Antipyretic Analgesics

1
Chapter 6

• Antipyretic Analgesics
• Nonsteroidal Anti-inflammatory Agents

2
Section 2

• Nonsteroidal Antiinflammatory Agents

3
Request and propose

• Master the classification of NSAIDs, the chemical
  structure and name, physico-
• chemical property, metabolism, and synthesis
• of Oxyphenbutazone, Indometacin, and
  Ibuprofen.
• Familiar with Mefenamic acid, Piroxicam,
  Diclofenac sodium and Naproxen.
• Get some information of Celecoxib.

4
Classification
pyrazolone
Oxyphenbutazone
Indoleacetic acid
Indometacin
Mefenamic acid
Anthranilic acid
1,2-benzothiazine
Piroxicam
Phenylacetic acid
Diclofenac sodium
Ibuprofen
Arylpropionic acid
5
Oxyphenbutazone(???)
4
5
1
3
2

• 4-Butyl-1-(4-hydroxyphenyl)-2-phenyl-3,5-pyrazolid
  inedione

6
Development

• While researching for antipyretics of the
  quinoline type, in 1884, Ludwig Knorr discovered
  the 5-pyrazolone now known as antipyrine?

antipyrine
aminophenazone
Metamizole sodium
Hypoleucocytosis(?????)and agranulocytosis(??????)
7
Development

• In 1946, Swiss developed Phenylbutazone with the
  basic structure of 3,5-pyrazolidinedione.

phenylbutazone
?-ketophenylbutazone
sulfinpyrazone
8
Development
oxyphenbutazone

• In 1961, the metabolite of phenylbutazone is
  oxyphenbutazone,which is also anti-inflammatory
  with less side effect.
• Later, Sulfinpyrazone and ?-ketophenyl-butazone
  were found to treat gout (??)and rheumatic
  arthritis (??????).

9
Relation between anti-inflammation and acidity
3
4
5
The proton was active due to the influence of
ketones in position 3 and 5.
10
Metabolism
OH
oxyphenbutazone
OH
phenylbutazone
?-hydrophenylbutazone
?-ketophenylbutazone
11
Physico-chemical property

• Heated with glacial acetic acid and hydrochloric
  acid, then sodium nitrite was added, the solution
  presents yellow finally ß-naphthol was added,
  some orange precipitation forms.

OH
12
Mefenamic Acid (????)
1
2
3

• 2-(2,3-Dimethylphenyl)aminobenzoic acid

13
Derivatives
Aspirin
14
Diclofenac Sodium(?????)

• Sodium 2-(2,6-dichloroanilino)phenylacetate

• Indicated for short- and long-term treatment of
  RA,
• OA, and ankylosing spondylitis(??????).
• Available as delayed-release tablets.

15
Chemosynthesis
Derivatives
16
Indomethacin(????)
4
3
5
1
2

• 1-(4- Chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-
  3-acetic acid

• A pale-white to yellow-tan crystalline powder.
• Soluble in ethanol and acetone and practically
  insoluble in water.
• Unstable in alkaline solution and sunlight.

17
Development

• Serotonin(5-???,???)may be the chemical
  pain-producing substance of inflammation
• Serotonin is concerned with Tryptophan(???)in
  vivo
• At the same time metabolic level of Tryptophan in
  the patients with rheumatalgia(???)is higher

18
Pharmacologic action

• Mechanism
• In clinic
• Side effects

Not anti-serotonin, but an inhibition of the
biosynthesis of prostaglandins.
Widely used as an anti-inflammatory analgesic in
RA, spondylitis(???), and OA, and to a lesser
extent in gout.
The most commons are gastric distress and
headache.
Also associated with peptic ulceration(?????),
blood disorders, and possible deaths.
Appear to be dose related. Not recommended for
use in children.
19
Derivatives
Indomethacin
Stronger anti-inflammatory action, and weaker
toxicity.
20
Ibuprofen(???)
S-() isomer

• a-Methyl-4-(2-methyl propyl)phenylacetic acid
• 2-(4-isobutylphenyl)propionic acid

21
Development of ibuprofen

• While researching for auxine(???), discovered
  that arylacetic
• acid possessed anti-inflammatory action.
• Ibufenac firstly go on the market.
• Introduction of the a-methy group on the acetic
  acid moiety to
• get Ibuprofen.
• A methy group was replaced by an ethyl group to
  get Butibufen
• whose anti-inflammation was similar as
  Ibuprofen with less
• gastrointestinal irritation.

Ibufenac
Butibufen
22
Development of ibuprofen
Ibufenac
Ibuprofen

• Although ibufenac was several times more potent
  than
• aspirin, it showed occasional hepatotoxicity
  in humans.
• When a methyl group was added to the acetic acid
  subunit,
• a much safer drug resulted (ibuprofen)with
  diminished
• gastrointestinal irritation and no
  hepato-toxicity, even in
• large doses.

23
Drugs commonly used
name Chemical structure potency name Chemical structure potency
Ibuprofen 1/10 Indoprofen 2
Fluprofen 5 Pirprofen 1
Ketoprofen 1.5 Naproxen 1
24
Metabolism of Ibuprofen
25
SAR of Ibuprofen
26
Chemical synthesis
Friedel-Crafts reaction
Hydrolysis, De-carboxyl, rearrangement
aß-epoxy ester
Darzens Reactionhydrolysis, decarboxyl,
rearrangement
27
Darzens Reaction
28
Naproxen(???)
1
2
S()isomer
3
6
4
5

• ()6-Methoxy-a-methyl-2-naphthaleneacetic acid

• White to off-white crystal.
• Sparingly soluble in acidic solutions, freely
  soluble in
• alkaline solutions, and higly soluble in
  organic or lipid-like
• solutions.

