Pharmocology/Pharmokinetics: Unclear overall

• Propylene glycol: absorbed by GI tract, Vd 0.6L/kg, may be absorbed percutaneously through damaged skin areas, 12-45% excreted unchanged in the urine, otherwise metabolized in the liver
• • WHO maximum allowable intake 25 mg/kg

Metabolic Pathways and Active Metabolites:

• Propylene glycol -> lactaldehyde->lactic acid by alcohol dehydrogenase
  • Then to pyruvate

Toxicity/Mechanism of Toxicity:

• Much more likely to be symptomatic from pod exposure vs regular detergent. Unclear  whether the significant adverse health effects observed with laundry detergent pod exposures relate to unique ingredients, differences in pH or other chemical properties.
• Ethoxylated alcohols may cause gastric irritation and lethargy
• Direct contact may cause irritation of the oropharynx and esophagus
• Aspiration and resulting pulmonary toxicity may occur with or without coincident CNS
  depression and vomiting

​​Propylene Glycol

• Cardiovascular: hypotension, bradycardia, widening of the QRS interval, increased T wave amplitude
• Neurotoxicity: Ethanol and/or PG may contribute to the CNS depression
  o Smaller infants have a decreased ability to clearPG
  o Case studies of seizures in lowbirthweight infants receiving 3g daily in parenteral multivitamins
• Hyperosmolarity, elevated osmolar gap, metabolic acidosis following metabolism
• Nephrotoxicity: rental tubular necrosis
• Is the dose of propylene glycol high enough in Tide Pods to cause significant long term
  damage? Unclear

Treatment:

• Topical exposure: Irrigation
• Ingestion: Supportive care, airway protection, IVF, oxygen 

​

Authored by Dr. Enola Okonkwo

 
Introduction
Artemether Lumefantrine is an oral medication which is used in treatment of chloroquine resistant uncomplicated malaria.  Artemether Lumefantrine falls within the drug class of Artemisinin-based combination therapies which have been found to be highly effective in treating malaria and are substantially less toxic than quinoline antimalarials.  Artemisins are derived from a Chinese medicinal herb which comes from the sweet wormwood plant (1).   Artemether Lumefantrine, known by the brand name Coartem, is the most widely used artemisinin based combination therapy used in Africa and is one of three medications recommended by the CDC as first line oral treatment for uncomplicated falciparum malaria within the United States (2). 

Structure

​1 tablet = 20mg artemether and 120 mg lumefantrine. 
Dosing is weight based.  For patients > 35 kg they are taking 4 tablets per dose twice daily for 3 days. 
 
Pharmacology/Pharmacokinetics:
Absorption/Distribution/Metabolism/Excretion
 
Artemeter is rapidly absorbed.  Peak plasma level of artemeter is approximately 2 hours. The half-life after ingestion is 2 hours (4-5). 95% of artemether is protein bound but quickly undergoes metabolism to dihydroartemisin which is approximately 50% protein bound.  Half life of dihydroartemisin is also around 2 hours (5). Bioavailability increased 2-3 fold when consumed with food (4).
 
Lumefantrine – Initial absorption at approximately 2 hours. Peak plasma level approximately 6-8 hours.    Half life is 4-5 days.  It is highly protein bound and has a large volume of distribution.  High fat meals significantly increase absorption 16 fold (4). 
   
 
Significant Drug/Drug interactions
Numerous theoretic drug interactions have been reported.  However, there is scant data available reporting clinical effects of drug interactions.
-May enhance QTc prolonging effects
-May enhance toxic effects of other antimalarial or HIV medications
-May increase serum concentration of antipsychotics
-May decrease serum concentration of estrogen related contraceptives
-May decrease serum concentration of CYP3A4 Substrates
 
Metabolic Pathways and active metabolites
 
Arthemeter is metabolized by the liver to the active metabolite dihydroartemisinin primarily by CYP3A4/5. 
 
Lumefantrine is metabolized by the liver to desbutyl-lumefantrine by CYP3A4. 
 
Studies suggest that artemisins inhibit the sarco/endoplasmic reticulum Ca ATPases of the malaria parasite causing rapid reduction in the parasite (6-7).  The mechanism of lumefantrine is unknown but both agents inhibit nucleic acid and protein synthesis.  Artemether rapidly kills the majority of the parasite and lumefantrine goes on to kill the residual remaining parasite (4-5). 
 
Mechanism of Toxicity
 
Artemether Lumefantrine has been extensively used for the treatment of malaria and appears to have an excellent safety profile.  There are no reported overdoses or intentional ingestions.  There has been no evidence of significant systemic or local toxicity reported in any large human study (1, 20-21).  However, there is animal data and a few small human studies and case reports which suggest neurotoxicity and QT prolongation are possible toxic effects of artimisinins (14). 
 
