ADVERSE EFFECTS

Drugs & Aging 2 (1): 20-34, 1992 1170-229X/ 92/000I-0020/ $07.50/0 © Adis International Limited. All rights reserved. ORA160a

Salicylate Intoxication in the Elderly Recognition and Recommendations on How to Prevent It Chester Durnas and Barry J. Cusack Veterans Administration Medical Center, Boise, USA and University of Washington, Seattle, Washington, USA

COD ten ts

21 2I 22 22 22 22 23 13 23 24 24 25 25 27 28 28 28 28 29 29 29 29 29 30

31

Summary I. Salicylates 2. Pharmacokinetics 2.1 Absorption 2.2 Distribution 2.3 Protein Binding 2.4 Metabolism 2.5 Excretion 3. Pharmacodynamics 4. Systemic Toxicity 4.1 Acute Intoxication 4.2 Chronic Intoxication 4.3 Diagnosis of Salicylate Intoxication 4.4 Treatment 5. Organ Toxicity 5.1 Gastric 5.2 Small and Large Bowel 5.3 Hepatic 5.4 Renal 5.5 Pulmonary 5.6 Neurological 5.7 Endocrine 6. Drug Interactions 7. Prevention of Salicylate Intoxication 8. Conclusion

Salicylate Intoxication in the Elderly

Summary

21

Aspirin (acetylsalicylic acid) and its salicylate derivatives are effective antipyretic, analgesic, and anti-inflammatory agents that are still very widely used by the elderly despite the advent of newer, potentially safer nonsteroidal anti-inflammatory drugs (NSAIDs). However, none of the new NSAIDs have been proven to be more effective than aspirin or salicylic acid. Chronic salicylate intoxication which is most common in the elderly, may occur with therapeutic doses. Increased toxicity in older patients often appears due to inadvertent overdosage. Dual prescribing or additional use of nonprescription salicylates are some causes of unwitting long term toxicity. According to some studies, systemic clearance of salicylate (mainly by hepatic metabolism) is reduced with age, as is renal elimination. These changes are of increased importance in the elderly using high therapeutic doses of salicylates when metabolism is saturated and more unchanged drug is available for renal excretion. In the face of renal impairment, the risk of toxicity is increased. The diagnosis of acute salicylate intoxication generally does not pose diagnostic problems. Patients often present with a history of intentional overdose, with hyperventilation, fever, and nausea. The diagnosis can be confirmed by measuring serum salicylate concentrations. Chronic intoxication often poses a diagnostic dilemma with atypical presentations mimicking other disease states such as diabetic ketoacidosis, delirium, cerebrovascular accident, myocardial infarction or cardiac failure. The diagnosis of salicylate intoxication should be borne in mind when an older patient presents with recent deterioration in acitivities of daily living with no known cause. Plasma salicylate concentrations should be measured if salicylate intoxication is suspected, even if there is no documented history of salicylate ingestion. The risk of salicylate nephrotoxicity is also increased with age, and upper gastrointestinal haemorrhage is associated with increased mortality in older age groups. Treatment of acute toxicity consists of prompt recognition of salicylate intoxication, use of activated charcoal, correction of acid-base abnormalities, general supportive measures, and if concentrations are extremely high, dialysis can be effectively used. Chronic toxicity, which can occur even with marginally high salicylate concentrations, is treated with drug withdrawal and supportive therapy. Chronic salicylate toxicity can be averted by prescription of conservative doses of drug, avoidance of concomitant use of different salicylate preparations, and therapeutic monitoring to guide dosage. Renal function should be monitored to detect nephrotoxicity from chronic salicylate therapy. Patients should be regularly screened for evidence of gastrointestinal bleeding. Use of aspirin and other NSAIDs should be avoided, if possible, in older patients with a history of upper gastrointestinal haemorrhage. If aspirin therapy is required, misoprostol prophylaxis can be employed.

1. Salicylates Aspirin (acetylsalicylic acid) and the nonacetylated salicylates are used primarily for their antiinflammatory and analgesic activities in the treatment of chronic arthritic conditions, in certain soft tissue disorders associated with pain and inflammation, and as analgesics in relief of headaches and other painful conditions. Thus, they are widely used in the elderly population in whom many of these conditions are common (Bjelle 1989). Aspirin and other salicylates are widely available with and without prescription in a variety of preparations including buffered, buffered suspension, enteric-

coated and sustained release aspmn; as sodium salicylate, choline salicylate, and salsalate (salicylic salicylate), along with newer derivatives, such as aloxiprin, benorilate and diflunisal. Acute and chronic intoxication from aspirin and salicylate preparations are common, with the acute form occurring most often in children. By contrast, in older patients the most common form is chronic intoxication. The presentation of salicylate intoxication in the elderly patient often mimics other disease states, resulting in delay in making the correct diagnosis which can lead to increased mortality in this age group (Chapman & Proudfoot 1989 1989; Litovitz et al. 1990; McGuigan 1986, 1987).

