Problem sets
PS #7; Chapt 20 ; 1,18,20 (toxins etc)
PS #8; Chapt 10 ; 1,5a-k,10,12,27a-d.
(acids and bases)
PS #9; Chapt 23 ; 1,12,18a,b; 31,32
(drugs)
15. Medicines, Drugs
- part 1
chapter 23
Drugs: Licit and illicit
Licit: Aspirin, Tylenol, Ibuprofen, caffeine,
nicotine, codeine, morphine, ethanol,
steroids (birth control), ritalin, antibiotics
• Illicit: heroine, cocaine, marijuana, crystal
meth, ecstacy, LSD, steroids (anabolic)
• Pharmaceutical Industry: $, names,
placebos, addiction, OTC vs. prescription
drugs, most prescribed
Generally - a drug is any substance that brings
about a physiological, emotional or behavioral
effect in an individual.
Commonly- Drugs/medicines are compounds/
agents used for treating disease and
injuries, ie. to relieve pain or cure illness.
Lately, drugs carry the added connotation of
narcotics and addiction.
Chemotherapy (Paul Ehrlich, 1904) - the use of
chemicals, more toxic to disease -bearing organisms
than human cells, to control/cure infectious
diseases.
Paul Erlich
• Made 1st synthetic drug Salvarsan (also
called 606) in 1908 after the synthesis and
testing of a series of 606 arsenic containing
aromatic compounds: lead compd approach
• Diarsaphenamines
• Used to treat syphilis, until penicillins were
discovered in the 1940’s
Paul Erlich (1854-1915)
• Father of the modern pharmaceutical
industry
Drugs / Medicines/
Pharmaceuticals
Begin with:
drugs that affect the brain
and spinal cord (CNS,
Central Nervous System),
ie. for pain, fever, mood
(stimulants, tranquilizers),
also hallucinogens, narcotics.
Later survey:
steroids (from sex hormones to antiinflammatories), antibiotics, antivirals, heart
disease, allergies, anticancer, etc.
Evolution of a
Drug / Medicine
Investigate a 'folk medicine'
Isolate the 'active
ingredient' and prove
structure
Synthesize 'natural' compound
to confirm structure and provide material
Test for physiological effects; often multiple effects
Synthesize compounds with modified structure; to
emphasize desired properties to 'delete'
unwanted effects
Test for efficacy and safety
Aspirin a Case Study
The beneficial effects
of willow bark have
been known for
centuries:
In ancient Greece, Hippocrates suggested
chewing the bark for relief of fever
In 1763 Edward Stone addressed the Royal
Society in Britain on the benefits of 'willow
tea' for pain/fever.
1827 - isolation of salicin(glucose + salicyl alcohol)
1860 - 'break off' glucose and prepare salicylic acid
1875 - prepare sodium salt, to offset 'acidity'
1899 - introduction of ASA by Bayer
1893 - introduce phenacetin(acetanilide derivative)
1893 - introduce acetaminophen
2000 - Aspirin (Acetylsalicylic acid or ASA) is used
at ~100 billion tablets/yr worldwide. In NA,
~100 million tablets/day or ~20,000 tons/yr!
Salicylic Acid and Derivatives
CH2OH
OO
CH2OH
OH
HO
petroOH chemicals
COOH
(salicyl
alcohol)
salicin
OH
(willow bark)
COOH
O
O CCH3
acetylsalicylic
acid
salicylic acid
- +
COO Na
OH
sodium
salicylate
O
OCH3
OH
methyl
salicylate
Aspirin - Multiple
Physiological Effects
Analgesic – reduces
or eliminates pain.
Antipyretic - lowers or
eliminates fever.
Anti-inflammatory agent reduces or eliminates inflammation.
Anti-coagulant - inhibits the formation of blood clots
by decreasing platelet concentrations, ie.
decreases incidence of heart attacks resulting
from the formation of internal clots that can block
the flow of blood to the heart.
Daily Low Dose of 75-81 mg aspirin
• Maintains normal blood platelet aggregation
• Recommended for all men (particularly)
over 50 to reduce risk of strokes and heart
attacks due to blood clotting
• This new use was patented in 1990’s
Enterically coated Aspirin
• Coating of wax, cornstarch, methylcellulose, KOH,
methacrylic acid copolymer prevents capsule from
dissolving in stomach-goes to small intestine before
dissolution, thus helping to prevent stomach irritation
Modifications - the Good, the Bad ….
Aspirin and it's analogs exhibit varying effects and
are remarkably 'safe', when not overused.
