Drugs 30: 32-41 (1985)

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Interactions of NSAIDs with Diuretics and fj-Blockers Mechanisms and Clinical Implications

J. Webster Department of Therapeutics and Clinical Pharmacology, University of Aberdeen, Aberdeen

Summary Indomethacin attenuates the antihypertensi~'e effect 0/ both thiazide diuretics and ;J­adrenoceptor blocking drugs. The mechanisms o/these interactions are poorly understood but sodium and water retention. suppression 0/ plasma renin activity. alterations in adrenoceptor sensitivity and impaired synthesis 0/ vasodilator prostaglandins may all con­tribute to this effect. Other non-steroidal anti-inflammatory drugs (NSAIDs) may share this property of indomethacin but sulindac. which is a selective inhibitor of extrarenal prostaglandin synthesis. appears not to. This may have important clinical and theoretical implications. Clinicians must beware o/this potential interaction in any patient receiving treatment for hypertension.

NSAIDs may also inhibit the natriuretic response to diuretics with resultant adverse effects in patients with heart failure and other forms 0/ oedema. NSAIDs may also have adverse nephrotoxic effects which may be exacerbated by diuretic therapy.

The non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed and are commonly implicated in adverse drug reactions. These range from mild, nonspecific symptoms such as dizziness and indigestion to fatal complications such as thrombocytopenia and gastrointestinal haemor­rhage. Increasing awareness of such adverse reac­tions and the identification of new and unpredict­able toxicity have contributed in recent years to the imposition of restrictions by various regulatory authorities on the use of NSAIDs such as benoxa­profen, sustained-release indomethacin, indopro­fen, zomepirac, phenylbutazone and oxyphenbut­azone. In contrast, ibuprofen is now available without prescription in both the United Kingdom and the United States, having been considered by both the Committee for Safety of Medicines (CSM) and the Food and Drug Administration (FDA) to

have shown acceptable toxicity over many years of clinical use.

In spite of the recent publicity over the adverse effects of NSAIDs, their propensity to interact ad­versely with other drugs is not fully appreciated. Such interactions may not be as dramatic or Iife­threatening as the jaundice produced by benoxa­profen or the aplastic anaemias produced by phenylbutazone, but may be much more common than is generally recognised, reflecting the vast numbers of patients exposed to NSAIDs and other drugs. Another factor contributing to such inter­actions is that many patients requiring NSAIDs are elderly and require concomitant therapy for other diseases.

Many of these interactions are overlooked be­cause they result in loss of effect of existing therapy rather than augmented toxicity.

General Information

NSAID Interactions with Diuretics and fj-B1ockers

1. Interactions 0/ NSAIDs with Diuretics 1.1 Attenuation of Diuretic Action

The first observation that NSAIDs may interact with diuretics was made in 1962 when aspirin was shown to antagonise the action of spironolactone (Elliott, 1962). Since then, a number of reports have indicated that NSAIDs may antagonise the actions of , loop' diuretics, thiazides and potassium-sparing diuretics.

1.1.1 Mechanisms The interaction between NSAIDs and diuretics

is influenced by patient factors such as age, renal disease and cardiac failure, and by drug factors such as dose, duration of administration and pharma­cological profile. As a result, it can be difficult to attribute the interaction to one particular mech­anism. Many NSAIDs cause sodium and water re­tention, especially phenylbutazone and indometh­acin, and this tends to negate the action of diuretics in a global fashion. Possible mechanisms include pharmacokinetic interactions, effects on renal tu­bular handling of salt and water, and alterations in prostaglandin-mediated renal haemodynamics. These may coexist or may vary according to the type of diuretic used.

The interference by NSAIDs, especially indo­methacin, with the natriuretic effects of frusemide (furosemide) has been confirmed in several studies (Data et aI., 1978; Patak et aI., 1975), although the dose and duration of drug administration may be critical (Brater, 1979; Scherer and Weber, 1979). In an elegant study by Chennavasin et al. (1980) it was shown that indomethacin altered the disposi­tion of frusemide in man. Renal clearance of fru­semide was reduced, but so also was non-renal clearance. The delivery of frusemide into the urine and to the tubular sites of action was not altered and the pharmacokinetic changes were not suffi­cient to explain the impaired natriuretic response to frusemide. Indomethacin shifted the serum con­centration-response curve of frusemide to the right, while the urinary frusemide excretion-response curve was not altered. The maximum responses in both cases were decreased, indicating a non-com-

33

petitive pharmacodynamic inhibition of frusemide effects.

