Newer antidotal therapies (Proceedings)

Antidotes can be divided into three broad catagories: chemical antidotes, pharmacologic antidotes, and functional antidotes. Chemical antidotes act directly on the toxicant to make it less toxic and/or more readily excreted. Pharmacologic antidotes antagonize toxic agents at their receptor sites or through other macromolecules. Functional antidotes are agents that act on the symptoms of poisoning. In many cases, these antidotes have no real effect on the toxicant itself, but they lessen the severity of the clinical picture of the intoxicated patient.

Chemical antidotes: Chelators

Deferoxamine

Deferoxamine (Desferal®, Ciba) is a chelating agent approved for use in humans for the treatment of acute iron poisoning, chronic iron overload and treatment of chronic aluminum overload in patients on chronic dialysis. It has been used off label to treat iron toxicosis in animals. Deferoxamine forms a chelate complex with free iron, which is then excreted in the urine and bile. Deferoxamine is most effective within the first 24 hours, before the iron has been distributed to the tissues. The extrapolated animal dose for iron toxicosis is 40 mg/kg, IM, every 4-8 hours. The IM route is preferred, as too rapid IV administration can cause hypotension and pulmonary edema. The efficacy of deferoxamine can be increased by giving ascorbic acid after the gut has been cleared of iron. The deferoxamine-iron complex gives a salmon pink color to the urine ("vin rose"). Continue to chelate until urine clears or until serum iron levels return to normal.

DMSA (2,3-dimercaptosucinic acid, succimer)

Succimer (Chemet®, McNeil Consumer Products) is approved for the treatment of childhood lead poisoning. It has also been used to treat arsenic and mercury poisoning and does not bind iron, calcium or magnesium. Succimer is available as 100 milligram capsules. It is a structural analog to BAL (British Anti-Lewisite, dimercaprol) but has less potential to cause nephrotoxicity. Succimer is preferred over Ca-EDTA and penicillamine, as succimer can be given while lead is still in the GI tract (the other 2 increase lead absorption), it comes in an oral form, it has a lower incidence of causing GI upset and it is also less likely than the others to induce Zn deficiency. Succimer, however, is more expensive than the other options (capsules are approximately $4 apiece). Succimer can impart a 'sulfur' odor to patients while it is being administered; while this is an issue in human patients as it often results in poor compliance, the effect of this on compliance in veterinary patients is not known.

Although not approved for animal use, there are published doses for treating lead toxicosis. The dose for dogs and cats is 10 mg/kg PO TID for 10 days (administer on empty stomach; per rectum if animal is vomiting). Dosing for caged birds is 25-35 mg/kg PO BID 5 days a week for 3-5 weeks. Higher doses (80 mg/kg) have caused death in cockatiels. It is not uncommon for there to be a post-chelation rebound (or elevation) of blood lead levels. Most of the time, this is due to redistribution of the lead from bone and tissue stores in animals chronically exposed to lead. If lead levels are still increased and the animal is still symptomatic, a repeated round of therapy can be pursued. If the animal is asymptomatic, there is no need to retreat, even if lead levels are outside the normal ranges. Persistent elevations may suggest continued exposure to lead, so evaluation of the animal's environment may be indicated.

Intravenous lipid solutions

The use of intravenous lipid solutions (ILS) is an emerging treatment modality for emergency medicine. ILS have been used for years as a component of total parenteral nutrition (TPN) for critical human and veterinary patients, and had been investigated as a means of drug delivery of certain pharmaceuticals in humans. Originally utilized to attempt to reverse life-threatening cardiotoxicity in humans due to local anesthetic toxicosis, ILS administration has recently been introduced into veterinary emergency medicine where it is showing promise as a means to treat potentially life threatening toxicoses from select xenobiotic exposures. The exact mechanism of how ILS function as an antidote is not known, but there were 3 initially proposed mechanisms: 1) the ILS act as a pharmacological 'sink' for highly lipid soluble drugs, making them unavailable to reach receptor sites, 2) ILS increase myocardial energy stores, enabling myocytes to overcome the depressant effects of cardiotoxic drugs, and 3) ILS restore myocardial function by increasing intracellular calcium levels. Given that ILS have subsequently been used to manage non-cardiotoxic drug overdoses, it may be that the first explanation is the most likely: that binding of lipophilic drugs in the blood reduces free drug available to bind receptors.

