UMEM Educational Pearls - Toxicology

• Recently, a study was published which compared adverse drug events in patients who had received either fomepizole or ethanol for ethylene glycol or methanol poisoning.
• Importantly, this is the first trial which has compared these events head to head.
• Retrospectively, 172 charts over a 9 year period were reviewed. Toxicologists identified at least 1 ADR in 74 of 130 ethanol treated cases (57%) versus 5 of 42 fomepizole treated cases (12%).
• Severe ADRs occurred in 20% of ethanol treated patients vs 5% fomepizole treated patients.
• This adds further data to support the use of choosing fomepizole over alcohol for treatment of toxic alcohol poisonings

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Ondansetron (Zofran) has been off patent and its price has dropped to the point that it has supplanted promethazine (Phenergan) and even metoclopramide (Reglan) as the antiemetic of choice. With its low side-effect profile and known efficacy it is now being utilized in hyperemesis gravidarum and in pediatric gastroenteritis. - A cochrane review showed ondansetron to be both safe and effective in the pediatric population. Consider it prior to attempting oral rehydration therapy to increase effectiveness. - Dose: 0.1 mg/kg - you can give the oral dissolvable tablet (ODT) - ages 4-11 you can give 4mg ODT - Above age 11 the dosing is the same as an adult.

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Colchicine is a drug used for the treatment of acute gout attacks. It inhibits microtubule formation vital for cellular mitosis. It is also a drug with a narrow therapeutic index and lethal toxicity:

- Colchicine can be lethal at 0.5 mg/kg or even lower. Though this would be about 50 tablets and seems alot, remember it is prescribed 2 tablets initially then every hour until diarrhea presents (i.e. preliminary toxicity)

- Toxicity presents in 3 stages:

1. 0-24hrs: Nausea, vomiting, diarrhea
2. 1-7days: Sudden cardiac death, pancytopenia, renal failure, ARDS
3. >7days: Alopecia, myopathy, neuropathy (if they survive)

- No antidote, supportive care only available.

- Presentation is similiar to that of a radiation exposure

 

Overdoses of insulin glargine (Lantus) are rarely reported in the literature.  In fact, there are only 6 case reports.  We recently had a patient in our ED who was hypoglycemic from insulin glargine.  The hypoglycemic episode was quite prolonged (> 24 hours) in the ED before being the patient was transferred to the MICU.  Here are a few points to remember:

• Insulin glargine does not peak; it was designed to mimic basal islet cell insulin secretion.
• In the therapeutic setting, its effects can last up to about 24 hours.  In overdose the hypoglycemic effects have been reported to last up to 60-130 hours!
• Be prepared to give IV dextrose 5% or 10% infusion for the duration of the patient's hypoglycemic effect.  This can be supplemented with food.
• Octreotide will be ineffective for exogenous insulin poisonings because its effect comes from its ability to suppress insulin secretion from the pancreas.

Classical illicit recreational drugs like cocaine, ecstacy, and marajuana are sometimes difficult for teens to acquire. As a result, many are turning to their parents medicine cabinets as a source for recreational drugs.

[From the website drugabuse.gov] In 2008, 15.4 percent of 12th-graders reported using a prescription drug nonmedically within the past year. This category includes:

• amphetamines
• sedatives/barbiturates
• tranquilizers
• opiates other than heroin
  • hydrocodone, oxycodone

When adolescent patient presents to the ED, consider the possibility of a poly-pharmacy overdose. Always query parents about the presence of OTC and Rx medications in their home, and what is within reach of their kids.

While sedatives and analgesics are concerning, be alert for overdoses of more mundane medications like beta blockers and calcium-channel blockers which often pose a much more lethal threat. Consider overdose in adolescent patients with:

• GI or respiratory complaints
• Altered mental status (combative or somnolent)
• Abnormal vital signs
• History of depression or psychiatric illness

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Monitoring the Future Study: Trends in Prevalence of Various Drugs for 8th-Graders, 10th-Graders, and 12th-Graders

2005-2008 (in percent)*

	8th-Graders				10th-Graders				12th-Graders
	2005	2006	2007	2008	2005	2006	2007	2008	2005	2006	2007	2008
Any Illicit Drug Use
Lifetime Past Year Past Month	21.4 15.5   8.5	20.9 14.8   8.1	[19.0] [13.2]   7.4	19.6 14.1   7.6	38.2 29.8 17.3	36.1 28.7 16.8	35.6 28.1 16.9	34.1 26.9 15.8	50.4 38.4 23.1	48.2 36.5 21.5	46.8 35.9 21.9	47.4 36.6 22.3

Full chart available by clicking link in references.

