2. Epidemiología
• N-acetyl-p-aminofenol o paracetamol o acetaminofén
• Extensamente usado desde 1955
• Mas de 28 mill de dosis distribuidas 2003
• 89 mill en 2005 con hidrocodona
• Mas de 100.000 llamadas al centro de toxicología año
– 56.000 visitas a urgencias
– 2.600 hospitalizaciones
– 450 muertes por FHA
• La hepatotoxicidad por drogas es la mas grande causa de
FHA en EEUU
– Acetaminofén la principal causa de FHA (50%) y de las muertes
relacionadas con FHA
3. Farmacología
• Dosis terapéutica 325-1000 mg dosis
– 10-15 mg kg dosis niños c 4-6h
– Max 4 gr dia (80 mg kg niños)
• Rápida absorción GI con pico 90 min
– Pico a las 4h con sobredosis
• Concentración terapéutica 10-20 mg/ml
• Unión a proteínas mínima a dosis terapéuticas
• Vd 0.9 L/kg
• T1/2= 2-2.5 h, hasta 4h en enf hepática
6. Dosis
• Hepatotoxicidad
– Dosis única ≥7.5 – 10 gr en adultos o 150 mg kg
niños mayores de 6 años consumidos en menos
de 8 horas
– Dosis repetidas ≥ 10 gr en 24h o ≥ 6 gr en 24h por
mas de 48h
• Dosis máxima segura 4 gr
7.
8. Inicia a las 24-36h con pico a las 72h
TP mayor 180 seg mortalidad 90%
9. Síntomas
• Falla renal aguda: 10-25% en pacientes con
hepatotoxicidad significativa y hasta 50% de
los pacientes con FHA
– 1-3 días después de la ingestión, NTA
– Metabolitos tóxicos oxidados por la cit P450 en el
riñón
• Aumento de amilasas en FHA
– 0.3-5% de pancreatitis aguda severa
10. Probabilidad de toxicidad
Nomograma de Rumack-Matthew
%= AST mayor de 1000
Línea 200
CP mas de 200
60% hepatotox severa
5% mortalidad
CP mas de 300
90% hepatotox severa
24% mortalidad
Línea 150
Línea de tto
13. N Acetil Cisteína
• Precursor de la glutatión sintetasa
• Para todos los pacientes de alto riesgo o con
hepatotoxicidad
• Iniciar antes de la elevación de la ALT
• Repleta y mantiene los depósitos de glutatión hepático
• No hay RCT
• Series de casos que observan hepatotoxicidad fue poco
común cuando se administraba NAC dentro de 8h
después de la ingesta de acetaminofén
• Luego de 10h aumenta el riesgo 20-30%
14. N Acetil Cisteína
• En pacientes con injuria hepática establecida
mejora los días libres de trasplante
– Reducción 20-30% en la mortalidad
– En mecanismo:
• Mejora la perfusión hepática y la entrega de oxígeno, barrido
de radicales libres de O2 y nitrógeno y la producción de
energía por la mitocondria
• Ambas vías de tratamiento igualmente efectivos
– Reacciones anafilactoides con IV 10-20%
– Nauseas, vómito con VO 5%
15. N Acetil Cisteína
• Diferentes esquemas de tratamiento estudiados:
– 20-48h VO parecen ser efectivos, si los niveles son
menores de 10 mg/ml y si no hay aumento de ALT o INR
durante 20 h de tratamiento
– 48h IV es tan efectivo cuando se inicia en intoxicaciones
antes de las 24h postingesta
• 140 mg /kg DI + 70 mg /kg c 4h por 12 dosis
• Algunas recomendaciones repetir CP y ALT en final del
tto o a las 16h de la infusión y continuar tto si ALT está
elevada o CP es detectable, principalmente en:
– pacientes con ingesta luego de 8h
– ALT elevada
– CP mayor 300
16. • Recomendaciones en severa hepatotoxicidad:
– Régimen estándar IV 6.25 mg kg h hasta que el
paciente reciba trasplante o se reverse la
hepatotoxicidad
• AST O ALT hayan disminuido
• Encefalopatía resuelva
• INR menor 1.5
• Con CP indetectables
N Acetil Cisteína
17.
