Antidotes for Toxicological Emergencies

A Practical Review

Jeanna M. Marraffa, Pharm.D., DABAT; Victor Cohen, Pharm.D.; Mary Ann Howland


Am J Health Syst Pharm. 2012;69(3):199-212. 

In This Article

Antidotes for Cyanide Poisoning

In the United States, there are now two types of cyanide antidotes available. The Lilly Cyanide Antidote Kit was the first and, for many years, the only such kit available; it contained amyl nitrite, sodium nitrite, and sodium thiosulfate. This combination of agents is now available as the branded Cyanide Antidote Package or as the generic Cyanide Antidote Kit, and the components are sold separately by various manufacturers.[41] Nithiodote, recently approved by FDA, contains sodium nitrite and sodium thiosulfate.[42] In 2006, FDA approved hydroxocobalamin, a novel cyanide antidote, available as the branded Cyanokit.[43]

Cyanide binds to the ferric ion on cytochrome oxidase and abruptly halts the electron transport chain and aerobic respiration, producing profound toxic effects. Cyanide also preferentially binds to the ferric ion of methemoglobin, but endogenous concentrations of methemoglobin are quite low.

Exposure to cyanide can occur during house fires, industrial accidents, and attempted suicides, and cyanide is a potential agent of chemical warfare. Smoke inhalation is one of the more common sources of exposure to cyanide in the United States.[44,45] Suicide attempts involving the ingestion of commercially available cyanide salts have been reported.[46] Cyanide overdose has been reported among workers in the gold, jewelry, and textile industries, in which the salts are frequently used. Cyanide exposure causes rapid, severe systemic toxicity and rapid cardiovascular collapse. Although there is no rapid test for the diagnosis of cyanide poisoning, an elevated lactate concentration (>8 mmol/L, or 72 mg/dL)[47] and a venous blood gas with a high partial pressure of oxygen and a high oxygen saturation are, in the appropriate clinical context, highly suggestive of cyanide toxicity and warrant empiric antidotal therapy.

Amyl Nitrite and Sodium Nitrite

The mechanism of action of amyl nitrite and sodium nitrite as antidotes for cyanide poisoning is to produce methemoglobinemia and vasodilation.[48] Vasodilation may contribute to their therapeutic and adverse effects.

Intravenous sodium nitrite produces significant methemoglobinemia.[49] The cyanide bound to cytochrome oxidase is then preferentially bound to methemoglobin, forming cyanomethemoglobin. Rhodanese, an endogenous enzyme, then facilitates the formation of thiocyanate, a much less toxic metabolite, which is renally excreted.

The creation of methemoglobinemia through the use of nitrites for cyanide poisoning entails some risk and, in particular, may be detrimental or even lethal to a patient with smoke inhalation and concurrent carboxyhemoglobinemia or lung injury.[50] Neither carboxyhemoglobin nor methemoglobin is capable of carrying oxygen, so such patients can develop functional hypoxia. Therefore, the administration of the nitrite component of therapy for cyanide poisoning should be avoided in patients with smoke inhalation unless it can be demonstrated that the carboxyhemoglobin level is negligible. The dosage of nitrites should not be adjusted to achieve a predetermined methemoglobin concentration, since the formation of cyanomethemoglobin can potentially be misread as methemoglobin formation by an oximeter during patient monitoring. (A methemoglobin concentration above 20% should halt further nitrite administration.)

In the context of cyanide poisoning, the differences between nitrites lie in the route of administration and the degree of methemoglobinemia they produce.[49,51] Amyl nitrite is inhaled, produces a minimal amount of methemoglobin, and is designed to be administered pending the establishment of i.v. access, as is often the case in the prehospital setting. Sodium nitrite is administered intravenously and results in a methemoglobin concentration of about 15% in healthy adults.[49] In other scenarios of cyanide toxicity, particularly the intentional ingestion of cyanide salts, amyl nitrite can be given to adults as one ampul (0.3 mL) inhaled until i.v. access is obtained, followed by 300 mg (10 mL of 3%) i.v. sodium nitrite over two to four minutes.[41] Children should receive 6 mg/kg (0.2 mL/kg of 3%) sodium nitrite up to the adult dose, at the same rate. This dosing strategy has been established as safe in children with a hemoglobin concentration of ≥7 g/dL). Half of the recommended dosage can be administered if cyanide toxicity reappears or, for prophylaxis, two hours after the initial dosage.