Drugs & Aging 2 (1) 1992

22

Case reports indicate that the elderly seldom have a history of intentional drug overdose or prior psychiatric disorders, the majority becoming intoxicated accidentally through inadvertent misuse of both prescription and nonprescription salicylates (Anderson et al. 1976; Bailey & Jones 1988). Concurrent administration of other drugs that can affect salicylate kinetics or protein binding may also precipitate toxicity. Age-related changes in renal function (Rowe et al. 1976) can reduce the urinary excretion of salicylates and their metabolites. With aging, the Michaelis-Menten kinetics of salicylates are altered (Ho et al. 1985; Levy & Tsuchiya 1972a; Levy et al. 1972). Thus, because of reduced elimination of salicylic acid and its metabolites, the elderlyare predisposed to toxicity.

2. Pharmacokinetics 2.1 Absorption Following oral administration, the absorption kinetics of salicylate in humans follow a first-order process, with 68% of the aspirin dose reaching the systemic circulation unhydrolysed (Rowland et al. 1972). Plasma concentrations of aspirin rise rapidly following absorption, with peak concentrations occurring approximately 25 minutes after ingestion of soluble aspirin preparations (Morgan & Truitt 1965; Rowland et al. 1972). Absorption of enteric-coated preparations is slower, with peak concentrations occurring 4 to 6 hours after ingestion (Ross-Lee et al. 1982). Aspirin is rapidly hydrolysed to salicylic acid in the intestine wall and the liver, with a short elimination half-life of 15 to 20 minutes (Rowland & Riegelman 1968), corresponding to the increase of plasma salicylic acid concentrations (Netter et al. 1985). It should be noted that cutaneous absorption occurs from salicylate-containing rubefacients (Davidson 1971), and can be increased by up to 300% during exercise or on exposure to heat (Danon et al. 1986). Following oral administration, absorption of salicylate occurs rapidly by passive diffusion from the stomach (Hogden et al. 1957; Rowland et al. 1972), jejunum and ileum (Hogden et al. 1959;

Schanker et al. 1958). Rectal absorption of salicylate is also possible. Several studies (Castleden et al. 1977; Cuny et al. 1979; Montgomery et al. 1986; Salem & Stevenson 1977) did not show any significant differences between young and elderly subjects in the rate of absorption of salicylate. The main determinant of the rate of aspirin and salicylic acid absorption is the formulation of the drug itself(Martin 1971; Volans 1974). The bioavailability of oral aspirin is similar' in young and elderly volunteers (Greenblatt et al. 1986). 2.2 Distribution Salicylates are widely distributed throughout body fluids. The apparent volume of distribution (Vd) of salicylic acid is concentration-dependent, and ranges from 9.6 to 12.7L in adults (Graham et al. 1977). Some studies showed an increase in Vd and a slower rate of elimination in the elderly (Cuny et al. 1979; Roberts et al. 1983). More recent studies, however, did not show any significant differences in Vd for total drug (Greenblatt et al. 1986; Ho et al. 1985), but a decrease in the Vd for free salicylates in elderly subjects (Greenblatt et al. 1986). Thus, it does not appear that aging inevitably alters the distribution of salicylate. In patients with low serum albumin concentrations the Vd is increased (Ho et al. 1985). 2.3 Protein Binding Salicylic acid is primarily bound to serum albumin (Reynolds & Cluff 1960). It is 80 to 90% bound at therapeutic plasma concentrations (1.1 to 2.2 mmolfL) [Wanwimolruk et al. 1982]. With increasing total plasma salicylate concentrations, the free (non-protein-bound) fraction increases; this effect may be more pronounced with age (Lesko et al. 1985). High protein binding increases the probability of drug displacement interactions with concomitant administration of other highly proteinbound agents such as oral anticoagulants or oral hypoglycaemic agents (table I). The clinical importance of such protein-binding displacement in-

