DIAGNOSIS AND TREATMENT
`
`Acetaminophen
`
`BARBARA AMEER, R.Ph,; and DAVID J. GREENBLATT, M.D,; Boston, Massachusetts
`
`Acetaminophen is an effective mild analgesic and antipyretic
`agent. In double-blind, controlled experimental pain studies
`of short duration, acetaminophen is superior to placebo and
`produces analgesia comparable to that produced by aspirin.
`The frequency of adverse reactions to therapeutic doses of
`acetaminophen is low, as is that of aspirin. Overdosage with
`acetaminophen, however, may result in irreversible
`hepatotoxicity. Since clinical manifestations of intoxication
`can be of slow onset, physicians may tend to delay initiation
`of definitive therapy. Intravenous cysteamine, and possibly
`oral methionine, appear to be effective in preventing
`hepatotoxicity if they are administered with 10 h of drug
`ingestion. Physicians should be aware of the potential danger
`of acetaminophen overdosage and alerted to its clinical
`manifestations.
`
`ACETAMINOPHEN (paracetamol, JV-acetyl-para-amino-
`phenol) is commonly used as a mild analgesic and antipy-
`retic. Alone or in combination with other drugs, it is
`found in more than 200 formulations promoted for symp-
`tomatic relief of pain, cough, and colds (Table 1) (1). Its
`popular use is partly due to the low incidence of adverse
`effects relative to aspirin (2), At therapeutic doses, ad-
`verse effects rarely occur with acetaminophen. However,
`overdoses of the drug have been associated with fatal
`hepatotoxicity. Because acetaminophen is widely avail-
`able and forcefully promoted as a "safe" aspirin substi-
`tute, there is a need to reevaluate its status as an analges-
`ic-antipyretic agent in clinical medicine.
`
`History
`Acetaminophen was synthesized at Johns Hopkins
`University in 1877 and was first used in clinical medicine
`in 1893 by von Mehring (3), Its use did not become ex-
`tensive until 1949, when Brodie and Axelrod recognized
`it as the principal active metabolite of acetanilid and phe-
`nacetin. In 1950 acetaminophen was marketed in the
`United States as a substitute for phenacetin in an analges-
`ic mixture. After a few case reports of blood dyscrasias,
`the manufacturer recalled the drug in 1951; the following
`year it was again made available but only by prescription.
`
`• From the Clinical Pharmacology Unit, Department of Medicine. Mas:
`chusetts General Hospital; Boston, Massachusetts.
`
`20 2
`
`Since 1955 acetaminophen has been marketed without
`prescription in the United States (3),
`
`Pharmacologic Properties
`Analgesia and antipyresis are the major therapeutic ac-
`tions of acetaminophen. The drug is devoid of anti-in-
`flammatory and antirheumatic properties (4). Acetami-
`nophen's mechanism of action appears to be related to its
`inhibition of prostaglandin biosynthesis.
`
`ANIMAL PHARMACOLOGY
`In 1953 Frommel observed that acetaminophen elevat-
`ed the pain threshold of rabbits given electric shock (5).
`Boreus and Sandberg (6) gave oral doses to rats and pro-
`duced analgesia comparable to that of phenacetin. Signifi-
`cant analgesia was produced within 1 h and diminished
`over the following 2 h (7).
`In dogs, fever produced by intravenous pyrogens was
`decreased significantly by simultaneous administration of
`acetaminophen. In guinea pigs with fever induced by a
`vaccine, acetaminophen's antipyresis was similar to that
`produced by phenacetin (5).
`
`EARLY HUMAN STUDIES
`In an experimental pain study, Flinn and Brodie (8)
`found that the threshold for pain due to cutaneous heat
`radiation was elevated within 30 minutes of acetamino-
`phen ingestion. The maximum rise in threshold, achieved
`at 2,5 h postingestion, was 30% above control. Within 4
`h of drug administration, the threshold returned to nor-
`mal. These effects were comparable to those of acetanilid.
`Pain relief in 27 cancer patients was similar with ac-
`etaminophen (600 mg) or aspirin (600 mg) in a double-
`blind, placebo-controlled study (9). Patients with muscu-
`loskeletal pain reported better analgesia from acetamino-
`phen than from aspirin (10), In two double-blind studies,
`pain relief in patients with chronic rheumatic disease was
`comparable from acetaminophen and a codeine analgesic
`mixture (11), while patients with arthritis reported a co-
`deine compound to be superior to acetaminophen (12).
