Section 13.2 Drugs (Book 3B, Chapter 36)

1
Section 13.2 Drugs(Book 3B, Chapter 36)
2
Syllabus for consideration
3
Syllabus for consideration (12.6)
4
overview

• Drugs and medicine an introduction
• Key stages of drug development
• Some common drugs
• Dangerous drugs
• Chiral drugs

5
overview

• Drugs and medicine an introduction
• Key stages of drug development
• Some common drugs
• Dangerous drugs
• Chiral drugs

6
Drugs and medicine

• Drugs chemical substances producing
  physiological effects on human body
• Often act by altering a range of biological
  processes
• Carefully researched, monitored by doctors or
  pharmacists or else extremely hazardous
• Medicine Drugs prescribed by doctors
• Poisons if drugs taken abusively excessive
  intake death (e.g. excessive paracetamol (a
  painkiller,???????) coma or death)

7
Drugs and medicine

• Most drugs are natural products modified by
  chemical reactions or are synthetic chemical
  substances.
• Categorized according to their use
• Painkillers (???)
• Antacids (???)
• Antibiotics (???)
• Cancer drugs (???) etc.
• Categorized according to their biological
  effects
• Narcotics (???)
• Analgesics (???)
• Hallucinogens (???)
• Depressants (???)
• Stimulants (???)
• Tranquillizers (???)etc.

8
Drugs and medicine (3B 194 196)

• In ancient times, drugs discovery related to
  finding of natural products showing medicinal
  effects
• From extracts of animals, plants and even
  minerals
• Nowadays, drug development is a systematic
  process including stages of
• Lead compound discovery (???????)
• Molecular structural modeling (????)
• Dosage formulation (????)
• Safety tests and trials (?????????)
• Approval from government monitoring agency (????)
• Two examples aspirin (????) and cisplatin (??)

9
overview

• Drugs and medicine an introduction
• Key stages of drug development
• Some common drugs
• Dangerous drugs
• Chiral drugs

10
Key stages of drug development

• Aspirin
• Cis-platin

11
Key stages of drug development

• Aspirin (Book 3B, p.191 p.192)
• Cis-platin

12
Key stages of aspirin developmentLead compound
discovery

• Aspirin development originated from discovery of
  medicinal use of the bark of the willow tree (??)
  240 years ago
• In 1827, a Scottish physician used extracts to
  treat acute rheumatism (???)
• Active ingredient found to be salicin (???)
  (isolated from willow bark and flowers of
  meadowsweet (??????) plant)

13
Key stages of aspirin developmentMolecular
modiFication)

• 1870, Prof von Nencki discovered salicin was
  converted to salicylic acid (???) in the body.
• Synthesis of salicylic acid and prescribed to
  cure fevers
• BUT salicylic acid causes serious burns and
  irritation to oral cavity, oesophagus and
  stomach.
• ? patients taking salicylic acid ulcers (??)

14
Key stages of aspirin developmentmolecular
modification

• Reduce side effect, use sodium hydroxide to
  neutralize carboxylic acid group
• i.e. use sodium salicylate instead
• This salt derivative works as an antipyretic
  (???) and the irritation (??) is reduced.

15
Key stages of aspirin developmentmolecular
formulation

• BUT sodium salicylate tastes awful and the
  patient would vomit badly if a large dose is
  taken.
• 1897 Felix Hofmann from Bayer synthesized a new
  compound by acetylation of the phenol group
  producing acetyl salicylic acid (or ASA).
• ASA a mild irritant, a reasonable taste, good
  fever-reducing and pain relieving properties

16
Key stages of drug development dosage
formulation

• ASA large scale synthesis
• Initially as a powder in packers and later made
  into tablets
• Today ASA formulations include additives like
  buffers.

