STIMULANTS

More signal controllers: c-AMP/c-GMP

O

OHOH

Base'

OPOH

HOO

O

OH

Base'

OP

OHO

O

AMP/GMP c-AMP/c-GMP

N

N N

N

NH2

N

N

OH

H2N

Adenine

Guanine

adenosine monophosphate cyclic-AMP

guanosine monophosphate cyclic-GMP

Signaling chemical (eg. NO) binds to an enzyme (adenylate or guanylate cyclase)

stimulates synthesis of c-AMP or c-GMP from ATP (adenosine triphosphate) or GTP (guanosine triphosphate)

c- AMP or c-GMP causes Ca2+ ions to flow OUT of the muscles, which causes the muscles to relax

c-AMP and c-GMP are broken down by enzymes called PHOSPHODIESTERASES (PDE’s) so anything that inhibits these enzymes, keeps c-AMP/c-GMP around longer and enhances their effects

Caffeine: inhibits PDE that breaks down c-AMP raises c-AMP levels, increases flow of Ca2+ ionsstimulates heart muscles (as does adrenalin)

Viagra: blocks PDE-5 (mainly in the penis)c-GMP higher so muscles remain relaxed, increases bloodflow into penis, erection stays around longer

Salbutamol (Ventolin): a -agonist (mimics adrenalin) activates cyclase enzyme, increase c-AMP keeps airways expanded (rather than inhibiting PDE-4 enzymes)

Many drugs act on this signaling mechanism:

-Blockers (Atenolol):Inhibit adenylate cyclase: reduces production of c-AMP, which decreases relaxation of muscles and LOWERS blood pressureNOTE: opposite effect from salbutamol – asthmatics can’t take these!

Mechanism of action for c-AMP:normally activates phosphorylation of serine, threonine, tyrosine (amino-acids), changing the shape of the enzyme which permits flowof Ca2+ ions from their storage sites

CAFFEINE

N

N N

N

O

O

RCH3

CH3

R = CH3 Caffeine

R = H Theobromine

Caffeine = Trimethylxanthine, a purine dione

EFFECTIVE DOSE ~ 200 mg

two cups of coffee or ca. 4 cans Coke

LETHAL DOSE ~ 10 g LD50 (rabbits, mice) ~200mg/kg

Source Caffeine content (mg)

Coffee (6 oz) 100-150

Tea (6 oz) 50-80

Cola (12 oz = 350 mL) 30-50

Jolt type (12 oz) up to 72

NO-DOZ (per pill) 60-100

Dexatrim (per pill) 200

Chocolate contains related theobromine (ca. 50-250 mg per 65 g bar

Caffeine: PDE inhibitor AND Adenosine ANTAGONIST

adenosine is a nerve modulator that slows down nerve activity during sleep and dilates the brain blood vessels

Caffeine blocks the A1 sites in the brain so cell nerve action speeds up and blood vessels contract (hence use of caffeine in ANACIN, EXCEDRIN and CAFERGOT to relieve headaches/migraines)

Pituitary gland senses nerves firing: concludes an emergency exists, releases adrenalin that increases respiration, heart rate and allows more blood flow to muscles from skin (feels cold)

STRYCHNINE

N O

N

O

H

H

H

Very cheap alkaloid, comes from seed of a tree in India

LETHAL DOSE 30-100 mg,

< 1mg/kg iv or oral

In use > 400 y as a rodent poison

Very strongly excites brain, but overload gives convulsions,

cuts off the breathing, death

Contracts all voluntary muscles, ‘smile of death’

Has been used to cut heroin, though not safely!

Extremely bitter, can detect at about 1-10 ppm

NICOTINE

N

N

CH3

LIQUID bp = 250oC

Salts, e.g. nicotine sulfate are crystalline (pesticides)

It is biphasic - it both excites and relaxes

When smoked, it is absorbed fast, (lungs have about 90x area of skin), reaches brain 10-15 s: causes a rapid release of adrenalin

increases: heart rate, blood pressure, breathing rate, but diverts blood from peripheries (cold feet)

it excites the brain

it is an AGONIST for the brain acetylcholine receptors, stimulates the cholinergic pathways,

causes release of stored dopamine: pleasant, happy, excited feeling

increases endorphin production: feel pain less

causes release of glutamate: enhances memory (used for Alzheimer’s, Tourette’s)

increases blood sugar levels: brain thinks muscles need more sugar, so blocks some insulin release (hyperglycemia)

increases base metabolic rate: stop smoking, gain weight brain may also send a signal to eat less, while nicotine is present