23

Salicylate Intoxication in the Elderly

teractions, although widely mentioned, has not been clearly established, and in reality may differ from theoretical predictions (Seelin et al. 1980). 2.4 Metabolism Aspirin is hydrolysed by nonspecific esterases to salicylic acid in gastric and intestinal mucosa, liver, plasma and other body tissues. Sex, age and disease-state differences in aspirin hydrolysis were noted in some (Gupta & Gupta 1977; Ho et al. 1985; Menguy et al. 1972; Tmavska & Tmavsky 1983; Windorfer et al. 1974), but not all (Rainsford et al. 1980; Roberts et al. 1983; Williams 1985; Williams et al. 1989) studies. Approximately 5% of the aspirin dose is excreted unchanged by the kidney. Metabolism of salicylate is complex, involving both conjugation and oxidative reactions (fig. 1). Salicylic acid is conjugated with glycine to form salicyluric acid, and with glucuronic acid to form salicyl phenolic glucuronide; these 2 metabolic pathways are saturable and follow Michaelis-Menten kinetics (Levy & Tsuchiya 1972a; Levy et al. 1972). Thus, Paulus et al. (1971) demonstrated that increasing the aspirin dose from 60 to 100 mgfkgj day raised the plasma salicylate concentration by 300%. Conjugation of salicylic acid with glucuronic acid also yields salicyl acyl glucuronide, and microsomal oxidation of salicylic acid yields gentisuric acid (Levy et al. 1972). Approximately 14% of salicylic acid is excreted unchanged in the urine (Levy et al. 1972). Salicylate can also induce its own metabolism by increasing the synthesis of salicyluric acid (Bochner et al. 1987; Day et al. 1983; Furst et al. 1979; Rumble et al. 1980). There is little alteration in the pharmacokinetics of acetylsalicylic acid with age (Ho et al. 1985; Roberts 1983). However, the effect of age on elimination of salicylate is controversial with disagreement between studies, probably due to differences in subject selection, dose of drug, sample size and study conditions. There was decreased clearance of salicylate in elderly patients compared to young subjects in some (Cuny et al. 1979; Stevenson et al. 1979) but not all (Ho et al.

1985) studies. An important cause of variability may be the degree of frailty in the elderly patients as suggested by Netter et al. (1985) in which there was no overall effect of age on salicylatic clearance but the free concentrations of salicylate were elevated in a subgroup of frail, bedridden elderly patients. In healthy subjects, Montgomery et al. (1986) showed that total salicylate clearance was not affected by age. On the other hand, free salicylate was decreased in healthy elderly subjects in a study by Greenblatt et al. (1986), but not in that of Roberts et al. (1983). There is, therefore, no clear consensus regarding the effect of age on salicylate pharmacokinetics. Based on these data it appears prudent to use conservative doses of aspirin, most particularly in frail older patients. 2.5 Excretion Following metabolism of salicylate in the liver, the metabolites are excreted by the kidneys. The proportion of salicylate directly excreted by the kidney is less than 10%. Because of decreased renal function that occurs with aging (Rowe et al. 1976), excretion of salicylate and metabolites is diminished (Ho et al. 1985). At high doses, with saturation of metabolism, the proportion of drug excreted as salicylate is increased, which may lead to accumulation of salicylic acid in the plasma in the elderly, particularly those with compromised renal function.

3. Pharmacodynamics Salicylates, aspirin as well as other nonsteroidal anti-inflammatory drugs (NSAIDs), inhibit cyclooxygenase, which converts arachidonic acid to prostaglandins E2 and F2 (Vane 1971), thromboxane A2 (Pedersen & FitzGerald 1984), and prostacyclin. There have been no studies that demonstrate age difference as a factor in the susceptibility of cyclooxygenase to salicylates. Aspirin and salicylates are weakly acidic with pKa (the pH at which 50% of the drug is ionised) of 3 to 5. This has some functional significance, since these drugs will con-

Drugs & Aging 2 (1) 1992

24

Hepatic metabolism

Renal excretion

Conjugation with glucuronic acid

Conjugation with glucuronic acid

Michaelis-Menten kinetics

Conjugation with glycine

--+ Flrst-order kinetics

-+ Microsomal oxidation

Fig. 1. Metabolism of aspirin and salicylates (after Needs & Brookes 1985). The numbers in parentheses indicate percentage of drug as individual metabolites following ingestion of a 3g dose of aspirin (Levy et al. 1972). Key: ASA = aspirin; GA = gentisic acid; GU = gentisuric acid; SA = salicylic acid; SAG = salicyl acyl glucuronide; SPG = salicyl phenolic glucuronide; SU = salicyluric acid.

centrate in relatively acid fluids such as in inflamed joints, gastric mucosa and the renal medulla. The onset of analgesic effects generally occurs within I hour, and time to peak serum concentration ranges from 0.5 to 5 hours. The anti-inflammatory effects may not be apparent for I to 2 weeks, and time to maximum effect varies from I to 4 weeks. There is no evidence that these actions are affected by aging.