Basic structural features are:
a) 2-hydroxybenzoic acid; acetylsalicylic acid
b) 4-aminophenol(OH-benzene); acetaminophen
c) 2-phenyl propanoic acid; ibuprofen
a) = Aspirin. ~5% have some intestinal bleeding
b) = Tylenol. No bleeding but not anti-inflammatory
c) = Motrin/Advil. Little bleeding& anti-inflammatory;
best for arthritis(NSAID)
Other Analgesics
O
HO
NH2
CH3CH2O
p-amino phenol
acetaminophen(Tylenol)
–not anti-inflammatory-
NHCCH3
phenacetin(bannedkidney damage, etc.)
CH3CHCH2
CH3
CHCOOH
CH3
ibuprofen(Motrin/Advil)
–not anticoagulant-
How Aspirin Works
COOH
arachidonic acid
COX2
enzyme
Aspirin
O
COOH
CH3
HO
OH
a prostaglandin
induces pain, blood clotting,
labour, sleep regulation
...and (possibly) the Ugly
There can be possible complications to adults from
the anti-coagulant properties of ASA when used
frequently and in quantity.
But the danger to children is much greater, eg.
the LD50 of ~1.5g/kg means 40-50 tablets could
kill a 10kg(22lb) child.
can induce Reye's Syndrome(nausea, lethargy
=> death) in children treated for 'fever' from
smallpox / flu.
Solution - 'child-proof' caps and warning labels on
containers have been very effective.
From Acids
to Bases
Alkaloids are basic(alkaline), bitter-tasting,
nitrogen-containing compounds (amines) that are
found in plants and that produce physiological
reactions of various kinds and intensity.
eg. Morphine,codeine, caffeine, nicotine
A narcotic* (opiate) is a substance that
produces a stupefying, dulling effect that induces
sleep. Usually very effective analgesics also.
* from narcosis = a state of profound stupor
Morphine:
Analgesic... and ?!
(Morpheus Roman god of dreams)
~10% of dried juice
(opium) from seed
pod of oriental
poppy.
Pros: one of most powerful analgesics known
'soothes'/calms(19th cent. 'patent medicines')
antitussive = cough suppresant
Cons: confusion, euphoria, depresses respiratory
system, chronic constipation, lethargy
addictive
Morphine binds to opiate receptor sites in the brain.
ie. doesn’t interfere with the transmission of a pain
signal but changes the reception of that signal.
Morphine
Analogs/Derivatives
Codeine - analgesic, not sleep inducing, not very
addictivecough syrups (55,000kg/yr)
Heroin - euphoria, stupor, analgesic, very addictive
Morphine & Analogs
CH3
morphine
N
O
HO
OH
CH3
codeine
N
CH3
N
heroin
CH3O
O
OH
O
O
H3C
O
O
O
CH3
Other Morphine Analogs
Naloxone: an “antagonist’-binds to heroin receptor
site-used to treat heroin overdoses
Methadone – long term treatment for heroin
addition. No euphoria or withdrawal symptoms, but
addictive. Allows return to “normalcy” if maintained
Dextromethorphan - non-addictive, antitussive
Fentanyl - analgesic/anesthetic in surgery (100x
morphine); Moscow ‘hostage incident’(2002)
Multi-faceted Cocaine:
the power & the gory
Leaves of the coca plant eastern slopes of the
Andes mountains
(Columbia, Ecuador, Peru)
stimulant, pain reliever, but =>=> addictive
increases stamina, reduces fatigue =>=> used by
Peruvian Indians to 'survive'(walking hours in
snow with heavy loads and little food)
constricts blood vessels, local anesthetic =>=>
many deaths from 'overdoses'
Cocaine'Techniques' = Applied Chemistry
Cocaine = alkaloid = amine
ie. base  forms HCl salt (ionic), thus water-soluble
and easily ingested by 'snorting' through the
watery mucous membranes of the nose or
by direct injection
as 'free' base(crack) it is more volatile and can reach
the brain in 15 seconds when heated and
inhaled by smoking (Peruvian Indians mix
coca leaves with lime)
Cocaine and Analogs
Cocaine - stimulant,
intense euphoria,
analgesic, addictive.
