Transcript FSC402H Cocaine and Other Stimulants

FSC402H
Cocaine and Other
Stimulants
0ctober 28, 2003
STIMULANTS
A COMPOUND WHICH INCREASES BRAIN
ACTIVITY
 COCAINE
 AMPHETAMINES
AMPHETAMINE & METHAMPHETAMINE
MDMA & MDA
 PMA
 EPHEDRINE & PSEUDOEPHEDRINE
 CAFFEINE, NICOTINE, + + +
COCAINE
COCAINE
- cocaine
comes from the coca plant
- grows primarily in Andean Region in South America
U.S. government Public Domain photo
COCAINE
-extracted cocaine
- whitish powder
- bitter
- crystalline
- odorless
- numbing
Public domain photo from Indiana University
COCAINE - HISTORY
records date back to 3000 B.C. – believed to be a gift from God
15th Century – Coca Plantations – Incas – Peru
Early 1500s – Spanish take over Inca plantations
- landowners must pay 10% of crop as tax
COCAINE - HISTORY
Late 1500s – Labourers in Spanish Silver mines supplied with coca
leaves
1580 - coca leaves brought to Europe – Not much interest
1600 - mid 1800’s – few mentions of coca in literature
COCAINE - HISTORY
1850 – used in throat surgery
1855 – cocaine first extracted
1863 – Angelo Mariani – Vin
Mariani patented
= coca extract +
Bordeaux Wine
1870 – Vin Mariani sold (7.2
mg cocaine/oz.)
COCAINE - HISTORY
1870 Parke Davis – manufactures fluid extract of coca
1883 – Theodor Aschenbrant reports in German Medical
Journal re: administration of cocaine to Bavarian
Army to enhance endurance
**** Read by SIGMUND FREUD****
Publishes ÜBER COCA
1884 – used as anaesthetic in eye surgery
COCAINE - HISTORY
1886 – COCA COLA = cocaine + caffeine
1891 – cocaine removed from coca cola
COCAINE - HISTORY
COCAINE - HISTORY
1905 – snorting becomes popular
1910 – first record of nasal damage from cocaine
1912 – 5000 cocaine related deaths – U.S.
1914 – listed as a narcotic – over the counter sales
stopped
1920-1970 – cocaine use subsides
COCAINE - HISTORY
1970 - Comprehensive Drug Abuse Prevention &
Control Act (U.S.)
- Cocaine is put in Schedule II (high potential for
abuse but has medicinal use)
1985 – est. 5.7 million Americans chronic cocaine users
(3% of population)
1992 – est. 1.5 million Americans chronic cocaine users
Levine – recent survey – 11.3% of Americans >12 have
used cocaine
COCAINE - HISTORY
1981 – 1 kg. Cocaine =
$55,000
1984 – 1 kg. Cocaine =
$25,000
Production of Cocaine by
Merck
1862 – ¼ lb
1883 – ¾ lb
1884 – 3179 lb
1886 – 158,352 lb
100 kg coca leaves  1 kg paste  800 g cocaine HCl
COCAINE - HISTORY
COCAINE - MEDICINAL
Topical Anaesthetic – upper respiratory tract & eye
vasoconstrictive properties are desirable
- Rapid absorption
- Dosage = varies and depends on area to be
anaesthetized
- Maximum – 200 mg/ 70 kg adult
- Supplied as 4% and 10% solutions
-2-4% eye; 5-10%  nasal pharnyx
COCAINE - ILLICIT
Cocaine HCl:
Coke, Snow, Nose Candy, Dust, White
Lady, Blow, Flake, Gold Dust, Happy
Dust, Toot
Freebase Cocaine:
Crack, Rock
Cocaine + Heroin: speedball
Cocaine + Phencyclidine: Tick
- to increase alertness, relieve fatigue,
feel stronger, feel more decisive,
- used to counteract the “down” feeling
of tranquilizers or alcohol
- used for euphoric effects
COCAINE - ILLICIT
Speedball – Cocaine + Heroin
COCAINE - ILLICIT
Modes of
Administration
Snorting
Smoking
Injection (intravenous)
Oral
COCAINE - ILLICIT
Peak (min)
Subjective
effects*(min)
Time to Onset
