1. “Cocaine is a Hell of a Drug” Alex Thurman www.grammy.com

2. My Objectives Review the history, chemistry, and pharmacology of cocaine Discuss the acute and chronic effects of cocaine use with a focus on cocaine adulterants and metabolites

3. Your Objectives Learn something new about the history of cocaine (good for cocktail parties) Be able to relate the pharmacologic actions of cocaine and cocaine adulterants/metabolites to their pathologic effects

4. Outline History, chemistry, and pharmacology of cocaine Desired and undesired effects of cocaine use Case presentations and discussion

5. Cocaine Second most popular illegal recreational drug in USA USA is world’s largest consumer Estimated USA cocaine market >$70 billion in street value in 2005 Use transcends racial and socioeconomic groups

6. Cocaine In the USA (2012 data), there are… –1.6 million current cocaine users aged 12 years or older –~1800 cocaine initiates per day Most frequently used illicit drug among patients presenting to ED

7. History Earliest known use of coca leaf is by Native South Americans –evidence of communal coca leaf chewing with lime (CaCO 3 ) –traces of coca found in Peruvian mummies –extensive archeological evidence for coca leaf chewing from 6th century CE –mixture of coca leaves and saliva may have been used as an anesthetic for trephination

8. History Coca alkaloid first isolated by Friedrich Gaedcke in 1855, named erythroxyline Albert Niemann developed an improved purification process in 1860, renamed cocaine Cocaine first used as an anesthetic in 1884 by Koller and Jellinek

9. History Cocaine-containing products marketed by USA manufacturer Parke-Davis in 1885 “[Parke-Davis cocaine products] supply the place of food, make the coward brave, the silent eloquent, and render the sufferer insensitive to pain."

10. History Georgia banned sale of cocaine in 1902 California limited sale of cocaine only to those with a physician’s prescription in 1907 Harrison Narcotics Act of 1914 regulated and taxed the production, importation, and distribution of cocaine Classified as a Schedule 2 substance in the Controlled Substances Act of 1970

11. Chemistry Crystalline tropane alkaloid derived from the leaves of the coca plant (Erythroxylum coca) Cocaine = benzoylmethylecgonine (C 17 H 21 NO 4 ), a weak base (pKa = 8.6)

12. Chemistry Two chemical forms: 1.hydrochloride salt 2.free base Both consist of the same cocaine molecule and exert the same pharmacological actions Differ in physical properties, which allow different routes of administration

13. Chemistry Hydrochloride salt (cocaine-HCl) –produced by dissolving alkaloid form in HCl, forming a pearly white powder –can be consumed via oral, intranasal, or intravenous routes –also readily absorbed across rectal and vaginal mucosae –cannot be smoked

14. Chemistry Free base –produced by alkalinization of salt with weak base then extraction with nonpolar solvent –solvent is evaporated, yielding free base –variable color and texture –vaporizes at ~90°C with minimal pyrolytic destruction, rapidly absorbed when smoked –difficult to use intravenously

15. Adulterants Purity of street-purchased cocaine is <50% on average, often <5% Frequently adulterated (“cut”) with other powdery substances –sugars –local anesthetics –stimulants

16. Contaminants Street cocaine may also contain contaminants introduced during processing –NaHCO 3 (baking soda) –acetone –benzene

17. Metabolism Serum half-life of cocaine = 0.5-1.5 hours Cocaine metabolized via… –hydrolysis of ester groups → benzoylecgonine, ecgonine methyl ester, ecgonine –N-demethylation → norcocaine → N- hydroxynorcocaine Renally excreted, benzoylecgonine is major urinary metabolite

18. ecgonine methyl ester ecgonine norcocaine cocaine benzoylecgonine BChE, hCE-2 CYP3A hCE-1 BChE, hCE-2 Allen, Ann Clin Biochem. 2011 major metabolite

19. Mechanism of Action 1.Triple reuptake inhibitor → indirect sympathomimetic effect 2.Nonspecific Na + channel blocker –anesthesia (low doses) –sudden cardiac death (high doses) 3.Increases concentration of excitatory amino acids in CNS

20. Desired Effects Psychostimulation –increased energy, alertness –feelings of well-being/euphoria –increased self-confidence, sociability, sexuality –decreased fatigue, appetite, and need for sleep Effects last 15-60 minutes, depending on dosage and route of administration

