17. Medicines, Drugs - part 2

The Pharmaceutical IndustryWorldwide, in 2007,~ $800 billion was spent on legal/ ethical 'medications‘ (doesn't include vitamins/minerals/herbals). By 'continent': N.America ~44%, W.Europe ~25%, Japan ~16%,

Latin America ~ 6%, Asia Pacific ~4%, other ~6%

NB. Where is Africa?? No money; not important!

OTC - from A(antacids) to Z(zits)

Est. ~75% of all 'illnesses' are treated from the drug-store shelves. In USA ('97) there were: 144 categories; ~2000 compounds(some 'inactive')

~300,000 formulations/products.

OTC = Over The Counter, ie. non-prescription

North Americans self-medicate ~10x/mo/person

Over The Counter (OTC) Cold Medications

Type of Ingredient Name

Decongestant Pseudoephedrine

Antitussive Dextromethorphan (cough suppressant)

Expectorant Guaifenesin (loosen fluids in cough)

Analgesic/Antipyretic Acetaminophen (diminish pain/fever)

Antihistamine Chlorpheniramine

Caffeine Stimulant

OTC - Common Sense

• Choose single-ingredient products, specific for your condition • Save $$ - choose generics • Read labels; follow instructions • Pay attention to cautions and interactions with alcohol or other medications • Always mention OTC preparations to your MD

Or…. take chicken soup, gargle with salt/water, use a water vaporizer and get some sleep

Psychology and Drug Price

Expensive placebo’s work better than cheap ones!

• Double blind study: 2 placebos. Patients told cost of “new pain reliever” (10 cents vs 2.50 $per pill)

• Pain relief much higher in group taking the expensive pill

• Globe and Mail: March 2008

The Business of WellnessResearch/Development-synthesis 20 - 25% (~ 35% on Human Clinical Evaluation for DIN - Drug Identification Number) Production/Scale-Up ~20% Patents/Licensing ~10% (17 yrs for a 'brand name' patent) + ‘delays’ Marketing (Advertising) ~10% For every: 10,0000 - starting compounds 10 - to preclinical trials 5 - to human trials 1 - to market

New Product Development* 12 -15 years(7 yrs. of ‘clinical trials’) $300 - $400 million 3 of 10 'pay back' 'block-buster' = $1 billion(life-time sales) Some Companies: AstraZeneca, Bayer, Bristol Myers/ Squibb, Glaxo-Smith-Kline, Warner Lambert Hoffman LaRoche, Novartis, Merck(US), Pharmacia, Pfizer, G D Searle, Eli Lilly

In Canada: Merck Frosst, BioChem Pharma,(Apotex#)

Ratiopharm#. Proprietary/'Brand-name'* vs Generic#.

Brand/Trade - only by manufacturer (proprietary)

ie Tylenol , Motrin

Generic - generally accepted 'chemical name' (for 'easy' recognition by health professionals)

ie acetaminophen, ibuprophen

Patent protection

• Brand name is protected in perpetuity• Active component has protection for 17 years in

Canada• After that, Generic Co’s can make the drug and sell

it under another name• Many legal disputes (IP law) Gowlings in Ottawa• Polymorphs (different crystalline forms) can be

patented • New applications of old drugs can be patented

Brand names!

• Who thinks them up?

• Big business!!

• But getting tougher to find simple ones : beware of similarities

• Some are brilliant “Viagra” “Levitra” Celebrex (anti-inflammatory)

World Top 10 prescription drugs in 2008

• Lipitor Pfizer : lowers cholesterol 13.8B$• Plavix BMS: atherosclerotic events 8.3• Nexium AstraZeneca :Acid reflux symptoms 7.7• Serentide GlaxoSmith Kline :asthma 7.5• Enbrel Amgen: rheumatoid arthritis 5.6• Seroquel AstraZeneca: bipolar disorder,schizophrenia 5.1• Zyprexa Eli Lilly: schizophrenia 5.1

• Risperdal J&J : schizophrenia 5.0• Remicade Centocor: Crohn’s Disease, Rheumatoid arth. 4.7• Singulair Merck: asthmas, Allergies 4.6• Overall sales increase vs. 2007: 8.3%

Compounds with a common tetracyclicstructure and a variety of physiological functionsdepending on functional group arrangement.

Cholesterol(animal fat)OH

Steroids

Are all steroids anabolic?

• Consider cholesterol, cortisone etc.