17
Key stages of aspirin development safety tests
and human trials

• Two stages
• Preclinical trial
• Clinical trial
• Preclinical trials
• On tissue samples and live animals
• Provide useful information on the drugs
  absorption, distribution (transportation inside
  the body), metabolism and elimination in the
  body.
• Clinical trial
• Involve human testing
• Ethical and legal issues
• To be conducted under stringent legal approval by
  a recognized ethical committee
• If pass all the trials certificates

18
Key stages of aspirin development market approval

• Aspirin synthesized and marketed by Bayer
  Company
• Initially as a powder than as a 500 mg tablet
• One of the first drugs in the world to be
  available in a standardized dosage.

19
Key stages of drug development

• Aspirin
• Cis-platin (3B, p.193)

20
Key stages of cis-platin developmentLead
compound discovery

• Discovered accidentally in 1961 by a biophysicist
  (Prof Barnett Rosenberg)
• Studying effect of electromagnetic radiation on
  the growth of E.coli.
• After the experiment, bacteria growth inhibited
  by electrolysis product of the Pt electrodes.
• Rosenberg Growth of E. coli. Was inhibited by a
  square planar complex, cisplatin
  (cis-dichlorodiamineplatinum(II)) and light
• Further investigated by other chemists

21
Key stages of cis-platin development lead
compound discovery

• Rosenberg use of cis-platin in animal tests in
  1968
• Cis-platin
• capable of stopping the rapid cell division in
  bacteria at concentrations that are effective yet
  without significant toxicity.
• Reduce the size of cancerous tumors in mice
• Cisplatin use in anti-cancer treatment

22
Key stages of cis-platin developmentmolecular
modification

• Rosenberg noticed that the trans isomer is
  thermodynamically more stable, it is a much less
  active complex for cancer treatment
• Other chemical derivatives (change its ligands)
  potent anti-tumor variants of cis-platin

23
Key stages of cis-platin development molecular
modification

• Common features in cis-platin and its
  derivatives
• Geometries (all square planar)
• All electrically neutral
• Two cis-monodentate ligands or a bidentate ligand
• Cyclic ligands can enhance the antitumor
  activities of the complexes BUT the solubility of
  complex would be decreased

24
Key stages of cis-platin development dosage
formulation

• Serious difficulties in formulation
• Side effects
• Nausea (????)
• Vomiting (??)
• Renal failure (???)

25
Key stage of cis-platin development safety test
and human trials

• In vivo studies (????) almost discontinued due
  to the toxicity
• Clinical trial
• Cvitkovic and coworkers aggressive diuresis
  (????) in minimizing renal damage
• Gralla et al. using antiemetic drugs (???)
  resolving nausea and vomiting problems

26
Key stages of cis-platin developmentmarket
approval

• Administered in a chloride containing solution
• Side effects several drugs taken together
• Mannitol (???) increase urine flow (deal with
  renal failure)
• Injecting anti-emetics (???) minimize nausea and
  vomiting
• Since 1970s, treat various cancers
• Ovarian
• Testicular
• Lung

27
overview

• Drugs and medicine an introduction
• Key stages of drug development
• Some common drugs
• Dangerous drugs
• Chiral drugs

28
Over-the-counter drugs and prescription drugs
(3B, p.197)

• Over-the-counter drugs
• Aspirin
• Acetaminophen
• Vitamin C
• Prescription drugs
• Albuterol
• Amlodipine
• Loratadine
• Amoxicillin
• Omeprazole

29
Over-the-counter drugs

• Aspirin

30
Over-the-counter drugs

• Analysis of aspirin
• (See handout)

31
Over-the-counter drugs

• Acetaminophen (paracetamol, p-acetaminophenol)
• An analgesic that relieves pains such as
  headaches
• Less corrosive to stomach and is an alternative
  to aspirin
• Present in Panadol, Saridon, Tylenol and Fortolin

32
Over-the-counter drugs

• Vitamin C (Ascorbic acid)

33
Common names of prescription drugs (3B, p.198)
34
Common names of drugs use common names for
easier reference (3B, p.198)

• Albuterol (???)
• Asthma medicine (???)

35
Common names of drugs use common names for
easier reference (3B, p.198)

• Amlodipine (????)
• Reduces blood pressure
• Peripheral arterial vascodilator (??????????)

