36 year old male with PMHx of IDDM and depression was prescribed a new drug by his psychiatrist for psychogenic erectile dysfunction. He presented to the hospital 16 hours after taking 350mg of this drug. He was drowsy and confused on presentation with a BP of 130/80 and HR of 150 with atrial fibrillation, which he had no history of. He was having rigors and retrosternal pain. He had no other co-ingestions. His rectal temperature was 35.5C. He was well-perfused peripherally. His laboratory studies were otherwise unremarkable. He was admitted for altered mental status and for new atrial fibrillation, which spontaneously resolved within 24 hours.

• Yohimbe extract is an indole alkaloid derived from the bark of a West African evergreen (Pausinystalia yohimbe) - Active ingredient is yohimbine
• Grows primarily in west Africa and Congo
• Past studies show possible usefulness in vascular, diabetic and psychogenic impotence[1] 
• ‘Street uses’ include as an aphrodisiac, hallucinogen, and dietary supplement (to be used for “fast weight-loss” and “body-building supplementation”).
• Available by prescription (Yocon, Aphrodyne, Testomar) or over the counter

Pharmacology/Uses:

• Predominantly alpha-2-antagonist - Increases release of norepinephrine and dopamine by blocking the pre and post-synaptic alpha-2-adrenoceptors, therefore acting as a CNS stimulant
• Effects are somewhat opposite of clonidine (alpha-2-agonist) & can be synergistic with co-ingestants (e.g. caffeine). 
• Also has moderate affinity to alpha-1-adrenoceptors
• Use in dieting/bodybuilding: Promotes sympathetic activity by central and peripheral mechanisms; therefore, administration prior to exercise boosts lipolysis and serum FFA levels[6].

Use in erectile dysfunction: 

• FDA-approved drug as of 1995 for treatment of impotence.
• Previously widely used in veterinary medicine for treatment of impotent breeding stallions
• Alpha-2 adrenoceptors mediate erection-inhibiting impulses in CNS
• Also believed to enhance central sexual impulse by blocking the alpha-2-adrenoceptors in the locus ceruleus in the brain[8].
• Also shown to have relaxant effect on corpus cavernosum/increase in NO content in dose-dependent manner in rats, however, more recent studies in rabbits did not show benefit from yohimbine.
• Meta-analysis in 1998 of seven clinical trials did show superiority over placebo for treatment of ED, however, not used routinely in urological practices.
• Recommended dosing is 16mg a day taken in 3 divided doses, suggested treatment period is no longer than 10 weeks. [10]

Pharmacokinetics:

• Rapidly absorbed and maximum plasma concentrations are achieved in less than 1 hour of oral administration. Metabolized by liver and kidneys. Crosses blood-brain barrier.
• Average oral dose of 5-15mg produces a therapeutic whole blood level range of 40-400 ng/mL
• Plasma half-life of roughly 35 minutes[2], however, latency in response of about 2-3 weeks after initiation of treatment of erectile dysfunction.
• Overdoses leading to neurotoxic effects seen up to 5,000 ng/mL
• Case report of 37-year-old bodybuilder who ingested 5000mg of yohimbine during a competition and presented with malaise, vomiting, and repeated seizures secondary to it’s neurotoxic effects in acute ingestion.

Clinical toxicity:

• Nausea, GI irritation, agitation, anxiety, hypertension, diaphoresis, mydriasis, priapism[9] and bronchospasm due to central adrenergic activity.
• Symptoms begin to show around 20-30mg yohimbine. LD50 is around 40mg/kg.
• MAOi effect
• Contraindicated in hypotension, diabetes, heart/liver/kidney disease and schizophrenia
• Case report of atrial fibrillation secondary to severe toxicity, likely due to noradrenergic blockade in CNS [4].
• Thought to cause peripheral alpha-1-blockade at higher doses, leading to peripheral vasodilation and hypothermia[3, 4].

Treatment:

• Supportive care and benzodiazepines as needed
• Clonidine can be used to treat yohimbine-associated hypertension[5].

References

1. Morales et al. The effectiveness of yohimbine in the treatment of organic impotence J Urol 1987
2. Owen et al. The pharmacokinetics of yohimbine in man. Eur J Clin Pharmcol 1987
3. Starke K et al. Preferential blockade of presynaptic alpha receptors by yohimbine. Eur J Pharmacol 1975.
4. Varkey S. Overdose of Yohimbine. BMJ 1992.
5. Anderson C et al. Case Study: Two fatal case reports of acute yohimbine intoxication. J Anal Toxicol 2013.
6. McCarty MF. Pre-exercise administration of yohimbine may enhance the efficacy of exercise training as a fat loss strategy by boosting lipolysis. Med Hypotheses 2002.
7. Saad MA et al. Potential effects of yohimbine and sildenafil on erectile dysfunction in rats. Eur J Pharmacol 2013.
8. Corazza O et al. Sexual Enhancement Products for Sale Online: Raising Awareness of the Psychoactive Effects of Yohimbine, Maca, Horny Goat Weed, and Ginkgo biloba. BioMed Research Intl 2014.
9. Myers A et al. Refractory Priapism Associated with Ingestion of Yohimbe Extract. J Med Toxicol 2009.
10. FDA guidelines on yohimbe bark extract / yohimbine

Other sources used include Goldfrank’s 10th edition, Haddad’s 3rd edition, and The Poison Review (www.thepoisonreview.com)
​
Authored by: Dr. Michael Mollo M.D.

