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“Cocaine is a Hell of a Drug”
Alex Thurman
www.grammy.com
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
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
Outline
• History, chemistry, and pharmacology of
cocaine
• Desired and undesired effects of cocaine
use
• Case presentations and discussion
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
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
History
• Earliest known use of coca leaf is by
Native South Americans
– evidence of communal coca leaf chewing with
lime (CaCO3)
– 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
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
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."
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
Chemistry
• Crystalline tropane alkaloid derived from
the leaves of the coca plant (Erythroxylum
coca)
• Cocaine = benzoylmethylecgonine
(C17H21NO4), a weak base (pKa = 8.6)
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
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
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
Adulterants
• Purity of street-purchased cocaine is
<50% on average, often <5%
• Frequently adulterated (“cut”) with other
powdery substances
– sugars
– local anesthetics
– stimulants
Contaminants
• Street cocaine may also contain
contaminants introduced during
processing
– NaHCO3 (baking soda)
– acetone
– benzene
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 → Nhydroxynorcocaine
• Renally excreted, benzoylecgonine is
major urinary metabolite
Allen, Ann Clin Biochem. 2011
norcocaine
major metabolite
CYP3A
hCE-1
benzoylecgonine
cocaine
BChE, hCE-2
BChE, hCE-2
hCE-1
ecgonine methyl ester
ecgonine
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
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
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
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
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…
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…
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
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
Case 1
• Lesions on lower extremities continued to
expand and became infected
• Necrotic areas on face led to nasal autoamputation
• Transferred to burn unit when skin
involvement reached ~35% TBSA
• Bilateral above-knee amputations
performed due to overwhelming infection
What happened?
What’s levamisole?
Levamisole
• Levo stereoisomer of tetramizole, a
synthetic imidazothiazole derivative
• Developed as a veterinary antihelmenthic
in 1960s
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
Levamisole
• DEA first identified levamisole-adulterated
cocaine in 2003
• Levamisole in cocaine seized by DEA…
– 2006:
– 2007:
– 2008:
– 2009:
detected in <5%
<10%
coincides with first reports
~40%
of agranulocytosis and
cutaneous vasculopathy in
~70%
cocaine users
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
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
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
Laboratory Features
• Leukopenia, neutropenia
• Drug-induced autoantibody production
(ANA, APAs, ANCAs)
• Anti-human neutrophil elastase antibody is
highly specific for cocaine-levamisole
exposure
Histopathology
• Small-vessel thrombotic vasculopathy with
or without associated leukocytoclastic
vasculitis
• Also RBC extravasation, epidermal
necrosis, other nonspecific findings
Pathophysiology
• Drugs with reactive thiol groups act as
haptens
• Anti-neutrophil autoantibody production →
immune-mediated destruction →
leukopenia, neutropenia
• Pathogenesis of vasculopathy largely
unknown
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
Treatment
•
•
•
•
Cocaine abstinence
Supportive care for skin lesions
Glucocorticoids used but of unclear benefit
Consider G-CSF for neutropenia
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
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
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)
Case 2
• An urgent electrocardiogram (ECG) is
obtained…
Case 2
• An urgent electrocardiogram (ECG) is
obtained…
…followed by emergent direct current
defibrillation
Case 2
• Defibrillation restores circulation, but
patient is still minimally responsive
• Head CT obtained…
Case 2
• Defibrillation restores circulation, but
patient is still minimally responsive
• Head CT obtained…
…followed by brain MRI…
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
Case 2
• Labs:
– plasma ethanol: 200 mg/dL (<10 mg/dL)
– urine toxicology screen: positive for cocaine,
otherwise negative
Case 2
• Patient admitted to the stroke unit
• On hospital day 2, a significant decline in
neurologic status was noted
• Repeat head CT ordered…
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
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
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
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!”)
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
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
norcocaine
cocaethylene
CYP3A
EtOH
Allen, Ann Clin Biochem. 2011
hCE-1
benzoylecgonine
cocaine
BChE,hCE-1-mediated
hCE-2
transesterification
BChE, hCE-2
of cocaine with EtOH
hCE-1
ecgonine methyl ester
ecgonine
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
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
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
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.
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References
9.
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