UMEM Educational Pearls - Toxicology

Alcohol-Drug Interactions

• There are a number of medications that produce the disulfiram-like reaction when ingested with alcohol.
• The disulfiram reaction is a very uncomfortable reaction characterized by severe flushing, and may be accompanied by tachycardia and hypotension.
• Although we always think of metronidazole, there have been well described cases of bactrim causing this reaction.
• Tinidazole, a new antiprotozoal used in the treatment of trichomonas, causes this as well.
• Patients should be advised to avoid alcohol for 24 hours after metronidazole, and 72 hours after bactrim and tinidazole.

Other common medications that produce this reaction:

1. Sulfonylureas: chlorpropamide, tolbutamide, glyburide

2. Cardiovascular medications: Isosorbide dinitrate, nitroglycerin

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• Elemental Mercury is found in manometers, some mercury switches and thermometers.
• Elemental Mercury is also in the CFLs (Compact Fluoroscent Lightbulbs) that are popular now due to rising energy cost (approx 4 mg)
• Organic mercury found in seafood is only toxic in high consistent doses - though has been catastrophic. See attached picture which was the award winning Time magazine cover of the year showing a mother holding her child who had congenital disfigurement due to mercury being dumped into Minamata Bay
• Elemental Mercury is mostly a neurotoxin causing personality changes, nervousness, shyness and depression.
• Acrodynia is pain and pink discoloration of hands and feet due to mercury poisoning in children.

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•  Therapeutic concentration considered 10-20 mg/dL
•  Some hospitals report in "mg/L" thus a level of 110 mg/L is therapeutic
•  Symptoms of Toxicity usually > 40 mg/dL
•  Consider Hemodialysis in any patient with a serum concentration >100 mg/dL

First Line Therapy:  Urine Alkalinization (pH >7.5) by administrating NaHCO3

Other Indications for Hemodialysis in Salicylate Poisoned Patient:

1. Renal Failure
2. CHF
3. Acute Lung Injury
4. Persistent CNS disturbances
5. Refractory metabolic acidosis or electrolyte abnormality
6. Hepatic insufficiency with coagulopathy

• Metformin is the most commonly prescribed oral diabetic mediction in US
• Relative contraindication is in renally impaired patients, they are susceptible to the lactic acidosis
• Lethal adverse effect is the increase production of lactate
• ED patient with an anion gap metabolic acidosis, check for metformin and check the lactate
• The lactic acidosis is often severe (>10 mmol/L) and carries a high mortality rate that has been estimated at >40%
• Correction of pH and emergent hemodialysis are essential

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 ADOLESCENT DRUG ABUSE

• "Pharming" is prescription drug abuse
• Teens will take medications from their home medicine cabinets, mix them in bags together indiscriminately and make "trail mix" to pass around parties
• "Cheese" is a combination of heroin with cough and cold preparations. The heroin concentration in cheese is typically between 2-8% compared to 30% found in black tar heroin, and is considered "starter heroin"

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•  Dapsone has been used to treat leprosy but more commonly to in brown recluse spider bites and to prevent PCP pneumonia and toxoplasmosis in our HIV population
• It can cause methemoglobinemia: a reduced form of iron (ferrous to ferric) in the Hb molecule that decreases your oxygen carrying capacity. 
• Due to its color, cyanosis is a predominant symptom out of proportion to symptoms.
• Treatment: Methylene Blue 1-2 mg/kg IV
• Pitfall: Dapsone's long half-life may cause reoccurrence of MetHb and require retreatment

Here is a short list of medications that will actually prevent a patient from being anticoagulated by coumadin. These medications will make it difficult for the patient to reach therapeutic levels and need to be warned about this drug-drug interaction with coumadin:

• Antacids
• Antihistamines
• Barbituates
• Carbamazepine
• Cholestyramine
• Corticosteroids
• Griseofulvin
• OCPs
• Phenytoin
• Rifampin
• Vitamin K