20% intravenous fat emulsion (IFE) may be useful to resuscitate severe cardiotoxicty due to fat-soluble drugs; the so-called lipid rescue. Propofol is a fat soluble anesthetic agent that is formulated and delivered in 3% IFE. If 20% IFE is not immediately available, can I use propofol as a substitute for 20% IFE?

What is Intravenous Lipid Emulsion?

• Also called ILE, Lipid resuscitation therapy (LRT), LipidRescue, or Intralipid
• Composed of  medium- and long-chain triglycerides, free fatty acids, and phospholipids
• Is a component of TPN

How does it work?

• Think of lipid rescue as dialysis for lipophilic drugs. IFE acts as a lipid sink, sequestering fat soluble drugs away from critical organ tissue
• Has shown promise in rat and dog models for treating lipid-soluble cardiotoxins 
• First successful clinical case report in 2006 - patient arrested immediately after interscalene block with bupivacaine and mepivacaine - after 20 min of ACLS, gave 100mL of Intralipid and had pulse/BP within a few minutes
• Theory of the “lipid sink”: draws medications into the lipid sink and away from target organs, but multiple theories exist 

What can it treat?

• ACMT says that there is no “standard of care” for this treatment yet
• Considered if patient is hemodynamically unstable from a substance with high lipid solubility and patient is unresponsive to standard therapies
• Local anesthetics have a more clear indication
• Other possible substances described in case reports: calcium-channel blockers, beta blockers, TCAs, antipsychotics, bupropion, chloroquine, glyphosate, and cocaine

How do you give it?

• 20% lipid emulsion (e.g. Intralipid) given as 1.5 ml/kg bolus over 2-3 minutes. 
• Follow immediately with infusion of Intralipid at a rate of 0.25 ml/kg/min
• May repeat bolus if patient remains in asystole or PEA 
• May increase infusion or even re-bolus if after an initial response, patient becomes unstable again
• Therapy should be stopped after 1 hour, or less, if the patient’s clinical status permits

Are there any adverse reactions?

• ILE has been associated with pancreatitis, fever, hematuria, and DVT
• Just like TPN - also associated systemic infections, especially fungemia 
• Animal studies show risk of acute lung injury

What lab tests are altered?

• AST
• Hgb
• Met-Hgb
• Electrolytes
• Coags
• ABG
• ASA? unknown

Why do people think Propofol will work?

• Propofol is in a medium/large chain triglyceride lipid emulsion, so it is also a fat emulsion, just like ILE
• However there have been some misquoted studied that lead people to believe that Propofol has proven efficacy as an antidote 
• One article that studied pressors (epinephrine and vasopressin for bupivacaine induced cardiac arrest in pigs) misquoted a study by Dr. Weinberg (MD behind “Lipid Rescue”) and stated that propofol treats bupivacaine toxicity
• Dr. Weinberg refuted this misquote in an editorial: “We have never recommended use of propofol for treating bupivacaine overdose, and strongly suspect that its use in cardiac arrest will impede resuscitation”​

Have any studies been performed?

• Ohmura 1999: In pigs: propofol vs sevoflurane 
• Higher doses of bupivacaine in propofol group to induce dysrhythmias, seizures, or 50% reduction of heart rate
• Zimmer 2007: Case report:  patient received BOTH propofol and intralipid
• Mauch 2011: In piglets: propofol with sevoflurane vs sevoflurane alone.  No change in toxic dose of bupivacaine between the groups
• Yilmaz 2014: Rat study with different preparations of propofol, propofol in intralipid, propofol in medialipid, or saline.  

                       * End points of: time to first dysrhythmia, times to 25% and 50% reduction in HR or BP, and time to asystole

                      * Propofol in intralipid group had longer time to each adverse outcome than the other groups

• Güngör 2015: Case report - 76 y.o. female had interscalene block with bupivacaine. Patient became unresponsive and seized, thus was intubated with thiopental and atracurium. Propofol infusion was started. 
• Bupivacaine levels were drawn just after intubation (1.6) and at the conclusion of the surgical case (undetectable at 135 min). Toxic level is 2-4. In the study discussion the authors believe that the Bupivacaine should have still been detectable and attribute this decrease to the propofol. 

What did I take away from this?

• Propofol has only been studied in animals or case reports
• Many of these are giving intralipid with propofol
• NEVER been used/studied in anything other than local anesthetic toxicity
• In severe toxicities that involve hemodynamic collapse (indication for lipid emulsion therapy), giving a medication that causes hypotension doesn’t seem to make sense

References:

• Antidotes For Overdose: Timely And Effective Counteraction, EM critical care, July 2014
• American College of Medical Toxicology (ACMT) National Office -  Interim guidance for the use of lipid resuscitation therapy
• Rosenblatt MA, Abel M, Fischer GW, et al. Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest. Anesthesiology. 2006;105(1):217-218.
• Mauch J, Kutter AP, Martin Jurado O, Spielmann N, Frotzler A, Bettschart-Wolfensberger R, Weiss M. [Bupivacaine toxicity and propofol anesthesia : animal study on intravascular bupivacaine injection]. Anaesthesist.  2011 Sep;60(9):814-8. doi: 10.1007/s00101-011-1898-8. Epub 2011 Jul 3. German. PubMed PMID: 21725675.
• Zimmer C, Piepenbrink K, Riest G, Peters J. [Cardiotoxic and neurotoxic effects after accidental intravascular bupivacaine administration. Therapy with lidocaine propofol and lipid emulsion]. Anaesthesist. 2007 May;56(5):449-53. German. PubMed PMID: 17277955.
• Weinberg G, Hertz P, Newman J. Lipid, not propofol, treats bupivacaine overdose. Anesth Analg. 2004 Dec;99(6):1875-6; author reply 1876. PubMed PMID: 15562099.
• A Comparison of Epinephrine and Vasopressin in a Porcine Model of Cardiac Arrest After Rapid Intravenous Injection of Bupivacaine, Mayr, Viktoria
• Güngör İ, Akbaş B, Kaya K, Çelebi H, Tamer U. Sudden developing convulsion during interscalene block: Does propofol anesthesia diminish plasma bupivacaine level? Agri. 2015 Jan;27(1):54-7. doi: 10.5505/agri.2015.82160. PubMed PMID: 25867875.
• Ohmura S, Ohta T, Yamamoto K, Kobayashi T. A comparison of the effects of propofol and sevoflurane on the systemic toxicity of intravenous bupivacaine in rats. Anesth Analg. 1999 Jan;88(1):155-9. PubMed PMID: 9895084
• Yilmaz M, Celebi H, Akcali D, Gurel N. Pre-treatment of bupivacaine-induced cardiovascular depression using different lipid formulations of propofol. Acta Anaesthesiol Scand. 2014 Mar;58(3):298-302. doi: 10.1111/aas.12263. Epub 2014 Jan 20. PubMed PMID: 24438483

Introduction: Domoic acid is a marine excitatory neurotoxin secreted by pseudo-nitzschia diatoms and various species of chondria armata red algae which are found throughout the world. The toxin is bio-accumulated in marine animals such as shellfish, anchovies and sardines and is then passed to humans who ingest them. It is temperature stable when accumulated in the tissues of shellfish and is not inactivated by cooking or freezing.  The toxin is a water soluble, tri-carboxylic acid which is very closely related to kainic acid, a neurotoxin found in seaweed and is a structural analogue of endogenous glutamic and aspartic acids. Domoic acid induces a constellation of symptoms in humans known as Amnesic Shellfish Poisoning. Only one recorded event of this has occurred and took place in 1987 on the eastern coast of Prince Edward Island. 147 patients ingested mussels containing the toxin. 1/3 of these eventually developed neurologic symptoms including permanent short term memory deficits, seizure and coma. There were 4 fatalities.

As of 2015 the western coast of the United States is currently experienced the largest pseudo-nitzschia bloom in ten years prompting closure of many commercial fisheries.

Structure: 

Pharmacology/Pharmacokinetics: Domoic acid is a water soluble tri-carboxylic acid that is absorbed orally. Systematic investigations of volume of distribution do not appear to have been yet undertaken. However, given its chemical structure as a hydrophilic organic acid its lipophilicity is likely low. Similarly it should have difficultly crossing the blood brain barrier. Studies have shown that the molecule is excreted almost exclusively by the kidneys with the molecule largely intact suggesting very little in vivo metabolism. Studies conducted in rats showed a renal clearance rate of less than 10 ml/min/kg. This appears to show large variability between species with primate studies showing an excretion approximately ten times slower than that observed in rats.

Toxic doses also appear to vary greatly between species. Data obtained in humans is scarce and is largely restricted to data gathered during the 1987 Prince Edward Island event. Findings shown below:

Oral Dose (mg/kg)                                                                 Clinical Symptoms
- 0.2-0.3                                                                              No observable effects
- 0.9- 2.0                                                                                        GI symptoms
- 1.9-4.2                                                                         Seizure, disorientation, coma

Interestingly, Domoic Acid has also been used as an anti-helminthitic in Japan for quite some time. One study from the late 1950’s reports doses of 0.4-0.8 mg/kg given to Japanese children with no apparent side effects. The LD50 in studies conducted in mice was found to be 3.6 mg/kg.

Domoic acid does appear to concentrate in the amniotic fluid of pregnant mammals with one study showing 24% of the serum value. It is not readily cleared from this space and thus likely poses significant developmental risks. It does appear to enter breast milk of lactating mammals as well.

Metabolic Pathways and active metabolites: Available data does not show evidence of extensive metabolism in mammals. It appears to be excreted largely intact almost exclusively through the kidneys.

Toxicity/Mechanism of Toxicity: Domoic acid is an excitatory neurotoxin and appears to exert effects on ionotropic glutamatergic receptors in the CNS, particularly the AMPA, NMDA and kainite subtypes. It binds with high affinity to these receptors causing an excessive influx of calcium which disrupts intracellular calcium currents, triggering apoptosis and leading to neuronal death. The mechanism is very similar to glutamatergic excitatory toxicity.

Of note, the hippocampus contains a high concentration of susceptible receptors and is thus disproportionately affected likely leading to the signature clinical finding of permanent short term memory deficits.