4. Systemic Toxicity 4.1 Acute Intoxication Acute salicylate intoxication usually poses few diagnostic problems. The lethal acute dose in adults is approximately 20 to 25g. When ingested in such amounts, as occurs in suicide attempts, salicylate directly stimulates the respiratory centre (probably

due to local uncoupling of oxidative phosphorylation in the brainstem), resulting in increased depth and frequency of respiration with respiratory alkalosis. As a compensatory mechanism, there is increased urinary excretion of bicarbonate, sodium, potassium and water, leading to dehydration and hypokalaemia. The loss of bicarbonate decreases the buffering capacity of the body, leading to development of metabolic acidosis, which is exacerbated by the presence of salicylic acid itself (Henry & Volans 1984). Salicylic acid interferes with carbohydrate, protein and lipid metabolism, leading to increased plasma lactic and pyruvic acid levels, further compounding the metabolic acidosis. Hypoglycaemia also occurs. Uncoupling of oxidative phosphorylation results in dissipation of energy as heat, leading to hyperpyrexia, diaphoresis and further dehydration. Left untreated, severe

Salicylate Intoxication in the Elderly

toxicity progresses to coma and eventually death (Segar & Holliday 1958; Temple 1981).

4.2 Chronic Intoxication

Chronic salicylate intoxication usually occurs in older persons (Anderson et al. 1976; Bailey & Jones 1990; Grigor et al. 1987), typically while ingesting therapeutic doses of salicylates; e.g. 1.5 to 3 g/day. Consuming excessive salicylates unknowingly in rubifacient topical preparations such as oil of wintergreen (methyl salicylate) can also cause toxicity. It is rarely due to intentional overdose. The elderly may rarely volunteer a history of salicylate use, unless specifically asked; many older patients are unaware that several over-the-counter (OTC) oral analgesic preparations or analgesic balms contain aspirin or salicylates. Elderly patients who see more than I physician may be prescribed several salicylate-containing drugs. Polypharmacy is common in older patients with several coexisting chronic diseases, and concomitant drugs can interfere with salicylate metabolism, protein binding or excretion (table I), contributing to toxicity. In comparison to younger patients, the diagnosis of salicylate intoxication in older persons is often delayed for up to 72 hours following hospitalisation (Anderson et al. 1976). Such delay is often associated with increased mortality (Anderson et al. 1976; Chapman & Proudfoot 1989; McGuigan 1986, 1987). Presenting symptoms of chronic salicylate intoxication are protean, suggesting other diagnoses. Neurological problems, such as confusion, delirium, agitation, hyperactivity, restlessness and movement disorders tend to predominate. Stupor, hallucinations, papilloedema and dysarthria are also noted (Greer et al. 1965). Additionally, tachypnoea, dyspnoea, tachycardia, ventricular arrhythmias, pulmonary oedema, cerebral oedema, renal failure, hypoglycaemia, hypovolaemia, congestive heart failure (Anderson et al. 1976; Greer et al. 1965; Segar & Holliday 1958) or hearing loss (Mongan et al. 1973) may be also observed.

25

4.3 Diagnosis of Salicylate Intoxication Acute salicylate intoxication in adults is relatively simple to diagnose. There is seldom a loss of consciousness initially. Patients often complain of gastrointestinal distress, nausea and tinnitus. Commonly, patients hyperventilate, and give a history of aspirin or salicylate ingestion. Neurological features such as confusion, delirium and coma signify severe intoxication. The diagnosis of aspirin or salicylate intoxication is readily confirmed by measuring plasma salicylate concentration. As a screening test, 10% ferric chloride (Brenner & Simon 1982), or the Phenistix® reagent strips can indicate the presence of salicylates in the urine (Done 1978). The diagnosis of chronic intoxication is, however, often difficult. In most cases the presenting symptoms point to other diagnostic possibilities (Anderson et al. 1976; Bailey & Jones 1989; Greer et al. 1965). Although disturbances in the acid-base balance are common, up to 35% of patients can have normal total serum carbon dioxide level, and normal serum anion gap (Bailey & Jones 1989). Age-related decline in hearing acuity prevents many elderly from appreciating tinnitus associated with elevated plasma salicylate concentrations (Mongan et al. 1973), which is often used as an aid in the titration of salicylate dose. However, one study showed an increased incidence of tinnitus in rheumatoid arthritis patients over 65 years compared to younger counterparts, despite taking smaller doses of aspirin (Grigor et al. 1987). The diagnosis of chronic salicylate intoxication should be kept in mind whenever there is a rapid and unexplained onset of delirium or confusion, or when previously independent elderly individuals quickly become unable to care for themselves. The possibility of salicylate intoxication should be included in the differential diagnosis when an elderly patient presents with symptoms similar to ethanol intoxication, diabetic ketoacidosis, pulmonary oedema, with cardiac arrhythmias or has unexplained acid-base disturbances.