`
`MECHANISM OF ACTION
`Aspirin and aspirinlike drugs block the biosynthesis of
`prostaglandins from arachidonic or structurally related
`fatty acid precursors (13). Such precursors and the en-
`zyme responsible for prostaglandin synthesis are distrib-
`uted widely throughout the body (14). Aspirin and aspi-
`
`Annals of Internal Medicine 87:202-209, 1977
`
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`Table 1. Brand Names of Acetaminophen-Containing Products Available in the United States*
`
`Aceta
`Acetagesic
`Actamin
`Akes-N-Pain
`Al-Ay Modified
`Algecol
`AUylgesic
`AUylvon
`Alumadrine
`Amaphen
`Amino-Bar
`Aminodyne
`Amphenol
`Anapap
`Anaphen
`Anelix
`Anodynos
`Anuphen
`Apadon
`Apamide
`Apap
`Apapalone
`Arthralgen
`Arthrol
`Bancaps
`Bancaps-S
`Banesin-Forte
`Bayer Non-Aspirin
`Bexahist
`Biophens-S
`Bowman
`B-Pap
`Bromo Quinine
`Bromo Seltzer
`Burgesic
`Butigetic
`Calm Aids
`Capex
`Capital
`Capron
`Cen-Apap
`Cerose Compound
`Chexit
`Chlor-A-Tyl
`Christodyne-DHC
`Coastaldyne
`Coastalgesic
`Codalan
`Codap
`Codimal
`Codrene
`Coldene
`Colrex
`Comeback
`Conacetol
`Conar-A
`Conex
`Cory-ban D
`Corzans
`Co-Tylenol
`Covangesic
`Dapa
`Dapase
`Darvocet-N
`Datril
`Day Care
`
`Scotgesic
`Midran
`Scotuss
`Midrin
`Minotal
`Sedacane
`Mydocalm
`Sedalgesic
`Sedapap
`Myolate
`Sedragesic
`Naldegesic
`Siaico
`Naldetuss
`N-C-P
`Sinacet
`N-D Gesic
`Sinacon
`Nebs
`Sinaphen
`Neopap
`Sinarest
`Singlet
`Neo-Pyranistan
`Sinoze
`Neo-Synephrine Compound
`Sinubid
`Neo-Vadrin
`Nilain
`Sinudan
`Nilprin
`Sinu-Lets
`Sinulin
`Nokane
`Novahistine
`Sinumal
`Sinus Tab
`Nylorac PB
`Nyquil
`Sinustat
`Sinutab
`Opacedrin
`Sinuwes
`Ornex
`Ossonate-Plus
`SK-Apap
`Soltice Decongestant Tablets
`Panitol
`Spantuss
`Panodynes
`Spendrisin
`Panritis
`St. Joseph
`Parafon Forte
`Stopain
`Parten
`Sub-Due
`Partuss-A
`Sunril
`Partuss T.D.
`Supac
`Pavadon
`Super-Anahist
`Pedituss
`Supercitin Sugar Free
`Pedric
`Suppress
`Percocet-5
`Symptomax
`Percogesic
`Tabalgin f
`Pertussin Plus
`Taper
`Phenahist
`T-Caps
`Phenaphen
`Tega-Code
`Phendex
`Tegapap
`Phrenilin
`Temetan
`Pirin
`Tempra
`Presalin
`Tenlap
`Prodolor
`Tenol
`Proval
`Teragen
`Pyradyne
`T-Gesic
`Pyrapap
`Trendar
`Pyrihist
`Triaminicin
`Quiet-Nite
`Triaprin
`Quiet World
`Trigesic
`Renpap
`Trind
`Rentuss
`Trind-DM
`Repan
`Tussagesic
`Rhinex
`Tussapap
`Rhinidrin
`Two-Dyne
`Rhinogesic
`Tylaprin
`Rhinspec
`Tylenol
`Romex
`Valadol
`Romilar
`Valihist
`S.A.C. Sinus
`Valorin
`Salatin'
`Vannor
`Saleto
`Vanquish
`Saleto-D
`Windolor
`Salimeph
`Wygesic
`Salphenyl
`X-otag Plus
`Sanspen
`Zenex
`Santussin
`•Adapted in part from ANONYMOUS: Brand names of acetaminophen-ccntaining products. Pediatrics 52:885, 1973, with permission of the publisher.