Based on ASPCA APCC experience, favorable results with ILS have been obtained in some cases of toxicosis due to Baclofen, moxidectin, ivermectin, diltiazem, and amlodipine, although not all animals in which ILS were utilized responded or made full recoveries. In some instances where full recovery did not occur, response was sometimes seen but animals were euthanized due to financial reasons before full treatment could be completed. In others, there was poor to no response to the ILS, which may relate to the initial dose of the toxicant, other medical issues with the patient, insufficient ILS being used, or other as yet undetermined factors. Some drugs with long half lives (e.g. calcium channel blockers) have required multiple dosing of lipids, as signs returned after several hours. In theory, ILS should work for any highly lipophilic drug. ILS have the additional advantage of being quite inexpensive to stock (~ $20 for 1 liter); APCC has received reports of some human hospital pharmacies over charging veterinarians as much as $150-200 for a bag of ILS. It should be noted that this therapeutic modality is not approved for any species and should be considered only in situations where life-threatening signs not responsive to other therapies are present.

ILS have a good safety profile based on years of experience with their use as TPN components. With chronic use, potential side effects have included pyrogenic reactions and lipid overload, which may result in pulmonary compromise; these findings have not been reported with antidotal use of ILS. ILS can alter diagnostic tests due to induction of lipemia. In theory, over aggressive use of ILS may trigger pancreatitis in predisposed animals (to date, this has not been reported); therefore when using multiple doses of ILS, it is recommended that the serum be evaluated for the presence of lipemia prior to dosing and that dosing be suspended until any lipemia has resolved. There are several dosing regimens that have been utilized in the management of toxicoses. One regimen utilizes 20% lipid solution with an initial bolus of 1.5 mL/kg administered over 10-20 minutes followed by 0.25 mL/kg/min for 1 hour; repeat dosing can be given at 3-4 hour intervals (or when serum no longer lipemic). Other dosing regimens as well as other information on ILS therapy can be found at www.lipidrescue.org.

Chemical antidotes: Immunotoxicotherapy

Crotalidae polyvalent immune Fab (ovine)

Crotalidae polyvalent immune Fab (ovine) (CroFab®, Fougera) is approved for the management of patients with North American crotalid snake envenomation. The antivenin has been show to cross react with 10 North American crotalid species. In a recent study, CroFab® was given to 115 dogs presented to several veterinary emergency hospitals in the western US. The CroFab® gave "excellent results" although some dogs did require more than one vial (average dosing was 1.25 vials) (personal communication, Michael Peterson). This study also reported significantly less reactions to the CroFab® product compared to Ft. Dodge equine antibody antivenin (advantage of Fab over whole IgG).

Early use (within 6 hours of snakebite) is recommended to prevent clinical deterioration and the occurrence of systemic coagulation abnormalities. Crotalid Fab is diluted in 250 mL of saline and infused over 60 minutes, with monitoring for development of an allergic reaction during the first 10 minutes. Recurrence of local symptoms of crotalinae envenomation following CroFab® treatment has been reported in people, probably due to the short half-life of the antivenin. Cost is approximately $1400/2 vials.

Digoxin immune Fab

Digoxin immune Fab (Digibind®, Burroughs Wellcome) is produced from specific digoxin antibodies from sheep and will bind directly to digoxin or digitoxin and inactivate it.?Antidigitoxin Fab fragments have an affinity for digoxin that is much higher than the affinity of digoxin for its sodium-potassium ATPase target. Digibind® has sufficient cross reactivity and can also be effective against bufotoxins (Bufo toads) and plants containing cardiac glycosides (see Table 1).

