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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
Later survey: steroids (from sex hormones to anti- inflammatories), antibiotics, antivirals, heart disease, allergies, anticancer, etc.
Begin with: drugs that affect the brain and spinal cord (CNS, Central Nervous System), ie. for pain, fever, mood (stimulants, tranquilizers), also hallucinogens, narcotics.
Evolution of a Drug / Medicine
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
Investigate a 'folk medicine' Isolate the 'active ingredient' and prove structure
Aspirin - a Case Study
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.
The beneficial effects of willow bark have
been known for centuries:
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!
OO
CH2OH
CH2OH
OHOH
OH
COOH
OH
COOH
O CCH3
O OO
OH
CH3COO Na
OH
- +
Salicylic Acid and Derivatives
salicin (willow bark)
acetylsalicylic acid
sodium salicylate
methyl salicylate
(salicyl alcohol)
salicylic acid
petro- chemicals
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)
NH2OH
CHCOOHCH3CHCH2
CH3 CH3
CH3CH2O NHCCH3
O
Other Analgesics
p-amino phenolphenacetin(banned-kidney damage, etc.)
acetaminophen(Tylenol) –not anti-inflammatory-
ibuprofen(Motrin/Advil) –not anticoagulant-
COOH
O
OH
COOH
CH3
OH
How Aspirin Works
arachidonic acid
a prostaglandin induces pain, blood clotting,
labour, sleep regulation
COX2 enzyme Aspirin
...and (possibly) the UglyThere 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.
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
From Acids to Bases
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 addictivecough syrups (55,000kg/yr)
Heroin - euphoria, stupor, analgesic, very addictive
OOH OH
N
CH3
OCH3O OH
N
CH3
OO O
N
CH3
O
CH3
O
CH3
Morphine & Analogs
morphine
codeine
heroin
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)
Other Morphine Analogs
Naloxone: an “antagonist’-binds to heroin receptor site-used to treat heroin overdoses
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
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 - stimulant, intense euphoria, analgesic, addictive.
Scopolamine - “truth drug”, preoperative sedative
CO2CH3
O2C
N
CH3
OO
CH2OH
N
CH3
N
O
OO
CH2OH
CH3
Cocaine & ‘Relatives’
cocaine
atropine scopolamine
CO2CH3
O2C
N
CH3
NH2O2C
N N
NH
O
Cocaine Analogs
cocaine
Lidocaine(xylocaine) Procaine(novocaine)
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'
Addiction … Dr. Freud & friends
The PEA Connection
Many psychoactive compounds contain the -phenylethylamine substructure(or similar). PEA itself induces a 'high' similar to 'being in love'!
CH2 CH2
NH2
-Phenylethylamine
OH
OH
NH2
N
NH2NH2 COOH
OH
OH
NH(CH3)
OH
Some Neurotransmitters
(nor)epinephrine
dopamine
-aminobutyric acid serotonin
NH2
OH CH3
NH2
OH
NHCH3
OH
OH
Stimulants
Phenylpropanolamine(PPA) diet loss, ‘cold meds’ (banned 2001)
Benzedrine (N-CH3= methamphetamine
methedrine/speed)
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
O
NHCH3
OH
OH
HOOC
HNH2
NCH2 C C
Anti ‘Parkinson’s’ Agents
L - DOPA
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………………
CH
COOCH3
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 !
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
The Double-Blind Study –
Divide, randomly, a large number of people into two
groups:
N
O
CH3O
NH
N
CH3
OO
N
N
OCH3
Other Morphine Analogs
Demerol (spinal ‘taps’)
Fentanyl (70% of surgery in USA)
Methadone (withdrawal therapy)
Dextromethorphan (cough suppresant)
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
Endorphins - Natural Human 'Narcotics'
NH
O
O
NH
NH
O
O
NH
O
H3N
OH
An Enkephalin
Morphine analog
?
pentapeptide
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).
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
Humans…. Successes & Failures
Tranquilizers(antianxiety): benzodiazepines, buspirone Antipsychotics(anti-schizophrenia): reserpine (Indian snakeroot), chlorpromazine, Li2CO3; also narcotics
Psychomimetics - 'Downers'
Sedatives(+!) : barbiturates, carbamates Depressants: ethanol Anesthetics(?) : glue/gasoline sniffing
Antipsychotics for Schizophrenia, etc.
O
O
OCH3OCH3
OCH3
NH
N
OCH3O
CH3O
OMe
S
NN(CH3)2
Cl
reserpine
chlorpromazine
N
CH3
N
O
Cl NO
N
N
F
O
O
+-
N
N
O
Cl
Cl
H
OH
H
N
O
O
NN
NN
Benzodiazepines/Diazepams(GABA enhancers)
Diazepam (Valium)
Rohypnol (date-rape drug)
Lorazepam (ativan)
Buspirone
N
NO
O
O
N
NS
O
O
Sedatives - (GABA agonists)
O
C O O CNH2
O
H2N
Phenobarbital = Barbituates = Thiopental (Luminal) (Pentothal)
Carbamate = Meprobamate(Equanil, Miltown)
Psychomimetics - 'Uppers'
Stimulants: cocaine, adrenaline/epinephrine, amphetamines(benzedrine, methedrine (speed/ice); also caffeine, nicotine, ritalin, ? Hallucinogens: LSD, marijuana, PCP(angel dust), mescaline, psilocin
Antidepressants: Zoloft, Prozac,
Nardil(MAO), Elavil; also L-Dopa/Deprenyl
NHCH3
Cl
Cl
CH2CH2 NHNH2
Antidepressants
Zoloft1 (sertraline)
Prozac1 (fluoxetine)
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
NH
OH
N(CH3)2
NH
NCH3
CON(C2H5)2
NOCH3
H3CO
OCH3
NH2
Hallucinogens
Psilocin (‘magic mushrooms)
Lysergic acid diethyl amide
(LSD)
Mescaline(peyote cactus)
Phenylcyclidine
PCP (Angel dust) veterinary anesthetic