Grand Rounds: Ethanol and Toxic Alcohols, a Review

Introduction to Ethanol and Toxic Alcohols, a Review

-Includes fallacies of urine drug screening and the pros/cons of using Phenobarbital for Ethanol withdrawal

1. Ethanol and Toxic Alcohols, a Review 6/12/2024 Borns, ME 1

2. Structures 1 2

3. Ethanol 1 Rapidly absorbed from GI tract. Peak blood levels about 30-60 minutes after ingestion Enhanced Absorption: rapid gastric emptying, taken without food or if the solution is diluted Delayed absorption: pylorospasm (looking at you ASA, and also higher concentrations of EtOH in stomach) food in the stomach, coingested drugs V olume of distribution is gender dependent due to difference in body fat percentages: 0.6 L/kg in men and 0.7 L/kg in women Activated Charcoal or gastric lavage for decontamination? Mechanism of action? 3

4. Tolerance, Dependence, Withdrawal (Components and Timeline) 6 4

5. Ethanol Metabolism CYP2E1 Alcohol Dehydrogenase Unchanged in urine 2 What drugs are active at this step and used as Ethanol abuse deterrents? 5

6. Ethanol and Gluconeogenesis 3 6

7. Alcoholic Ketoacidosis 4 Will a urinalysis accurately reflect ketonemia? 7

8. Limitations of CIWA scoring in ED 7 8

9. 6 9

10. PAWSS 6 10

11. Toxic Alcohols Methanol Ethylene Glycol Isopropanol Longer carbon chain -> more intoxicating Bind poorly to charcoal (maybe gastric lavage if substance was just consumed and large volume) 11

12. Osmolar Gap Anion Gap Osmolar Gap 12

13. Isopropanol 9 What everyday item contains isopropanol? What is the clinical presentation? Which gaps? To Fomeipozole or not to Fomepizole? Hemodialysis? 13

14. Ethylene Glycol 9 What everyday items contain Ethylene Glycol? What is the clinical presentation? Glycolic Acid Oxaclic Acid Toxic Levels 9 14

15. Methanol 9 What everyday items contain Methanol? What is the clinical presentation? Toxic Levels Hallmarks Toxic Levels 12 15

16. Ethylene Glycol and Methanol Decontamination 9 Charcoal NG tube 16

17. Starting ADH Blockade 9 (1) Empiric initiation if poisoning is strongly suspected, for example: Ingestion history (witnessed or reported). Markedly elevated anion gap without alternative explanation, in a context consistent with toxic alcohol poisoning. (2) If the patient is known to have an ethylene glycol or methanol level >20 mg/dL (or methanol >6.2 mM or ethylene glycol >3.2 mM) 17

18. Stopping ADH Blockade 9 Stop when levels of toxic alcohol are known to be undetectable or at a safe level (<20 mg/dL, or methanol <6.2 mM, or ethylene glycol <3.2 mM) In many cases, dialysis may be required to clear parent alcohols and facilitate discharge from the hospital. Alcohol dehydrogenase blockade can be stopped some hours after hemodialysis, once labs confirm that there is no rebound in toxicity 18

19. Indications for Dialysis (1) Acidosis Metabolic acidosis (pH <7.15) Anion gap >24 mM (calculated as Na – Cl – Bicarb) (2) End-organ damage, e.g. Coma, seizure Vision changes Renal failure (this may also inhibit clearance of various substances) (3) Methanol or ethylene glycol level >50 mg/dL in absence of EtOH or fomepizole therapy >60 mg/dL in context of ethanol therapy >70 mg/dL in context of fomepizole therapy 19

20. Fomepizole Regimen Initial dose 15 mg/kg IV, then 10 mg/kg IV Q12 hours for four doses (two days), then 15 mg/kg IV Q12 hours Fomepizole induces its own metabolism, so the dose needs to be raised over time. Increase the dose during hemodialysis to q4hr. If the last dose was >6 hours previously, give an additional dose when initiating dialysis In most hospitals, pt does not need to be in ICU if using Fomepizole for ADH blockade (as opposed to Ethanol) and they only need intermittent HD 20

