1803-1805: First isolation of Morphine from opium

plant by German pharmacist Friedrich Sertürner

Sertürner called the isolated alkaloid substance “Morphium”
named after the greek God of Dreams Morpheus

F. Sertürner

This was the FIRST alkaloid EVER to be isolated from ANY plant!
Thus, he was the first person to isolate the active ingredient
from a medical plant
• Until the isolation of Morphine it was believed
that all natural products from plants are acids
• Sertürner started testing morphine first on
stray dogs then on himself and 3 friends. They
almost died from OD and had to take an
emetic…
• Sertürner started testing morphine first on stray dogs
then on himself and 3 friends. They almost died from
OD and had to take an emetic…

• Why did they not use it via iv?

1803: Morphine isolated from crude opium
1827: commercial production of Morphine by German
pharmaceutical company Merck

Years later: Addiction potential was discovered

1843: Dr. Alexander Wood of Scotland invents the syringe and

injects patients with morphine. He injected his wife with
Morphine in 1850 – she died from respiratory depression…
1874: German pharmaceutical company Bayer converts
Morphine into Diacetylmorphine aka ____________

Around 2 times more potent that Morphine

Also more addicting !

1897: Bayer synthesizes Aspirin

1874: German pharmaceutical company Bayer converts
Morphine into Diacetylmorphine aka ____________

Around 2 times more potent that Morphine

Also more addicting !

1897: Bayer synthesizes Aspirin

1898: Bayer markets Diacetylmorphine under “Heroin” as a
“non-addictive” morphine substituent

1899: Bayer markets Acetylsalycilic acid under “Aspirin”

Ironically Aspirin required a prescription whereas heroin did
not !
Spanish Heroin add for children:
Heroin for irritation and bronchitis
Bayer and Merck started the
modern pharmaceutical
industry by developing three
of the world’s most popular
analgesics:

Morphine, Heroin and Aspirin

Morphine Biosynthesis -
How human neuroblastoma cells
make morphine:

Source:
PNAS June 14, 2005 102 (24) 8495-8500;
https://doi.org/10.1073/pnas.0503244102
Used in treatment of opioid
dependency
Valdez CA, Leif RN, Mayer BP (2014) An Efficient, Optimized
Synthesis of Fentanyl and Related Analogs. PLoS ONE 9(9):
e108250. https://doi.org/10.1371/journal.pone.0108250
How much is a lethal dose of Fentanyl ?
2 mg of Fentanyl

A lethal dose L
Source: World Drug Report
https://www.unodc.org/wdr2018/prelaunch/WDR18_Booklet_3_DRUG_MARKETS.pdf
How do opioids work?

Source: https://www.naabt.org/faq_answers.cfm?ID=6
 How do opioids work?

From: http://www.copeaustralia.com.au/home-mobile/naloxone/
First line treatment for opioid overdose

Naloxone
aka Narcan

administered intranasally
From: http://www.copeaustralia.com.au/home-mobile/naloxone/
 Cocaine

Coca plant
- Today: most commonly used drug Erythroxylum novogranatense var. novogranatense
worldwide after cannabis
- Extracted from coca plant,
native to South America (S.A.)
- Indigenous S.A. peoples have chewed
leaves for 1000s of years
- When Spanish arrived in S.A. they first ignored aboriginals claims that the leaf gave them
strength and energy
- Once they found it was true they taxed leaf at 10% and started chewing it mixed w/ tobacco
- 1855: Cocaine alkaloid first isolated in Germany
- 1879: Cocaine used for treatment of morphine
addiction
- 1886-1906: A "pinch of coca leaves" was
included in the original 1886 recipe for Coca-
Cola, though the company began using
decocainized leaves in 1906 when the Pure
Food and Drug Act was passed.
Nice collection of a lot of old-school adds for substances we consider to be unsafe for general
consumption:
http://www.pharmacytechs.net/blog/old-school-medicine-ads/
 Sigmund Freud on the effects of Cocaine
…”exhilaration and lasting euphoria,
which in no way differs from the normal
euphoria of the healthy person. You
perceive an increase of self-control and
possess more vitality and capacity for
work. In other words, you are simply
normal, and it is soon hard to believe
you are under the influence of any drug.
Long intensive physical work is
performed without any fatigue. This
result is enjoyed without any of the
unpleasant after-effects that follow
exhilaration brought about by alcoholic
beverages. No craving for the further
use of cocaine appears after the first, or
even after repeated taking of the
drug…”