Inhaled
IV
20-30
1-5
30-60
50-90
15-30
15-60
45-90
3-5
immediate
(inhale + IV)
(2mg/kg – 115-246 mg dose)
Intranasal
min
Oral
>30 min
COCAINE - ILLICIT
Duration of Effects
Dependent on mode of administration and dose
The faster the onset, the stronger the high, the shorter
the duration
COCAINE - ILLICIT
Metabolism:
Half life cocaine = 30-90 minutes
Enzymatic Hydrolysis
Cocaine  Ecgonine Methyl Ester
cholinesterase
Cocaine + EtOH  Coca ethylene
COCAINE - ILLICIT
Metabolism:
Half life cocaine = 30-90 minutes
Half life benzoylecgonine = 5-7 hours
Spontaneous Hydrolysis
Cocaine  Benzoylecgonine
- both enzymatic and spontaneous breakdown can be
minimized with use of NaF and refrigeration (4oC)
- pH dependent  pH =  breakdown
- enzymatic hydrolysis affected > spontaneous
COCAINE - ILLICIT
Affects area of brain associated with pleasure and reward
- nucleus accumbens
Interferes with reuptake of dopamine (DA) from synapse
With chronic use
-  DA transporters
-  DA receptor
COCAINE - ILLICIT
Blood Concentrations – Recreational Use
Inhaled
IV
Dose(mg)
42
25
Cmax(mg/dL) 0.006-0.03 0.02-0.08
Dose(mg)
200
Cmax(mg/dL) 0.25
Surgical Patients – Max. 0.05mg/dL
Intranasal
32
0.004-0.009
COCAINE - ILLICIT
Blood Concentrations
300 mg cocaine, 5 hourly doses, oral
Mean cocaine = 0.1 mg/dL
Mean benzoylecgonine = 0.4 mg/dL
Postmortem Cases – death not related to cocaine
Mean benzoylecgonine = 0.02-0.24 mg/dL
COCAINE - ILLICIT
Low Dose (<20mg)
Effects:
- constricted peripheral
- euphoria, sense of well being
- dilated pupils
- exaggerated reflexes
- increased temperature
- postponement of
mental/physical fatigue
- increased heart rate
blood vessels
- increased blood pressure
- increase self confidence
- increased respiratory rate
- increase speed on simple
tasks
- decreased appetite
COCAINE - ILLICIT
Higher Doses Result in:
-all those of lower dose plus
- rapid, irregular heart beat
- dizziness
- loss of coordination
- feeling of restlessness
- collapse
- anxiety
- cold sweat
- delusions
- blurred vision
- paranoia
COCAINE - ILLICIT
Long term effects
- addiction
- irritability and mood disturbances (mood swings)
- restlessness
- paranoia
- hypersensitivity to sensory stimuli (auditory
hallucinations)
- unreal sensations (crawling insects)
COCAINE - ILLICIT
Long term effects
- sleep/eating/sexual disorders
- destruction of nasal passage (if snorting)
- social problems - ADDICTION
COCAINE - ILLICIT
Subject to Tolerance
with continued use, require more of the
drug to achieve the same effect
Results in Withdrawal Effect on Cessation
- apathy
- long periods of sleep
- irritability
- depression
- disorientation
COCAINE - ILLICIT
Blood Concentrations – Fatalites
ANYONE’S GUESS
N= 59 cocaine related deaths
Cocaine = not detected – 1.2 mg/dL
Benzoylecgonine = 0.009 – 3.1mg/dL
N = 3 I.V. deaths
Cocaine = not detected – 0.3 mg/dL
Benzoylecgonine = 0.11 – 0.74 mg/dL
COCAINE - ILLICIT
Overdose
- agitation
- increased body temperature
- hallucinations/delirium
- convulsions
- unconciousness
- death - cardiac arrest or seizure, followed by
respiratory arrest
COCAINE - ILLICIT
John Entwistle (The Who)
- Died June 27, 2002
- Age 57
- Medication for a heart problem
- COD: “Heart attack, brought
about by a significant amount of
cocaine in his system, amount
unknown?”
