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New Way Chemistry for Hong Kong A-Level Book 3A11

DrugsDrugs

36.136.1 IntroductionIntroduction

36.236.2 Development of Aspirin and Development of Aspirin and ciscis-Platin-Platin

36.336.3 Key Stages of Drug DevelopmentKey Stages of Drug Development

36.436.4 Over-the-Counter Drugs and Prescription Over-the-Counter Drugs and Prescription

DrugsDrugs

36.536.5 Narcotics and their Adverse EffectsNarcotics and their Adverse Effects

36.636.6 Stimulants and their Adverse EffectsStimulants and their Adverse Effects

3366



36.36.11 IntroductionIntroduction



36.1 Introduction (SB p.190)

Medicines and DrugsMedicines and Drugs

• Medicines

used to cure and prevent diseases

• Drugs

alter the way that our body functions




Medicines and DrugsMedicines and Drugs

• Most medicines contain drugs

but some drugs are not medicines

• Example:

Alcohol and nicotine are not medicines but they are drugs

• Some drugs may or may not be medicines depending on one’s state of health




Drugs Derived from Folk Drugs Derived from Folk RemediesRemedies• Since ancient times

man has used natural materials to relieve pains, heal injuries and cure diseases

• Many of these folk remedies have been shown to be very effective




Drugs Derived from Folk Drugs Derived from Folk RemediesRemedies• With latest scientific and technological

advancement

active ingredients of folk remedies have been isolated (e.g. by

chromatography) from the natural medicines

their structures are identified(e.g. by M.S. or IR)




Drugs Derived from Folk Drugs Derived from Folk RemediesRemedies• Example:

Morphine – extracted from the poppy Papaver somniferum

• Morphine

powerful painkiller

unless used carefully, morphine can be harmful to our

bodies




Drugs Derived from Folk Drugs Derived from Folk RemediesRemedies

Poppies provide morphine

http://www.poppies.org/gallery/




Drugs Derived from Folk Drugs Derived from Folk RemediesRemedies• Example:

Salicylic acid – isolated from willow bark

• Salicylic acid

the precursor of aspirin




Drugs Derived from Folk Drugs Derived from Folk RemediesRemedies

Willow bark contains salicylic acid, which is the precursor of aspirin



36.36.22Development Development

of Aspirin of Aspirin andand

cis-Platincis-Platin



36.2 Development of Aspirin and cis-Platin (SB p.191)

AspirinAspirin

• For a long time, the bark of the willow tree (salix alba)

used as a traditional medicine

relieve the symptom of fever

• http://en.wikipedia.org/wiki/Aspirin




AspirinAspirin

• In the 1860s, chemists showed

salicylic acid (2-hydroxybenzoic acid) in willow bark

as active ingredient COOH

OH




AspirinAspirin

• By 1870, salicylic acid was widely used as

painkiller (analgesic)

fever depressant (antipyretic)

anti-inflammatory medication




AspirinAspirin

• The undesirable side effects of salicylic acid

1. irritating and damaging the lining of the mouth and stomach2. causing allergy to some

people




AspirinAspirin

• Molecular modification is necessary

give a derivative

effective as salicylic acid but has less undesirable side effects




AspirinAspirin

Structures of (a) salicylic acid; (b) aspirin

(a) (b)




Acetylation of salicylic acid to produce aspirin

In 1897



Aspirin is a common over-the-counter drug.

Prescription drugs – prescribed by doctors




AspirinAspirin

Aspirin is only slightly soluble in water. Suggest how you can prepare a water-soluble ‘aspirin’.

COOH

O Na

COO-Na+

O

OO

NaOH, NaHCO3 not suitable ∵ hydrolysis




Example 36-2Example 36-2




AspirinAspirin

1.17 1011

• At present, aspirin is still widely used in the world

35000 tonnes of aspirin are produced annually (each tablet has 300 mg aspirin)

Calculate the total number of aspirin tablets produced per year.




AspirinAspirin

• Recent researches have shown that small daily doses of aspirin may help prevent diseases

such as heart attack, stroke, and the blindness and kidney damage suffered by many patients with

diabetesCheck Point 36-2Check Point 36-2

Anti-platelet( 薄血丸 )




ciscis-Platin-Platin

• In 1964, the biophysicist, Barnett Rosenberg and his research group were studying the effect of an electric field on the growth of bacteria

A platinum-containing substance extracted from the bacterial culture inhibited cell division

http://en.wikipedia.org/wiki/Cisplatin





square planar

cis-diamminedichloroplatinum(I

I) [Pt(NH3)2Cl2]





• cis-platin alters the DNA of the cancer cell

when the cell tries to replicate, its DNA cannot be copied correctly

the cell dies





• The geometry of cis-platin is important to its action

• The geometrical isomer of cis-platin, trans-platin, was ineffective in treating cancer




transtrans-Platin-Platin

Structure of trans-platin. It is ineffective in treating cancer.