`t British product.
`
`Demerol-APAP
`Dengesic
`Desa-Hist AT
`Dialog
`Dimindol
`Dolanex
`Dolene AP-65
`Dolmar
`Dolopar
`Dolor
`Drinacet
`Drinophen
`D-Sinus
`Duadicin
`Dularin
`Duo-Gesic
`Duoprin
`DU0-3X
`Duradyne
`Duramid
`Dynosal
`Elixodyne
`Empracet
`Endecon
`Enpayne
`Enz-Cold
`Esemgesic
`Esgic
`Euphene
`Excedrine
`Febridol
`Febrinol
`Febrogesic
`Febrolin
`Fendol
`Fendon
`Flavahist
`Gaysol
`G-l;G-2;G-3
`Guaiamine
`Hasacode
`Her-Caps
`Histalets
`Histogesic
`Histosal
`Hi-Temp
`Hycomine Compound
`Indogesic
`Isomel
`Janupap
`Kiddies Siaico
`Kleer
`Koly-Tabs
`Koryza
`Lestemp
`Liquiprin
`Liquix-C
`Lyteca
`Maranox
`Maxigesic
`Medache
`Med-Apap
`Medigesic
`Menalgesia
`Mense
`Metrogesic
`
`Ameer and Greenblatt • Acetaminophen
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`drug is rapidly absorbed from the gastrointestinal tract,
`reaching peak plasma levels within 40 to 60 minutes of
`ingestion (22). Binding to plasma proteins is variable but
`considerably less extensive than that of aspirin (23). A
`case report provides evidence of placental transfer of ac-
`etaminophen in humans (24).
`Rate of absorption of acetaminophen is faster from an
`alcoholic solution than from tablet or suspension formu-
`lations (25). Delayed gastric emptying may decrease the
`rate of absorption (26).
`Acetaminophen is metabolized in the liver, and the
`metabolic products are excreted by the kidney. The elimi-
`nation half-life ranges from 2 to 4 h in healthy persons
`(27-32). In cases of acetaminophen overdosage or in pa-
`tients with liver disease, the apparent elimination half-life
`is prolonged (32, 33). In renal dysfunction, however, the
`half-life is unchanged (31).
`After ingestion of a radiolabelled dose of acetamino-
`phen, 84% of the radioactivity was recovered in the urine
`within 12 h and 90% after 24 h (34). Using high-resolu-
`tion anion-exchange chromatography, Mrochek and as-
`sociates (35) observed that 100% of a 1950-mg oral dose
`was recovered in the urine within 24 h in two healthy
`male adults. The mean percentage of drug and metabo-
`lites recovered in the urine was 63% for glucuronide con-
`jugates, 34% sulfate conjugates, 3 % cysteine conjugate,
`and 1 % free drug. The relative amounts of metabolites
`reported by Mrochek and associates parallel the findings
`of others (36, 37). Thus, renal clearance of unchanged
`acetaminophen contributes very little to its total metabol-
`ic clearance. Since hepatic stores of sulphate and glucuro-
`nide are limited, acetaminophen overdose results in a
`larger percentage of the dose being oxidized to cysteine
`and mercapturic acid conjugates (38).
`Clements and Prescott (39) infused acetaminophen (12
`mg/kg) intravenously in four healthy subjects. Reliable
`pharmacokinetic analysis of acetaminophen was possible
`for three of these subjects (Table 2). As reported by oth-
`ers (27-32), the apparent elimination half-life ranged
`from 1.7 to 3.1 h. The volume of distribution ranged from
`0.83 to 1.36 litres/kg and the total metabolic clearance
`from 5.15 to 5.57 ml/min-kg. In all cases the hepatic
`extraction ratio was estimated to fall between 0.245 and
`0.265, indicating that about 25% to 26% of an oral dose
`of acetaminophen will fail to reach the systemic circula-
`tion due to first-pass metabolism.
