Toxicology
Acetylcysteine (mucomyst ®, cetylev™ )
Mechanism of action: Acetaminophen Overdose: Acetaminophen is absorbed from the upper gastrointestinal tract with peak plasma levels occurring between 30 and 60 minutes after therapeutic doses and usually within 4 hours following an overdose. It is extensively metabolized in the liver to form principally the sulfate and glucoronide conjugates which are excreted in the urine. A small fraction of an ingested dose is metabolized in the liver by isozyme CYP2E1 of the cytochrome P-450 mixed function oxidase enzyme system to form a reactive, potentially toxic, intermediate metabolite. The toxic metabolite preferentially conjugates with hepatic glutathione to form nontoxic cysteine and mercapturic acid derivatives, which are then excreted by the kidney. Recommended therapeutic doses of acetaminophen are not believed to saturate the glucuronide and sulfate conjugation pathways and therefore are not expected to result in the formation of sufficient reactive metabolite to deplete glutathione stores. However, following ingestion of a large overdose, the glucuronide and sulfate conjugation pathways are saturated resulting in a larger fraction of the drug being metabolized via the cytochrome P-450 pathway and therefore, the amount of acetaminophen metabolized to the reactive intermediate increases. The increased formation of the reactive metabolite may deplete the hepatic stores of glutathione with subsequent binding of the metabolite to protein molecules within the hepatocyte resulting in cellular necrosis. Acetylcysteine I.V. Treatment: ------------------------------ I.V. (Acetadote®): Loading dose: 150 mg/kg over 60 minutes. Maintenance dose: 50 mg/kg infused over 4 hours followed by 100 mg/kg infused over 16 hours. Note: To avoid fluid overload in patients <40 kg and those requiring fluid restriction, decrease volume of D5W proportionally. ------------------------------ Inhalation, nebulization (face mask, mouth piece, tracheostomy): Acetylcysteine 10% and 20% solution (Mucomyst®) (dilute 20% solution with sodium chloride or sterile water for inhalation); 10% solution may be used undiluted Children and Adults: 3-5 mL of 20% solution or 6-10 mL of 10% solution until nebulized given 3-4 times/day; dosing range: 1-10 mL of 20% solution or 2-20 mL of 10% solution every 2-6 hours Inhalation, nebulization (tent, croupette): Children and Adults: Dose must be individualized; may require up to 300 mL solution/treatment Diagnostic bronchogram: Nebulization or intrathecal: Adults: 1-2 mL of 20% solution or 2-4 mL of 10% solution administered 2-3 times prior to procedure Supplied: Solution, as sodium (Mucomyst®): 10% [100 mg/mL] (4 mL, 10 mL, 30 mL); 20% [200 mg/mL] (4 mL, 10 mL, 30 mL) Drug UPDATES: CETYLEV™ (acetylcysteine) effervescent tablets for oral solution Initial U.S. Approval: 2016 Mechanism of Action: INDICATIONS AND USAGE: DOSAGE AND ADMINISTRATION: HOW SUPPLIED: |
Charcoal
CLINICAL PHARMACOLOGY Activated Charcoal: Activated charcoal is produced by pyrolysis of organic material, such as wood, and an activation process which cleanses and fragments the charcoal by exposure to an oxidizing gas compound of steam, oxygen, and acids at high temperatures resulting in increased surface area through the creation of numerous external and internal pores. These pores serve as reservoirs to adsorb substances admixed with activated charcoal, making it a useful adsorbent for specified toxins. Activated charcoal is pharmacologically inert and is not absorbed in the gastrointestinal tract.Activated charcoal will adsorb a variety of organic and inorganic substances, but is especially effective in adsorbing compounds within a molecular weight range of l00 to 1,000 Daltons (AMU's). Several other physiologic and physicochemical factors influence the adsorptive capacity of activated charcoal including: pH, charcoal:drug ratio, gastric contents, and adsorption kinetics. DOSAGE AND ADMINISTRATION ----------------------------------------------------- 1 - 12 years of age: Adults (over 12 yrs.): 50 gm [96 gm sorbitol] (240 ml) ----------------------------------------------------- ----------------------------------------------------- ---------------------------------------- Children: 1 g/kg as a single dose; if multiple doses are needed, additional doses can be given as 0.25 g/kg every hour or equivalent (ie, 0.5 g/kg every 2 hours) or >1 year-12 years: 25-50 g as a single dose; smaller doses (10-25 g) may be used in children 1-5 years due to smaller gut lumen capacity Children >12 years and Adults: 25-100 g as a single dose; if multiple doses are needed, additional doses may be given as 12.5 g/hour or equivalent (ie, 25 g every 2 hours) ---------------------------------------- Supplied: Liquid, activated: Liquid, activated [with sorbitol]: Pellets, activated (EZ-Char™): 25 g |