21. Adverse Effects Cocaine produces end-organ toxicity in essentially every organ system In general, adverse effects are similar regardless of route of ingestion Most adverse effects can be predicted by indirect sympathomimetic activity and/or Na + channel blockade

22. Case 1 44-year-old female with asthma and hypertension presents for evaluation of a painful rash Rash has been present for 2-3 months and affects her cheeks, nose, ears, and extremities She also reports a long history of crack abuse

23. Case 1 Physical exam shows multiple erythematous to violaceous, geographic, purpuric macules and patches Some lesions exhibit central ulceration, others have an overlying black eschar Affected areas include the extremities…

24. Case 1 Physical exam shows multiple erythematous to violaceous, geographic, purpuric macules and patches Some lesions exhibit central ulceration, others have an overlying black eschar Affected areas include the extremities… …cheeks, ears…

25. Case 1 Physical exam shows multiple erythematous to violaceous, geographic, purpuric macules and patches Some lesions exhibit central ulceration, others have an overlying black eschar Affected areas include the extremities… …cheeks, ears… …and nose

26. Case 1 Labs: –CBC: WBCs 2,600/μL, neutrophils 900/μL –ESR: 47 mm/hr (0-20 mm/hr) –ANA: positive, 1:80 –lupus anticoagulant: positive –anti-cardiolipin antibodies: negative –ANCA: strong positive, perinuclear pattern –urine toxicology screen: positive for cocaine –urine GC-MS: positive for levamisole

27. Case 1 Lesions on lower extremities continued to expand and became infected Necrotic areas on face led to nasal auto- amputation Transferred to burn unit when skin involvement reached ~35% TBSA Bilateral above-knee amputations performed due to overwhelming infection

28. What happened? What’s levamisole?

29. Levamisole Levo stereoisomer of tetramizole, a synthetic imidazothiazole derivative Developed as a veterinary antihelmenthic in 1960s

30. Levamisole Previously used as immunomodulatory agent in humans Levamisole-associated neutropenia first reported in 1977, cutaneous vasculopathy in 1978 Withdrawn in 1999 due to reports of serious adverse events

31. Levamisole In adverse cutaneous reactions reported in children receiving therapeutic levamisole… –reactions occurred following prolonged therapy –purpura had a predilection for ears and malar area –associated autoantibodies included APAs and ANCAs –histpathology showed thrombotic vasculopathy with variable vasculitis

32. Levamisole DEA first identified levamisole-adulterated cocaine in 2003 Levamisole in cocaine seized by DEA… –2006: detected in <5% –2007: <10% –2008: ~40% –2009: ~70% coincides with first reports of agranulocytosis and cutaneous vasculopathy in cocaine users

33. Why cut with levamisole? 1.Increase profits 2.Potentiation of psychotropic effects of cocaine –levamisole inhibits MAO and COMT → increased DA and NE transmission –evidence of synergy in non-human in vivo assays 3.Use as a marker/signature compound

34. So what happened? Syndrome has been termed… –cocaine-levamisole thrombotic vasculopathy –levamisole-induced vasculopathy with ecchymosis and necrosis (LIVEN) –cocaine-levamisole cutaneous vasculopathy syndrome True incidence unknown, but more common in females and chronic cocaine users

35. Clinical Features Tender, non-palpable purpura in a retiform/reticular distribution, generally occurring 1-4 days post-exposure Symmetric involvement of ears, malar region, and nasal tip is characteristic Often accompanied by malaise, fatigue, arthralgias

36. Laboratory Features Leukopenia, neutropenia Drug-induced autoantibody production (ANA, APAs, ANCAs) Anti-human neutrophil elastase antibody is highly specific for cocaine-levamisole exposure

37. Histopathology Small-vessel thrombotic vasculopathy with or without associated leukocytoclastic vasculitis Also RBC extravasation, epidermal necrosis, other nonspecific findings

38. Differential Diagnosis Systemic ANCA-associated vasculitis Septic vasculitis APS Cryoglobulinemia Warfarin necrosis

39. Pathophysiology Drugs with reactive thiol groups act as haptens Anti-neutrophil autoantibody production → immune-mediated destruction → leukopenia, neutropenia Pathogenesis of vasculopathy largely unknown

40. Detection Currently, no commercial test to detect levamisole in clinical samples Most commonly detected via MS-based methods, but window for detection is small Alternatively, can test samples from drug paraphernalia Some argue that evidence of cocaine exposure is sufficient for the diagnosis

