Analgesic

1. 1
Chapter 6
Antipyretic Analgesics
&
Nonsteroidal Anti-inflammatory
Agents

2. 2
Section 2
Nonsteroidal
Antiinflammatory Agents

3. ANALGESICS
 Analgesics are the agents that relieve the pain without the loss
of consciousness or altering the other modalities.
 Generally they are used for the relief of moderate to severe
pain.
 Narcotics analgesics are the agents that cause sleep in
conjunction with their analgesic effect.
 If a narcotic is used for a prolong time , it may cause mental
and physical dependence.
 Physical dependence may lead to withdrawal side effects when
we stop taking the medicine.
Antipyretics
 Are the drugs which are used to decrease the
elevated temperature of the body.

5. 5
Purpose
 Master the classification of NSAIDs, the
chemical structure and name, physico-
chemical property, metabolism, and synthesis
of Oxyphenbutazone, Indomethacin, and
Ibuprofen.
 Familiar with Mefenamic acid, Piroxicam,
Diclofenac sodium and Naproxen.
 Get some information of Celecoxib.

6. Classification
1-NARCOTIC ANALGESICS:- include opiod analgesics
e.g, morphine and pethidine.
2-NON NORCOTICS/NSAIDS
Salicylic acid derivative

7. 7
Classification
pyrazolone
Indoleacetic acid
Anthranilic acid
1,2-benzothiazine
Arylpropionic acid
Phenylacetic acid
N
N
OH
O
O
Oxyphenbutazone
Indomethacin
Mefenamic acid
Piroxicam
Diclofenac sodium
Ibuprofen
N
O
H
OH
N
O
OH
O
O
Cl
O
OH
ONa
NH
Cl
Cl
O
S
N
NH N
O
OH
O O

9. ANTHRANILIC ACID DERIVATIVE
SYNTHESIS OF ASA
 Asprin can be obtained by the acetylation of salicylic
acid either with a mixture of acetic acid and acetic
anhydride in the presence of H2SO4
OR
 WITH THE ACETIC ANHYDRIDE IN THE PRESENCE
OF PYRIDINE.

11. Synthesis

12. Synthesis

13. SOLUBLE ASPRIN
(calcium acetyl salicylic acid)
Calcium Acetylsalicylic acid (CASA) is
prepared by the action calcium
ethoxide/methoxide and acetyl salicylic
acid and used in patients with gastric ulcer.

14. Sodium Salicylate
Sodium salicylate is much lesser acidic than other salicylic acid derivative.
It has no gastric irritation and can be used in individuals having hypersensitivity to
asprin.
It can enter CNS by crossing BBB and cause sedation and drowsiness and seduction in
large dose.

15. Phenyl salicylate
HEAT,120 C
POCl3
Used as antipyretics and internal antiseptic
It is not usually hydrolysed in stomach but in the intestine it gradually hydrolyzed
Into salicylic acid and phenol respectivrly.Liberted phenol exerts antiseptic action
Without any undue toxic effect.
Thus the administration of the drugs on above criteria is commonly termed as
Salol principle.
Compounds in which both acid and phenol/alcohol remain active is called salols.

23. MEDICINAL USES
 Acetylsalicylic acid (ASA) belongs to the
group of medications called analgesics
(pain relievers), antipyretics (fever
reducers), anti-inflammatories
(inflammation reducers), and platelet
aggregation inhibitors (anticlotting
agents). It works by interfering with the
production of compounds in the body
that cause pain, fever, inflammation,
and blood clots.

24.  Acetylsalicylic acid (ASA) is used to relieve pain,
fever, and inflammation in various conditions such
as lower back and neck pain, the flu, common cold,
burns, menstrual pain, headache, migraines,
osteoarthritis, rheumatoid arthritis, sprains and strains,
nerve pain, toothache, muscle pain, bursitis
(inflammation of a bursa, a fluid-filled sac located
around joints and near the bones), and following
surgical and dental procedures. ASA is also used for
rheumatic fever in combination with other
medications. In these situations, ASA is used on an
as-needed basis.