Neurotoxicity was especially common in animal studies both clinically and histologically (8-10, 14).  In vitro studies have postulated that neurotoxicity results secondary to ATP depletion of neurons and free radical generation created by the breakdown of artemisins (Schmuck 2002, Smith 1998) . Toover et. el wrote a review article cautioning that neurotoxic effects may also occur in humans more frequently than previously thought, though many critics viewed their review as bias (8, 13).  There are a small number of case reports within humans suggesting that artemisins contributed to neurologic symptoms such as anxiety, tremor, and ataxia (8, 15-16).  A small study looking at construction workers treated with arthemeter suggested that individuals had hearing loss following the administration of artemether (17).  Obviously, this study is limited by a serious potential confounder and attempts to reproduce these results have failed (18). 
 
One case report of delayed hemolytic anemia, not thought to be related to malaria was reported (19).
 
Clinical Toxicity
 
Given patients taking artemether lumefantrine have malaria, it is difficult to distinguish between symptoms caused by the disease state of malaria versus symptoms which may be attributed to medication toxicity.  Clinical toxicity appears to be very rare or possibly underreported.  A large review of 188 studies including over 9,000 patients found no serious clinical toxicity (21). This review article used methodology similar to Cochrane review and reported transient neutropenia in 1.3%, reticulocytopenia (0.6%), elevated liver enzymes (0.9%), and transient bradycardia and prolonged QT (1.1%).  The most common side effects reported were gastrointestinal.  The authors conclude that Artemether Lumefantrine is a safe and efficacious drug. 
 
Common adverse events (4, 20-21)
Abdominal pain
Anorexia
Vomiting
Diarrhea
Headache
dizziness.
Pruritis and Rash < 2%
 
Laboratories
No specific toxicology labs are available
 
Management of Toxicity
No accepted recommendations regarding toxicity given the scarcity of data suggesting toxicity.
Below are general recommendations based off of literature review:
Avoid concurrent use of additional antimalarial medications
Use caution administering additional drugs which can prolong QT
Use caution in hypokalemia and replete electrolytes as needed
Use caution in patients with prolonged QT
Obtain EKG as screening for arrhythmia
 
References:
 
1.  Hien, T. T., White, N. J., & White. (1993). Qinghaosu. The Lancet, 341(8845), 603–608. https://doi.org/10.1016/0140-6736(93)90362-K
 
2. Center for Disease Control. (2009). Guidelines for treatment of malaria in the United States. Treatment Table Update, May, (770), 855–857. Retrieved from http://scholar.google.com/scholar?hl=en&btnG=Search&q=intitle:Guidelines+for+Treatment+of+Malaria+in+the+United+States#1
 
3.  Amin, N. C., Fabre, H., Blanchin, M.-D., Montels, J., & Aké, M. (2013). Determination of artemether and lumefantrine in anti-malarial fixed-dose combination tablets by microemulsion electrokinetic chromatography with short-end injection procedure. Malaria Journal, 12, 202. https://doi.org/10.1186/1475-2875-12-202
 
4.  Waning, B., & Montange, M. (2015). Access Pharmacy. Retrieved from http://accesspharmacy.mhmedical.com/content.aspx?bookid=438&sectionid=40428529
 
5.  White, N. J., Van Vugt, M., & Ezzet, F. (1999). Clinical pharmacokinetics and pharmacodynamics of artemether-lumefantrine. Clinical Pharmacokinetics. Adis International Ltd. https://doi.org/10.2165/00003088-199937020-00002
 
6.  Krishna, S., Pulcini, S., Moore, C. M., Teo, B. H. Y., & Staines, H. M. (2014, January). Pumped up: Reflections on PfATP6 as the target for artemisinins. Trends in Pharmacological Sciences. https://doi.org/10.1016/j.tips.2013.10.007
 
7.  Eckstein-Ludwig, U., Webb, R. J., Van Goethem, I. D. A., East, J. M., Lee, A. G., Kimura, M., … Krishna, S. (2003). Artemisinins target the SERCA of Plasmodium falciparum. Nature, 424(6951), 957–961. https://doi.org/10.1038/nature01813
 
8.  Toovey, S. (2006, October 10). Are currently deployed artemisinins neurotoxic? Toxicology Letters. https://doi.org/10.1016/j.toxlet.2006.06.001
 
9.  Genovese, R. F., Newman, D. B., Li, Q., Peggins, J. O., & Brewer, T. G. (1998). Dose-dependent brainstem neuropathology following repeated arteether administration in rats. Brain Research Bulletin, 45(2), 199–202. https://doi.org/10.1016/S0361-9230(97)00339-0
 
10.  Petras, J. M., Young, G. D., Bauman, R. A., Kyle, D. E., Gettayacamin, M., Webster, H. K., … Brewer, T. G. (2000). Arteether-induced brain injury in Macaca mulatta. I. The precerebellar nuclei: The lateral reticular nuclei, paramedian reticular nuclei, and perihypoglossal nuclei. Anatomy and Embryology, 201(5), 383–397. https://doi.org/10.1007/s004290050326
11.  Schmuck, G., Roehrdanz, E., Haynes, R. K., & Kahl, R. (2002). Neurotoxic mode of action of artemisinin. Antimicrobial Agents and Chemotherapy, 46(3), 821–827. https://doi.org/10.1128/AAC.46.3.821-827.2002
 
12.  Smith, S. L., Maggs, J. L., Edwards, G., Ward, S. A., Park, B. K., & McLean, W. G. (1998). The role of iron in neurotoxicity: a study of novel antimalarial drugs. Neurotoxicology, 19(4–5), 557–559.
 
