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NCKU Course No.: CHE 7081

Pain
An unpleasant sensory and emotional experience
止痛藥 associated with actual or potential tissue
Medicines for Pain damage, or described in terms of such damage.

and Palliative Care

-- IASP (International Association for the Study of Pain)

 Pain is always subjective.

- Aspirin  Pain can occur in the absence of tissue damage.
Usually this happens for psychological reasons. If
they regard their experience as pain, and if they
report it in the same ways as pain caused by
tissue damage, it should be accepted as pain.
Gordon Tsai

Types of Pain Palliative Care

 Acute pain starts suddenly and is short-term
 Chronic pain lasts for a longer period of time
 Breakthrough pain often happens in between regular, scheduled
painkillers
 Bone pain happens when cancer is affecting a bone
 Soft tissue pain happens when organs, muscles or tissues are
damaged or inflamed
 Nerve pain happens when a nerve is damaged
 Referred pain is when pain from one part of your body is felt in
another
 Phantom pain is when there is pain in a part of the body that has
Palliative care is a multidisciplinary approach for
people with life-limiting illnesses by providing
specialized medical and nursing care.
It focuses on providing the terminal ill patient
with relief from the symptoms, such as pain,
physical stress, and mental stress.
The goal of such therapy is to improve quality of
life for both the patient and his/her family.
Wikipedia

been removed
 Total pain includes the emotional, social and spiritual factors that
affect a person’s pain experience.

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MEDICINES FOR PAIN AND Steroidal anti-inflammatory drugs

PALLIATIVE CARE
 Mild Pain - Non-steroidal anti-inflammatory drugs Corticosteroids are steroid hormones
(NSAIDs)  Suppress inflammation and immunity
Acetylsalicylic acid - Aspirin®
 Assist in the breakdown of fats, carbohydrates,
Ibuprofen – Brufen®, Advil® , and Motrin® OTC and proteins.
Paracetamol (Acetaminophen) - Tylenol® and Panadol®
 Regulate the balance of salt and water in the
body.
 Moderate to Severe Pain - Opioid analgesics
(may lead to addition)
Codeine Corticosteroids are used to treat conditions such as
Oxycodone arthritis, colitis, asthma, bronchitis, allergic reactions, and
Morphine
Prescription skin rashes.
Fentanyl

Common Opiate Agonists Natural Painkillers

Codeine
Codeine is used to relieve mild to moderate pain and coughing. It is commonly

Willow bark
abused among young adults. Codeine is often combined with sugary drinks to
create a mixture referred to as “purple drank” or “sizzurp.”

Fentanyl
(柳樹皮)
Fentanyl is a synthetic painkiller that is up to 100 times as potent as morphine. It is
only prescribed in cases of severe pain. When used in conjunction with other
painkillers such as heroin, fentanyl can quickly lead to overdose and other
dangerous side effects, including death.
Turmeric (薑黃)
Morphine
Morphine has been touted as a godsend for people suffering from severe chronic
Cloves (丁香)
pain. It is also one of the most addictive substances known and responsible for a
large amount of unintentional drug-related deaths nationwide.

Oxycodone
Oxycodone is sold under different brand names including OxyContin and Percocet.
It is a widely prescribed painkiller and has a high potential for abuse.

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Chemical Structure Outline

What is Aspirin?
Acetylsalicylic acid
Aspirin®
What is it for and how does it work?
Salicylic acid

Major Adverse Effects

Ibuprofen
(Brufen®, Advil® , and Motrin®)

Synthesis and Production Process

Synthesis
Paracetamol
(Acetaminophen) Assay
(Tylenol® and Panadol®) Stability

Aspirin（Wikipedia) What is it for and how does it work?

https://www.youtube.com/watch?v=9mcuIc5O-DE
Aspirin, also known as acetylsalicylic acid (ASA),
is a medication used to treat pain, fever, and
inflammation.
CAS No.: 50-78-2
Formula: C9H8O4
M.W.: 180
Density: 1.40 g/mL
M.P.: 135oC
B.P: 140oC
Solubility: 3 mg/mL
In water
2-acetoxybenzoic acid

It is on the World Health Organization's List of Essential

Medicines, the most effective and safe medicines needed
in a health system.
A CAS Registry Number, also referred to as CAS Number, is a unique numerical identifier assigned by the
Chemical Abstracts Service (CAS) to every chemical substance described in the open scientific literature.

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Aspirin – Mechanism of Action Aspirin – Mechanism of Action

Nociceptor Arachidonic acid
Nociceptors

Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4(ω-6).

A nociceptor is a type
of receptor at the end of
a sensory neuron's
axon that responds to
damaging or potentially
Arachidonic acid is freed from a phospholipid molecule by the enzyme
damaging stimuli by phospholipase A2 (PLA2), which cleaves off the fatty acid, but can also be
sending danger signals generated from DAG by diacylglycerol lipase.
to the spinal cord and The enzymes cyclooxygenase-1 (COX-1) and -2 (COX-2) metabolize
the brain. This process arachidonic acid to Prostaglandin G2 and then prostaglandin H2, which in
is called nociception. turn may be converted to various prostaglandins to reduce clotting and
inflammation.
Four types of sensory neurons
and their receptor cells. Wikipedia Wikipedia

Aspirin – Mechanism of Action Aspirin Usages

Cell
Membrane  Aspirin is used as a nonsteroidal anti-inflammatory drug
(NSAID). For pain or fever, effects typically begin within 30
minutes. Specific inflammatory conditions in which it is
used include Kawasaki disease, pericarditis (心包炎), and
rheumatic fever (風濕熱).

 It is also an antiplatelet (抗血小板) drug which suppresses

the normal functioning of platelets.