Sodium Thiosulfate

As noted above, cyanide is metabolized by the enzyme rhodanese to a less toxic metabolite, thiocyanate, which is renally eliminated. However, this metabolic pathway is capacity limited. Thiosulfate enhances the activity of rhodanese by donating a sulfur group, thereby increasing the amount of thiocyanate that rhodanese can produce.[52] Sodium thiosulfate is relatively well tolerated, but there is a potential for nausea and vomiting, as well as rate-related hypotension.

Because of its relatively favorable adverse-effect profile, sodium thiosulfate should be given to all patients with suspected cyanide toxicity, including those with smoke inhalation. The recommended dosage of sodium thiosulfate for adults is 12.5 g i.v. (50 mL of 25% solution); for pediatric patients, it is 0.5 g/kg i.v. (2 mL/kg of 25% solution) up to the adult dose. One half of the initial dose can be administered two hours later if toxicity reappears or as a preventive measure. Intravenous sodium thiosulfate should be administered either as a bolus injection or infused over 10–30 minutes immediately after sodium nitrite via the same i.v. line.[41]


Vitamin B12a, or hydroxocobalamin, detoxifies cyanide and forms cyanocobalamin, which is renally excreted. Hydroxocobalamin is an appealing cyanide antidote because it is relatively safe, does not compromise the blood's oxygen-carrying capacity, and, unlike the nitrites or sodium thiosulfate, does not produce hypotension. These features make hydroxocobalamin an ideal agent for empiric use in patients with smoke inhalation who are suspected to have cyanide toxicity.[53,54] Hydroxocobalamin has been found effective for the treatment of acute cyanide poisoning in animal models; in one study of laboratory dogs rendered cyanide toxic, mortality was greatly reduced among dogs given hydroxocobalamin in comparison with those given placebo (21% versus 82%, respectively).[55]

In healthy volunteers, the use of hydroxocobalamin has been linked to chromaturia, dose-dependent erythema, headache, GI distress, pruritus, dysphagia, and infusion-site reactions. Allergic reactions are less frequent but occasionally are severe enough to require intervention. In one study, 25% of volunteers who received hydroxocobalamin experienced a substantial rise in diastolic blood pressure, and three also had a rise in systolic blood pressure; these blood pressure changes were attributed to the effects of hydroxocobalamin on nitric oxide scavenging.[56] A delayed pustular rash appeared on the face and neck of a few participants in that study and took several weeks to resolve.

Hydroxocobalamin is known to cause a reddish discoloration of the urine that typically resolves within 48 hours.[57] Once hydroxocobalamin is administered, the use of laboratory tests that depend on colorimetric techniques is no longer valid, as both hydroxocobalamin and cyanocobalamin are bright red and will cause interference; assays for bilirubin, creatinine, aspartate transaminase (AST), iron, glucose, magnesium, and hemoglobin and most urine assays are among the tests affected. There was a recent case report of a hydroxocobalamin-related colorimetric change resulting in problems with hemodialysis; the machine interpreted the discoloration as a blood leak and shut down automatically.[58] Discoloration of urine by hydroxocobalamin also has been reported to interfere with a spectroscopic assay for urinary thiocyanate that is often used to confirm cyanide exposure.

The use of hydroxocobalamin can also skew the results of serum carboxyhemoglobin determinations, falsely increasing or falsely decreasing the measured concentration. Therefore, if possible, blood samples should be drawn before the administration of hydroxocobalamin.[59–62]

The empiric adult dose of hydroxocobalamin is 5 g, which can be infused over a period of 15 minutes, with the infusion repeated if necessary; the pediatric dose is 70 mg/kg, up to a maximum of the adult dose, administered at the same infusion rate.[43]

There are no published data on the compatibility of hydroxocobalamin with other substances, and the drug should therefore not be administered through the same line as other agents.[43] If another line is not available, sodium thiosulfate can be administered through the same line after hydroxocobalamin administration is completed, with care taken to avoid mixing and inactivating the hydroxocobalamin with sodium thiosulfate.

Implications for the Pharmacist Cyanide toxicity should be considered in patients with sudden cardiovascular collapse, especially in the appropriate context of occupational exposure (e.g., laboratory or industrial work) or in a fire victim with hemodynamic instability, elevated lactic acid, or coma. Cyanide antidotes should be immediately available in the ED.