13.  Toovey, S. (2006, October 10). Are currently deployed artemisinins neurotoxic? Toxicology Letters. https://doi.org/10.1016/j.toxlet.2006.06.001
 
14.  Brewer, T. G., Peggins, J. O., Grate, S. J., Petras, J. M., Levine, B. S., Weina, P. J., … Schuster, B. G. (1994). Neurotoxicity in animals due to arteether and artemether. Transactions of the Royal Society of Tropical Medicine and Hygiene, 88, 33–36. https://doi.org/10.1016/0035-9203(94)90469-3
 
15.  Miller, L. G., & Panosian, C. B. (1997). Ataxia and slurred speech after artesunate treatment for falciparum malaria. New England Journal of Medicine, 336(18), 1328. https://doi.org/10.1056/NEJM199705013361818
 
16.  Franco-Paredes, C., Dismukes, R., Nicolls, D., & Kozarsky, P. E. . (2005). Neurotoxicity Due to Antimalarial Therapy Associated with Misdiagnosis of Malaria. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America, 40(11), 1710–1711. https://doi.org/10.1086/430180
 
17.  Toovey, S. (2006). A case-control auditory evaluation of patients treated with artemether-lumefantrine. American Journal of Tropical Medicine and Hygeine 74, 939-940. 
 
18.  Hutagalung, R., Htoo, H., Nwee, P., Arunkamomkiri, J., Zwang, J., Carrara, V. I., … Nosten, F. (2006). A case-control auditory evaluation of patients treated with artemether-lumefantrine. American Journal of Tropical Medicine and Hygiene, 74(2), 211–214. https://doi.org/74/2/211 [pii]
 
19.  Hasegawa, C., Kudo, M., Maruyama, H., Kimura, M. (2017). Severe delayed haemolytic anaemia associated with artemether-lumefantrine treatment of malaria in a Japanese traveler. Journal of Infection and Chemotherapy.  In press.  https://doi.org/10.1016/j.jiac.2017.10.008
 
20.  Alkadi, H. O. (2007, November). Antimalarial drug toxicity: A review. Chemotherapy. https://doi.org/10.1159/000109767
 
21.  Ribeiro, I. R., & Olliaro, P. (1998). Safety of artemisinin and its derivatives. A review of published and unpublished clinical trials. Medecine Tropicale : Revue Du Corps de Sante Colonial, 58(3 Suppl), 50–53. Retrieved from http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=med4&NEWS=N&AN=10212898
 
 
 

Introduction to ADHD

• ADHD is the most well-known and researched neurodevelopmental disorder of childhood
• Approximately 5-6% of children and 2-3% of adults
• Both genetic and environmental factors are implicated
• The genes that are thought to code for ADHD are involved in the heritability of autism spectrum disorders and Tourette’s disorder
• In general, there are three types of ADHD; Inattentive, Hyperactive and Combined

 
History of Amphetamines

• First synthesized in 1887 and then first marketed in 1932 as a nasal decongestant
• Both amphetamine and methamphetamine were supplied as stimulants for soldiers and prisoners of war in WW II
• In the 1970s FDA made amphetamines schedule II and use declined
• However, increased use with derivatives methamphetamines and MDMA

Pharmacology/Pharmacokinetics:

• Absorption/Distribution/Metabolism/Excretion
  • Absorption – all are rapidly absorbed, with bioavailability that ranges between 60% and 90% depending on the route of administration, peak serum concentrations between 3-6 hours
  • Distribution – most compartments of the body, most are relatively lipophilic and readily cross the BBB, Vd from 3-33 L/kg depending on the substance
  • Metabolism – all are metabolized in the liver, however, the pathway depends on the specific substance, most involve CYP2D6
  • Excretion – renal elimination of the parent compound is substantial, also acidification of the urine can increase elimination, but usually not recommended

 
Therapeutic levels

• Not generally obtained given lack of clinical relevance

 
Significant Drug/Drug Interactions

• MAOI use, as well as linezolid or methylene blue may cause hypertensive crisis

 
Metabolic Pathways and active metabolites

• Depending on the amphetamine, many active metabolites can be formed
• Dealkylation and demethylation are mainly performed by CYP1A2, CYP2D6 and CYP3A4, also performed by flavin monooxygenase

Diagnostic Testing and Laboratories

• Chem 8, EKG and cardiac monitoring/observation for at least 6 hours, depending on presentation
• Can obtain UDS to assess presence of amphetamines, however, clinical exam and history is key
  • Many immunoassays have high rate of false positives and false negatives
  • Many substances are similar to amphetamines and may cross-react with the immunoassay
  • False negatives may occur with MDMA and cathinones
• Can consider further testing including but not limited to CBC, UA, CPK, coagulation studies, CXR, CT scan of the head and LP depending on clinical situation

 
Treatment/Management

• As with all presentations, manage ABCs and gain IV access and place patient on monitor
• Vital signs, rapid glucose and complete physical exam, importantly quickly obtain internal temperature
• Hyperthermia requires rapid external and even potentially internal cooling
• Benzodiazepines are first line for both agitation and hypertension/tachycardia
• If hypertension persists and you have attempted to control agitation with benzos, can considering a-adrenergic antagonists like phentolamine and peripheral vasodilators like nitroprusside and nitroglycerin
• Use antipsychotics with caution, have not been shown to be as effective as benzos and may lower seizure threshold, alter temperature regulation, cause acute dystonia and precipitate cardiac dysrhythmias
• If concerned for rhabdomyolysis, maintain UOP of at least 1-2 mL/kg/h
• Need to be suspicious for body packers and stuffers with these substances, treat accordingly

 
What is Stuttering? What causes it?

