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