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Drugs & Aging 2 (1) 1992

Table I. Aspirin and salicylate drug interactions (after Miners 1989) Drug

Effect

Comment

Reference

Acetazolamide

Protein binding displacement and inhibition of renal tubular secretion of acetazolamide,

t Risk of salicylate toxicity at

Anderson et al. (1978). Sweeney et al. (1986)

anti-inflammatory doses, unlikely at low doses

t f u of both drugs Activated charcoal

~ Absorption of salicylate

Antacids (oral)

Alkalinisation of urine; renal excretion of salicylates

Anticoagulants (oral)

/3-Blockers Caffeine Captopril

t

t Rate of absorption and t C max of salicylates Salicylate-induced inhibition of platelet function, possible protein binding displacement of anticoagulants ~ Antihypertensive effect t C max, t AUC

of salicylate ~ Antihypertensive effect ~ Renal prostaglandin synthesis

Cholestyramine

t t max

Cimetidine

Possible ~ C max, t tv. of salicylate; possible inhibition of metabolism ~ C" of salicylate; induction of metabolism

Corticosteroids

of salicylate by 200%

Diflunisal

~ C"

Dichlorphenamide

Protein displacement of salicylate

Dipyridamole

t C max, t AUC,

of diflunisal

Fenoprofen

probable esterase inhibitor t Potential for GI bleeding C max , esterase inhibitor t CL, ~ tv. of fenoprofen

Flurbiprofen

t CL,

Ethanol

t

Gold Heparin sodium

Ibuprofen

protein binding displacement of flurbiprofen t Risk of hepatotoxicity Salicylate-induced platelet inhibition

~

CSs, protein binding

displacement of ibuprofen

Useful in the treatment of acute intoxication Serum concentrations can change with marked alteration in antacid dose More rapid onset of action (of minor clinical significance) Risk of haemorrhage. Concurrent use not recommended

Levy & Tsuchiya (1972b), Neuvonen et al. (1978) Hansten & Hayton (1980), Levy (1979)

Of minor clinical significance Of minor clinical significance Monitor blood pressure and renal function Avoid concurrent use, or separate dosing by 3 to 4 hours Of minor clinical significance

Chalmers & West (1984) Yoovathaworn et al. (1986) Moore et al. (1981)

t Risk of GI bleeding. Higher

Baer et al. (1987), Graham et al. (1977), Klinenberg & Miller (1965) Schultz et al. (1979)

t

aspirin doses may be needed to achieve therapeutic levels Concurrent use not recommended t Risk of salicylate intoxication, concurrent use not recommended Of minor clinical significance Concurrent use not recommended Concurrent use not recommended Concurrent use not recommended Monitor liver function t Risk of haemorrhage; concurrent use not recommended, consider alternative analgesic Concurrent use not recommended

Leonards & Levy (1969), Mason & Winer (1981,1983) Donaldson et al. (1982)

Hahn et al. (1972) Trnavska et al. (1985)

Cowan et al. (1984)

Nitelius et al. (1985) Deykin et al. (1982), Roine et al. (1990) Rubin et al. (1973) Brooks & Khong (1977) Davis et al. (1977) Heiden et al. (1981)

Grennan et al. (1979)

27

Salicylate Intoxication in the Elderly

Table I. contd

Drug

Effect

Comment

Reference

Indomethacin

+Absorption, +resorption, +CL, t biliary clearance of

Concurrent use not recommended

Kwan et at (1978)

Isoxicam

t CL, protein binding

Concurrent use not recommended Concurrent use not recommended Monitor concentrations of both drugs, and liver function

Esqulval et al. (1984), Grace et at (1986) Williams et al. (1981)

Of minor clinical significance

Ross-Lee et at (1983), Volans (1975)

Minor Clinical significance Concurrent use not recommended t Potential for hypoglycaemia, monitor blood glucose

Spahn et al. (1986) Furst et at (1987), Segre et al. (1974) Wishinsky et al. (1962), Richardson et al. (1986)

t Potential for salicylate toxicity.