Several investigations have shown that activa­tion of renal prostaglandin synthesis accompanies the natriuresis induced by loop diuretics and it seems likely that prostaglandins such as PGE2 and PGI2 (prostacyclin) mediate both the natriuresis and the increase in renal blood flow produced by such drugs (Attallah, 1979; Ciabattoni et aI., 1979). Nonspecific inhibitors of cyclo-oxygenase, such as indomethacin, block the activation of renal pros­taglandins and attenuate the response to diuretics such as frusemide (Mackay et aI., 1984). Sulindac is a selective inhibitor of extrarenal cyclo-oxygen­ase (Ciabattoni et aI., 1980) and does not inhibit the natriuretic response to frusemide. This sup­ports the hypothesis of a pharmacodynamic inter­action based on inhibition of renal prostaglandin synthesis.

Degree of Inhibition in Relation to Site of Action Diuretics acting at different sites along the renal

tubule may differ in the degree to which their ac­tions may be attenuated by NSAIDs (Favre et aI., 1983). The original observation that aspirin blocks the natriuresis induced by spironolactone (Elliott, 1962) has been confirmed by Tweeddale and Ogil­vie (1973) who showed that a single 600mg dose of aspirin produced a profound inhibition of the natriuretic response to spironolactone in subjects receiving fludrocortisone. Both indomethacin and diflunisal have been shown to inhibit the natri­uretic response to spironolactone in normal volun­teers (Favre et aI., 1983). In a study designed to elucidate the mechanisms of these interactions, Ramsay et aI., (1976) showed that aspirin reduced the fractional urinary excretion of canrenone, the principal unconjugated metabolite of spironolact­one. These authors proposed that the most likely explanation for this pharmacokinetic interaction was competition between aspirin and canrenone for active secretion in the proximal renal tubule. Thus it is possible that both pharmacokinetic and phar­macodynamic factors may contribute to this inter­action.

NSAID Interactions with Diuretics and ,a-Blockers

NSAIDs undoubtedly antagonise the natriuretic effects of 'loop' diuretics (Brater, 1979; Patak et aI., 1975). It has been suggested that prostaglandins also mediate the diuretic action of thiazides (Kramer et aI., 1980), but another study found that inhibition of prostaglandin synthesis by either indomethacin or diflunisal did not alter the natriuretic effect of hydrochlorothiazide (Favre et aI., 1983).

There is no doubt that prostaglandins are im­portant mediators of renin release (Frolich et aI., 1976; Glasson et aI., 1979), and inhibition of renal prostaglandin synthesis appears to inhibit activa­tion of the renin-angiotensin-aldosterone system by all types of diuretic.

1.1.2 Clinical Implications The principal adverse clinical effect of the at­

tenuated natriuretic response to diuretics by NSAIDs is worsening of cardiac failure. Phenyl­butazone has long been recognised as a cause of cardiac decompensation, and both oedema and cardiac failure are contraindications to its use. It is likely that many other NSAIDs interact ad­versely with diuretics in this way, such as ibupro­fen (Yeung Laiwah and Mactier, 1981) and pirox­icam (Fowler and Arnold, 1983), but such interactions may be overlooked or dealt with by increasing the medication used to treat the heart failure. Patients at greatest risk would appear to be the elderly and those with renal insufficiency.

A recent study has thrown some further light on both the underlying mechanisms and clinical sig­nificance of this interaction (Dzau et aI., 1984). These authors found that urinary metabolites of PGE2 and prostacyclin were increased in patients with severe congestive heart failure and that such changes occurred principally in patients with as­sociated hyponatraemia. They postulated that in such patients there is concomitant activation of the renin-angiotensin-aldosterone system - which is predominantly vasoconstrictor - and of the renal prostaglandin system - which is predominantly va­sodilator. Activation of these systems serves to maintain circulatory and renal homeostasis. Dis­turbance of this homeostatic mechanism by inhi­bition of prostaglandin synthesis resulted in

34

haemodynamic deterioration. When indomethacin was given orally either as a single 75mg dose or as four 50mg doses at intervals of 6 hours, patients with cardiac failure and a serum sodium concen­tration under 135 mmol/L showed a significant de­crease in cardiac index, and increases in capillary wedge pressure, mean arterial pressure and sys­temic vascular resistance (fig. I).