41. Treatment Cocaine abstinence Supportive care for skin lesions Glucocorticoids used but of unclear benefit Consider G-CSF for neutropenia

42. Prognosis Syndrome is self-limited WBCs rebound in 5-10 days Skin lesions resolve over weeks to months Autoantibodies normalize in 2-14 months Complete abstinence is necessary as symptoms can recur on re-challenge

43. Case 2 44-year-old female brought into the Emergency Department after being found unresponsive on the sidewalk Endotracheal tube was placed at the scene by Emergency Medical Services Patient is known to abuse cocaine and alcohol

44. Case 2 Vital signs show elevated blood pressure (187/99 mmHg) Patient unresponsive to verbal commands, minimally responsive to painful stimuli Exam concerning for stroke (right hemiplegia, right facial palsy, brisk reflexes on right, positive Babinski sign)

45. Case 2 An urgent electrocardiogram (ECG) is obtained…

46. Case 2 An urgent electrocardiogram (ECG) is obtained… …followed by emergent direct current defibrillation

47. Case 2 Defibrillation restores circulation, but patient is still minimally responsive Head CT obtained…

48. Case 2 Defibrillation restores circulation, but patient is still minimally responsive Head CT obtained… …followed by brain MRI…

49. Case 2 Defibrillation restores circulation, but patient is still minimally responsive Head CT obtained… …followed by brain MRI… …and MRA of the head and neck

50. Case 2 Labs: –plasma ethanol: 200 mg/dL (<10 mg/dL) –urine toxicology screen: positive for cocaine, otherwise negative

51. Case 2 Patient admitted to the stroke unit On hospital day 2, a significant decline in neurologic status was noted Repeat head CT ordered…

52. Case 2 Patient admitted to the stroke unit On hospital day 2, a significant decline in neurologic status was noted Repeat head CT ordered… …followed by urgent hemicraniectomy

53. Case 2 After 34 relatively uneventful days in the stroke unit, patient was discharged to a skilled nursing and rehabilitation facility No significant recovery of motor function on right side

54. Cocaine and EtOH One of the most common recreational drug combinations in the USA –75-85% of cocaine users co-ingest EtOH –EtOH users are 6 times more likely to have used cocaine in the last month –the most common two-drug combination that results in drug-related death

55. Cocaine and EtOH Why use both? –classical conditioning (“This is how I’ve always partied!”) –enhanced euphoria (“It’s more fun!”) –moderate undesirable effects (“I can keep on partying!”)

56. Cocaine and EtOH Why not to use both? –increases the potency, bioavailability, half-life, and volume of distribution of cocaine –associated with a significant increase in cardiac and neurovascular events –results in the formation of cocaethylene, an active cocaine metabolite

57. Cocaethylene Formation –metabolism of cocaine altered by presence of EtOH (transesterification vs. hydrolysis) –must ingest EtOH prior to cocaine –cocaethylene accounts for up to 17% of metabolites formed during cocaine and EtOH coingestion

58. cocaethylene ecgonine methyl ester ecgonine norcocaine cocaine benzoylecgonine BChE, hCE-2 CYP3A hCE-1 EtOH hCE-1 BChE, hCE-2 Allen, Ann Clin Biochem. 2011 hCE-1-mediated transesterification of cocaine with EtOH

59. Cocaethylene Pharmacologic actions similar to cocaine Relative to cocaine, cocaethylene shows… –increased affinity for dopamine transporters –decreased affinity for serotonin and norepinephrine transporters –increased affinity for Na + channels –similar adverse effect profile –longer half-life

60. Cocaethylene What does it all mean? –potentiates cardiotoxic effects of cocaine and EtOH –contributions to other adverse effects are additive –presence of detectable cocaethylene associated with an increased likelihood for ICU admission

61. It’s over… what should I remember? 1.Cocaine is a tropane alkaloid... 2....that is usable by humans as a hydrochloride salt or a free base... 3....and can cause a number of adverse affects... 4....particularly when adulterated with levamisole... 5....or co-ingested with EtOH