- Ruled: Not overdose, accidental
COCAINE - ILLICIT
Blood Concentrations – Interpretation
- recreational concentrations overlap with fatal
concentrations – dependent on tolerance
- breakdown of cocaine in vitro to benzoylecgonine
- route of administration
- possible redistribution
COCAINE - ILLICIT
Blood Concentrations – Interpretation
Cause of death is often attributed to cocaine overdose
based on:
- scene
- history
- any amount of benzoylecgonine
COCAINE - ILLICIT
Non-Biological – Interpretation
- cocaine is everywhere
Over a seven-year period, Dr. Jay Poupko and his colleagues
at ToxicologyConsultants Inc. in Miami have repeatedly
tested currency in Austin, Dallas,Los Angeles, Memphis,
Miami, Milwaukee, New York City, Pittsburgh, Seattle and
Syracuse. He also tested American bills in London. "An
average of 96 percent of all the bills we analyzed from the
11 cities tested positive for cocaine.”
From: PRESUMED GUILTY Copyright, 1991, The Pittsburgh Press Co.By Andrew Schneider and Mary Pat Flaherty
The Pittsburgh Press
COCAINE - ILLICIT
Cocaine Psychosis:
= cocaine-induced excited delirium
- Severe hyperthermia (104-108oC)
- Extreme agitation
- Delirium
- Bizarre and violent behaviour (fear, panic, shouting,
physical violence, thrashing)
- Extreme strength
- Associated with binging
COCAINE - ILLICIT
Cocaine Psychosis:
- Very similar in presentation to sudden onset of deaths
in schizophrenics
- Death occurs as individual calms
- Concentrations often lower than those expected from
fatalities
COCAINE - ILLICIT
Cocaine and Newborns:
- Cocaine can cross the Placenta
Approximately 1/3 of absorbed cocaine enters
fetus
- Effect on baby?
- Some say tend to be smaller, less healthy
- Simone & Koren – long term effects – none
- report in Calgary Herald states 1/16 babies in
Toronto show exposure to cocaine; 10/120
needed resuscitative efforts
COCAINE - ILLICIT
Human Performance
Fischman & Schuster 1980
– cocaine (100 mg intranasally) can reverse
reaction time impairment induced by
sleep deprivation
- did not show increased reaction time by
cocaine alone
- first tested by Freud in 1885 – n = 1
COCAINE - ILLICIT
Human Performance
-  sensitivity to light
- other studies
- performance
- counteracts deficiencies caused by EtOH
- CRASH that follows high
AMPHETAMINES
Amphetamine
(Benzedrine, Dexedrine,
speed, metabolite of
methamphetamine)
Methamphetamine
(Desoxyn, meth, crystal,
crank, ice)
AMPHETAMINES
Designer Amphetamines
- Methylenedioxymethamphetamine
(MDMA, ecstasy,adam, XTC)
- Methylenedioxyamphetamine
(MDA,eve, metabolite of MDMA)
- Paramethoxyamphetamine (PMA)
AMPHETAMINES
HISTORY
1930 – Benzedrine introduced into market
- inhaler to treat nasal congestion
1937 – Tablet form available for narcolepsy and
minimal brain dysfunction (ADHD) in children
WWII – Large use in military
1950-70 – large increase in use
1970-now – decline in amphetamines, increase in
designer amphetamines
USE APPEARS TO BE REGIONAL
AMPHETAMINES
HISTORY
USE in Military
reported to have been discontinued BUT…
CBC News Online, January 14, 2003
-report on the bombing of Canadian troops in Afghanistan by U.S.
Pilots
“Defence lawyers for the pilots have said they would argue that the
forcible use of the drug dextroamphetamine (Dexedrine) – known
on the street as “speed”, in the military as “go-pills” – was to blame
for the incident.”