 Aspirin is also used long-term to help prevent heart

(血栓素) attacks, strokes, and blood clots in people at high risk.
Aspirin given shortly after a heart attack decreases the
risk of death.

 Aspirin may also decrease the risk of certain types of

Reduced Inflammation,
cancer, particularly colorectal cancer (結腸直腸癌).
Reduced Clotting Fever, and Pain.
Wikipedia

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Outline Aspirin - Side Effects

What is Aspirin?  It causes stomach ulcers and stomach bleeding.

The bleeding risk is greater among those who are
older, drink alcohol, take other NSAIDs, or are on
What is it for and how does it work? blood thinners.

 The symptom may get worse for those who have

Major Adverse Effects asthma.

 High doses may result in ringing in the ears (耳鳴).

Synthesis and Production Process
 It is not recommended in the last part of
pregnancy.

 It is not recommended for children with infections

because of the risk of Reye's syndrome.

Mechanism of Action and Side Effects

Outline
https://www.youtube.com/watch?v=0YZ1vDzi_SM

What is Aspirin?

What is it for and how does it work?

Major Adverse Effects

Synthesis and Production Process

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Aspirin – History of Development Aspirin – History of Development

https://www.thoughtco.com/history-of-aspirin-4072562
 Aspirin, is a prodrug of salicylic acid which is found in the leaves of the
willow tree (柳樹), has been used as medicine for at least 3500 years.
The Ebers Papyrus, an Egyptian medical text from ca. 1543 BC, mentions
use of willow and myrtle (another salicylate-rich plant) to treat fever and
pain.

 In 1853, chemist Charles Frédéric Gerhardt treated sodium salicylate

with acetyl chloride to produce acetylsalicylic acid for the first time.
Willow Tree Charles Frédéric Gerhardt
 In 1897, scientists at Bayer began studying acetylsalicylic acid as a less- (1816 – 1857, French Chemist)
irritating replacement for common salicylate medicines.

 In 1899, Bayer had named the drug Aspirin and was selling it around the
world. The word Aspirin was Bayer's brand name.

 Aspirin is one of the most widely used medications globally with an

estimated 40,000 tons (50 to 120 billion pills) being consumed each year.

 The wholesale cost in the developing world as of 2014 is 0.002 to 0.025 Baby Aspirin
USD per dose. 1917 Ad Chinese advertising poster of the (La Felguera plant in Asturian town, Spain)
In New York Times Bayer company for aspirin, 1935

Aspirin Synthesis (Bayer Process) Aspirin Synthesis (Bayer Process)

Esterification
. The product will be analyzed by four different methods: melting point,
[H+] titration, spectroscopic assay, and HPLC.

100oC  The melting point range of pure aspirin is 138-140 oC and the melting
point range of the salicylic acid starting material is 158-161 oC. If
impurities are present in your crude sample, the melting point range for
your product will be different from the range of pure aspirin.
Salicylic Acid Acetic Anhydride Acetylsalicylic Acid Acetic Acid
(C7H6O3) (C4H6O3) (C9H8O4) (C2H4O2)
 From the titration of your sample, the moles of acetylsalicylic acid present
can be determined assuming that there is not a large percentage of an
acid impurity present in your crude sample.
1. Salicylic acid is reacted with acetic anhydride (in excess) at low pH and 100oC.
 The spectroscopic analysis of aspirin will involve the complexing of
2. At the end of reaction, add water to precipitate aspirin due to its low solubility iron(III) to the deprotonated form of salicylic acid (salicylate ion) to give a
to water. purple solution. Only the salicylate ion complexes to iron(III). Your aspirin
3. The “crude aspirin” is obtained by filtration to remove acetic acid which product as well as a commercial aspirin tablet will be compared to a
remains in the water phase. standard 0.15% ferric-salicylate solution.
4. The “purified product” is obtained through recrystallization of the crude product
in hot ethanol.  High performance liquid chromatography.

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High Performance Liquid Chromatography Aspirin Synthesis (Bayer Process)

HPLC Assay
Column: Ascentis Express RP-Amide
(10 cm x 4.6 mm I.D., 2.7 μm particles)
Mobile Phase: A:B=65:35
A: water with 0.1% TFA;
B: acetonitrile with 0.1% TFA
Method: Isocratic
Flow Rate: 1 mL/min
Column Temp.: 30 oC
Detector: UV, 250 nm
injection: 5 μL

UV-Visible Spectra Aspirin Synthesis (Bayer Process)

for Aspirin and Salicylic Acid
Stability

In the presence of
moisture, aspirin may
decompose (hydrolysis)
into salicylic acid and
acetic acid. This reaction
is the reverse of the
synthesis reaction.

The maximum allowable

amount of free salicylic
acid in an aspirin sample
is 0.15% salicylic acid.

Edwards, LJ, Trans. Faraday Soc., 1950, 46:723.

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Total Synthesis from Benzene Summary

Aspirin

Mechanism of Action
Sulfonation
Sulfonation of benzene to produce benzenesulfonic acid by heating benzene
under reflux with concentrated sulfuric acid for several hours. Adverse Effects
Formation of Phenolate
Benzenesulfonic acid reacts with sodium hydroxide (NaOH) at 300-350 oC to Synthesis and Production Process
form phenoxide ion which further acidified to form phenol.
Synthesis
The Kolbe–Schmitt reaction (Kolbe process) Assay
It is a carboxylation chemical reaction by heating sodium phenoxide (the
sodium salt of phenol) with carbon dioxide under high pressure (100 atm, 125 Stability
oC), then treating the product with sulfuric acid. The final product is an aromatic

hydroxy acid which is also known as salicylic acid (the precursor to aspirin).

Q & A