lithium toxicity. Individual NSAIDs The currently available NSAIDs exhibit a variety of molecular structures and it is usual to classify these drugs by their chemical class. Clinical trials in rheumatoid arthritis and osteoarthritis, however, rarely find substantial differences in response to average doses of NSAIDs whatever their structure, and this no doubt reflects their common mode of action. Some 60% of patients will respond to any NSAID and many of the remainder will respond to a drug from another group. A structural classification is nevertheless used here as it provides a logical framework; furthermore, specific toxicity profiles tend also to relate to chemical group (see below). Summary data on NSAIDs licenced in the UK are given in Table 15.2. ADVERSE EFFECTS A general account of the unwanted effects of NSAIDs is given on page 283. In addition, adverse reactions that feature within particular chemical classes of NSAID appear below, together with comments on some individual drugs. Paracetamol: see below. Salicylic acids: see aspirin, below. Acetic acids. Indomethacin may cause prominent salt and fluid retention. Headache is common, often similar to migraine, and is attributed to cerebral oedema; it can be limited by starting at a low dose 285 15 NFLAMNATION , ARTHRITIS AN D NSAIDS TABLE 15.2 Nonsteroidal anti-inflammatory drugs licenced in the UK Chemical class Para-amino phenol Salicylic acids Acetic acids Fenamic acid Propionic acids Enolic acids Non-acid drugs Generic name paracetamol aspirin diflusinal benorilate indometacin acemetacin sulindac diclofenac sodium etodolac ketorolac mefanamic acid ibuprofen fenbufen fenoprofen flurbiprofen ketoprofen naproxen tiaprofenic acid piroxicam meloxicam tenoxicam azapropazone phenylbutazone nabumetone celecoxib aceclofenac rofecoxib Compound acetaminophen acetylsalicylic acid salicylate salicylate-paracetamol ester indole indole indene phenylacetic acid pyranocarboxyate ketorolac trometerol fenamate propionic acid propionic acid propionic acid propionic acid propionic acid propionic acid propionic acid oxicam oxicam oxicam benzotriazine pyrazone napthylalkanone coxib phenylacetoxyacetic acid coxib Half-life (t'/ 2 ) 2h 15 min 7-1 5 h 4h 3h 8h 2h 7h 5h 3h 2h lOh 3h 4h 1 h I4h 2h 45 h 20 h 72 h I8h 72 h 22 h lOh 4h I7h Usual adult dose 1 gqid 300-900 mg q.d.s. maximum 4 g daily 500-1 000 mg daily in 1 or 2 doses 1. 5 g q.d.s. initially 50-75 mg daily as 1 or 2 doses, maximum 200 mg daily 60 mg b.d. or t.d.s. 200 mg b.d. 75- 1 50 mg daily in 2 divided doses 600 mg o.d. 500 mg t.i.d. 1. 6-2.4 g daily in divided doses 300 mg in a.m. and 600 mg nocte, or 450 mg b.d. 300-600 mg t.d.s. or q.d.s., maximum 3 g daily 1 50-200 mg daily in divided doses, maximum 300 mg daily 1 00-200 mg in 1-4 divided doses 250-500 mg b.d. 600 mg in 2-3 divided doses 20 mg o.d. 7.5-15 mg o.d. 20 mg o.d. 1.2 g daily in 2 or 4 divided doses 1 g nocte, additional 500 mg — 1 g o.d. if necessary 200-400 mg daily in divided doses lOOmgb.d. 1 2.5-25 mg o.d. and increasing slowly. Vomiting, dizziness and ataxia occur. Allergic reactions occur and there is cross- reactivity with aspirin. Indomethacin may aggravate pre-existing renal disease. Drugs of this group are best avoided where there is gastroduodenal, renal or central nervous system disease or in the presence of infection. Unusually among the NSAIDs, adverse effects of sulindac on the kidney may be less likely as the active (sulphide) metabolite of sulindac appears not to inhibit renal prostaglandin synthesis. Fenamic acid. The principal adverse effects of mefenamic acid are diarrhoea, upper abdominal dis- comfort, peptic ulcer and haemolytic anaemia. Elderly patients who take mefenamic acid may develop nonoliguric renal failure especially if they become dehydrated, e.g. by diarrhoea; the drug should be avoided or used with close supervision in the elderly. Propionic acids. The main advantage of the 286 15 members of this group is a lower incidence of adverse effects particularly in the gastrointestinal tract, and especially with ibuprofen at low dose. Nevertheless epigastric discomfort, activation of peptic ulcer and bleeding may occur. Other effects include headaches, dizziness, fever and rashes. Enolic acids. Note the generally long t l / 2 of each member of this group, and in consequence the anticipated time to reach steady state in plasma (5 x t l / 2 ). Adverse effects are those to be expected with NSAIDs in general, gastrointestinal and central nervous system complaints being the commonest. Toxic reactions are relatively frequent with aza- propazone which should be used only in rheumatoid arthritis, ankylosing spondylitis and acute gout when other drugs have failed. Phenylbutazone is also relatively toxic (gastrointestinal, hepatic, renal, bone marrow); it is rarely indicated except in ankylosing spondylitis under