Anabolic Steroids Promote rapid muscle growth & stamina (more workouts)

NHN

OH

O

O

4-Androstene-3,17-dione (Mark McGuire 90’s)

Stanozolol (Ben Johnson ’88 Olympics)

Detection: Mass Spectrometry of Drug metabolites in urine

• Each compound has a unique “pattern”

Male Sex Hormones (Androgens)

Testosterone: also in females ,but only~2 % of level in males; biosynthesized from cholesterol; affects libido in both!

Androsterone

OH

O

O

OH

The next generation of cheating

• Idea-just take more testosterone: undetectable because the body makes it anyway!

Doping in Sports: Testosterone

• Floyd Landis tests positive for abnormal amounts of testosterone: forfeits Tour de France cycling championship in July 2006

The tests and the Dope

• Testosterone (T) is an anabolic (muscle enhancing steroid)

• Epi-testosterone (E) is a stereoisomer, differing only in stereochemistry of the chiral centre in the D-ring, BUT it has no anabolic effects

• If T is administered, the excretion rate of urinary T increases and that of E decreases

Measure the T/E ratio in urine!

• The average for adult men is 1, and very rarely exceeds 4

• Landis had a T/E ratio of 11.

• Based on this test, he looks guilty

• But he claimed someone tampered with his urine

Adding epitestosterone

• Some have tried to beat the Urine T/E ratio test by taking in additional E

• Thus another test needed to be developed

Kinetic Isotope Effect (KIE)

• Biggest effect is in C-H vs C-D bond breakage

• Rates of C-D bond breaking can be up to 7 times slower than C-H

• Effects for 12C-H vs. 13C-H are obviously smaller, but bonds involving the heavier isotope are always harder to break

Other bonds to be broken

• 13C-O vs. 12C-O

• 13C-12C vs 12C-12C

Experimentally

• Rates of 12C vs 13C have been measured to differ by up to 8% in one reaction: 12C is always faster

• So enrichment 12C/13C =1.08 for one reaction

• If 5 reactions: enrichment =1.08x1.08x1.08x1.08x1.08 ie. 1.46 or 46%!

Isotope ratio test (new ~2004)

• Synthetically derived T has a slightly lower amount of the 13C isotope than does T produced in the body (Because more reactions needed to make it synthetically than in the body) : 13C isotope reacts more slowly than 12C).

• This is the well known Kinetic Isotope effect!

• Mass spectrometry (detects isotopic abundances) used to measure the 13C to 12C ratio in testosterone Landis also failed this test………..verdict GUILTY

Manny Ramirez : LA Dodgers

May 12, 2009 Manny gets caught!

• Urine showed elevated testosterone level

• Also high testosterone/epitestosterone ratio; between 4:1 and 10:1

• Synthetic or “Manny made”?

• World anti-doping lab (Montreal) asked to do carbon isotope test-find low 12C/13C ratio

• Result: Manny used synthetic testosterone

• 50 game suspension (without pay) by MLB

Female Sex Hormones (Estrogens)

OH

O

OH

OH

OH

O

Progesterone (‘pregnancy hormone)

Estrone

Estradiol

Steroids cont’d: Evolution of the BC pill

• 1st step (1960’s) progesterone (pregnancy hormone, prevents ovulation) was administered

• Worked well if injected, but not effective if taken orally; not acceptable for mass use

• Synthesis of “progesterone like” compds• Similar structure except for D ring

substituents

Progestins

• Stopped ovulation • Could be taken orally• But small amount of “breakthrough bleeding”• Inclusion of a small amount of estrogen

controls this• “Combination Pill” : Progestin and estrogen• Dosage 1/day for 21 days, off for 7, can miss

one

‘The Pill’ (Birth Control)

OH

OH

O

OH

Ethynylestradiol (synthetic estrogen)

Norethindrone (synthetic progestin)

+

Side effects of the Pill

• “minor”: headaches, some dizziness

• “major” : combined with smoking, risk of blood clots

• Risk increases with age and long term use

The morning after pill RU-486

• Blocks the implantation of a fertilized egg in the uterine wall

• Developed in France

O

OH(CH3)2N

Antibacterials and Antibiotics

Many OTC and some prescription: growing problem of resistance to

antibiotics!

Dr. Joseph Lister

• UK 1871

• found that mould inhibited growth of bacteria

• “discovered” antiseptic surgery by killing bacteria

• “Listerine” named after him

Listerine and other mouthwashes

• Often contain up to 25% alcohol

• Long term use of high alcohol mouthwashes increases risk of oral cancer

• Does Listerine kill germs? Yes, but many more remain

• Salt water rinse an effective alternative

• Or use enzyme based ones

Serious infections: gingivitis, trench mouth

• Require much stronger mouthwash than any OTC available: See your Dentist or MD

• Careful tooth brushing and flossing and thorough rinsing with water are best preventative measures

Sulfa Drugs: the 1st antibacterials

• Benzene sulfonamides-not antibiotics, but did inhibit bacterial growth by disrupting folic acid synthesis

• Developed in Germany 1932 (1st wonder drugs) could be applied as powders to wounds in the field WWII.