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Serotonin is a neurotransmitter that has central and peripheral effects. It regulates the secretion of ADH from the hypothalamus and also controls the chemoreceptive trigger zone (CTZ) which induces emesis. Here are a list of medications categorized by the way they affect serotonin. Remember, any combination of these agonists could precipitate serotonin syndrome:

Enhance 5-HT synthesis: L-tryptophan

Direct HT agonists: Ergots, metoclopramide, sumatriptan, buspirone

Increase 5-HT release: amphetamines, cocaine, dextromethorphan, MDMA, L-dopa

Inhibit 5-HT breakdown: MAOIs, Linezolid

Inhibit 5-HT re-uptake: SSRIs (paxil), amphetamines, carbamazapine, tramadol, TCAs, citalopram, trazodone, lamotrigine, meperidine

 

Goldfrank's sniffing bar: no this is not a pub where toxicologist's hang out but rather a bar that assists with teaching the recognition of odors related to toxicology. Certain drugs and compounds have a distinct aroma.

The following is a list odors, see if you can name a medication or compound that has that odor - scroll down further to see the corresponding answers (if you really got all 5 email me and convince me):

1) Bitter Almond

2) Rotten Eggs

3) Wintergreen

4) Garlic

5) Sweet, Fruity (acetone)

 

Answers:

1) Cyanide; 2) N-acetylcysteine or Hydrogen Sulfide; 3) Methylsalicylate (like bengay); 4) Arsenic, organophosphate insecticides; 5) Chloroform, chloral hydrate

Add metoclopramide (Reglan) to the laundry list of medications with black box warnings from the FDA. Why was a black box warning added?

• Long-term metoclopramide use has been linked to tardive dyskinesia (involuntary and repetitive body movements) even after the drug is no longer being taken.
• Risk factors: Long-term or high-dose use, elderly, female gender.
• Recommended that metoclopramide treatment not exceed 3 months.

• None really.
• Just be aware of the dopamine antagonist effects (EPS - dystonic reactions) that are possible whenever you order metoclopramide in the acute setting.
• These effects can be treated effectively with an anticholinergic agent, such as diphenhydramine or benztropine.

Clevidipine

• A new intravenous antihypertensive agent
• Has a very rapid onset (2-4 min) and offset (5-15 min), in contrast to the available IV calcium channel blocker nicardipine, which has a duration of action of 3-6 hours
• Contraindicated in patients with soy or egg allergies, and in those with defective lipid metabolism
• Most common ADR's reported were headache, nausea, and vomiting
• Initiate at 1-2 mg/hr, most respond at doses between 4-6 mg/hr
• Maximum recommended dose is 16 mg/hr
• Costs between $86 to $140 per 50 mg vial

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As the economy worsens and our patients pay for more prescriptions out of pocket, here are some tips that may help you better serve your patients: 1) Ondansetron (zofran) is now off patent. Write generic on your script for zofran - for pediatrics the ODT (dissolving tablets) - are all much cheaper ($0.50 to $1.00 per pill or ODT). IV formulation is now cheaper than phenergan. Reglan is probably still the cheapest in most pharmacies. 2) Typical $4 antibiotics are the following: SMP-TMZ (Bactrim), Cephalexin, Amoxicillin, Penicillin, Ciprofloxacin. 3) Albuterol MDIs are now much more expensive because they have to be CFC free. Unfortunately, after this federal regulation, patients will have difficulty getting these inhalers which can be quite expensive. If you write a script and the patient is self-pay, they are going to have difficulty. Hospitals are beginning to discourage "to go" inhalers and even pills due to the fact that insurance companies DO NOT reimburse these costs - only IV meds.

Rocuronium is fast becoming the agent of choice for RSI in the Emergency Department. Here is a head to head comparison of the two drugs to understand why:

	Rocuronium	Succinycholine
Dose	1-1.2mg/kg	1mg/kg
Onset	1-1.5min	1min
Duration	7-12min	30-40min
Histamine Release	No	Minimal Yes
CVS Effect	Tachycardia rare	Severe Brady rare
Other Adverse Effect	No fasciculations, No ICP effect, No Rhabdo	Fasciculations, increase ICP, rhabdo, movement of displaced Fxs

 

You have a 44 y/o female patient with an arterial line monitoring her blood pressure which is reading 302/156 mm Hg.  Her heart rate is 140 bpm.  Her history reveals she is taking a monoamine oxidase inhibitor (MAOI) and has inadvertantly ingested tyramine at her friend's cheese/wine party.   What do you do?