21. Osmolar Gap Utility 9 8 21

22. Progression of the Gaps 9 22

23. 11 What our urine drug screen tests for: Amphetamines Barbiturates Benzodiazepines Cannabinoids (THC) Cocaine Opiates PCP MDMA Fentanyl Methadone 23

24. Common Types of Urine Drug Screens 10 Enzyme linked immunoassay (EIA) kits: Screening test for illicit substances amphetamine/methamphetamine, (marijuana, PCP, cocaine, “opiates” (morphine/codeine) Inexpensive, fast, point of care or lab Detects class of substance, not specific medication Will be negative for hydrocodone, hydromorphone, oxycodone, methadone, buprenorphine, benzodiazepines (particularly clonazepam) unless specific test kit for those meds is in use High false positive rates caused by numerous prescribed or OTC meds This is what ECUHMC uses typically Gas chromatography/Mass Spectroscopy (GCMS) More expensive, labor intensive Confirming test identifies specific meds and their metabolites. Use to confirm patient is taking prescribed meds and not taking non-prescribed meds High sensitivity False positives still occur 24

25. Common False Positives on EIA Kits 10 Amphetamines/methamphetamine: bupropion, tricyclic antidepressants, phenothiazines , propranolol, labetalol, OTC cold rx , ranitidine, metformin, selegiline , trazodone, Abilify , phentermine, zolpidem. Vicks Nasal Spray can test positive even on GCMS Barbiturates: phenytoin Benzodiazepines: sertraline, zolpidem, NSAIDs LSD: amitriptyline, doxepin, sertraline, fluoxetine, metoclopramide, haloperidol, risperidone, verapamil PCP: dextromethorphan, diphenhydramine, doxylamine , NyQuil , tramadol, venlafaxine (Effexor), NSAIDs, imipramine Propoxyphene: methadone, cyclobenzaprine ( Flexeril ), doxylamine ( Ny-Quil ), diphenhydramine (Benadryl), imipramine Cannabinoids (on EIA not GCMS): pantoprazole ( Protonix ), efavirenz ( Sustiva , Atripla ), very high dose NSAIDs, promethazine, zolpidem? Cocaine: fluconazole, zolpidem? Opioids: False positive EIA testing: quinolones ( oflox , gati ), dextromethorphan, diphenhydramine (Benadryl), doxylamine , rifampin, verapamil, poppy seeds, zolpidem? Oxycodone on EIA: naloxone (in Suboxone )? 25

26. Common False Positives on GCMS 10 Morphine: from codeine, heroin (for a few hours) and poppy seeds for 48 hrs Hydromorphone: from morphine, codeine, hydrocodone, heroin Oxycodone: from hydrocodone Oxymorphone : from oxycodone Codeine: from hydrocodone Fentanyl: from trazodone Methadone: from quetiapine (Seroquel), diltiazem and verapamil (rare); doxylamine , Benadryl (EIA +, GCMS neg ) Tramadol: from venlafaxine 26

27. Phenobarbital for EtOH Withdrawal 13 L ong half-life (~3-4 days). Doses that are administered over the course of 1-2 days will  accumulate . The goal of giving additional doses is to gradually  up-titrate  the total body phenobarbital level to a therapeutic concentration. This is  different  from most drugs (e.g. lorazepam), where repeated doses are needed to maintain a stable drug level D rug level is a  linear  function of the amount of phenobarbital administered. A predictable linear relationship allows weight-based doses to reproducibly achieve therapeutic drug levels. The volume of distribution is ~0.65 L/kg. Al lows serum level to be estimated from the administered dose using the formula below 27

28. 28 13

29. Phenobarbital advantages over Benzodiazepines 13 Benzodiazepine dependence on endogenous GABA Targeting GABA alone w/ Benzos vs targeting GABA and Glutamate w/ Barbiturates Paradoxical Agitation Phenobarbital has more predictable pharmacokinetics than benzodiazepines Phenobarbital has more predictable pharmacodynamics than benzodiazepines Phenobarbital has a greater therapeutic index than benzodiazepines Half-life of phenobarbital allows for precise dose-titration and gentle auto-tapering Phenobarbital may be superior for prevention of seizure Phenobarbital levels can be measured and levels have meaning ( ie is someone over or under-medicated) IV, IM, oral routes of administration for phenobarbital Phenobarbital has less of a sedating effect than benzodiazepines so it can be given prophylactically to asx pts (can’t really do this w/ benzos b/c they will sedate asx pts) Propylene glycol intoxication Phenobarbital is widely available and inexpensive (If the drug exists and theoretically ECU is supposed to have it, what’s the likelihood that it will have a shortage at some point?) 29