• Superceded by less toxic antibiotics in 1944

isolated from moulds or bacteria, eg. penicillins, cephalosporins, erythromycin, streptomycin, but sometimes 'synthetic', eg. chloramphenicol, fluoroquinolones Antibacterial agent = antimetabolite (starves the bacteria, often of folic acid), eg. sulfa drugs

Antibiotics - the Wonder Drugs

Antibiotic = a compound that kills bacteria (by destroying bacterial cell walls.

Discovery of penicillin(20th century’s most important one?)

1928 , Alexander Fleming grew Staphylococcus bacteria on an agar medium

• Noticed inhibition of bacterial growth around a blue-green mould accidental contaminant

1928-1940

• Fleming grew a pure mould culture: discovered it was Penicillium notatum

• Later isolated the pure chemical “antibiotic”component, named it “penicillin”

• But needed a good large scale source of the mould

Antibiotics – Mass production of penicillin

-following a world-wide search, a mouldy canaloupe in Peoria Ill, in 1942 was found to contain the highest quality penicillin!

Led to mass production(start of Pfizer) 2.3 million tons available to Allied Soldiers for the Normandy invasion in 1944.

Penicillins('28-'44) - the -Lactams

The first class of 'broad spectrum' antibiotics; still the most prescribed worldwide.

S

N

COOHO

NHO

R

Penicillin – the general structure

Alexander Fleming 1881-1955

• Nobel Prize for Medicine/Physiology in 1945

• Knighted in 1944

Penicillin from fermentation

• Pharmaceutical grade obtained

The Process

• Start “cold stored” penicillium culture on agar plate• Transfer to “shake flasks” ,with food (Sugars) and

nutrients (ammonium salts), aa’s needed for growth • Resulting suspension can be transferred to seed

tanks for further growth• Transfer to larger fermentation tank (30,000 gallons)• After 3-5 days , isolation• Temp, pH, mixing essential, sterilized air pumped

in.

Semi-synthetic derivatives

• Original penicillin was excreted too rapidly-urine recycling in early patients for recovery of the drug

• Chemists modify original structure for different properties and bio-availablity

the 'Evolution' of Penicillins - 1 step ahead!

S

N

COOHO

NHO

R

CH3O

CH3O

NO

Cl

NO

CH2

CH2 O

CHNH2

CH

NH2

OH

penicillin G

penicillin V

ampicillin

amoxicillin

methicillincloxacillin oxacillin

Incapacitating those 'Nasty Bugs'

• -lactams(penicillins) - breakdown cell walls

• tetracyclines/erythromycin/streptomycin - inhibit various aspects of protein synthesis

• fluoroquinolones('cipro') - inhibit DNA replication

Varied structures indicate varied 'mechanisms' to kill bacteria. eg.

Some Antibiotics and Their Uses

Penicillins – ear/skin/respiratory/digestive/urinary infections, syphilis, scarlet fever. Tetracyclines – respiratory/urinary infections, acne, bronchitis, whooping cough, typhus fever. Cephalosporins – ear/throat/skin/urinary infections Chloramphenicol – typhoid fever, meningitis, eye/ear infections Erythromycins – skin/eye/respiratory/tissue infections, diphtheria. Spectinomycin – gonorrhea Gentamycin – bone/skin/lungs/abdomen infections

OTC Antibiotics

C

CHNH2

CH3

CHCH2CH3

O

L-Asn D-Asp L-His

L-Lys D-Orn L-Ile

L-Ile D-Glu L-Leu

D-Phe . . . . . . . . . . . . .

OH

NH2

O

OHOH

O

O

OHOH

CH2NH2

ONH2O

NH2NH2

O

OH

CH2NH2

HOH2C

NH

NH2

O

O

N

S

Cl

COOH

Bacitracin

Cefaclor(cephalosporin)

Neomycin

Some Tetracyclines;prescription needed

CH3

O OH OOH

OH N(CH3)2

OH

CONH2OH

OOH

Cl N(CH3)2

OH

OOH

CONH2

OH CH3

OH

Chlorotetracycline (Aureomycin)

Doxycycline

Partly due to overuse*(abuse?), partly because bacteria have short life-cycles there is a serious

and increasing problem of emergence of antibiotic-resistant bacteria.