Scopolamine - “truth drug”,
preoperative sedative
Atropine - heart stimulant (popular poison in
Middle Ages, from deadly nightshade/
belladonna), eye drops
Novocaine - topical anesthetic (dentistry)
anesthetic - causes unconsciousness and/or
insensitivity to pain
Cocaine & ‘Relatives’
CH3
N
CO2CH3
O2 C
cocaine
CH3
CH3
N
N
O
O
atropine
O
O
CH2OH
scopolamine
O
CH2OH
Cocaine Analogs
CH3
N
CO2CH3
O2 C
cocaine
N
N
O2 C
Lidocaine(xylocaine)
NH2
O
HN
Procaine(novocaine)
Addiction … Dr. Freud & friends
Addiction can take several forms:
Physiological effects: watery eyes/nose, sweating
goose flesh, yawning, dilated pupils, convulsions
that occur during withdrawal, eg. heroin
Psychological dependence: the uncontrollable desire
for another euphoric 'high' when depression
occurs after a 'hit' subsides, eg. cocaine
Tolerance: increasing dosage to obtain the same
'results'
The PEA Connection
CH2 CH2
NH2
-Phenylethylamine
Many psychoactive compounds contain the
-phenylethylamine substructure(or similar).
PEA itself induces a 'high' similar to 'being in love'!
Some Neurotransmitters
HO
HO
HO
NH(CH3)
(nor)epinephrine
HO
NH2
HO
H2N
dopamine
NH2
COOH
-aminobutyric acid
N
serotonin
HO
CH3
Stimulants
NH2
NH2
Phenylpropanolamine(PPA)
diet loss, ‘cold meds’
(banned 2001)
Benzedrine
(N-CH3= methamphetamine
methedrine/speed)
HO
HO
NHCH3
HO
Epinephrine(adrenaline)
Silken Laumann
• Tested positive for PPA and lost her 1995
Pan Am gold medal
• Took Benadryl to fight a cold
Bennies
• Benzedrine: stimulants often used by
Baseball players (pitchers) to get hopped up
and put more speed on the fastball (they
think!)
• Jim Bouton’s 1969 book “Ball Four” diary
of life on road with NY Yankees, Seattle
Pilots, Houston Astros
A must read for baseball fans
• A “Classic”
Crystal Meth
• Crystalline form of methamphetamine
(methedrine or speed)
• Same as benzedrine except N-CH3.
• Easily made from pseudoephedrine (in
decongestant medications)
• Can be snorted , smoked, injected or
swallowed
Pseudoephedrine to crystal meth
• Remove OH group!
But……..when smoked in its
crystalline form
• Produces effects similar to, but longer
lasting than crack cocaine
Devastating Effects
• After 10 years of use
Danger from west to east
• Crystal meth labs started in US midwest
• Reached Ontario in ~2001
• Possession, trafficking and production now
can carry penalty up to life imprisonment in
Canada
Ecstasy
• Semi-synthetic, patented by Merck in 1914
and then abandoned for ~60 years
• Used in late 70’s for psychotherapy
• Popular at raves
• Mood elevator
• Raises blood pressure, heart rate, body
temp.
Can be lethal
• Deaths reported from
dehydration
• Should not be taken if
any cardiovascular
disorder or high blood
pressure
• Synthetic
intermediates have
unique odour
O
NHCH3
O
Anti ‘Parkinson’s’
Agents
OH
HOOC
H2N
H
OH
L - DOPA
N
CH2 C C
Deprenyl
Stereochemistry is important
• The D-isomer of DOPA is inactive!
• Synthesis of Chiral Drugs is now a major
effort in Pharmaceutical Industry
• Avoids possible harmful effects of other
“handed” version-Thalidomide tragedy in
early 1960’s
Ritalin(Methyl Phenidate)
• Prescription drug for
ADHD (attention
deficit hyperactivity
disorder)
• CNS stimulant-details
of mechanism of
action not yet known
• BUT………………
COOCH3
CH
When end of term comes
• The little white pill
Ritalin: “Competitive edge?”
• U. Vic students using it as a “cognitive
enhancing drug” (Metro, Ottawa 2008)
• “brain doping”
• Boosts studying powers
• Ethical issue: unfair advantage??
• Nature: 2008 study~20% of students using
drugs such as “Provigil” to fight fatigue
Placebos - the
Power of the Mind
A placebo is a harmless and, normally, ineffective
substance given to someone who complains of a
particular ailment, simply to please and pacify them.
The placebo effect - people experience typical drug
effects when they believe they have taken a drug but
actually have not (in pain relief maybe endorphins).
In general, ~30% placebo effect
Can a positive mental attitude 'cure‘ a disease?
Placebo Effect
- the Test !
