Harrison's Chapter e50: Poisoning and Drug Overdosage

8/9/2019 Harrison's Chapter e50: Poisoning and Drug Overdosage

1/16

50-1

C H A P T E R e

5 0

P o i s o n i n

g a n d D r u

g O v e r d

o s a g e

C H A P T E R e 5 0 Poisoning and Drug

OverdosageMark B. Mycyk

Poisoning refers to the development of dose-related adverse effectsfollowing exposure to chemicals, drugs, or other xenobiotics. Toparaphrase Paracelsus, the dose makes the poison. In excessiveamounts, substances that are usually innocuous, such as oxygenand water, can cause toxicity. Conversely, in small doses, substancescommonly regarded as poisons, such as arsenic and cyanide, can beconsumed without ill effect. Although most poisons have predict-able dose-related effects, individual variability in the response to agiven dose may occur because of genetic polymorphism, enzymaticinduction or inhibition in the presence of other xenobiotics, oracquired tolerance. Poisoning may be local (e.g., skin, eyes, orlungs) or systemic depending on the route of exposure, the chemicaland physical properties of the poison, and its mechanism of action.The severity and reversibility of poisoning also depend on the func-tional reserve of the individual or target organ, which is influencedby age and preexisting disease.

EPIDEMIOLOGY

More than 5 million poison exposures occur in the United Stateseach year. Most are acute, accidental (unintentional), involve asingle agent, occur in the home, result in minor or no toxicity, andinvolve children younger than 6 years of age. Pharmaceuticals areinvolved in 47% of exposures and 84% of serious or fatal poison-ings. Unintentional exposures can result from the improper use ofchemicals at work or play; label misreading; product mislabeling;mistaken identification of unlabeled chemicals; uninformed self-medication; and dosing errors by nurses, pharmacists, physicians,parents, and the elderly. Excluding the recreational use of ethanol,

attempted suicide (deliberate self-harm) is the most commonreported reason for intentional poisoning. Recreational use of pre-scribed and over-the-counter drugs for psychotropic or euphoriceffects (abuse) or excessive self-dosing (misuse) are increasinglycommon and may also result in unintentional self-poisoning.

About 20–25% of exposures require bedside health profes-sional evaluation, and 5% of all exposures require hospitalization.Poisonings account for 5–10% of all ambulance transports, emer-gency department visits, and intensive care unit admissions. Up to30% of psychiatric admissions are prompted by attempted suicide via overdosage. Overall, the mortality rate is low:


2/16

50-2

P A R T 1

8

P o i s o n i n

g ,D r u

g O v e r d

o s e , a n

d E n v e n

o m

a t i o n

Increased pulse, blood pressure, respiratory rate, temperature,and neuromuscular activity characterize the stimulated physiologicstate: sympathetic, antimuscarinic (anticholinergic), hallucinogenpoisoning, and drug withdrawal ( Table e50-1). Other featuresare noted in Table e50-2 . Mydriasis, a characteristic feature of allstimulants, is most marked in antimuscarinic (anticholinergic)

poisoning since pupillary reactivity relies on muscarinic control;in sympathetic poisoning (e.g., cocaine), pupils are also enlarged,but some reactivity to light is observed. The antimuscarinic (anti-cholinergic) toxidrome is also distinguished by the presence of hot,dry, flushed skin; decreased bowel sounds; and urinary retention(Table e50-1). Other stimulant syndromes increase sympathetic

TABLE e50-1 Differential Diagnosis of Poisoning Based on Physiologic StateStimulated Depressed Discordant Normal

SympatheticsSympathomimeticsErgot alkaloidsMethylxanthines

Monoamine oxidase inhibitorsThyroid hormones

Anticholinergics Antihistamines Antiparkinsonian agents Antipsychotics AntispasmodicsBelladonna alkaloidsCyclic antidepressantsMuscle relaxantsMushrooms and plants

HallucinogensCannabinoids (marijuana)LSD and analoguesMescaline and analoguesMushroomsPhencyclidine and analogues

Withdrawal syndromesBarbituratesBenzodiazepinesEthanolOpioidsSedative-hypnoticsSympatholytics

Sympatholytics

α 1-Adrenergic antagonistsα 2-Adrenergic agonists

ACE inhibitors

Angiotensin receptor blockers Antipsychoticsβ-Adrenergic blockersCalcium channel blockersCardiac glycosidesCyclic antidepressants

Cholinergics AcetylcholinesteraseinhibitorsMuscarinic agonistsNicotinic agonists

Opioids AnalgesicsGI antispasmodics

HeroinSedative-hypnotics

Alcohols AnticonvulsantsBarbituratesBenzodiazepinesGABA precursorsMuscle relaxantsOther agentsGHB products

AsphyxiantsCytochrome oxidase inhibitorsInert gasesIrritant gases

Methemoglobin inducersOxidative phosphorylationinhibitors

AGMA inducers Alcohol (ketoacidosis)Ethylene glycolIronMethanolSalicylateToluene

CNS syndromesExtrapyramidal reactionsHydrocarbon inhalationIsoniazid

LithiumNeuroleptic malignantsyndromeSerotonin syndromeStrychnine

Membrane-active agents Amantadine Antiarrhythmics Antihistamines AntipsychoticsCarbamazepineCyclic antidepressantsLocal anestheticsOpioids (some)

OrphenadrineQuinoline antimalarials

Nontoxic exposurePsychogenic illnessToxic time-bombs

Slow absorption

AnticholinergicsCarbamazepineConcretion formersExtended-release phenytoinsodium capsules (DilantinKapseals)Drug packetsEnteric-coated pillsDiphenoxylate-atropine (Lomotil)OpioidsSalicylatesSustained-release pills

ValproateSlow distribution

Cardiac glycosidesLithiumMetalsSalicylate

ValproateToxic metabolite

AcetaminophenCarbon tetrachlorideCyanogenic glycosidesEthylene glycolMethanolMethemoglobin inducersMushroom toxinsOrganophosphate insecticides

ParaquatMetabolism disruptors

Antineoplastic agents Antiviral agentsColchicineHypoglycemic agentsImmunosuppressive agentsMAO inhibitorsMetalsSalicylateWarfarin

Abbreviations: ACE, angiotensin-converting enzyme; AGMA, anion-gap metabolic acidosis; CNS, central nervous system; GABA,γ -aminobutyric acid; GHB, γ -hydroxybutyrate;GI, gastrointestinal; LSD, lysergic acid diethylamide; MAO, monoamine oxidase.