*In 1999 EU used 4700 metric tons of antibiotics for farmed animals(35% of total; ~50% in NA!)).

•There are antibiotic-resistant strains of malaria, TB,

typhoid, and gonorrhea (1 in 7 new cases!). •TB is increasing in NA, especially among poor. • More reports of 'killer staph infections' in hospitals.

(C-Difficile)

Antibiotic Resistance - can we win?

Anti-malarials

Malaria:infects 300-500 million /year

~2 million deaths (mostly Sub-Saharan Africa)

Transmitted by female Anopheles mosquito

Microscopic parasites in saliva-multiply in human red blood cells

Why no antimalarial drug?

• Viewed as an African problem

• No money in it for the Pharmaceutical industry

Quinine and malaria treatment

• Used since ~1600, in bark of S.A.cinchona tree

• Isolated and named in 1817 (Inca for bark “quina”

• Inhibits the parasite’s heme polymerase

• Not recommended for malaria prevention because of side effects and poor tolerability

• High dosage required 8mg/kg every 8 hours: or .56g x3 = 1.68g/day for 70kg person

• If therapy is stopped, relapse occurs

Quinine

• An alkaloid

• Also antipyretic, analgesic, anti-inflammatory, anti-smallpox

Quinine in Tonic Water

• British “colonial’ days-quinine was added to water in an attempt to prevent malaria

• Still present~ 20mg per can

• Need ~ 80 gin and tonics to get proper dose

• Bitter taste-so add gin and lemon/lime!

Tonic water

• ~80 cans per day to treat malaria!

Synthetic Antimalarial drugs

• Chloroquine

Chloroquine

• Used to prevent and treat malaria• BUT…many adverse side effects: itch, mood

changes, blurred vision• Dangerous in overdose: doubling the normal

dosage can be fatal• Malaria parasites now have developed

widespread resistance to it• New drugs needed

Perhaps some hope for Africa

• International Public-private partnership funding research on antimalarial drugs

• Chinese antimalarial herbal medicine extract “Artemisinin”

But too expensive to extract

• Synthetic analogues being made

• Hoffman La Roche (Basel)

• OZ277 looks promising

Development of OZ277

• Funded and coordinated by Malaria Venture (Swiss non-profit organization)

• OZ277 being synthesized in India by Ranbaxy Laboratories on multi-kg scale

• Kills the malaria parasite

• Peroxide unit essential for activity

DDT; An effective insecticide,but…….

• Some resistance to it now shown by Anopheles mosquitos

• Use curtailed in 1970’s : environmental pollution

• WHO currently advises use of 12 different insecticides, including DDT

• Bednets also effective, since Anopheles feed at night

World’s Top 10 Therapies 2008 (# of prescriptions:in order)

• Anticancer• Lipid regulators• Respiratory agents• Anti ulcer• Antidiabetic• Antidepressant• Antipsychotic• Heart drugs• Anti-epileptics• Erythropoieten (EPO) : Stimulates red blood cell formation

in premature infants (also used illegally in blood doping)

Drugs by Physiological Function

• Central Nervous System (CNS) Activea) anesthetics, b) hypnotics & sedatives, c) for psychiatric disorders, d) convulsive disorders, e) muscle relaxants, f) analgesics & antipyretics, g) CNS stimulants

• Local Anesthetics • Drugs Acting at Nerve Junctions • Allergenics • Cardiovascular Drugs a) digitalis, b) antiarrythmics, c) vasodilators, d) antihypertensives, e) anti atherosclerosis • Renal (kidney) Function

Drugs by Physiological

Function….cont’d

• Uterine Action • AntiParasitics • Hormones • Vitamins • Antiviral Agents

• Blood Related Diseases • for Neoplastic (eg. cancer) Diseases • AntiMicrobials: synthetic & natural antibiotics • Digestants, Antiseptics/Fungicides

Intrabody Communication

Two major lines of chemical communication between our external and internal environments 1) CNS - neurons/synapses/neurotransmitters 2) Circulatory System - O2 transport, antibodies, hormones, etc.

Hormones = chemical messengers Produced in special(endocrine) glands, transported through circulatory system to other parts of the body (heart, liver, kidneys, etc.) to influence a variety of

physiological effects(metabolism, reproduction, growth, etc.)

Some HormonesName Gland Structure Effect

HGH Oxytocin Thyroxine Insulin Cortisol Aldosterone Adrenaline Estradiol Progesterone Testosterone

Pituitary Pituitary Thyroid

Pancreas Adrenal Adrenal Adrenal Ovary Ovary Testis

protein peptide

a.a.deriv. protein steroid steroid

a.a.deriv. steroid steroid steroid

body growth uterine contract’n.

cell metabolism glucose metab. protein -> carbo

Na+ concn. emergency stimulus stimul. female

char. reg. menst. cycle. stimul. male

char.