25.  Because of the antiplatelet (anticlotting) properties of ASA, it may be
used under the supervision of your doctor to:
 prevent a first nonfatal heart attack in people who are at increased risk
of having a heart attack as determined by their doctor (factors that
increase your risk of heart attack include: smoking, high blood
pressure, high cholesterol, inactive lifestyle, stress, and being
overweight)
 prevent a second heart attack or stroke
 reduce the risk of "mini-stroke" or transient ischemic attack (TIA)
 reduce the clotting properties of platelets for people who have had
carotid artery surgery to prevent the recurrence of TIA and for people
receiving hemodialysis through a silicone rubber access
 prevent blood clots for people who have had a total hip replacement

26.  ASA can also be used during a heart attack to
reduce the risk of dying from the heart attack.
 Your doctor may have suggested this
medication for conditions other than those
listed in these drug information articles. As
well, some forms of this medication may not be used
for all of the conditions discussed here. If you have
not discussed this with your doctor or are not sure
why you are taking this medication, speak to your
doctor. Do not stop taking this medication
without consulting your doctor.

29. ADVERSE EFFECT
 Contact your doctor if you experience these side effects and
they are severe or bothersome. Your pharmacist may be able
to advise you on managing side effects.
 heartburn or indigestion
 mild-to-moderate abdominal or stomach cramps, pain, or discomfort
 bruising more easily
 confusion
 dizziness
 fainting
 nausea or vomiting
 pain, buzzing or ringing in ears
 severe or continuing abdominal or stomach pain, cramping, or burning
 unusual tiredness or weakness

30. Stop taking the medication and seek immediate
medical attention if any of the following occur:
any loss of hearing
bleeding
signs of stomach bleeding, such as bloody or black, tarry
stools
swelling of the mouth and throat
symptoms of an allergic reaction, e.g.:
difficulty breathing
hives
itchy skin rash

31. SAR of salicylates
 Side effects of the salicylates particularly the GIT effects are appear
to be associated with the presence of carboxylic acid functional group.
SO
 Substitution on carboxylate or hydroxyl groups may lead to change in
potency and toxicity.
 Substitution of ring decreases the activity.
 Reducing acidity of the carboxylic group i.e converting to an amide,
salicylamide maintain the analgesic action of the salicylic acid
derivative but eliminate the anti inflammatory properties.
 Placing the hydroxyl group meta or para to the carboxylic group
abolishes the activity.
 Substitution of halogens on the ring enhances the toxicity and
potency.
 Substitution of salicylic acid at 4-position of salicylic acid increases
anti inflammatory activity.

32. Diflunisal is a non-steroidal anti-
inflammatory drug (NSAID). It was
developed by Merck Sharp & Dohme in
1971 after showing promise in a research
project studying more potent chemical
analogs of aspirin. It was first sold under
the brand name Dolobid, marketed by
Merck & Co., but generic versions are now
widely available. It is available in 250 mg
and 500 mg tablets. As of 2013, the drug
was in clinical trials as a potential
treatment for transthyretin-related
hereditary amyloidosis.
NSAIDs such as diflunisal may cause
ulcers, bleeding, or holes in the stomach or
intestine.
diflunisal

33. 33
Mefenamic Acid
2-[(2,3-Dimethylphenyl)amino]benzoic acid
NH
OH
O
1
2
3
III-Anthranilic Acid Derivative

44. 44
Derivatives
HO O
O O
NH
OH
O
O
OH
NH
Cl
Cl
O
OH
NH
F
F
F
O
OH
NH
Cl
¼×
ÂÈ
·ÒÄÇ
Ëá
Meclofenamic acid
·ú·ÒÄÇ
Ëá
Flufenamic acid
ÂÈ
·ÒÄÇ
Ëá
Chlofenamic acid
O
OH
O
O
Aspirin