Thus, in patients with cardiac failure, NSAIDs may cause deleterious effects by a number of mechanisms, including inhibition of synthesis of vasodilator prostaglandins, interference with natri­uretic mechanisms in the renal medulla (Oliw et aI., 1976), and attenuation of the natriuretic action

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ventricular filling pressure, mean arterial pressure and systemic

vascular resistance before (0) and after (E'J) administration of

indomethacin in 23 patients with heart failure who underwent

haemodynamic evaluation and who were grouped according to

their serum sodium concentration (reproduced with permission

from Dzau et aI., 1984).

NSAID Interactions with Diuretics and tl-Blockers

of diuretics. It is also possible that some NSAIDs may have deleterious effects on coronary perfusion (Friedman et aI., 1981).

In patients with cardiac failure due to ischaemic heart disease, this may adversely affect ventricular function and indirectly reduce the benefit of drugs used to treat the heart failure.

Clinicians should be aware of this important interaction and should exercise great care in the use of NSAIDs in patients with cardiac failure, es­pecially if the failure is severe and associated with hyponatraemia, or if the patient is elderly and has renal impairment.

1.2 Attenuation of Antihypertensive Effect

In spite of the widespread use of thiazide di­uretics as antihypertensive therapy for over 20 years, their mode of action is incompletely under­stood. Extracellular volume depletion and reduced cardiac output occur in the initial phase of treat­ment, whereas after several weeks of treatment cardiac output returns to normal and total peri­pheral resistance falls (Conway and Lauwers, 1960). It had appeared that the ability of the kidneys to excrete sodium was essential to the antihyperten­sive effect of diuretics (Bennett et aI., 1917) but a

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Propranolol Bendrofluazide

35

study in patients with chronic renal failure has raised the possibility of a mechanism independent of sodium loss (Jones and Nanra, 1979).

Direct evidence is lacking of a specific vasodi­lator effect of thiazide diuretics but there is con­siderable evidence in animals that these drugs re­duce vascular reactivity to both angiotensin II (Weinberger et aI., 1972) and noradrenaline (nor­epinephrine) [Eckstein et aI., 1962, 1966]. In man, chlorothiazide reduces both local (Jackson and Duff, 1963) and systemic (Fries el aI., 1960) vas­cular reactivity to noradrenaline, the latter being at least partly reversible by volume replacement.

Indomethacin pretreatment has been noted to attenuate the antihypertensive effects of thiazides (Lopez-Ovejero et aI., 1978; Watkins et al., 1980) [fig. 2]. Some doubt has recently been raised about the clinical importance of this interaction (Koop­manset al., 1984) but even this report demon­strates a transient adverse interaction of indometh­acin with hydrochlorothiazide. Several mechanisms for this interaction have been proposed.

1.2.1 Mechanisms The first possible mechanism is that NSAIDs

may themselves exhibit a pressor effect, negating the relatively mild antihypertensive action of thia-

Erect

Propranolol Bendrofluazide

Fig. 2. Effects on supine and erect blood pressures of adding either indomethacin (~), 100mg daily for 3 weeks, or placebo (0) to

hypertensive patients receiving treatment with bendrofluazide (n = 5) or propranolol (n = 8); * P < 0.05; ** P < 0.01 [reproduced

with permission from Watkins et aI., 1980).

NSAID Interactions with Diuretics and {:1-Blockers

zides. Intravenous indomethacin administration may cause a short-lived rise in blood pressure (Dzau et at., 1984; Nowak and Wennmalm, 1978). In patients with Parkinsonism and postural hypoten­sion, indomethacin reduced forearm blood flow, significantly reduced the fall in blood pressure on standing, and lessened orthostatic symptoms (Abate et at., 1979). However, there is little evidence to suggest that long term oral therapy has a significant pressor effect in normal or hypertensive subjects.

NSAIDs may cause sufficient fluid retention to reverse the volume depletion caused by diuretics. This might more readily explain the reversal of the short term antihypertensive effect of diuretics than the long term effect, when volume depletion is less evident. Nevertheless, this must be considered as a partial explanation, at least, for this interaction.

