FSC402H Cocaine and Other Stimulants 0ctober 28, 2003.

FSC402HFSC402HCocaine and Other Cocaine and Other StimulantsStimulants

0ctober 28, 20030ctober 28, 2003

STIMULANTS

A COMPOUND WHICH INCREASES BRAIN ACTIVITY

COCAINE

AMPHETAMINES

AMPHETAMINE & METHAMPHETAMINE

MDMA & MDA

PMA

EPHEDRINE & PSEUDOEPHEDRINE

CAFFEINE, NICOTINE, + + +

COCAINE COCAINE

COCAINE COCAINE

- cocaine comes from the coca plant

- grows primarily in Andean Region in South America

U.S. government Public Domain photo

COCAINE COCAINE

-extracted cocaine

- whitish powder

- bitter

- crystalline

- odorless

- numbing

Public domain photo from Indiana University

COCAINE - HISTORYCOCAINE - 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


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


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.)


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


1886 – COCA COLA = cocaine + caffeine

1891 – cocaine removed from coca cola


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


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


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 - MEDICINALCOCAINE - MEDICINAL

Topical Anaesthetic – upper respiratory tract & eyevasoconstrictive 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 - ILLICITCOCAINE - ILLICITCocaine HCl: Coke, Snow, Nose Candy, Dust, White Lady, Blow, Flake, Gold Dust, Happy Dust, Toot

Freebase Cocaine: Crack, Rock

Cocaine + Heroin: speedballCocaine + 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 - ILLICITCOCAINE - ILLICIT

Speedball – Cocaine + Heroin

http://www.findagrave.com/cgi-bin/fg.cgi?page=pis&GRid=77&PIgrid=77&PIcrid=640801&PIpi=76044&


Modes of Administration

Snorting

Smoking

Injection (intravenous)

Oral


Inhaled IV Intranasal Oral

Peak (min) 20-30 1-5 30-60 50-90

Subjective 3-5 15-30 15-60 45-90 effects*(min)

Time to Onset immediate min >30 min

(inhale + IV)

(2mg/kg – 115-246 mg dose)


Duration of Effects

Dependent on mode of administration and dose

The faster the onset, the stronger the high, the shorter the duration


Metabolism:Half life cocaine = 30-90 minutes

Enzymatic HydrolysisCocaine Ecgonine Methyl Ester

cholinesterase

Cocaine + EtOH Coca ethylene


Metabolism:Half life cocaine = 30-90 minutesHalf life benzoylecgonine = 5-7 hours

Spontaneous HydrolysisCocaine Benzoylecgonine

- both enzymatic and spontaneous breakdown can be minimized with use of NaF and refrigeration (4oC)- pH dependent pH = breakdown- enzymatic hydrolysis affected > spontaneous


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


Blood Concentrations – Recreational UseInhaled IV Intranasal

Dose(mg) 42 25 32Cmax(mg/dL) 0.006-0.03 0.02-0.08 0.004-0.009 Dose(mg) 200Cmax(mg/dL) 0.25

Surgical Patients – Max. 0.05mg/dL


Blood Concentrations

300 mg cocaine, 5 hourly doses, oralMean cocaine = 0.1 mg/dLMean benzoylecgonine = 0.4 mg/dL

Postmortem Cases – death not related to cocaineMean benzoylecgonine = 0.02-0.24 mg/dL

COCAINE - ILLICITCOCAINE - ILLICITLow Dose (<20mg) Effects:

- euphoria, sense of well being

- exaggerated reflexes

- postponement of mental/physical fatigue

- increase self confidence

- increase speed on simple tasks

- constricted peripheral blood vessels

- dilated pupils

- increased temperature

- increased heart rate

- increased blood pressure

- increased respiratory rate

- decreased appetite


- rapid, irregular heart beat

- loss of coordination

- collapse

- cold sweat

- blurred vision

Higher Doses Result in:

-all those of lower dose plus

- dizziness

- feeling of restlessness

- anxiety

- delusions

- paranoia


Long term effects

- addiction

- irritability and mood disturbances (mood swings)

- restlessness

- paranoia

- hypersensitivity to sensory stimuli (auditory hallucinations)

- unreal sensations (crawling insects)


Long term effects

- sleep/eating/sexual disorders

- destruction of nasal passage (if snorting)

- social problems - ADDICTION


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 - ILLICITCOCAINE - ILLICITBlood Concentrations – Fatalites

ANYONE’S GUESS

N= 59 cocaine related deathsCocaine = not detected – 1.2 mg/dLBenzoylecgonine = 0.009 – 3.1mg/dL

N = 3 I.V. deathsCocaine = not detected – 0.3 mg/dLBenzoylecgonine = 0.11 – 0.74 mg/dL


Overdose

- agitation

- increased body temperature

- hallucinations/delirium

- convulsions

- unconciousness

- death - cardiac arrest or seizure, followed by respiratory arrest


John Entwistle (The Who)John Entwistle (The Who)

- Died June 27, 2002- Died June 27, 2002

- Age 57- Age 57

- Medication for a heart problem - Medication for a heart problem

- COD: “Heart attack, brought - COD: “Heart attack, brought about by a significant amount of about by a significant amount of cocaine in his system, amount cocaine in his system, amount unknown?”unknown?”

