Drugs of Abuse
Part I
Rebecca Burton-MacLeod
R4, Emerg Med
Preceptor: Dr. S. McPherson
Core Rounds
Mar 1st, 2007
Drugs of abuse
• Hallucinogens:
– LSD, mescaline, marijuana, mushrooms, PCP
• Stimulants:
– Amphetamines, caffeine, cocaine
• Depressants:
– Alcohol, benzos, opioids
• Inhalants:
– Volatile solvents, propellants, nitrites, nitrous oxide
• OTC preparations:
– Phenylpropanolamine, ephedrine, pseudoephedrine
Almost any drug can be abused…!
Case
• 42F brought to ED after being found
confused by roomate. C/o cough and
chills x1wk. Last night out “partying” with
friends, and this a.m. difficult to awaken.
• O/e: 38.5 HR 124 BP 98/72 sats 91%r/a
• Investigations?
• Thoughts?
• Immediate mgmt?
Take-home
• Always go through your differential…
Cocaine
Quiz
• Which artist sings a song entitled “Cocaine
cowgirl”…hint, they played at Mac Hall in
mid-January 2007?
• A) the Tragically Hip
• B) Shania Twain
• C) Matt Mays
• D) Garth Brooks
Cocaine
• Natural alkaloid found in
leaves of Erythroxylon
coca
• Grows abundantly in
Mexico, South America,
West Indies, Indonesia
• Long hx of use…in 6th
century Peruvians
chewed leaves for
social/religious reasons
• First used as local
anaesthetic in 1884
Cocaine
• In early 20th century, used briefly as
ingredient in Coca-cola!!!
Medical uses
• Used as topical anesthetic for medical
procedures (scopes, etc)
• Max safe total dose is 1-3ml/kg body
weight (4-10% soln)
• Avoid if pt is: febrile, hepatic disease,
known plasma cholinesterase defic, drugs
that alter neurotransmitter metabolism
(MAOI’s)
Metabolism
Cocaine
N-demethylation
Nonenzymatic hydrolysis
Plasma
cholinesterase
Norocaine
Minor metabolite
Ecgonine methyl ester
Benzoylecgonine
Major metabolite: 30-50%
About 40%
Detected in urine
tox screens as
longest half-life
(usually up to 4872hrs)
Modes of abuse
•
•
•
•
Intranasal
Smoked
IV
Ingested
Pharmacokinetics
Mechanisms of action
• Blockade of fast Na channels
– Local anesthetic effect
– Type 1A and 1C
antidysrhythmic properties
• Interferes with re-uptake of
neurotransmitters by nerve
terminals
– Vasoconstriction
– Systemic effects due to
alpha/beta adrenergic, DA,
SE stimulation
Na channel blockade
Effects of Na channel blockade
• Impaired conduction
• Increased inotropy
– Seen early before catecholamine response
• Widened QRS
• Terminal avR 40msec rightward axis
deviation
Clinical manifestations
• Hyperthermia
– Vasoconstriction dec heat dissipation, inc psychomotor activity,
direct stimulatory effect on thermoregulatory centers, stimulates
livers calorigenic activity
• Neuro effects
– Anxiety, agitation, seizures
– Cerebrovascular events such as SAH, ICH, CVA, TIA, cerebral
vasculitis, migraine-HA type s/o
• Cardiac effects
– Dysrhythmias, MI, cardiomyopathy, endocarditis, aortic
dissection
• Pulmonary/upper airway effects
– Asthma exacerbations, pneumothorax, pneumomediastinum,
acute lung injury, diffuse alveolar hemorrhage, pneumonia,
BOOP, talc lung, upper airway burn and abscesses
Cont’d
• Skeletal muscle effects
– rhabdo
• Ophthalmic effects
– Corneal abrasions/ulcerations, CRAO, bilateral blindness from
diffuse vasospasm
• Uteroplacental/perinatal effects
– IUGR, inc SA, abruptio placentae, fetal prematurity, neonatal
withdrawal symptoms
• GI effects
– Hepatotoxic, mesenteric ischemia
• Psych effects
– Tolerance, addiction, tactile hallucinations common (Magnan’s
sign), withdrawal
Cocaine
Hyperthermia
Cardiac effects
• How does cocaine contribute to MI?
–
–
–
–
–
–
Vasospasm
Inc platelet aggregation
Inc atherosclerosis
Tachycardia/hypertension
Inc myocardial oxygen demand
Thrombus formation
**risk of MI is increased 24x in first hour following use**
Cocaine and MI’s
• First case of cocaine related MI in 1982
Coleman DL. West J Med. 1982. 136:444.
