UMEM Educational Pearls - Toxicology

• 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

 Did you know how many toxicities and adverse effects amiodarone has? Many are severe, and many VERY common.

1. CARDIAC: hypotension with rapid infusion, prolonged QT, torsades

2. NEUROLOGIC problems occur in 20-40%, including malaise, ataxia, and peripheral neuropathies

3. ENDOCRINE: hypothyroidism and hyperthyroidism

4. GI problems occur in 25%

5. OPHTHALMOLOGIC disturbances include optic neuropathy, papilledema, and photosensitivity

6. SKIN: blue grey pigmentation

7. PULMONARY: pulmonary fibrosis

Both dealing with the adverse effects from therapeutic administration, like when you order it on the floors or take yourself - to the overdose setting. Here is a brief list of the common sleep aids, MOA and toxicity. (Zolpidem or Ambien gets the award for most entertaining adverse effect of "Sleep Eating")

• "Unisom": there are multiple formulations, most have diphenhydramine or some derivative. Toxicity is anticholinergic and Na channel blockade in overdose. Be aware that some have doxylamine which causes atraumatic rhabdomyolysis.
• Zolpidem (Ambien): Nonbenzodiazepine hypnotic, with sedation as the primary effect though the reports of hallucinations, "sleep eating" and "sleep coitus" have been made famous.
• Eszopiclone(Lunesta): Nonbenzodiazepine hyponitic, mechanism of action unknown. Does not require a controlled substance Rx but is expensive. Toxicity: metallic taste next day, minimal toxicity reported.

Tamiflu (oseltamivir)

• Must be administered within 48 hours of onset of symptoms
• Patient must be 1 year or older
• Rare cases of anaphylaxis, Stevens-Johnson, TEN and erythema multiforme have been reported.
• Not proven safe in pregnancy nor harmful.

Here are a couple of herbals touted as aphrodesiac's and the toxcity associated with them (the price of love):

Chan Su or "Love Stone" - A chinese herbal that is suppose to be topically applied, unfortunately all of the instructions are in chinese and those who ingest it will die a digoxin-like death. It has a compound that is essentially a potent digoxin-like substance.

Yohimbine - herbals that contain this can cause priapism -  shocker

We have seen this lovely  bug infect our patients and have to instutitue therapy. But do you know what is the first line drug and which one has now become second line due to its toxicity? Here is the short list:

First Line Therapy: Permethrin (Nix) - least toxic, only causes local irritation

Second Line Therapy: Crotamiton (Eurax) - again local irritation

Third LIne Therapy: Lindane - SEIZURES if you leave it on too long or put on too much. Children were particularly susceptible and relatively contraindicated.

Here is a list of drugs that can cause hyperkalemia either at therapeutic levels or in overdose:

Amiloride, ACEI, Beta Blockers, Cardiac Glycosides, FLuoride

Heparin, NSAIDS, Penicillin (the Pen VK formulation), Spironolactone

Succinycholine and triamterene

With the aging population, bisphosphonate use will continue to increase. They promote bone growth by inhibiting osteoclast action and resorption of bone. Unfortunately, they have their side effects and the FDA has sent out a recent warning that affects us all:

• [Posted 01/07/2008] FDA informed healthcare professionals and patients of the possibility of severe and sometimes incapacitating bone, joint, and/or muscle (musculoskeletal) pain in patients taking bisphosphonates.

If a patient presents with severe bone/joint pain, check the med list to see if they are on a bisphosphonate - they may not be faking the pain. This can occur days, weeks or even years after initiation of dose

Levetiracetam

• A new anticonvulsant that is 100% renally eliminated
• Does not require therapeutic drug monitoring like phenytoin
• The IV form does not cause skin necrosis or have cardiotoxicity like phenytoin
• Is being investigated in benzodiazepine-refracory status epilepticus (1)
• Fairly safe drug even in overdose (Barrueto et al ;) )

Knake et al. Intravenous levetriacetam in thetreatment of benzodiazepine-refractory status epilepticus. J Neurol Neurosurg Psychiatry 2007 Sept 26; Epub

                                      Phenytoin po      Phenytoin IV       Fosphenytoin

Time to therapeutic       6.4 hrs                  1.7 hrs                 1.3 hrs

Adverse Events              0.69/pt                   1.86/pt                 1.87/pt

Also to take into account  is that the adverse events with IV phenytoin include soft-tissue necrosis if there is extravasation of infusion. The cardiotoxicity seen with phenytoin and fosphenytoin is largely due to the propylene glycol diluent and thus not seen with oral loading or even in oral overdosing.

You decide, at least you have the data to properly evaluate the risk:benefit ratio.

Ketorolac: an NSAID that gained popularity since it is not an opioid, has excellent anti-inflammatory/analgesic effects and is given IM or IV. Also has been used in renal colic secondary to smooth muscle relaxation (Prostaglandin mediated) in the ureters. You should know:

• When given IV or IM still causes PUD and has caused GI perforations.
• Renal Insufficiency is larger concern with this NSAID than others.
• Consider misoprostol for GI complications.
• Use for acute pain, limit the number doses given and don't prescribe for more than 3 days. I generally don't prescribe it at all, use another NSAID for outpatient treatment.

Corelli et al. Renal Insufficiency and ketorolac. Ann Pharmacother. 1993; 27(9): 1055-7

Lithium: Hypothyroidism (5-15% of pts) and goiter (37% of pts), mechanism unclear

Amiodarone (37% Iodine by weight): Hyper or Hypothroidism

Beta-Blockers: by blocking peripheral conversion of T4 to T3 cause hypothyroidism

Corticosteroid: same as beta-blockers but can also cause transient thyrotoxicosis (Jod-Basedow effect)

Iodine, Iodinated contrast, radiactive iodine all can cause hypothyroidism but iodinated contrast material can actually induce thyrotoxicosis and thyroid storm from unknown mechanism.