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Kent Quickstad, RPh.St. Luke’s Boise Medical Center

Boise, Idaho

ISHP Spring Meeting

April 12, 2014

An Abbreviated History of Pharmacy

Or

An Abbr Hx of Rx

History of Pharmacy

Doing something a bit different today

Nothing to disclose

Not an expert on the subject:

By definition I have not traveled over 250 miles to get here

Promise you I will not quote any “p” values or numbers needed to treat

And the important question …….

Ok, so let’s do some time traveling……

Lunch will be in about 1 hour

Time traveling – need traveling companions and a time machine

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Our traveling companions today:

Sherman and Mr. PeabodyThe Way Back Machine

……or we could wait until the movie comes out

Changes…..

often hard to keep up with

The hydrogen car

Changes are often the result of trial

and error

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Early references to drugs:

� Manufacture of beer

� Bible and ancient Greek and Roman writings referenced wine

� Use as a analgesic before operations

� Topical antiseptic

� Aid to digestion

� “Pick-me-up” tonic or stimulant after fainting episodes

� Oldest and most widely used drug in the world?

10,000 BC – Alcohol

Early references to drugs:

Cannabis sativa – the hemp plant – marijuana

Indigenous to central and western Asia

Described as a “delight giver” and “liberator of sin”

Focus of controversy thru history

WHO 147 million people of 2.5% of world’s population use annually

Legalized in 20 states plus the District of Columbia for medical use with a doctor’s recommendation and in 2 states (Washington and Colorado) for recreational use

3,000 BC – Cannabis

Pharmacy in ancient Egypt

“Pharmacy” – Egyptian term pharmaki and Greek pharmakon

Related to Egyptian word pharagia = the art of making magic

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The Ebers Papyrus

Undamaged scroll over 20 yards long

Medical treatise from ancient Egypt dates back to 1550 BC but contains materials from 5 – 20 centuries earlier

811 prescriptions – 700 drugs

Plant and animal materials interspersed with 12 references to spells and incantations – Begins with a prayer

Later documents have less references to spells – increased importance of drugs as the treatment of choice

Castor oil and senna – constipation

Poppy – induce sleep

Coffee 800s

Discovery of coffee is vague – based upon legend

Popular belief – 800s Arabian goat keeper observed “goats merrily running around instead of sleeping after feeding on coffee plant berries”.

1600s – coffee houses springing up through Europe

Second most consumed beverage in the world?

83% of Americans adults drink coffee – average 3 cups per day (USA Today 4/9/2013)

Starbucks – 2012:17,572 stores in 55 countries$13.29 billion annual revenue

The Middle Ages

Don’t know much about the Middle Ages,looked at the pictures and turned the pages…..

The Black Death – peaking in Europe 1348 – 1350

Killed 75 – 200 million peopleReduced Europe’s population 30 – 60%2010 – 2011 DNA evidence – pathogen gram-negative bacterium Yersinia pestis

Carried by Oriental rat fleasTransmitted by bites of fleas or through the air

Treatment – blood letting and boil lancing, burning aromatic herbs or bathing in rosewater or vinegar

Today – streptomycin, gentamycin, tetracycline, chloraphenicol, levofloxacin

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Apothecary

Term that came about in 1325 – 1375 in Middle English

Derived from the Latin apothēcārius seller of spices and drugs

A druggist; a pharmacist

A pharmacy or drug store

Digitalis

Digitalis purpurea (purple gloved finger – foxglove)Reported use in the 1400s

1775 – Dr. William Wethering – England – Investigated a herbal tea used for the treatment of “dropsy” – excessive accumulation of fluid form congestive heart failure – Isolated digitalis as the active ingredient