Digoxin-specific Antibody Fragments

Digoxin-specific antibody fragments (Fab) are lifesaving agents in the management of toxicity associated with the use of digoxin and other cardioactive steroids, including digitoxin and those derived from oleander, fox glove, lily of the valley, and toad venom.[63] They are safe and effective in both adults and children with acute or chronic toxicity.[64–69]

Digitalis, the most widely used cardioactive steroid, has a narrow therapeutic index.[64,68] Cardioactive steroids act on the heart to enhance contractility, act on the conduction system of the heart to produce a variety of effects, and also act on the autonomic nervous system. The agents' toxicity is related to an exaggeration of those effects and often involves an increase in intracellular calcium. Electrocardiographic changes secondary to digoxin toxicity can be marked and highly variable.

In patients with acute digoxin poisoning, empiric treatment with digoxin-specific Fab should be considered in any patient exhibiting consequential rhythm or conduction disturbances, including symptomatic bradycardia or progressive heart block unresponsive to atropine; ventricular arrhythmias such as ventricular tachycardia or fibrillation; or a serum potassium concentration of >5.0 meq/L in the absence of another identifiable cause.[70,71] Significant nausea and vomiting after an acute digoxin overdose might also warrant the use of digoxin-specific Fab, since conduction disturbances are likely to follow. This form of therapy also should be considered if there is firm evidence of ingestion of >4 mg of digoxin by a child or >10 mg by an adult, as those total body loads of digoxin will almost certainly cause significant cardiac toxicity as the digoxin moves from the blood compartment to the heart.

The indications for digoxin-specific Fab therapy in cases of chronic digoxin poisoning are less clear but similar to those for cases of acute poisoning. Treatment with digoxin-specific Fab should be considered in any patient with a life-threatening or potentially life-threatening dysrhythmia, including severe sinus bradycardia or heart block unresponsive to atropine, as well as ventricular ectopy, tachycardia, or fibrillation.[71–73] GI complaints are less common in the context of chronic digoxin poisoning, but confusion and an altered mental status are more frequent in the elderly and might suggest the need for digoxin-specific Fab in a patient with a chronically elevated serum digoxin concentration (>2.5 ng/mL). Patients at risk for chronic digoxin toxicity include elderly patients with declining renal function, patients who have received inappropriate dosages of digoxin, patients with electrolyte abnormalities, and patients administered drugs known to inhibit the elimination of digoxin.

Digoxin-specific Fab is generally well tolerated. The adverse-effect profile includes the potential for hypokalemia, worsening of heart failure, a rapidly conducted ventricular rate, and, rarely, allergic reactions.[64]

The dosage calculation for digoxin-specific Fab can be made according to the known ingested digoxin dose, according to the serum digoxin concentration, or empirically. The empiric dosing for acute toxicity is 10–20 vials (each 38- or 40-mg vial binds 0.5 mg of digoxin); the empiric dosing for chronic toxicity is 3–5 vials for adults and 1–2 vials for children.[73] To calculate a dosage using a known serum digoxin concentration, the concentration (in nanograms per milliliter) is multiplied by the patient's weight (in kilograms) and divided by 100; the result is rounded up to the nearest integer to arrive at the required number of vials.

Implications for the Pharmacist The goal of treatment with digoxin-specific Fab is to reverse digoxin-induced cardiotoxicity. Monitoring should include electrocardiography and serum potassium determinations. Once digoxin-specific Fab has been administered, serum digoxin concentrations are no longer useful in dosage calculation, as there is a resultant increase in the total digoxin concentration; therefore, repeat digoxin concentrations should not be obtained for 24 hours.[74,75]


The intentional ingestion of benzodiazepines is a common cause of overdoses.[2] Flumazenil is a competitive antagonist at the benzodiazepine-receptor binding site on γ-aminobutyric acid-A. Typically, when benzodiazepines are ingested in overdose, the patient exhibits a toxidrome, or toxic syndrome, of CNS depression with relatively normal vital signs. Deaths attributed solely to the oral ingestion of benzodiazepines are rare.

While the idea of using flumazenil to reverse benzodiazepine toxicity may be tempting, the risks usually outweigh the benefits.[76,77] In a benzodiazepine-dependent patient, flumazenil can precipitate symptoms of benzodiazepine withdrawal, including seizures.[77–80] Additionally, in cases of multiple-drug ingestion, flumazenil may remove the protective effect of the benzodiazepine and unmask cardiac arrhythmias and seizures.[76,77,80] Therefore, the use of flumazenil in overdose patients is discouraged unless it can be determined with certainty that only a benzodiazepine was ingested and that the patient is not benzodiazepine dependent and has no history of seizure.