18.
19. Otras medidas
• 858 pacientes en UK
– 60/95 en lista de trasplante fueron llevados a cx
• 73% sobrevivieron al alta y 58% sobrevivieron en promedio 9
años
• Otro estudio 1.144 pacientes, 54% por
acetaminofén
– No en lista 697 (34 vs 31%)
– En lista pero no trasplantados 177 (83 vs 59%)
– En lista y trasplantados 270 (53 vs 72%)
• Sobrevida a 2 años por no acetaminofén y si acetaminofén
20. Otras medidas
• Tres mecanismos de acción principales:
– Modulacion del metabolismo del acetaminofén
– Modulación de citoquinas y quimoquinas y del
sistema inmune innato
– Modulación de la injuria por estrés oxidativo
• Cimetidina, telmisartán coenzima Q 10
• Agentes biológicos IL 6, 11, 22 y anti-
interferón gama
21.
22. Salicilatos
• Grupo de quimicos derivados del acido
salicílico
• El acido acetil salicílico es metabolizado a
acido salicílico o salicilato después de la
ingestión
• Derivado de la salicina, ingrediente activo de
la corteza del sauce, usada hace 2,500 años
para tratar la fiebre y el dolor
• También en frambuesas, almendras y tomates
23.
24. Epidemiología
• 21,000 intoxicados en EEUU en 2004
• 43 muertes y mas de 12,000 requirieron
manejo hospitalario
• La restricción de las ventas ha disminuido las
intoxicaciones, el trasplante y la muerte
•
26. Metabolismo
• Principal:
• Interferencia del metabolismo aeróbico= desacople de
la fosforilación oxidativa mitocondrial= metabolismo
anaeróbico = conversión de piruvato a lactato = ac
láctica
• Metabolismo anaeróbico ineficiente= menos energía
para producir ATP y menos liberado durante el
metabolismo de la glucosa = calor y fiebre
• Depleción del glucógeno, gluconeogénesis,
catabolismo de proteínas y AGL = hipoglicemia
•
27. PK
• pKa ASA = 3
– Si pH=3, la mitad esta en forma ionizada
– En medio ácido mas droga se absorberá comparado
con tejidos menos ácidos o mas alcalinos
– Además causa espasmo del esfinter pilórico,
incrementa el tiempo de tránsito gástrico y prolonga
el tiempo de ASA en el medio acido del estómago,
mas absorción
– Formas dérmicas no se absorben a tejidos profundos
• Metabolismo hepático por conjugación con
glicina
28. Cambios acido base
• Alcalosis respiratoria
– Por estimulación directa del CR
• Trastornos mixtos
• Acidosis metabólica
29. Manifestaciones clínicas
• Fase inicial. Presentación temprana
– Sintomas leves, hiperventilación
– Sys GI pueden no estar presentes
– Tinitus
– Agitación, taquicardia e incremento del trabajo
respiratorio
– Laboratorio
• Nomales o alcalosis respiratoria
30. • Presentación tardía
– Dx diferencial con sepsis, IAM; agitación o enf psiquiátrica
– Los niveles no reflejan la concentración total de ASA
– Tomar niveles seriados + gases arteriales
• Muerte
– Pérdida de la compensación
– Acidosis metabólica severa y déficit de volumen=
disfunción miocárdica e hipoTA
– Depresion del SNC con convulsiones por hipoxia e
hipoglucemia
– Edema cerebral y edema pulmonar
Manifestaciones clínicas
Drug hepatotoxicity is currently the single greatest cause of acute liver failure (ALF) in the U.S. and several other Western countries [1]. Acetaminophen (APAP) is foremost among the drugs responsible. By itself, APAP overdose is the most common etiology of ALF
more than 56,000 emergency room visits, 2600 hospitalizations, and an approximate 450 deaths caused by ALF
The therapeutic dose of APAP is 325 to 1000 mg/dose (10–15 mg/kg/dose in children), given every 4 to 6 hours, with a maximum recommended daily dose of 4 g (80 mg/kg in children). Although the US Food and Drug Administration (FDA) Advisory Committee proposed a decrease in the maximum daily dose from 4000 to 3250 mg, this recommendation has not been implemented.10 After oral ingestion, APAP is rapidly absorbed from the gastrointestinal tract with peak concentrations being achieved within 90 minutes. 1,11 Therapeutic serum concentrations range from 10 to 20 mg/mL. The presence of food in the stomach may delay the time to peak concentration, but not the extent of absorption.1,11 With overdose ingestion, peak serum concentrations generally are
