Link to 2.1.1.2 Nonsteroidal Anti-inflammatory Drugs Teaching Resources
Link to Problems for Discussion

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DRUGS INCLUDED IN THIS CATEGORY

Alclofenac	Floctafenine	Oxyphenbutazone
Apazone	Flufenamic acid	Phenylbutazone
Azapropazone	Flurbiprofen	Pirazolac
Benoxaprofen	Ibuprofen	Piroxicam
Bufexamac	Indomethacin	Pirprofen
Carprofen	Indoprofen	Proquazone
Clometacin	Isoxicam	Sulindac
Diclofenac	Ketoprofen	Suprofen
Diflunisal	Ketorolac	Tenidap
Dipyrone	Lornoxicam	Tenoxicam
Droxicam	Meclofenamate	Tiaprofenic acid
Etodolac	Meclofenamic acid	Tolmetin
Etofenamate	Mefenamic acid	Zomepirac
Felbinac	Nabumetone
Fenbufen	Naproxen
Fenoprofen	Oxaprozin

OVERVIEW

NSAID overdose is not generally associated with significant morbidity. In our experience of 310 consecutive admissions over the last 15 years, no patients have died and only nine have had significant morbidity (4 episodes of renal failure and 5 convulsions) attributable to their NSAID overdose. However, occasionally, large ingestions are reported to cause coma, metabolic acidosis, acute renal failure, bradycardia, hypotension, seizures, or death. Mefenamic acid causes seizures much more commonly than other NSAIDs. There is no specific antidote and treatment is generally supportive. Activated charcoal and generous fluid replacement is usually all that is required.

MECHANISM OF TOXIC EFFECTS

In therapeutic concentrations, NSAIDs act by inhibiting the enzyme cyclo-oxygenase and preventing the production of prostaglandins from arachidonic acid. This can lead to a large variety of adverse effects in therapeutic use, some of which may occur with a single dose (e.g. gastrointestinal irritation, prolonged bleeding time, asthma, fluid retention in people with intravascular volume depletion, drug interactions). However, cyclo-oxygenase is generally maximally inhibited with therapeutic doses and few of the acute toxic effects are attributable to this action. Thus, toxicity is not necessarily similar between different NSAIDs and it is likely that there is a wide range of toxicity both quantitatively and qualitatively between these drugs. This is evident for mefenamic acid, which causes seizures much more commonly than other NSAIDs. The mechanism for these non-class related effects are obscure.

A number of these drugs will uncouple oxidative phosphorylation at toxic doses, which may partly explain the development of metabolic acidosis and CNS effects.

KINETICS IN OVERDOSE

Absorption

Most NSAIDs are very rapidly absorbed with peak concentrations in therapeutic use occurring after to 2 hours. There is minimal first-pass metabolism for most of these drugs (except for diclofenac) and so bioavailability is usually greater than 90%.

Distribution

NSAIDs are generally highly protein bound (>95-99%) and have relatively small volumes of distribution (<0.5 L/kg).

Metabolism - Elimination

There is a wide range of routes of elimination and half-lives for these drugs (see table).
Pharmacokinetic parameters of NSAIDs that may be relevant in overdose