45.  Flufenamic acid
2—{[3-(Trifluoromethyl)phenyl]amino}benzoic acid.
Uses anti-inflammatory

46. Synthesis

47. MOA
 Mefenamic acid has demonstrated analgesic, anti
inflammatory and anti pyretic properties in human
clinical studies and in classical animal test system.
These effects may be due to its dual action on
prostaglandins. It inhibits the enzymes of
prostaglandin synthesis and also antagonizes the
action of prostaglandin at receptor sites. These
effects may also be responsible for its
effectiveness in the treatment of primary
dysmeorrhea.

48. Structure Activity relationships
 Substitution on the anthranilic acid ring reduce
activity.
 The most active anthranilic acid derivatives have
substituents at position 2`,3` and 6`of the ring
attached to the anthranilic acid nitrogen.
 Replacing the –NH- function in fenamic acids
produces less active compounds. Thus ether,
ketones, and thioether are essentially inactive.

49.  The carboxylic function is required at the 2-position
for biological activity.
 Isomeric 3-carboxy or 4-carboxy derivatives are
inactive.
 A tetrazole function can substitute for carboxylic acid
function with retention of anti-inflammatory activity.
 On the basis of structure-activity relationships for
indomethacin and other NSAIDs, and anti-
inflammatory receptor site consisting of two non
coplaner hydrophobic regions and a cationic centre.

50.  The anti-inflammatory receptor consists of a
largely flat area, a trough to accommodate an
out-of-plane group (such as an aryl ring
acting possibly by charge–transfer type of
interaction) and a cationic site to
accommodate an acidic anion.

51. uses
 Treatment of primary dysmenorrhoea
 Inflammation and fever
 Soft tissue and dental pain

52. IV-Aryl acetic Acids:
 The largest group of NSAIDS is
represented by this class:
 Aryl and propanoic acid derivative

53. Aryl propionic Acids
 Ibuprofen Brufen®
 2-(4-isobutylphenyl)propionic acid
 It is a NSAID used for the treatment of
mild to moderate pain.

54. IBUPROFEN
 Ibuprofen is more potent than asprin
 But less potent than Indomethcin in
anti inflammatory activity and inhibition
Of prostaglandin biosynthesis.
It produces moderate degree of gastric
Irritation.

55. 55
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-methyl group on the acetic acid moiety to
get Ibuprofen.
 A methyl group was replaced by an ethyl group to get Butibufen
whose anti-inflammation was similar as Ibuprofen with less
gastrointestinal irritation.
O
OH
O
OH
²¼
Ìæ²¼
·Ò
Butibuf en
4-Ò춡»ù±½
ÒÒ
Ëá
Ibufenac
Ibufenac Butibufen

56. 56
Development of ibuprofen
OH
O
OH
O
 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.
Ibufenac Ibuprofen

57. 57
Drugs commonly used
O
OH
N
O O
OH
O
OH
F
N
O
OH
Cl
name Chemical structure potency name Chemical structure potency
Ibuprofen 1/10 Indoprofen 2
Fluprofen
5
Pirprofen
1
Ketoprofen 1.5
Naproxen
1
O
O
OH
OH
O
O

58. SYNTHESIS OF IBUPROFEN

62. SAR OF IBUPROFEN
 The substitution of an α-methyl group
on the alkanoic acid portion of acetic
acid derivatives enhances anti
inflammatory action and decreases
many side effects e.g acetic acid
analogue of ibuprofen,ibufenac(p-
isobutyl phenyl acetic acid) is less
potent and more hepatotoxic than
ibuprofen.

63. Ibufenac(p-isobutyl phenyl acetic acid)

64. USES
 Treats fever and pain,
 cold or flu,
 migraine
 Inflammation
 Headache
 Toothache
 Back pain
 Arthritis, including juvenile arthritis
 Menstrual cramps
 Minor injuries
 .