• Conditions producing hypertensive crisis from catecholamine surges (phenylephrine overdose, cocaine, tyramine interactions, pheochromocytoma) can be treated with phentolamine
• Phentolamine is a nonspecifc alpha blocking agent which produces peripheral vasodilation with a resultant fall in blood pressure in most patients.
• Other uses include extravasation of some vasopressors (e.g. norepineprhine)
• May see an increase in HR after administration (once alpha blockade is established, beta-blocker can be administered)
• Dose: 5-15 mg IV/IM
• Duration: 30-45 minutes

There have been multiple case reports of patients who have had coronary stents who have been on clopidogrel for > 1 year who have developed coronary thrombosis after clopidogrel cessation. There are also reports of patients who have developed DVTs likewise after clopidogrel cessation. In vivo studies in diabetics have demonstrated increased platelet and inflammatory markers after clopidogrel withdrawal. It appears that abrupt discontinuation of clopidogrel may lead to a thrombotic state in susceptible patients.

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Rodenticides have taken many forms. The following is a list of some of the more interesting ones either due to the mechanism of toxicity or how it is lethal. All of these are also toxic to people.

1) Strychnine - Glycine Antagonist at the post-synaptic spinal cord neurons - patient or rat will have convulsion of the extremeties but will be awake, alert and in extreme pain. Essentially look like generalized seizure except awake. Treatment: Benzodiazepines, Analgesia, Supportive

2) Brodifacoum - Long Acting Coumarin - rat eats, later develops elevated INR then tries to run through thin cracks in the wall or takes a little too high of a jump, then boom - subdural or some other internal hemorrhage. In human, they can stay anticoagulated for weeks after an overdose. Treatment: Vitamin K and large padded room

3) Cholecalciferol - Vitamin D precursor - there are big blocks of this drug in the NY and other subway systems. Rat nibbles, gets hypercalcemic, then gets thirsty because of this. Rat runs out into middle of subway to drink out of puddle then - splatt - the M train to Brooklyn comes along. Treatment: IVF, Loop Diuretics, Bisphosphonates

 

Octreotide

• Somatostatin-analog that supresses insulin secretion but also treats acromegaly, esophageal varices and secretory diarrhea
• Sulfonylurea-induced hypoglycemia requires frequent monitoring and administration of intravenous dextrose
• Octreotide is considered antidotal therapy since it turns off insulin secretion that is caused by sulfonylureas
• Recent article by Fasano et al Ann Emerg Med 2008 showed that octreotide 75 mcg SQ one-time in the ED was superior to "traditional" therapy with fewer recurrent hypoglycemic episodes during the patient's hospitalization.
• Excellent article worth reading, even if its just the abstract

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Tetrodotoxin - Sodium Channel blocker - Extremely toxic causes paresthesias, dysrhythmias and paralysis - Found in the sushi called Fugu (From the Pufferfish) - Eating the sushi is considered a delicacy and goal is to get just enough of the toxin to get perioral paresthesias after eating. - Also found in the blue-ringed octopus, angelfish and parrot fish. Enjoy your seafood and take a look at the attached pic of actual fugu.

Attachments

• 0901152329_fugu_0111.jpg (145 Kb)

A few previous pearls have touched on identifying drugs that cause QT prolongation.  In our patient population, methadone is one of the more common causes of drug-induced prolonged QT syndrome.  Of 692 physicians surveyed (35% family practitioners, 25% internests, 22% psychiatrists, and 8% self-identified addiction specialists) only 41% were aware of methadone's QT-prolonging properties and just 24% were aware of methadone's association with torsade de pointes.

 

Now that you know, what do you do when a patient on methadone presents with a QTC of 580 msec and intermittent runs of vtach and torsade de pointes?

 

The answer is... the exact same thing you would do with any other patient who presents this way, regardless of the cause.

• Give magnesium sulfate 2 gm IV for torsade de pointes
• Check magnesium and potassium levels.  If low (which they often are), replete.
• Monitor continuous EKG.

Buprenorphine, an alternative to methadone, is not associated with prolonged QT syndrome.

 

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Although we tend to think of ACS with cocaine use, there are many other serious complications, including:

• Agitation, psychosis, and anxiety
• Hyperthermia
• Vascular headache of withdrawal
• Seizures
• Hemorrhagic stroke (many of these patients have an underlying vascular abnormality)
• Ischemic stroke
• Acute Renal Failure
• Crack Lung: acute pulmonary syndrome that occurs after inhaling freebase cocaine presents as fever, dyspnea, hypoxemia, diffuse alveolar infiltrates, and respiratory failure
• Intestinal perforations

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Watch out for tradename and generic name's of medications.

They can get the patient and yourself into trouble:

• coumadin: warfarin, jantoven
• diphenhydramine: unisom, benadryl, tylenol PM

Classic example is my own case: Insert a central line in a patient - subclavian - and shortly after completion am alerted the patient's INR is 25. No adverse outcome but when I reviewed the med list, I did not see coumadin or warfarin and assumed I was in the clear. Patient was on jantoven.

Happy Holidays

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