AMPHETAMINE – MEDICINAL
Dexedrine = Dextroamphetamine Sulphate
Indications
-adjunctive treatment of narcolepsy
- 5-60 mg daily
-hyperkinetic behaviour in children
- 2.5-40 mg daily
- epilepsy
- parkinsonism
METHAMPHETAMINE – ILLICIT
Illicit Amphetamines
- names interchanged but mostly methamphetamine
- methylated amphetamine enters brain more readily
- supplied as cystals, chunks, powders,
- off-white-yellow
- loose, capsules, tablets
- various sizes, colors
- various INGREDIENTS, PURITY, DOSE
METHAMPHETAMINE – ILLICIT
Modes of Administration:
- Intranasal (snorted)
- Smoked
- Injected (intravenous)
- Oral (tablet, capsule)
METHAMPHETAMINE – ILLICIT
Time to Onset
- dependent on method of administration
IV = smoking
(immediately)
< intranasal
(min)
Duration of Effects
- generally 2-4 hours
< oral
(>30 min)
METHAMPHETAMINE – ILLICIT
Elimination:
Methamphetamine half-life = 6-15 hours
Amphetamine half-life = 7-34 hours
Methamphetamine  Amphetamine  Norephedrine



Deamination; p-Hydroxylation; Conjugation
- normal conditions – 43% excreted unchanged
- acidic urine – 76% excreted unchanged
- alkaline urine – 2% excreted unchanged
METHAMPHETAMINE – ILLICIT
Blood Concentrations:
Amphetamine:
10 mg – 0.0035mg/dL at 2 hours
30 mg – 0.011 mg/dL at 2 hours
Methamphetamine:
10 mg – 0.003 mg/dL at 1 hour
30 mg – 0.009 mg/dL (0.006-0.03)
N = 9 Fatalities not due to drugs
Methamphetamine conc. = 0.14 – 1.3 mg/dL
METHAMPHETAMINE – ILLICIT
Blood Concentrations:
Drivers (Methamphetamine)
N= 26
0.001– 0.19 mg/dL
- showed signs of nervousness, rapid speech,
confusion, agitation, irrational or violent behaviour
METHAMPHETAMINE – ILLICIT
Effects:
similar to cocaine
- Euphoria
- increased alertness
- increased heart rate
- irregular heart beat
- increased respiratory rate
- increased blood pressure
- decreased appetite
- loss of coordination
- hyperthermia
- perspiration
- blurred vision
- anxiety
- delusions
- feeling of restlessness
METHAMPHETAMINE – ILLICIT
Effects of Chronic Use:
- Malnutrition
- skin disorder
- disease from vitamin deficiency
- weight loss
- Paranoia, Mental illness
METHAMPHETAMINE – ILLICIT
Concentrations in Fatalities:
Amphetamine:
0.05 – 4.1 mg/dL
Methamphetamine:
0.009 - 4.0 mg/dL
METHAMPHETAMINE – ILLICIT
Effects of Overdose:
- Agitation
- Hyperthermia
- Intracranial hemorrhage
- Hallucinations
- Confusion
- Convulsions
- Death (Cardiac Arrhythmia, Respiratory Failure)
METHAMPHETAMINE – ILLICIT
Blood Concentrations – Interpretation
- recreational concentrations overlap with fatal
concentrations - dependent on tolerance
- death may not be immediate – concentrations
decrease
- redistribution
- chirality (d > l)
METHAMPHETAMINE –
ILLICIT
Human Performance
- improves alertness and performance in lab studies
- epidemiological evidence shows methamphetamine
adversely affects skills required for driving
PARAMETHOXYAMPHETAMINE (PMA)
Designer amphetamine compound
Taken orally in pill/tablet form
Usually misrepresented as “Ecstasy”
May be more potent
Stimulant but with  hallucinogenic effects
PARAMETHOXYAMPHETAMINE (PMA)
Martin. J. Anal. Tox. J. Anal. Tox. 25:649-651, 2001
2 fatal cases in year 2000
History indicative teenagers taking XTC (MDMA)
Found PMA – 0.06 - 1.3 mg/dL
EPHEDRINE
-originally derived from an asiatic shrub,
Ephedra equisetina
http://www.shamanshop.net/store/proddetail.cfm/ItemID/6224.0/CategoryID/8500.0/SubCatID/0.0/file.htm
EPHEDRINE
- originally grown and processed stem & leaf
sections. Drunk as a tea.