Effects are SHORT LIVED Half-life (1/2) = ~ 60 mins

Liver oxidizes about 80%, lungs do some, rest is excreted

Although cigarettes can contain up to 9 mg nicotine per cigarette, smoking is not an efficient means of taking in nicotine: only ca. 0.2-1 mg absorbed – remainder burns (a good thing)

LETHAL DOSE 8-10mg injected; 50mg oral

NOTE: kids can easily kill themselves chewing tobacco or eating the equivalent of 2 nicotine patches

SMOKING

Canada: 1965 (50% smoke); 1994 (31%); 2004 (20%); 2006 (15%)

Estimate: 140,000 new cancer cases per year,

67,400 deaths smoking related

US >400,000 deaths smoking related

Estimated deaths per 10,000 weekly users:

smoking 85; alcohol 21; cocaine 30

tumor cells: activated by acetylcholine; nicotine activates acetylcholine receptors, so stimulates tumor growth

Addiction: appears to be highly addictive given trouble quittingMarketing estimates: >1.3B smokers, sold ~1.5B$ cessation products in 2005

ZYBAN (Bupropion.HCl) 1997

[also sold as Wellbutrin

an anti-depressant]

Cl

O

NH-tBu.HCl

Dose: 150mg (purple, wax coated) pill morning and night

As anti-depressant is a weak inhibitor of the re-uptake of adrenalin, so probably releases dopamine, which reduces the nicotine withdrawal problems

Is it effective?

Drug is taken for 7 weeks then reduce dose during weeks 8-9

Results: % refraining from smoking at given # of weeks

PLACEBO Habitrol Patch 300mg Zyban Patch + Zyban

21mg/day Nic.

7 weeks 23% 36% 49% 58%

10 weeks 20% 29% 41% 48%

26 weeks 13% 18% 30% 33%

52 weeks 8% 12% 23% 28%

COCAINE

NCH3

COOCH3H

H

O O

NCH3

H

O

O

CH2OHHN

Tropane alkaloids COCAINE (-) ATROPINE

Atropine: from belladonna plants (night shades): increase pupils, decrease secretions (saliva, mucous production)

Hyoscyamine, scopolamine from Datura (Jimson’s weed are Voodo (Haiti) zombie drugs.

Cocaine: from COCA tree (Bolivia, Peru, Colombia)

Coca

Belladonna

Datura

The free base: bp 188oC, smoked for fast (<15 s) high, lasts ~ 10 min

Cocaine.HCl is SNOW, white crystals, mp 195oC, snorted (not smoked) destroys nose linings, leading to infections, lasts ~ 1h

DOSE: 25-100 mg

expensive habit since it costs ~ $100/g

Snow cooked with NaHCO3 gives CRACK (free base) cocaine:

Cocaine.HCl + NaHCO3 → Cocaine + NaCl + H2O + CO2

Cocaine was common in Europe, eg. Freud, 1884

American dentist Koller used it in dentistry which led eventually to benzocaine and other local anethetics

Originally it was in Coca-Cola (60 mg) until 1903!

ACTION: Cocaine prevents re-uptake of DOPAMINE and adrenalin and so keeps the nerve cells firing (but afterwards get depression)

Cocaine effects:

increases heart rate

increases blood pressure

elevates body temperature

dilates the pupils (opposite of heroin)

enhanced effects with alcohol - so care!

However rapidly metabolized, so effects only last ~ 1 h

HIGHLY ADDICTIVE

lab animals self administer coke over food, water

Cheap to isolate (~$3/g) but expensive on the street:

200-500 kg of coca leaves give 1 kg cocaine:

Cost: $3500 (Colombia) but retails for about $800,000 in the US when cut to 10%

CHEAP SUBSTITUTES FOR COKE - THE AMPHETAMINES

Ar

R OH

H

ephedrine

adrenalin (epinephrine)

HO

HONH2

NHMe

HO H

Me H

NHMe

HOH

HO

HO

NH2

HOH

Me H

PPA phenylpropanolamine

DOPAMINE

= chiral

ADRENALIN AND DOPAMINE are the natural body stimulants

they are CATECHOLAMINEs or -phenylethylamines

Adrenalin (epinephrine)

It is the primary stimulant of the adrenergic system

increases heart, blood pressure, alertness

bronchodilator (OTC inhalers available in US!!)

Epinephrine Inhalers Denied ExemptionDecember 26, 2008

The FDA denied the request for “essential-use” designation for epinephrine inhalers. This means that CFC-propelled epinephrine delivery devices will be unavailable after 12/31/2011. These inhalers are available over-the-counter, and can be found under brand names such as Asthmahaler™, Primatene™ Mist, or Bronitin™ Mist. Since these were readily available, patients had become accustomed to easy access in cases where they lost or misplaced prescription bronchodilators. Patients need to be informed of this change.