• Condition in which the normal pattern, rhythm, or timing of speech is disrupted, may be characterized by repetition and prolongation of words, phrases, and sounds, as well as hesitations or pauses that interrupt speech flow
• Can be developmental, psychogenic, result of a medication effect and secondary to brain injuries

 
Multiple Case Reports Discussing Stuttering Associated with ADHD Medications

• A 1991 case report of a 3 year old with two separate trials of stimulants, each of which resulted in stuttering
  • 2.5 mg BID methylphenidate and then pemoline 9.375 mg
  • After 18 months, no recurrence of stuttering
  • They hypothesized that stuttering a result of increased dopaminergic neurotransmission
• A 2015 case report of a 7 year old trialed on methylphenidate and developed stuttering
  • previously healthy with no family or personal history of speech difficulty or stuttering
  • diagnosed with ADHD and started on 10mg daily of methylphenidate
  • 10 days later developed stuttering, decided to stop medication, and stuttering gone in 7 days
  • They noted that methylphenidate had even been used to treat stuttering in previous cases
  • Case report from 1996 reporting sertraline induced stuttering
    • Sertraline was discontinued, and stuttering stopped
    • Akathisia has been noted to be induced by sertraline and this could be potentially related to serotonergic inhibition of the dopaminergic neurons whose cell bodies are located in the ventral tegmental area versus serotonergic inhibition of the dopamine pathways in the nigrostriatum
    • Needs more research whether this is related to speech abnormalities 

• Similarities between stuttering and dystonia are indicated and can possibly be related to the dopamine system
• A study in a bird model did show a relationship to amphetamine administration and their songs
  • Amphetamine administration increased the stereotypy of syllable structure and sequencing as well as vocal motor repetition
  • Amphetamine increased the degree to which stereotyped sequences of syllables were completed before song determination
  • Dopaminergic activity in cortical and basal ganglia structures found to be elevated in stuttering

​
References

1. Alm PA. Stuttering and the basal ganglia circuits: A critical review of possible relations. Journal of communication disorders. 07/2004;37(4):325-369. doi: 10.1016/j.jcomdis.2004.03.001.
2. Alpaslan AH. Stuttering associated with the use of short-acting oral methylphenidate. Journal of clinical psychopharmacology. 12/2015;35(6):739-741. doi: 10.1097/JCP.0000000000000403.
3. Burd L. Stuttering and stimulants. Journal of clinical psychopharmacology. 02/1991;11(1):72-73.
4. Christensen RC. A case of sertraline-induced stuttering. Journal of clinical psychopharmacology. 02/1996;16(1):92-93.
5. Dopheide JA, Pliszka SR. Attention Deficit/Hyperactivity Disorder. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com.libproxy.lib.unc.edu/content.aspx?bookid=1861&sectionid=146063877. Accessed February 19, 2018.
6. Jang DH. Amphetamines. In: Hoffman RS, Howland M, Lewin NA, Nelson LS, Goldfrank LR. eds. Goldfrank's Toxicologic Emergencies, 10e New York, NY: McGraw-Hill; 2015. http://accesspharmacy.mhmedical.com.libproxy.lib.unc.edu/content.aspx?bookid=1163&sectionid=65097893. Accessed February 19, 2018.
7. Matheson LE. Catecholaminergic contributions to vocal communication signals. The European journal of neuroscience. 05/2015;41(9):1180-1194. doi: 10.1111/ejn.12885.
8. Rabaeys H. Influence of methylphenidate on the frequency of stuttering: A randomized controlled trial. The Annals of pharmacotherapy. 10/2015;49(10):1096-1104. doi: 10.1177/1060028015596415.

 