36
Common names of drugs use common names for
easier reference (3B, p.198)

• Prilosec (Omeprazole,????)
• Treatment of heartburn, stomach ulcers

37
Common names of drugs use common names for
easier reference (3B, p.198)

• Loratadine (????)
• Antihistamine (????)

38
Common names of drugs use common names for
easier reference (3B, p.198)

• Amoxicillin (???????????)
• Antibiotic (???)

39
overview

• Drugs and medicine an introduction
• Key stages of drug development
• Some common drugs
• Dangerous drugs
• Chiral drugs

40
Dangerous drugs

• Narcotic drugs
• Morphine and heroin
• Stimulant drugs
• Ketamine, methamphetamine and phenylethylamine

41
Dangerous drugs

• Narcotic drugs
• Morphine and heroin
• Stimulant drugs
• Ketamine, methamphetamine and phenylethylamine

42
Dangerous drugs Narcotic drugs (????)

• Chemical substances relieving pain by numbing the
  senses, inducing sleep
• Highly addictive
• Many countries ban their imports manufacture or
  possession
• Commonly abused narcotic drugs
• Morphine (??)
• Heroin (???)

43
Dangerous drugs Narcotic drugs(3B, p.199)

• Opium (??) and morphine (??)
• From opium puppy (??)
• A mixture of alkaloids,?????(organic bases)
• Most abundant alkaloid morphine (10 opium)

44
Dangerous drugs narcotic drugs

• Morphine and its analogues most effective
  painkillers BUT strong addiction
• Codeine (???) less addictive while less
  pain-killing
• Replacing the hydroxyl group by methoxy group

45
Dangerous drugs narcotic drugs

• Heroin (3B, p.199)
• Two hydroxyl groups replaced by two acetoxy
  groups
• More powerful narcotic BUT more addictive

46
Danerous drugs Heroin

• Precursor chemicals
• Acetic anhydride (CH3 C O CCH3)
• 
  
• O O
• Acetyl bromide (CH3COBr)
• Acetyl chloride (CH3COCl)
• Acetone ((CH3COCH3)
• Ethyl ether (CH3CH2OCH2CH3)

47
Methadone (???)
http//en.wikipedia.org/wiki/Methadone accessed
on 28/12/2007
48
Comparing structures of heroin and methadone
Heroin
49
Cannabis (??)

• Contains Cannabinoids Some examples

http//en.wikipedia.org/wiki/Cannabinoids
accessed on 28/12/2007
50
Cannabis
51
Dangerous drugs narcotic drugs(3B, p.200)

• Adverse effects (????) of narcotics
• Dependence (??)
• Respiratory depression (????)
• Drowsiness (????)
• Death in high dosages
• Severe withdrawal symptoms????(cramps??,
  sweating??, running nose???and tearing)
• Illegal in trafficking and possession in many
  countries

52
Dangerous drugs

• Narcotic drugs
• Morphine and heroin
• Stimulant drugs
• Ketamine, methamphetamine and phenylethylamine

53
Dangerous drugs stimulant drugs (?????)

• Chemicals causing an increase of alertness and
  physical awareness (???????????????) in the body
• Often addictive
• Increase pulse rate and respiratory rate
• Addicts of stimulants indulge (??) in the
  temporary feeling of a boost of energy (????????)
  brought on by the drug
• To counter the effect of depressants???(e.g.
  sleeping pills???)

54
Dangerous drugs stimulant drugs

• Ketamine (???) (3B, p.201)
• A stimulant patented (??) in 1963
• A general anesthetic (???) if properly prescribed
• Dream-like feelings hallucinations(??), deliria
  (????)
• Also named Ketalar K?

55
Dangerous drugs stimulant drugs

• Ketamine (???)