Reference: Goldfrank's Textbook of Toxicologic Emergencies, 6th Edition

Trandermal Delivery Systems

• Uses a gradient (high concentration drug in patch) and a matrix to facilitate transdermal absorption
• Patch often contains up to 100x the amount of drug that is on the label (ex: fentanyl 100mcg/hr actually = 10 MILLIGRAMS of fentanyl in patch)
• When prescribing the following will increase absorption: sweating, heat, swallowing the patch, trying to eat the gel in the patch
• Fentanyl and clonidine are the two most lethal patches on the market in regards to toxicity.
• Rarely needed in the ED, shouldn't be prescribed except in rare instances

"Ketofol" (Ketamine plus propofol)

• Given for conscious sedation, for all age groups
• Takes advantage of properties of both agents
• Ketamine generally produces hypertension, does NOT produce respiratory depression, has an emergence phenomena, and has analgesic properties
• Propofol causes hypotension and respiratory depression, has NO analgesic properties, and may blunt both nausea and emergence phenomena seen with ketamine
• Given as a 1:1 ratio of ketamine and propofol, both 10 mg/ml
• Dose is usually 1-3 ml aliquots; median dose in a recent study was 0.75 mg/kg
• Median recovery 15 minutes (5-45 minutes; 80% recovered in less than 20 minutes)

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Pool Cleaner Toxicity - Chlorine Gas Exposure 

The "shock" treatment that is utilized in pool cleaner is often contained in a large plastic container and is calcium hypochlorite. Chlorine gas accumulates in the small amount of airspace found in the container. If a future patient opens the container either in an enclosed space or within close proximity of the face that allows for large inhalational exposure.

• Toxicity looks like CHF with hypoxia, rales and acute lung injury on CxR
• Chlorine gas will bind hydrogen ion in the aveoli forming HCl - hydrochloric acid
• Nebulized NaHCO3 would theoretically neutralize this acid but has not been found to improve clinical outcome though it has been found to improve symptoms.
• Supportive care and observation including CxR  4-6 hours after exposure are necessary since the effects of the chlorine gas may be delayed.

 Toxicology Trivia for $1000 - These are in fruits of the "rose" family and in some roots that contain cyanogenic glycosides and other cyanide containing compounds. It would actually take a fair amount of work to ingest enough to reach toxicity:

• Bitter almonds
• Apricot kernels
• Peach pits
• Plum sees
• Apple and pear seeds
• Cassava (actually have to wash the root prior to eating - skin contains the CN)
• Lima Beans

• Adolescents abuse inhalational agents due to lack of access to ETOH and illicit drugs
• Often halogenated hydrocarbon propellants like computer cleaner and paint stripper
• Sensitizes the myocardium to catecholamines
• Child is caught huffing and is frightened causing a catecholamines surge then v-fib arrest
• This was reported in a 1970 case series and "Sudden Sniffing Death" was coined (1)
• Actual treatment would be to administer B-Blocker in this instance (theoretical)

Bass. Sudden Sniffing Death. JAMA 1970.

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 How to recognize a truly toxic mushroom ingestion (remember one mushroom can be lethal!):

1) Onset of GI symptoms within 3 hours from time of ingestion: USUALLY NONTOXIC

- Control nausea and  vomiting

- Look for toxidrome: hallucinations, muscarinic symptoms, lethargy

2) Onset of GI symptoms greater than 5 hrs is associated with more toxic mushrooms

- High degree of suspicion for a cyclopeptide mushroom (Amanita phylloides)

- Follow liver enzymes and consier referral to liver transplant center

 Hemodialysis

• Ethylene Glycol
• Methanol
• Lithium
• Salicylate
• Theophylline (Hemoperfusion)
• Ethanol (rarely needed but can be done)
• Isopropanol (rarely done)

CAVH or CVVH: Lithium, Procainamide, Aminoglycosides, Methotrexate

Exchange Transfusion (pediatrics mostly): Salicylate and Theophylline

1) No IV - Try naloxone in a nebulizer - Dose: 2-4 mg  and saline in your nebulizer container.