• Tests on animals conducted to investigate

1. how this compound affects cell division in mammalian cells

2. toxic side effects

3. different dose levels

Clinical tests on patients





• The most severe side effects:

nausea

vomiting

toxicity to the kidney

toxicity to the bone marrow





The use of cis-platin as an anticancer agent

Used in chemotherapy



36.36.33Key Stages ofKey Stages of

Drug Drug DevelopmentDevelopment



36.3 Key Stages of Drug Development (SB p.194)

Key Stages of Drug DevelopmentKey Stages of Drug Development

1. Lead compound(導引化合物 ) discovery

2. Molecular modification

3. Safety tests and human trials

4. Formulation(配方 ) development

5. Approval for marketing




The process of drug testing and approval for human use

preclinical




Lead compound discoveryLead compound discovery

• Lead compound

a compound with some desired biological activities

can be characterized and modified to produce other compounds

with better therapeutic effects but less unwanted side effects





• Development of lead compound

1. Understand how the body functions at molecular levels both normally and abnormally

2. Identify the drug target responsible for a specific disease

3. Develop the lead compound with therapeutic actions on the drug target





• Computer programs can be used to facilitate the design of chemical

structures that are effective

• Hundreds of thousands of compounds are screened to find out the lead compound which shows most desirable effects.

Combinatorial Chemistry : involves the rapid synthesis or the computer simulation of a large number of different but structurally related molecules or materials




Molecular modificationMolecular modification

• The lead compound may have undesirable side effects

• Researchers need to modify the molecular structure of the lead compound

improve its performance




Safety Tests and Human TrialsSafety Tests and Human Trials

• Once the lead compounds have been identified and modified

1. Pre-clinical 1. Pre-clinical

ResearchResearch

• Using cell cultures in a petri dish

to determine the effectiveness of compounds




• The most effective compounds are then subject to animal assays

• Both short-term and long-term testing are conducted on animals

to investigate the mechanisms, toxicity and adverse side effects

1. Pre-clinical 1. Pre-clinical

ResearchResearch




• The first time that the drug is tested on humans

• Generally, 20 to 80 healthy volunteers,

but sometimes patients are involved in this phase of research

2. Clinical Research2. Clinical Research

(a) Phase (a) Phase

11




To investigate

the metabolism, the structure-reactivity relationships, the mechanism of action and the side effects of the drug in humans


(a) Phase (a) Phase

11




• The purpose of phase 2 clinical research is to determine

the effectiveness of the drug to treat patients with a

specific disease or condition

common short-term side effects or risks


(a) Phase 2(a) Phase 2




• These studies are conducted on a larger scale than the phase 1 studies

several hundreds of patients are involved

2. Clinical 2. Clinical

ResearchResearch(a) Phase (a) Phase

22




• Phase 3 clinical research aims to

provide more information about the effectiveness and the safety of the drug

a still greater no. of patients are involved to allow scientists to extrapolate the results of clinical research to the general population


(a) Phase 3(a) Phase 3




Formulation DevelopmentFormulation Development

• There are various routes of administration of a drug

• Each route requires different types of formulation





• For oral route

the drug can be in the form of tablets, capsules or liquid

• For parenteral( 非口服的 ) route

it can be in ampoules( 針劑 ) or intravenous fluid( 靜脈注射液 )





• Researchers have to find out

which formulation of the drug brings the greatest effect

is the most suitable to the patients




Approval for Approval for MarketingMarketing• When the drug has passed all the

phases of the clinical research

the pharmaceutical company of the drug needs to make a formal application to the regulatory authority (like Food and Drug Administration in the US) for approving




Approval for MarketingApproval for Marketing

• The application must include

a description of how the drug was manufactured

results and analyses from the tests of the drug on both animals and humans





• The application must provide sufficient information for the regulatory authority to make several critical decisions:

whether the drug is safe and effective

whether its benefits outweigh its risks





whether the manufacturing methods used to make the drug are adequate for ensuring the purity and integrity of the drug

whether the drug’s labelling information is appropriate





• Phase 4 clinical research is done after the drug has been approved to be sold in the market