56
Dangerous drugs stimulant drugs

• Ecstasy (MDMA, ?? Fing Tau Pills)

http//www.3dchem.com/molecules.asp?ID60
accessed on 28/12/2007
57
Dangerous drus ecstasy

• Precursor chemicals
• Safrole (???)
• Isosafrole
• Piperonal
• 3,4-Methylenedioxy-phenyl-2-propanone

http//www.chemblink.com/products/94-59-7.htm
accessed on 28/12/2007
http//potency.lbl.gov/chempages/ISOSAFROLE.html
accessed on 28/12/2007
http//www.inchem.org/documents/jecfa/jecmono/v44a
je32.htm accessed on 28/12/2007
http//www.isomerdesign.com/Cdsa/scheduleUN.php?sc
hedule3sectionALLstructureC accessed on
28/12/2007
58
Dangerous drugs LSD ???

• Lysergic acid diethylamide (LSD)

http//en.wikipedia.org/wiki/LSD accessed on
28/12/2007
59
Dangerous drugs lsd
http//www.isomerdesign.com/Cdsa/scheduleUN.php?sc
hedule3sectionALLstructureC accessed on
28/12/2007

• Precursor chemicals
• Ergotamine Ergometrine
  Lysergic acid

60
Dangerous drugs stimulant drugs

• Methamphetamine (??????)
• A member of amphetamine ???? family
• Causes a release of dopamine ??? and
  noradrenaline ?????? from the CNS
• Feelings of arousal ????, euphoria ??, strength
  ????, self-assertion ??, enhanced motivation ????
  and focus ???, diminished need for sleeping or
  eating
• Last for many hours as amphetamine is not readily
  broken down by body

61
Dangerous drugs stimulant drugs

• Methamphetamine
• After-effects (???)
• Lows of intense mental depression (????)
• Fatigue (??)
• due to the depletion of dopamine
• An illegal drug
• Common names speed ?????, chalk ????
• Also known as ice ??? as methamphetamine
  hydrochloride in form of clear chunky????crystals

62
Dangerous drugs stimulant drugs

• Methamphetamine (3B, p.202)

63
Dangerous drugs Amphetamine-type stimulant
http//www.isomerdesign.com/Cdsa/scheduleUN.php?sc
hedule3sectionALLstructureC accessed on
28/12/2007

• Precursor chemicals
• Ephedrine Pseudoepherdrine 1-phenyl-2-
• propanone
• Phenylacetic acid Norephedrine

64
Dangerous drugs stimulant drugs

• Phenylethylamine (????) (3B, p.202)
• Resembles amphetamines
• Increase blood glucose level and blood pressure
  to enhance alertness and a sense of well being
  and contentment (???????)
• Prescribed to treat narcolepsy (???)
• Found in chocolates
• High dosage a physiological effect similar to
  ketamine

65
Dangerous drugs stimulant drugs

• Phenylethylamine (????)

66
Dangerous drugs stimulant drugs

• Ketamine and methamphetamine illegal stimulants
  in HK
• Adverse effect (3B, p.203)
• Prolonged abuse will cause
• Insomnia (??)
• Depression (??)
• Loss of appetite (????)
• Eventually
• Heart and kidney failure (???????)

67
Other dangerous drugs Mandrax (Methaqualone ??,
??? )

• sedative hypnotic drug

http//www.indopedia.org/Methaqualone.html
accessed on 28/12/2007
http//www.indopedia.org/Methaqualone.html
accessed on 28/12/2007
68
Other dangerous drugs Mandrax (Methaqualone)
http//www.isomerdesign.com/Cdsa/scheduleUN.php?sc
hedule3sectionALLstructureC accessed on
28/12/2007

• Precursor chemicals
• Anthranilic acid
• N-acetylanthranilicacid

69
Other dangerous chemicals angel dust
(Phencyclidine, PCP Tenocyclidine, TCP)

• Originally used as anaesthetic (??)
• Exhibits a hallucinogenic (??) effect

http//en.wikipedia.org/wiki/Tenocyclidine
accessed on 28/12/2007
http//en.wikipedia.org/wiki/Phencyclidine
accessed on 28/12/2007
70
Other dangerous chemicals angel dust (PCP TCP)
http//www.isomerdesign.com/Cdsa/scheduleUN.php?sc
hedule3sectionALLstructureC accessed on
28/12/2007