achieved within 4 hours, but may be delayed beyond 4 hours after overdose of extended-release preparations or when drugs that delay gastric emptying time (eg, anticholinergics, opiates) are coingested.12,13 Protein binding is minimal at therapeutic doses with a volume of distribution of approximately 0.9 L/kg.11 The serum half-life of APAP is 2 to 2.5 hours; however, it is prolonged to more than 4 hours in patients with hepatic injury and chronic liver disease, and in those who ingested extendedrelease preparations. At therapeutic doses, approximately 85% to 90% of APAP undergoes phase II conjugation to sulfated and glucoronidated metabolites (about two-thirds through glucuronidation and one-third through sulfation in adults, whereas sulfation is predominant in children up to 12 years), which are then excreted in the urine.1,11,15 About 2% of APAP is excreted in the urine unchanged.
The remaining APAP (up to 10%) undergoes phase I oxidation by the hepatic cytochrome P-450 (CYP) pathway (primarily responsible by CYP2E1) to a toxic, highly reactive intermediate, N-acetyl-para-benzoquinoneimine (NAPQI).1,11,15 Small amount of NAPQI produced from normal doses of APAP is rapidly conjugated by hepatic glutathione (GSH), forming nontoxic mercaptate and cysteine compounds that are then excreted in the urine
A single acute ingestion of greater than or equal to 7.5 to 10 g in adults or 150 to 200 mg/kg in children older than 6 years (all APAP consumed within 8 hours) is likely to cause hepatotoxicity and requires prompt evaluation and therapeutic intervention.1 Repeated overdoses of greater than or equal to
10 g in a 24-hour period or greater than or equal to 6 g per 24-hour period for greater than or equal to 48 hours may be associated with subsequent hepatotoxicity and the patient should undergo evaluation in a health care facility
Acute renal failure develops in 10% to 25% of patients with significant hepatotoxicity and is encountered in more than 50% of those with ALF.58,59 It often becomes evident around 1 to 3 days after ingestion and often manifests as acute tubular necrosis, either alone or in combination with hepatic necrosis.58,59 The mechanism of nephrotoxicity is thought to be related to the toxic metabolites of APAP oxidized by CYP in the kidney.59 Acute renal failure is typically reversible, although it may worsen over 7 to 10 days and occasionally may require renal replacement therapy before the recovery occurs.58,59 An elevated serum amylase is frequently seen in patients with APAP poisoning particularly in patients with ALF, whereas clinical acute pancreatitis occurs rarely (0.3%–5%).60,61 Several cases of severe acute pancreatitis associated with APAP, however, have been reported,60,61 and therefore the possibility of APAP
poisoning should be kept in mind in patients presenting with ALF and pancreatitis. Clinical presentation of patients with single overdose versus repeated overdoses is somewhat similar. Patients who unintentionally ingest above the therapeutic APAP doses are more likely to present late (when hepatotoxicity is already recognized clinically) and are more likely to have known risk factors for hepatotoxicity, especially chronic alcohol use.32,62 In addition, this group of patient tends to have higher rates of morbidity and mortality than those who attempted suicide, even though the latter had taken higher total amount of APAP
The Rumack-Matthew nomogram is a valuable tool for handling patients with single acute ingestion who present to a health care facility within 24 hours (Fig. 2).1,66–70 This nomogram was constructed in the 1970s to estimate the likelihood of hepatotoxicity caused by APAP for patients with a single ingestion at a known time.1,66–70 To use the nomogram, patient’s serum APAP concentration is plotted in line with time interval.