1785 – An Account of the Foxglove and Some of Its Medical Uses

Recognized toxicity and narrow margin between safety and toxicity

1800s - Careless use �number of deaths � fell into disfavor

1875 – digitoxin isolated 1930 – digoxin isolated

Today – Treatment of CHF and abnormal heart rhythms

1806 Friedrich Wilhelm Serturner - German apothecary apprentice

Isolated a chemical from opium that caused profound sleep in dogs

Morpheus – Greek god of dreams

Opium known as early as 2500 BC

Paregoric – tincture of opium

Early 1700s – diarrhea, expectorant, teething pain in children

1817 – Serturner isolated pure “morpheum”

Administered to himself and 3 young boys – all almost died from overdoses

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Morphine

Alkaloids isolated following morphine:

1818 – strychnine1820 – quinine1821 – caffeine1832 – codeine, atropine, colchicine1860 – cocaine1898 - heroin

Morphine – remains the gold standard against which all other analgesics are compared

Alexander Wood – Scottish physician – perfected the hypodermic syringe in 1853

Analgesic use exploded in American Civil War (1861- 1865)

Indiscriminate use – high post war morphine addiction“army disease” and the “soldier’s disease”

One Night Cough Syrup 1888

May 1886 – Coca-Cola

John Pemberton – Pharmacist from Atlanta, Georgia

“Pemberton’s French Wine Coca” – Popular nerve tonic, stimulant and headache remedy – sold in drug stores

Atlanta prohibition law – reformulation removed the wine and added sugar � possessing the “valuable tonic and nerve stimulant properties of the coca plant and coca nuts”

John Pemberton

Ideal “temperance drink” – cured morphine addiction, dyspepsia, neurasthenia and impotence

1890’s advertisementDrink Coca-Cola 5¢

Original formula contained caffeine in addition to an estimated 9 mg of cocaine per glass (removed in 1903)

May 1886 – Coca-Cola

34 mg of caffeine per 12 ounces today

Sold in approximately 200 countries worldwide

Most popular soft drink in the world today?

Las Vegas Strip Coca-Cola Museum

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Soda Fountains

Mainstay of drug stores and ice cream shops

“Glory years” 1890s – 1960s

Ancient Roman’s established settlements near natural mineral water carbonated springs for medicinal and therapeutic benefits(i.e. Bath, England)

Philadelphia 1809 – soda water sold in an apothecary for 6 cents a glass

Popular in American by end of Civil War

Associated with drug stores due to development of carbonated water by chemists and touted medicinal benefits

Ancient Greeks – Willow bark for fighting fever

Felix Hoffmann – Bayer in Germany Searching for a treatment for his father’s rheumatism and pain – chemically synthesizes a stable form of ASA

1899 – Bayer distributes ASA powder to physicians

1915 – ASA becomes available without a prescription and is manufactured as a tablet

1948 – Dr. Lawrence Craven – California GP – 400 men he prescribed ASA hadn’t suffered any heart attacks

“An aspirin a day” could dramatically reduce the risk of heart attacks

1897 Aspirin – acetylsalicyclic acid

1969 – Bayer ASA went to the moon with the Apollo astronauts

1970’s – ASA role of prostaglandin inhibition is discovered

1988 – FDA recognition of ASA for decreasing the risk or recurrent MI and TIAs

1996 – MIT invention survey – Twice as many people chose ASA as an invention then could not live without over the personal computer

1998 – Expanded evidence of low dose ASA in the prevention of cardiovascular disease

The most widely used drug of modern times?

1952 – Children’s chewable is introduced

Aspirin

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FDA history - the Beginnings

1906 – Pure Food and Drug Act:

Prohibited interstate commerce of adulterated or misbranded food and drugs

Drugs must meet standards of strength and purity

Division of Chemistry US Department of Agriculture, Washington DC 1883

1862 – single chemist in the US Department of Agriculture

1906 Upton Sinclair “The Jungle”

1916Heparin

1916 – Heparin discovered at John Hopkins University by Jay McLean and William Henry Howell