• Precursor chemical Piperidine

71
Other dangerous drugs cocaine???

• A stimulant drug

http//en.wikipedia.org/wiki/Cocaine accesed on
27/12/2007
72
Other dangerous drugs cocaine
http//www.isomerdesign.com/Cdsa/scheduleUN.php?sc
hedule3sectionALLstructureC accessed on
28/12/2007

• Precursor chemicals
• Potassium permanganate
• Methyl ethyl ketone
• Toluene
• Sulphuric acid
• Hydrochloric acid

73
Other dangerous drugs GHB (Gamma
hydroxybutyrate, ??? )

• Originally used as a sleep-aid

74
Other dangerous drugs benzodiazepine (BZD,???)

• Sedative, hypnotic drug
• (???????)
• As tranquillizers (???)
• Surreptitiously slipped into
• the drink of the intended victim

http//en.wikipedia.org/wiki/Benzodiazepine
accessed on 28/12/2007
75
Benzodiazepines
http//en.wikipedia.org/ accessed on 28/12/2007
76
Poster from Customers excise Department
77
Poster from Customers excise Department
(http//www.isomerdesign.com/Cdsa/scheduleUN.php?s
chedule3sectionALLstructureC accessed on
28/12/2007)
78
Viagra (Sildenafil citrate)
79
For treatment of obesity Sibutramine (????)

• trade name Meridia in the USA, Reductil in Europe
  and other countries)
• Structurally related to amphetamines

Amphetamine
Sibutramine http//en.wikipedia.org/wiki/Sibutrami
ne accessed on 28/12/2007
80
For treatment of obesity Dexfenfluramine (??????)
http//en.wikipedia.org/wiki/Dexfenfluramine
accessed on 28/12/2007
81
overview

• Drugs and medicine an introduction
• Key stages of drug development
• Some common drugs
• Dangerous drugs
• Chiral drugs

82
Syllabus for consideration

• 11.4 Under relevant activities (3rd column)
• Search and present information ion chiral drugs

83
Chiral drugs

• What is chirality?
• 3 types of stereoisomers
• Importance of chirality in drug development
• Chiral drugs in daily life

84
Chiral drugs

• What is chirality?
• 3 types of stereoisomers
• Importance of chirality in drug development
• Chiral drugs in daily life

85
What is chirality?

• Chirality is the property possessed by a
  molecule with such spatial arrangement of atoms
  that it cannot superimpose on its mirror image.
• The object and mirror image pair of molecules has
  the same constituents and structural formula.
• Their relationship with each other is similar to
• our left and right hands.

86
What is chirality?

• The carbon atom of a simple chiral centre has
  four different groups arranged tetrahedrally.
• Isomers of such nature are called enantiomers.

87
Chiral drugs (????)

• What is chirality?
• 3 types of stereoisomers
• Importance of chirality in drug development
• Chiral drugs in daily life

88
3 types of stereoisomers (?????)

• Enantiomers
• Diastereomers
• Geometrical isomers.

89
Enantiomers (?????)

• Enantiomers are two stereoisomers containing
  asymmetric carbon atoms related as
  non-superimposable object and mirror images.
• If an enantiomer rotates polarized light to the
  right or in a clockwise direction, it is said to
  be the () or the dextrorotatory isomer.
• If the plane polarized light is rotated to the
  left or in a counter-clockwise direction, the
  isomer is called as the (-) or the levorotatory
  isomer.
• Enantiomers are identical in chemical and
  physical properties except for the direction of
  rotation of plane polarized light.

90
Diastereomers (??????)

• Diastereomers are stereoisomers that are not
  related as object and mirror images.
• They contain at least two asymmetric carbon
  atoms.
• Unlike enantiomers, the physical and chemical
  properties of diastereomers can differ and it is
  not unusual for them to have different melting
  and boiling points, refractive indices,
  solubility, etc.

???
????
91
Geometrical isomers (?????)