Flumazenil also may serve a role in the treatment of children who present with altered mental status in whom possible ingestion of a benzodiazepine is suspected as the sole toxic exposure. In this scenario, invasive diagnostic techniques such as computed tomography of the head and lumbar puncture may be avoided. In such cases, flumazenil therapy will not reduce the required ED observation time; but if the child improves clinically, flumazenil can help confirm the diagnosis of benzodiazepine toxicity.

Flumazenil can also be used to reverse CNS depression associated with benzodiazepine administration during procedural sedation if the patient is known not to be benzodiazepine dependent. The initial dosage of flumazenil is 0.2 mg/min administered via a slow i.v. infusion. In the context of conscious sedation, many patients respond to total doses of 0.4 mg while some patients may require a total dose of up to 1 mg.[81] The reversal of benzodiazepine toxicity occurs rapidly after flumazenil administration; if resedation occurs, doses can be repeated at intervals of no less than 20 minutes. Resedation after flumazenil therapy is most likely to develop if >10 mg of midazolam or a longer-acting benzodiazepine is used for conscious sedation. No more than 3 mg of flumazenil should be given in one hour. In general, if resedation is not observed within two hours of the administration of a 1-mg dose of flumazenil, subsequent serious resedation is unlikely.[81,82]

Implications for the Pharmacist Due to the associated risk–benefit ratio, flumazenil is rarely indicated in the management of acutely poisoned patients.[76] These patients often have an unclear history, which makes the administration of flumazenil potentially dangerous. Flumazenil does not consistently reverse hypoventilation secondary to benzodiazepine use.[80] In the rare instances when flumazenil may be considered, it is important to ascertain that the patient is not taking benzodiazepines chronically, has a normal electrocardiogram, and is not experiencing toxicity due to a polydrug ingestion. In the context of reversal of conscious sedation, it is important to ensure that the patient has no contraindications to flumazenil, as described above.

Intravenous Fat Emulsion

Intravenous fat emulsion (IFE) has long been used to supply calories in the form of free fatty acids to patients requiring parenteral nutrition. More recently, fatty acid emulsion has been used as an antidote for drug-induced cardiovascular collapse;[83–88] the first supportive studies were laboratory investigations demonstrating the successful use of fatty acid emulsion in increasing the lethal threshold in animal models of bupivacaine-induced cardiac toxicity.[85,88,89] Since those early animal studies, there have been multiple case reports of patients successfully resuscitated after cardiovascular collapse due to toxicity from local anesthetics.[80–84] Those promising results led investigators to hypothesize that IFE would produce similar results in other scenarios of drug toxicity caused by lipid-soluble drugs such as CCBs, β-blockers, and tricyclic antidepressants.[95–98] A case report by Sirianni et al.[99] demonstrated the role of IFE in reversing the effects of an intentional overdose of bupropion and lamotrigine. The mechanism of action has not been precisely elucidated, but the "lipid sink" theory (i.e., lipophilic molecules of a local anesthetic partition into a lipemic plasma compartment, making them unavailable to the tissue) is foremost at this time;[95] other actions that might contribute to the beneficial effects of IFE include the direct activation of myocardial calcium channels[100] and the modulation of myocardial energy by providing the heart with energy in the form of fatty acids.[84,95]

Despite the promising case reports, research on the risks and benefits of IFE as an antidote for toxin-induced cardiovascular collapse remains in the discovery phase. Recently reported data from animal studies suggest that IFE has very limited adverse effects at the doses currently recommended.[101] Potential IFE-related adverse events include the development of fat embolism, or sludging, as well as interference with certain laboratory analyses due to the resultant lipemic blood;[86] other unknowns include the potential for drug interactions with other therapeutic interventions such as HIET.

IFE should be considered a first-line antidote for bupivacaine- induced toxicity.[86,87,90–93] It should also be considered in a patient with presumed toxin-induced cardiovascular collapse after the failure of advanced supportive care measures, including other accepted antidotal therapy. In addition to local anesthetics, potentially toxic agents that should be considered possibly amenable to IFE therapy include those that are lipophilic and toxic to the myocardium (e.g., tricyclic antidepressants; CCBs, especially verapamil and diltiazem; bupropion; propranolol).