	Time to peak concentration (Tmax) (h)	Plasma Protein Binding (%)	Urinary Excretion (%)	Half-life (hours)
Azapropazone	4	>99	65	12 - 24
Carprofen		>99	3 - 5	9 -16
Diclofenac #		>99	<1	1 - 2
Diflunisal	2 - 3	>99	3 - 9	8 -13 *
Etodolac	2	>99	<1	7
Fenbufen	1 - 1.5	>99	<2	8 - 17
Fenoprofen	1 - 2	99	30	3
Flufenamic acid		>90	<1	9
Flurbiprofen	1 - 2	99	<1	3 - 6
Ibuprofen	1 - 2	>90	1	2.0
Indomethacin	2	99	16	2.6 - 11.2
Ketoprofen	0.5 - 2	99	<1	1.5 - 4.0
Ketorolac	0.5 - 1	>99	58	4 - 10
Meclofenamic acid	0.5 - 1	99	2 - 4	2 - 4
Mefenamic acid	2 - 4	>99	<6	2 - 4
Nabumetone (6-MNA 1 )	8	99	<1	22 -34
Naproxen	1 - 4	>99	<1	13
Oxaprozin slow		>99	1 - 4	48 - 72
Oxyphenbutazone		>98	<2	27 - 64
Phenylbutazone	2	98	1 - 3	70‡
Piroxicam	3 - 5	99	4 - 10	50
Sulindac (Sulindac sulphide 1)	2	>94	<1	11 - 19‡
Tenoxicam	1 - 6	>98	<1	60 - 75
Tiaprofenic acid	1	98	<5	2
Tolmetin	0.5 - 1	>99	7	1 - 5

• * Non-linear kinetics
• 1 Active metabolites
• ‡ Extensive enterohepatic recycling
• # Significant first-pass metabolism

CLINICAL EFFECTS

Gastrointestinal effects

Minor gastrointestinal irritation, nausea, vomiting, abdominal pain and diarrhoea, are common.
Macroscopic gastrointestinal bleeding seems to be quite uncommon (c.f. therapeutic use) but has been reported to complicate overdoses of NSAIDs with long half-lives (e.g. phenylbutazone, piroxicam).

Metabolic effects

Metabolic effects, including respiratory alkalosis, metabolic acidosis, hyponatraemia, hyperkalaemia, hypokalaemia and hypoglycaemia have been reported, in particular with phenylbutazone and oxyphenbutazone. Vomiting may contribute to electrolyte imbalance and dehydration. These metabolic effects may be due to uncoupling of oxidative phosphorylation, thus intracellular and CNS glucose concentrations might be low despite a normal blood glucose. Thus, patients with significant CNS effects should receive an IV glucose bolus to see if they respond.

Central nervous system effects

Mild CNS effects such as nausea, vomiting, tinnitus, confusion and headache are quite commonly reported. Serious complications such as seizures and coma are quite unusual. It should be remembered that CNS effects may be caused by electrolyte disturbance or hypoglycaemia as well as direct toxicity. Seizures occur rarely (< 2%) except in mefenamic acid and phenylbutazone overdoses.

Renal effects

Acute renal failure has been reported after overdose or single doses of a number of NSAIDs including benoxaprofen, fenoprofen, ibuprofen, mefenamic acid, diclofenac, naproxen, piroxicam, and sulindac.

Renal failure is usually reversible and generally occurs in "at-risk" patients such as those with dehydration, heart failure, liver failure, renal impairment who have relative or absolute intravascular volume depletion. Out of 310 patients with NSAID overdose at our centre, 4 have had acute renal failure, which resolved over several days. Two were young men who had ingested naproxen (7,500 & 25,000 mg) some days previously and only presented when symptoms developed. A unique syndrome of haemorrhagic cystitis has been described with short term use of tiaprofenic acid.

Hepatic effects

Rises in transaminases have been reported but are not clinically significant. We have had 14/310 patients with NSAID overdose with minor elevations of their ALT, however two had ingested paracetamol and one a very large amount of ethanol.

Haematological effects

The bleeding time is prolonged due to a reversible inhibition of thromboxane production leading to reduced platelet aggregation. NSAIDs differ in duration of effect from less than 1 day for those with short half lives to 2 weeks or more for those with long half lives. (See Pharmacokinetic values)

INVESTIGATIONS

In large or clinically severe overdoses the following should be monitored

• full blood count
• electrolytes & glucose
• renal function
• Liver function tests
• arterial blood gases
• coagulation studies

Abnormalities occur rarely, but appear to be most frequent in mefenamic acid and phenylbutazone overdoses.

Blood concentrations
NSAID plasma concentrations are not widely available and have not been shown to be useful for the evaluation and management of overdose.