S. Freud in his paper “Über Coca” 1884

Freud concluded his paper by recommending seven conditions to be treated with
cocaine therapy:

• as a mental stimulant
• as a possible treatment for digestive disorders
• as an appetite stimulant in case of wasting diseases
• as a treatment for morphine and alcohol addiction
• as a treatment for asthma
• as an aphrodisiac
• as a local anaesthetic

Implications:

1862 – Merck produces ¼ pound of cocaine.

1884 – Freud publishes his paper on Cocaine
1884 – Merck produces 3,179 pounds of cocaine.
1886 – Merck produces 158,352 pounds of cocaine

Target patients: Soldiers (addicted to morphine while at war “Soldiers Disease”)

 When did opiates and other drugs
become regulated by law?

https://www.naabt.org/laws.cfm
Shows regulation timeline in the US
 Drug Regulation
Harrison Act of 1914:

- All opium and coca products require strict

accounting

- Upper limits on the amount of opium, opium

derived products, and cocaine allowed in
products available to the public

- Taxation !
 What are Narcotics?
From Greek “to make numb”

What is classified as a narcotic ?

Is cocaine a narcotic ?

Is marijuana (cannabis) a narcotic ?

 What are Narcotics?
From Greek “to make numb”

Medical sense: opiates and opioids, most importantly

morphine and heroin and derivatives.

Legal sense: all substances that are totally prohibited

or used in violation to government regulation. This
includes cannabis and cocaine.

à Higher penalties for possession of drugs that are

classified as narcotics !
How is white powdery cocaine made from the coca plant leaves?
https://www.youtube.com/watch?v=KQil-3FFa64

https://www.youtube.com/watch?v=7tlwW2DKzlc&has_verified=1
 How does cocaine work?
Cocaine in the brain: In the normal neural communication process, dopamine is released
by a neuron into the synapse, where it can bind to dopamine receptors on neighboring
neurons. Normally, dopamine is then recycled back...

https://www.drugabuse.gov/publications/research-reports/cocaine/how-does-cocaine-produce-its-effects
 Atropine
Occurs naturally in plants of the nightshade family (e.g. belladonna, henbane,
mandrake)

Berries are highly toxic; causes bizarre delirium

and hallucinations

Long History as medicine, poison and cosmetic:

- Ancient Romans used it as poison

- Used to make poison-tipped arrows
- before middle-ages used as anesthetic for surgery
often in combination with opium

Deadly Nightshade (Atropa Belladonna)

 Medical use:
4th Century BC: Theophrastus used mandrake for
treatment of wounds, sleeplessness and as love
potion

1st century AD: Dioscorides used mandrake wine

as anaesthetic

Cosmetic use:
to enlarge (dilute) pupils in eye (via eyedrops).
Black Henbane (Hyoscyamus niger) Famously done by Cleopatra. (last century BC)
Popular again during Renaissance and briefly in
late 19th / early 20th century Paris.