`Miller, Roberts, and Fischer (29) studied acetamino-
`phen metabolism and elimination kinetics in neonates,
`children, and adults. Although there were no age-related
`differences in the total clearance, the route of conjugation
`differed among the groups. The major metabolite found
`in the urine of adults and 12-year-olds was the glucu-
`ronide conjugate. In contrast, neonates and children
`(aged 3 to 9 years) excreted primarily the sulfate conju-
`gate (29, 40), suggesting that infants and children have a
`limited capacity to conjugate phenolic drugs with glucu-
`ronic acid. Sulfate conjugation represents an alternate,
`compensatory metabolic pathway. If this alternate route
`is not available, excessive drug accumulation could result
`(29).
`
`rinlike drugs interfere with one or more of these enzymes;
`this probably accounts for their mechanism of action
`(15).
`Collier and Schneider (16) showed that intraperitoneal
`injection of prostaglandins in mice produced pain mani-
`fested by a writhing response. Equivalent doses of mor-
`phine were required to inhibit the writhing response to
`three different prostaglandins, whereas variable doses of
`aspirin were required. Collier and Schneider conclude
`that morphine's primary site of action is in the central
`nervous system (CNS), whereas aspirin acts at the site
`where pain is generated.
`In one clinical study (17), E-type prostaglandins were
`infused subdermally to mimic the continuous release of
`endogenous prostaglandins. In addition to overt pain pro-
`duced during the infusion, there was a persistent hyper-
`algesia, that is, increased sensitivity to pressure or inject-
`ed bradykin and histamine. Thus, prostaglandins appear
`to increase the sensitivity of pain receptors to mechanical
`and chemical stimuli (17). Aspirin injected before prosta-
`glandin administration did not prevent the hyperalgesia,
`suggesting that aspirin inhibits the synthesis of prosta-
`glandins but does not alter their end-organ effects.
`Pyrogens may increase production and release of pros-
`taglandins anywhere in the CNS; fever, however, occurs
`only when an E-type prostaglandin acts on the anterior
`hypothalamus (18). Feldberg and associates (19) injected
`pyrogens intravenously and intraventricularly to cats.
`The ensuing fever and elevated prostaglandin-E, activity
`in cerebrospinal fluid were decreased by intraperitoneal
`injection of acetaminophen, aspirin, or indomethacin.
`Nonsteroidal anti-inflammatory drugs also appear to
`act through inhibition of prostaglandin synthesis (20).
`Although acetaminophen is a prostaglandin synthetase
`inhibitor, the drug does not have anti-inflammatory ac-
`tion. This paradoxical observation may be explained by a
`differential sensitivity of prostaglandin synthetase from
`different tissues. Flower and Vane (21) found that rabbit
`and dog brain synthetase was sensitive to inhibition by
`acetaminophen while dog spleen enzyme was not. Thus,
`analgesic-antipyretics devoid of anti-inflammatory prop-
`erties may more strongly inhibit the synthetase system in
`the CNS than the synthetase in peripheral tissue (15, 21).
`
`Pharmacokinetics
`Acetaminophen is a weak acid with a
`
`of 9.5. The
`
`204
`
`August 1977 • Annals of Internal Medicine • Volume 87 • Number 2
`
`Table 2. Pharmacokinetic Variables for Acetaminophen After Intra-
`venous Injection in Humans*
`
`Subject
`2
`
`1
`
`3.05
`1.36
`5.15
`
`2.10
`1.00
`5.50
`
`Elimination half-life, //
`Volume of distribution, litre/kg
`Total clearance, ml/min-kg
`Extent of first-pass metabolism t.
`26.5
`26.2
`24.5
`% of oral dose
`* Adapted from Reference 39 (CLEMENTS JA, PRESCOTT L F : Data point
`weighting in pharmacokinetic analysis: intravenous paracetamol in man.
`/ Pharm Pharmacol 28:707-709, 1976).
`t Assuming hepatic blood flow of 21 ml/min " kg.
`
`3 1
`
`.72
`0.83
`5.57
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`Clinical Effects
`ANALGESIA
`The analgesia produced by acetaminophen has been
`studied mainly in postpartum women with episiotomy
`pain. This model is useful because the patient population
`is a relatively homogeneous group of females between the
`ages of 16 and 39. Furthermore, the pain is of similar
`origin and uncomplicated by inflammation. Thus, the
`model is specific for pain and is not influenced by anti-in-
`flammatory effects of the drug. Finally, patients generally
`are not seriously ill and their pain is not associated with
`much anxiety or emotional disturbance that might exac-
`erbate their perception of pain. A disadvantage of the
`model is that the pain is of short duration and not condu-
`cive to crossover studies.
