Antipyretic and Analgesics1
Antipyretic and Analgesics1
Fever usually results from microbes such as bacteria or viruses triggering the body’s defence
mechanisms. This activates certain types of cells, some of which release the substance
interleukin. Prostaglandin is another chemical released by the body that plays a part in this
process. Prostaglandin is induced by bacterial pyrogens and is produced in the CNS.
Interleukin affects the hypothalamus, which is the part of the brain that regulates body
temperature, signalling it to raise the temperature by a few degrees. Prostaglandins causes
inflammation.
Antipyretic analgesics or febrifuges are remedial agents that lower the temperature of the
body in pyrexia i.e., in situations when the body temperatures has been raised above normal.
In therapeutic doses they do not have any effect on normal body temperature. They exert
their action on the heat-regulating centre in the hypothalamus. Analgesics may be defined
as–‘agents that relieve pain by elevating the pain threshold without disturbing
consciousness or altering other sensory-modalities’. Besides, ‘pain’ may also be defined in
psychological perspective as—‘a particular type of sensory experience distinguished by
nerve tissue from sensations, such as : touch, heat, pressure and cold’
Nonsteroidal anti-infl ammatory drugs (NSAIDs) are used primarily to treat infl
ammation, mild-to-moderate pain, and fever. Specific uses include the treatment of
headache, arthritis, sports injuries, and menstrual cramps. Aspirin is used to inhibit the
clotting of blood and prevent strokes and heart attacks in individuals at high risk. NSAIDs
are also included in many cold and allergic preparations.
Classification
These derivatives possess analgesic and antipyretic actions but lack anti-inflammatory effects.
Acetanilide was introduced into the therapy 1886 as an antipyretic–analgesic agent, but was
subsequently found to be too toxic, having been associated with methemoglobinemia and
jaundice. Phenacetin was introduced in the following year and was widely used, but was
withdrawn recently because of its nephrotoxicity. Acetaminophen (paracetamol) was
introduced in 1893 and it remains the only useful agent of this group used as an antipyretic–
analgesic agent.
Paracetamol
Paracetamols exist as white crystalline powder, sparingly soluble in water, soluble in alcohol,
and very slightly soluble in methylene chloride
Mechanism of Action
It causes antipyresis by exerting its action on the hypothalamic heat-regulating centre, and
analgesia by enhancing the pain threshold profile appreciably. It is found to lack the anti-
inflammatory activity of salicylates. Paracetamol primarily inhibits COX-2 in the brain. This
inhibition reduces the production of prostaglandins, which are signaling molecules involved
in inflammation, pain, and fever. By lowering prostaglandin levels in the brain, paracetamol
helps alleviate pain and reduce fever.
Therapeutic Application
1- As anti-pyretic: to reduce body temperature during fever.
2- As Analgesic: to relieve headache, toothache, myalgia etc.
3- It is the preferred anti-pyretic and analgesic in patients with peptic ulcer, haemophilia,
bronchial asthma and children.
Synthesis
Mechanism of Action
Salicylic acid derivatives works by inhibition of cyclooxygenase (COX) enzymes( COX-
1 and COX-2) leading to reduced prostaglandin synthesis and consequent anti-
inflammatory, analgesic, and antipyretic effects.
Therapeutic Application
1. Salicylates posses antipyretic, analgesic, and anti-inflammatory properties.
2. Salicylates promote the excretion of uric acid and they are useful in the treatment of
gouty arthritis.
3. Salicylates (aspirin) have ability to inhibit platelet aggregation, which may contribute
to heart attack and strokes, and hence, aspirin reduces the risk of myocardial infarction.
4. In addition, a recent study suggested that aspirin and other NSAIDs might be protective
Acetylation of salicylic acid with acetic anhydride yields aspirin. The crude product may
be recrystallized from benzene, mixture of acetic acid and water (1 : 1) or various other
non-aqueous solvent. Dose : Usual, adult, oral 300 to 650 mg every 3 or 4 hours ; or 650
mg to 1.3 g as the sustained- release tablet every 8 hours ; Rectal, 200 mg to 1.3 g 3 or 4
times a day.
Salol
It may be prepared by heating together salicylic acid and phenol at 120°C in the presence
of phosphorus oxychloride or carbonyl chloride (COCl2)
Salsalate
It is prepared by the condensation of two moles of salicylic acid in the presence of thionyl chloride.It
has antipyretic, analgesic and anti-inflammatory properties similar to those of Aspirin.
It may be prepared by mixing together a paste of salicylic acid in distilled water with
sufficient pure sodium carbonate in small lots at intervals. The reaction mixture is filtered through
iron-free filter paper and evaporated to dryness under reduced pressure. Caution must be taken to
avoid contact with iron which will alter the original white colour of the product.
Structure Activity Relationship of Salicylic acid derivatives
1. Substitution on either the carboxyl or phenolic hydroxy groups may affect the
potency and toxicity.
2. Reducing the acidity of the COOH, e.g., the corresponding amide
(salicylamide), retains the analgesic action of salicylic acid but i devoid of anti-
inflammatory properties.
3. Placing the phenolic hydroxyl group meta or para to the carboxyl group abolishes
the activity.
4. Substitution of halogen atoms on the aromatic ring enhances potency and toxicity.
5. Substitution of aromatic rings at the 5-position of salicylic acid increases anti-
inflammatory activity (diflunisil).
6. Substitution on either the carboxyl or phenolic hydroxyl group may affect the
potency and toxicity. Benzoic acid itself has only week activity.