62. References 1.Allen KR. Screening for drugs of abuse: which matrix, oral fluid or urine? Ann Clin Biochem. 2011 Nov; 48 (Pt 6): 531-41. 2.Ananthan D, Shah S, Koya HH, Patel A, Graziano S. Levamisole tainted cocaine: an emerging health issue. QJM. 2014 Aug; 107 (8): 655-656. 3.Arora NP, Jain T, Bhanot R, Natesan SK. Levamisole-induced leukocytoclastic vasculitis and neutropenia in a patient with cocaine use: an extensive case with necrosis of skin, soft tissue, and cartilage. Addict Sci Clin Pract. 2012 Sep 24; 7 (1): 19. 4.Ching JA, Smith DJ Jr. Levamisole-induced necrosis of skin, soft tissue, and bone: case report and review of literature. J Burn Care Res. 2012 Jan-Feb; 33 (1): e1-e5. 5.Dy IA, Wiernik PH. Cocaine-levamisole thrombotic vasculopathy. Semin Thromb Hemost. 2012 Nov; 38 (8): 780-782. 6.Farooq MU, Bhatt A, Patel M. Neurotoxic and cardiotoxic effects of cocaine and ethanol. J Med Toxicol. 2009 Sep; 5 (3): 134-138. 7.Formeister EJ, Falcone MT, Mair EA. Facial Cutaneous Necrosis Associated With Suspected Levamisole Toxicity From Tainted Cocaine Abuse. Ann Otol Rhinol Laryngol. 2014 Jul 11. pii: 0003489414542087. [Epub ahead of print] 8.Glauser J, Queen JR. An overview of non-cardiac cocaine toxicity. J Emerg Med. 2007 Feb; 32 (2): 181-186.

63. References 9.Graf J, Lynch K, Yeh CL, Tarter L, Richman N, Nguyen T, Kral A, Dominy S, Imboden J. Purpura, cutaneous necrosis, and antineutrophil cytoplasmic antibodies associated with levamisole-adulterated cocaine. Arthritis Rheum. 2011 Dec; 63 (12): 3998-4001. 10.Graf J. Rheumatic manifestations of cocaine use. Curr Opin Rheumatol. 2013 Jan; 25 (1): 50-55. 11.Jacob RS, Silva CY, Powers JG, Schieke SM, Mendese G, Burlingame RW, Miller DD, Wolpowitz D, Graber E, Mahalingam M. Levamisole-induced vasculopathy: a report of 2 cases and a novel histopathologic finding. Am J Dermatopathol. 2012 Apr; 34 (2): 208-213. 12.Lee KC, Ladizinski B, Federman DG. Complications associated with use of levamisole-contaminated cocaine: an emerging public health challenge. Mayo Clin Proc. 2012 Jun; 87 (6): 581-586. 13.Magliocca KR1, Coker NA, Parker SR. The head, neck, and systemic manifestations of levamisole- adulterated cocaine use. J Oral Maxillofac Surg. 2013 Mar; 71 (3): 487-492. 14.Patel MB, Opreanu M, Shah AJ, Pandya K, Bhadula R, Abela GS, Thakur RK. Cocaine and Alcohol: A Potential Lethal Duo. Am J Med. 2009 Jan;122 (1): e5-6. 15.Pennings EJ, Leccese AP, Wolff FA. Effects of concurrent use of alcohol and cocaine. Addiction. 2002 Jul; 97 (7): 773-783. 16.Pozner CN, Levine M, Zane R. The cardiovascular effects of cocaine. J Emerg Med. 2005 Aug; 29 (2): 173-178. 17.Souied O, Baydoun H, Ghandour Z, Mobarakai N. Levamisole-contaminated cocaine: an emergent cause of vasculitis and skin necrosis. Case Rep Med. 2014; 2014:434717.

64. References 9.Tallarida CS, Egan E, Alejo GD, Raffa R, Tallarida RJ, Rawls SM. Levamisole and cocaine synergism: a prevalent adulterant enhances cocaine's action in vivo. Neuropharmacology. 2014 Apr; 79: 590-595. 10.Tran H, Tan D, Marnejon TP. Cutaneous vasculopathy associated with levamisole-adulterated cocaine. Clin Med Res. 2013 Feb; 11 (1): 26-30. 11.Wiener SE, Sutijono D, Moon CH, Subramanian RA, Calaycay J, Rushbrook JI, Zehtabchi S. Patients with detectable cocaethylene are more likely to require intensive care unit admission after trauma. Am J Emerg Med. 2010 Nov; 28 (9): 1051-1055. 12.www.samhsa.gov 13.www.uptodate.com 14.www.wikipedia.org