• The main purposes of phase 4 are to find

more about the side effects and safety of the drug





• The main purposes of phase 4 are to find

what the long-term risks and benefits are

how well the drug works when it is used more widely than in clinical

research





• The process of developing and testing a new drug is a lengthy one

• it takes about 10 years to develop a drug at a cost of 1 billion US dollars

Check Point 36-3Check Point 36-3



36.36.44 Over-the-Over-the-Counter Drugs Counter Drugs

and Prescription and Prescription DrugsDrugs

7B



36.4 Over-the-Counter Drugs and Prescription Drugs (SB p.197)

Over-the-Counter Drugs and Over-the-Counter Drugs and Prescription Drugs Prescription Drugs

• Drugs can be divided into two categories based on how they can be bought

Over-the-counter (non-prescription) drugs

Prescription drugs

Check Point 36-4Check Point 36-4



Name Structure Uses

Aspirin

(e.g. Cortal)

• As analgesics and antipyretics

Acetaminophen

(e.g. Panadol)

• As analgesics and antipyretics

Structure and uses of some common over-the-counter drugs




O

O

OH

O CH3

Aspirin

Analgesics and antipyretics

2-(acetyloxy)benzoic acid

1

2



OH

NH CH3

O Acetaminophen

Analgesics and antipyretics

N-(4-hydroxyphenyl)acetamide

1

4



Name Structure Uses

Vitamin C • Helps maintain elasticity of the skin, aids the absorption of iron and improves resistance to infection

• Essential for the formation of collagen and intercellular material, bone and teeth and for healing of wounds

Structure and uses of some common over-the-counter drugs




O

O

OH

OH

OH

OH

Vitamin C

Helps maintain elasticity of the skin, aids the absorption

of iron and improves resistance to infection.

1

23

4

51

2

5-(1,2-dihydroxyethyl)-3,4-dihydroxyfuran-2(5H)-one

O

furan

O

O

furan-2(3H)-one

O

O

furan-2(5H)-one



Name Structure Uses

Albuterol • For treating asthma, emphysema( 肺氣腫 ) and chronic bronchitis

• Dilates the bronchial airways by relaxing the surrounding muscles

Amoldipine • As an anti-hypertensive

Structure and uses of some common prescription drugs




OH

OH

OH

NH

CH3 CH3

CH3 Albuterol

Treating asthma, emphysema and chronic

bronchitis

4-[2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol

1

241

2



Name Structure Uses

Amoxicillin

(E.g. Augmentin)

• As an antibiotic used to treat bacterial infections

Omeprazole • Suppresses secretion of gastric acid

• Used for the treatment of duodenal and gastric ulcers and gastroesophageal reflux disease( 胃酸倒流病 )

Structure and uses of some common prescription drugs




Name Structure Uses

Chlorpheniramine

(e.g. Coltalin, Dristan)

Brompheniramine

(e.g. Neosed, 樂信 )

• Relieves nasal and non-nasal symptoms of common cold and allergies (e.g. runny nose, itchy eyes, watery eyes, sneezing)

• As an antihistamine

Loratadine

(e.g. 幸福安泰敏 )

- Ditto -


Br



Halogenated pheniramines are up to 20-fold more potent than pheniramine



36.36.55Narcotics and Narcotics and their Adverse their Adverse

EffectsEffects



36.5 Narcotics and their Adverse (SB p.199)

• Morphine – pain relief

• Heroin – no medical use

• Methadone – treatment of narcotic drug addiction

• Opium – not medical use

Examples : -

Narcotic analgesics(Narcotic analgesics( 麻醉鎮痛劑麻醉鎮痛劑 ))




Unlike aspirin, narcotic analgesics

produce euphoria, a feeling of great happiness or well-

being

are addictive





• Heroin and morphine are

obtained by evaporating the sap of the opium poppy

generally called opiates





Morphine and HeroinMorphine and Heroin

• About 5000 years ago, the Babylonians used crude opium to relieve pains

• The alkaloid morphine was first isolated from the opium poppy (Papaver somniferum) in 1803