specialist supervision. Nonacidic drugs. COXIBs are associated with fewer gastrointestinal adverse effects, but otherwise the general profile of adverse reactions to NSAIDs applies. The possibility that COXIBs may be asso- ciated with increased risk of thrombotic cardio- vascular events is the subject of pharmacovigilance studies. More extensive accounts of paracetamol and aspirin are given below, because of the importance and widespread use of these drugs. PARACETAMOL (ACETAMINOPHEN) (PANADOL) This popular domestic analgesic and antipyretic for adults and children can be bought over the counter in the UK. It is a major metabolite of the now obsolete phenacetin (see p. 284). Its analgesic efficacy is equal to that of aspirin but in therapeutic doses it has only weak anti-inflammatory effects (for this reason it is sometimes deemed not to be an NSAID). Para- cetamol inhibits prostaglandin synthesis in the brain but hardly at all in the periphery; it does not affect platelet function. Paracetamol is effective in mild to moderate pain such as that of headache or dysmenorrhoea and it is also useful in patients who should avoid aspirin because of gastric intolerance, a bleeding tendency or allergy, or because they are aged < 12 years. N D I VI DUAL NSAIDS Pharmacokinetics. Paracetamol (i l / 2 2h) is well absorbed from the alimentary tract and 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-benzoquinoneimine (NABQI), is highly reactive chemically. This substance is normally rendered harmless by conjugation with glutathione. But the supply of hepatic glutathione is limited and if the amount of NABQI formed is greater than the glutathione available, then the excess metabolite oxidises thiol (SH-) groups of key enzymes, which causes cell death. This explains why a normally safe drug can, in overdose, give rise to hepatic and renal tubular necrosis (the kidneys also contain drug oxidising enzymes). Dose. The oral dose is 0.5 to 1 g every 4 to 6 h, maximum daily dose 4 g. Adverse effects. Paracetamol is usually well- tolerated by the stomach because inhibition of prostaglandin synthesis in the periphery is weak; allergic reactions and skin rash sometimes occur. Heavy, long-term daily use may predispose to chronic renal disease. Acute overdose. Severe hepatocellular damage and renal tubular necrosis can result from taking 150 mg/kg (about 10 or 20 tablets) in one dose, which is only 2.5 times the recommended maximum daily clinical dose. Patients specially at risk are: • those whose enzymes are induced as a result of taking drugs or alcohol for their livers and kidneys form more NABQI and • those who are malnourished (chronic alcohol abuse, eating disorder, HIV infection) to the extent that their livers and kidneys are depleted of glutathione to conjugate with NABQI (see above). The INR (prothrombin time) is preferred to plasma bilirubin and hepatic enzymes as a monitor of liver damage, and renal impairment is better assessed by plasma creatinine than urea (which is metabolised by the liver). The clinical signs (jaundice, abdominal pain, hepatic tenderness) do not become apparent for 24^18 h and liver failure, when it occurs, does so between 2 and 7 days after the overdose. It is vital 287 15 NFLAMMATION, ARTHRITIS AND NSAIDS that this delay be remembered for lives can be saved only by effective anticipatory action (see below). The plasma concentration of paracetamol is of predictive value; if it lies above a semilogarithmic graph joining points between 200 mg/1 (1.32 mmol/1) at 4 h after ingestion to 50 mg/1 (0.33 mmol/1) at 12 h, then serious hepatic damage is likely. Patients who are enzyme induced or malnourished (see above) are regarded as being at risk at 50% of these plasma concentrations (plasma concentrations measured earlier than 4 h are unreliable because of incomplete absorption). The general principles for limiting drug absorption apply (Ch. 9) if the patient is seen within 4 h. Activated charcoal by mouth is effective but the decision to use it must take into account its capacity to bind an oral antidote (methionine). Specific therapy is directed at replenishing the store of liver glutathione which combines with and so dim- inishes the amount of toxic metabolite available to do harm. Glutathione itself cannot be used as it penetrates cells poorly but N-acetylcysteine (NAC) (Parvolex) and methionine are effective as they are precursors for the synthesis of glutathione. NAC is more effective because its conversion into glutathione requires fewer enzymes; also, it is administered by i.v. infusion which is an advantage if the patient is vomiting. 