Heparin package, Connaught Medical Research Laboratories, 1950s

1935 – First human clinical trials

1937 – Heparin realized to be a safe, readily available and effective blood anticoagulant

“Miracle blood lubricant”

Pharmaceutical grade heparin is derived from mucosal tissues of slaughtered meat animals such and pig intestine or cow lung

Heparin

Anticoagulant – Prophylaxis and treatment of thromboembolic disorders

Pulmonary embolism, deep vein thrombosis, atrial fibrillation, myocardial infarction, cardiovascular surgery, coatings for catheters/laboratory tubes

Heparin – large molecule that targets the anti-thrombin IIa activity

Mid 1990s - Low molecular weight heparins (LMWH) target anti-factor Xa

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Advantages:

�Reduced risk of osteoporosis and heparin induced thrombocytopenia (HIT)

�Longer duration of action

�Administered on an outpatient basis

�APPT monitoring not required

Low molecular weight heparins

Lovenox – enoxaprin (3/1993)

Fragmin – dalteparin (12/1994)

Innohep – tinzaparin (7/2000)

Arixtra – fondaparinux (12/2001)

2008 heparin contamination and recall

2007 - 800 US injuries and over 80 deaths linked to allergic reactions with unfractionedheparin

2 x that as compared to prior years

Nausea, hypotension, chest pain, fainting, throat swelling

Contaminated heparin coming from Chinese manufacturing plants

Oversulfated chondroitin sulfate – found to make up 2-50% of total drug content of some of the samples tested

Baxter – supplier of about 50% of heparin sold in US – Limited recall January 2008 – then later recalled all heparin vials and flushes

Contaminate found in LMWHs in Europe but not in US or Canada

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2008 heparin contamination and recall

FDA mandate all heparin products coming into the US be tested for the contaminant

Overseas program “FDA Beyond Our Borders” – requires regulation of products where they are produced – program will start in China

Chinese manufacturing plant responsible was never inspected by the FDA

Deliberately added to the crude heparin or the result of sloppy production?

Google search “lawyers heparin recall” – 82,200 hits

The Pure Food and Drug Act of 1906 provided for which of the following requirements:

Quiz time – Have you been paying attention?

A) Prohibited interstate commerce of adulterated or misbranded food and drugs

B) Drugs had to be shown safe before marketing

C) Drugs must meet standards of strength and purity

D) A & C

E) All of the above

Yes! You have been paying attention

Fredrick Banting

1921Insulin

Hormone produced by the pancreas

Isolated in 1921 at the University of Toronto

Type I diabetes – death sentence

Treatment prior to insulin essentially starved the patients - children fed “a cup of cooking oil a day”

1922 – First human injection – 5 to 18 ml IMImpurities � Local reactions at injection site - Differing purity � hypoglycemia

1923 – Dr. Banting - Nobel prize in Medicine/Physiology

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Insulin

1936 – Protamine zinc insulin – 24 – 36 hours duration

1950 – NPH introduced

1956 –Tolbutamide (sulfonamides)First oral antidiabetic agents came on the market

1980 – Recombinant DNA “human” insulin was first tested in humans in England

1982 – Humulin R and Humulin N FDA approval to Eli Lily

2000 – Lantus approved to Sanofi Aventis

January 2006 – FDA approved Exubera (Pfizer) – First inhaled insulinMarketed in summer 2006

October 2007 – Exubera withdrawn from market due to lack of acceptance by patients and prescribers

Alexander Fleming(8/6/1881 – 3/11/1955)

1928Penicillin

One of the earliest discovered and most widely used antibiotics

1928 – Alexander Fleming – bacteriologist –St. Mary’s Hospital – London

Plate culture of Staph aureus contaminated with a blue green mold (penicillin

notatum)� killed bacteria

1929 – Fleming published his work noting that the discovery might have therapeutic value if it could be produced in quantity

Penicillin – The wonder drug

1939 – World War II

Howard Florey & Ernst Chain – Oxford Task of finding new medicines to treat wounded soldiers

Penicillin was being mass-produced in 1944

1940 – priceless1943 - $20 per dose1946 - $0.55 per dose

Penicillin

Fleming, Florey and Chain - Nobel Prize for Medicine in 1945

Countless number of lives it has saved

Opened door to other antibiotic development

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Antibiotics – A time table:

Between 1944 – 1972 – Human life expectancy increase by 8 yearsContributed to by the development of antibiotics?