`In all of the five double-blind, placebo-controlled trials
`in episiotomy patients, analgesia produced by acetamino-
`phen was significantly superior to placebo (41-45). An-
`algesia was measured by patients' reports of pain relief
`and reduction of pain intensity, by the investigator's glob-
`al evaluation, and by the need for supplemental analges-
`ics after the one-dose trial. When acetaminophen was
`tested at single doses of 650 mg and 1000 mg, no "ceiling
`effect" was observed (42).
`Acetaminophen has been compared to other mild anal-
`gesics, including aspirin, propoxyphene, codeine, and
`combinations of these drugs. The clinical trials reviewed
`below used a placebo control, a double-blind study design
`(except where noted), and more than one means of assess-
`ing pain.
`Comparable single doses of aspirin and acetaminophen
`produced statistically indistinguishable degrees of analge-
`sia. Study populations consisted of patients with mild to
`moderate pain due to orthopedic surgery (acetamino-
`phen, 1000 mg, versus aspirin, 600 mg) (46) or unresecta-
`ble cancer (acetaminophen versus aspirin, 650 mg of
`each) (47). Similar results were found in a postpartum
`pain study that was not double-blind (acetaminophen
`versus aspirin, 1200 mg of each) (43).
`In two trials with postpartum patients, 1000 mg of ac-
`etaminophen was more effective than 65 mg of propoxy-
`phene hydrochloride or a combination of propoxyphene,
`aspirin, and caffeine. The difference was significant with
`respect to patient reports of pain intensity and relief and
`the investigator's overall evaluation (41, 45).
`Combinations of acetaminophen (600 mg) with co-
`deine (30 mg) or of acetaminophen (1000 mg) with pro-
`poxyphene (65 mg) were superior to acetaminophen
`alone in postpartum patients (44) and patients with rheu-
`matoid arthritis (48).
`Since most studies involved single doses, results cannot
`be extrapolated to chronic use or to other kinds of pain.
`Analgesic efficacy may depend on the cause of pain.
`Cooper and Beaver (49) reported that the peripherally
`acting analgesics, acetaminophen (600 mg) and aspirin
`(650 mg), were more effective than codeine (60 mg) in
`relieving moderate to severe pain in ambulatory patients
`after oral surgery. With the episiotomy pain model, on
`the other hand, a dose of only 30 mg of codeine was
`
`statistically superior to 600 mg of acetaminophen (44).
`
`ANTIPYRESIS
`In a placebo-controlled trial comparing the antipyretic
`action of aspirin and acetaminophen in infants and chil-
`dren, effects of both drugs were significantly superior to
`those of placebo (50). In three studies using aspirin as an
`antipyretic standard, there was no significant difference
`between equivalent doses of the two drugs over a 6-h
`period (51-53). One of these studies (51) was particularly
`well designed and showed no significant difference be-
`tween the time of onset, time of peak (3 h postingestion),
`and duration of antipyretic action (6 h postingestion) for
`the two drugs. The other two studies had deficiencies in
`their study design. In one trial (52) about one third of the
`children continued to receive antibiotics, which may have
`influenced the course of the fever. In the other (53), the
`52 patients were not matched for age, nor were they ran-
`domly assigned to treatment groups; the acetamiiiophen-
`treated group also had a lower initial temperature.
`
`Unwanted Effects
`NEPHROPATHY
`Since acetaminophen is a metabolite of phenacetin,
`acetaminophen has long been viewed as a possible cause
`of renal damage. To date, chronic abuse of analgesic mix-
`tures containing acetaminophen as the major component
`has been associated with only three cases of renal papil-
`lary necrosis (54-56). As in the case of phenacetin, it is
`difficult to implicate one drug when a mixture of analges-
`ics are consumed.
`Chronic use of acetaminophen has been studied in
`rheumatic outpatients. Among patients whose major an-
`algesic consumption was acetaminophen (at least 1 g dai-
`ly for a year or more), none had clinically significant
`renal impairment (57). Although the potential for caus-
`ing nephrotoxicity with chronic use is unclear, there is no
`evidence that acetaminophen causes renal damage with
`short-term use of therapeutic doses.