The Double-Blind Study –
Divide, randomly, a large
number of people into two
groups:
1) the control group receives a placebo,
2) the test group receives authentic medication
Two sets of examiners, each 'blind' to the other:
1) codes each pill,
2) distributes the pills to the two test groups
Other Morphine Analogs
N
Demerol
(spinal ‘taps’)
CH3
N
O
O
Methadone
(withdrawal therapy)
H3C
O
H
N
O
N
N
Fentanyl
(70% of surgery in USA)
CH3O
Dextromethorphan
(cough suppresant)
Endorphins - Natural Human 'Narcotics'
It was discovered(1973), from research on opiate
receptors, that the human brain has its own
narcotic analgesics. These are small peptides
named endorphins/ enkephalins(pentas) that
selectively intervene with signals of deep, severe
pain but not other nerve signals.Twist into same 3D
shape to fit on same 'receptors' as morphine.
Effects(?): pain relief from acupuncture
'high' experienced by marathon runners
no pain for wounded soldier during battle
An Enkephalin
Morphine
analog
?
O
H3N
N
H
H
N
O
O
N
H
H
N
O
pentapeptide
HO
O
Receptors: polysaccharides/polypeptides attached
to cell walls to receive/fit specific molecules that are
'messengers/signals' for some specific metabolic
reaction.
eg. when opiate receptors interact with narcotic
molecules some signal flowing through the nervous
system is blocked/altered.
Antagonists are compounds that counteract/block
the action of a drug; eg. for heroin.
Agonists are molecules that mimic the action of a
drug(but usually not all the actions of that drug).
Humans…. Successes & Failures
Psychoactive/psychotropic drugs have some effect
on the human mind/mental processes.
In NA 1 of 10 people suffer from 'mental illness' and
receive much relief from psychoactive drugs.
Worldwide: ~$400 billion/yr spent on 'illegal' drugs;
more than is spent on food.
In USA: ~$200 billion/yr; ~25% on heroin(from mid& far East).
Worldwide: cocaine = ~2000 tons/yr(75% from
central/south America); ~70% is consumed in US
Psychomimetics
- 'Downers'
 Sedatives(+!) :
barbiturates,
carbamates
 Depressants: ethanol
 Anesthetics(?) :
glue/gasoline sniffing
 Tranquilizers(antianxiety): benzodiazepines,
buspirone
 Antipsychotics(anti-schizophrenia): reserpine
(Indian snakeroot), chlorpromazine, Li2CO3;
also narcotics
Antipsychotics for
Schizophrenia, etc.
N
N(CH3)2
Cl
S
chlorpromazine
CH3O
OCH3
OCH3
N
N
H
O
CH3O
reserpine
O
O
OMe
OCH3
Benzodiazepines/Diazepams(GABA enhancers)
CH3
N
Cl
O
N
Diazepam
(Valium)
N
-O
+
N
O
H
N
O
Cl
N
Lorazepam
(ativan)
O
N
N
N
N
O
N OH
Cl
F
Rohypnol
(date-rape drug)
N
O
H
Buspirone
Sedatives (GABA agonists)
O
H2NC O
O
O CNH2
Carbamate =
Meprobamate(Equanil, Miltown)
O
O
N
N
O
S
N
N
O
Phenobarbital
(Luminal)
O
= Barbituates
= Thiopental
(Pentothal)
Psychomimetics
- 'Uppers'
 Antidepressants:
Zoloft, Prozac,
Nardil(MAO),
Elavil;
also L-Dopa/Deprenyl
 Stimulants: cocaine, adrenaline/epinephrine,
amphetamines(benzedrine, methedrine
(speed/ice); also caffeine, nicotine, ritalin,
? Hallucinogens: LSD, marijuana, PCP(angel
dust), mescaline, psilocin
Antidepressants
NHCH3
Cl
Zoloft1
(sertraline)
Prozac1
(fluoxetine)
Cl
CH2CH2 NHNH2
Nardil2(phenelzine)
2008 Study on Antidepressants
• Prozac only effective on extremely
depressed patients
• No effects on moderate or low depression
vs. placebo
• But: if presently on antidepressants, should
not abruptly stop use
• But……………………
Geriatric depression
• Often successfully treated with Zoloft
• Commonly used in Nursing Homes
Endorphins and the Placebo effect
• Brain scans have shown that brain
chemistry is altered when placebo’s are
taken.
• Release of endorphins –causes pain relief
Hallucinogens
CON(C2H5)2
OH
N(CH3)2
NCH3
N
H
Psilocin
(‘magic mushrooms)
HN
Lysergic acid
diethyl amide
(LSD)
OCH3
H3CO
NH2
OCH3
Mescaline(peyote cactus)
Phenylcyclidine
N
PCP
(Angel dust)
veterinary anesthetic