Discovery of antibiotics over past 70 years(smellslikescience.com)

Peaked in the 1960sDevelopment taperingAntimicrobial resistance?Profitability for manufacturers?FDA approval?Infectious Disease Society of America initiative - “Bad Bugs Need Drugs” – 10 new systemic antibiotics by 2020

Things aren’t always as they seem…..

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Sulfanilamide known as an antibiotic

Need for a liquid for children

Harold Cole Watkins – Chief chemist and pharmacistS.E. Massengill Company – Bristol, Tenn.

Solvent – diethylene glycol – antifreeze

1937 – Elixir of Sulfanilamide

Elixir of sulfanilamide – looked good – tasted fine – raspberry flavor

September/October -105 deaths/353 patients in 15 states – renal toxicity

No required testing for safety

Watkins committed suicide in January 1939

FDA History - 1938

1906 Pure Food and Drug Act – now obsolete

1938 – Federal Food, Drug and Cosmetic Act

� FDA approval before marketing required

� Drugs had to be shown safe before marketing

� Directions for safe use required

� Differentiation between prescription and OTC drugs

FDR – June 25, 1938

Lash Lure �blindness

1940 Warfarin Winter 1921 – 1922 Alberta, Canada and North Dakota

Cattle observed to bleed excessively after eating spoiled clover

“Sweet clover disease”

1940 – Karl Paul Link - University of Wisconsin-Madison – Isolated dicoumarol

First marketed in 1940 as a rodenticide

Synthetic derivative warfarin – Wisconsin Alumni Research Foundation (WARF)

First approved for medical use in 1954

Earliest patients – President Dwight Eisenhower 1955 – after heart attack

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The Nobel Prize for Medicine in 1945 was presented to Alexander Fleming, Howard Florey and Ernest Chain for their work with which one of the following:

Let’s test your knowledge once again:

A) Elixir of Sulfanilamide

B) Birth control pills

C) Penicillin

D) Aspirin

Penicillin right!

Fleming, Florey and Chain would be proud of you

1942 - Nitrogen mustard

From war gas to cancer chemotherapy

July 12, 1917 – Allied troops in Belgium bombarded with German mustard gas-charged shells

Blistering effects on skin, eye and respiratory tract

Allied soldiers (and their dogs and horses) were issued gas masks

2 years later observation of decreased white blood cells and break down of lymph tissue

1942 - Nitrogen mustard

Yale pharmacologists Louis Goodman and Alfred Gilman

Worked with nitrogen mustard derivatives

HN2 – Mustragen

Over next 10 years other alkylating agents developed:

LeukeranMyleranCytoxan

1946 published � shrink tumors of lymphoid cells � treatment of lymphoma (Hodgkin’s disease)

Cancer treatment no longer limited to radiation and surgery

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1956 – Idaho Society of Hospital Pharmacists charteredDues were $5 per yearDon Ness was the first PresidentISHP meets at ISPA convention in McCall

1961 – ISHP became an official Chapter of ASHPNeeded 10 members to become an affiliate

1967 – First dues increase - $10 per year

1979 – Tie for President-elect – Decided by a coin flip

1980 – CE becomes mandatory in IdahoISHP did not become a ACPE provider until 1992

1972 (?) - First Annual meeting held in Sun ValleyISHP breaks from ISPA and meets with IHA

ISHP

1991 - Student Chapter established at ISU

1990 – 1994 – Annual Meeting held at Elkhorn Resort

1995 – Name changed to the Idaho Society of Health-System PharmacistsAnnual meeting moved back to Sun Valley