Clinical Toxicity/Presentation: The clinical presentation during acute exposure is characterized by two phases of symptoms. Mild acute GI symptoms such as nausea and vomiting are often seen within the first 24 hours. CNS symptoms such as headache, dizziness, confusion, disorientation, seizures, short term memory loss, motor weakness, and coma are generally seen in the first 48 hours following exposure. Other side effects observed included cardiac dysrhythmia, hypotension, and increased respiratory secretions.

Studies performed in sea lions which are primary consumers of the pseudo-nitzschia diatom and thus chronically exposed have shown that chronic sub-lethal exposure may cause epilepsy and cardiomyopathy.

The demographic appeared to be most heavily affected were those over 65 years of age. This is likely due to decreased renal function and decreased integrity of the blood-brain barrier secondary to aging.

Laboratories: Clinical lab studies are likely of little use in the acute phase beyond a chemistry screen to assess renal function. Rapid ELISA as well as chromatography are available for the detection of domoic acid directly.

Treatment/Management: Largely supportive. Data from the 1987 incident showed that seizures were largely able to be managed by benzodiazepines and phenytoin. Due to the renal excretion of the toxin, dialysis may theoretically play a role in those with renal impairment, however this has not yet been investigated.

 By Dr. Andrew Johnson, PGY2

References
1.     Teitelbaum, MD, J., Zatorre, Ph.D, R., Carpenter, MD, S., Gendron, MD, D., Evans, Ph.D, A., Gjedde, MD, A., & Cashman, MD, N. (1990). Neurologic Sequelae of Domoic Acid Intoxication Due to the Ingestion of Contaminated Mussels. New England Journal of Medicine, 322(25), 1781-1787.
2.     Pulido, O. (2008). Domoic Acid Toxicologic Pathology: A Review. Marine Drugs, 6(2), 180-219.
3.     Jeffery, B., & Barlow, T. (2004). Amnesic Shellfish Poisoning. Food Chemical Toxicology, 42(4), 545-557.
4.     Ramsdell, J., & Frances, G. (2014). Domoic Acid Epileptic Disease. Marine Drugs, 12(3), 1185-1207.
5.     Lefebvre, K., & Robertson, A. (2010). Domoic acid and human exposure risks: A review. Toxicon, 56, 218-230.

Introduction:

• Alcohol causes an imbalance in the inhibitory GABA and excitatory NMDA receptors
  
• Benzodiazepines (benzos) have been shown effective in the prevention and treatment of AWS (alcohol withdrawal syndrome)
  
• Higher doses of benzos place patients at risk for respiratory depression, aspiration, and intubation
  
• Benzo monotherapy may not be effective enough to control symptoms and may worsen delirium
  
• Multiple studies have shown benzodiazepine use is associated with longer ventilator times, longer ICU/hospital stays, and higher ICU delirium rates
  
• Dexmedetomidine (Dex) is a sedation medication and recently has been proposed as an alternative to using benzos for treatment of AWS
  
• Dex is unique in that it does not depress respiratory drive at therapeutic doses and causes arousable sedation
  
• Dex was recently approved for use in non-intubated patients
  
• Dex decreases sympathetic activity; which may help in the treatment of AWS
  

Structure:
C13H17CIN2

Pharmacology/Pharmacokinetics: Comparing Alpha2 Agonists

Treatment/Management:

• Dexmedetomidine can be used for alcohol withdrawal
  
• Rayner showed 61% reduction in benzo dosing with adding Precedex and 20% reduction in AWS score
  
• However, Crispo studied 61 nonintubated patients with AWS and showed that Dex had more adverse drug affects and similar intubation rates/length of stay compared to benzos
  
• Mueller showed that Dex decreased benzo use in the short term, but not long term in tx of AWS
  
• Lizotte, VanderWeide, Savel, and Wong showed Dex is associated with lower benzo use in severe AWS
  
• More research is needed: No studies have used Dexmedetomidine to treat alcohol withdrawal without supplemental benzos