3/16

50-3

C H A P T E R e

5 0

P o i s o n i n

g a n d D r u

g O v e r d

o s a g e

activity and cause diaphoresis, pallor, and increased bowel activ-ity with varying degrees of nausea, vomiting, abnormal distress,and occasionally diarrhea. The absolute and relative degree of vitalsign changes and neuromuscular hyperactivity can help distinguishamong stimulant toxidromes. Since sympathetics stimulate theperipheral nervous system more directly than do hallucinogens or

drug withdrawal, markedly increased vital signs and organ ischemiasuggest sympathetic poisoning. Findings helpful in suggesting theparticular drug or class causing physiologic stimulation includereflex bradycardia from selective α -adrenergic stimulants (e.g.,decongestants), hypotension from selective β-adrenergic stimulants(e.g., asthma therapeutics), limb ischemia from ergot alkaloids,rotatory nystagmus from phencyclidine and ketamine (the onlyphysiologic stimulants that cause this finding), and delayed cardiacconduction from high doses of cocaine and some anticholinergicagents (e.g., antihistamines, cyclic antidepressants, and antipsy-chotics). Seizures suggest a sympathetic etiology, an anticholinergicagent with membrane-active properties (e.g., cyclic antidepressants,orphenadrine, phenothiazines), or a withdrawal syndrome. Closeattention to core temperature is critical in patients with grade 4physiologic stimulation ( Table e50-2).

Decreased pulse, blood pressure, respiratory rate, temperature,

and neuromuscular activity are indicative of depressed physiologicstate caused by “functional” sympatholytics (agents that decreasecardiac function and vascular tone as well as sympathetic activity),cholinergic (muscarinic and nicotinic) agents, opioids, and sedative-hypnotic γ -aminobutyric acid (GABA)-ergic agents ( Tables e50-1and e50-2 ). Miosis is also common and most pronounced inopioid and cholinergic poisoning. The latter is distinguished fromother depressant syndromes by the presence of muscarinic and

nicotinic signs and symptoms ( Table e50-1). Pronounced cardiovascular depression in the absence of significant CNS depressionsuggests a direct or peripherally acting sympatholytic. In contrast,in opioid and sedative-hypnotic poisoning, vital sign changes aresecondary to depression of CNS cardiovascular and respiratorycenters (or consequent hypoxemia), and significant abnormalitiesin these parameters do not occur until there is a marked decreasein the level of consciousness (grade 3 or 4 physiologic depression,

Table e50-2). Other clues that suggest the cause of physiologicdepression include cardiac arrhythmias and conduction disturbances(due to antiarrhythmics, β-adrenergic antagonists, calcium-channelblockers, digitalis glycosides, propoxyphene, and cyclic antidepressants),mydriasis [due to tricyclic antidepressants, some antiarrhythmics,meperidine, and diphenoxylate-atropine (Lomotil)], nystagmus(due to sedative-hypnotics), and seizures (due to cholinergic agents,propoxyphene, cyclic antidepressants).

The discordant physiologic state is characterized by mixed vitalsign and neuromuscular abnormalities as observed in poisoningby asphyxiants, CNS syndromes, membrane-active agents, andanion-gap metabolic acidosis (AGMA) inducers ( Table e50-1). Inthese conditions, manifestations of physiologic stimulation andphysiologic depression occur together or at different times duringthe clinical course. For example, membrane-active agents can causesimultaneous coma, seizures, hypotension, and tachyarrhythmias.Alternatively, vital signs may be normal but the patient has alteredmental status or is obviously sick or clearly symptomatic. Early,pronounced vital sign and mental status changes suggest asphyxiantor membrane-active agent poisoning; the lack of such abnormalitiessuggests an AGMA inducer; and marked neuromuscular dysfunc-tion without significant vital sign abnormalities suggests a CNSsyndrome.

A normal physiologic status and physical examination may bedue to a nontoxic exposure, psychogenic illness, or poisoning by“toxic time-bombs,” agents that are slowly absorbed, slowly distrib-uted to their sites of action, require metabolic activation, or disruptmetabolic processes ( Table e50-1). Because so many medicationsare now reformulated in a once-a-day form for patient convenienceand adherence, “toxic time-bombs” are increasingly common.Diagnosing a nontoxic exposure requires that the identity of theexposure agent be known or that a toxic time-bomb exposure hasbeen excluded and that the time since exposure exceeds the longest

known or predicted interval between exposure and peak toxicity.Psychogenic illness (fear of being poisoned, mass hysteria) may alsooccur after a nontoxic exposure and should be considered whensymptoms are inconsistent with the exposure history. Anxiety reac-tions resulting from a nontoxic exposure can cause mild physiologicstimulation ( Table e50-2) and be indistinguishable from toxicologiccauses (Table e50-1) without ancillary testing or a suitable periodof observation.

Laboratory assessment may be helpful in the differential diagno-sis. An increased AGMA is most common in advanced methanol,ethylene glycol, and salicylate intoxication but can occur in anypoisoning that results in hepatic, renal, or respiratory failure;seizures; or shock. The serum lactate concentration is more com-monly low (less than the anion gap) in the former and high (nearlyequal to the anion gap) in the latter. An abnormally low anion gapcan be due to elevated blood levels of bromide, calcium, iodine,

lithium, or magnesium. An increased osmolal gap—a differencebetween the serum osmolality (measured by freezing point depres-sion) and that calculated from the serum sodium, glucose, andblood urea nitrogen of >10 mmol/L—suggests the presence of alow-molecular-weight solute such as acetone; an alcohol (benzyl,ethanol, isopropanol, methanol); a glycol (diethylene, ethylene,propylene); ether (ethyl, glycol); or an “unmeasured” cation(calcium, magnesium) or sugar (glycerol, mannitol, sorbitol).

TABLE e50-2 Severity of Physiologic Stimulationand Depression in Poisoning andDrug Withdrawal

Physiologic Stimulation

Grade 1 Anxious, irritable, tremulous; vital signs normal;diaphoresis, flushing or pallor, mydriasis, and

hyperreflexia may be presentGrade 2 Agitated; may have confusion or hallucinations but is able

to converse and follow commands; vital signs mildly tomoderately increased

Grade 3 Delirious; unintelligible speech, uncontrollable motorhyperactivity; moderately to markedly increased vitalsigns; tachyarrhythmias possible

Grade 4 Coma, seizures, cardiovascular collapse

Physiologic Depression

Grade 1 Awake, lethargic, or sleeping but arousable by voiceor tactile stimulation; able to converse and followcommands; may be confused

Grade 2 Responds to pain but not voice; can vocalize but notconverse; spontaneous motor activity present; brainstemreflexes intact

Grade 3 Unresponsive to pain; spontaneous motor activity absent;brainstem reflexes depressed; motor tone, respirations,and temperature decreased

Grade 4 Unresponsive to pain; flaccid paralysis; brainstem reflexesand respirations absent; cardiovascular vital signsdecreased


4/16

50-4

P A R T 1

8

P o i s o n i n

g ,D r u

g O v e r d

o s e , a n

d E n v e n

o m

a t i o n

Ketosis suggests acetone, isopropyl alcohol, salicylate poisoning,or alcoholic ketoacidosis. Hypoglycemia may be due to poisoningwith β-adrenergic blockers, ethanol, insulin, oral hypoglycemicagents, quinine, and salicylates, whereas hyperglycemia can occurin poisoning with acetone, β-adrenergic agonists, caffeine, calciumchannel blockers, iron, theophylline, or N -3-pyridylmethyl- N ′- p-nitrophenylurea [PNU (Vacor)]. Hypokalemia can be caused bybarium, β-adrenergic agonists, caffeine, diuretics, theophylline,

or toluene; hyperkalemia suggests poisoning with an α-adrenergicagonist, a β-adrenergic blocker, cardiac glycosides, or fluoride.Hypocalcemia may be seen in ethylene glycol, fluoride, and oxalatepoisoning.