Deferasirox - jadenu® tablets
Drug UPDATES: JADENU® (deferasirox) tablets [Drug information / PDF] Click link for the latest monograph Dosing: Click (+) next to Dosage and Administration section (drug info link) Initial U.S. Approval: 2015 Mechanism of Action: JADENU (deferasirox) is an orally active chelator that is selective for iron (as Fe3+). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Although deferasirox has very low affinity for zinc and copper there are variable decreases in the serum concentration of these trace metals after the administration of deferasirox. The clinical significance of these decreases is uncertain. INDICATIONS AND USAGE: 1.2 Treatment of Chronic Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes 1.3 Limitation of Use HOW SUPPLIED: 90mg, 180mg, 360 mg tablets |
Deferoxamine (desferal ®)
Iron-chelating agent. Dosing (Adults): Acute iron intoxication: 1 gram IV/IM initially, then 500 mg every 4 hr for 2 doses, then subsequent doses of 500 mg every 4-12 hr as needed. MAX 6 g/day. Note: IV route is used when severe toxicity is evidenced by systemic symptoms (coma, shock, metabolic acidosis, or severe gastrointestinal bleeding) or potentially severe intoxications (serum iron level >500 mcg/dl). When severe symptoms are not present, the I.M. route may be preferred (per manufacturer). Chronic iron overload: 0.5-1 g/day IM, plus 2 g IV per unit of blood. Max of 1 g/day with no transfusion, 6 g/day if 3 or more units of infused blood or packed red blood cells. Alternative: 1-2 g SC (20-40 mg/kg/day) infused over 8-24 hr . Administration: IM route preferred for all patients with acute iron intoxication not in shock. IV administration only for patients in state of cardiovascular collapse and then only by slow infusion. Maximum IV rate: 15 mg/kg/hr for first 1000 mg. Subsequent IV dosing, if needed - Maximum rate 125 mg/hr. Renal Dosing: crcl <10 ml/min: Administer 50% of dose. Supplied: Injection (powder for reconstitution): 500 mg, 2 g |
Digoxin immune fab (digibind ®)
Reconstitution: Dissolve each vial with 4 ml sterile water (do not shake). May be further diluted with normal saline. Infuse over 30 minutes-- must use 0.22 micron filter. If cardiac arrest is imminent, may give as a bolus.
CLINICAL PHARMACOLOGY The affinity of DIGIBIND for digoxin is in the range of 109 to 1011 M-1, which is greater than the affinity of digoxin for (sodium, potassium) ATPase, the presumed receptor for its toxic effects. The affinity of DIGIBIND for digitoxin is about 108 to 109 M-1. DIGIBIND binds molecules of digoxin, making them unavailable for binding at their site of action on cells in the body. The Fab fragment-digoxin complex accumulates in the blood, from which it is excreted by the kidney. The net effect is to shift the equilibrium away from binding of digoxin to its receptors in the body, thereby reversing its effects. ----------------------------------- Manifestations of life-threatening toxicity include severe ventricular arrhythmias such as ventricular tachycardia or ventricular fibrillation, or progressive bradyarrhythmias such as severe sinus bradycardia or second or third degree heart block not responsive to atropine. Ingestion of more than 10 mg of digoxin in previously healthy adults or 4 mg of digoxin in previously healthy children, or ingestion causing steady-state serum concentrations greater than 10 ng/mL, often results in cardiac arrest. Digitalis-induced progressive elevation of the serum potassium concentration also suggests imminent cardiac arrest. If the potassium concentration exceeds 5 mEq/L in the setting of severe digitalis intoxication, therapy with DIGIBIND is indicated. CONTRAINDICATIONS ----------------------------------- Digoxin Immune Fab
Fab dose based on serum drug level postdistribution: Digitoxin: No. of vials = digitoxin (ng/mL) x body weight (kg) divided by 1000 If neither amount ingested nor drug level are known, dose empirically as follows: For chronic toxicity: 6 vials; for infants and small children </=( 20kg), a single vial may be sufficient DigiFab™: 40 mg |
Flumazenil (romazicon ®)