Another hypothesis is that thiazides may ex­hibit their antihypertensive effect directly on ar­teriolar tone. This would be compatible with the principal net haemodynamic effect of long term thiazide therapy in hypertension, namely a reduc­tion in total peripheral resistance. The possible me­diator of such an effect has aroused speculation but no mechanism has yet been established. Prosta­cyelin is synthesised in blood vessel walls and is a potent vasodilator (Armstrong et at., 1978). It is possible that prostacyclin may be an important en­dogenous mediator of arteriolar tone and a deter­minant of blood pressure. Inhibition of prostacy­clin biosynthesis by NSAIDs might therefore be expected to alter vascular responsiveness and this could explain the loss of effect of thiazides. One recent study suggested that both short term (3 days) and long term (10 weeks) therapy with bendroflu­azide 10mg daily in hypertensive patients were as­sociated with significant increases in plasma con­centrations of 6-keto-PGFlm the principal metabolite of prostacyclin, (Webster et at., 1980). In this study the principal urinary metabolite of PFG2" was also increased by 1 0 weeks of therapy with bendrofluazide. At the time, these results were thought to support the hypothesis that bendroflu­azide may have stimulated the biosynthesis of a vasodilator prostaglandin such as prostacyclin. Since then, however, some doubts have emerged

36

about the validity of the assay used in that study for 6-keto-PGFla in plasma and it now seems cer­tain that prostacyclin does not circulate as a sys­temically active hormone (Blair et at., 1982; Fitz­gerald et at., 1981). Analytical problems continue to plague the'assessment of prostaglandin synthesis in vivo, and the question of whether thiazides stim­ulate the systemic biosynthesis of vasodilator pros­taglandins remains unanswered.

A recent and important development in the understanding of this interaction has been the demonstration that sulindac, unlike indomethacin, may enhance rather than attenuate the antihyper­tensive effects of thiazide diuretics (Steiness and WaldorfT, 1982). As already mentioned, sulindac differs from indomethacin in being a selective in­hibitor of extrarenal prostaglandin biosynthesis (Ciabattoni et at., 1980). This suggests that inhi­bition of renal prostaglandin synthesis may be the key to the interaction between NSAIDs and thia­zides in hypertension.

A series of clinical studies has suggested that in­domethacin attenuates the effect of most anti­hypertensive drugs in a nonspecific way and fur­thermore that other NSAIDs such as aspirin and naproxen do not share this interaction (Chalmers et at., 1983). These results are a little difficult to reconcile with the hypothesis that inhibition of prostaglandin biosynthesis is the principal mech­anism underlying the indomethacin effect.

1.2.2 Clinical Implications Whatever the exact mechanism, the effect of

NSAIDs is an important cause of inadequate blood pressure control in hypertensive patients. Both antihypertensive drugs and NSAIDs are prescribed to such vast numbers of patients that their coad­ministration is likely to be frequent. In a recent analysis of patients followed up in the Aberdeen Hypertension Clinic, 2.5% of all patients had re­ceived an NSAID at some time for coexisting rheu­matic disorders. This is likely to be an underesti­mate.

Patients in whom NSAIDs contribute to severe or refractory hypertension may be uncommon but are relatively easy to identify provided clinicians

NSAID Interactions with Diuretics and ,a-Blockers

are aware of the possible interaction. More difficult to identify are the many patients whose blood pres­sure control is marginally suboptimal but who may escape rigorous clinical audit. Evidence is emerg­ing that the level of blood pressure achieved during follow-up is an important predictor of adverse cardiovascular events (Australian Therapeutic Trial in Mild Hypertension, 1980). Even a partial atten­uation of antihypertensive drug action may ad­versely affect prognosis, and the problem will be overlooked unless clinicians aim to achieve strict 'target pressures'.

All hypertensive patients receiving NSAIDs should have their blood pressure monitored more frequently than usuai. If blood pressure control is unsatisfactory, the NSAID should be stopped. If there is a continuing need for NSAID therapy, then a trial of an alternative drug such as sulindac should be undertaken.

1.3 Nephrotoxicity

It is increasingly recognised that NSAIDs pro­duce a variety of toxic effects on the kidney. The various syndromes of NSAID-associated nephro­toxicity have recently been reviewed by Clive and Stoff (1984).