The electrocardiogram (ECG) can be useful for rapid diagnos-tic purposes. Bradycardia and atrioventricular block may occurin patients poisoned by α -adrenergic agonists, antiarrhythmicagents, beta blockers, calcium channel blockers, cholinergic agents(carbamate and organophosphate insecticides), cardiac glycosides,lithium, or tricyclic antidepressants. QRS- and QT-interval prolon-gation may be caused by hyperkalemia, various antidepressants,and other membrane-active drugs ( Table e50-1). Ventricular tachy-arrhythmias may be seen in poisoning with cardiac glycosides,fluorides, membrane-active drugs, methylxanthines, sympathomi-metics, antidepressants, and agents that cause hyperkalemia orpotentiate the effects of endogenous catecholamines (e.g., chloralhydrate, aliphatic and halogenated hydrocarbons).

Radiologic studies may occasionally be useful. Pulmonary edema[adult respiratory distress syndrome (ARDS)] can be caused bypoisoning with carbon monoxide, cyanide, an opioid, paraquat,phencyclidine, a sedative-hypnotic, or salicylate; by inhalationof irritant gases, fumes, or vapors (acids and alkali, ammonia,aldehydes, chlorine, hydrogen sulfide, isocyanates, metal oxides,mercury, phosgene, polymers); or by prolonged anoxia, hyper-thermia, or shock. Aspiration pneumonia is common in patientswith coma, seizures, and petroleum distillate aspiration. Thepresence of radiopaque densities on abdominal x-rays suggeststhe ingestion of calcium salts, chloral hydrate, chlorinated hydro-carbons, heavy metals, illicit drug packets, iodinated compounds,potassium salts, enteric-coated tablets, or salicylates.

Toxicologic analysis of urine and blood (and occasionally ofgastric contents and chemical samples) can sometimes confirmor rule out suspected poisoning. Interpretation of laboratory data

requires knowledge of the qualitative and quantitative tests usedfor screening and confirmation (enzyme-multiplied, fluorescencepolarization, and radio-immunoassays; colorimetric and fluoro-metric assays; thin-layer, gas-liquid, or high-performance liquidchromatography; gas chromatography; mass spectrometry), theirsensitivity (limit of detection) and specificity, the preferred bio-logic specimen for analysis, and the optimal time of specimensampling. Personal communication with the hospital laboratoryis essential to understand institutional testing capabilities andlimitations.

Rapid qualitative hospital-based urine tests for drugs of abuseare only screening tests that cannot confirm the exact identity ofthe detected substance and should not be considered diagnostic orused for forensic purposes: False-positive and false-negative resultsare common. A positive screen may result from other pharmaceu-ticals that interfere with laboratory analysis (e.g., fluoroquinolones

commonly cause “false-positive” opiate screens). Confirmatorytesting with gas chromatography/mass spectrometry (GC/MS) canbe requested, but often takes weeks to obtain a reported result. Anegative screening result may mean the substance is not detectableby the test used or that its concentration is too low for detectionat the time of sampling. In the latter case, repeating the test at alater time may yield a positive result. Patients symptomatic fromdrugs of abuse often require immediate management based on the

history, physical examination, and observed toxidrome withoutlaboratory confirmation (e.g., apnea from opioid intoxication).When the patient is asymptomatic, or when the clinical picture isconsistent with the reported history, several studies have shownqualitative screening is neither clinically useful nor cost-effective.Thus, qualitative drug screens are of greatest value when evaluatingpatients with severe or unexplained toxicity such as coma, seizures,cardiovascular instability, metabolic or respiratory acidosis, and

nonsinus cardiac rhythms. In contrast to qualitative drug screens,quantitative serum tests are useful for evaluating patients poisonedwith acetaminophen (Chap. 305 ), alcohols (including ethyleneglycol and methanol), anticonvulsants, barbiturates, digoxin, heavymetals, iron, lithium, salicylate, and theophylline, as well as forcarboxyhemoglobin and methemoglobin. The serum concentrationin these cases guides clinical management, and results can often beavailable within an hour.

The response to antidotes is sometimes useful for diagnosticpurposes. Resolution of altered mental status and abnormal vitalsigns within minutes of IV administration of dextrose, naloxone,or flumazenil is virtually diagnostic of hypoglycemia, narcoticpoisoning, and benzodiazepine intoxication, respectively. Theprompt reversal of dystonic (extrapyramidal) signs and symptomsfollowing an IV dose of benztropine or diphenhydramine confirmsa drug etiology. Although complete reversal of both central andperipheral manifestations of anticholinergic poisoning by physo-stigmine is diagnostic of this condition, physostigmine may causesome arousal in patients with CNS depression of any etiology.

Poisoning and Drug OverdoseTREATMENT

GENERAL PRINCIPLESTreatment goals include support of vitalsigns, prevention of further poison absorption (decontamination),enhancement of poison elimination, administration of specificantidotes, and prevention of reexposure (Table e50-3 ) . Specifictreatment depends on the identity of the poison, the route andamount of exposure, the time of presentation relative to thetime of exposure, and the severity of poisoning. Knowledge ofthe offending agents’ pharmacokinetics and pharmacodynamicsis essential.

During the pretoxic phase , prior to the onset of poisoning,decontamination is the highest priority, and treatment is basedsolely on the history. The maximum potential toxicity basedon the greatest possible exposure should be assumed. Sincedecontamination is more effective when accomplished soonafter exposure, and when the patient is asymptomatic, the initialhistory and physical examination should be focused and brief.It is also advisable to establish IV access and initiate cardiacmonitoring, particularly in patients with potentially seriousingestions or unclear histories.

When an accurate history is not obtainable and a poison caus-ing delayed toxicity (“toxic time-bomb”) or irreversible damageis suspected, blood and urine should be sent for appropriatetoxicologic screening and quantitative analysis. During absorp-tion and distribution, blood levels may be greater than those intissue and may not correlate with toxicity. However, high bloodlevels of agents whose metabolites are more toxic than the parentcompound (acetaminophen, ethylene glycol, or methanol) mayindicate the need for additional interventions (antidotes, dialysis).Most patients who remain or become asymptomatic 6 h afteringestion are unlikely to develop subsequent toxicity and canbe discharged safely. Longer observation will be necessary forpatients who have ingested toxic time-bombs, agents that areslowly absorbed, slowly distributed to their sites of action,


5/16

50-5

C H A P T E R e

5 0

P o i s o n i n

g a n d D r u

g O v e r d

o s a g e

require metabolic activation, or disrupt metabolic processes(Table e50-1). During the toxic phase , the time between the onsetof poisoning and the peak effects, management is based primar-ily on clinical and laboratory findings. Effects after an overdoseusually begin sooner, peak later, and last longer than they do aftera therapeutic dose . A drug’s published pharmacokinetic profilein standard references such as the Physician’s Desk Reference (PDR ) is usually different from its toxicokinetic profile inoverdose. Resuscitation and stabilization are the first priority.Symptomatic patients should have an IV line, oxygen saturationdetermination, cardiac monitoring, and continuous observa-tion. Baseline laboratory, ECG, and x-ray evaluation may alsobe appropriate. Intravenous glucose (unless the serum level isdocumented to be normal), naloxone, and thiamine should be

considered in patients with altered mental status, particularlythose with coma or seizures. Decontamination should also beconsidered, but it is less likely to be effective during this phasethan during the pretoxic one.