• 91 MI’s reviewed from previous reports:
– 81 males, avg age 32.8yrs
– Time to onset: mean 30min, max 24hrs
– Tobacco used in 87%, other risk factors rare
– Atherosclerotic HD in 31%, thrombosis
without atherosclerotic HD in 24%
Hollander and Hoffman. J Emerg Med. 1992; 10:169.
Cocaine and MI
• Unrelated to dose or route administered or
frequency of use
– Reported in 200-2000mg
– Found after taking by any route
– Occurs in habitual or first-time users
• All CP pts should be asked about cocaine
use…found in urine tox screen of 14-25%
of urban ED non-traumatic CP pts
Hollander JE et al. Ann Emerg Med. 1995. 26:671.
Cocaine and MI
Increased oxygen demand
• Increased
catecholamines with
cocaine:
– Norepi 345-622mg/L
(normal 0-90mg/L)
– Epi 135-202mg/L
(normal 0.55mg/L)
• Resultant
hypertension and
tachycardia
Karch. Ann Emerg Med. 1987; 16:481.
Vasospasm
• Human volunteer study of pts given IN
cocaine while undergoing cardiac cath
– Coronary sinus blood flow decreases
– Left coronary art diameter decreases
– Coronary vascular resistance increases
– Effects reversed by phentolamine
– Effects exacerbated by propanolol
Lange RA. NEJM. 1989. 321;1557.
Lange RA. Ann Intern Med. 1990. 112;897.
Thrombus formation
• Cocaine use results in
increased tissue
plasminogen activator
inhibitor activity
• Impaired thrombolysis
Moliterno DJ. Am J Med. 1994. 96;492.
Increased platelet aggregation
• Effects on endothelium:
– Loss of NO
– Impaired relaxation
– Impaired inhibition of platelet aggregation
• Effects on platelets:
– Inc responsiveness to thromboxane and
prostacycline
– Increased aggregation
Tonga G. Hemostasis. 1985; 15:100.
Increased atherosclerosis
• Animal studies:
– Rabbits fed high-cholesterol diet did not develop
atherosclerotic HD, but rabbits with cocaine added to
diet all developed AHD
Langner RO. FASEB. 1989. 3;297.
• Human studies:
– Higher (than expected for age) rate of atherosclerosis
on cocaine abusing pts undergoing cath
– Up to 77% of pts undergoing cath following MI due to
cocaine will have some abnormality of their CA
Kontos MC. J Emerg Med. 2003. 24:9.
Investigations
•
•
•
•
•
EKG
CXR
TNT
CK
Echo
• Must be relied on more heavily as hx is
usually not useful!!!
EKG
• Abnormalities occur in 90% of pts using
cocaine who develop an MI
• Up to 43% of cocaine abusers without MI
will meet show STE>0.1mV
• Sensitivity 36%
• Specificity 90%
Lange RN et al. NEJM. 2001. 345(5):351.
Cardiac enzymes
• CK often unreliable as frequently elevated due
to rhabo
• TNT more specific for cardiac issues
• Study comparing elevation of CK and CK-MB
with TNI/T:
– N=19 pts with cocaine abuse and CP
– Elevated CK in 14pts, but no pts had elevated
troponins
– No pts diagnosed with MI
McLaurin et al. Ann Clin Biochem. 1996. 33;183.
Observation and CP
•
•
•
•
•
N=344 pts with cocaine and CP
12% admitted directly to hospital
Remainder were observed x12h
30day f/u
None of 302 pts died from CV causes
(mortality – 2 died from GSW/heroin OD)
• 1.6% had non-fatal MI during this period
(all pts continued to use cocaine after d/c)
Weber JE et al. NEJM. 2003. 348:510.
Management ?
Management
•
•
•
•
•
•
•
•
Oxygen
ASA
Nitro
Benzos
CaCB
Phentolamine
Beta-blockers?
Thrombolytics?
Benzos
• N=40 pts with cocaine
and CP
– NTG-12
– Diazepam-13
– Both-15
• Received q5min until
symptoms resolved
• CP improved similarly
for both agents
Bauman BM. Acad Emerg Med.
2000. 7:878.