65. Ibuprofen is an NSAID (non-steroidal anti-inflammatory drug)
that is commonly used for the relief of symptoms of arthritis,
fever, primary dysmenorrhea (menstrual pains), and as an
analgesic (a medication given to reduce pain without resulting in
loss of consciousness). Ibuprofen also has an antiplatelet effect
(protects from blood clots), though less than aspirin. The World
Health Organization (WHO) includes ibuprofen in its "Essential
Drugs List"; a list of minimal medical needs for a basic health care
system

66. WORKING OF IBUPROFEN
 Ibuprofen blocks the production of prostaglandins,
substances our body releases in response to illness
and injury. Prostaglandins cause pain and swelling
(inflammation); they are released in the brain and
can also cause fever.
Ibuprofen's painkilling effects kick in soon after a
dose is taken. Ibuprofen's anti-inflammatory effects
can take a bit longer, sometimes a few weeks.

67. Side effects
 The most common side-effects include: Diarrhea
 Nausea
 Vomiting
 Dyspepsia (upper abdominal pain, bloating, indigestion)
 Any pain in the stomach or intestines
 The following side-effects are also possible, but less common: Dizziness (if
you experience this, don't drive or operate heavy machinery)
 Edema (fluid retention, bloating)
 Hypertension (elevated blood pressure)
 Stomach inflammation
 Ulcers in the digestive system
 Rash, and some other allergic reactions
 Worsening of asthma symptoms

68. Aryl acetic Acids:
 Diclofenac Voltral®
 2-[(2,6-dichlorophenyl)amino]benzene acetic.
 It is a NSAIDs with balanced cox-1 and cox-2
inhibiting effect.

69. DESCRIPTION
 Diclofenac Na is perhaps the most widely used NSAID in the
world.
 Diclofenac Tablets are benzene acetic acid derivatives.
 the chemical name is 2-[(2,6-dichlorophenyl)amino]benzene
acetic mono sodium salt.
 Diclofenac possess structural characteristics of both arylalkanoic
acid and anthranilic acid class of anti inflammatory, analgesic
and antipyretic properties.
 It is twice as potent as indomethacin and 450 times as potent
as asprin.
 As analgesic, it is 6 times more potent than indomethcin and 40
times more potent as aspirin.
 As an antipyretic, it is twice as potent as indomethacin and over
350 times as potent as apirin.

71. synthesis

72. 72
Chemosynthesis
NaOH
Cl
Cl
N
O
AlCl3
ClCH2COCl
OH
Cl
Cl
ONa
O
NH
Cl
Cl
NH2
H
N
Cl
Cl
Derivatives
·ÒÂÈ
Ëá
Fenclofenac
ÍÐÃÀ
Í¡
Tolmetin
O
N OH
O
×ô
ÃÀ
Ëá
Zomepirac
OH
O
N
Cl
O
HO
O
O
Cl
Cl

73. SAR
 The function of two O-chloro groups is
to force the anilino-phenyl acid portion
In recognizing and binding the NSAID
to active site of cyclooxygenase
enzyme.

74. Structure activity relationships
 All agents posses a centre of activity can be
represented by carboxylic acid function, enolic function
hydroxamic acid function, a sulfonamide or tetrazole.
 The activity of ester and amide derivatives of
carboxylic acid is attributed to the metabolic hydrolysis
product.
 The center of acidity is located on carbon atom
adjacent to a flat surface represented by aromatic or
heteroaromatic.
 Increasing the distance to two to three carbons
diminish activity.

75.  Derivatives of aryl or heteroaryl acetic or propionic
acids are most common.
 Substitution of methyl group on the carbon atom
separating the acid centre from the aromatic ring
increase the anti-inflammatory activity.
 Group larger than methyl decrease activity.
 A second area of lipophilicity which is generally
noncoplaner with aromatic or heteroaromatic ring
enhance activity. The lipophilic function may consist
of an addition aromatic ring or alkyl group.