• Geometrical isomers are molecules with a
  carbon-carbon double bond and they are not
  optically active.
• When the groups attached to each end of the
  double bond are on the same side, the
  stereoisomer is named as cis-isomer when the
  groups are on the opposite sides, the
  trans-isomer designation is used.

92
Chiral drugs

• What is chirality?
• 3 types of stereoisomers
• Importance of chirality in drug development
• Chiral drugs in daily life

93
Why is chirality important in drugdevelopment?

• Biological systems like that of human beings have
  been known to exhibit chirality.
• This is reflected by the existence of chirality
  of drug receptor areas and the requirement of
  chiral specificity on drugs.
• In order to understand the biological effect of
  drugs, we have to distinguish the three main
  phases of their action.

94
Why is chirality important in drugdevelopment?

• The first phase is the initial receptor
  differentiation phase, where different drugs have
  different affinity and tissue specificity due to
  receptor (??) differentiation and distribution
  for the parent compound formed.
• The second phase is the absorption, distribution,
  metabolism and excretion phase, where the type of
  bioavailability (?????) is determined.
• The third phase is the interaction of the drug
  with the molecular site of action, leading to the
  observed therapeutic effect (??).

95
Why is chirality important in drugdevelopment?

• The three phases of action are based on the
  receptor theory, similar to the lock-and-key
  hypothesis proposed by the famous scientist Emil
  Fischer.
• Receptor molecules in the body are proteins that
  exhibit high affinities for the binding of
  molecules with certain structures.
• This is completely analogous to enzyme-substrate
  binding.
• Mismatching of drug molecules with the targeted
  receptors may cause undesirable side effects such
  as requirement of higher dosage and increased
  toxicity.

96
Why is chirality important in drugdevelopment?

• All pharmacological activity may reside in one
  enantiomer.
• The therapeutic inactive isomer is regarded as an
  impurity that possesses a different or
  undesirable pharmacological entity.
• This situation may become even more acute if the
  active enantiomer exhibits a low therapeutic
  value or there is clinically significant
  toxicity.
• A well-known example of therapeutic-specific pair
  is the R- and S-enantiomers of thalidomide (the R
  and S designation, after Cahn, Ingold and Prelog,
  is a way of naming enantiomers by their
  structures).

97
Why is chirality important in drugdevelopment?
98
Why is chirality important in drugdevelopment?

• The R-enantiomer is an effective sedative (???),
  which is a medication with calming and soothing
  effect that relieves anxiety(????) and promotes
  sleep(??).
• However, the S-enantiomer may cause teratogen
  (??) formation.
• A teratogenic foetus is one with deficient,
  redundant, misplaced or grossly misshapen
  parts.(???????????????????)
• S-Thalidomide was shown to be responsible for
  over 2,000 cases of serious birth defects in
  children born of women who took it during
  pregnancy.

99
Chiral drugs

• What is chirality?
• 3 types of stereoisomers
• Importance of chirality in drug development
• Chiral drugs in daily life

100
What drugs in our daily life are chiral?

• Chirality is an essential dimension in
  pharmacology.
• Worldwide sales of chiral drugs in
  single-enantiomer forms continue to grow.

101
What drugs in our daily life are chiral?

• The commonly used single-enantiomer drugs are
  grouped as follows
• Cardiovascular disease (???)
• Atorvastatin calcium (?????)
• Simvastatin (????)
• Pravastatin sodium (?????)and
• Valsartan (???)
• Central nervous system(????????)
• Paroxetine hydrochloride (??????)and
• Sertraline hydrochloride (?????)

102
What drugs in our daily life are chiral?

• The commonly used single-enantiomer drugs are
  grouped as follows
• Respiratory (??????)
• Fluticasone propionate (???????) and
• Salmeterol (????)
• Hematology (????)
• Clopidogrel bisulfate (???????)
• Gastrointestinal (????)
• Esomeprazole magnesium (???????)
• Antibiotic (???)
• Amoxicillin and (??????)
• Potassium clavulanate (?????)

103
overview

• Drugs and medicine an introduction
• Key stages of drug development
• Some common drugs
• Dangerous drugs
• Chiral drugs