Measures that enhance poison elimination may shorten theduration and severity of the toxic phase. However, they are notwithout risk, which must be weighed against the potential benefit.

Diagnostic certainty (usually via laboratory confirmation) is gen-erally a prerequisite. Intestinal (or “gut”) dialysis with repetitivedoses of activated charcoal (also termed multidose activatedcharcoal ) can enhance the elimination of selected poisons suchas theophylline or carbamazepine. Urinary alkalinization mayenhance the elimination of salicylates and a small number of otherpoisons. Chelation therapy can enhance the elimination of selectedmetals. Extracorporeal elimination methods are effective for many

poisons, but their expense and risk make their use reasonable onlyin patients who would otherwise have an unfavorable outcome.

During the resolution phase of poisoning, supportive careand monitoring should continue until clinical, laboratory,and ECG abnormalities have resolved. Since chemicals areeliminated sooner from the blood than from tissues, bloodlevels are usually lower than tissue levels during this phaseand again may not correlate with toxicity. This is particularlytrue when extracorporeal elimination procedures are used.Redistribution from tissues may cause a rebound increase inthe blood level after termination of these procedures. Whena metabolite is responsible for toxic effects, continued treat-ment might be necessary in the absence of clinical toxicity orabnormal laboratory studies.

SUPPORTIVE CARE The goal of supportive therapy is to main-tain physiologic homeostasis until detoxification is accomplishedand to prevent and treat secondary complications such as aspi-ration, bedsores, cerebral and pulmonary edema, pneumonia,rhabdomyolysis, renal failure, sepsis, thromboembolic disease,coagulopathy, and generalized organ dysfunction due to hypox-emia or shock.

Admission to an intensive care unit is indicated for thefollowing: patients with severe poisoning (coma, respiratorydepression, hypotension, cardiac conduction abnormalities, car-diac arrhythmias, hypothermia or hyperthermia, seizures); thoseneeding close monitoring, antidotes, or enhanced eliminationtherapy; those showing progressive clinical deterioration; andthose with significant underlying medical problems. Patientswith mild to moderate toxicity can be managed on a generalmedical service, intermediate care unit, or emergency depart-ment observation area, depending on the anticipated durationand level of monitoring needed (intermittent clinical observa-

tion versus continuous clinical, cardiac, and respiratory moni-toring). Patients who have attempted suicide require continuousobservation and measures to prevent self-injury until they are nolonger suicidal.

Respiratory Care Endotracheal intubation for protectionagainst the aspiration of gastrointestinal contents is of para-mount importance in patients with CNS depression or seizuresas this complication can increase morbidity and mortality rates.Mechanical ventilation may be necessary for patients withrespiratory depression or hypoxemia and to facilitate therapeuticsedation or paralysis in order to prevent or treat hyperthermia,acidosis, and rhabdomyolysis associated with neuromuscularhyperactivity. Since clinical assessment of respiratory functioncan be inaccurate, the need for oxygenation and ventilation isbest determined by continuous pulse oximetry or arterial blood-gas analysis. The gag reflex is not a reliable indicator of the need

for intubation. A patient with CNS depression may maintain air-way patency while being stimulated but not if left alone. Drug-induced pulmonary edema is usually noncardiac rather thancardiac in origin, although profound CNS depression and car-diac conduction abnormalities suggest the latter. Measurementof pulmonary artery pressure may be necessary to establish thecause and direct appropriate therapy. Extracorporeal measures

TABLE e50-3 Fundamentals of PoisoningManagement

Supportive Care

Airway protectionOxygenation/ventilationTreatment of arrhythmiasHemodynamic support

Treatment of seizuresCorrection of temperature abnormalitiesCorrection of metabolic derangementsPrevention of secondary complications

Prevention of Further Poison Absorption

Gastrointestinaldecontamination Gastric lavage Activated charcoal Whole-bowel irrigation Dilution Endoscopic/surgical

removal

Decontamination of other sites Eye decontamination Skin decontamination Body cavity evacuation

Enhancement of Poison Elimination

Multiple-dose activatedcharcoal

Alteration of urinary pHChelation

Extracorporeal removal Hemodialysis Hemoperfusion Hemofiltration Plasmapheresis Exchange transfusionHyperbaric oxygenation

Administration of Antidotes

Neutralization by antibodiesNeutralization by chemicalbinding

Metabolic antagonismPhysiologic antagonism

Prevention of Reexposure

Adult educationChild-proofing

Notification of regulatory agenciesPsychiatric referral


6/16


7/16

50-7

C H A P T E R e

5 0

P o i s o n i n

g a n d D r u

g O v e r d

o s a g e

lumen, allowing the charcoal-toxin complex to be evacuatedwith stool. Charged (ionized) chemicals such as mineral acids,alkalis, and highly dissociated salts of cyanide, fluoride, iron,lithium, and other inorganic compounds are not well adsorbedby charcoal. In animal and human volunteer studies, charcoaldecreases the absorption of ingestants by an average of 73%when given within 5 min of ingestant administration, 51%when given at 30 min, and 36% at 60 min. Side effects of char-

coal include nausea, vomiting, and diarrhea or constipation.Charcoal may also prevent the absorption of orally adminis-tered therapeutic agents. Complications include mechanicalobstruction of the airway, aspiration, vomiting, and bowelobstruction and infarction caused by inspissated charcoal.Charcoal is not recommended for patients who have ingestedcorrosives because it obscures endoscopy.

Gastric lavage should be considered for life-threateningpoisons that cannot be treated effectively with other decontamina-tion, elimination, or antidotal therapies (e.g., colchicine). Gastriclavage is performed by sequentially administering and aspirat-ing ~5 mL fluid per kilogram of body weight through a no. 40French orogastric tube (no. 28 French tube for children). Exceptfor infants, where normal saline is recommended, tap water isacceptable. The patient should be placed in Trendelenburgand left lateral decubitus positions to prevent aspiration (even

if an endotracheal tube is in place). Lavage decreases ingestantabsorption by an average of 52% if performed within 5 min ofingestion administration, 26% if performed at 30 min, and 16%if performed at 60 min. Significant amounts of ingested drugare recovered in


8/16

50-8

P A R T 1

8

P o i s o n i n

g ,D r u

g O v e r d

o s e , a n

d E n v e n

o m

a t i o n

in patients with decreased gut motility. Sorbitol and othercathartics are absolutely contraindicated when administeringmultiple doses of activated charcoal because of electrolyte andfluid shifts.

