Common Antidotes in Brief

1. Common Antidotes in Brief Dr. M Foroughian Emergency Department Mashhad University of Medical Sciences

2. NAC…indications: • N-Acetylcysteine (NAC) is the cornerstone of therapy in lethal acetaminophen overdose. • NAC also has a role in limiting toxicity caused by glutathione depletion and free radical formation, such as from carbon tetrachloride, chloroform, and possibly valproic acid. • Finally, NAC is useful in the management of fulminant hepatic failure. • prevention of further renal impairment in patients with CRF administered a radiographic-contrast agent • hepatorenal syndrome. • exposure to certain metals such as cobalt and chromium NAC

3. Acetaminophen toxicity: • A toxic exposure to acetaminophen is suggested when a patient ≥6 y ingests (1) >10 grams or 200 milligrams/kg as a single ingestion, • (2) >10 grams or 200 milligrams/kg over a 24-hour period, or • (3) >6 grams or 150 milligrams/kg per 24-hour period for at least 2 consecutive days. • For children <6 years old, ingestion of 200 milligrams/kg or more of acetaminophen as a single ingestion or over an 8-hour period, or of 150 milligrams/kg per 24-hour period for the preceding 48 hours is considered a toxic exposure. NAC

4. Clinical use of NAC in acetaminophen toxicity: • Rumack-Matthew nomogram • results of blood tests will not be available within 8 hours of the ingestion • Increasing LFT NAC

5. NAC

6. NAC Doses: • The 21-hour intravenous NAC protocol is: (preferred) • 150 mg/kg loading dose over 60 minutes,(+200 cc DW5%) • 50 mg/kg over 4 hours, + (500cc DW5%) • 100 mg/kg over 16 hours, + (1 L DW5%) for a total dose 300 mg/kg. • The 72-hour oral regimen is: • 140-mg/kg loading dose followed by 70 mg/kg for 17 additional doses, for a total dose of 1330 mg/kg. • If hepatic failure intervenes, IV NAC should be administered at a dose of 150 mg/kg in D5W infused over 24 hours NAC

7. IV or Oral NAC: • We now recommend IV NAC for essentially all patients without asthma or bronchospasm and no history of a prior anaphylactoid reaction or contraindication to IV NAC, and in patients in whom the development of an anaphylactoid reaction can be tolerated. • Oral NAC should be considered when it is unlikely that the full course of therapy is indicated. NAC

8. Adverse reaction of NAC: • NAC is FDA Pregnancy Category B. • If angioedema or an anaphylactoid reaction characterized by hypotension, shortness of breath or wheezing, flushing, or erythema occurs, the NAC should be stopped and standard symptomatic therapy instituted. Once the reaction resolves NAC can be carefully readministered after an hour. • If the reaction persists or worsens, discontinue IV NAC and consider switching to oral NAC. • Adverse reactions confined to flushing and erythema are usually transient, and NAC may be continued with meticulous monitoring. • Urticaria can be managed with diphenhydramine with the same precautions. NAC

9. NAC

10. Glucagon: • Its traditional role is to reverse life-threatening hypoglycemia in diabetic patients who are unable to ingest dextrose in the outpatient setting. • In medical toxicology, however, glucagon is used in the management of -adrenergic antagonist and calcium channel blocker overdoses Glucagon

11. PHARMACOKINETICS • In human volunteers, after a single IV bolus, the effects of glucagon on the heart begin within 1–3 minutes, are maximal within 5–7 minutes, and persist for 10–15 minutes. • The time to maximal glucose concentration is 5–20 minutes, with a duration of action of 60–90 minutes. • Smooth muscle relaxation begins within 1 minute and lasts 10–20 minutes. Glucagon

12. ROLE IN OVERDOSES WITH -ADRENERGIC ANTAGONISTS • Overdoses with -adrenergic antagonists are particularly dangerous and are manifested by hypotension, bradycardia, prolonged atrioventricular conduction times, depressed cardiac output, cardiac failure, and death • Glucagon increases contractility, restores the sinus node function after sinus node arrest, increases atrioventricular (AV) conduction time, and improves survival. • Glucagon has successfully reversed bradydysrhythmias and hypotension in patients previously unresponsive to multiple other drugs, and should be administered early in the management of patients with severe overdoses Glucagon

13. ROLE IN CALCIUM CHANNEL BLOCKER OVERDOSE • CCB overdoses produce a constellation of clinical findings similar to those recognized with -adrenergic antagonist overdoses, including hypotension, bradycardia, heart block, and myocardial depression. • Glucagon reverses the myocardial depression produced by nifedipine, diltiazem, and verapamil. Glucagon

14. REVERSAL OF HYPOGLYCEMIA • Glucagon stimulates the breakdown of glycogen in the liver to glucose • Glucagon, however, requires time to act and may be ineffective in a patient with depleted glycogen stores. • Patients with type 2 diabetes are also more likely to respond than are patients with type 1 diabetes. Glucagon