`
`HEMOSTASIS
`The effects of acetaminophen on hemostasis have been
`compared to those of aspirin. In normal volunteers re-
`ceiving a single dose of acetaminophen (975 mg or 1950
`mg) and multiple doses of acetaminophen (1.9 g daily for
`6 weeks), no change in bleeding time or platelet aggrega-
`tion was observed. In contrast, a single dose of 975 mg of
`aspirin prolonged the bleeding time (58). Similar results
`with single doses of aspirin or acetaminophen were found
`by Sutor, Boure, and Owen (59) and by Mielke and Brit-
`ten (60). Hemophilic patients receiving aspirin (60) or
`multiple doses (58) of acetaminophen showed no signifi-
`cant changes in bleeding time.
`In the studies cited, acetaminophen did not produce
`immediate or delayed effects on sihall vessel hemostasis,
`as measured by bleeding time. Thus, acetaminophen ap-
`pears to be the mild analgesic of choice for conditions in
`which aspirin's antiplatelet effect would be undesirable.
`Such conditions probably include hemophilia, thrombo-
`cytopenia, and after surgical procedures. Short-term ac-
`
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`mates based on clinical observations and extrapolation
`from animal data.
`Before effective treatment was found, acetaminophen
`poisoning often resulted in hepatotoxicity. Of 60 over-
`dose cases seen in a treatment unit specializing in liver
`disease, 49 progressed to liver damage (67). A 20% mor-
`tality rate was observed and attributed to fulminant he-
`patic failure (67). The 2% of cases that proved fatal in
`another series of patients were attributed to acute hepatic
`failure with severe coagulation disturbances (69).
`Onset of symptoms is gradual after an overdose of ac-
`etaminophen. Within the first 12 to 24 h, pallor, nausea,
`and vomiting appear. Microscopic
`liver damage is
`thought to occur rapidly, but clinical evidence of hepato-
`toxicity may not become evident until 4 to 6 days after
`ingestion. There is an initial sharp rise in serum aspartate
`aminotransferase (AST or SGOT, serum glutamic oxala-
`cetic transaminase) and alanine aminotransferase (ALT
`or SGPT, serum glutamic pyruvic transaminase), which
`return to normal levels within 1 to 2 weeks. Mild acido-
`sis, jaundice, and prolongation of the prothrombin time
`may also occur. In acute hepatic necrosis, coagulation
`disorders may be severe and may include disseminated
`intravascular coagulation (70).
`Liver tissue in acetaminophen-induced hepatic necrosis
`shows centrilobular reticulum collapse and congestion.
`Cirrhosis rarely occurs (67). Since drug-metabolizing
`functions may be impaired, other drugs required during
`the 2- to 3-week period after a severe intoxication proba-
`bly should be administered in reduced dosages (71).
`
`MECHANISM OF HEPATOTOXICITY
`A metabolite of acetaminophen is probably responsible
`for centrilobular liver necrosis after overdoses. Pretreat-
`ment of rats and mice with phenobarbital, a stimulant of
`metabolic enzymes, enhances production of the toxic me-
`tabolite and potentiates hepatic necrosis (72). Conversely,
`pretreatment with a metabolic enzyme inhibitor, such as
`piperonyl butoxide or cobaltous chloride, protects against
`hepatic necrosis in animals (72).
`Once formed, the toxic metabolite of acetaminophen
`binds covalently to liver macromolecules, producing liver
`necrosis (73). Covaient binding is dose-dependent, and
`the extent of binding influences the severity of the liver
`necrosis. Within 1 to 2 h of the peak level of binding,
`necrosis appears (73).
`The cytochrome P-450-dependent, mixed-function oxi-
`dase in liver microsomes mediates the binding. Cyto-
`chrome P-450 also mediates the conversion of 2-acetyl-
`aminofluorene to its toxic AT-hydroxy metabolite. The
`toxic metabolite of acetaminophen may also be an N-hy-
`droxy derivative (74, 75).
`Normally, in-vivo giutathione protects tissues against
`electrophilic attack by drug metabolites and other alkyl-
`ating agents. Acetaminophen depletes hepatic giuta-
`thione (76). Only after endogenous supplies of giuta-
`thione are exhausted does covaient binding to the liver
`occur.