Urinary Alkalinization Ion trapping via alteration of urine pHmay prevent the renal reabsorption of poisons that undergoexcretion by glomerular filtration and active tubular secretion.Since membranes are more permeable to nonionized moleculesthan to their ionized counterparts, acidic (low-p K a ) poisonsare ionized and trapped in alkaline urine, whereas basic onesbecome ionized and trapped in acid urine. Urinary alkalinization(producing a urine pH ≥7.5 and a urine output of 3–6 mL/kgbody weight per hour by adding sodium bicarbonate to an IVsolution) enhances the excretion of chlorophenoxyacetic acidherbicides, chlorpropamide, diflunisal, fluoride, methotrexate,phenobarbital, sulfonamides, and salicylates. Contraindicationsinclude congestive heart failure, renal failure, and cerebraledema. Acid-base, fluid, and electrolyte parameters should bemonitored carefully. While making theoretical sense for someoverdoses (amphetamines), acid diuresis is never indicated andis potentially harmful.

Extracorporeal Removal Hemodialysis, charcoal or resinhemoperfusion, hemofiltration, plasmapheresis, and exchangetransfusion are capable of removing any toxin from thebloodstream. Agents most amenable to enhanced eliminationby dialysis have low molecular mass (


9/16

50-9

C H A P T E R e

5 0

P o i s o n i n

g a n d D r u

g O v e r d

o s a g e

TABLE e50-4 Pathophysiologic Features and Treatment of Specific Toxic Syndromes and PoisoningsPhysiologicCondition, Causes Examples Mechanism of Action Clinical Features Specific Treatments

Stimulated

Sympathetics (see also Chap. 394)

Sympathomimetics α 1-Adrenergic ago-nists (decongestants):phenylephrine, phe-nylpropanolamineβ2-Adrenergic ago-nists (bronchodilators):albuterol, terbutalineNonspecific adrener-gic agonists: amphet-amines, cocaine,ephedrine

Stimulation of central andperipheral sympatheticreceptors directly or indi-rectly (by promoting therelease or inhibiting thereuptake of norepinephrineand sometimes dopamine)

Physiologic stimulation(Table e50-2); reflexbradycardia can occurwith selective α 1 ago-nists; β agonists cancause hypotension andhypokalemia.

Phentolamine, a nonselectiveα 1-adrenergic receptor antagonist,for severe hypertension due toα 1-adrenergic agonists; propranolol, anonselective β blocker, for hypotensionand tachycardia due to β2 agonists;labetalol, a β blocker with α -blockingactivity, or phentolamine with esmolol,metoprolol, or other cardioselec-tive β blocker for hypertension withtachycardia due to nonselective agents(β blockers, if used alone, can exac-erbate hypertension and vasospasmdue to unopposed α stimulation);benzodiazepines; propofol.

Ergot alkaloids Ergotamine, methy-sergide, bromocrip-tine, pergolide

Stimulation and inhibi-tion of serotonergic andα -adrenergic receptors;

stimulation of dopaminereceptors

Physiologic stimulation(Table e50-2); formica-tion; vasospasm with limb

(isolated or generalized),myocardial, and cerebralischemia progressing togangrene or infarction;hypotension, bradycardia,and involuntary movementscan also occur.

Nitroprusside or nitroglycerine forsevere vasospasm; prazosin (anα 1 blocker), captopril, nifedipine,

and cyproheptadine (a serotoninreceptor antagonist) for mild-to-moderate limb ischemia; dopaminereceptor antagonists (antipsychotics)for hallucinations and movementdisorders

Methylxanthines Caffeine, theophylline Inhibition of adenosinesynthesis and adenosinereceptor antagonism;stimulation of epineph-rine and norepinephrinerelease; inhibition ofphosphodiesterase result-ing in increased intracel-lular cyclic adenosine andguanosine monophosphate

Physiologic stimulation(Table e50-2); pronouncedgastrointestinal symptomsand β agonist effects (seeabove). Toxicity occurs atlower drug levels in chronicpoisoning than in acutepoisoning.

Propranolol, a nonselective β blocker,for tachycardia with hypotension;any β blocker for supraventricularor ventricular tachycardia withouthypotension; elimination enhanced bymultiple-dose charcoal, hemoperfu-sion, and hemodialysis; indications forhemoperfusion or hemodialysis includeunstable vital signs, seizures, and atheophylline level of 80−100 µg/mLafter acute overdose and 40 −60 µg/mLwith chronic exposure.

Monoamineoxidase inhibitors

Phenelzine, tranylcy-promine, selegiline

Inhibition of monoam-ine oxidase resulting inimpaired metabolismof endogenous cate-cholamines and exogenoussympathomimetic agents

Delayed or slowly progres-sive physiologic stimulation(Table e50-2); terminalhypotension and bradycar-dia in severe cases.

Short-acting agents (e.g., nitroprusside,esmolol) for severe hypertensionand tachycardia; direct-acting sym-pathomimetics (e.g., norepinephrine,epinephrine) for hypotension andbradycardia

Anticholinergics

Antihistamines Diphenhydramine,doxylamine,pyrilamine

Inhibition of central andpostganglionic parasym-pathetic muscarinic cho-linergic receptors. At highdoses, amantadine, diphen-hydramine, orphenadrine,phenothiazines, andtricyclic antidepressants

have additional nonanticho-linergic activity (see below).

Physiologic stimulation(Table e50-2); dry skinand mucous membranes,decreased bowel sounds,flushing, and urinary reten-tion; myoclonus and pickingactivity. Central effects mayoccur without significant

autonomic dysfunction.

Physostigmine, an acetylcholin-esterase inhibitor (see below)for delirium, hallucinations, andneuromuscular hyperactivity.Contraindications include asthma,nonanticholinergic cardiovasculartoxicity (e.g., cardiac conductionabnormalities, hypotension, and

ventricular arrhythmias).

Antiparkinsonianagents

Amantadine,trihexyphenidyl

(continued )


10/16


11/16

50-11

C H A P T E R e

5 0

P o i s o n i n

g a n d D r u

g O v e r d

o s a g e

TABLE e50-4 Pathophysiologic Features and Treatment of Specific Toxic Syndromes andPoisonings (Continued )

PhysiologicCondition, Causes Examples Mechanism of Action Clinical Features Specific Treatments

Calcium channelblockers

Diltiazem, nifedipineand other dihydro-pyridine derivatives,verapamil

Inhibition of slow (type L)cardiovascular calciumchannels (class IV antiar-rhythmic effect).