1.3.1 Mechanisms Water and electrolyte balance may be disturbed

by NSAIDs. Sodium retention and oedema are common, affecting over 10% of patients receiving NSAIDs and contributing to the loss of efficacy of diuretics. Occasionally, severe hyponatraemia may result from inhibition of free water excretion (Walker et ai., 1981). This may occur if there is pre-existing renal impairment (Blum and A viram, 1980) and may be exacerbated if diuretics are co­administered. Hyperkalaemia may also occur (Goldszer et ai., 1981). This might not in itself be a serious disadvantage in patients receiving either a 'loop' diuretic or a thiazide but might be haz­ardous in patients receiving potassium-sparing di­uretics.

A more serious problem is the precipitation of acute renal failure by NSAIDs. It is generally ac-

37

cepted that NSAIDs do not impair renal function in normal subjects but that inhibition of prosta­glandin synthesis may have serious adverse effects on renal function when superimposed on hypo­volaemia, salt depletion, cardiac failure or cirrho­sis. This supports the hypothesis that prostaglan­dins may act to maintain renal homeostasis under adverse conditions.

A recent study has provided further persuasive evidence in support of this hypothesis (Ciabattoni et ai., 1984). In patients with chronic glomerular disease, urinary excretion of 6-keto-PGF la, the sta­ble hydrolysis product of prostacyclin, appeared to be reduced. In these patients ibuprofen, a non-se­lective inhibitor of cyclo-oxygenase, increased serum creatinine and reduced the renal clearance of creatinine and para-aminohippurate. In con­trast, sulindac did not impair renal function, de­spite inhibiting extrarenal cyclo-oxygenase.

1.3.2 Clinical Implications Patients receiving diuretic therapy may be at in­

creased risk of NSAID-induced renal failure. Re­versible acute renal failure occurred in 2 healthy medical students receiving indomethacin and triamterene as part of a research study (Favre et ai., 1982). A similar interaction has not been ob­served with other diuretics but may be more dif­ficult to detect and attribute to drugs in patients with coexisting renal disease.

Great care should be taken to avoid the com­bination of NSAIDs and diuretics in patients with renal disease, cirrhosis or cardiac failure as well as in elderly patients who usually have reduced renal reserve.

2. Interaction 0/ NSAIDs with ~-Blockers 2.1 Attenuation of Antihypertensive Action

Indomethacin has been reported to attenuate the antihypertensive effect of propranolol in man (Du­rao et ai., 1977; Watkins et ai., 1980). A similar interaction has also been observed between indo­methacin and pindolol (Durao et ai., 1977), ox­prenolol (Salvetti et ai., 1982a) and atenolol (Sal­vetti et ai., 1982b). Flurbiprofen attenuates the

NSAID Interactions with Diuretics and ,8-Blockers

antihypertensive response to single doses of pro­pranolol (Webster et aI., 1983). In contrast, other NSAIDs such as sulindac (Salvetti et aI., 1984), na­proxen and aspirin (Chalmers et aI., 1983) appear not to exhibit this interaction.

This interaction is not only of clinical import­ance but also may contribute to an understanding of the mode of action of tJ-blockers in hyperten­sion.

2.1.1 Mechanisms The mechanism by which tJ-blockers lower blood

pressure remains uncertain. Several explanations have been proposed, including negative cardiac inotropic (Donoso et aI., 1967) and chronotropic effects (Dollery et aI., 1969), inhibition of renin re­lease (Birkenhager et aI., 1977; Buhler et aI., 1972; Hollifield et aI., 1976), central nervous system ef­fects (Lewis, 1976) and presynaptic inhibition of neurotransmitter release (Langer, 1976).

Initially, systemic vascular resistance rises after tJ-blockade (Frolich et aI., 1968). During long term tJ-blockade cardiac output remains suppressed (Tarazi and Dunstan, 1972) but the initial effects on peripheral resistance are reversed (Cohn, 1983). The autoregulatory mechanisms underlying this apparent delayed vasodilator response to long term tJ-blockade remain unclear (Guyton et aI., 1974). Largely because of these uncertainties, the mech­anism underlying the interaction between NSAIDs and tJ-blockers is also poorly understood.

The possibility exists that long term use of 1'1-blockers may stimulate the synthesis of vasodilator prostaglandins, such as PGE2 and prostacyclin, that these may mediate some of the haemodynamic ef­fects of long term tJ-blockade, and that inhibitors of prostaglandin synthesis may negate these effects. Such an hypothesis is superificially attractive but fails to explain a number of observations.