Table 1. Cross-reactivity of antidigoxin Fab fragment with plant cardiac glycosides

Treatment with Fab fragments should be considered in those patients who fail to respond to conventional therapy. Signs of severe toxicity might include severe ventricular arrhythmias (ventricular tachycardia, ventricular fibrillation), progressive bradyarrhythmias (severe sinus bradycardia), or second or third degree heart block not responsive to atropine. The dosage varies based on the amount of digoxin to be neutralized. The best situation is to have a human hospital run digoxin levels and then dosing is based on those results. The dose of Digibind® is calculated: Digibind® dose (number vials) = [Serum Digoxin Concentration (ng/mL) x Patient's weight (kg)] / 100. The next best method is to estimate the body load of digoxin ingested (almost impossible with toads or plants). Body load is estimated as dose ingested x 0.8. The formula is then: Digibind® dose (number vials) = [Body load (mg) / 0.5 (mg/vial)]. If either of these methods are not feasible then it is suggested that 1-2 vials be administered and the effects observed. Each vial of Digibind® contains 38 mg which will bind approximately 0.6 mg of digoxin or digitoxin. Reconstitute each vial with 4 mL of sterile water or isotonic saline. Administer slow IV over 30 minutes, infused through a 0.22 micron filter (if possible). Digibind® can be a life saving treatment however, it is expensive ($2200/5 vials).

Chemical antidotes: Enzyme inhibitors

Fomepizole (4-MP, 4-methylpyrazole)

Fomepizole (Antizol-Vet®, Orphan Medical) is a competitive inhibitor of alcohol dehydrogenase. It was approved for use in dogs to treat ethylene glycol (EG) toxicosis in 1997. Each vial contains 1.5 g of fomepizole and the reconstituted solution is 50 mg/ml. Shelf life is 72 hours once reconstituted. The advantages of fomepizole are that is does not induce hyperosmolality, CNS depression, and diuresis (vs. ethanol). Dogs may be treated as late as 8 hrs post ingestion and still have a favorable prognosis. Fomepizole may still be effective as late as 36 hrs post-ingestion of EG. The recommended dosing regime for dogs is an initial IV injection of 20 mg/kg (give over 15-30 minutes), followed by 15 mg/kg slow IV at 12 hours and again at 24 hours. A last dose of 5 mg/kg IV is given at 36 hours after the first injection. Since fomepizole slows down the metabolization of EG, serum levels may still be detectable at 72 hours after ingestion. If the EG test is still positive after the last dose continue treatment at 5 mg/kg IV every 12 hours unitl test is negative.

Fomepizole is not labeled for cats but preliminary clinical trial results suggest that high doses of fomepizole in the cat (125mg/kg slow IV infusion loading, then 31.25 mg/kg at 12, 24, 36 hrs post EG ingestion) are safe and effective when therapy is initiated within 3 hours following EG ingestion. [Note: at 3 hrs post lethal dose EG administration, 100% recovery with fomepizole, 25% recovery with ethanol. At 4 hrs post EG, 100% mortality with fomepizole and ethanol was noted in these studies. Other than calcium oxalate crystals in the urine, no biochemical evidence of renal impairment was noted out to 2 weeks post EG exposure and fomepizole.

Pharmacologic antidotes: Receptor antagonists

Flumazenil

Flumazenil (Romazicon®, Roche) is an imidazobenzodiazepine derivative, which antagonizes the CNS actions of benzodiazepines. Flumazenil binds to and rapidly displaces benzodiazepines from the benzodiazepine receptor, thereby reversing their sedative and anxiolytic effects within 1-2 minutes. It is indicated in people for diagnosis of benzodiazepine overdose and reversal of benzodiazepine sedation and respiratory depression. Use in animals is usually limited to those at risk of respiratory depression. The dose is 0.01 mg/kg, IV, for both dogs and cats and can be repeated if severe depression returns. The half-life for flumazenil is about 1 hour, so repeated injections may be needed. Flumazenil may also be given intratracheally in an emergency situation. Flumazenil is contraindicated in patients suspected of tricyclic antidepressant overdoses as it can cause seizures.