​

-This is exceptionally frequent compared to epidemiological data from European countries where atypical parkinsonism accounts for only approximately 5% of all cases
- A higher proportion of patients with atypical parkinsonism (consumed soursop fruit 97%; consumed herbal tea 83%) than patients with Parkinson’s disease (fruit 59%; herbal tea 18%) or control with no Parkinson symptoms (fruit 60%; herbal tea 43%).
-When directly injecting rats for one month with the estimated amounts of annonacin ingested in a year by eating one fruit daily, this induced neurodegeneration in the basal ganglia and mesencephalon (Champy et al., 2004) -As an indication of its potential toxicity, an adult who consumes one fruit or can of nectar a day is estimated to ingest over 1 year the amount of annonacin that induced brain lesions in rats receiving purified annonacin by intravenous infusion.
-Multiple studies showing toxicity in vitro to dopaminergic neurons
-Cultured neurons treated with low doses of annonacin exhibit hallmarks of tauopathy, including increased tau concentration, tau hyperphosphorylation, cell death and somatodendritic redistribution of hyperphosphorylated tau which is that same pathophysiology of progressive supranuclear palsy.
-Studied as a cytotoxic agent for use in cancer chemotherapy
-Extract from the seeds and leaves have IC50 comparable to doxorubicin at .57μg/mL (seed) and .36μg/mL (leaves) compared to .11μg/mL (doxorubicin) in leukemia cells.
-Mechanism of action is via annonacin, the acetogenin causing mitochondrial membrane potential disruption. It inhibits NADH dehydrogenase on Complex I of the electron transport chain. Creates reactive O2 species that can damage DNA and other components of mitochondria
-Annona muricata leaf extract reduced the tumor's size and weight, showed anti-metastatic features, and induced apoptosis in vitro and in vivo of the 4 T1 breast cancer cell lines. Furthermore, it decreased the level of nitric oxide and malondialdehyde in tumor while also increased the level of white blood cell, T-cell, and natural killer cell population. 

​

Pharmacology
-LD 50 >2g/kg
-In IV administration to Rats 3800 and 7600 μg/kg daily caused neurodegeneration over a period of 28 days -it appears that chronic consumption causes the neurodegeneration
​
Presentation
-Levodopa resistant parkinsonism similar to progressive supranuclear palsy
-PSP presents with loss of balance, bradykinesia, rigidity, problems controlling eye movements, issues with speech and swallowing
-Patients in Guadaloupe:
-early postural instability
-supranuclear oculomotor dysfunction
-greater frequency of patients with tremor as compared to typical PSP
-greater frequency of patients with hallucinations as compared to typical PSP

Laboratories
-no laboratory evidence of annonacin toxicity
-annonacin can be identified in brain neurons on autopsy

Treatment/Management
-stop ingestion of soursop
-poor response to levodopa or other parkinson’s treatment agents 

​

Likely mechanism of enhanced effect
 
By increasing gastric pH, the absorption of methadone is increased
 
Angeles-Carlos, et al. (2001):
-Omeprazole 2mg/kg iv 2hr prior to methadone
-rate of absorption faster (k(01) = 0.31 +/- 0.04 min(-1) vs 0.05 +/- 0.007 min(-1)
-peak plasma concentration greater (197.41 +/- 33.70 versus 83.54 +/- 7.97 ng/mL) 
            -time to reach Cmax shorter (11.23 +/- 1.32 versus 39.18 +/- 1.74 min)
            -however, no significant effect on analgesia as assessed by tail twitch testing
 
DeCastro, et al. (1996):
Omeprazole 2mg/kg PO with methadone 5mg/kg PO in rats
            -C­max­ 156 vs 51 ngml-1
            -significant differences in respiratory depression, arterial pCO2
            -replicated with HCO­3 and acidic methadone solution

Other potential mechanisms
Inhibition of P-glycoprotein
-Rodriguez, et al. (2004): Methadone cleared from CNS via P-glycoprotein
            -Administration of valspodar, a P-gp inhibitor, increased analgesic effect of methadone in rats
             three-fold
-Pauili-Magnus, et al. (2001): omeprazole, lansoprazole, pantoprazole inhibit P-glycoprotein
-used digoxin as P-glycoprotein substrate
-no studies directly observing effect on methadone

Inhibition of CYPC19
-Liu, et al. (2005): omeprazole strongly inhibits CYPC19 in vitro
-unlikely to impact methadone metabolism significantly given difference in T1/2

Take home message
-Good theoretical basis for potential interaction between omeprazole and methadone via enhanced absorption with increased gastric pH
-Weaker theoretical basis for interaction via P-glycoprotein and CYP enzyme inhibition
-Never demonstrated in humans in experimental setting
 

​References:
National Center for Biotechnology Information. PubChem Compound Database; CID=4095, https://pubchem.ncbi.nlm.nih.gov/compound/4095 (accessed Nov. 14, 2017).
 
National Center for Biotechnology Information. PubChem Compound Database; CID=4594, https://pubchem.ncbi.nlm.nih.gov/compound/4594 (accessed Nov. 14, 2017).

Carlos MA, DuSouich P, Carolos R, Suarez E, Lukas JC, Calvo R. Effect of omeprazole on oral and intravenous RS-methadone pharmacokinetics and pharmacodynamics in the rat. Journal of Pharmacologic Science 200
DeCastro J, Aguirre C, Rodriguez-sasiain JM, Gomez E, Garrido MJ, Calvo R. The effect of changes in gastric pH induced by omeprazole on the absorption and respiratory depression of methadone. (1996). Biopharmaceutics & Drug Disposition, 1996(17);551-63
Rodriguez M, Ortega I, Soengas I, Suarez E, Lukas JC, Calvo R. Effect of P-glycoprotein inhibition and brain distribution in the rat. (2004) Journal of Pharmacy and Pharmacology. Mar; 56(3):367-74.
Pauli-Magnus C, Rekersbrink S, Klotz U, Fromm M. Interaction of omeprazole, lansoprazole, and pantoprazole with P-glycoprotein. (2001). Naunyn-Schmiedeberg’s Archives of Pharmacology 364(6); 551-57.
Liu KH, Kim MJ, Shon JH, Moon YS, Seol SY, Kang W, Cha IJ, Shin JG. Stereoselective inhibition of cytochrome P450 forms by lansoprazole and omeprazole in vitro. (2005). Xenobiotica Jan;35(1):27-38.