HGH

Another illegal “supplement”

Dangerous side effects

Lyle Alzado (NFL) Brian tumors

Legal supplements for atheletes

• Creatine, an amino acid (body makes~1-2 gr/day)

• Seems to produce an increase in creatine phosphate, which is used to convert ADP to ATP, the main E source for muscle cells

• Used medically to treat ALS (degenerative muscle disease)

Creatine

• Highest selling supplement ever! No known hazards with long term use. Not a steroid/not anabolic.

HRT (Hormone replacement therapy)

• Menopausal women experience “hot flashes”

• Body is reacting to a decreased supply of estrogen

• “confused” hypothalamus: part of the brain controlling appetite, sleep, temperature and sex hormones)

Solution: HRT (or is it?)

• Until 2002, estrogen was given to stop hot flashes and also to help with bone density issues

• Drug used was “Premarin”, a mixture of estrogen like compounds (Wyeth Pharmaceuticals)

• Origin pre…..mar…….in extracted from….?

Pregnant Mares Urine

• ~22,000 in Canada’s PMU farms

HOT hormones

• Estrone (a ketone in D ring) isolated from PMU has similar have ~same activity as estradiol, the principal human estrogen

Dangers of HRT (2002) Study

• Women’s Health Initiative (WHI) report sponsored by NIH in USA

• Extended use of estrogens in HRT increases risk of heart attack, stroke, breast and uterine cancer

• Decisions: do benefits outweigh risks???

• Many women still think so.

Steroids from the Adrenal Cortex

Aldosterone (mineralocorticoid) - regulates exchange of Na+, K+, H+ in most cells; promotes water retention

(Hydro)cortisone - controls glucose prod'n in all cells; (glucocorticoid) inhibits inflammatory response in cells (dilate blood vessels-redness & swelling) =>=>=>

O

CH3 H

OCO

CH H

H

OHCH2OH

Corticoids or corticosteroids (anti-inflammatory)

OHO OH

OH

O

OHO OH

O

O

Cortisone(adrenal cortex)

Prednisone (synthetic: one C=C extra)

Cortisone and Prednisone: Steroidal Anti-inflammatory drugs (SAID’s)

• Both cortisone (natural: injected) ) and Prednisone (synthetic: pills) act almost instantaneously to reduce inflammation in joints and other body tissue

• Wonder drugs???..............unfortunately not

Many side effects include

• Sodium ( hence water) retention --swelling• Increased appetite• Increased fat deposits• Sweating at night• Acne• Depletion of immune system• Increased sun sensitivity• Increased hair growth• Candida (yeast type infection) growth (oral)

OH

OH

OH

OO

Cardiac Active Steroids

Digitoxigenin (aglycone) (isolated from Digitalis-foxglove plant)

Digoxin (the active form)

• Same structure as digitoxigenin except 3 glucose units bonded to C-3 of A ring

Why are many active steroids glycosylated?

• Facilitates transport across cell membranes and hence entry into the cell

Effects of Digoxin (Digitalis)

• Treatment of irregular heart beat

• But Digoxin has a narrow therapeutic index ie.only a small margin between effectiveness and toxicity

• Also potentially dangerous interactions with some antibiotics and adrenaline

Nurse Charles Cullen 2003

• Admitted to killing >40 hospital patients in NJ and Penn with overdoses of Digoxin

• Not eligible for parole for 396 years!

Nurse Susan Nelles (Ontario)

• Charged in 1981 with murder of 4 babies at Sick Children’s hospital by overdoses of digoxin

• Exonerated, no other charges laid

• Given honorary degree from Queens U. in 1999 for work in promoting integrity in nursing

Commercial synthesis of hormones

• Russell Marker (1903-1995)

• 1934 (Penn State U)

• Devised a 4 step synthesis of progesterone from tubers of a wild yam found in Mexico

• No $ backers in US (too risky!)

• Mexico City phonebook : “Laboratorios Hormona”

Diosgenin (YAM tuber extract)

Syntex Corporation

• Founded by Marker in 1944 in Mexico City

• Now based in Palo Alto CA.

• World’s largest commercial supplier of Steroids, Hormones etc.

Antiviral agents

• In general, viruses are harder to handle than bacteria!