Patients with an APAP level above a line between 200 mg/mL at 4 hours and 25 mg/mL at 16 hours after ingestion, known as the “200 line” or the “probable
toxicity line,” are at risk for developing severe hepatotoxicity (defined as AST >1000 IU/L) in which N-acetylcysteine (NAC) treatment is recommended even in the absence of clinical or laboratory evidence for toxicity at the time.1,66–71 Without NAC treatment, patients with APAP concentrations above the “200 line” have an approximate 60% incidence of severe hepatotoxicity with 5% mortality. Patients with APAP concentrations above the parallel “300 line” or “high toxicity line” have a subsequent 90% incidence of severe hepatotoxicity with 24% mortality.66,71 After the generation of these data, the FDA then imposed an arbitrary 25% safety margin on the “200 line,” which resulted in a parallel line staring at 150 mg/mL at 4 hours, known as the “150 line” or
the “treatment line,” and that has been most commonly used in the United States,
N-Acetylcysteine NAC, a GSH precursor, is an established antidote for APAP poisoning and should be administered in all patients with APAP hepatotoxicity or in patients at significant risk for developing hepatotoxicity. The key to effective treatment is to initiate therapy before the onset of ALT elevation. When given early after acute APAP overdose, NAC provides cysteine for the replenishment and maintenance of hepatic GSH stores, thus providing more substrate for the detoxification of the reactive metabolites. Furthermore, it may also enhance sulfation pathway and directly reduce NAPQI
There has been no randomized placebo-controlled trial (such trials were considered unethical) evaluating the efficacy of NAC for APAP overdose.100
Several case series have observed that severe hepatotoxicity was uncommon (<5%–10%) when NAC was administered within 8 hours after acute APAP overdose, whereas delays beyond 10 hours were associated with an increased risk of hepatotoxicity (20%–30%).1,70,73,101
Patients with established liver injury may also benefit from NAC because it has been shown to improve LT-free survival among patients with APAP-induced ALF (w20%–30% reduction in mortality).102,103 Instead of detoxifying NAPQI, the potential mechanisms of NAC in this state are of improving hepatic perfusion and oxygen delivery, scavenging reactive oxygen and nitrogen species, and refining mitochondrial energy production.1,15 Apart from APAP hepatotoxicity, the beneficial effects of NAC have also been observed in patients with early comagrade encephalopathy and with non-APAP ALF
Given the disparity between a prespecified treatment duration of the two regimens, alternative dosing schedules have been further studied; the 72-hour oral course seems to be too long and the 20-hour IV course may be too short.69 Shorter courses of oral NAC (20–48 hours) have been evaluated and seem to be effective, particularly if a repeat APAP level is less than 10 mg/mL and there was no increase in serum ALT or INR after a minimum treatment duration of 20 hours.110–114 Alternative 48-hour IV regimen (140 mg/kg loading followed by 12 doses of 70 mg/kg every 4 hours) is also effective in APAP overdose patients who present within 24 hours.115 Some experts have recommended an individualized approach for IV NAC by repeating APAP and ALT levels at the end of a 16-hour infusion period and continuing treatment if the ALT was elevated or if APAP concentration was detectable. This strategy may be particularly important in the patient who presents 8 hours after ingestion
most experts have advised a standard IV regimen while continuing a final infusion rate of 6.25 mg/kg/h until the patient receives LT or hepatotoxicity reverses (ALT or AST have peaked and are decreasing, encephalopathy resolves, and INR <1.5) with undetectable serum APAP concentration.