- Ruled: Not overdose, - Ruled: Not overdose, accidentalaccidental


Blood Concentrations – Interpretation

- recreational concentrations overlap with fatal concentrations – dependent on tolerance

- breakdown of cocaine in vitro to benzoylecgonine

- route of administration

- possible redistribution



Cause of death is often attributed to cocaine overdose based on:

- scene- history- any amount of benzoylecgonine


Non-Biological – Interpretation

- cocaine is everywhereOver 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 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 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 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


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


Human Performance

- sensitivity to light

- other studies

performance

- counteracts deficiencies caused by EtOH

- CRASH that follows high

AMPHETAMINESAMPHETAMINES

Amphetamine

(Benzedrine, Dexedrine, speed, metabolite of methamphetamine)

Methamphetamine

(Desoxyn, meth, crystal, crank, ice)


Designer Amphetamines

- Methylenedioxymethamphetamine (MDMA, ecstasy,adam, XTC)

- Methylenedioxyamphetamine(MDA,eve, metabolite of MDMA)

- Paramethoxyamphetamine (PMA)


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


HISTORYUSE 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 – MEDICINALAMPHETAMINE – 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 – ILLICITMETHAMPHETAMINE – 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


Modes of Administration:

- Intranasal (snorted)

- Smoked

- Injected (intravenous)

- Oral (tablet, capsule)


Time to Onset

- dependent on method of administration

IV = smoking < intranasal < oral(immediately) (min) (>30 min)

Duration of Effects

- generally 2-4 hours


Elimination:Methamphetamine half-life = 6-15 hoursAmphetamine 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


Blood Concentrations:Amphetamine:10 mg – 0.0035mg/dL at 2 hours30 mg – 0.011 mg/dL at 2 hours

Methamphetamine:10 mg – 0.003 mg/dL at 1 hour30 mg – 0.009 mg/dL (0.006-0.03)

N = 9 Fatalities not due to drugsMethamphetamine conc. = 0.14 – 1.3 mg/dL


Blood Concentrations:

Drivers (Methamphetamine)

N= 26 0.001– 0.19 mg/dL

- showed signs of nervousness, rapid speech, confusion, agitation, irrational or violent behaviour


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


Effects of Chronic Use:

- Malnutrition- skin disorder- disease from vitamin deficiency- weight loss

- Paranoia, Mental illness


Concentrations in Fatalities:

Amphetamine:

0.05 – 4.1 mg/dL

Methamphetamine:

0.009 - 4.0 mg/dL


Effects of Overdose:

- Agitation- Hyperthermia- Intracranial hemorrhage- Hallucinations- Confusion- Convulsions- Death (Cardiac Arrhythmia, Respiratory Failure)



- recreational concentrations overlap with fatal concentrations - dependent on tolerance

- death may not be immediate – concentrations decrease

- redistribution

- chirality (d > l)

METHAMPHETAMINE – METHAMPHETAMINE – ILLICITILLICIT

Human Performance

- improves alertness and performance in lab studies

- epidemiological evidence shows methamphetamine adversely affects skills required for driving

PARAMETHOXY-PARAMETHOXY-AMPHETAMINE (PMA)AMPHETAMINE (PMA)

Designer amphetamine compound

Taken orally in pill/tablet form

Usually misrepresented as “Ecstasy”May be more potent

Stimulant but with hallucinogenic effects

PARAMETHOXY-PARAMETHOXY-AMPHETAMINE (PMA)AMPHETAMINE (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

EPHEDRINEEPHEDRINE

-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

EPHEDRINEEPHEDRINE

- 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.

EPHEDRINEEPHEDRINE

- 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.

EPHEDRINEEPHEDRINE

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

EPHEDRINEEPHEDRINE

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

EPHEDRINEEPHEDRINE

Also found in

Legally available energizers, nutritional supplements and dietary teas

http://store2.yimg.com/I/mte1999_1724_226006

PSEUDOEPHEDRINEPSEUDOEPHEDRINE

- 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

EPHEDRINEEPHEDRINE

- White powder

- Usually supplied as tablets

- Bitter taste

- Soluble in water

EPHEDRINEEPHEDRINE

- closely related in structure to methamphetamine

- CNS actions much less potent

- CNS actions much longer acting

- peripheral actions similar to epinephrine

EPHEDRINEEPHEDRINE

Dosage:

Typical Adult Dosage:

30-60 mg orally 3-4 X/day

EPHEDRINEEPHEDRINE

Dosage:

From Web Site – Erowid

Oral Ephedrine DosageThreshold 5-10 mgLight 10-20 mgCommon 15-30 mgStrong 30-50 mgHeavy 50+ mg

EPHEDRINEEPHEDRINE

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

EPHEDRINEEPHEDRINEBlood 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 mg0.0095-0.006 mg/dL

20 yr male – survived 2.3 mg/dL

EPHEDRINEEPHEDRINE

Effects:

- potent bronchial muscle relaxant- dilates bronchioles- increased energy- increased alertness- decreased appetite- vasoconstriction- increase blood pressure - increased heart rate

EPHEDRINEEPHEDRINE

Effects at higher doses:

- anxiety- heart palpitations- vomiting- tremors- insomnia- hyperthermia

EPHEDRINEEPHEDRINE

Effects of chronic use:

- allegedly linked to strokes, heart attacks- law suits in U.S. re: Ma Huang

- amphetamine like psychosis (confusion, paranoia

EPHEDRINEEPHEDRINE

Concentrations in Fatalities

Sudden death in 3 yr old male – 0.27 mg/dL

N = 5 0.35 – 2.1 mg/dL

EPHEDRINEEPHEDRINE

Overdose:- restlessness- anxiety- dizziness- tremor- confusion- hallucinations- delerium- convulsions- aggressive behaviour

-

- cerebral hemorrhage- high heart rate- high blood pressure- irregular heart beat- hyperthermia

- Death

EPHEDRINEEPHEDRINE

Interpretation:

- redistribution ??

EPHEDRINEEPHEDRINE

Human Performance

- improves mental and motor performance in those who are fatigued

- does not enhance performance in those who are alert and attentive

FSC402H Cocaine and Other Stimulants 0ctober 28, 2003.

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