Human Infectious Diseases

Bacterial Origin Viral origin

Cholera Diphtheria Dysentery Gonorrhea Plaque Syphilus Tetanus Tuberculosis Typhoid fever Whooping cough

AIDS Chicken pox Common cold Encephalitis Gastroenteritis Genital Herpes German measles Hepatitis Influenza

Measles Meningitis Mumps Pneumonia Polio Rabies Shingles Smallpox Warts Yellow fever

Viruses - the other Infectious 'Enemy'

A virus contains a core of DNA or RNA(never both) wrapped in a protective shell(usually protein, maybe some carbos/lipids). Does not have any 'functional/ reactive' proteins , thus cannot grow and reproduce by itself.

Viruses are parasites. They invade other organisms (the host), take over their 'metabolic machinery' to reproduce and eventually kill those cells and move on. Viruses do not have alot of metabolic reactions to 'mess up' chemically. What to do? =>=>

Fighting Viruses, #1 - VaccinesVaccination/Innoculation/Immunization*

A weakened strain of the virus is injected into the host so that antibodies can be produced against

that specific virus(an 'invading' compound). These antibodies are then always ready to protect against future exposure to that particular virus(sometimes!).

*Can occur 'naturally' if you survive an attack of, eg. chicken pox/measles/polio(!). But doesn't work for colds/'flu/HIV (many strains/always mutating).

Fighting Viruses, #2 - Antiviral agents

General: stop DNA synthesis with modified nucleic acids For HIV*: inhibit production of the protein sheath (proteases, reverse transcriptase inhibitors) with non-nucleosidic compounds(since ~'96)

*Worldwide: ~100 million people infected(Africa!) ~60 million already dead

O

OH OH

OHN

NN

NH2

O

O

N

N

NH

NNH2

O

OH

O

OHN

NH

O

CH3

O

N3

Typical ‘Nucleosidic’ Antivirals

Acyclovir(anti Herpes)

Ribavirin/Virazole (anti AIDS)

AZT(azidothymidine) (anti AIDS)

Arthritis and NSAIDSRheumatoid diseases occur when the body mounts

an immunological attack against its own tissue, usually connective tissue, eg. rheumatoid arthritis.

Controlled by cortisone-like steroidscorticoids), but to avoid 'side effects' from prolonged use many

patients/physicians prefer NSAIDS* to alleviate pain, swelling and tissue destruction. Also 'side effects',

ie. kidney problems, intestinal bleeding.

*aspirin/ASA, (not acetaminophen/Tylenol),

ibuprofen/ Motrin, naproxen, diclofenac

Non Steroidal AntiInflammatory Drugs

O CH3O

COOH COOH

NH

Cl

ClCOOH

H3CO

COOH

ASA Ibuprofen

Naproxen (Aleve)

Diclofenac

NSAIDS of Y2K: COX-2 inhibitors analgesics, anti-inflammatories AND minimize intestinal bleeding- block buster pain killers!

O

SO3Me

O

NN

SO3H

RVioxx (Merck)

Celebrex (Pfizer/Searle)

Deadly side effects of Vioxx!

• Sept 30, 2004, Merck pulled Vioxx off the market after its own research showed that the “blockbuster painkiller” doubled the risk of heart attacks and strokes

• Massive lawsuits filed by >47,000 plaintiffs

• Nov 9, 2007. Merck agrees to pay 4.85 Billion $ to settle these suits, but only binding if at least 85% of all plaintiffs agree

Immune Response - Antibody vs Antigen

An antibody* is a specific protein(immunoglobulin, -globulin) that is synthesized by white blood cells(B-

lymphocytes) to eliminate/inactivate a pathogen that enters our body. These 'invading' compounds are usually disease-bearing bacteria or viruses. The

'action' occurs in the extracellular fluids, including the circulatory system.

The invading material that causes antibody generation is termed an antigen.

* often lasts indefinitely; we can immunize with a vaccine (weakened virus or bacteria).

If the 'invading material' gets by this first line of defense and enters a cell, eg. a virus, then another

immune system springs into action, the T-cells.

If the T-cells get inactivated, eg. by HIV, then the result is Acquired Immune Deficiency Syndrome

(AIDS). That person has no immune protection and eventually succumbs to some disease.

Antibody - Antigen complex

Immune Response - the Down Side

The immune system cannot distinguish 'good' from 'bad' antigens. Hence organ transplants can be 'rejected' so that immuno-suppressants must be used with potentially dangerous consequences.

An overactive or misdirected immune system can attack its own tissue, eg.

• multiple sclerosis(nerve sheaths) • rheumatoid arthritis(connective tissue in joints) • type1 diabetes(cells for insulin in the pancreas)

Allergies - Immune Response Reversal

The body generates an antibody to some antigen. On subsequent exposure when the antibody/antigen reaction occurs, certain cells(especially in nose and bronchial system) are disrupted and release some

potent chemicals of which the best known is histamine(from the amino acid, histidine).