29
SAR
30
Metabolism of Nabumetone
Nabumetone
Nabumetone serves as a prodrug to it metabolite,
6-methxoxy-2-naphthylacetic acid.
31
Pharmacologic action

• Like aspirin, inhibits prostaglandin synthetase
  and prolongs blood-clotting time.
• Its potency for inhibit prostaglandin
  synthetase
• is stronger 12 times than Asprin,
• stronger 10 times than phenylbutazone,
• stronger 3-4 times than ibuprofen,
• but is weaker 300 times than indomethacin.

Recommended for use in rheumatoid and gouty
arthritis.
Also available over-the-counter (OTC).
32
Naproxen

• Side effects

Dizziness(??), drowsiness(??), and nausea, with
infrequent mention of gastrointestinal tract
irritation.
Not recommended for pregnant or
lactating(??)women or children under 16.
Risk of heart attack or stroke.
33
Piroxicam(????)
4
3
2
1

• 4-Hydroxy-2-methyl-N-(2-pyridinyl)-2H-1,2-benzothi
  azine
• -3-carboxamide-1,1- dioxide
• Systematic (IUPAC) name
• (8E)-8-hydroxy-(pyridin-2-ylamino)methyl
  idene-9-methyl-10,10-dioxo-10?6-thia-9-azabicyclo
  4.4.0deca-1,3,5-trien-7-one
• 
  fromhttp//en.wikipedia.org/wiki/Piroxicam

34
Piroxicam

• Piroxicam is a non-steroidal anti-inflammatory
  drug used to relieve the symptoms of rheumatoid
  and osteoarthritis act as an analgesic.
• Used in veterinary medicine(??)to treat certain
  neoplasias expressing cyclooxygenase (COX)
  receptors, such as bladder(??), colon(??), and
  prostate(???)cancers.
• Manufacturerd by Pfizer under the tradename
  Feldene.
• Other brand names "Brexidol", "Brexin", "Erazon",
  "Felden", "Feldoral", "Hotemin", "Pirox von ct",
  "Proponol", "Reumador", "Tracam", "Veral",
  "Vurdon".

35
Mechanism

• Represents a class of acidic inhibitors of
• prostaglandin synthetase.
• Non-steroidal anti-inflammatory drug.
• A non-selective COX inhibitor possessing both
• analgesic and antipyretic properties.
• It undergoes enterohepatic circulation(????).
• Very long acting, with a plasma half-life of
  50h.
• Requiring a dose of only 20 to 30mg once
  daily.
• Giving results similar to those from 25 mg
  of
• indometacin or 40mg ibuprofen 3 times a day.

36
Adverse effects

• Result in gastrointestinal toxicity,
  tinnitus(??), dizziness(??), headache, rash(?),
  and pruritus(??). The most severe adverse
  reactions are peptic ulceration(?????)and
  gastrointestinal bleeding.
• Approximately 30 of all patients receiving daily
  doses of 20 mg of piroxicam experience side
  effects.
• May cause skin to become more sensitive to
  sunlight. Avoidance of sunlight and use of
  sunscreen is recommended.

37
Derivatives
Piroxicam
Isoxicam
sudoxicam
tenoxicam
meloxicam
Methyl group was introduced, no gastrointestinal
tract irritation.
mrthy
38
Celecoxib (????)
F-substitution is best
Other name Celebrex.
5-m ring with an electro-withdrawing group
It is a COX-2 inhibitor
39
Oxyphenbutazone
Piroxicam
Diclofenac Sodium
Indomethacin
Mefenamic Acid
Naproxen
Ibuprofen
40
Exercise(1)

• Which of the following drugs only relieve fever
  and pain,without antiinflammatory

1. Metamizole sodium
2. Aspirin
3. Paracetamol
4. Naproxen
5. Piroxicam

v
41
Exercise (2)

• Whose activity in the following drugs is similar
  to the structure

1. Phenobarbital
2. adrenalin
3. Ibuprofen

D. Diphenhydramine E. Nifedipine
v
42
Exercise (3)

1. Diclofenac sodium
2. Ibuprofen
3. Aspirin

D. Indometacin E. Paracetamol
A

• Sodium O-(2,6-dichloroanilino) phenylacetate
• 1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-ace
  tic acid

D
43
Exercise (4)

• Which of the following items match Ibuprofen

1. Belong to NSAIDs
2. Be used for gout
3. Possesses a chiral carbon, and racemic body used
   in clinic
4. Contains isobutyl in its chemical structure
5. Used as an anti-ulcerative drug

v
v
v
44
Exercise (5)
B
C
A
E
D
F
B

• Piroxicam
• Ibuprofen
• Naproxen

F
E
45
Case study (1)

• Six months ago, GZ began playing tennis ball
  during his lunch hour with one of his colleagues.
  
• Today, he visited his physician complaining of
  sore elbow.
• His physician has diagnosed the problem as
  bursitis, and wants to prescribe treatment for
  the problem.

46
Q

• Which of the agents should not be used in the
  patient? Explain your answer using the chemistry
  of the compounds.

47
Case study (2)

• A two-year-old child is rushed to the emergency
  room of your hospital by his distraught mother.
• She tells the E.R. staff that her boy ate
  approximately half of a full bottle of Tylenol
  (acetaminophen) tablets.
• Along with gastric lavage, you recommend the po
  administration of a 5 solution of Cysteine

48
Q1 and Q2

• How is acetaminophen normally metabolized? Based
  on this metabolic route, what medical emergency
  is facing this child?
• What is the chemical rational for the
  administration of Cysteine