• Absorption: Poor oral bioavailability - 5-12%

 

• Volume of distribution: humans 0.664L/kg; distribution half-life of 2.3 minutes

 

• Onset of action: Peak serum levels and initial effect seen within 2 minutes of IV administration; peak effect within 15 minutes (early studies suggested quicker peak effect).

 

• Metabolism:
  • Though the half-life measured in the serum is 16-23 minutes, the observed half-life of plasma cholinesterase inhibition is 83-100 minutes with full recovery seen within 3 hours of cessation of infusion
  • Suspected that 90% of physostigmine is metabolized by the liver within 2 minutes. The rest is metabolized locally by cholinesterase. Elimination half-life 16-23 minutes

 

• Indications:
  • Peripheral or central anticholinergic manifestations
    • Peripheral: dry mucosa, dry skin, flushed face, mydriasis, hyperthermia, decreased bowel sounds, urinary retention, tachycardia
    • Central: agitation, delirium, hallucinations, seizures, coma

 

• Dosing: 1-2mg (0.02mg/kg, max 0.5mg in children) infused over 5-10 minutes, can redose in ~15 minutes if no effect, redose in ~1 hour if initial effect that wanes
  • Comes in 2mL, 1mg/mL ampules
  • Case reports of infusion after initial doses lost effect (below)

 

• Major interactions
  • Suspected interactions like RAD, intestinal/bladder obstruction
  • Potentiation of paralysis with succinylcholine administration, potential inhibition/reversal of paralysis with non-depolarizing paralytic administration
  • Physostigmine salicylate injection contains sodium metabisulfite; can cause anaphylactoid reactions in patients with sulfa allergies

 

• Management
  • Before use, want to obtain ECG for potential QRS or QTc changes, (QRS < 100msec, PR < 200msec)
  • Continue cardiac monitoring with pulse oximetry

 

• Use as an antidote
  • Once was commonly used as an antidote in a wide range of anticholinergic poisonings
  • However, use declined after case reports were published linking physostigmine use in TCA overdose to asystole (patients in cited literature had prolonged QRS intervals)
  • More recent reviews have found little evidence that TCA ingestion or ECG changes should be used as a contraindication to physostigmine use for anticholinergic syndromes
    • Cited issues seem to be speed of physostigmine infusion
  • Many papers that support use as a bolus (dosing as above)
  • Shown to be superior to benzodiazepines in controlling anticholinergic agitation and delirium
    • Improved efficacy, decreased rates of intubation
  • Has been given as a continuous infusion for persistent anticholinergic symptoms in overdose

 

• Clinical toxicity
  • Cholinergic crisis:  sweating, salivation, vomiting, diarrhea, urinary incontinence, bronchorrhea, bradycardia, hypotension, weakness, paralysis
  • Potential to cause seizure
  • Recommended to have atropine at the bedside of patients receiving physostigmine in the instance of overshooting the therapeutic target (especially with infusions)

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
References
Arens, AM et al. Safety and effectiveness of physostigmine: a 10-year retrospective review. Clin Toxicol (Phila). 2017 Jul 13:1-7.
Beaver KM, Gavin TJ. Treatment of acute anticholinergic poisoning with physostigmine. Am J Emerg Med. 1998 Sep; 16(5):505-7.
Buck ML and Reed MD. Use of nondepolarizing neuromuscular blocking agents in mechanically ventilated patients. J Clin Pharm. 1991 Jan;10(1):32-48.
Burns MJ, Linden CH, Graudins A, Brown RM, Fletcher KE. A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning. Ann Emerg Med. 2000 Apr; 35(4):374-81.
Dawson, Andrew H., and Nicholas A. Buckley. Pharmacological Management of Anticholinergic Delirium ‐ Theory, Evidence and Practice. British Journal of Clinical Pharmacology 81.3 (2016): 516–524. PMC. Web. 18 Sept. 2017.
Hail SL, Obafemi A, Kleinschmidt KC. Successful management of olanzapine-induced anticholinergic agitation and delirium with a continuous intravenous infusion of physostigmine in a pediatric patient. Clin Toxicol (Phila). 2013 Mar; 51(3):162-6.Knapp  S, Wardlow  ML, Albert  K  et al.: Correlation between plasma physostigmine concentrations and percentage of acetylcholinesterase inhibition over time after controlled release of physostigmine in volunteer subjects. Drug Metab Dispos.1991;19:400–404.Pentel, P and Peterson, CD. Asystole complicating physostigmine treatment of tricyclic antidepressant overdose. Ann Emerg Med. 1980 Nov;9(11):588-90.
Rosenbaum, Christopher, and Steven B. Bird. “Timing and Frequency of Physostigmine Redosing for Antimuscarinic Toxicity.” Journal of Medical Toxicology 6.4 (2010): 386–392. PMC. Web. 18 Sept. 2017.
Phillips, Michelle A. et al. Use of a Physostigmine Continuous Infusion for the Treatment of Severe and Recurrent Antimuscarinic Toxicity in a Mixed Drug Overdose. Journal of Medical Toxicology 10.2 (2014): 205–209. PMC. Web. 18 Sept. 2017.
Schneir AB, Offerman SR, Ly BT, Davis JM, Baldwin RT, Williams SR, Clark RF. Complications of diagnostic physostigmine administration to emergency department patients. Ann Emerg Med 2003; 42: 14–9.
Suchard, JR. Assessing physostigmine's contraindication in cyclic antidepressant ingestions. J Emerg Med. 2003 Aug;25(2):185-91.
Triggle, DJ. Mitchell, JM, and Filler, R. The pharmacology or physostigmine. CNS Drug Reviews, Vol. 4, No. 2, 1998. 87-136.
Watkins JW, Schwarz ES, Arroyo-Plasencia AM, Mullins ME. The Use of Physostigmine by Toxicologists in Anticholinergic Toxicity. J Med Toxicol. 2015 Jun; 11(2):179-84.
 