These particular antigens are called allergens.

Often the effects are minor, eg. runny nose, itchy

eyes, sneezing and can be suppressed by taking an antihistamine. About 10% of NA suffer from some allergy; about 2 million Canadians have 'hay fever'.

Antihistamines - OTC Bestsellers

N

NH

NH2

N

NH

SNHN

H

NNC

N

OHOH

Ph

Ph

R

Histamine

Cimetidine(Tagamet) Terfenadine(Seldane), R=CH3

Fexafenadine(Allegra),R=COOH

Anaphylaxis - Life-threatening Allergies

Allergic reactions can intensify to sore throat, skin rashes and migraines.

Food allergies are particularly difficult to diagnose.

Life threatening effects include constricted breathing and severe blood pressure drop(requiring immediate injections of adrenaline and /or

prednisone) and are termed anaphylaxis. Often these reactions are associated with penicillin, insect

venom, shellfish and nuts

NHCH3

OH

Asthma – a Bronchial AllergyAsthma is an allergic reaction that causes swelling of the bronchial passages and lungs. The most effective treatments(still symptomatic) are to reduce swellings with anti-inflammatory steroids or enlarge restrictions

by bronchial dilators(ephedrine or albuterol).

D = ephedrine(dilator) L= pseudoephedrine (decongestant)

Heart Disease : A major killer

Multifaceted: Heredity and lifestyle both important

Keeping your Heart Pumping

In NA 'heart disease' causes ~40% of all deaths accounts for ~40% of all prescription drug sales (~$100 million) Don't be a statistic: no smoking, not overweight, adequate 'cardio' fitness

keep sodium/alcohol low, lots of 'natural' antioxidants.

In 24hrs the human heart pumps 8000L of blood and beats 100,000 times (~70 beats/min)!

Heart Disease - multifacetedMajor categories(interrelated): ischemic coronary artery disease (inadequate O2 to heart) heart arrhythmia(abnormal heart beat) hypertension(high blood pressure) congestive heart failure

'Heart medications' try to: increase blood(O2) supply normalize rhythm lower blood pressure prevent blockage of blood vessels

Vascular BlockageFor blood clots or thickness

Mild: platelet inhibitors(thinners), eg. aspirin Medium: anticoagulants/anticlotting, eg. heparin, warfarin(rat poison) Severe: thrombolytics('clot busters' or 'clot eating' enzymes), eg. streptokinase, plasmin

For blockage by fatty plaque(artherosclerosis) divert/slow cholesterol production in liver with cholesterol-lowering drugs, eg. Lipitor (a '...statin')

Keep the Blood Flowing!

O

O O

OH

O

OOH

O

O

Warfarin (anti coagulant)

a ‘…statin’ (anti-cholesterol)

Hypertension - many causes, many 'cures'

Eliminate water - decreases Na+, decreases blood volume; use diuretics, eg. thiazides Eliminate angina(chest pain) - expand blood vessels; use vasodilators, eg. nitroglycerin Slow down stimulation(adrenaline) of heart muscle by blocking -andrenergic receptors; use '- blockers', eg. propanolol Control Ca++ involved in muscle contraction; use Ca channel blockers, eg. nifedipine Control Angiotensin(pressure elevating 'factor'); use ACE inhibitors, eg. captopril(a '….pril')

AntiHypertensive Heart Medications

SNH

NH

Cl

SO

ONH2

O O

CHCH2ONO2

CH2 ONO2

ONO2

N COOH

OCH3

SH

H3CO2C

CH3 CH3

CO2CH3

NO2

NH

O NH

OH

Hydrochlorothiazide

Nitroglycerine

Captopril

PropanololNifedipine

Heart Attack! (Myocardial Infarction)

Relief of severe pain use strong analgesics, eg. morphine, demerol (narcotics!) Control heart beat Too slow; use stimulants, eg. adrenaline, atropine, digoxin Too fast; use sedatives/tranquilizers Irregular(arrythmia); use smooth muscle relaxants, eg. lidocaine

Cancer = out-of-control cell growthCan be benign or malignant. Can affect almost every organ/tissue. Over 100 different 'types'

WHO estimates causes as: 80-90% 'environmental' (30% cigarette smoking,

30%diet/lack of exercise, 10%occupational

exposure, etc.) 10-20%genetics & viruses ~20% of NAmericans will contract some form of cancer. Some success in establishing 'cures', eg. skin, Hodgkin's, childhood leukemia, but some 'failures', eg. lung, pancreas. Early detection is critical but difficult.