Physiologic depression(Table e50-2), atrioventric-ular block, organ ischemiaand infarction, hyperglyce-mia, seizures. Hypotensionis usually due to decreasedvascular resistance ratherthan to decreased cardiacoutput. Onset may bedelayed for ≥12 h afteroverdose of sustained-release formulations.

Calcium and glucagon for hypoten-sion and symptomatic bradycardia.Dopamine, epinephrine, norepineph-rine, atropine, and isoproterenol areless often effective but can be usedadjunctively. High-dose insulin (withglucose and potassium to maintaineuglycemia and normokalemia),intravenous lipid emulsion therapy,electrical pacing, and mechanicalcardiovascular support for refractorycases.

Cardiac glycosides Digoxin, endogenouscardioactive steroids,foxglove and otherplants, toad skinsecretions(Bufonidae sp.)

Inhibition of cardiacNa+, K +-ATPase membranepump.

Physiologic depression(Table e50-2); gastrointes-tinal, psychiatric, and visualsymptoms; atrioventricularblock with or without con-comitant supraventriculartachyarrhythmia; ven-tricular tachyarrhythmias.

Hyperkalemia in acutepoisoning. Toxicity occursat lower drug levels inchronic poisoning than inacute poisoning.

Digoxin-specific antibody fragmentsfor hemodynamically compromisingdysrhythmias, Mobitz II or third-degreeatrioventricular block, hyperkalemia(>5.5 meq/L; in acute poisoning only).Temporizing measures include atropine,dopamine, epinephrine, and externalcardiac pacing for bradydysrhythmias

and magnesium, lidocaine, or phenytoin,for ventricular tachydysrhythmias.Internal cardiac pacing and cardioversioncan increase ventricular irritability andshould be reserved for refractory cases.

Cyclicantidepressants

Amitriptyline,doxepin, imipramine

Inhibition ofα -adrenergic,dopaminergic, GABA-ergic,histaminergic, muscarinic,and serotonergic receptors;inhibition of sodium channels(see membrane-activeagents); inhibition of nor-epinephrine and serotoninreuptake.

Physiologic depression(Table e50-2), seizures,tachycardia, cardiacconduction delays(increased PR, QRS, JT,and QT intervals; terminalQRS right-axis deviation)with aberrancy and ven-tricular tachydysrhythmias.

Anticholinergic toxidrome(see above).

Hypertonic sodium bicarbonate (orhypertonic saline) and lidocaine forventricular tachydysrhythmias associ-ated with QRS prolongation. Use ofphenytoin is controversial. Avoid classIA, IC, and III antiarrhythmics.

Cholinergics

Acetylcholin-esterase inhibitors

Carbamate insecti-cides (aldicarb, car-baryl, propoxur) andmedicinals (neostig-mine, physostigmine,tacrine); nerve gases(sarin, soman, tabun,

VX) organophosphateinsecticides (diazinon,chlorpyrifos-ethyl,malathion)

Inhibition of acetylcho-linesterase leading toincreased synaptic acetyl-choline at muscarinic andnicotinic cholinergic recep-tor sites

Physiologic depression(Table e50-2). Muscarinicsigns and symptoms: sei-zures, excessive secretions(lacrimation, salivation,bronchorrhea and wheez-ing, diaphoresis), andincreased bowel and blad-der activity with nausea,vomiting, diarrhea,abdominal cramps, andincontinence of feces andurine. Nicotinic signs andsymptoms: hyperten-sion, tachycardia, musclecramps, fasciculations,weakness, and paraly-sis. Death is usually dueto respiratory failure.Cholinesterase activity inplasma and red cells


12/16

50-12

P A R T 1

8

P o i s o n i n

g ,D r u

g O v e r d

o s e , a n

d E n v e n

o m

a t i o n



Sedative-hypnotics (see also Chap. 393)

Anticonvulsants Carbamazepine,

ethosuximide,felbamate, gabapentin,lamotrigine, levetirace-tam, oxcarbazepine,phenytoin, tiagabine,topiramate, valproate,zonisamide

Potentiation of the inhibi-

tory effects of GABA bybinding to the neuronalGABA-A chloride chan-nel receptor complex andincreasing the frequency orduration of chloride chan-nel opening in response toGABA stimulation. Baclofenand, to some extent, GHBact at the GABA-B receptorcomplex; meprobamate,its metabolite carisop-rodol, felbamate, andorphenadrine antagonizeN -methyl-D-aspartate(NDMA) excitatory recep-tors; ethosuximide, val-proate, and zonisamidedecrease conductionthrough T-type calciumchannels; valproatedecreases GABA degrada-tion, and tiagabine blocksGABA reuptake; carbam-azepine, lamotrigine,oxcarbazepine, phenytoin,topiramate, valproate, andzonisamide slow the rateof recovery of inactivatedsodium channels. Someagents also have α 2 ago-nist, anticholinergic, andsodium channel-blockingactivity (see above andbelow).

Physiologic depression

(Table e50-2), nystagmus.Delayed absorption canoccur with carbamazepine,phenytoin, and valproate.Myoclonus, seizures,hypertension, andtachyarrhythmias canoccur with baclofen,carbamazepine, andorphenadrine.

Benzodiazepines , barbiturates, or

propofol for seizures.

Barbiturates Short-acting: but-abarbital, pentobarbi-tal, secobarbitalLong-acting: pheno-barbital, primidone

Hemodialysis and hemoperfusion maybe indicated for severe poisoning bysome agents (see “ExtracorporealRemoval,” in text).

Benzodiazepines Ultrashort-acting:estazolam, mida-zolam, temazepam,triazolam

Short-acting: alpra-zolam, flunitrazepam,lorazepam, oxazepamLong-acting: chlordi-azepoxide, clon-azepam, diazepam,flurazepamPharmacologicallyrelated agents:zaleplon, zolpidem

Tachyarrhythmias can alsooccur with chloral hydrate.

AGMA, hypernatremia,hyperosmolality, hyperam-monemia, chemical hepa-titis, and hypoglycemia canbe seen in valproate poi-soning. Carbamazepine andoxcarbazepine may producehyponatremia from SIADH.

See above and below for treatment ofanticholinergic and sodium-channel(membrane) blocking effects.

GABA precursors γ -Hydroxybutyrate(sodium oxybate;GHB),γ -butyrolactone(GBL), 1,4-butanediol.

Some agents can causeanticholinergic and sodiumchannel (membrane)blocking effects (see aboveand below).

Muscle relaxants Baclofen, carisoprodol,cyclobenzaprine,etomidate, metax-alone, methocarba-mol, orphenadrine,propofol, tizanidineand other imidazolinemuscle relaxants.

Other agents Chloral hydrate,ethchlorvynol, glute-thimide, meprobam-ate, methaqualone,methyprylon

(continued )


13/16

50-13

C H A P T E R e

5 0

P o i s o n i n

g a n d D r u

g O v e r d

o s a g e



Discordant

Asphyxiants

Cytochromeoxidase inhibitors

Cyanide, hydrogensulfide

Inhibition of mitochon-drial cytochrome oxidase,thereby blocking electrontransport and oxida-tive metabolism. Carbonmonoxide also binds tohemoglobin and myoglobinand prevents oxygen bind-ing, transport, and tissueuptake (binding to hemo-globin shifts the oxygendissociation curve to theleft).