By Dr. Patrick Jackson, MD

References:
∗ Albertson T, Chenoweth J, Ford J, et. al.  Is it prime time for alpha2-adrenocepter agonists in the treatment of withdrawal syndromes?  J Med Toxicol.  2014; 10(4):369-381.
∗ Bryczkowski S, Lopreiato M, Yonclas P, et. al.  Risk factors for delirium in older trauma patients admitted to the surgical intensive care unit.  J Trauma Acute Care Surg.  2014; 77(6):944-951.  
∗ Crispo A, Daley M, Pepin J, Harford P, Brown C.  Comparison of clinical outcome in nonintubated patients with severe alcohol withdrawal syndrome treated with continuous-infusion sedatives: Dexmedetomidine versus benzodiazepines.  Pharmacotherapy.  2014; 34(9):910-917.
∗ DeMuro J, Botros D, Wirkoski E, Hanna A.  Use of dexmedetomidine for the treatment of alcohol withdrawal syndrome in critically ill patients: A retrospective case series.  J Anesth.  2012; 26(4)601-605.
∗ Flower O, Hellings S.  Sedation in traumatic brain injury.  Emerg Med Int.  2012; e-published.
∗ Lizotte R, Kappes J, Barte B, et. al.  Evaluating the effects of dexmedetomidine compared to propofol as adjunctive therapy in patients with alcohol withdrawal.  Clin Pharmacol.  2014; 31(6):171-177.
∗ Lonardo N, Mone M, Nirula R, et. al.  Propofol is associated with favorable outcomes compared with benzodiazepines in ventilated intensive care unit patients.  American Journal of Respiratory and Critical Care Medicine.  2014; 189(11):1383-1394.
∗ Mancl E, Brophy G.  Time to wake up: A historical perspective on modernized sedation management.  Society of Critical Care Medicine.  2013; e-published.
∗ Mazanikov M, Udd M, Kylanpaa L, et. al.  Dexmedetomidine impairs success of patient-controlled sedation in alcoholics during ERCP: A randomized, double blind, placebo-controlled study.  Surg Endosc.  2013; 27(6):2163-2168.  
∗ Muller S, Preslaski C, Kiser T, et. al.  A randomized, double-blind, placebo-controlled dose range study of dexmedetomidine as adjunctive therapy for alcohol withdrawal.  Crit Care Med.  2014; 42(5):1131-1139.
∗ Muzyk A, Kerns S, Brudney S, Gagliardi J.  Dexmedetomidine for the treatment of alcohol withdrawal syndrome: Rationale and current status of research.  CNS Drugs.  2013; 27(11):913-920.
∗ Rayner S, Weinert C, Jepsen S, Broccard A.  Dexmedetomidine as adjunct treatment for severe alcohol withdrawal in the ICU.  Ann Intensive Care.  2012; 23(1):12.
∗ Riihioja P, Jaatinen P, Haapalinna A, et. al.  Effects of dexmedetomidine on rat locus coeruleus and ethanol withdrawal symptoms during intermittent ethanol exposure.  Alcohol Clin Exp Res.  1999; 23(3):432-438.
∗ Riihioja P, Jaatinen P, Oksanen H, et. al.  Dexmedetomidine, diazepam, and propranolol in the treatment of ethanol withdrawal symptoms in the rat.  Alcohol Clin Exp Res.  1997; 21:801-804.
∗ Roberts D, Hall R, Kramer A, et. al.  Sedation for critically ill adults with severe traumatic brain injury: A systematic review of randomized controlled trails.  Crit Care Med.  2011; 39(12)2743-2751.
∗ Tolonen J, Rossinen J, Alho H, Harjola V.  Dexmedetomidine in addition to benzodiazepine-based sedation in patients with alcohol withdrawal delirium.  Eur J Emerg Med.  2013; 20(6):425-427.
∗ Traeger J, Popa A, Makii J.  Dexmedetomidine for acute alcohol withdrawal.  Society of Critical Care Medicine.  2014, e-published.  
∗ Savel R, Kupfer Y.  Using dexmedetomidine as adjunctive therapy for patients with severe alcohol withdrawal syndrome: Another piece of the puzzle.  Crit Care Med.  2014; 42(5)1298-1299.
∗ VanderWeide L, Foster C, MacLaren R, et. al. Evaluation of early dexmedetomidine addition to the standard of care for severe alcohol withdrawal in the ICU: A retrospective controlled cohort study.  J Intensive Care Med.  2014; e-published.  
∗ Wong A, Benedict N, Kane S.  Multicenter evaluation of pharmacologic management and outcomes associated with severe resistant alcohol withdrawal.  J Crit Care.  2015; 30(2):405-409.  

Alpha-PVP (aka “Flakka” or “Gravel”)

Introduction:
-Also referred to as Alpha-pyrrolidinovalerophenone, alpha-pyrrolidinopentiophenone, (RS)-1-phenyl-2-(1-pyrrolidinyl)-1-pentanone
-Cathinone is a natural stimulant found in the khat plant
-Synthetic cathinones, aka “Bath salts”, refer to a collective group of compounds that are highly potent stimulants and are similar to MDMA, cocaine, and methamphetamine
-The most common compound found in bath salts is MDPV (3,4-methylenedioxypyrovalerone)
-Alpha-PVP is not a “second generation bath salt”; it was actually first synthesized in the 1960’s
-Alpha-PVP has been recently been linked to multiple reported deaths in Florida
-Alpha-PVP was added to the controlled substance list in the USA in 2014

Structure:
-Alpha-PVP typically comes in a crystal form
-Formula: C15H21NO

Pharmacology/Pharmacokinetics:
-Alpha-PVP’s mechanism of action is believed to involve inhibition of the reuptake of norepinephrine, dopamine, and serotonin
-Rat studies have showed that alpha-PVP is both an uptake blocker of norephinephrine/dopamine and stimulates dopamine release

Absorption/Distribution/Metabolism/Excretion:
Absorption
-Can be taken orally, sublingually, injected, vaporized, or intranasal
-Onset of desired effects (euphoria) in 5-30 minutes and lasts for 1-3 hours.  However, the undesired side effects (including psychosis) can last days
Distribution
-Postmortem studies have found alpha-PVP uniformly distributed among multiple tissues (blood, brain, muscle, CSF, lung, kidney, and liver)
Metabolism
-Six phase I metabolites have been identified
-Lactam is the major metabolite
Excretion
-A study of postmortem alpha-PVP levels showed the highest concentrations were found in urine and the lowest concentrations were found in the liver → suggesting the drug is excreted chiefly by the renal system