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 > 150 mg/kg, without waiting for the measurement of the plasma concentration • plasma concentration indicates the likelihood of liver damage (above) • there is any uncertainty about the amount taken or its timing. NAC is administered i.v. 150 mg/kg in dextrose 5% (200 ml) over 15 min; then 50 mg/kg in dextrose 5% (500 ml) over 4 h; then 100 mg/kg in dextrose 5% (1000 ml) over 16 h, to a total of about 300 mg/kg in 20 h. While it is most effective if administered within 8 h of the overdose, evidence shows that treatment continuing up to 72 h yet provides benefit. The INR and serum creatinine should be measured daily. If the INR exceeds 2 there is risk of infection and gastric bleeding, and an antimicrobial plus either sucralfate or a histamine H 2 receptor antagonist should be given prophylactically. The patient should be kept well hydrated and in fluid balance; falling urine output, indicative of acute renal tubular necrosis, will necessitate measures to improve urine flow (see Chapter 23). A paracetamol-methionine combination (co-methi- amol; Pameton) has been marketed, the methionine content ensuring that hepatic glutathione concen- trations are maintained when the drug is used in therapeutic (and over-) dose. But the problem of ensuring that this is used by the people most likely to benefit from such prophylaxis has not been solved since paracetamol is on direct sale to the public and this proprietary preparation is more expensive than generic paracetamol. A more simple measure, reduction of the pack-size in which paracetamol is sold to the public, appears to have reduced the use of paracetamol as a means of deliberate self-harm. 9 ASPIRIN (ACETYLSALICYLIC ACID) Aspirin (acetylsalicylic acid) was introduced in 1899; it is by far the commonest form in which salicylate is taken. The bark of the willow tree (Salix) contains salicin from which salicylic acid is derived; it was used for fevers in the 18th century as a cheap substitute for imported cinchona (quinine) bark. Mode of action. Acetylsalicylic acid is unique among NSAIDs in that it also irreversibly inhibits COX by acylating the active site of the enzyme, so preventing the formation of products including thromboxane, prostacyclin and other prostaglandins, until more COX is synthesised. Acetylsalicylic acid is rapidly hydrolysed to salicylic acid in the plasma. Salicylic acid also has an anti-inflammatory action but additionally exerts important effects on respi- ration, intermediary metabolism and acid-base balance, and it is highly irritant to the stomach. The anti-inflammatory, analgesic and antipyretic actions of aspirin are those of NSAIDs in general 1 Hawton K et al 2001 British Medical Journal 322: 1203. 288 [...]... 57-62 Parkin J, Cohen B 2001 An overview of the immune system Lancet 357:1777-1789 Seymour H E, Worsley A, Smith J M, Thomas S H L 2001 Anti-TNF agents for rheumatoid arthritis British Journal of Clinical Pharmacology 51: 201-208 Sneader W 2000 The discovery of aspirin: a reappraisal British Medical Journal 321:1591 Walker-Bone K et al 2000 Medical management of osteoarthritis British Medical Journal... multidisciplinary approach with physiotherapy, occupational therapy and adjustment on the part of the patient all being important SYMPTOMATICTREATMENT NSAIDs provide much symptomatic relief and improve clinical indicators of disease activity such as joint swelling, but do not improve its outcome, i.e joint destruction The current strategy for treating rheumatoid arthritis is to start treatment with specific... inhibits pyrimidine synthesis and prevents T-cell proliferation, which is thought to be important in the pathogenesis of rheumatoid arthritis The onset of action is faster than other DMARDs, providing clinical benefit in 4-6 weeks As the drug is retained in the body for 2 years, elimination therapy with either cholestyramine or activated charcoal may be necessary if a change to another DMARD is planned... pericarditis), complete bed rest is advised and a corticosteroid should be used instead of aspirin since the latter may precipitate cardiac failure Prednisolone should be given in a dose sufficient to suppress clinical and laboratory (ESR, plasma viscosity, C-reactive protein) signs of inflammation; 10-15 mg/d is usually adequate in adults, and specific therapy for cardiac failure may also be necessary Neither... depression may also cause CO2 retention Adults who have taken a single large quantity usually develop a respiratory alkalosis Metabolic acidosis suggests severe poisoning Often, a mixed picture is seen clinically In children under 4 years, severe metabolic acidosis is more likely than respiratory alkalosis, especially if the drug has been ingested over many hours (mistaken for sweets) Treatment Serial . L 2001 Anti-TNF agents for rheumatoid arthritis. British Journal of Clinical Pharmacology 51: 201-208 Sneader W 2000 The discovery of aspirin: . times more likely than low-dose ibuprofen to cause such adverse effects). Clinical trial evidence in general appears to support the theory that