• Its addictive properties were known from early times





Morphine Heroin

Glacial acetic acid

CH3COOH

• In 1898, morphine was acetylated to produce diacetylmorphine, or heroin

More addictive





• Morphine

used in cases of acute and chronic servere pain and on the battlefield

50 times as potent as aspirin

Etorphine : 2000 times as potent as morphine

Org. Chem notes p.19





morphine hydrochloride




OHHOO

N+Cl-

CH3H

OHHOO

N

CH3

HCl

Draw the structures of morphine hydrochloride

Why is morphine converted to morphine hydrochloride ?To make it more soluble in water





heroin




Adverse Effects of Use of Adverse Effects of Use of Morphine and HeroinMorphine and Heroin

drowsiness

respiratory depression

nausea and vomiting

develop tolerance(耐藥性 ) and physical dependence (心理依賴 /成癮 )

Tolerance : higher doses are needed to produce the same effect





Characteristics of dependence:

daily use

inability to stop usage

constant or repeated intoxication(中毒 ) overdose

withdrawal symptoms(斷癮跡象 )




Withdrawal symptoms(斷癮跡象 )

watery eyes

runny nose

yawning

loss of appetite

irritability(煩躁 ), tremors(震顫 )

panic(驚惶 ), chills(感到寒冷 )

sweating, cramps(痙攣 )





• Unlike depressants (e.g. alcohol and barbiturates(巴比妥酸鹽 )),

they usually do not cause physical damage to the brain, liver, or heart

• Unlike stimulants,

they do not induce psychotic experiences





• Heroin abusers are prone to numerous life-endangering conditions

tend to neglect their health

fail to detect common signs of illness

frequently resort to intravenous injection of opiates with shared

needles





Commonly observed problems:

the transmission of HIV, AIDS, viral hepatitis (hepatitis B virus)

inflammation of the heart’s lining(心膜 )

blood poisoning

tetanus(破傷風 ),

malaria(瘧疾 ), syphilis(梅毒 )





Commonly observed problems:

blood vessel inflammation

heart valve(心瓣膜 ) infection

malnutrition

festering sores(膿瘡 ) on the arms and legs

the toxic effects of overdose




New government posters against drug abuse



http://www.nd.gov.hk/en/antidrug_resources.htm



36.36.66Stimulants and Stimulants and their Adverse their Adverse

EffectsEffects



36.6 Stimulants and their Adverse Effects (SB p.200)

Stimulants(興奮劑 )

a drug that increases the activity of various parts of our nervous system

provides us a temporary sense of alertness and well-being as

well as relief from fatigue

can be used to boost endurance and productivity as well as to suppress

appetite




Examples of stimulants : -

Amphetamine (Yaba, Ice)

Cocaine (crack, snow)

Ecstasy(搖頭丸 /忘我 /狂喜 /E 仔 )




Ketamine(Ketamine( 氯胺酮氯胺酮 ))

• Not a stimulant

• Also known as K, Ket, special K, or Kitty

• Belongs to a class of drugs called “dissociative(解離 / 人格分裂 )anaesthetics”

A dissociative drug is one which reduces (or blocks) signals to the conscious mind from other parts of the brain

Dissociative disorder 解離症 / 人格分裂




• First used on American soldiers during the Vietnam War, but it is often avoided now

it can cause unpleasant out-of-body experiences

• Still used widely in veterinary medicines, and for certain human applications

Ketamine(Ketamine( 氯胺酮氯胺酮 ))




Keto group

2o amine*

* chiral centre

Ketamine(Ketamine( 氯胺氯胺酮酮 ))



NHCH3

O

Cl

C13H16ClNO

1

2

12

93

cyclohexanone

2-(2-chlorophenyl)

2-(methylamino)

2-(2-chlorophenyl)

-2-(methylamino)

Ketamine(Ketamine( 氯胺氯胺酮酮 ))




• At low doses

causes an increase in heart rate

gives a mild, dreamy feeling and drowsiness

Adverse Effects of Use of Ketamine




• At higher doses

produce a hallucinogenic effect( 幻覺 )

may cause the users to feel very far away from their body

this effect is referred to as entering a “K-Hole”, and has

been compared to a near death experience with sensations of rising above one’s body





• Frequent intake of ketamine can cause

depression

nausea

impaired long-term memory and cognitive difficulties

impaired motor function, respiratory and heart problems





• Frequent intake of ketamine can cause

a tremendous physiological/psychological dependence

addiction





Phenylethanamine andPhenylethanamine andSubstituted PhenylethanaminesSubstituted Phenylethanamines

