STIMULANTS
More signal controllers: c-AMP/c-GMP
NH 2
N
N
O
HO P O
OH
Base'
Base'
O
O
HO
OH OH
N
N
O
P O
OH
O
N
OH
Guanine
H2N
AMP/GMP
Adenine
N
c-AMP/c-GMP
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
Many drugs act on this signaling mechanism:
Caffeine: inhibits PDE that breaks down c-AMP
raises c-AMP levels, increases flow of Ca2+ ions
stimulates heart muscles (as does adrenalin)
Viagra: blocks PDE-5 (mainly in the penis)
c-GMP higher so muscles remain relaxed, increases blood
flow into penis, erection stays around longer
Salbutamol (Ventolin): a b-agonist (mimics adrenalin)
activates cyclase enzyme, increase c-AMP keeps airways
expanded (rather than inhibiting PDE-4 enzymes)
b-Blockers (Atenolol):
Inhibit adenylate cyclase: reduces production of c-AMP, which
decreases relaxation of muscles and LOWERS blood pressure
NOTE: 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 flow
of Ca2+ ions from their storage sites
CAFFEINE
O
R
O
N
N
CH3
N
N
R = CH3 Caffeine
R=H
Theobromine
CH3
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
Coffee (6 oz)
Caffeine content (mg)
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
H
N
LETHAL DOSE 30-100 mg,
< 1mg/kg iv or oral
H
N
Very cheap alkaloid, comes
from seed of a tree in India
H
O
O
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
LIQUID bp = 250oC
N
N
CH3
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 (t1/2) = ~ 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 quitting
Marketing estimates: >1.3B smokers, sold ~1.5B$ cessation
products in 2005
ZYBAN (Bupropion.HCl) 1997
[also sold as Wellbutrin
an anti-depressant]
O
Cl
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
N
CH3
N
CH3
COOCH3
N
H
O
H
O
H
H
CH2OH
O
O
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
Datura
Belladonna
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
HO
HO
HO
HO
NH2
HO
DOPAMINE
R
OH
adrenalin (epinephrine)
H
NH2
NHMe
Me H
ephedrine
H
= chiral
NHMe
HO
HO H
Ar
H
Me H
PPA phenylpropanolamine
ADRENALIN AND DOPAMINE are the natural body stimulants
they are CATECHOLAMINEs or b-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 Exemption
December 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.
HO
HO
HO
HO
NH2
HO
DOPAMINE
Ar
H
NHMe
OH
adrenalin (epinephrine)
HO
HO H
H
NH2
NHMe
Me H
ephedrine
R
H
Me H
PPA phenylpropanolamine
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
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
HO
HO
HO
HO
NH2
HO
DOPAMINE
NHMe
adrenalin (epinephrine)
HO
HO H
Ar
H
H
NH2
NHMe
Me H
ephedrine
Me H
PPA phenylpropanolamine
R
H
OH
THE AMPHETAMINES
MeNH
NH2
Ar
NH2
H
CH3
active isomer
Amphetamine (benzedrine)
O
O
CH3
CH3
Methamphetamine (methedrine)
O
NH2
CH3
MDA
methylenedioxy-amphetamine
O
MeNH
CH3
MDMA
methylenedioxy-methamphetamine
ECSTACY
AMPHETAMINE - Benzedrine (racemic)
First synthesized 1927; amine is an oil,
but salts are crystalline and soluble in water
NH2
CH3
First as a nasal spray, but high was soon discovered
Pills: 5, 10, 15 mg approved for use against narcolepsy
Increases: respiration, blood pressure, alertness, concentration
Decreases: fatigue
Very popular with: truck drivers, students, athletes
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
Ar
NH2
H
CH3
METHAMPHETAMINE - Methedrine - SPEED - ICE
MeNH
(it forms nice ice-like crystals)
CH3
active form is [+] (S)
The free base can be smoked, high lasts for hours, cheaper,
longer than cocaine
‘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):
NHMe
NHMe
O
I H
HO H
NHMe
Me H
ephedrine
NHMe
Me H
NHMe
MDMA, ECSTACY, X, E’s
O
O
safrole
MeNH
CH3
O
O
is a street source, add H2O/ox, then as above
ecstacy
MDMA, ECSTACY, X, E’s
O
MeNH
CH3
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