Bluestone et al. (1969)

indomethacin

Ketoprofen Methotrexate

Metoclopramide

Metoprolol Naproxen Oral hypoglycaemic agents

Probenecid

Salicylamide Sulfinpyrazone Tolmetin Valproic acid

displacement of isoxicam t CL, protein binding displacement of ketoprofen Inhibition of renal tubular excretion of methotrexate. Protein binding displacement of methotrexate t Gastric emptying, +staSis, earlier absorption, t Cmax of salicylate t Cmax of salicylate Protein binding displacement; t CL of naproxen Protein binding displacement, and +CLR of hypoglycaemic drugs; hypoglycaemic property of salicylates +Uricosuric action with low salicylate doses; inhibition of CLR of salicylate Mutual inhibition of glucuronidation +Uricosuric action with low salicylate doses Protein binding diplacement, t CL of tolmetin Protein binding displacement, inhibition of metabolism concentrations, increased urinary clearance of valproate

Monitor plasma uric acid and salicylate concentrations t Potential for toxicity Avoid concurrent use Concurrent use not recommended Concurrent use not recommended Monitor valproic acid concentrations. Use alternative analgesic

Aherne et at (1978), Liegler et at (1969)

Levy & Procknal (1968) Oyer et at (1966) Cressman et al. (1976) Abbott et al. (1986), Orr et al. (1982)

Abbreviations and symbols: t = increased; + = decreased; Cmax = peak plasma drug concentration; tmax = time to peak plasma area under the plasma concentration-time curve; Css plasma drug concentration at steady-state; drug concentration; AUC CL = plasma clearance of the total drug; CLR = renal clearance of the drug from plasma; fu = unbound fraction of drug in plasma; tv. = terminal half-life of the drug.

=

4.4 Treatment Initially attention should be paid to ventilatory and circulatory support. Salicylates delay gastric emptying, and the drug may accumulate in the stomach. If the drug is not evacuated it will continue to be absorbed, particularly after ingestion of sustained release tablets (Todd et al. 1981) where

=

the absorption can continue for several hours, with the peak concentrations occurring in 24 to 50 hours (Brooks et al. 1978). Following emesis or lavage, activated charcoal should be administered with a cathartic to prevent the development of intestinal obstruction with charcoal (Watson et al. 1986). Multiple doses of activated charcoal do not contribute greatly to further salicylate excretion (Kir-

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Drugs & Aging 2 (I) 1992

shenbaum et al. 1990). Dialysis is very effective in the treatment of massive salicylate overdose (Winchester et al. 1981). No specific antidotes are available for salicylate intoxication; the objectives should be to correct any electrolyte, fluid or metabolic imbalance, hypotension, hypoventilation and augment salicylate excretion (Proudfoot 1983). Administration of sodium bicarbonate (1 to 2 mEqJkg), to maintain the urinary pH level at pH 8 or greater (but with careful attention to avoid fluid overload) increases urinary drug excretion. A more detailed discussion of the management of salicylate intoxication has been published in a previous issue of this journal (Klein-Schwartz & Oderda 1991).

5. Organ Toxicity 5.1 Gastric Roth (1986) introduced the term NSAID gastropathy, referring to a range of peptic lesions which are associated with long term aspirin, salicylate or other NSAID therapy. Aspirin and other NSAIDs are associated with ulceration and erosions, predominantly in the antral and prepyloric regions of the stomach and particularly in the older population (Graham & Smith 1986; Griffin et al. 1988, 1991; Roth & Bennett 1987). NSAID-induced peptic lesions are associated with significant blood loss in the elderly. The blood loss may be less pronounced with use of some forms of salicylates such as choline salicylate (Pierson et al. 1961) and salsalate (Mielants et al. 1981), while it may be more pronounced with choline magnesium trisalicylate than aspirin (Mitchell et al. 1984). The blood loss of NSAID gastropathy is associated with significant morbidity and mortality. Haemorrhage or perforation related to NSAID therapy is correlated with the age of the patient (Johnson & Day 1991a). The probability of a fatal event from bleeding or perforated gastric ulcer is increased 300% for those aged over 70 years in comparison with those under 50 (Armstrong & Blower 1987). The high prevalence of NSAID gastropathy has led the United States Food and Drug