experience of 858 patients admitted with APAP-induced hepatotoxicity in the United Kingdom, 60 of 95 patients listed for LT underwent the procedure.6 Of 60 patients transplanted, 73% survived to discharge and 58% survived at an average of 9 years post-LT. When compared with patients who had LT from other causes of ALF, the incidence of psychiatric disease (principally depression) and 30-day mortality were greatest in the APAP group, but
for those who survived beyond 30 days, there was no difference in long-term survival rates between APAP and non-APAP groups.6 Adherence to follow-up appointments and compliance with immunosuppressive regimens were lower in the APAP overdose group, and was not predicted by any identifiable premorbid psychiatric conditions
(1) Not listed for LT (N5 697); (2) listed but not transplanted (N5177); and (3) listed and transplanted (N 5 270). The 2-year survival among non-APAP and APAP etiology in Groups 1, 2, and 3 was 34% and 31%, 83% and 59%, 53% and 72%, respectively
Other potential treatment options for APAP hepatotoxicity have been evaluated chiefly by three main mechanisms of action: (1) modulation of APAP metabolism, (2) modulation of cytokines and chemokines and the innate immune system, and (3) modulation of oxidative stress-related injury. Cimetidine, an inhibitor of CYP enzymes, theoretically may decrease the formation of NAPQI. In animal models, protection against APAP hepatotoxicity using a combination of cimetidine and NAC was better than that found with either agent alone.117 However, the use of cimetidine as an adjunct to NAC has shown no benefit in human studies.118,119 Several biologic agents, such as inducible protein-10, macrophage inducible protein-2, interleukin-6, -11, -22, and
anti–interferon-g, have been demonstrated to decrease susceptibility for APAP toxicity in experimental models.120,121 Telmisartan122 and coenzyme Q10123 can alleviate oxidative stress injury associated with APAP in animal models. However, to our knowledge, none of these agents have come to the clinical phase of study.
The term salicylate refers to any of a group of chemicals that are derived from salicylic acid. The best known is acetylsalicylic acid (aspirin). Acetylsalicylic
acid is metabolized to salicylic acid (salicylate) after ingestion. The salicylates originally were derived from salicin, the active ingredient
in willow bark, which Hippocrates used 2500 years ago for treating pain and fever [1,2]. Salicylates also occur naturally in many plants such as strawberries,
almonds, and tomatoes
Salicylate is a metabolic poison. Understanding the pathophysiology of its metabolic effects can help to understand the clinical manifestations of toxicity.
The metabolic derangements induced by salicylate poisoning are multifactorial, but the principal pathophysiologic mechanism in salicylate poisoning
is interference with aerobic metabolism by means of uncoupling of mitochondrial oxidative phosphorylation [15a,16]. This leads to the interruption of a series of enzyme-mediated mitochondrial functions and increased anaerobic metabolism with cellular conversion of pyruvate to lactate and rapid development of lactic acidosis
Salicylate is a metabolic poison. Understanding the pathophysiology of its metabolic effects can help to understand the clinical manifestations of toxicity.