Significant Drug/Drug Interactions:
-Co-ingestion of alcohol, other stimulants, and other illicit drugs has been shown to enhance the effects of the drugs
-A large proportion of the fatal cases of alpha-PVP have involved co-ingestions of multiples drugs and alcohol

Toxicity/Mechanism of Toxicity:
-LD50 has not been determined
-The potency and efficacy of alpha-PVP and MDPV are very similar in rat studies
-Rat studies showed increased locomotor signs with doses ranging from 1mg/kg to 30mg/kg
-A few case reports of drug-related fatalities with serum alpha-PVP levels have been reported:  0.1mg/L, 0.29mg/L, 0.52mg/L, 0.901mg/L
-All serum levels determined by liquid-mass-mass spectrometry method
-There is a significant overlap between concentrations tolerated by individuals and those reported in drug-related fatalities → alpha-PVP concentration alone does not determine toxicity

Clinical Toxicity/Presentation:
-Increased dopamine causes euphoria, increased activity, and hyperstimulation
-Increased norepinephrine increases heart rate and blood pressure
-Increased serotonin can cause hallucinations, delirium, and paranoia
-Severe agitated delirium and aggressive behavior have been reported
-Life threatening severe toxicity: Serotonin syndrome, hyperthermia, hypotension, rhabdomyolysis, acute renal failure, liver failure, cardiac dysrhythmias, seizures
-Chronic exposure:  May lead to physical and psychological dependence with withdrawal symptoms

Laboratories/Where it is made:
-Mainly manufactured in China and India and then shipped to America by legal delivery companies
-Unknown if manufactured in America currently

Treatment/Management:
-Treatment is symptomatic and supportive
-Benzodiazepines for sedation/delirium/seizures/tachycardia/hypertension
-IVF’s for dehydration frequently indicated
-GI decontamination is not recommended.  Single dose of activated charcoal may be considered for possible co-ingestion, but usually not clinically indicated.  Hemodialysis is not effective for elimination.
-Labs: Obtain electrolytes, renal function, hepatic enzymes, and CPK level
-Serum drug levels are NOT clinically useful and NOT readily available
-Obtain EKG and continuous cardiac monitoring
-Frequent temperature monitoring and institute cooling measures as warranted (Hyperthermia is an indicator of severe toxicity)
-Dispo:  Minimal observation of 6-8 hours.  If patient has persistent CNS stimulation, persistent tachycardia, seizures, or dysrhythmias →then warrants admission
-Poison center should be consulted

By: Dr. Patrick Jackson

References:

1. Aarde S, Creehan K, Vandewater S, et. al.  In vivo potency and efficacy of the novel cathinone alpha-PVP and 3,4-methylenedioxypyrovalerone: self-administration and locomotor stimulation in male rats.  Psychopharmacology.  2015
2. Eiden C, Mathieu O, Cathala P, et. al.  Toxicity and death following recreational use of 2-pyrrolidino valerophenone.  Clin Toxicol.  51(9):899-903, 2013.
3. “Flakka” (alpha-PVP).  National Institute of Drug Abuse.  April 6, 2015.  http://www.drugabuse.gov/drugs-abuse/emerging-trends
4. Gatch M, Dolan S, & Forster M.  Comparative behavioral pharmacology of three pyrrolidine-containing synthetic cathinone derivatives.  J Pharmacol Exp Ther.  2015.
5. Jones S.  Trending now: Flakka/Gravel/Alpha-PVP, and what you need to know.  Drug Policy Alliance.  April 10, 2015.  http://www.drugpolicy.org/blog/trending-now-flakka-gravel-alpha-pvp-and-what-you-need-know 
6. Kaizaki A, Tanaka S, & Numazawa S.  New recreational drug 1-phenyl-2-(1-pyrrolidinyl)-1-pentanone (alpha-PVP) activates central nervous system via dopaminergic neuron.  The Journal of Toxicological Sciences.  39(1):1-6, 2014.
7. Logan B.  Emerging designer drug monograph: Alpha-PVP.  SOFT Designer Drug Monographs.  2013.  http://www.soft-tox.org/files/Designer_Drugs/Alpha-PVP.pdf
8. Marinetti L & Antonides H.  Analysis of synthetic cathinones commonly found in bath salts in human performance and postmortem toxicology: Method development, drug distribution and interpretation of results.  J Anal Toxicol.  37(3):135-146, 2013.
9. Marusich JA, Antonazzo KR, Wiley JL, et. al.  Pharmacology of novel synthetic stimulants structurally related to the “bath salts” constituent 3,4-methylenedioxypyrovalerone (MDPV).  Neuropharmacology.  87:206-213, 2014.
10. Negreira N, Erratico C, Kosjek T, et. al.  In vitro phase I and phase II metabolism of alpha-pyrrolidinovalerophenone (alpha-PVP), methylenedioxypyrovalerone (MDPV) and methedrone by human liver microsomes and human liver cytosol.  Anal Bioanal Chem.  2015
11. Sauer C, Peters F, Haas C, et. al.  New designer drug alpha-pyrrolidinovalerophenone (PVP): studies on its metabolism and toxicological detection in rat urine using gas chromatographic/mass spectrometric techniques.  Journal of Mass Spectrometry.  44(6):952-964, 2009.  
12. Waugh L, Bailey K, Clay D, et. al.  Deaths involving the recreational use of alpha-PVP.  AAFS Proceedings. Abstract presentation.  2013.