Atipamezole

Atipamezole (Antisedan®, Pfizer) is an a2-adrenergic antagonist labeled for use as a reversal agent for medetomidine, but it can also be used to treat several toxicoses. Atipamezole can be used to reverse other a2-adrenergic agonists (amitraz, xylazine, bromonidine, clonidine and tizanidine). Atipamezole quickly reverses the hypotension and bradycardia seen in these toxicoses. After IM administration in the dog, peak plasma levels occur in about 10 minutes. Atipamezole has an average plasma elimination half life of about 2-3 hours (vs. yohimbine half life of 1.5-2 hr in dogs) and may need to be repeated.

Functional antidotes

Bisphosphonates

Bisphosphonates are synthetic analogs of pyrophosphate that bind to the hydroxyapatite found in bone. Pamidronate (Aredia®, Novartis) inhibits osteoclastic bone resorption and was developed to treat hypercalcemia of malignancy in people. Pamidronate can be used in dogs for treating hypercalcemia secondary to cholecalciferol toxicosis. The recommended dose of pamidronate for dogs is 1.3 - 2.0 mg/kg as a slow IV infusion in 0.9% sodium chloride over 2-4 hours. The advantage of pamidronate over salmon calcitonin is that it has long lasting effects (may need to repeat once in 5-7 days). Do not use in combination with calcitonin. The downside of pamidronate is that it is expensive ($275-400/vial), however, when compared to length of hospitalization and the labor involved in the repeated doses of calcitonin, the cost is comparable.

New antidotal uses for older drugs (teaching old dogs new tricks)

Cyproheptadine

Cyproheptadine(Periactin®, Merck) is an antihistamine (H1 blocker) that also has serotonin antagonistic activity. Cyproheptadine has been used in veterinary medicine for its antihistaminic and appetite-stimulant effects (cats) and is now being used to help treat serotonin syndrome. Serotonin syndrome is a condition caused by serotonin excess within the CNS and is characterized in dogs by tremors, seizures, hyperthermia, ataxia, vomiting, diarrhea, abdominal pain, excitation or depression, and hyperesthesia. Serotonin syndrome has been associated with the use of drugs that increase brain serotonin levels (e.g. selective serotonin reuptake inhibitors, amphetamines) in humans and after accidental ingestion of 5-hydroxytryptophan (serotonin precursor) in dogs. The recommended dose for dogs is 1.1 mg/kg PO or per rectum every 1-4 hours until signs subside.

N-acetylcysteine

N-acetylcysteine (NAC, mucomyst) is the N-acetyl derivative of L-cysteine, a naturally occurring amino acid. Although originally used as a mucolytic agent in people, NAC has become an important part of managing acetaminophen overdoses in people and animals. Because of NAC's ability to minimize oxidative damage to the liver from acetaminophen, NAC had been investigated for its ability to prevent damage from other hepatotoxins. A recent study on Amanita phalloides (death cap mushroom) poisoned people showed that the use of a protocol similar to that used for acetaminophen toxicosis (high dose) was effective in preventing permanent hepatic injury in 10 of 11 people.

Dantrolene

Dantrolene (Dantrium®, Procter & Gamble Pharm.) has been mostly used in veterinary medicine for the prevention and treatment of malignant hyperthermia syndrome. Dantrolene may also be used to treat the malignant hyperthermia-like reaction seen in dogs after the ingestion of hops (Humulus lupulus). Hops are used in the brewing of beer. Recommended dose of dantrolene is 2-3 mg/kg, IV, or 3.5 mg/kg, PO, as soon as possible after ingestion.