2) When using naloxone IV, use following dose: 0.05 mg IV - you will find it reverses the respiratory depression without inducing withdrawal. Anesthesia doses naloxone in micrograms, we often overdose our patients. The effect is delayed and not as pronounced as the 0.4 mg blast that causes nausea, vomiting, diarrhea, agitation - all not desirable in the ED.

SUICIDE RISK WITH ANTIEPILEPTICS

• On January 31st, the FDA released a warning about an increased risk of suicidality in patients recently started on antiepileptics
• They analyzed data across 199 placebo controlled trials, looking at 11 agents in a total of 43,892 patients
  
• Patients taking antiepileptics were found to have twice the suicide ideations and attempts as those on placebo.
• Although the overall risk was very small (0.43% vs 0.22%), it is consistent across the board, and particularly evident in those with epilepsy.

Drugs in the analysis included:
Carbamazepine (Carbatrol, Equetro, Tegretol, Tegretol XR)
Felbamate (Felbatol)
Gabapentin (Neurontin)
Lamotrigine (Lamictal)
Levetiracetam (Keppra)
Oxcarbazepine (Trileptal)
Pregabalin (Lyrica)
Tiagabine (Gabitril)
Topiramate (Topamax)
Valproate (Depakote, Depakote ER, Depakene, Depacon)
Zonisamide (Zonegran)

Interestingly, other agents including varenicline (a partial nicotinic antagonist, for smoking cessation), levetiracetam (Keppra), zolpidem (Ambien), oseltamivir (Tamiflu), isotretinoin (Accutane), and other agents have been noted to have an increased rate of bizarre and aggressive behavior.  

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There is actually very little data that actually supports the administration of activated charcoal (AC) to the poisoned patient.  AC works by binding the toxin and preventing its absorption from the GI tract. Here are some of the practical points:

• Most effective if given within one hour of the overdose
• Do not give if patient is sedated, going to be sedated or has a chance for seizure
• Always assess risk of aspiration versus possibly binding drug by asking the following:

1. Is this drug dangerous enough that I have to try to prevent its absorption?
2. Can this drug cause sedation, seizures or impair protective airway reflexes?
3. Do I lack an antidote or alternative treatment?

Once you have assessed your risk:benefit ratio, then administer AC. Of note, it definitely works in the right situation as noted in a landmark article that showed a decrease in mortality following poisoning by oleander - a plant that contains a digoxin like substance.(1)

1 - de Silva HA, et al. Multiple-dose activated charcoal for treatment of yellow oleander poisoning: a single-blind, randomised, placebo-controlled trial. Lancet 2003: 361(9373):1935-8.

Heparin FDA Alert

In case you had not heard, there was a major recall of Baxter's Heparin. It was responsible for dozens of deaths in the USA and an investigation was launched. It has been found that the contaminant comes from manufacturing plants in China. The most concerning part is that it looks like it was chemically synthesized sulfated chondroitin. This brings the suspicion of intentional adulteration. First lead in toys now cartilage in our heparin - what's next?

Some fascinomas of Heparin:

• Overdose of heparin is treated with either time or protamine
• Protamine can actually worsen anticoagulation if you give too much
• Dose of Protamine: 1 mg of Protamine neutralizes 90 USP Units of Heparin but you must cut dose in half if 30 minutes have passed from heparin dose

News link for FDA Heparin Alert:

http://www.fda.gov/medwAtch/safety/2008/safety08.htm#HeparinInj2

• A triptan that is a serotonin agonist
• SQ administration better
• High first pass effect and thus not effective often PO
• Sulfhemoglobinemia see with high dose PO
• Adverse Effects: MI and ischemia , CVA
• Be wary with elderly, hx of CAD/CVA or hx of cocaine use