​

• Offending Agents
  • EtOH Withdrawal
    •   Most common etiology of withdrawal induced cardiomyopathy
    •  Chronic EtOH use alters neurotransmitter and receptor biology
    •  Increasing insensitivity to GABA (tolerance) with a secondary increasing of the number of glutamate receptors to allow normal state of arousal in the setting of increased inhibitory  tone.
    • Sudden withdrawal of EtOH decreases inhibitory tone resulting in unopposed excitatory signaling from glutamate pathways
    • Peripherally presents as tremulousness and autonomic/sympathetic hyperactivity
  • Benzodiazepine withdrawal
    • TTC seen in few case reports following acute benzodiazepine withdrawal
    • Presumed similar mechanism to EtOH
  • Opioid withdrawal
    • Case reports after long acting opioid methadone
    • Sympathetic surge resulting in echocardiographic findings of TTC
  • Methamphetamine and cocaine cardiomyopathy
    • Seen during acute intoxication rather than withdrawal period
    • Adrenergic surge can cause TTC or can exacerbate underlying vascular disease
• Evaluation & Treatment
  • Patient may present with chest pain, shortness of breath, or other findings suggestive of LV failure
  • EKG can show nonspecific findings or anterior ST elevations with minor enzyme elevations
    • If there is concern for ACS PCI if available
    • If no critical coronary disease, ventriculogram may show characteristic shape
  • Echocardiogram with hyperactive basal segments and akinetic apex
  • Supportive Care
    • Ionotropic support if needed
    • Anticoagulation
    • Fluid balance management
    • Benzodiazepines, alpha-2 agents as tolerated
  • Symptoms often resolve spontaneously in 1-4 weeks 

 
 
References:
Stout BJ, Hoshide R, Vincent DS. Takotsubo Cardiomyopathy in the Setting of Acute Alcohol Withdrawal. Hawai’i Journal of Medicine & Public Health. 2012;71(7):193-194.
 
Peng TJ, Patchett ND, Bernard SA. Takotsubo Cardiomyopathy and Catatonia in the Setting of Benzodiazepine Withdrawal. Case Reports in Cardiology. 2016;2016:8153487. doi:10.1155/2016/8153487.
 
Spadotto V, Zorzi A, ElMaghawry M, Meggiolaro M, Pittoni GM. Heart failure due to “stress cardiomyopathy”: a severe manifestation of the opioid withdrawal syndrome. European Heart Journal Acute Cardiovascular Care. 2013;2(1):84-87. doi:10.1177/2048872612474923.

Authored by: Russell Trigonis, MD

​Introduction

• One of the most potent opioids created, known as Wildnil.
• This was originally created to sedate large mammals.
• Commonly used as positron emission tomography scan radioligand

Pharmacology

• Carfentanil acts predominately on mu opioid receptors as a strong competitive agonist.
  • Opiate receptors are G-protein receptors in which binding of the opiate stimulates GTP -> GDP. This decreases the intracellular cAMP by inhibiting adenylate cyclase. This hyperpolarizes the cell and reduces neurotransmitter release.
• Biological half-life 7.7 hours
• Potency 10,000 times of morphine and 100 times of fentanyl.
• Formulation: 10ml vial at 3mg/mL
• 0.005-0.02 mg/kg given to animals for sedation

Clinical Toxicity

• Altered level of consciousness -> Coma
• Respiratory depression
• Miosis

Case Reports               

• Moscow theater hostage crisis
  • Russians responded by pumping “undisclosed chemical agent” into ventilation system
  • Some report naloxone was used as an antidote
  • Carfentanil was identified on the clothing of some victims
    
    

Laboratory Identification

• Will not be positive on routine opioid drug screen

 

• Felt not to cross react with fentanyl immunoassays
• Dedicated gas chromatopgraphy mass/spectrometry has been able to identify the drug as cause of death in certain case reports