Cancer Deaths in Canada (2002, est.)

Cancer - starts with DNA damage(?)

Fairly general agreement that DNA damage (radiation, viruses, chemicals) is the cause.

Two 'suspects' are mutations of: oncogenes, that promote cell growth tumor supressor gene, that inhibit cell growth

How to Stop it(?)

Try to remove all 'out-of-control' cells and allow normal cells to regain control -

1) remove by surgery 2) kill with radiation

3) kill by using chemotherapy

Cancer Deaths – some good, some bad!

women men

Oral Colon/rectum Pancreas Lung Melanoma Breast Cervix Uterine Ovarian Prostate Testis Bladder Leukemia

Cancer – 5 year Survival Rates(%)

51 55 3 13 81 75 66 82 39 72 90 77 33

Cancer Chemotherapy - some Generalities

Inhibit blood supply

DNA 'modifiers': cross-link, eg. cis-platin; alkylating agents, eg. cyclophosphamide(from 'mustard gases); 'fake' nucleic acids, eg. 5-fluoro uracil, 6-mercaptopurine; change shape(doxorubicin)

Interfere with an essential nutrient of the cell, eg. methotrexate for folic acid uptake

Cancer Chemotherapies - GeneralOH

OH

O

O

CH3

NH2

O OH

COCH2OH

OH

O

OCH3

N(CH2CH2Cl)2P

O

NH

O

Pt

Cl

NH3

Cl

H3N

Cyclophosphamide

CisplatinDoxorubicin

Cis-platin: mode of Action

• Pt binds to N atom of guanine DNA base

• Disrupts out of control (and normal) protein synthesis

• Side effects: hair loss

NH

NH

O

F

O

N

N

N

NH

SH

N

N

N

NNH2

NH2

N

CH3

NH

O

COOH

COOH

Cancer Chemotherapies - General

5-Fluorouracil

6-Mercaptopurine

Methotrexate

Cancer Chemotherapy - Specifics

vincristine(leukemia), taxol(ovary, cervix), tamoxifen(breast), actinomycin(Hodgkin's),

estradiol(prostate), testosterone(breast)

Cancer Chemotherapies - Specific O

O

CH3CO OOH

OOC6H5C

O

OH

OC6H5

O

OH

NH

O

C6H5C

O

O

C6H5

C6H5

N(CH3)2

Taxol

Tamoxifen

Taxol (semi synthetic)

• Isolate from bark of pacific Yew tree, then modify it chemically

• Acts by cutting off blood supply to tumor

Thalidomide(early ’60’s)

Chirality in Drugs

D = antidepressant (morning sickness)

L = teratogen (birth defects)

NH

N

O

O NH

O O

H

NH

N

O

O NH

O O

H

Differing Opinions

• US Pharmaceutical Co. Smith , Kline, French rejected thalidomide as a “useless drug”

• German/Swiss firm of CIBA-Geigy deemed it useful and rat studies showed no adverse effects of either isomer. “Not toxic” LD50 value 600x higher than NaBr.

• Market approval in 1959

Tragic results of selling the mixture

• “Suffer the Children” (1979) Andre Deutch pub. Insight team of London (UK) Times

• On Canadian Market April /61 until March/62

• Taken off market 3 months after Europe banned it due to severe teratogenic effects if taken during the 1st trimester of pregnancy

The return of Thalidomide (1992)

• Now marketed in pure D form. Used to treat complications arising from bone marrow transplants

• Used in treating leprosy

Ibuprofen: prototypical NSAID

Albuterol (Ventolin, bronchial inhalers)

(+) = analgesic (-) = no serious side effects

D = bronchial dilator L = serious side effects

Mixture removed in ’90 & chiral isomer introduced in ’96.

COOH*

OH

OH

NHC(CH3)3

OH

*

Chiral Synthesis

• Biggest challenge in Organic chemistry

• Devise ways to produce only one “handed form” of a molecule (saves $, materials) and side effects of unwanted isomer

• Use Chiral auxillaries (templates)

2001 Nobel Prize in Chemistry

• Barry Sharpless (Scripps, MIT) Chiral epoxidation

• William Knowles (Monsanto), Ryogi Noyori (Nagoya Univ.) : chiral hydrogenation using a chiral rhodium catalyst

• Led to 1st commercial Synthesis of L-DOPA (Parkinson’s) with no D isomer

Global Sales of Chiral Drugs

• Annual sales of single enantiomer (ie handed drugs) expected to be 15 Billion $ in 2008

• Syngenta (Swiss) operates the largest scale chiral hydrogenation plant in the world