Mandrake plant
(Mandragora autumnalis)
 Atropine mechanism of action
Atropine structure (enantiomeric mix / racemic):

compare to atropine

acetylcholine (ACh) a neurotransmitter

that is normally bound by muscarinic receptors acetylcholine

Neurotransmitter: a chemical released by neurons (nerve cells) to send signals to

other cells

ACh released by motor neurons of nervous system and activates muscles also
involved in the ANS

Autonomous Nervous System (ANS):

- regulates the functions of internal organs
- acts unconciously (non voluntary)
- regulates heart-rate, digestion, respiratory rate, pupillary response, urination,
sexual arousal, also reflexes (coughing, sneezing, swallowing and vomiting)
ANS has two branches with opposite actions:

Sympathetic NS: “Fight or Flight” e.g. pupils are diluted facilitating far sight

Parasympathetic NS: “Rest and Digest” e.g. pupils are constricted facilitating
near sight

ACh neurotransmitter binds to muscarinic receptors and activates

parasympathetic responses

Atropine is a competitive, reversible antagonist of the muscarinic ACh

receptor. i.e. it blocks the action of ACh

It’s considered a parasympathetic inhibitor or a antimuscarinic drug (a type

of anticholinergic drug)
Source: http://www.drbuckeye.com/dr-ns-approach
Medicinal applications of Atropine
• Optometry
• Treatment of bradycardia (slow heart rate
under 60 beats / min)
• Antidote for organophosphate poisoning
caused by nerve agents
e.g. Tabun, Sarin, Soman, VX
Remember: Acetycholine (ACh) activates the Parasympathetic NS (Rest and Digest)
 Chapter 4

Introduction to FDA law and

Clinical testing
IND = Investigational New Drug Application
NDA = New Drug Application

Source: Nature Reviews: Drug Discovery

 The different phases of clinical trials:

Pharmacokinetics = the study of the time course of drug absorption, distribution,

metabolism, and excretion.
 Short Videos that explain clinical
trials
• https://www.youtube.com/watch?v=dsfPOpE-
GEs

• https://www.youtube.com/watch?v=CUR2tL5
n6X0
 Important Terminology
• Principal Investigator (PI)
Person who takes responsibility for the safety and team /
research actions of a clinical trial at a specific site.

• Study Coordinator
No medical education, but educated in carrying out clinical trials,
coordinate scheduling, contact families to see if they have
questions about drug compliance etc. Very important job!

• IND: Investigational New Drug

How you refer to a drug that is being studied before it reaches
FDA approval
 Important Terminology (continued)
• DSMB: Data Safety and Monitoring Board
Group of people appointed independent of a clinical trial who
independently assess safety data. Monitors for participant safety.

• Placebo Controlled
Majority of drug studies have a phase that is placebo controlled. Tests
effectiveness of an IND treatment against something that looks like the
treatment but has no active ingredients. “placebo effect”: when an
individual takes a substance that they perceive to be a medication they
can physically feel better. So it is important to know what the effects are of
the act of taking a perceived medication vs actually taking the medication.

• Double Blinded
- Neither the Researcher nor the Participant know if they are receiving
the drug or a placebo
- Prevents bias in study data
Done in early phases, prevents researcher as well as the participant form
consciously or unconsciously favoring the effects of the drug.
 Preclinical Studies
• Drug development begins with extensive laboratory research
- Discovery, mechanism of action (MOA), effect

• Can involve years of experiments in animal and cell models

- Toxicology studies: does the drug cause cancer ? Does it change DNA
(mutagen) ? Could it be harmful to pregnancy ? etc
- Pharmacokinetic studies: How a drug is broken down by a body?

• If this research is successful, then researchers can send the data to the
FDA for approval to initiate research / testing in humans.

… VERY FEW compounds actually make it to the FDA for testing

 Harsh reality:
Only 5 in 5,000 drugs that enter preclinical testing progress to human testing.

One of these 5 drugs that are tested in people is approved.

The chance for a new drug to actually make it to market is thus only 1 in
5,000.

The average time from invention to market for a new drug is 12 YEARS!