`Figure 1 illustrates the proposed disposition of acetam-
`inophen in the body, including the production of the tox-
`
`MERCAPTURIC ACIO
`CELL OEATH
`Figure 1. Proposed pathways of acetaminophen disposition. Adapt-
`ed from Reference 75 (POTTER WZ, THORGEIRSSON SS, JOLLOW D J :
`Acetaminophen-induced hepatic necrosis. V. Correiation of hepatic
`necrosis, covaient binding and giutathione depletion in hamsters.
`Pharmacology 12:129-143, 1974, p. 140), with permission of the
`authors and editor.
`
`etaminophen therapy causes no interaction with oral an-
`ticoagulants (61). A slight potentiation of oral anticoagu-
`lant action has been observed after 1 to 2 weeks of repeat-
`ed daily treatment with acetaminophen (650 mg four
`times daily) (62). The clinical significance of this interac-
`tion is not established, but it suggests that prothrombin
`times should be closely monitored in anticoagulant-treat-
`ed patients for whom long-term acetaminophen adminis-
`tration is necessary.
`Two cases of thrombocytopenia associated with ac-
`etaminophen appear in the literature (63, 64). One of
`these cases appeared to be an immune thrombocytopenia
`(64).
`Repeated aspirin ingestion causes some gastrointestinal
`bleeding. Regular long-term ingestion (4 or more days a
`week) is associated with major upper gastrointestinal
`bleeding and benign gastric ulcers (65). Short-term use of
`acetaminophen does not appear to cause gastrointestinal
`bleeding. In one study 45 inpatients received 4 g of ac-
`etaminophen for 5 consecutive days. There was no signifi-
`cant difference in fecal blood loss during the drug trial as
`compared to the control period. In contrast, 10 patients
`receiving a 5-day trial of aspirin (2.6 g/day) had a signifi-
`cant increase in fecal blood loss (66). No studies on the
`long-term effects of acetaminophen on gastrointestinal
`bleeding have been done to date.
`
`Poisoning
`CLINICAL MANIFESTATIONS
`In adults with normal liver function, 15 g of acetami-
`nophen may produce serious
`intoxication (32, 67).
`Chronic ingestion of alcohol and drugs that induce drug-
`metabolizing enzymes lowers the toxic dose to about 10 g
`(32, 34, 67, 68). These figures, however, are only esti-
`
`2 0 6
`
`August 1977 • Annals of Internal Medicine • Volume 87 • Number 2
`
`P-450 MIXED FUNCTION OXIOASE
`I
`HO-N-COCHj
`
`POSTULATED
`TOXIC
`INTERMEDIATES
`
`NUCLEOPHILIC CELL
`lACROMOLECULES
`
`HNCOCH5
`
`LCELL
`MACROMOLECULES
`
`OH
`
`IN
`
`C O C H ,
`
`OH
`
`II
`
`GLUTATHIONE
`
`HNCOCHj
`
`OH
`I
`
` KINDERFARMS Ex. 1015
` KINDERFARMS LLC. v. GENEXA INC.
` PGR2023-00051
`
`
`Page 5 of 9
`
`

`

`ic metabolite and protection by glutathione (75). As the
`dose of acetaminophen is increased to hepatotoxic levels,
`hepatic glutathione is depleted and a smaller fraction of
`the dose is excreted as a mercapturic acid conjugate. In
`the absence of glutathione, the electrophilic metabolite of
`acetaminophen arylates liver macromolecules, resulting
`in cell death (77).
`
`TREATMENT
`Standard modes of treatment of poisoning have been
`used with varying degrees of success. Hemodialysis (78)
`and peritoneal dialysis (79) have little effect on the clini-
`cal course. Activated charcoal significantly reduces the
`drug's absorption when administered 30 minutes after
`acetaminophen (25) but not when administered 60 min-
`utes after ingestion (22). As with other toxic ingestions,
`gastric aspiration and lavage are effective within the first
`few hours of overdose. Supportive therapy has included
`parenteral fluids, antiemetics, and phytonadione, fresh
`frozen plasma, or clotting factors. None of these meas-
`ures, however, markedly alters the clinical course.
`Protection from hepatotoxicity has been attempted
`with amino acid precursors of glutathione, since gluta-
`thione itself does not penetrate cells easily (33). In
`animals, both methionine and cystine decreased hepato-
`toxicity (80, 81). Cysteine induced repletion of liver glu-
`tathione in mice, but the mechanism of this protective
`effect is not clear (82). In humans, methionine and cys-
`teamine (/3-mercaptoethylamine) have been used, the lat-
`ter with much success.