1999 – Establishment of the Idaho Research and Education Foundation

2006 – 50th Anniversary of ISHP

1981 – 25th Anniversary of ISHP

2001 – Speaker from New York took a cab from Boise to Sun Valley ($700)

“It only looked like about an inch on the map”

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Late 1950s -Thalidomide – Europe

Sedative/treatment of morning sickness

Birth defects – stunted growth of arms and legs > 10,000 children

phocomelia (flipper-like arms or legs)

1962 – Kefauver – Harris Amendment

Efficacy had to be proven prior to marketing

Manufactures required to report adverse effects

FDA oversight:

•100,000 manufactures within the US

•More than 800,000 products manufactured domestically

•More than 300,000,000 imported products

$0.20 of every dollars spent by American consumers

FDA’s 2014 FY President’s budget = $4.6 billion

Increase of $821 million (21%) over FY 2012

2012 13,496 employees

FDA 2014

Human Drugs Program – 27.7% of total budget

Source – Dept. HHS FDA (FY 2014) Justification of Estimates for Appropriations Committees (525 pages)

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Drug oversight:

FDA – Food and Drug Administration

FDA’s mission:

•Foods are safe, wholesome and properly labeled

•Human drugs and vaccines are safe and effective

•Blood used for transfusions and blood products are safe and in adequate supply

•Medical devices are safe and effective

•Transplanted tissues are safe and effective

•Animal drugs and medicated feeds are safe and effective and food from treated animals is safe for human consumption

•Radiation-emitting electronic products are safe

•Cosmetics are safe and properly labeled

Safety and efficacy

The dynamics of pharmacy

Approval time goals:1992 Prescription Drug User Fee Act (2002)

Standard Review – 10 monthsPriority Review (fast track) – 6 months

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Drug Approval Process

From the lab to the pharmacy shelf:

Only 1 in 1000 compounds from the lab makes it into human testing

Only 1 in 5000 compounds makes it from the lab to the market

Average of 12 years

New Drug Application – typically about 100,000 pages

Cost of $350 million (for one successful drug)

Average cost to develop a drug (including the cost of failures):

� 1970s = $140 million� Mid 1980s = $320 million� Late 1990s = $800 million� Early 2000s = $1.2 billion (Source – PhRMA 2013 Profile)

Forbes 8/11/2013 – “The Cost Of Creating A New Drug Now $5 Billion…”

PhRMA

Pharmaceutical Research and Manufactures of America

Research & Development investments

1980 $2 billion

2007 $44.5 billion

2012 (est.) $48.5 billion

1964 - Surgeon General’s landmark report – tied smoking to health problems

American Medical Association –severed it’s ties to Big Tobacco

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Birth control pills

1957 – FDA approves “the pill”

Enovid – estrogen and progesterone combinationsevere menstrual disorders

1960 – FDA approval for contraceptive use

1962 – 1.2 million women in US use BCPs

1963 – 2.3 million

1988 – Enovid removed from the market

(Availability of several other oral BCPs, hormonal contraceptive injections, implantable pellets, patches and rings)

Viagra (sidenafil) 1998

Initially tested in 1980s – treat high blood pressure and angina

Unanticipated side effect – produced erections

Pfizer - 1998 – first orally active drug approved in US for treating impotence (erectile dysfunction)

One of the first lifestyle drugs for direct-to-consumer advertising(allowed by FDA in 1997)

Senator Bob Dole and Pele as spokesmen

Worldwide 2012 sales $2.05 billion

Reported 3 million users

Issued on November 10, 1972 to honor the 100,000 professional men and women pharmacists who serve American health.

Pharmacy Facts

May 2012 – Bureau of Labor:National 281,560 pharmacistsIdaho 1,360

May 2012 – Bureau of Labor:National 353,340 pharmacy techniciansIdaho 1,530

How many pharmacists and

technicians today?