Developing a new prescription medicine that gains marketing approval is

estimated to cost drugmakers ca $1.5 billion - $2.6 billion
 Phase I
• Assess the safety of a drug .
- Typically lasts several months or longer
- Testing occurs typically in healthy volunteers

• Determine the pharmacokinetics of the drug in humans

- How the drug is absorbed, broken down in the body and
finally excreted

• Evaluate the side-effects that may occur at different dosages

 Phase II
• Tests the efficacy of a drug . Most pivotal point of trials !
- Typically lasts months to years
- Testing occurs typically in people with specific diseases

• Often randomized trials

- One group of patients receive the experimental drug, while a second
group receives the placebo

• Often these studies are “blinded”

- Neither the patients not the researches are aware of who has received
the drug or placebo to prevent any bias.

• 1/4th of all experimental drugs successfully complete phase II trials

 Phase III

• Provides investigators and the FDA with more complete information

about the drug’s effectiveness and possible adverse reactions .
- Typically lasts years
- Testing occurs typically in 100s – 1000s of people with specific diseases

• If Phase 3 is successful, investigators can seek FDA approval to market the

drug

• 70-90% of all experimental drugs that enter Phase 3 studies are

successful
 Phase IV

• Post Marketing Surveillance Trial AFTER a drug (or device) has been FDA
approved

• Goals at this stage:

- Compare the drug with other drugs already in the market
- Monitor a drug’s long-term effectiveness
- Determine cost-effectiveness

• Finding in phase IV can result in a drug being taken off the market or
restricted
 Phase IV fails:

Rofecoxib is nonsteroidal anti-inflammatory drug (NSAID)

Marketed as VIOXX for treatment of arthritis.
Removed from market by Merck in 2004 (during Phase IV) !
 The Fall of Vioxx:
Chemical name: rofecoxib
On the market for 5.5 YEARS (May 20, 1999 to Sep. 30, 2004)
Use: NSAID (pain relief)
Manufacturer: Merck

During the 5.5 years it was on the market, more than 80 million people were
prescribed Vioxx

Cause for recall: increased risk of heart attack and stroke;

linked to about 27,785 heart attacks or sudden cardiac deaths
between May 20, 1999 and 2003
__________________________________________________________________

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1299263/
Vioxx's Phase III trials: 8,076 patients. (very large ironically)

Did not reliably detect rare adverse events (prevalence of 1%–

2% )
(compared with placebo)

How it got removed:

Post-market study aimed to determine if rofecoxib prevented
the malignant transformation of colon polyps and excluded
patients with heart disease.

First 18 months: no link of Vioxx with increased risk of

cardiovascular events.

However, 3.5% of patients taking rofecoxib for more than 18

months suffered either a myocardial infarction or stroke,
compared with 1.9% in the placebo group!
= excess risk of 16 infarcts or strokes per 1,000 people taking
the drug !!!
Vioxx Add with
Olympic gold medalists Dorothy Hamill.
 List of 35 FDA-Approved
Prescription Drugs Later Pulled
from the Market
https://prescriptiondrugs.procon.or
g/view.resource.php?resourceID=00
5528
Off-label Marketing
Among the things Kardashian neglected to mention:

- The drug hasn't been studied in women with a rare complication of pregnancy that causes
extreme morning sickness.
- It's not recommended for women sensitive to various drugs.
- And the drug label comes with warnings and precautions for activities requiring mental
alertness.
1997: Congress Passes Law (FDAMA) Requiring Trial Registration

The first U.S. Federal law to require trial registration was the Food and Drug
Administration Modernization Act of 1997 (FDAMA).

Section 113 of FDAMA (FDAMA 113) required the

Specifically, FDAMA 113 required that the registry

conducted under investigational new drug applications to
test the effectiveness of experimental drugs for patients with serious or life-threatening
diseases or conditions.

The information in the registry was intended for a wide audience, including individuals
with serious or life-threatening diseases or conditions, members of the public, health care
providers, and researchers.
 NIH Clinical Trials Website
launched in 2000
https://clinicaltrials.gov

https://clinicaltrials.gov/ct2/show/results/NCT0
2724644?cond=Cellulite&cntry=US&state=US%3
AVA&rank=1