Drugs of AbusePart I

Rebecca Burton-MacLeodR4, Emerg Med

Preceptor: Dr. S. McPhersonCore RoundsMar 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

Norocaine Ecgonine methyl ester Benzoylecgonine

N-demethylation Plasma cholinesterase

Nonenzymatic hydrolysis

Major metabolite: 30-50% About 40%Minor metabolite

Detected in urine tox screens as longest half-life (usually up to 48-72hrs)

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 1982Coleman 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 propanololLange 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 CAKontos 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 MIMcLaurin 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 Na-channel 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 drug-facilitated 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 airway-protective 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 self-control)

• 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 ?