Propofol basics:

• Short acting, intravenous general anesthetic
  
• Sedation dose typically 0.3-4 mg/kg/hr
  
• Anesthesia dose 4-12 mg/kg/hr
  
• Rapid onset and short duration
• Propofol infusion syndrome first described in 1990

 
Mechanism PRIS:

• Propofol inhibits transport of fatty acids into the mitochondria and inhibits electron transport chain causing build up of fatty acid metabolites and decreased ATP
  
• Made worse by a patient who is critically ill, has depleted carbohydrate stores, and thus relies on fatty acid breakdown for energy
  

 
Clinical features:

• Metabolic acidosis
  
• Cardiovascular collapse: Hypotension, treatment resistant bradycardia, and Brugada pattern on EKG

• Rhabdomyolysis/acute renal failure
  
• Elevated triglycerides
  
• Hepatomegaly
  
• Elevated lactate
  
• 30% mortality
  

 
Risk factors:

• Younger age (think higher doses propofol and less carbohydrate stores)
  
• People on high doses/long duration of propofol
  
• Exogenous glucocorticoids and vasopressors
  

 
Prevention:

• Limit propofol to 4 mg/kg/hr for less than 48 hours
  
• Note: cases of PRIS have still been described even with short duration/doses of propofol
  
• Consider screening high risk patients with lactate, CPK, EKG, or triglycerides
  

 
Treatment:

• Stop the propofol
  
• Provide carbohydrates
  
• Hemodialysis for acidosis
  
• ECMO if all else fails
  

 
References:
Diedrick, D, Brown D. Propofol Infusion Syndrome in the ICU. Journal of  Intensive Care Medicine. 2011; 26 (2) 59-72. .
 
Rosen DJ, Nicoara A, Koshy N, Wedderburn RV. Too much of a good thing? Tracing the history of the propofol infusion syndrome.  J Trauma. 2007;63(2):443-447.

Bleeding in Pregnancy:
SSRI use 1-2% of all pregnant females

Large Swedish study looking at pregnancy registry, unblinded
n = 500 with SSRI use, 39,000 controls
2.6/2.1 OR elevated risk for PPH/PP anemia
484 mL mean blood loss with SSRI vs 398 mL without SSRI

Clinical Implications:
No overwhelmingly convincing evidence available as of yet
Given bleeding state of pregnancy as well as predilection of SSRIs for bleeding, risk/benefits should be weighed

GI Bleeding

• 2014 Systematic Review with 15 case-control studies, four cohorts
  
• NNH was 3,177 and 881 in low and high risk groups
  
• Increased risk was 1.66-1.68 in the case control and cohort 
  
• studies
  
• With NSAID use the risk of upper GI bleeding was increased to OR of 4.25
  

Clinical Implications:
Although flawed, pathophysiology and studies combine for reasonable mechanism.  Likely should be avoided if possible.

PPI Therapy:

• Multiple studies - case controls - reporting decreased bleeding with SSRI w/ PPI use de Abajo et al found 9.1 OR SSRI and no PPI, 1.3 WITH PPI
• Targownik hospitalized GI bleeding OR ratio of 0.39 with use of PPI with SSRI
  

Summary:
Do we need to consider bleeding risk when prescribing SSRIs? 

• Keep SSRI in mind when looking at medication list and assessing bleeding risk
  

Greatest risk for SSRI 

• When used in conjunction with NSAIDs
  

Should PPIs be prescribed in conjunction with SSRIs?

• If NSAIDs are frequently used by patient then reasonable to also prescribe PPI
  

Do any recent studies provide strong enough evidence against use for pregnancy, CVA?

• Evidence suggest tendencies towards increased bleeding but only minimally statistically significant, except for combined SSRI and PPI use.

• Mercury is a naturally occurring heavy metal
  
• Found in elemental, inorganic, and organic forms
• Reacts with sulfhydryl groups in the body to inhibit enzymatic action, rapidly distributes to many organ systems

  Elemental Mercury – used for home metallurgy, gold smithing, thermometers

• Highly volatile at room temperature
  
• 75-80% absorbed via inhalation
  
• Inhalation-> CNS and Kidney Accumulation -> Significant pulmonary effects, but survivable!
  

Guiterrez, F.  Leon, L.  Elemental Mercury Embolism to the Lung.  N Engle J Med 2000; 342: 1791. June 15, 2000.  

Inorganic Mercury

• Usually via intentional ingestion, found in chemistry labs
• Acute exposure can cause hemorrhagic gastroenteritis, shock, ATN
• Chronic exposure responsible for mad hatter syndrome – abdominal pain, tremors, erethism, neurasthenia
• Oral Exposure-> Renal distribution ->GI and Renal symptoms
  
  

Organic Mercury

• Used in some antiseptics, chemical companies to make phenols
• Fat soluble, rapidly bioaccumulates in fish and higher predators
• Neurologic symptoms: ataxia, tremor, visual symptoms, dysarthria
• Oral Exposure -->CNS/Renal/Liver distribution -> Primary Neurologic symptoms
  
  

Lab Evaluation:

• Whole blood level of limited use, poor clinical coorelation
• Hair/Toenail levels also possible, poor correlation in acute exposure
• CBC for anemia, BMP for renal function

Management

• Skin decontamination :  carefully, mercury can vaporize and should not be vaccumed, more than 2 teaspoons requires a specialized team to remove from the hospital setting
• Mercury Decon Kit : Calcium polysulfide to convert to cinnabar
• Elemental Mercury may require intubation and pulmonary support
• Inorganic mercury will require copious IVF for severe third spacing and GI losses.  Can consider charcoal but may be dangerous
• Organic Mercury: Aggressive decontamination

Antidotes – Chelation Therapy!

