DRUGS

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15. Medicines, Drugs -
part 1 chapter 23
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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.


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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 anti- inflammatories),
antibiotics, antivirals, heart disease,
allergies, anticancer, etc.
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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
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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.
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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!
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Salicylic Acid and Derivatives
petro- chemicals
(salicyl alcohol)
salicin (willow bark)
salicylic acid
methyl salicylate
acetylsalicylic acid
sodium salicylate
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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.
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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 1990s

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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

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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-infammatory
best for arthritis(NSAID)
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Other Analgesics
p-amino phenol
phenacetin(banned-kidney damage, etc.)
acetaminophen(Tylenol) not anti-inflammatory-
ibuprofen(Motrin/Advil) not anticoagulant-
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How Aspirin Works
arachidonic acid
COX2 enzyme
Aspirin
a prostaglandin induces pain, blood
clotting, labour, sleep regulation
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...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 gt
death) in children treated for 'fever' from
smallpox / flu. Solution - 'child-proof'
caps and warning labels on
containers have been very effective.
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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. caffeine, nicotine

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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
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Morphine Analgesic... and ?!
(Morpheus - Roman god of
dreams)
10 of dried juice (opium) from seed pod of
oriental poppy.

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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. doesnt interfere with the
transmission of a pain signal but changes the
reception of that signal.
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Morphine Analogs/Derivatives
Codeine - analgesic, not sleep inducing, not very
addictive?cough syrups
(55,000kg/yr) Heroin - euphoria, stupor,
analgesic, very addictive
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Morphine Analogs
morphine
codeine
heroin
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Other Morphine Analogs
Demerol(Meperidine) - less
nausea, spinal tap
Methadone - no stupor, blocks heroin 'rush',
addiction therapy (but addictive)
Dextromethorphan - non-addictive, antitussive
Fentanyl - analgesic/anesthetic in surgery (100x
morphine) Moscow hostage
incident(2002)
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Other Morphine Analogs
Demerol (spinal taps)
Methadone (withdrawal therapy)
Fentanyl (70 of surgery in USA)
Dextromethorphan (cough suppresant)
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Super Narc !
105 x morphine stops an elephant!
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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
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An Enkephalin
Morphine analog
?
pentapeptide
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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).
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Science Progresses
In 70s a chem. grad student made/ sold illegal
demerol and developed severe symptoms of
Parkinsons. Contaminated with MPTP, now
important for research.

MPTP (N-Me-4-Phenyl-1,2,5,6-Tetrahydro
Pyridine)
demerol
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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 gtgt
addictive increases stamina, reduces fatigue
gtgt used by Peruvian Indians to
'survive'(walking hours in snow with
heavy loads and little food) constricts blood
vessels, local anesthetic gtgt many
deaths from 'overdoses'
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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)
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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
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Cocaine Relatives
cocaine
atropine
scopolamine
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Cocaine Analogs
cocaine
Lidocaine(xylocaine)
Procaine(novocaine)
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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'
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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
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The PEA Connection
?-Phenylethylamine
Many psychoactive compounds contain the
?-phenylethylamine
substructure(or similar). PEA
itself induces a 'high' similar to 'being in
love'!
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Some CNS Neurotransmitters
(Nor)Epinephrine(Adrenaline) - stimulant, blood
pressure (NB.- agonist
enhances antagonist
depresses).
Serotonin - mood, appetite,
sensory perception, sleep, body
temperature
Dopamine - behavioural stability,
voluntary muscle coordination

GABA(?-aminobutyric acid) - inhibitory/modulating
effects
CNS has 12 billion neurons with 10 trillion
synapses 100 neurotransmitters each with several
functions
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Some Neurotransmitters
(nor)epinephrine
dopamine
?-aminobutyric acid
serotonin
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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
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Antipsychotics for Schizophrenia, etc.
chlorpromazine
reserpine
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Benzodiazepines/Diazepams(GABA enhancers)
Diazepam (Valium)
Rohypnol (date-rape drug)
Lorazepam (ativan)
Buspirone
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Sedatives - (GABA agonists)
Carbamate
Meprobamate(Equanil, Miltown)
Phenobarbital Barbituates
Thiopental (Luminal)
(Pentothal)
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Problem set assignments

• PS 7 Chapt 20 1, 18, 20 Poisons, toxins,
  hazards, risks
• PS8 Chapt 10 1, 5, 10, 12, 27 Acids and Bases

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Psychomimetics - 'Uppers'
? Antidepressants Zoloft,
Prozac(SSRI), Nardil(MAO),
Elavil(tricyclics)
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
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Stimulants
Benzedrine (N-CH3
methamphetamine methedrine/speed)
Phenylpropanolamine(PPA) diet loss, cold meds
(banned 2001)
Epinephrine(adrenaline)
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Silken Laumann

• Tested positive for PPA and lost her 1995 Pan Am
  gold medal
• Took Benadryl to fight a cold

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Bennies

• Benzedrine stimulants often used by Baseball
  players (pitchers) to get hopped up and put more
  speed on the fastball (they think!)
• Jim Boutons 1969 book Ball Four diary of life
  on road with NY Yankees, Seattle Pilots

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A must read for baseball fans

• Ball Four

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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

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Pseudoephedrine to crystal meth

• Remove OH group!

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But..when smoked in its crystalline form

• Produces effects similar to, but longer lasting
  than crack cocaine

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Devastating Effects

• After 10 years of use

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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

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Ritalin

• Prescription drug for ADD (attention deficit
  disorder)
• Used widely for treatment of hyperactive children
• BUT

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When end of term comes

• The little white pill

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Ritalin Competitive edge?

• U. Vic students using it as a cognitive
  enhancing drug (Metro, Ottawa Feb.11 2008)
• brain doping
• Boosts studying powers
• Ethical issue unfair advantage??

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Ecstasy

• Semi-synthetic, patented by Merck in 1914 and
  then abandoned for 60 years
• Used in late 70s for psychotherapy
• Popular at raves
• Mood elevator
• Raises blood pressure, heart rate, body temp.

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Can be lethal

• Deaths reported from dehydration
• Should not be taken if any cardiovascular
  disorder or high blood pressure
• Synthetic intermediates have unique odour

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Anti Parkinsons Agents
L - DOPA
Deprenyl
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Stereochemistry is important

• The D-isomer of DOPA is inactive!

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Antidepressants
Prozac1 (fluoxetine)
Zoloft1 (sertraline)
Nardil2(phenelzine)
Elavil3(amitriptylene)
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2008 Study on Antidepressants

• Prozac , Paxil etc. 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

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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.

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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?
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Endorphins and the Placebo effect

• Summer Barrett (2)
• Brain scans have shown that brain chemistry is
  altered when placebos are taken.
• Release of endorphins causes pain relief

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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
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Hallucinogens
Lysergic acid diethyl amide (LSD)
Psilocin (magic mushrooms)
Phenylcyclidine PCP
(Angel dust) veterinary anesthetic
Mescaline(peyote cactus)
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End of material for Quiz 2

• Friday March 14 at 530 PM
• Problem Set 9
• Chapt 23 1, 12, 18, 31, 32
• Answers posted on the course website

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Quiz 2 coverage

• From Chemistry of Cooking (slide 87 in unit
  10 to here).
• Final (April 24 _at_ 2 PM ) covers complete terms
  material