76. 76
Uses of Diclofenac Sodium
Sodium 2-[(2,6-dichloroanilino)phenyl]acetate
ONa
NH
Cl
Cl
O
Indicated for short- and long-term treatment of RA,
OA, and ankylosing spondylitis.
Available as delayed-release tablets.

77. N
O
OH
O
O
Cl
Indomethacin
Indoleacetic acid

78. 78
Indomethacin
1-(4- Chlorobenzoyl)-5-methoxy-2-methyl-1H-
indole-3-acetic acid
N
O
OH
O
O
Cl
1 2
3
4
5
A pale-white to yellow-tan crystalline powder.
Soluble in ethanol and acetone and practically insoluble in water.
Unstable in alkaline solution and sunlight.

79. Indomethacin
 It is still one of the most potent NSAIDs in use,
possessing approximately 25 times the activity of
phenylbutazone.
 It is more potent than aspirin and acetaminophen.
 CN: 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-
indol-3-acetic acid.

80. 80
Development
 Serotonin 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
N
H
NH2
HO
N
H
HO
O
OH
NH2
5-ôÇ
É«°·
Serotonin
É«°±Ëá
Tryptophan

82. 82
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.

83. 83
Derivatives
N
O
OH
O
O
Cl
Stronger anti-inflammatory action,
and weaker toxicity.
Sulindac M
K-715 Zidom
etacin
O
H
F
O
S
O
O
H
O
O
Cl
N
O
H
O
O
O
N3
Indomethacin

84. SYNTHESIS OF PARACETAMOL(ACETAMINOPHEN)

85. VI-Pyrazolinone derivatives
 Metamizole Novalgin®, Baralgin®
 It has strong analgesic spasmolytic and
antipyretic but no anti-inflammatory
properties.

86. VII-Acidic enolic compounds
1. Pyrazolidine 3,5-diones
Oxyphenbutazone Tanderil®
Anti-inflammatory
N
N
OH
O
O

87. 2. Aryl sulfonamides (oxicames):
Piroxicam
Anti-inflammatory
4-Hydroxy-2-methyl-2H-1,2-benzothiazine-3-[N-(2-
pyridyl)carboxamide]-1,1-dioxide
4-Hydroxy-2-methyl- 2H-1,2-benzothiazine-3-Pyridyl
carboamide 1,1-Dioxide

88. 3-oxo-1,2-benzothiazolin-1,1-dioxide-2-
acetate

89.  The isomerization of methyl 3-oxo-1,2-
benzothiazolin-1,1-dioxide-2-acetate (I) by
means of sodium methoxide in DMSO gives
methyl 3,4-dihydro-4-oxo-2H-1,2-
benzothiazine-1,1-dioxide-3-carboxylate (II),
which is methylated with methyl iodide and
NaOH in methanol giving methyl 3,4-dihydro-
2-methyl-4-oxo-2H-1,2-benzothiazine-1,1-
dioxide-3-carboxylate (III). Finally, this
product is treated with 2-aminopyridine (A) in
refluxing xylene.

90. SAR
 Oxicams are a class of nonsteroidal
anti-inflammatory drugs (NSAIDs)
structurally related to the enolic acid
class of 4-hydroxy-1,2-benzothiazine
carboxamides.
 Oxicams are structurally distinct from
all other NSAIDs, exhibiting a novel
binding pose in the COX active site.

91. uses
 ANALGESIC AND ANESTHETIC DRUGS, Analgesic
Drugs, Ankylosing Spondylitis, Treatment of,
Antiarthritic Drugs, METABOLIC DRUGS, Non-Opioid
Analgesics, Osteoarthritis, Treatment of, Rheumatoid
Arthritis, Treatment of, Treatment of Disorders of
Purine and Pyrimidine Metabolism, Treatment of
Gout, TREATMENT OF MUSCULOSKELETAL &
CONNECTIVE TISSUE DISEASES, Non-Steroidal
Antiinflammatory Drugs