`Unlike glutathione, cysteamine does not appear to
`combine with the toxic metabolite of acetaminophen to
`form an inactive complex. Cysteamine may act by in-
`creasing glutathione stores or, more likely, preventing
`formation of the toxic metabolite (83, 84). As expected,
`the interval between acetaminophen ingestion and ad-
`ministration of cysteamine is critical (34, 85).
`Protection against acetaminophen-induced hepatotox-
`icity by cysteamine has been demonstrated by Prescott,
`Park, and Proudfoot (86). The "control" group consisted
`of poisoning cases treated before cysteamine was avail-
`able. None of the 19 patients treated with cysteamine
`within 10 h of ingestion had significant liver or kidney
`damage. In contrast, 7 1 % of the "retrospective" control
`subjects developed liver damage, as indicated by both as-
`partate and alanine aminotransferase levels. An earlier
`study from the same poison center reported similar find-
`ings (33).
`The results of one randomized control trial challenge
`the need for prompt administration of cysteamine (87).
`However, the study does not define the critical interval
`between ingestion and cysteamine therapy; therefore the
`author's conclusion that cysteamine treatment was no
`better than supportive therapy alone may not be justified
`by the data.
`A recent study by Prescott and associates (85) confirms
`the efficacy of cysteamine and suggests that further stud-
`ies using control groups receiving only supportive thera-
`py may no longer be ethically justified. The investigators
`compared the efficacy of intravenous cysteamine, L-me-
`
`thionine, D-penicillamine, and supportive therapy alone
`(85). The risk of liver damage, as indicated by the plasma
`acetaminophen concentration 4 h after ingestion, was
`comparable among patients in all four treatment regi-
`mens. In the group receiving only supportive therapy, all
`16 patients with plasma levels exceeding 300 /Ltg/ml de-
`veloped severe liver damage. Three of these patients died
`because of liver failure, and four others developed acute
`renal failure. In contrast, of the 23 patients receiving the
`additional treatment of cysteamine within 10 h, none de-
`veloped severe liver damage or renal dysfunction {P <
`0.001).
`A 20-g dose of L-methionine was superior to suppor-
`tive therapy alone but less effective than cysteamine (85).
`Side effects of L-methionine, however, were less severe
`than with cysteamine. A higher dose of L-methionine
`might have provided more protection but also might have
`been more toxic. The potential risks and benefits of this
`agent in relation to dosage require further study.
`D-Penicillamine was abandoned after possible drug-in-
`duced renal toxicity in two of the five cases in which it
`was administered (85).
`In a preliminary uncontrolled investigation, oral me-
`thionine was of value in preventing liver damage (88).
`However, based on extensive experience and consistent
`results, cysteamine is preferred over L-methionine for
`acetaminophen intoxication. In the study by Prescott and
`associates (85), a loading dose of 2 g of cysteamine base
`administered within 10 h of the ingestion followed by an
`infusion of 1.6 g over 20 h provided protection for severe
`liver damage.
`Side effects during intravenous cysteamine administra-
`tion include flushing, drowsiness, a rapid onset of ano-
`rexia, and repeated vomiting. These effects persist up to
`36 h after the infusion is discontinued (33, 87). Several
`episodes of acetaminophen overdosage were accompanied
`by cardiotoxicity and renal toxicity (87, 89), but it has
`not been established whether those effects were attributa-
`ble to liver failure, cysteamine, acetaminophen overdos-
`age, or other drugs taken with acetaminophen.
`Since only a few acetaminophen overdosage cases will
`be at risk of developing severe hepatic damage, and since
`cysteamine is far from innocuous, criteria for cysteamine
`therapy are needed. Both the elimination half-life and
`serum concentrations of acetaminophen have been used
`to predict hepatocellular damage (32, 33, 90). Single se-
`rum levels are of value only if the time since ingestion is
`known. Levels over 300 ju,g/ml 4 h after ingestion are
`associated with severe hepatic lesions, while levels under
`120 jug/ml usually are not.
`In addition to serum levels, liver function tests assist in
`the prediction of hepatic damage. Based on the upper
`limits of normal for several liver function tests, a "liver
`damage score" was employed by Prescott and a