30. Phenobarbital Disadvantages 13 W rong diagnosis F ailure to keep track of the total phenobarbital dose (Should not exceed 20-30 mg/kg) U se of phenobarbital to suppress a personality disorder C aution when combining phenobarbital and benzodiazepines 30

31. Phenobarbital Contraindications 13 Pregnancy Advanced cirrhosis : Patients with borderline hepatic encephalopathy are at high risk of oversedation. Phenobarbital should generally be avoided in any patient with a history of hepatic encephalopathy. If phenobarbital is utilized in a patient with hepatic dysfunction, it should be dose-reduced Drug interaction  with an essential medication that isn't easily dose-adjusted Acute intermittent porphyria Prior chronic phenobarbital use, or prior phenobarbital loading:  Not a contraindication to using phenobarbital, but be careful about giving a  loading dose  to someone who already has a therapeutic level Recent receipt of sedating medications (especially benzodiazepine) : Phenobarbital will function  synergistically  with benzodiazepines, which could lead to excessive sedation. Not an absolute contraindication; phenobarbital may often be used safely by giving  smaller ,  divided  doses Multiple active neurological problems . Relative contraindication. For patients with  fluctuating levels of consciousness , there is an increased risk that phenobarbital could lead to over-sedation (when  combined  with a deterioration in the underlying neurologic status) 31

32. References Themes, U. F. O. “Alcohols.” Anesthesia Key, 13 June 2016, aneskey.com/alcohols/. Accessed 10 June 2024. “Ethanol (Alcohol) Metabolism: Acute and Chronic Toxicities.” The Medical Biochemistry Page, 14 May 2020, themedicalbiochemistrypage.org/ethanol-alcohol-metabolism-acute-and-chronic-toxicities/. “Gluconeogenesis.” Iiab.me, 2018, medbox.iiab.me/ kiwix /wikipedia_en_medicine_2019-12/A/Gluconeogenesis. Accessed 10 June 2024. “POTD: Alcoholic Ketoacidosis.” Maimonides Emergency Medicine Residency, 18 Feb. 2019, www.maimonidesem.org/blog/potd-alcoholic-ketoacidosis. Accessed 10 June 2024 . Stokol , Tracy. “Renal Contribution to Metabolic Alkalosis.” EClinpath , eclinpath.com/chemistry/acid-base/compensation/renal-concentration/. Accessed 10 June 2024. Wolf, Chelsea, et al. “Management of Alcohol Withdrawal in the Emergency Department: Current Perspectives.” Open Access Emergency Medicine, vol. Volume 12, no. 1, Mar. 2020, pp. 53–65, https://doi.org/10.2147/oaem.s235288 . “CIWA- Ar Explained in Detail - Caregiverology .” Caregiverology.com, www.caregiverology.com/ciwa-ar.html . ToxTidbits 2016 Item Type Newsletter/Magazine. 2016. Farkas, Josh. “Ethylene Glycol & Methanol Poisoning.” EMCrit Project, 23 Jan. 2020, emcrit.org/ ibcc /alcohols/. Urine Drug Testing – Ordering and Interpretation, medicine.umich.edu/sites/default/files/downloads/MOC DRUG TESTING ORDERING AND REFERENCE.pdf. Accessed 16 May 2024. Ewan Evans·Haematology·January 12, 2022·Last updated:November 6. “Coagulation Cascade: Intrinsic + Extrinsic.” Geeky Medics , 6 Nov. 2023, geekymedics.com/the-coagulation-cascade/. “Methanol Poisoning.” MedLink Neurology, www.medlink.com/articles/methanol-poisoning . “Alcohol Withdrawal.” EMCrit Project, emcrit.org/ ibcc / etoh /. 32