Benzos
Beta-blockers
• Teaching is that AVOID
• Unopposed alpha effects may actually
worsen outcomes
• ++ studies
Beta-blockers
• N=30 human volunteers for cardiac cath and randomized
IN saline or cocaine
–
–
–
–
Arterial pressure increased
Coronary sinus blood flow decreased
Coronary vascular resistance increased
Coronary arterial diameters decreased
• Intra-coronary propanolol given after initial
measurements
– No change in arterial pressure
– Further decreased coronary sinus blood flow (p<0.05)
– Further increased coronary vascular resistance (p<0.05)
Lange RA et al. Ann Intern Med. 1990. 112(12):897.
Beta-blockers cont’d
• N=15 volunteers
• Similar procedure as before, except
labetolol vs. N/S given post-cocaine
– Labetolol reduced MAP
– No significant change in coronary artery area
• Labetolol does not alleviate coronary
vasoconstriction
Boehrer JD et al. Am J Med. 1993. 94(6):608.
Beta-blockers cont’d
Thrombolytics ?
• + case reports of catastrophes following lytic
administration in cocaine pts
– Hypertensive
– Inc risk of neuro complications
– Lower rate of thrombosis (relative to other MI pts)
• Much preferable to undergo angio
• Trial NTG, ASA, benzos first and if unable to get
to cath lab, may consider lytics
• Bottomline: try to avoid!!!
Lange RA et al. NEJM. 2001. 345(5):351.
Dysrhythmias
Dysrhythmias
• Increases ventricular irritability and lowers
threshold for fibrillation
• Prolongs QRS/QT as a result of Nachannel blocking properties
• Increases intracellular Ca concentrations
which causes afterdepolarizations and
triggers ventricular arrhythmias
• Reduces vagal activity which increases
cocaine’s sympathomimetic activities
Mgmt
• If wide-complex tachy:
– Bicarb
– Lidocaine
• AVOID class 1a antiarrhythmic drugs
(procainamide, quinidine) as may worsen
QRS / QT widening and slow metabolism
of cocaine
• Correct lytes
• Overdrive pacing as indicated
Case
• 19F from Mexico; arrived in Calgary today.
En route, c/o palpitations, diaphoretic,
slightly agitated. EMS brought pt from
YYC to ED.
• Denies any drug use, previously healthy
• While in ED, becomes ++hypertensive,
tachycardic. Seizes x1.
• Any thoughts…mgmt?
Body packers
• In 7mo period during ’01-’02, 193 arrests
were made at New York Kennedy Int’l
airport for body packing
• Most commonly cocaine/heroin, but may
also swallow packets with amphetamines,
ecstasy, marijuana
• For clarification…body stuffers are people
who ingest small amounts of drug for fear
of arrest
Body packers
• Carry about 1kg of
drug on average
• From 50-100 packets
each containing up to
10gm of drug
• Each packet contains
life-threatening dose
Diagnosis
• Hx—often unreliable
• o/e—worsening symptoms despite
treatment
• Investigations:
– XR
– CT
– Urine tox screen
XR
• Multiple radio-dense
FB
• “rosette like finding”
• “Double-condom” sign
• Sensitivity 85-90%
CT
• FB surrounded by
small amount of gas
• ?sensitivity
• Case reports of false
negatives
• May be able to help
differentiate package
contents based on
Hounsfield units
Urine tox
• Poor sensitivity (?37%)
• If package recently ruptured, may not
indicate positive results on urine tox
screen
• Not recommended as part of routine
evaluation
General mgmt
• MDAC
• WBI with PEG
• Avoid oil-based laxatives as may
compromise the integrity of packets
• Endoscopy usually not recommended
• Most pts will require immediate surgery if
clinically decompensate or failure to pass
packets
Management
• Naloxone infusion if suspect heroin
• If cocaine, then pt requires immediate
surgical removal of packet(s)
– Temporizing measures including treatment
previously mentioned
– Aggressive benzos, bicarb,
phentolamine/nitroprusside, hyperthermia
mgmt with possible ETT/paralysis
• Watch for GI obstruction/perforation!!!
Disposition
• After 3 packet-free stools following 12hrs
of WBI and a subsequent negative
contrast radiography pt may be considered
for d/c
• If pt is reliable historian and packet count
is correct and negative contrast
radiography, then may consider d/c
• Otherwise admit/surgery!