Signs and symptoms ofhypoxemia with initialphysiologic stimulationand subsequent depres-sion (Table e50-2); lacticacidosis; normal PO 2 andcalculated oxygen satura-tion but decreased oxygensaturation by co-oximetry(that measured by pulseoximetry is falsely elevatedbut is less than normal andless than the calculatedvalue). Headache andnausea are common withcarbon monoxide. Suddencollapse may occur withcyanide and hydrogensulfide exposure. A bitteralmond breath odor may benoted with cyanide inges-tion, and hydrogen sulfidesmells like rotten eggs.

High-dose oxygen. IV hydroxocobala-min or IV sodium nitrite and sodiumthiosulfate (Lilly cyanide antidote kit)for coma, metabolic acidosis, andcardiovascular dysfunction in cyanidepoisoning.

Methemoglobininducers

Aniline derivatives,dapsone, localanesthetics, nitrates,nitrites, nitrogenoxides, nitro- andnitrosohydrocarbons,phenazopyridine,primaquine-typeantimalarials,sulfonamides.

Oxidation of hemoglobiniron from ferrous (Fe2+) toferric (Fe3+) state preventsoxygen binding, transport,and tissue uptake (methe-moglobinemia shifts oxygendissociation curve to theleft). Oxidation of hemoglo-bin protein causes hemo-globin precipitation andhemolytic anemia (manifestas Heinz bodies and “bite

cells” on peripheral bloodsmear).

Signs and symptoms ofhypoxemia with initialphysiologic stimulation andsubsequent depression(Table e50-2), gray-browncyanosis unresponsive tooxygen at methemoglobinfractions >15–20%, head-ache, lactic acidosis (atmethemoglobin fractions>45%), normal PO 2 andcalculated oxygen satura-

tion but decreased oxygensaturation and increasedmethemoglobin fraction byco-oximetry (oxygen satu-ration by pulse oximetrymay be falsely increased ordecreased but is less thannormal and less than thecalculated value).

High-dose oxygen. Intravenous meth-ylene blue for methemoglobin fraction>30%, symptomatic hypoxemia, orischemia (contraindicated in G6PDdeficiency). Exchange transfusionand hyperbaric oxygen for severe orrefractory cases.

AGMA inducers Ethylene glycol Ethylene glycol causesCNS depression andincreased serum osmolal-ity. Metabolites (primarilyglycolic acid) cause AGMA,CNS depression, and renalfailure. Precipitation ofoxalic acid metabolite ascalcium salt in tissues andurine results in hypocal-cemia, tissue edema, andcrystalluria.

Initial ethanol-like intoxica-tion, nausea, vomiting,increased osmolar gap,calcium oxylate crystalluria.Delayed AGMA, back pain,renal failure. Coma, sei-zures, hypotension, ARDSin severe cases.

Sodium bicarbonate to correctacidemia. Thiamine, folinic acid,magnesium, and high-dose pyridox-ine to facilitate metabolism. Ethanolor fomepizole for AGMA, crystalluriaor renal dysfunction, ethylene glycollevel >3 mmol/L (20 mg/dL), and forethanol-like intoxication or increasedosmolal gap if level not readily obtain-able. Hemodialysis for persistent

AGMA, lack of clinical improvement,and renal dysfunction. Hemodialysisalso useful for enhancing ethyleneglycol elimination and shorteningduration of treatment when ethyleneglycol level >8 mmol/L (50 mg/dL).

(continued )


14/16

50-14

P A R T 1

8

P o i s o n i n

g ,D r u

g O v e r d

o s e , a n

d E n v e n

o m

a t i o n



AGMA inducers Iron Hydration of ferric (Fe3+)ion generates H+. Non-transferrin-bound ironcatalyzes formation offree radicals that causemitochondrial injury, lipidperoxidation, increasedcapillary permeability,vasodilation, and organtoxicity.

Initial nausea, vomiting,abdominal pain, diarrhea.

AGMA, cardiovascular andCNS depression, hepatitis,coagulopathy, and sei-zures in severe cases.Radiopaque iron tabletsmay be seen on abdominalx-ray.

Whole-bowel irrigation for large inges-tions. Endoscopy and gastrostomy ifclinical toxicity and large number oftablets still visible on x-ray. IV hydra-tion. Sodium bicarbonate for acidemia.IV deferoxamine for systemic toxicity,iron level >90 µmol/L (500 µg/dL).

Methanol Methanol causes ethanol-like CNS depression andincreased serum osmolality.Formic acid metabolitecauses AGMA and retinaltoxicity.

Initial ethanol-like intoxica-tion, nausea, vomiting,increased osmolar gap.Delayed AGMA, visual(clouding, spots, blindness)and retinal (edema, hypere-mia) abnormalities. Coma,seizures, cardiovasculardepression in severe cases.Possible pancreatitis.

Gastric aspiration for recent inges-tions. Sodium bicarbonate to correctacidemia. High-dose folinic acid orfolate to facilitate metabolism. Ethanolor fomepizole for AGMA, visual symp-toms, methanol level >6 mmol/L(20 mg/dL), and for ethanol-likeintoxication or increased osmolalgap if level not readily obtainable.Hemodialysis for persistent AGMA,lack of clinical improvement, and renaldysfunction. Hemodialysis also usefulfor enhancing methanol eliminationand shortening duration of treatmentwhen methanol level >15 mmol/L(50 mg/dL).

Salicylate Increased sensitivity ofCNS respiratory center tochanges in P O 2 and PCO 2 stimulates respiration.Uncoupling of oxidativephosphorylation, inhibitionof Krebs cycle enzymes,and stimulation of carbohy-drate and lipid metabolismgenerate unmeasuredendogenous anions and

cause AGMA.

Initial nausea, vomiting,hyperventilation, alkalemia,alkaluria. Subsequentalkalemia with both respi-ratory alkalosis and AGMA,and paradoxical aciduria.Late acidemia with CNSand respiratory depression.Cerebral and pulmonaryedema in severe cases.Hypoglycemia, hypocal-

cemia, hypokalemia, andseizures can occur.

IV hydration and supplemental glucose.Sodium bicarbonate to correctacidemia. Urinary alkalinization forsystemic toxicity. Hemodialysis forcoma, cerebral edema, seizures, pul-monary edema, renal failure, progres-sive acid-base disturbances or clinicaltoxicity, salicylate level >7 mmol/L(100 mg/dL) following acute overdose.

CNS syndromes

Extrapyramidalreactions

Antipsychotics (seeabove), some cyclicantidepressants andantihistamines.

Decreased CNS dopamin-ergic activity with relativeexcess of cholinergicactivity.

Akathisia, dystonia,parkinsonism

Oral or parenteral anticholinergicagent such as benztropine ordiphenhydramine.