Treatment/Management

• Naloxone
  • Mu opioid receptor inverse agonist
  • IV, IM, SubQ (onset of action 2-5 mins), Intranasal (onset of action 3-5 mins)
  • Biological half life elimination: Intranasal ~2 hours, IM, IV, SubQ 0.5-1.5 hours
  • Duration = 30-120 mins (IV shorter duration than IM)
  • Adult dosing 0.4-4mg, child dosing 0.1 mg/kg/dose, re-dosing every 2-3 minutes
  • Animal studies suggest dosing adequate response to proper dosing of naloxone to carfentanil ingestion
  • Consideration of naloxone gtt especially in highly potent opioids such as carfentanil
    • Can start gtt at X mg / hour that were needed to reach GCS 15
• Respiratory and hemodynamic support
  • Intubation
  • Vasopressors
• Observation Period
  • 2-4 hours 

Grey Death
 

• Looks like concrete mixing powder -> either chunky rock-like material or grey fine powder
• Combination drug of highly potent opioids including different mixtures of heroin, fentanyl, carfentanil, and U-47700
• Can be injected, inhaled, ingested, or absorbed through mucous membranes
  • Touching the powder does not result in direct intoxication
• Use routine universal precautions
  • Take caution if there are any breaks in skin

References1–7
1.             Milone MC. Laboratory testing for prescription opioids. J Med Toxicol. 2012;8(4):4086. doi:10.1007/s13181-012-0274-7.
2.             Moresco A, Larsen RS, Sleeman JM, Wild MA, Gaynor JS. USE OF NALOXONE TO REVERSE CARFENTANIL CITRATE-INDUCED HYPOXEMIA A CARDIOPULMONARY DEPRESSION IN ROCKY MOUNTAIN WAPITI (CERVUS ELAPHUS NELSONI). J Zoo Wildl Med. 2001;32(1):81-89. doi:10.1638/1042-7260(2001)032[0081:UONTRC]2.0.CO;2.
3.             Klebacher R, Harris MI, Ariyaprakai N, et al. Incidence of Naloxone Redosing in the Age of the New Opioid Epidemic. Prehospital Emerg Care. 2017:1-6. doi:10.1080/10903127.2017.1335818.
4.             Swanson DM, Hair LS, Strauch Rivers SR, et al. Fatalities Involving Carfentanil and Furanyl Fentanyl: Two Case Reports. J Anal Toxicol. 2017:1-5. doi:10.1093/jat/bkx037.
5.             Pathan H, Williams J. Basic opioid pharmacology: an update. Br J pain. 2012;6(1):11-6. doi:10.1177/2049463712438493.
6.             CARFENTANIL | C24H30N2O3 - PubChem. Available at: https://pubchem.ncbi.nlm.nih.gov/compound/carfentanil#section=Top. Accessed August 15, 2017.
7.             Feasel MG, Wohlfarth A, Nilles JM, Pang S, Kristovich RL, Huestis MA. Metabolism of Carfentanil, an Ultra-Potent Opioid, in Human Liver Microsomes and Human Hepatocytes by High-Resolution Mass Spectrometry. AAPS J. 2016;18(6):1489-1499. doi:10.1208/s12248-016-9963-5.
 


Authored by: Katie Lupez, MD

Introduction
-Etomidate is an intravenous nonbarbiturate hypnotic
-Developed in the 1970s, found to be an effective hypnotic [1]
-Used as anesthesia induction agent and for first decade, used as sedative infusion
-Discovered to cause adrenal suppression and increased mortality in some critically ill patients
-Now predominately used as sedative medication in rapid sequence intubation (RSI)

​Structure

- Available as 2mg/mL solution in 35% propylene glycol solution
- Available in lipid solution in Europe, reportedly less pain on infusion
- Sedative bolus at 0.2-0.4mg/kg, general anesthesia with continuous infusion of 30-100ug/kg/min

Pharmacology/Pharmacokinetics [1]
- pKa of 4.2 and is hydrophobic at physiologic pH
- Formulated in 35% propylene glycol to increase solubility
- 75% protein bound with large volume of distribution 74.9 L/kg due to high fat solubility
- Three compartment model of pharmacokinetics for single bolus of etomidate
​

​Compartment 1: rapid distribution into highly perfused tissue
Compartment 2: redistribution into peripheral tissues (muscles)
Compartment 3: terminal metabolism

- Onset of action in <1min, duration is approximately 5 min
- Metabolism dependent on hepatic esterase activity, which hydrolyzes to carboxylic acid and an ethanol leaving group
- Carboxylate metabolite mostly excreted in urine
- Metabolic t1/2 ranges from 2-5 hours
- Elderly or ill patients require lower etomidate doses due to reduced protein binding and reduced clearance

​Mechanism of Action:
- Non barbiturate hypnotic active at the GABAA receptor, specifically the β2 and β3
- Etomidate positively modulates GABAA activation by agonists
- Slow postsynaptic current decay, prolonging postsynaptic inhibition
- Blocks 11β-hydroxylase in the steroidogenesis pathway [2]
- Nitrogen atom of the imidazole ring interacts with the active binding site of the enzyme