Amphetamines
Trivia
• Which artist recently released a song with
lyrics as follows:
• “…baby you know my pedigree, ex-dealer,
used to move ‘phetamines…”
• A) Celine Dion
• B) Akon
• C) 50 cent
• D) Avril Lavigne
Amphetamines
• Methamphetamines became primary
substance of abuse amongst pts seeking
drug treatment in 1990’s
• Most common illicit drug produced in
clandestine labs in US (15, 944 in 2004)
• MDMA most commonly used
amphetamine by teenagers/college
students
Designer amphetamines
• Amphetamine analogs
• Ex:
– Methcathinone (“cat”)
– 3,4-methylenedioxyamphetamine (MDA, “love
drug”)
– 3,4-methylenedioxyethamphetamine (MDEA,
“Eve”)
– 3,4-methylenedioxymethamphetamine
(MDMA, “ecstasy”)
Pharmacology
• Release catecholamines from presynaptic
terminals
– Mainly DA, NE, also SE
• Block reuptake of catecholamines by
competitive inhibition
• Prevent breakdown of catecholamines
Pharmacokinetics
• Lipophilic and easily cross BBB
• Large volumes of distribution
• Varied half-life:
–
–
–
–
Amphetamine 8-30hrs
Methamphetamine 12-34hrs
MDMA 5-10hrs
Phentermine 19-24hrs
• Repetitive use/binging may cause drug
accumulation and considerably prolong half-life
Clinical symptoms
• ++ similar to cocaine
• Longer duration of effects (often up to
24hrs)
• Less likely to cause seizures,
dysrhythmias, MI
• More dominant psychosis with
amphetamines
Clinical Manifestations
• CV—hypertension, tachy, dysrhythmias,
MI, aortic dissection, vasospasm
• CNS—hyperthermia, agitation, seizures,
ICH, anorexia, choreoathetoid
movements, paranoid psychosis
• Systemic—diaphoresis, mydriasis,
tremor, nausea
• Other—rhabdo, muscle rigidity, acute lung
injury, ischemic colitis
Investigations
• Lytes, Cr
• EKG
• Qualitative urine immunoassay:
– Turnaround time is several hours
– Lots of false positives and false negatives
– True positive means pt has used
amphetamine analog within last several days
– Thus…do not use!
General Management
•
•
•
•
•
•
Similar to cocaine
Agitation—benzos prn
Seizures—benzos, barbiturates, propofol
Hyperthermia—external cooling, benzos
Decontamination—AC for oral ingestions
Hypertension—benzos,
phentolamine/nitroprusside
Specific scenarios
• 18M was at dance club all nite, friends
witnessed him take “a little white pill”. Pt
brought to ED after seized x1. No prior
seizure hx. Currently confused and
restless. HR 102, BP 133/85, T 37.8
• Management?
• Investigations?
Case cont’d
• Urine tox—pos amphetamines and
benzos, nil else
• Na 109 K 3.2 Cl 98 CO2 20 gluc 5.6
• EKG—NSR
• Any thoughts?
MDMA
• Significant hyponatremia can be seen with
“ecstasy”:
– Increase release of vasopressin
– Often large free-water intake
– Often Na loss from physical exertion
MDMA
• 3,4-methylenedioxy-methamphetamine
• methylenedioxy group addition conveys
hallucinogenic properties
Mechanism of action
• ++ serotonin release
• Also dopamine and norepi release
• Acute administration also leads to
decrease in SE reuptake transporter
function and numbers; recovery may take
several weeks
• Repetitive dosing leads to permanent
damage to serotonergic neurons
Flomenbaum et al. Goldfrank’s toxicologic emergencies. 8th ed. 2006.
Drug contamination
• Variation in content & dose
– 25 different types of ‘ecstasy’ pills given to
investigators by users
– Virtually none contained solely MDMA
– Ephedrine, ketamine, acetaminophen,
caffeine common adulterants
Sherlock et al. J Accid Emerg Med 1999. 16: 194-97
Thanks Sarah…
Case
• 24F was at rave and friends encouraged
her to try some “E”. Brought to ED feeling
“unwell”…
• PMHx: asthma, depression
• Meds: ventolin, paxil
• HR 145, BP 164/95, T 38.3
• Mydriasis, diaphoretic, confused, tremors
and clonus in LE
• Any thoughts ?
Serotonin s/o
Serotonin s/o
• Increased
SE release
•Decreased SE reuptake
Boyer EW et al. NEJM. 2005. 352:1112.
G-hydroxybutyric acid
GHB
• Used as sports supplements with
?anabolic effects
• Dietary health supplements for “sleep and
sexual enhancement”
• Recreational drugs “club drugs”
• Chemical submission agent for drugfacilitated sexual assault
• Licit medical uses: therapy for narcolepsy
Epidemiology
• In 2002 in US:
– 1386 exposures to GHB (>2x increase from
1996)
– 85% required treatment in healthcare facility
– 272 major outcomes, 3 deaths
• In Spain, responsible for 3.1% of
toxicologic emergencies (2nd highest illicit
drug)
Flomenbaum, et al. Goldfrank’s Toxicologic Emergencies. 8th ed. 2006.
