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Nonsteroidal anti-inflammatory drugs NSAIDs are widely used, and their gastrointestinal effects account for an estimated 1200 deaths per year in the UK.. The underlying mechanisms which

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,

15 I N F L A M N A T I O N , A R T H R I T I S A N D N S A I D S

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-carbon1 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 constitutive2 (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.

Phospholipase A2 (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 PGF2

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

I N F L A M N A T I O N

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 (PGE2 and PGI2)

• renal homeostasis (PGE2 and PGI2)

• vascular homeostasis (PGI2 and TXA2)

• uterine function, embryo implantation and labour (PGF2)

• regulation of the sleep-wake cycle (PGD2)

• body temperature (PGE2)

Synthetic analogues of prostaglandins are being

used in medicine, namely:

• PGI2: epoprostenol (inhibits platelet aggregation,

used for extracorporeal circulation and primary pulmonary hypertension)

• PGEr- 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)

• PGE2: dinoprostone (used as cervical and vaginal

gel to induce labour and for late therapeutic abortion)

• PGF2a: 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

Plasminogen

(in cell wall)

15 I N F L A M N A T I O N , A R T H R I T I S A N D N S A I D S

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) (hypo-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

N O N S T E R O I D A L A N T I - I N F L A M M A T O R Y D R U G S ( N S A I D S ) 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 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 t1/, values in plasma tend to group

into those that are short (1-5 h) or long (10-60 h)

Differences in t1/^ 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.

15 I N F L A M M A T I O N , A R T H R I T I S A N D N S A I D S

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 H2

-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).

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 D l V I D U A L N S A I D S

• 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

15 N F L A M N A T I O N , A R T H R I T I S A N D N S A I D S

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 )

2 h

15 min 7-1 5 h

4 h

3 h

8 h

2 h

7 h 5h

3 h

2 h

l O h

3 h

4 h

1 h I4h

2 h

45 h

20 h

72 h

I 8 h

72 h

22 h

l O h

4 h 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

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 V I D U A L N S A I D S

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

15 N F L A M M A T I O N , A R T H R I T I S A N D N S A I D S

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 H2 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.