The use of IFE for the reversal of cardiotoxicity is not approved by FDA, and the dosing of IFE for this indication is unclear. Based on the published case reports of the successful use of IFE, a reasonable dosing strategy in adults is 20% IFE 100 mL (or 1.5 mL/kg) administered over 1–2 minutes by i.v. push. The bolus dose can be repeated if necessary.[99] Some reports described the use of a continuous infusion of IFE at a rate of 0.25–0.5 mL/kg/min for 30–60 minutes after the bolus dose. The maximum dose of IFE has not been established.[83,84]

Implications for the Pharmacist IFE has changed the management of bupivacaine-induced cardiotoxicity.[87] Before the use of IFE, patients with cardiac arrest secondary to bupivacaine use were rarely resuscitated.[92,93] Today, IFE should be used in any patient with bupivacane-induced cardiac toxicity. The likely scenario for IFE use in the ED is treatment of a patient experiencing toxin-related cardiovascular collapse who is not improving with aggressive standard resuscitation measures and other accepted antidotal therapies. Toxins that are lipophilic and cause cardiac toxicity are most likely to respond to IFE therapy, but data supporting such use of IFE are limited.


N-acetylcysteine (NAC) is a lifesaving therapy in the management of acetaminophen poisoning.[102–109] While acetaminophen is still present in the plasma, NAC acts as an antidote, primarily by replenishing glutathione stores. Secondarily, it acts as a glutathione substitute and replenishes sulfate. These mechanisms of action all serve to either limit the formation of the toxic metabolite or to detoxify it; in this way, if NAC is administered in a timely fashion, acetaminophen toxicity can be prevented.[108,109]

The Rumack-Matthew[106] nomogram is used to predict whether patients will develop hepatotoxicity, defined as a serum AST concentration of >1000 units/L, based on an initial plasma acetaminophen concentration obtained four or more hours after a single acute ingestion of acetaminophen. Indications for the initiation of NAC include a serum acetaminophen level on or above the Rumack-Matthew nomogram; situations in which a serum acetaminophen level is not available within eight hours of a potentially toxic ingestion; and hepatotoxicity, as defined by clinical symptoms or liver enzyme elevations above baseline.

Once fulminant hepatic failure has occurred, whether it is acetaminophen related or not, and even when all of the acetaminophen has already been metabolized, i.v. NAC therapy is still beneficial and may be life saving. In patients with acetaminophen-induced fulminant hepatic failure, i.v. NAC decreased mortality by 50% relative to use of a placebo.[110] NAC is believed to work through antioxidant and antiinflammatory effects, some related to glutathione formation, to improve oxygen delivery and utilization. Intravenous NAC improves cerebral, cardiac, and renal blood flow, resulting in the improved function of extrahepatic organs. NAC may also be beneficial in preventing or treating the hepatotoxicity associated with carbon tetrachloride,[111,112] Amanita phalloides,[113] and other toxins.[114,115]

Although no head-to-head studies comparing i.v. and oral NAC have been published, both routes are believed to be equally efficacious when NAC is administered within eight hours of an acetaminophen overdose;[116] NAC is effective and beneficial when given later, although the rate of hepatotoxicity increases. However, only i.v. NAC is demonstrated to be beneficial in patients with fulminant hepatic failure.[110,117] Theoretically, oral administration should provide a higher concentration of NAC to the liver due to the high extraction ratio, and i.v. dosing should provide a higher serum NAC concentration that may be more beneficial at extrahepatic sites.

The FDA-approved dosing of i.v. NAC is 150 mg/kg as a loading dose infused over 1 hour followed by 50 mg/kg over 4 hours and 100 mg/kg over 16 hours. Anaphylactoid reactions can occur, particularly with the loading dose, which is a concern in the ED; the manufacturer recommends that the loading dose be given over 60 minutes to minimize this risk.[118] In the event of an anaphylactoid reaction, discontinuing the infusion is the first step, to be followed by supportive therapy. Once the reaction abates, i.v. NAC therapy can be restarted at a much slower infusion rate or oral NAC can be administered. In patients with severe reactive airway disease, oral NAC (which rarely produces an anaphylactoid reaction) might be preferred to i.v. NAC. Improper dilution or dosing has resulted in overdoses of NAC, leading to hyponatremia, cerebral edema, and death.[105,110,117,119]