15. DOSING • An initial IV bolus of 50 μg/kg infused over 1–2 minutes is recommended (3–5 mg in a 70-kg person). • Higher doses may be necessary if the initial bolus is ineffective, and up to 10 mg may be used in an adult. • In many cases, the bolus dose is followed by a continuous infusion of 2–5 mg/h (up to 10 mg/h) in 5% dextrose in water, which can then be tapered as the patient improves. Glucagon

16. Sodium Bicarbonate • Sodium bicarbonate (NaHCO3) is a nonspecific antidote effective in the treatment of a variety of poisonings by means of a number of distinct mechanisms. • It is most commonly employed to reverse the cardiotoxicity of xenobiotics that block sodium channels, enhance the elimination of weak acids by trapping them in the urine, and to correct life-threatening acidosis generated from toxic alcohols. Sodium Bicarbonate

17. Tricyclic Antidepressants • Sodium bicarbonate can reverse the cardiotoxic effects of (TCAs) and other type IA and type IC antidysrhythmics. • The most common indications are conduction delays manifested by QRS >0.10 seconds, Ravr 3 mm, or RBBB , wide-complex tachydysrhythmias, and hypotension. • In situations in which the QRS duration is less than 0.10 seconds (given the negligible risk of seizures or dysrhythmias), prophylactic use of sodium bicarbonate is not indicated. Sodium Bicarbonate

18. Doses in TCA: • One to 2 mEq of sodium bicarbonate per kg body should be administered intravenously as a bolus over a period of 1–2 minutes. • Sodium bicarbonate can then be repeated as needed to achieve a blood pH of 7.50–7.55 • The end point of treatment is a narrowing of the QRS interval. • Because sodium bicarbonate has a brief duration of effect, a continuous infusion is usually required after the intravenous bolus. Sodium Bicarbonate

19. Bicarbonate in Salicylates • Sodium bicarbonate is indicated in the treatment of salicylate poisoning for most patients with evidence of significant systemic toxicity • For the patient with acidemia, rapid correction is indicated with intravenous administration of 1–2 mEq/kg body weight of sodium bicarbonate. • Pay attention to hypokalemia Sodium Bicarbonate

20. Bicarbonate in Phenobarbital • Although cardiopulmonary support is the most critical intervention in the treatment of patients with severe phenobarbital overdose, sodium bicarbonate may be a useful adjunct to the general supportive care • Phenobarbital is a weak acid (pKa 7.24) that undergoes significant renal elimination • However, this beneficial effect was less than the effect achieved by multiple-dose activated charcoal (MDAC), which reduced the half-life to 19 hours. Sodium Bicarbonate

21. Atropine: • Atropine is the prototypical antimuscarinic drug • It is a competitive antagonist at both central and peripheral muscarinic receptors, that is used to treat symptomatic exposures to muscarinic agonists and acetylcholinesterase inhibitors such as organic phosphorous pesticides and organic phosphorus chemical warfare nerve agents. • The duration of action of atropine is dose and route dependent and may last 24 hours or longer, depending on the particular end point being evaluated. Atropine

22. PHARMACOKINETICS • Atropine is absorbed rapidly from most routes of administration, including inhalation, oral, and IM. • Oral ingestion of 1 mg of atropine produced maximal effects on heart rate and on salivary secretions at 1 and 3 hours respectively. The plasma concentrations of atropine are similar at 1 hour following either 1 mg IV or IM in adults. • Following IM administration of 0.02 mg/kg in adults, the absorption rate and elimination rates were 8 minutes and 2.5 hours, respectively. Atropine

23. INDICATIONS • For the treatment of organic phosphorous and carbamate poisoning, atropine is used either alone or in combination with 2-PAM. • Additional indications include poisoning by muscarine-containing mushrooms, cholinergic medications, and to a lesser extent, to reverse bradycardia induced by cardioactive steroids, -adrenergic antagonists, and calcium channel blockers. Atropine

24. DOSAGE • The dosage of atropine for organic phosphorous pesticide poisoning is considerable variation in recommendations. • However, experience suggests that atropine should be initiated in adults in doses of 1–2 mg IV for mild to moderate poisoning and 3–5 mg IV for severe poisoning with unconsciousness. • This dose can be doubled every 3–5 minutes as needed. • The most important end point for adequate atropinization is clear lungs and the reversal of the muscarinic toxic syndrome. • Once this end point has been achieved, a maintenance dose of atropine may need to be started. An additional approach is to administer 10–20% of the loading dose as an IV infusion every hour initially, with meticulous frequent reevaluation and titration. Atropine

25. ADVERSE EFFECTS AND TOXICITY • When too much atropine is administered, the patient demonstrates classic signs of peripheral anticholinergic toxicity: hot, dry, flushed skin, urinary retention, absent bowel sounds, tachycardia, mydriasis, and central anticholinergic activity, including restlessness, confusion, and hallucinations or CNS depression. • Atropine is classified by the FDA as pregnancy category C. Atropine crosses the placenta and may cause tachycardia in the near term fetus. Atropine