• All bind to target to increase urinary elimination
• Early chelation provides better outcomes given symptoms and history consistent with mercury exposure

Dimercaprol (BAL) – Acute elemental and inorganic mercury

• 5 mg/kg/dose q4h IM x 48 hours
• 2.5 mg/kg q6 hr x 48 hours
• 2.5 mg/kg q12 hr x 7
• Also useful in lead, arsenic

Succimer (DMSA): oral alternative for stable patients or those with chronic toxicity from elemental and inorganic mercury

• 10 mg/kg PO TID x 5 days
• 10 mg/kg PO BID x 14 days
  
  

Organic mercury currently is treated in the US with Succimer (DMSA), however in Europe there is an IV/Oral dithiol analog of BAL called DMPS

• Available OTC in Europe, greater water solubility and available in oral forms
• 250 mg IV q4hrs for first 48 hours
• 250 mg IV q6hrs for the next 48 hours
• 250 mg IV q8hrs for the next 48 hours
• 300 mg PO TID for 7 weeks

References
1. Aaseth J, Skaug MA, Cao Y, Andersen O. Chelation in metal intoxication-Principles and paradigms. J Trace Elem Med Biol. 2014
2. Cao Y, Skaug MA, Andersen O, Aaseth J. Chelation therapy in intoxications with mercury, lead and copper. J Trace Elem Med Biol. 2014;
3. George GN, Prince RC, Gailer J, et al. Mercury binding to the chelation therapy agents DMSA and DMPS and the rational design of custom chelators for mercury. Chem Res Toxicol. 2004;17(8):999-1006.
4. Sue Y.  Chapter 96.  Mercury.  In: Nelson LS, Lewin NA, Howland M, Hoffman RS, Goldfrank LR, Flomenbaum NE.  Eds.  Goldfrank’s Toxicologic Emergencies, 9e.  New York, NY: McGraw-Hill 2011. 
5. Guiterrez, F.  Leon, L.  Elemental Mercury Embolism to the Lung.  N Engl J Med 2000; 342: 1791. June 15, 2000.
6. Aaseth J, Jacobsen D, Andersen O, Wickstrøm E. Treatment of mercury and lead poisonings with dimercaptosuccinic acid and sodium dimercaptopropanesulfonate. A review. Analyst. 1995;120(3):853-4.
7. Aposhian HV, Maiorino RM, Gonzalez-ramirez D, et al. Mobilization of heavy metals by newer, therapeutically useful chelating agents. Toxicology. 1995;97(1-3):23-38.
8. Aposhian HV, Bruce DC, Alter W, Dart RC, Hurlbut KM, Aposhian MM. Urinary mercury after administration of 2,3-dimercaptopropane-1-sulfonic acid: correlation with dental amalgam score. FASEB J. 1992;6(7):2472-6.
9. Aaseth J, Skaug MA, Cao Y, Andersen O. Chelation in metal intoxication-Principles and paradigms. J Trace Elem Med Biol. 2014;
10. Cao Y, Skaug MA, Andersen O, Aaseth J. Chelation therapy in intoxications with mercury, lead and copper. J Trace Elem Med Biol. 2014;
11. Nielsen JB, Andersen O.  Effect of four thiol-containing chelators on disposition of orally administered mercuric chloride.  Hum Exp Toxicol.  1991; 10: 423-430.
12. Planas-bohne F. The effect of 2,3-dimercaptorpropane-1-sulfonate and dimercaptosuccinic acid on the distribution and excretion of mercuric chloride in rats. Toxicology. 1981;19(3):275-8.
13. Clarkson TW, Magos L, Cox C, et al. Tests of efficacy of antidotes for removal of methylmercury in human poisoning during the Iraq outbreak. J Pharmacol Exp Ther. 1981;218(1):74-83.
14. Ruha AM. Recommendations for provoked challenge urine testing. J Med Toxicol. 2013;9(4):318-25.
15. Bates N. Metallic and inorganic mercury poisoning. Emerg Nurse. 2003;11(1):25-31.
16. Guha mazumder DN, De BK, Santra A, et al. Randomized placebo-controlled trial of 2,3-dimercapto-1-propanesulfonate (DMPS) in therapy of chronic arsenicosis due to drinking arsenic-contaminated water. J Toxicol Clin Toxicol. 2001;39(7):665-74.
17. Muran PJ. Mercury elimination with oral DMPS, DMSA, vitamin C, and glutathione: an observational clinical review. Altern Ther Health Med. 2006;12(3):70-5.
18. .Rooney JP. The role of thiols, dithiols, nutritional factors and interacting ligands in the toxicology of mercury. Toxicology. 2007;234(3):145-56.