Endogenous GHB
• Neurotransmitter—putative
• Released in Ca-dependant manner after neuron
depolarization
• Binds to GHB-specific receptors
• Activation causes increased cGMP which
modulates other neurotransmitters
• Inhibits GABA release in thalamus in low doses
• Inhibits DA release and results in accumulation
of DA in presynaptic cells
• Also affects serotonergic, cholinergic, and opioid
systems
Exogenous GHB
• Weak direct agonistic effect on GABA-B
receptor mediated mechanisms
• Rapid absorption from GI tract—15min
onset
• Peak effect 90-120min
• Half-life 30min
Clinical presentation
• 30mg/kg = CNS
depression,
myoclonus
• 50mg/kg =
unconsciousness
• 60mg/kg = coma
• Tolerance can shift
this to the right
s/s
• Resp—bradypnea, apnea
• CNS—miosis, hallucinations,
disorientation, agitation to lethargy, stupor,
coma, seizures, myoclonus
– Violent rousal when gag reflex tested!!
• Systemic—hypotension, bradycardia,
salivation, vomiting
Investigations
• EKG—prominent U waves
• Blwk usually normal
Management
• Supportive care
• Many pts will have adequate airwayprotective reflexes despite being comatose
• Hypotension—IV fluids
• Bradycardia—rarely requires treatment
• Trial of naloxone is acceptable
• No role for GI decontamination as rapid
absorption from GI tract
Disposition
• Coma usually lasts 1-2hrs
• May last slightly longer if intubated
• If co-ingestants then symptoms may be
prolonged
• Emergency phenomena may be ++
prolonged (lasting up to 2wks)
• Bottomline…Most pts with simple GHB
intoxication will be stable after 3-6hrs
Hallucinogens
Classification
• Lysergamides:
– LSD (D-Lysergic acid diethylamide)
– Lysergic acid hydroxyethylamide (morning glory)
• Indolalkylamines/tryptamines:
– Psilocin, psilocybin
• Tetrahydrocannabinoids:
– Marijuana, hashish
• Belladonna alkaloids:
– Jimsonweed, deadly nightshade, henbane
LSD
• Derived from ergot alkaloid of fungus
Claviceps purpurea
• Water-soluble, colourless, tasteless,
odourless powder
• Usually sold as liquid-impregnated blotter
paper, microdots, tiny tablets, liquid,
powder
LSD
• Usually po ingestion
• May also be taken IN, SL, smoking,
parenteral, conjunctival instillation
• No evidence for physiologic tolerance,
dependence, or withdrawal s/o
Pharmacokinetics
• Onset of action: 30-60min
• Peak effect: 3-5hrs
• Duration: 10-12hrs
• Current street dose is 20-80mcg (min
effective oral dose 20mcg)
Mechanism
• Bind to SE receptors
LSD chemical structure
Serotonin chemical structure
Clinical effects
• Sympathetic symptoms may precede hallucinogenic
effects
• Heightened awareness of auditory/visual stimuli
• Hallucinations (aud/visual)
• Synesthesia (confusion of senses)
• Depersonalization, enhanced awareness
• Other—piloerection, dizziness, muscle weakness, ataxia,
rhythmic dilation/constriction of pupils
• “bad trip”—anxiety, bizarre behaviour, combativeness,
panic reactions (frightening illusions, sense loss of selfcontrol)
• Often pts with “bad trip” present to ED!
Massive OD
• Report of 8pts with massive LSD OD:
– Hyperthermia
– Coma
– Resp arrest
– Hypertension
– Tachycardia
– Coagulopathy
Investigations
• Urine tox screens do not detect LSD
• GCMS can be done, but not clinically
useful:
– False-positive with fentanyl, sertraline,
haloperidol, verapamil
Management
• Decontamination with AC for pts who are
asymptomatic with recent ingestions; not
useful after symptoms appear
• Usually supportive care
• Hydration, sedation, quiet environment,
minimal stimuli
• “bad trip”—benzos prn
Chronic sequelae
• Psychotic reactions, severe depression,
flashbacks
• Hallucinogen-persisting perception d/o:
– Recurrence of perceptual symptoms experienced
while intoxicated
– Causes functional impairment
– Normal ophthalmologic testing suggests cortical
etiology
– Unclear etiology
– No proven treatment
Questions ?