Webster et al. (1984) have recently reported that flurbiprofen attenuated the hypotensive effect of single doses of propranolol. This effect was ob­served within 2 hours of oral ingestion of propran­olol. At this stage of treatment the predominant haemodynamic effect is a reduction in cardiac out­put, and total peripheral resistance may be in-

38

creased; furthermore, it was found that the hypo­tensive response to single doses of atenolol was not altered by flurbipTofen. This raised the possibility that atenolol and propranolol might differ at least in their short term antihypertensive mode of ac­tion.

In this study (Webster et aI., 1984) flurbiprofen had no effect on the suppression of post-exercise heart rate by either propranolol or atenolol. Sim­ilarly, indomethacin did not interfere with the in­hibition of exercise-induced tachycardia by meto­prolol (Rolf Smith et aI., 1983). These results suggest that NSAIDs do not interfere with cardiac tJl-adrenoceptors.

It has been suggested that inhibition of prosta­glandin synthesis might result in increased sensi­tivity of a-adrenoceptors (Bartter et aI., 1976; Rubin et aI., 1980). This may be clinically more apparent in the presence of a non-selective tJ-blocker such as propranolol than in the presence of a cardio­selective drug such as atenolol, and might be suf­ficient to offset the delayed vasodilator response to long term propranolol. However, this explanation would not account for the observation of Salvetti et al. (l982b) that indomethacin attenuates the hypotensive effect of atenolol, and the hypothesis remains speculative.

Another possible mechanism for the interaction between NSAIDs and propranolol may lie in the suppression of plasma renin activity that accom­panies administration of NSAIDs. Suppression of plasma renin activity is almost certainly an im­portant, though not exclusive, factor in the anti­hypertensive action of propranolol and certain other tJ-blockers (Harms et aI., 1978). Prior suppression of plasma renin activity might therefore attenuate the antihypertensive response. This hypothesis is certainly plausible, and may explain the interac­tion in some subjects.

In other studies, sulindac did not attenuate the antihypertensive action of atenolol (Salvetti et aI., 1982c). However, this study also showed that su­lindac suppressed plasma renin activity, which is rather surprising in view of its proposed action as a selective inhibitor of extrarenal prostaglandin synthesis. A series of studies by Chalmers and col-

NSAID Interactions with Diuretics and ~-Blockers

leagues (1983) tends to confirm this dissociation of changes in plasma renin activity induced by NSAIDs from their attenuation of the antihyper­tensive effects of /3-blockers. These authors also proposed that the interaction of indomethacin with antihypertensive drugs is a general effect and is in­dependent of the specific antihypertensive drug used. Other studies have confirmed that indo­methacin attenuates the antihypertensive effect of prazosin in some patients (Rubin et aI., 1980) and of captopril (Salvetti et aI., 1982c), in addition to its effects on thiazide diuretics as discussed above.

The possibility of a pharmacokinetic interaction between NSAIDs and /3-blockers was studied by Webster et al. (1983). They showed that flurbipro­fen had no effect on the disposition of either at­enolol, a hydrophilic, non-metabolised drug cleared by the kidney, or propranolol, a lipophilic drug that undergoes extensive hepatic extraction. Thus, al­though NSAIDs may alter hepatic microsomal en­zyme activity (Chalmers et aI., 1973), apparent he­patic blood flow (Feely and Wood, 1983) and renal elimination of some drugs (Chennavasin et aI., 1980), these factors would not appear to explain the attenuation of the effects of /3-blockers on blood pressure.

It is distinctly possible that several mechanisms may apply simultaneously, and that many con­founding factors (such as sodium balance, renin status, drug dosage, presence of other drugs and severity of hypertension) may influence the result­ant effect on blood pressure on combining NSAIDs with /3-blockers.

2.1.2 Clinical Importance The main clinical problem arising from inter­

action of NSAIDs with /3-blockers is loss of blood pressure control. As with the diuretics, this inter­action is often overlooked and underestimated. In­domethacin may be more likely to exhibit this interaction than other NSAIDs but there is a need for more reliable comparative data. Sulindac may offer an alternative choice of NSAID ifblood pres­sure control remains unsatisfactory.

Since heart rate response to /3-blockade seems to be unaffected by NSAIDs, it is unlikely that these

39

drugs will adversely affect the treatment of angina by /3-blockers. However, it should be borne in mind that indomethacin may adversely affect coronary blood flow in some patients (Friedman et aI., 1981). Furthermore, it might be predicted that cardiac failure might be more common or more severe as a consequence of combined NSAIDI/3-blocker therapy than as a consequence of either drug alone.