Administration to revise the labelling of all NSAIDs sold in the US to reflect concern about the gastrointestinal side effects seen with the long term use of these drugs (Department of Health and Human Services 1989). With continued salicylate ingestion, gastric lesions are resistant to traditional therapy, such as the H2-antagonist cimetidine aimed at resolution of peptic ulcer disease (Jaszewski et al. 1989; McCarthy 1989; O'Laughlin et al. 1981; Roth et al. 1987). The synthetic prostaglandin El analogue misoprostol can prevent most NSAID-induced gastric lesions (Graham et al. 1988; Jiranek et al. 1989). However, the cost-effectiveness of wide scale prophylaxis has been questioned (Edelson et al. 1990), with the recommendation that it should be limited to patients with a proven history of gastrointestinal tract haemorrhage. The use of enteric-coated aspirin has been associated with the formation of an aspirin bezoar, which can lead to gastric outlet obstruction (Baum 1984; Bogacz & Caldron 1987; Sogge et al. 1977) or perforation (Farrand et al. 1975). 5.2 Small and Large Bowel Small bowel ulcerations have been associated with the use of enteric-coated salicylates (Lima 1985), which can lead to small or large bowel perforation and haemorrhage (Langman et al. 1985). Problems involving the lower gastrointestinal tract, including severe diarrhoea and/or bleeding, are reported occasionally. Such patients need to be evaluated for tumour or occult inflammatory bowel disease. 5.3 Hepatic Liver injury secondary to salicylates is generally asymptomatic, or is accompanied by mild nonspecific symptoms, and is diagnosed as a result of abnormal laboratory results (Benson 1982; Zimmerman 1982). Most patients remain anicteric. Progressive liver disease (Okamura et al. 1965) or fatal hepatic necrosis (Koff & Galdabini 1977) may develop in approximately 4% of patients with el-

29

Salicylate Intoxication in the Elderly

evated liver enzymes, including aspartate transaminase (AST) and alanine transaminase (ALT). The elderly, and patients with connective tissue disorders such as rheumatoid arthritis and systemic lupus erythematosus, appear to be at increased risk for development of hepatocellular disease (Inacu 1972; Russell et al. 1971; Seaman & Plotz 1976). 5.4 Renal Reversible impairment in renal function has been associated with aspirin and salicylate use (Berg 1977; Burry & Dieppe 1976). In certain disease states such as congestive heart failure, renal artery stenosis, chronic renal failure (Abraham & Stillman 1987), hypotension and ureteral obstruction, maintenance of renal perfusion is dependent on increased local synthesis of prostaglandins (Morrison et al. 1977; Wilson et al. 1973). Prostaglandins E2 and 12 dilate renal arterioles and stimulate renin release. Blocking prostaglandin synthesis by salicylates may thus predispose the vulnerable patient to development of renal insufficiency. Other known risk factors for developing renal insufficiency while using NSAIDs include advanced age, particularly the seventh decade, presence of cardiovascular disease, and the concurrent use of a diuretic (Blackshear et al. 1983; Gurwitz et al. 1990). Case reports indicate that salicylate therapy has also been associated with minimal change nephrotic syndrome (Vales & Tovar 1987), tubulointerstitial toxicity, acute tubular necrosis and acute interstitial nephritis in the elderly (Nanra 1983). 5.5 Pulmonary Noncardiogenic pulmonary oedema due to salicylate intoxication (Heffner & Sahn 1981; Leatherman & Drage 1982; Walters et al. 1983) is described mainly in those over 50 years of age, who are more likely to be ingesting salicylates on a long term basis. These individuals frequently have a history of smoking and often present with neurological symptoms such as lethargy or confusion (Hefner & Sahn 1981; Walters et al. 1983). The

pathogenesis of pulmonary oedema probably results from increased vascular permeability to fluid and protein, without significantly affecting the pulmonary artery pressure. The magnitude of pulmonary oedema does not correlate with the aspirin dose (Bowers et al. 1977). 5.6 Neurological Neurological disturbances such as confusion, tinnitus, dizziness, transient myopia, lethargy, delirium and seizures occur predominantly in elderly patients (Anderson et al. 1976; Bailey & Jones 1989), and may be due in part to reduced brain glucose metabolism (Hill 1973; Thurston et al. 1970). These symptoms of salicylate toxicity are more common in elderly patients with metabolic acidosis than those without (Gabow et al. 1978; Proudfoot & Brown 1969). Abnormalities in the electroencephalogram (EEG) have been noted following an acute dose of 1.95g aspirin (Fink & Irwin 1982), and also with chronic intoxication (Brown & Wilson 1971). 5.7 Endocrine Salicylates possess hypoglycaemic activity. Inhibition of Krebs' cycle dehydrogenases and uncoupling of oxidative phosphorylation leads to increased glycolysis for energy production. Decreased gluconeogenesis and depletion of glycogen occur, which in the face of increased glucose demands leads to hypoglycaemia (Raschke et al. 1991). Salicylates also enhance insulin secretion (Baron 1982). Salicylate intoxication has been shown to be responsible for the development of hypoglycaemia and ketoacidosis in nondiabetic elderly patients (Arena et al. 1978; Reid et al. 1957). Salicylates can also potentiate the effect of oral hypoglycaemic agents such as chlorpropamide (Richardson et al. 1986) and tolbutamide (Cherner et al. 1963) [table I].