- 1887 – isolated ephedrine, the active
constituent
- Not popular until 1920’s in U.S. when used
for bronchodilating and decogesting.
EPHEDRINE
- Mormon sects, not allowed to drink coffee
because of religious conviction, use Ephedra
nevadensis as a coffee substitute.
- 'Mormon tea' stimulates differently and has
more sexual stimulating effects than coffee.
-Ephedra is therefore used in tantric rites as a
sexual stimulant.
EPHEDRINE
Medicinal Use:
- Decongestant
Found In:
- cold meds (alone or with other drugs)
- Omni-Tuss; Balminil Nasal Ointment;
I.D.M. solution; Ephedrine
- anti-asthmatic
- Tedral
EPHEDRINE
Also found in
-herbal
compounds such
as Ephedra and
Ma Huang
http://www.shamanshop.net/store/proddetail.cfm/ItemID/7386.0/CategoryID/8500.0/SubCatID/0.0/file.htm
EPHEDRINE
Also found in
Legally available
energizers,
nutritional
supplements and
dietary teas
http://store2.yimg.com/I/mte1999_1724_226006
PSEUDOEPHEDRINE
- naturally occuring, isomer of ephedrine
- common ingredient in over-the-counter meds
alone or with other drugs
- Contact Cold; Sudafed; Triaminic; Dristan;
Sinutab; Tylenol Sinus; Tylenol Allergy;
NeoCitran; Actifed; Benadryl; Benalyn;
CoActifed; Balminil; Robitussin; Advil Cold &
Sinus; Drixoral
- less adverse effects than ephedrine
EPHEDRINE
- White powder
- Usually supplied as tablets
- Bitter taste
- Soluble in water
EPHEDRINE
- closely related in structure to methamphetamine
- CNS actions much less potent
- CNS actions much longer acting
- peripheral actions similar to epinephrine
EPHEDRINE
Dosage:
Typical Adult Dosage:
30-60 mg orally 3-4 X/day
EPHEDRINE
Dosage:
From Web Site – Erowid
Oral Ephedrine Dosage
Threshold 5-10 mg
Light
10-20 mg
Common 15-30 mg
Strong
30-50 mg
Heavy
50+ mg
EPHEDRINE
Elimination:
- half-life – 5-7 hours
Ephedrine  Norephedrine
- slowly metabolized in liver to non-active
metabolites
- parent and metabolites excreted in urine
- mostly parent (70-80%)
- increases slightly with acidity of urine
EPHEDRINE
Blood Concentrations:
Ma Huang (19.4 mg ephedrine)
Peak conc. 0.08 mg/dL at 4 hours
Single Oral 24 mg
Peak conc. 0.01 mg/dL at 1 hour
Chronic Oral 45 mg
0.0095-0.006 mg/dL
20 yr male – survived 2.3 mg/dL
EPHEDRINE
Effects:
- potent bronchial muscle relaxant
- dilates bronchioles
- increased energy
- increased alertness
- decreased appetite
- vasoconstriction
- increase blood pressure
- increased heart rate
EPHEDRINE
Effects at higher doses:
- anxiety
- heart palpitations
- vomiting
- tremors
- insomnia
- hyperthermia
EPHEDRINE
Effects of chronic use:
- allegedly linked to strokes, heart attacks
- law suits in U.S. re: Ma Huang
- amphetamine like psychosis (confusion,
paranoia
EPHEDRINE
Concentrations in Fatalities
Sudden death in 3 yr old male – 0.27 mg/dL
N=5
0.35 – 2.1 mg/dL
EPHEDRINE
Overdose:
- restlessness
- anxiety
- dizziness
- tremor
- confusion
- hallucinations
- delerium
- convulsions
- aggressive behaviour
- cerebral hemorrhage
- high heart rate
- high blood pressure
- irregular heart beat
- hyperthermia
- Death
EPHEDRINE
Interpretation:
- redistribution ??
EPHEDRINE
Human Performance
- improves mental and motor performance in those
who are fatigued
- does not enhance performance in those who are
alert and attentive