26. Pralidoxime • Its only use is with atropine in the management of patients poisoned by organic phosphorus and carbamate pesticides • Continuous infusion is preferable to intermittent administration for patients with serious toxicity and a prolonged therapeutic course may be required • Pralidoxime is most efficacious at nicotinic sites, often improving muscle strength within 10–40 minutes of administration. Pralidoxime is synergistic with atropine and in addition liberates enzyme so that additional acetylcholine can be metabolized. Pralidoxime

27. INDICATIONS: • Pralidoxime should be administered to patients with suspected or confirmed exposure to organic phosphorous or carbamate insecticides and either any signs or symptoms of neuromuscular weakness or a significant atropine requirement (usually described as more than a typical age or weight based resuscitation dose of atropine). Pralidoxime

28. DOSING AND ADMINISTRATION • The optimal dosage regimen for pralidoxime is unknown. • Traditionally, the recommended initial adult dose is 1–2 g in 100 mL of 0.9% sodium chloride solution given intravenously over 15–30 minutes. • The pediatric dose is 20–40 mg/kg up to a maximum of 2 g as a loading dose given intravenously over 30 minutes. • These initial doses can be repeated in 1 hour if muscle weakness and fasciculations are not relieved • One recommendation is to administer a loading dose of 25–50 mg/kg (up to a maximum dose of 2.0 g) followed via continuous infusion of 10–20 mg/kg/h, up to 500 mg/h. Serious poisoning may require a continuous infusion of 500 mg/h in adults, and 10–20 mg/kg/h, up to 500 mg/h, in children Pralidoxime

29. DURATION OF TREATMENT: • In most cases, pralidoxime is continued for a minimum of 24 hours after symptoms have resolved • Alternatively, if serial determinations of RBC cholinesterase activity can be obtained in a timely fashion, restoration of a normal value seems a reasonable end point of therapy. • In all cases, patients should be observed for the reappearance of toxicity after termination of pralidoxime. • If symptoms return, therapy should be continued for a minimum of an additional 24 hours. Pralidoxime

30. ADVERSE EFFECTS • Transient dizziness, blurred vision, and elevations in diastolic BP may be related to the rate of administration. • Rapid IV administration has produced sudden cardiac and respiratory arrest as a consequence of laryngospasm and muscle rigidity. • Pralidoxime is listed as pregnancy category C. Pralidoxime

31. AVAILABILITY • Pralidoxime chloride (Protopam) is supplied in 20-mL vials containing 1 g of powder, ready for reconstitution with sterile water for injection. • Pralidoxime chloride is also available for IM administration by an autoinjectorcontaining 600 mg of pralidoxime in 2 mL of sterile water for injection with 20 mg benzyl alcohol and 11.26 mg glycine. • The 2-PAM autoinjector also comes packaged in a kit accompanied by an autoinjector containing 2 mg of atropine in 0.7 mL of a sterile solution containing 12.47 mg glycerin and not more than 2.8 mg phenol. • This kit is called a “Mark 1 Nerve Agent Antidote Kit (NAAK)” and is designed to be used IM by first responders in case of a nerve agent attack. Pralidoxime

32. Opioid Antagonists • Naloxan: • Apnea:2 mg Iv stat • LOC: • Addict: ¼ amp • Non – addict: 1 Amp • Maintenance: 2/3 loading dose /hr Naloxan

33. Digoxin-Specific AntibodyFragments (Fab) • Digoxin-specific antibody fragments are indicated for the management of patients with toxicity related to digoxin, digitoxin, and all natural cardioactive steroids (CAS), such as oleander. Dig-FAB

34. PHARMACOKINETICS • At 30 minutes after infusion of digoxin-specific antibody fragments, the free digoxin serum concentration is below the level of detection of the assay. Dig-FAB

35. ADVERSE EFFECTS AND SAFETY • Digoxin-specific antibody fragments also are very safe. • Reported adverse effects include hypokalemia as a consequence of reactivation of the Na+-K+-ATPase; withdrawal of the inotropic or AV nodal blocking effects of digoxin, leading to CHF or a rapid ventricular rate in patients with atrial fibrillation; and, rarely, allergic reactions. Dig-FAB

36. Dig-FAB

37. Dig-FAB

38. Dig-FAB

39. Flumazenil • Flumazenil is a competitive antagonist at the benzodiazepine receptor • Most individuals achieve complete reversal of benzodiazepine effect with a total IV dose of 1 mg. • When a benzodiazepine is given to achieve conscious sedation during a procedure, flumazenil appears safe and effective in the reversal of sedation and the partial reversal of amnesia and cognitive impairment. • Slow IV titration (0.1 mg/min) to a total dose 1 mg seems most reasonable. • Resedation may occur at 20–120 minutes, and it may be necessary to readminister flumazenil. Flumazenil

40. Thanks for your attention