SUBSTITUTES

EPHEDRINE from Ephedra, Ma Huang, Ginseng, Gingko ~1%

can easily be illegally converted to methamphetamine

l-ephedrine (erythro) (= 1R,2S)

pseudoephedrine (threo) (= 1S,2S)

used as a decongestant and bronchodilator

Ar

R OH

H

ephedrine

adrenalin (epinephrine)

HO

HONH2

NHMe

HO H

Me H

NHMe

HOH

HO

HO

NH2

HOH

Me H

PPA phenylpropanolamine

DOPAMINE

They are adrenergic agonists for adrenalin (epinephrine)

Jan 2002: Health Canada recalls all products with ephedra because of increased heart fibs and strokes

Jan 2004: FDA banned all food supplements with ephedra commonly used in ‘diet aides’ (questionable effectiveness)

Spring 2003: 24 yo Baltimore Orioles pitcher Steve Bechler dies taking an herbal source of ephedra for weight loss

PPA phenylpropanolamine (d,l-norephedrine)

was common in cold remedies (Triaminic, Alka Seltzer Cold)

usually as the racemate: ~ 6B doses per year!!!

FDA asks manufacturers to remove in 2000 because stroke risk increased 17x

HC removed Triaminic products in 2002

Ar

R OH

H

ephedrine

adrenalin (epinephrine)

HO

HONH2

NHMe

HO H

Me H

NHMe

HOH

HO

HO

NH2

HOH

Me H

PPA phenylpropanolamine

DOPAMINE

THE AMPHETAMINES

CH3

NH2

NH2

CH3H

Ar

active isomer Amphetamine (benzedrine)

CH3

MeNH

Methamphetamine (methedrine)

CH3

NH2O

O

CH3

MeNHO

O

MDA MDMAmethylenedioxy-amphetamine methylenedioxy-methamphetamine

ECSTACY

AMPHETAMINE - Benzedrine (racemic)First synthesized 1927; amine is an oil, but salts are crystalline and soluble in water

First as a nasal spray, but high was soon discoveredPills: 5, 10, 15 mg approved for use against narcolepsy

Increases: respiration, blood pressure, alertness, concentration Decreases: fatigueVery popular with: truck drivers, students, athletes

CH3

NH2

Minor side effect: appetite depression

diet pills: not effective and banned (Canada) for that use

The active enantiomer [+], is the dextro or D-isomer hence the names: Dexedrine [Glaxo] or Dexies (Note: the 80’s band Dexies Midnight Runners is named after this!)

Withdrawal effects are sleepiness, hunger so tends to be addictive

Output ~ 8 tons per year, 0.5B doses

LD very variable, in mice LD50 ~ 25 mg/kg

NH2

CH3H

Ar

METHAMPHETAMINE - Methedrine - SPEED - ICE

(it forms nice ice-like crystals)

active form is [+] (S)

The free base can be smoked, high lasts for hours, cheaper, longer than cocaine

CH3

MeNH

‘ICE’

boosts dopamine levels and destroys transporters:

this happens naturally as we age at about 5-6% loss per decade BUT METH results in about a 20% lowering of transporters (even after clean for a year): equivalent to a 3-decade aging - worse than coke or heroin

Extremely addictive

HC estimates that ~6% of Canadians have tried METH once

DOSE 10-50 mg, over 100 mg gives a very powerful mental rush, but risk of hemorrhage, heart fibs,...

Monoamine oxidases (MAO) enzymes get rid of METH (and dopamine), so if speed is used in large amounts, large amounts of MAO are mobilized, then between trips these work on dopamine, reduce it lower than normal, get depressed.

It is easily synthesized (with a risk of fires):

O NHMe NHMe

NHMe

HO H

Me Hephedrine

NHMe

I H

Me H

NHMe

MDMA, ECSTACY, X, E’s

O

Osafrole

is a street source, add H2O/ox, then as above

CH3

MeNHO

O

ecstacy

MDMA, ECSTACY, X, E’s CH3

MeNHO

O

ecstacy

The (S)-enantiomer is most active but usually racemic

E boosts serotonin (blocks the transporter protein that removes it) much more than dopamine, swamps the 5-HT1A receptors involved in sexual arousal, however it is not ‘a love drug’, since like PROZAC, people who use E frequently, tend to lose their appetite for sex, however do get ‘touchy-feely’ and a warm, fuzzy high, with lots of energy, hence popularity at RAVES

BUT: beware heat exhaustion, dehydration, inhibition of urination

Suicide Tuesday phenomenom: used Saturday, depressed Tuesday