CLINICAL PHARMACOLOGY Flumazenil, an imidazobenzodiazepine derivative, antagonizes the actions of benzodiazepines on the central nervous system. Flumazenil competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex. Flumazenil is a weak partial agonist in some animal models of activity, but has little or no agonist activity in man. Flumazenil does not antagonize the central nervous system effects of drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor (including ethanol, barbiturates, or general anesthetics) and does not reverse the effects of opioids. In animals pretreated with high doses of benzodiazepines over several weeks, flumazenil injection elicited symptoms of benzodiazepine withdrawal, including seizures. A similar effect was seen in adult human subjects. INDICATIONS AND USAGE Pediatric Patients (aged 1 to 17) CONTRAINDICATIONS -in patients with a known hypersensitivity to flumazenil or benzodiazepines. ----------------------------------------------- Overdose reversal: 0.2 mg IV over 30 seconds. If the desired level of consciousness is not obtained after waiting 30 seconds, a further dose of 0.3 mg IV over another 30 seconds may be given. Additional doses of 0.5 mg IV over 30 seconds at 1 minute intervals may be given up to a cumulative dose of 3 mg. In the event of re-sedation, repeated doses may be given at 20 minute intervals if needed. For repeat treatment, no more than 1 mg (given as 0.5 mg/min) should be given at any one time and no more than 3 mg should be given in any one hour. ----------------------------------------------- Parenteral: For I.V. use only; administer via freely running I.V. infusion into larger vein to decrease chance of pain, phlebitis
Resedation: Repeated doses may be given at 20-minute intervals as needed; repeat treatment doses of 1 mg (at a rate of 0.5 mg/minute) should be given at any time and no more than 3 mg should be given in any hour. After intoxication with high doses of benzodiazepines, the duration of a single dose of flumazenil is not expected to exceed 1 hour; if desired, the period of wakefulness may be prolonged with repeated low intravenous doses of flumazenil, or by an infusion of 0.1-0.4 mg/hour. Most patients with benzodiazepine overdose will respond to a cumulative dose of 1-3 mg and doses >3 mg do not reliably produce additional effects. Rarely, patients with a partial response at 3 mg may require additional titration up to a total dose of 5 mg. If a patient has not responded 5 minutes after receiving a cumulative dose of 5 mg, the major cause of sedation is not likely to be due to benzodiazepines. Supplied: |
Fomepizole (antizol ®)
CLINICAL PHARMACOLOGY Mechanism of Action: Antizol® (fomepizole) is a competitive inhibitor of alcohol dehydrogenase. Alcohol dehydrogenase catalyzes the oxidation of ethanol to acetaldehyde. Alcohol dehydrogenase also catalyzes the initial steps in the metabolism of ethylene glycol and methanol to their toxic metabolites. Ethylene glycol, the main component of most antifreezes and coolants, is metabolized to glycoaldehyde, which undergoes subsequent sequential oxidations to yield glycolate, glyoxylate, and oxalate. Glycolate and oxalate are the metabolic byproducts primarily responsible for the metabolic acidosis and renal damage seen in ethylene glycol toxicosis. The lethal dose of ethylene glycol in humans is approximately 1.4 mL/kg. Methanol, the main component of windshield wiper fluid, is slowly metabolized via alcohol dehydrogenase to formaldehyde with subsequent oxidation via formaldehyde dehydrogenase to yield formic acid. Formic acid is primarily responsible for the metabolic acidosis and visual disturbances (e.g., decreased visual acuity and potential blindness) associated with methanol poisoning. A lethal dose of methanol in humans is approximately 1-2 mL/kg. INDICATIONS AND USAGE CONTRAINDICATIONS -------------- Dosing: loading dose: 15 mg/kg, followed by 10 mg/kg every 12 hours x 4 doses, then 15 mg/kg every 12 hours thereafter until ethylene glycol levels <20 mg/dl. Dialysis should be considered in addition to fomepizole in the case of renal failure, significant or worsening metabolic acidosis, or a measured ethylene glycol level >50 mg/dl. Fomepizole is dialyzable and should be given q4h during hemodialysis. Supplied: |
Methylene blue
CLINICAL PHARMACOLOGY Methylene blue is Phenothiazin-5-ium, 3,7-bis (dimethylamino)-, chloride, trihydrate. It will produce two opposite actions on hemoglobin. Low concentrations will convert methemoglobin to hemoglobin. High concentrations convert the ferrous iron of reduced hemoglobin to ferric iron which results in the formation of methemoglobin. INDICATIONS DOSAGE AND ADMINISTRATION ---------- Supplied: Tablet (Urolene Blue®): 65 mg |