6. Drug Interactions Many elderly individuals have several coexisting disease states, requiring multiple drug regimens, predisposing them to potential adverse drug-

Drugs & Aging 2 (1) 1992

30

drug interactions (Nolan & O'Malley 1989). Numerous drug interactions occur between aspirin or other salicylates and other drugs, some of which can be predicted on the basis of the pharmacology of the drugs (Johnson & Day 1991b). For example, salicylates decrease platelet aggregation and can thereby enhance the potential for serious haemorrhage in patients taking oral anticoagulants or with hereditary disorders of haemostasis. Other drug interactions have been reported (Miners 1989), and the most common and clinically important are summarised in table I.

7. Prevention

0/ Salicylate Intoxication

The prevalence of arthritic conditions increases with age (Bjelle 1989) necessitating the frequent use of salicylates or other NSAIDs. Based on the description of metabolism and the pharmacokinetics of salicylates in the elderly, several precautions can be taken to reduce the risk of toxicity. If anti-inflammatory treatment is required in older patients it is prudent to use other NSAIDs with lower systemic toxicity. If salicylates are chosen, conservative doses (50 to 70% of usual adult dose) should be used, drawing attention to the risks of chronic toxicity. Salicylate doses should be reduced further in patients with other disorders that can lead to increased plasma drug concentrations, including impaired renal function and hepatic disease. Because toxicity can present in a subtle fashion, therapeutic drug monitoring should be employed to ensure that plasma concentrations remain well below toxic concentrations bearing in mind that in older patients receiving long term treatment significant toxicity can occur with plasma concentrations that are minimally elevated. The absence of tinnitus does not preclude salicylate intoxication in older patients (Mongan et al. 1973). Careful attention should be paid to the possibility of potential drug-drug interactions. Many elderly individuals take more than 1 drug, or see several physicians who may prescribe potentially incompatible drugs. Patients should be questioned regarding current drug use, and about visiting more than 1 physician, so that drug therapy can be co-

ordinated. To minimise the potential for drug-drug interactions, patient education must be the primary goal when prescribing salicylates. Patients should he instructed regarding concomitant use of OTC remedies which may contain salicylates, and to check with their physician regarding use of other drugs while taking therapeutic doses of salicylates. As previously discussed, salicylates can impair renal function in older patients, especially those with additional risk factors such as chronic renal insufficiency or widespread vascular disease. Because of decreased renal excretion of salicylate this can result in increased plasma concentration and potential salicylate intoxication. Furthermore, if significant uraemia with acidosis occurs, this leads to free un-ionised salicylate which can cross into cells more readily, leading to an increased volume of distribution and significant toxicity despite modest changes in total plasma concentration (Raschke et al. 1991). Since these metabolic changes are likely to develop early in the course of maintenance therapy, it is advisable to check renal function and salicylate concentrations in the first week of therapy. Rarely, the use of salicylates or NSAIDs leads to the development of hepatocellular damage. However, this process is clinically silent and can only be detected early by laboratory testing. Periodic evaluation of AST and ALT may identify those individuals at risk of liver damage, and if no other cause for elevation is found the drug should be stopped. The greatest morbidity and mortality results from salicylate-induced peptic lesions. Many elderly do not display symptoms of peptic disease, and the presentation of perforation or haemorrhage may be atypical (Cooper et al. 1988; Wroblewski & Ostberg 1990). Blood loss from gastropathy can be significant; in particular, older patients should be monitored frequently for occult faecal blood loss during salicylate therapy and haemoglobin levels should be checked on a periodic basis to detect the development of anaemia. The costeffectiveness of this approach has not been studied. In patients with a history of upper gastrointestinal haemorrhage, misoprostol, although expensive,

Salicylate Intoxication in the Elderly

should be used for prophylaxis if they are prescribed aspirin or other NSAIDs. In patients with such history, it is better to avoid aspirin and other NSAIDs if possible.

8. Conclusion Aspirin has been in use for over a hundred years, and it remains a standard against which all new NSAIDs are compared. Salicylates are inexpensive, particularly in nonprescription form, and remain relatively effective drugs for the treatment of pain syndromes and arthritic conditions that are so common in old age. For these reasons, they are still very widely used in elderly patients. However, older patients are at increased risk of chronic salicylate toxicity, gastrointestinal ulcer disease (with complications of perforation and haemorrhage), and renal impairment. Salicylates need to be used cautiously in older individuals; this means monitoring plasma drug concentrations, renal function and checking for gastrointestinal haemorrhage. Despite the expense of such monitoring, these drugs remain competitive in cost compared with newer NSAIDs. They remain a reasonable choice in long term therapy in the elderly provided they are carefully used.

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Correspondence and reprints: Dr Barry J. Cusack. VA Medical Center (III), Boise. ID 83702-4598. USA.