The metabolic derangements induced by salicylate poisoning are multifactorial, but the principal pathophysiologic mechanism in salicylate poisoning
is interference with aerobic metabolism by means of uncoupling of mitochondrial oxidative phosphorylation [15a,16]. This leads to the interruption of a series of enzyme-mediated mitochondrial functions and increased anaerobic metabolism with cellular conversion of pyruvate to lactate and rapid development of lactic acidosis
The inefficiency of anaerobic metabolism results in less energy being used to create ATP and release of the energy created during the metabolism of glucose in the electron transport chain as heat, so salicylate poisoned patients may become febrile [19]. The absence of fever, however, does not rule out salicylate poisoning
The pharmacokinetic profile of aspirin is unique and explains the unique characteristics of clinical poisoning. The ionization constant (pKa) of aspirin
is 3, which means that at a pH of 3, approximately half of the available chemical is in the ionized state. In an acidic environment like the stomach,
more of the drug will be absorbed compared with tissues at a higher pH [21]. The absorption of aspirin from the stomach can be delayed by the presence
of food in the stomach and the formulation of the aspirin, (eg, enteric coating of pills may create concretions and bezoars that limit available surface
area for absorption) [22]. Aspirin is thought to cause spasm of the pyloric sphincter, increasing gastric transit time and prolonging the time that aspirin
is in the acidic environment of the stomach, favoring increased
Respiratory alkalosis Salicylate toxicity initially will create a pure respiratory alkalosis because of direct stimulatory effects on the respiratory centers of the cerebral medulla. This is characterized in the blood gas by a decrease in the partial pressure of dissolved CO2 accompanied by an elevated pH and normal to
slightly lower levels of serum HCO3 [32]. There is some controversy as to whether pediatric aspirin poisoned patients demonstrate this phase of
acid–base derangement. Pediatric patients may present later in the course of the poisoning, or the centrally mediated hyperventilatory phase of aspirin
poisoning may be so subtle in children that it often is missed
Mixed acid–base disturbances As the poisoning progresses and more of the aspirin is absorbed into the serum and is incorporated into the mitochondria, uncoupling oxidative phosphorylation, lactic acid accumulates in the serum, and metabolic compensatory mechanisms are initiated [16]. Hyperventilation becomes a true compensatory mechanism in addition to the byproduct of central medullary stimulation [20]. This phase is characterized metabolically by a continued decrease in the pCO2, marked decline in measured HCO3 and possibly a decrease in serum pH, depending on the ability of the patient to maintain the respiratory demands of the developing acidosis and to retain bicarbonate in the kidney [37]. A common error at this stage of the poisoning is to acknowledge that the serum pH is close to 7.4 or slightly higher than 7.4, and assume that the patient is compensating adequately for the acidosis.
modest symptoms, and the hyperventilation may be mistaken for emotional excitation or anxiety. GI irritation may or may not be present, and tinnitus
or other symptoms of ototoxicity may be overlooked unless the physician specifically tests for them with direct questioning or confrontational hearing
testing. Vital signs may reflect emotional agitation and CNS stimulation with tachycardia, increased work of breathing (increased minute ventilation),
and overall autonomic up-regulation. Early in the course of acute poisoning, fever generally will be absent [39]. Clinical symptoms will be variable
if the patient ingested more than one drug, or the ingested aspirin formulation contained a CNS depressant, which might blunt the expected hyperventilation
and respiratory alkalosis
Laboratory values early in the course of aspirin poisoning will be largely normal or will reflect the direct stimulatory effect of salicylate on the cerebral
respiratory center. Serum aspirin levels may be elevated modestly (20 to 40 mg/dL), and blood gas analysis may demonstrate pure respiratory alkalosis
with elevated pH and low pCO2 with normal or near-normal HCO3 [39]. The decision to determine serum salicylate concentrations is not difficult.
Although serum salicylate levels may not be required to screen every asymptomatic overdose, liberal use of the laboratory to make the diagnosis
and follow resuscitative efforts is advisable
Late presentation As salicylate enters the mitochondria, dramatic changes in vital signs and clinical stability occur. Serum salicylate levels alone are not adequate to accurately assess and follow seriously poisoned patients [49]. Serum salicylate levels do not reflect the total body burden of salicylate, and so to evaluate the rapidly changing acid base status of an aspirin poisoned patient, serial salicylate levels should be accompanied by serial blood gas analysis [5].
Patients who present in the late phases of salicylate toxicity often are misdiagnosed as sepsis [50], myocardial infarction¿ [51], or as agitated or otherwise
psychiatrically disturbed
Myocardial depression and hypotension secondary to the acidosis and volume deficit occur, and CNS depression with seizures secondary to hypoxia, hypoglycemia, and direct CNS toxicity often precedes cardiopulmonary arrest