Naloxone (narcan ®)
CLINICAL PHARMACOLOGY Naloxone prevents or reverses the effects of opioids including respiratory depression, sedation and hypotension. Also, it can reverse the psychotomimetic and dysphoric effects of agonist-antagonists such as pentazocine. Naloxone is an essentially pure opioid antagonist, i.e., it does not possess the “agonistic” or morphine-like properties characteristic of other opioid antagonists. When administered in usual doses in the absence of opioids or agonistic effects of other opioid antagonists, it exhibits essentially no pharmacologic activity. Naloxone has not been shown to produce tolerance or cause physical or psychological dependence. In the presence of physical dependence on opioids, naloxone will produce withdrawal symptoms. However, in the presence of opioid dependence, withdrawal symptoms will appear within minutes of naloxone administration and will subside in about 2 hours. The severity and duration of the withdrawal syndrome are related to the dose of naloxone and to the degree and type of dependence. While the mechanism of action of naloxone is not fully understood, in vitro evidence suggests that naloxone antagonizes opioid effects by competing for the mu, kappa, and sigma opiate receptor sites in the CNS, with the greatest affinity for the mu receptor. When naloxone hydrochloride is administered intravenously (I.V.), the onset of action is generally apparent within two minutes; the onset of action is slightly less rapid when it is administered subcutaneously (S.C.) or intramuscularly (I.M.). The duration of action is dependent upon the dose and route of administration of naloxone hydrochloride. Intramuscular administration produces a more prolonged effect than intravenous administration. Since the duration of action of naloxone may be shorter than that of some opiates, the effects of the opiate may return as the effects of naloxone dissipate. The requirement for repeat doses of naloxone will also be dependent upon the amount, type and route of administration of the opioid being antagonized. Adjunctive Use in Septic Shock Because of the limited number of patients who have been treated, optimal dosage and treatment regimens have not been established. INDICATIONS AND USAGE Naloxone hydrochloride is also indicated for the diagnosis of suspected or known acute opioid overdosage. Naloxone hydrochloride injection may be useful as an adjunctive agent to increase blood pressure in the management of septic shock CONTRAINDICATIONS --------------------------------- Dosing: Opiate intoxication: >5 years or >/= 20 kg: 2 mg/dose; if no response, repeat every 2-3 minutes; may need to repeat doses every 20-60 minutes Narcotic overdose: Adults: I.V.: 0.4 to 2 mg every 2-3 minutes as needed; may need to repeat doses every 20-60 minutes, if no response is observed after 10 mg, question the diagnosis. Note: Use 0.1-0.2 mg increments in patients who are opioid dependent and in postoperative patients to avoid large cardiovascular changes. Intratracheal: Dilute to 1-2 mL with normal saline IV infusion: ( 2 mg/500 ml per manufacturer) - Usual infusion rate: @ 0.4 mg/hr (100 ml/hr)-titrate to respiratory rate/ level of consciousness. Supplied: |
Sodium polystyrene sulfonate (kayexalate ®)
Dosing (Adults): Hyperkalemia: 15 to 30 grams (60 ml) orally 1 to 4 times daily or 30-50 g rectally every 6 hours. Alternatively: 15 to 50 grams orally (bid-qid). PK: Onset: within 1 - 2 hours. Duration: 4 - 6 hours. Rectal route: Adults: 30 to 50 grams q6h. The enema should be retained for least 30 to 60 minutes and followed by a cleansing enema. After the initial cleansing enema, a soft, large rubber tube is inserted and secured at about 20 cm into the rectum with the tip well into the sigmoid colon. The resin suspension is introduced by gravity and flushed by an additional 50 to 100 ml fluid. The tube is clamped and left in place for several hours if possible. The colon is then flushed with up to 2 quarts of a non-sodium containing solution to remove the resin and to prevent necrosis. Exchange capacity is 1 mEq/gram in vivo, and in vitro capacity is 3.1 mEq/g, therefore, a wide range of exchange capacity exists such that close monitoring of serum electrolytes (potassium, sodium, calcium, magnesium) is necessary; ECG. Supplied: Suspension: 15 g/60 ml. |
Sorbitol
Reference(s)
National Institutes of Health, U.S. National Library of Medicine, DailyMed Database.
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