DIFFERENCES IN TOXICITY WITHIN THIS DRUG CLASS

It is likely that many of these drugs have their own spectrum of toxicity (as toxicity is mostly not due to the effect on cyclo-oxygenase that defines this class); however, little experience with many of these drugs has been reported. The high risk of seizures and other CNS effects with mefenamic acid and the generally more serious nature of phenylbutazone overdose are pertinent examples.

TREATMENT

Supportive

IV access and fluids should be given to patients who are dehydrated or unable to ingest adequate fluids. Avoiding any intravascular fluid depletion is likely to help prevent the development of renal failure. Abnormalities of electrolytes should be corrected.

GI Decontamination

Oral activated charcoal should be given to all patients who present within 1-2 hours of ingestion.
Gastric lavage would not be indicated in patients with unimpaired consciousness. Generous fluid replacement to counteract the volume depletion associated with gastrointestinal decontamination is particularly important to reduce the risk of renal toxicity.

Antidotes

There are no specific antidotes for the most serious manifestations. The gastrointestinal effects could presumably be antagonised by misoprostol but this would not generally be warranted.

Treatment of specific complications

Seizures
Seizures should be treated with IV glucose and then benzodiazepines (e.g. diazepam 5 to 10 mg IV).

Elimination enhancement
Most of these drugs have short half-lives and there is unlikely to be significant benefit from repeated doses of activated charcoal except perhaps for phenylbutazone and sulindac. Other methods of elimination enhancement, such as haemodialysis and haemoperfusion are not warranted.

LATE COMPLICATIONS, PROGNOSIS - FOLLOW UP

Death is extremely unusual but has been reported for fenoprofen, ibuprofen, and phenylbutazone.

Serious long term sequelae have not been reported and no follow up would normally be required after resolution of the clinical signs. The incidence of delayed renal injury is unknown.

REFERENCES

Steven A. Seifert; Alvin C. Bronstein; Thomas McGuire.Massive Ibuprofen Ingestion with Survival.Clinical Toxicology, Volume 38, Issue 1, 2000, Pages 55 – 57.
Alan H. Hall ab; Susan C. Smolinske a; Burt Stover a; Frances L. Conrad a; Barry H. Rumack ab.Ibuprofen Overdose in Adults.Clinical Toxicology, Volume 30, Issue 1 March 1992 , pages 23 - 37.
Per E. J. Kulling a; Eva A. Beckman a; A. S. M. Skagius a .Renal Impairment After Acute Diclofenac, Naproxen, and Sulindac Overdoses.Clinical Toxicology, Volume 33, Issue 2 March 1995 , pages 173 - 177.

Court H, Volans GN. Poisoning after overdose with non-steroidal anti-inflammatory drugs. Adverse Drug React Acute Poisoning Rev 1984;3:1-21.
Hall AH, Smolinske SC, Stover B, Conrad FL, Rumack BH. Ibuprofen overdose in adults. J Toxicol Clin Toxicol 1992; 30: 23-37.
Kulling PEJ, Backman EA, Skagius ASM. Renal impairment after acute diclofenac, naproxen and sulindac overdoses. J Toxicol Clin Toxicol 1995;33:173-177.
Halperin SM, Fitzpatrick R, Volans GN. Ibuprofen toxicity. A review of adverse reactions and overdose. Adverse Drug React Toxicol Rev 1993;12:107-128.
McElwee NE, Veltri JC, Bradford DC, Rollins DE. A prospective population-based study of acute ibuprofen overdose: complications are rare and routine serum concentrations are not warranted. Ann Emerg Med 1990;19:657-662.
Smolinske SC, Hall AH, Vandenberg SA, Spoerke DG, McBride PV. Toxic effects of non-steroidal anti-inflammatory drugs in overdose: An overview of recent evidence on clinical effects and dose-response relationships. Drug Safety 1990;5:252-274.
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