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Pharmacy Facts

Pharmacists:

National Idaho

Mean hourly wage $55.27 $52.73Mean annual wage $114,950 $109,680

Technicians:

National Idaho

Mean hourly wage $14.63 $14.62Mean annual wage $30,430 $30,400

The drug development and approval process includes all of thefollowing except:

Almost lunch time!

Does hypoglycemia distract from learning?

A) Discovery/Preclinical testing

B) Clinical trials

C) Budget for direct-to-consumer advertising

D) FDA review/approval

E) Post marketing testing

Right

(I guess hypoglycemia does not distract from learning)

Goodbye

Drug withdrawals:

Zomax (zomepirac) – 1983 With drawl due to anaphylactic reactions, renal failure

Exubera (human insulin) – 2007 Pfizer discontinued sales due to poor patient acceptance

Permax (pergolide) – 2007 Manufacturer initiated with drawl from market due to increased risk of heart valve damage

Trasylol (aprotinin) – 2007 Marketing suspension due to possible increased risk of death

Zelnorm (tegaserod) – 2007 Increased risk of angina, heart attack, stroke

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Goodbye

Recent drug withdrawals:

Mylotarg (gemtuzumab) 2010 – Withdrawn in US due to increased risks of veno-occlusive disease and a clinical trial that showed no benefit in acute myeloid leukemia (AML)

Avandia (rosiglitazone) 2010 – Withdrawn in Europe due to increase risk of heart attacks and death. Remains available in US

Darvocet/Darvon (propoxyphene products) 2010 – Risk of serious heart conditions and places patients at risk for cardiac death

Xigris (drotrecogin alfa) 2011 – Withdrawn by Lily worldwide due to lack of efficacy

New England Compounding Center – NECCFarmingham, Mass. Fall 2012

Methylprednisolone acetate - used in pain clinics for spinal injection for back and neck pain Doses administered between May 21 – September 24, 2012

Caused non-contagious fungal meningitis – Symptoms late August

Contaminated with mold exserohilum rostratum – found in sealed vials produced in August by NECC

17,676 doses shipped to 23 states, including Idaho

March 10, 2013 - CDC reports - 23 fatalities720 patients being treated for persistent fungal infections (1 case in Idaho)

Estimated 14,000 Americans may have received the contaminated steroid but attack rate 1% or less

NECC products shipped to over 1200 facilities

Quiz time – The final one!

Drugs have been removed from the market for which of the following reasons:

A) Poor product acceptance

B) Increased incidence of adverse effects

C) Lack of efficacy observed from post market surveillance

D) All of the above This is correct – strong work!

One more hour of ACPE for you!

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What haven’t we talked about?

Small pox vaccine – Edward Jenner – 1798

Influenza vaccines – Get your flu shot!

Hypertensive and cholesterol control therapies – CV disease - #1 killer USA

Homeopathic/natural medicines (NIH - 2008 US spending $33.9 billion)

Monoclonial antibodies “-mabs”

Colony stimulating factors – Epogen, Neupogen

HIV agents

Drug diversion

797 Compounding requirements

Medication errors

Etc.

References:

The Drug Book:From Arsenic to Xanax, 250 Milestones in the History of Drugs

Michael C. Gerald2013

Pharmacy - An Illustrated History

David L. Cowen and William H. Helfand1990

Websites

Smoking ads

http://lane.stanford.edu/tobacco/index.html

Taste of Raspberries, Taste of Death The 1937 Elixir Sulfanilamide Incident

http://www.fda.gov/aboutfda/whatwedo/history/productregulation/sulfanilamidedisaster/default.htm

PhRMA 2013 Profile

http://www.phrma.org/sites/default/files/pdf/PhRMA%20Profile%202013.pdf

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“Don't worry about the world coming to an end today.

It's already tomorrow in Australia.”

Charles Schultz