The FDA-approved dosing of oral NAC is 140 mg/kg as a loading dose followed by 70 mg/kg every four hours for a total of 17 doses. The oral dose must be repeated if emesis occurs within one hour. Although oral NAC is rarely associated with anaphylactoid reactions, nausea and vomiting occur frequently, may delay the time to administration of an effective dose, and often require the administration of an antiemetic.[120,121]

The benefits of NAC outweigh the risks in pregnant patients with acetaminophen toxicity who meet the criteria for NAC administration. Although there are conflicting data, i.v. NAC is often recommended with the belief that i.v. NAC more readily crosses the placenta.[122,123]

NAC should not be discontinued until the acetaminophen concentration is undetectable or lower than the level of sensitivity; the AST concentration is normal or significantly improved; the synthetic function of the liver has improved, as evidenced by an International Normalized Ratio of <2; and there is no evidence of an altered mental status due to hepatic encephalopathy.[124]

Implications for the Pharmacist The decision to treat with NAC must be made quickly and based on multiple factors, including the determination of a toxic acetaminophen level and the time since overdose. NAC is nearly 100% hepatoprotective if given within the first eight hours of an overdose, and its efficacy decreases every hour after that.[108] Although most effective if given early, NAC has a clear role in late therapy and has been shown to decrease mortality.[117,125]

NAC therapy should be continued until acetaminophen is undetectable, the AST concentration is improving, and evidence of hepatic failure is no longer present. If treatment is necessary beyond the standard 21-hour dosing regimen for i.v. NAC, the third part of the protocol (6.25 mg/kg/hr) should be continued. Unusually high or prolonged serum acetaminophen concentrations may require a change in the NAC protocol; consultation with a poison center is critical.


The most commonly used antidote in the ED setting,[2] naloxone is a competitive antagonist at all opioid receptors, including the μ-opioid receptor.[126,127] It is a well-established antidote for respiratory depression secondary to opioid toxicity. The efficacy and safety of naloxone are dose dependent. In a previously opioid-naive patient experiencing an opioid overdose, even high doses of naloxone can be given safely.[128] However, in an opioid-dependent patient, an inappropriate dose of naloxone has the potential to precipitate opioid withdrawal and to produce or worsen acute lung injury. Therefore, it is advisable to start with a dose of 0.04 or 0.05 mg in all patients and adjust the dose upward in increments of 0.04–0.05 mg; that approach can safely reverse the respiratory depressant effects of the opioids without producing unwanted and potentially dangerous withdrawal. Opioid withdrawal with abrupt catecholamine release, especially in an apneic patient, is likely to induce vomiting and aspiration or acute lung injury.

Although case reports have suggested that naloxone may be useful in reversing toxicity due to clonidine,[129,130] ibuprofen,[131] valproic acid,[132,133] and captopril,[134] the reported effects were quite variable, often minor, and usually inadequate.

Buprenorphine is a partial μ-agonist whose toxic effects cannot be easily reversed with naloxone. Buprenorphine has a very high affinity for the μ-receptor and most likely affects μ-receptor subtypes in a dose-dependent and variable manner; this makes reversal with naloxone tricky, and a bell-shaped dose–response curve has been described, indicating that a dose too low or too high will be ineffective. In one experimental model, adults required an i.v. naloxone loading dose of 2–3 mg followed by a continuous infusion of 4 mg/hr for one hour before the respiratory depressant effects of buprenorphine were reversed;[135–139] dosages greater than 4 mg/hr were actually ineffective, consistent with a bell-shaped dose–response relationship.

The i.v. route of naloxone administration is preferred due to a predictable, quick, and titratable onset of action. Oral or sublingual administration result in poor absorption and limited effects.[140] Although naloxone is well absorbed with other parenteral routes of administration (intralingual, endotracheal, intranasal, subcutaneous, and intramuscular), a delayed onset of action or difficulty in titrating the dose makes those routes less desirable.