• Phenylethanamine (or 2-phenylethan-1-amine) is an alkaloid and monoamine





• Phenylethanamine

believed to function as a neurotransmitter in the

human brain

found in many food like chocolate and is responsible for its

effects on mood, appetite and sense of well- beingChocolate as a

drug





• Phenylethanamine

may have psychoactive effects in sufficient quantities, but

quickly metabolized in our body





• Substituted Phenylethanamine

a broad and diverse class of compounds

include hormones, stimulants, hallucinogens( 迷幻劑 ) and

antidepressants( 抗鎮抑劑 )





Amphetamine

a homologue of phenylethanamine

carrying an methyl group

*





Amphetamine synthetic stimulant

used to suppress the appetite, control weight and treat disorders

including narcolepsy(渴睡症 ) and attention-deficit hyperactivity disorder (ADHD)





used recreationally and for performance enhancement

these uses are illegal in most countries

Amphetamine




Adverse Effects of Use of Amphetamine• The side effects:

insomnia(失眠 )

Irritability(煩躁 )

loss of appetite

hallucination(幻覺 )

heart and kidney failure

tolerance




Chronic users of amphetamines:

Adverse Effects of Use of Amphetamine

chronic heavy users generally fail to eat properly (Anorexia, 厭食症 )

develop various illnesses related to vitamin deficiencies and

malnutrition

psychologically dependent on amphetamines




more prone to illness

develop mental disturbance known as amphetamine psychosis(精神病 )

Adverse Effects of Use of AmphetamineChronic users of amphetamines:




The END



We do not want to rely on the natural products (like willow trees) as medicines (like salicylic acid). Why?

Medicines which are “natural products” (e.g. those which come directly from plants) may be difficult to obtain when needed. The supply may be seasonal, may depend on weather conditions and may be liable to contamination. Collecting plants from their natural habitat may cause harms to the environment. Back


Anise for Tamiflu



At the end of the 19th century, the compound phenol was already well-known in the pharmaceutical industry. Phenol has germicidal properties. It was also readily available and its molecular structure differs from that of 2-hydroxybenzoic acid by only one functional group.

Phenol 2-Hydroxybenzoic acid




(a) What extra atoms have to be added to phenol to give

2-hydroxybenzoic acid?Answer(a) 1 carbon atom and 2 oxygen atoms




(b) Suggest reagents and conditions necessary to bring about the change from phenol to 2-hydroxybenzoic acid.

Answer


(b) Carbon dioxide can be combined directly with phenol to give

2-hydroxybenzoic acid by careful control of the conditions. In an

alkaline medium, phenol is heated with carbon dioxide at 130°C

and under a pressure of 5 – 7 atm. Subsequent acid hydrolysis

yields salicylic acid. The reaction is known as the Kolbe-Schmitt

synthesis.

Back



Aspirin belongs to a class of organic compounds known as esters. Esterification of salicylic acid with a reagent is used to produce aspirin.

(a) Suggest reagents for converting salicylic acid to aspirin in the esterification.

(a) Ethanoyl chloride and ethanoic anhydride may be used.




Aspirin belongs to a class of organic compounds known as esters. Esterification of salicylic acid with a reagent is used to produce aspirin.

(b) Write a chemical equation for the reaction involved.


Answer




(b)



(b)


Back



(a) What is the lead compound of aspirin?

(a) 2-Hydroxybenzoic acid (or salicylic acid)




(b) Why is molecular modification of the lead compound of aspirin necessary?

(b) It is because the lead compound of aspirin has many undesirable effects. It irritates and damages the lining of the mouth and stomach.


Back



cis-Platin is a prescription drug.

(a) What is the meaning of a prescription drug?


(a) A prescription drug means that the use of the drug must be prescribed by a medical doctor.



cis-Platin is a prescription drug.

(b) Why is cis-platin regarded as a prescription drug?


(b) cis-Platin is a prescription drug because it has numerous side effects on our health.

A professional decision from the medical doctor is necessary for its adminstration.

Back



Based on the structural formula of ketamine shown above, answer the following questions:

(a) Give the molecular formula of ketamine.

Answer


(a) C13H16ClNO




(b) Name all the functional groups of ketamine.


Answer(b) Amine (secondary), ketone, halobenzene, benzene ring




(c) Mark the chiral centre of ketamine in its structural formula.


(c)

Back



(a) Is amphetamine a primary, secondary or tertiary amine?

(a) A primary amine




(b)

(*chiral

centre)

Amphetamine

(b) Mark the chiral centre of the molecule of amphetamine in its structural formula.

Back


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