UMEM Educational Pearls - Toxicology

Bisphenol A (BPA) is found in epoxy resins that line common food and beverage materials. There has been concern that this compound, like phthalates, may be causing harm through chronic low exposure. An epidemiologic study was performed and published in JAMA that has raised this question. Amazingly, the study did find that:

• Higher urinary BPA levels correlated with an increase incidence of: NIDDM, CAD and elevated liver enzymes
• Mechanism may be an estrogen effect, disruption of Beta-islet cell function and even obesity promoting effects
• Study was strictly epidemiologic but raises a serious public health concern that you will see in the news more

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Clinical Manifestations in relation to lead level in children:

• > 70 - 100 mcg/dL: Encephalopathy, increased ICP, anemia, vomiting
• 50 - 70 mcg/dL: Irritable, difficult child, abdominal pain, anorexia
• >10 mcg/dL: often asymptomatic, may develop impaired cognition, behavior, impaired fine-motor coordination, hearing and growth

Several antihypertensive agents raise intracranial pressure. Normal cerebral blood flow (CBF) is constant within normal cerebral perfusion pressure (CPP) ranges, recalling that CPP=MAP-ICP.

If CPP is outside the range in which autoregulation occurs, e.g. due to a structural lesion, ischemic stroke, or head trauma, CBF decreases and can adversely affect the patient.

• Nitroprusside
  • Vasodilates both cerebral arteries and veins, increasing ICP
  • Inhibits the normal vasoconstrictive response to hypocapnia
• Nitroglycerin
  • Causes cerebral venodilation, increasing ICP
  • Impairs vasodilatory response to hypercapnia
• Hydralazine (varying effects)
  • Vasodilates cerebral arteries > cerebral veins
  • Impairs cerebral autoregulation
• Nicardipine
  • Other calcium channel blockers increase ICP by vasodilating arteries
  • Has been used to treat vasospasm in SAH
  • Increases cerebral blood flow in patients with SAH and acute stroke

In patients with ischemic stroke or intracerebral pathology, labetalol or esmolol may be used to lower blood pressure without raising ICP. Nicardipine is recommended for use in patients with ischemic stroke or SAH but not in patients with brain injury

If the patient has NO structural abnormalities, but has hypertensive encephalopathy, nitroglycerin, nitroprusside, labetalol, esmolol, or nicardipine may be used.

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 Melamine

• In case you thought the chinese only sent their toxin filled products to the USA, a massive scandal has been occurring with their milk.
• Adding melamine to their milk, companies were able to get falsely elevated readings of protein which is measured by the government to make sure the milk was not watered down.
• 53,000 illnesses, over 12,000 hospitilizations and at least 4 infant deaths have been attributed to their milk supply - 20% of China's milk supply is thought to be contaminated
• Melamine or melamine resin is used to make plastics and involved in other polymeric reactions.
• Toxicity involves the creation of kidney stones - imagine the pain in these poor children
• These children died from renal failure from multiple kidney stones.
• Check the link below to the news article

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 Cheese Heroin: a slang term for the combination of heroin with an over-the-counter antihistamine

• The two are combined and forms a cheesy like powder that is different from pure heroin
• A string of deaths were reported between 2005-2007 in Texas, many adolscents
• This concoction is more often insufflated than smoked or injected
• Combines opioid effect with the anticholinergic confusion and hallucinations
• Scorpion was a heroin that was combined with scopolamine that had similiar effect

Treatment

• Find the anticholinergic toxidrome, place the foley and supportive care are mainstays
• Consider administration of physostigmine 1mg IV slowly over 2-5 minutes (call toxicologist)
• The anticholinergic effects will linger much longer than the heroin effects ( <1hr)

 Latrodectus sp (Black Widow Spider)

• The only indigenous neurotoxic insect  in the state of Maryland and found through many states in the US
• The "bite" often not visible and does not cause a necrotic lesion like the brown recluse
• Causes Acetycholine release from post-synaptic motor and sensory nerves
• This leads to intense muscle contraction and pain. There have been reports of a black widow spider on the leg and the patient undergoes ex lap surgery for suspected acute abdomen only to find out the abdominal muscles were fasciculating due to envenomation
• Treat with aggresive analgesia and benzodiazepines.
• Not often lethal with approximately 60-70 deaths in the US over 30 years

Take a look at a picture of the black widow on the following attachment

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Topical Lidocaine for local anesthesia

Disclosure: I have no financial or invested interest in the product or the company.

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Buprenorphine (Suboxone)

• Use in opioid maintenance therapy programs, doesn't have QT prolongation and less respiratory depression than methandone
• Patients must been maintained on <40mg of methadone for successful conversion to buprenorphine to take place
• Primary caregivers can prescribe after taking a course
• Partial agonist can actual precipitate withdrawal if patient takes a full opioid (say sneaking a little heroin before appointment)
• Suboxone is buprenorphine+naloxone, since naloxone has poor bioavailability when taken appropriately there is no effect but if the tablet is crushed and injected the patient will go into florid withdrawal.
• Use and abuse has been steadily increasing and death can still occur from overdose.
• Pain is difficult to manage in patient on buprenorphine since opioid effect will be blunted, buprenorphine is potent partial agonist.

 A recent landmark article has cited a connection between non-insulin dependent diabetes and low-level arsenic in our drinking water.

• Approximately 13 million in the USA are drinking water that contains Arsenic levels higher than EPA allowable standards
• This study controlled for organic arsenic (found in seafood) and was looking for the effect of inorganic arsenic which is the more toxic compound - don't have to stop eating sushi
• This study essentially found a dose response curve with people with lower arsenic levels having lower incidence of non-insulin dependent diabetes, those with higher levels, higher risk.

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 Navas-Acien A, Silbergeld EK, Pastor-Barriuso R, Guallar E.

 

Arsenic exposure and prevalence of type 2 diabetes in US adults.

JAMA. 2008 Aug 20;300(7):814-22.

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