3. Conclusions

Clinical investigators are faced with several im­portant restrictions on further research into the na­ture of these interactions, the drugs so affected and their dose-effect relationships.

In the past, many studies have been carried out in patients with mild uncomplicated hypertension. These are not necessarily the patients to suffer most from any potential NSAID interaction. Studies in more severe hypertension carry added risks and may be difficult to justify. Such studies may re­quire patients to take NSAIDs although there may be no clinical indication for the use of such drugs. Awareness of the serious unpredictable adverse ef­fects of NSAIDs makes it increasingly difficult to expose such patients or volunteers to such drugs unless there is a coexisting clinical indication for their use.

Patients with conditions requiring therapy with NSAIDs such as osteoarthritis, rheumatoid arth­ritis and ankylosing spondylitis may be considered for interaction studies with a reasonable prospect of some personal benefit. However, in these patients it may be difficult to justify withdrawal of NSAIDs and substitution by placebo for other than short term studies. Furthermore, the presence of joint pain, stiffness and disability may confound the interpretation of results. A recent study in patients with arthritis and coexisting hypertension treated with a variety of antihypertensive drugs has con­firmed the adverse effect on blood pressure of in­domethacin as compared with sulindac and para­cetamol (Lewis et aI., 1985).

Practical and ethical constraints imply that the collection of further reliable clinical information in this field is likely to be difficult. There will be a

NSAID Interactions with Diuretics and j3-Blockers

continuing need for careful observational studies in individual patients, but randomised studies are indispensible. The importance of patient selection, dose and duration of drug treatments, 'blind' ob­servers and accurate methods of measurement can­not be overemphasised.

References

Abate, G.; Polimeni, R.M.; Cuccurullo, F.; Puddu, P. and Lenzi, S.: Effects indomethacin on postural hypotension in Parkin­sonism. British Medical Journal 2: 1466-1468 (1979).

Armstrong, J.M.; Dusting, G.J.; Moncada, S. and Vane, J.R.: Cardiovascular actions of prostacyclin (PGI2) a metabolite of arachidonic acid which is synthesized by blood vessels. Cir­culation Research 43 (Suppl. I): 112-119 (1978).

Attallah, A.A.: Interaction of prostaglandins with diuretics. Pros­taglandins 18: 369-375 (1979).

Bartter, F.C; Gill, J.R.; Frolich, J.C; Bowden, R.E.; Hollifield, J.W. et al.: Prostaglandins are over produced by the kidneys and mediate hyperreninemia in Bartter's syndrome. Transac­tions of the Association of American Physicians 89: 77-91 (1976).

Bennett, W.M.; McDonald, W.1.; Kuehnel, E.; Hartnett, M.N. and Porter, G.A.: Do diuretics have antihypertensive properties in­dependent of natriuresis? Clinical Pharmacology and Thera­peutics 22: 499-504 (1977).

Birkenhager, W.H.; De Leeuw, P.W.; Wester, A.; Kho, L.T.; Van­dongen, R. and Falke, H.E.: Therapeutic effects of !3-adreno­ceptor blocking agents. Advances in Internal Medicine and Paediatrics 39: 117-134 (1977).

Blair, LA.; Barrow, S.E.; Waddel, K.A.; Lewis, P.1. and Dollery, CT.: Prostacyclin is not a circulatory hormone in man. Pros­taglandins 23: 579-589 (1982).

Blum, M. and Aviram, A.: Ibuprofen induced hyponatraemia. Rheumatology and Rehabilitation 19: 258-259 (1980).

Brater, D.C: Analysis of the effect of indomethacin on the re­sponse to furosemide in man: Effect of dose of furosemide. Journal of Pharmacology and Experimental Therapeutics 210: 386-390 (1979).

Buhler, F.R.; Laragh, J.H.; Baer, L.; Vaughan, E.D. and Brunner, H.R.: Propranolol inhibition of renin secretion: A specific ap­proach to diagnosis and treatment of renin-dependent hyper­tensive diseases. New England Journal of Medicine 287: 1209-1214 (1972).

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Address for correspondence and reprints: Dr J. Wehs/e/'. Uni­versity of Aberdeen. Department of Therapeutics and Clinical

Pharmacology. Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB9 2ZB (Scotland).