An initial naloxone dose of 0.04–0.05 mg i.v. in both opioid-dependent and opioid-naive adult patients is recommended.[140] Increasing the dose until reversal of respiratory depression maximizes the benefits while minimizing the potential for significant opioid withdrawal. Titration can be accomplished by doubling the dose every one to two minutes or escalating the dose from 0.05 mg to 0.1 mg to 0.4 mg to 2 mg to 10 mg. During dose titration, bag-valve mask ventilation should be used as necessary. Although there is not a consensus on the initial dose, starting with a lower dose of naloxone (0.04–0.05 mg) rather than the "standard" 2-mg dose is considered best practice. A lack of sufficient patient response to treatment with 10 mg of naloxone should call into question a diagnosis of isolated opioid toxicity. Patients experiencing an overdose of synthetic opioids (e.g., buprenorphine, fentanyl, methadone) often require higher doses of naloxone but generally respond to doses of 10 mg.

Due to the relatively short half-life of naloxone, the duration of its clinical effect is generally 30–90 minutes. This relatively brief duration of effect is critical to clinicians because the duration of effect of the opioid is frequently much longer than that of naloxone and, therefore, respiratory depression may recur. Repeat doses or a continuous infusion at an hourly dose equal to two thirds of the initial dose of naloxone may be necessary, so close monitoring of the patient is required in the ED. It is recommended that the naloxone infusion be started at two thirds of the hourly dose that was effective in reversing the respiratory depression. This is based on a pharmacokinetic study done in the 1980s.[140]


A long-acting synthetic analog of somatostatin, octreotide is used in toxicology to counteract the insulin-releasing properties of the sulfonylurea and miglitinide oral hypoglycemics.[141] –148 Sulfonylureas and miglitinides stimulate insulin release by binding to adenosine triphosphate (ATP)-sensitive potassium channels on the beta-islet cell of the pancreas, increasing intracellular ATP concentrations, which increases intracellular calcium concentrations. Octreotide inhibits pancreatic beta-islet cell insulin release via G-protein-coupled receptors[141,142] that inhibit cAMP production; this decreases intracellular calcium influx, thereby causing a decrease in insulin release.[143]

Octreotide is used as an adjunct to dextrose to manage hypoglycemia induced by sulfonylureas and other exogenous causes of insulin release.[142,144] –146 Octreotide limits the production of hypoglycemia and decreases the need for supplemental dextrose in such cases.

There are no published data from randomized clinical trials confirming the unique effects of octreotide in patients with sulfonylurea-induced hypoglycemia. One study of human volunteers confirmed the ability of octreotide to reduce dextrose requirements in fasting patients given sulfonylureas.[141] Case reports described the reversal of sulfonylurea-induced hypoglycemia with octreo-tide in both adults and children.[147] Vallurupalli[148] described two patients with sulfonylurea-induced hypoglycemia and congestive heart failure who had blood glucose concentrations of 31 and 36 mg/dL, respectively, due to inadequate oral intake of glucose and underlying renal failure. Despite repeat doses of dextrose, both patients remained hypoglycemic. One of those patients received two doses of octreotide 50 μg 12 hours apart; after the initial dose, the first blood glucose value was 62 mg/dL, and the concentration rose to 121 mg/dL after the second dose. In the second case reported by Vallurupalli, the patient initially received 25 μg of octreotide subcutaneously, but the hypoglycemia persisted until two additional doses of 50 μg given 12 hours apart were administered.

Adverse effects associated with several doses of octreotide are minimal and may include diarrhea and abdominal discomfort. Octreotide has a relatively benign adverse-effect profile with short-term use, and it is therefore recommended that octreotide be considered in any patient with recurrent hypoglycemia after a single dose of i.v. hypertonic dextrose (0.5–1 g/kg) when the differential diagnosis includes sulfonylurea toxicity. The use of i.v. dextrose should be followed by feeding the patient.

Subcutaneous administration is the most frequently described method of octreotide delivery in the scientific literature.[142,146] The usual adult dose of octreotide is 50 μg subcutaneously, with doses repeated every six hours as needed.

Implications for the Pharmacist Octreotide decreases insulin release from the pancreas when secondary to an insulin secretatogue. In otherwise healthy patients (i.e., patients without diabetes) with an intact pancreas, the administration of exogenous dextrose to reverse the hypoglycemia caused by ingestion of an oral hypoglycemic induces the pancreas to release more insulin, which can exacerbate the hypoglycemia. Some clinicians advocate the use of octreotide after the first hypoglycemic episode, although most suggest that it should be initiated after the second hypoglycemic event.[142] The duration of effect of the ingested xenobiotic causing the hypoglycemia should help determine the initial number of doses of octreotide and the duration of monitoring after the last dose of octreotide.


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