Isoniazid Interference with activationand supply of pyridoxal-5-phosphate, a cofactorfor glutamic acid decar-boxylase, which convertsglutamic acid to GABA,results in decreased levelsof this inhibitory CNS neu-rotransmitter; complexationwith and depletion ofpyridoxine itself; inhibi-tion of nicotine-adeninedinucleotide–dependentlactate and hydroxybutyratedehydrogenases resultingin substrate accumulation.

Nausea, vomiting, agitation,confusion; coma, respira-tory depression, seizures,lactic and ketoacidosis insevere cases.

High-dose intravenous pyridoxine(vitamin B6 ) for agitation, confusion,coma, and seizures. Diazepam orbarbiturates for seizures.

(continued )


15/16

50-15

C H A P T E R e

5 0

P o i s o n i n

g a n d D r u

g O v e r d

o s a g e



Lithium Interference with cellmembrane ion transport,adenylate cyclase andNa+, K +-ATPase activity, andneurotransmitter release.

Nausea, vomiting, diarrhea,ataxia, choreoathetosis,encephalopathy, hyper-reflexia, myoclonus, nystag-mus, nephrogenic diabetesinsipidus, falsely elevatedserum chloride with lowanion gap, tachycardia.Coma, seizures, arrhythmias,hyperthermia, and prolongedor permanent encephalopa-thy and movement disordersin severe cases. Delayedonset after acute overdose,particularly with delayed-release formulations. Toxicityoccurs at lower drug levelsin chronic poisoning than inacute poisoning.

Whole-bowel irrigation for large inges-tions. IV hydration. Hemodialysis forcoma, seizures, severe, progressive,or persistent encephalopathy orneuromuscular dysfunction, peaklithium level >4 meq/Lfollowing acute overdose.

Serotonin

syndrome

Amphetamines,

cocaine, dex-tromethorphan,meperidine, MAOinhibitors, selectiveserotonin (5-HT)reuptake inhibitors,tricyclic antidepres-sants, tramadol, trip-tans, tryptophan.

Promotion of serotonin

release, inhibition of sero-tonin reuptake, or directstimulation of CNS andperipheral serotonin recep-tors (primarily 5-HT-1a and5-HT-2), alone or incombination.

Altered mental status (agita-

tion, confusion, mutism,coma, seizures), neuromus-cular hyperactivity (hyper-reflexia, myoclonus, rigidity,tremors), and autonomicdysfunction (abdominal pain,diarrhea, diaphoresis, fever,flushing, labile hypertension,mydriasis, tearing, salivation,tachycardia). Complicationsinclude hyperthermia, lacticacidosis, rhabdomyolysis,and multisystem organfailure.

Serotonin receptor antagonist cypro-

heptadine, discontinue the offendingagent(s).

Membrane-activeagents

Amantadine, anti-arrhythmics (class Iand III agents;some β blockers),antipsychotics (seeabove), antihistamines(particularlydiphenhydramine),carbamazepine, localanesthetics (includingcocaine), opioids(meperidine, propoxy-phene), orphenadrine,quinoline antimalarials(chloroquine,hydroxychloroquine,quinine), cyclicantidepressants (seeabove).

Blockade of fast sodiummembrane channels prolongsphase 0 (depolarization)of the cardiac action poten-tial, which prolongs the QRSduration and promotesreentrant (monomorphic)ventricular tachycardia. ClassIa, Ic, and III antiarrhythmicsalso block potassiumchannels during phases2 and 3 (repolarization) ofthe action potential,prolonging the JT intervaland promoting early after-depolarizations and polymor-phic (torsades des pointes)ventricular tachycardia.Similar effects on neuronalmembrane channelscause CNS dysfunction.Some agents also blockα -adrenergic and cholinergicreceptors or have opioideffects (see above andChap. 393).

QRS and JT prolongation(or both) with hypotension,ventricular tachyarrhyth-mias, CNS depression,seizures. Anticholinergiceffects with amantadine,antihistamines, carbam-azepine, disopyramide,antipsychotics, and cyclicantidepressants (seeabove). Opioid effects withmeperidine and propoxy-phene (see Chap. 393).Cinchonism (hearing loss,tinnitus, nausea, vomiting,vertigo, ataxia, headache,flushing, diaphoresis) andblindness with quinolineantimalarials.

Hypertonic sodium bicarbonate(or hypertonic saline) for cardiacconduction delays and monomorphicventricular tachycardia. Lidocaine formonomorphic ventricular tachycardia(except when due to class Ibantiarrhythmics). Magnesium,isoproterenol, and overdrive pacing forpolymorphic ventriculartachycardia. Physostigmine foranticholinergic effects (see above).Naloxone for opioid effects (seeChap. 393). Extracorporeal removal forsome agents (see text).

Abbreviations: AGMA, anion-gap metabolic acidosis; ARDS, adult respiratory distress syndrome; ATPase, adenosine triphosphatase; CNS, central nervous system; GABA,γ -aminobutyric acid; GHB,γ -hydroxybutyrate; 5-HT, 5-hydroxytryptamine (serotonin); MAO, monoamine oxidase; PCO 2, partial pressure of carbon dioxide; PO 2, partial pressure ofoxygen; SIADH, syndrome of inappropriate antidiuretic hormone; VX, extremely toxic persistent nerve agent (no common chemical name).


16/16

50-16

P A R T 1

8

P o i s o n i n

g ,D r u

g O v e r d

o s e , a n

d E n v e n

o m

a t i o n

The author acknowledges the contributions of Christopher H. Lindenand Michael J. Burns to this chapter in previous editions of this text.

FURTHER READINGS

B GR: The role of activated charcoal and gastric emptying ingastric decontamination: A state-of-the-art review. Ann EmergMed 39:273, 2002

B J: Fomepizole for ethylene glycol and methanol poisoning.N Engl J Med 360:2216, 2009

B AC et al: 2008 Annual Report of the American Associationof Poison Control Centers’ National Poison Data System (NPDS):27th Annual Report. Clin Toxicol (Phila) 48:979, 2010

D RC et al: Expert consensus guidelines for stocking of anti-dotes in hospitals that provide emergency care. Ann Emerg Med54:386, 2009

E TB et al: The approach to the patient with an unknownoverdose. Emerg Med Clin North Am 25:249, 2007

F K et al: Intravenous lipid emulsion for local anesthetic toxicity:a review of the literature. J Med Toxicol 4:184, 2008

F MD et al (eds): Clinical Toxicology . Philadelphia, Saunders,2001

G MI et al (eds): Occupational, Industrial, andEnvironmental Toxicology . St. Louis, Mosby, 2003

H KJ: Acetylcysteine for acetaminophen poisoning. N Engl JMed 359:285, 2008

K TR, O’C PG: Management of drug and alcoholwithdrawal. N Engl J Med 348:1786, 2003

N LS et al (eds):Goldfrank’s Toxicologic Emergencies, 9th ed.New York, McGraw-Hill, 2010.

Documents

Harrison's Chapter e50: Poisoning and Drug Overdosage