Quinoline Derivatives
The basic quinoline nucleus, present in the quinine molecule, contributes to antipyretic activity to
a certain extent. Two quinoline derivatives first synthesized though possessed significant
antipyretic action, yet could not gain cognizance as a drug because of their high toxic effects on
the red blood corpuscles and damaging after-effect on kidneys. These were, thalline and 6-methoxy
quinoline.
Cinchophen may be prepared by the interaction of isatin and acetophenone in the presence of
excess of aqueous ammonia.
Dose: 300 to 600 mg.
Note: Because of its high toxicity, e.g., liver damage resulting in acute jaundice,
cinchophen has been completely withdrawn and replaced by safer drugs.
It occurs through the reaction of p-toluidine, ethyl pyruvate and benzaldehyde in the presence of a
small amount of nitrobenzene, when the products get condensed to form an intermediate
compound. This when subjected to dehydrogenation yields neocinchophen.
Dose: 500 mg.
Name R
R1
Phenyl butazone –H –C4H9
Oxyphenbutazone –OH –C4H9
Sulphinpyrazone –H –
(CH2)2SOC6H5
Therapeutic Application
Pyrazolones: Primarily used for pain relief, fever reduction, and in conditions with
significant inflammation. Dipyrone, in particular, is noted for its additional spasmolytic
effects.
Pyrazolidinediones: Primarily used in the management of inflammatory conditions like
rheumatoid arthritis and gout, with additional applications in pain relief and fever
reduction.
Synthesis
Phenazone
It may be prepared by the condensation of one mole each of phenyl-hydrazine and the lactim- form
of ethylacetoacetate when 1-phenyl-3-methyl-pyrazolone is obtained by the elimination of a mole
each of water and ethanol. The resulting product is subjected to methylation either with methyl
iodide or dimethyl sulphate to yield phenazone
As antipyretic, it possesses local anaesthetic and styptic actions and solutions containing 5% are
used locally as ear drops.
Phenylbutazone
N-Arylanthranilic Acid
N-arylanthranilic acids, commonly known as fenamates, are a class of nonsteroidal anti-
inflammatory drugs (NSAIDs) with anti-inflammatory, analgesic, and antipyretic properties.
These compounds are derivatives of anthranilic acid and include drugs such as mefenamic acid,
flufenamic acid, and tolfenamic acid, meclofenamic acid.
Mechanism of Action
Therapeutic Application
They are used to treat various conditions due to their anti-inflammatory, analgesic, and antipyretic
properties
Synthesis
Mefenamic Acid
Flufenamic Acid
Mechanism of Action
Aryl acetic acid derivatives work by inhibiting cyclooxygenase (COX) enzymes, specifically
COX-1 and COX-2. These enzymes are essential for converting arachidonic acid into
prostaglandins, which are compounds that mediate inflammation, pain, and fever. By blocking
COX enzymes, aryl acetic acid derivatives reduce prostaglandin synthesis, leading to decreased
inflammation, pain, and fever. This inhibition also impacts platelet aggregation and can reduce the
protective lining of the stomach, potentially causing gastrointestinal side effects. The overall effect
is an anti-inflammatory, analgesic, and antipyretic response.
Therapeutic Applications
Aryl acetic acid derivatives are primarily used for their anti-inflammatory, analgesic, and
antipyretic properties. Here are some of their main therapeutic applications:
Rheumatoid Arthritis
Osteoarthritis
Ankylosing Spondylitis
Acute Gouty Arthritis
Postoperative Pain
Dysmenorrhea
Musculoskeletal Pain
Bursitis and Tendinitis
Migraine
Diclofenac
Dose : 20 to 50 mg 3 times day. It is also given as a suppository.
Structure-Activity Relationship of Diclofenac
1. There are two benzene rings are present in diclofenac sodium. Both are essential and
unsubstituted. If we remove any one of the group, the therapeutic activity will be
terminated.
2. There is an amino bridge present in between two rings in diclofenac sodium. This bridge
is essential and unsubstituted. If we change the position or presence of this bridge, the
therapeutic activity will be terminated.
3. There are two chlorides present in diclofenac sodium at position 2 and 6. Both are essential
and unsubstituted. If we remove any one with other halogen or change the position, the
therapeutic activity will be terminated.
4. There is acetic acid present at position 1 in diclofenac sodium. It is essential and
Synthesis
Naproxen ketoprofen
flurbiprofen Ibuprofen
p-Isobutyl acetophenone is prepared by the acetylation of isobutyl benzene which upon treatment
with hydrocyanic acid yields the corresponding cyanohydrin. This on heating with hydrogen iodide
in the presence of red phosphorous helps to reduce the benzylic hydroxyl moiety ; further
hydrolysis of the nitrile groups gives the official compound.
Dose: Usual, oral adult, analgesia (dysmenorrhea), 200 to 400mg 4 to 6 times per day ; in
rheumatoid arthritis, osteoarthritis, 300 to 400mg 3 or 4 times daily.
Mechanism of Action
Heteroaryl acetic acid derivatives inhibit cyclooxygenase enzymes, particularly COX-1 and COX-
2. These enzymes convert arachidonic acid into prostaglandins and thromboxanes, which are key
mediators of inflammation, pain, and fever. By blocking COX enzymes, these drugs reduce the
production of prostaglandins. Prostaglandins play a crucial role in inflammation, pain
sensitization, and fever. Lowering prostaglandin levels results in reduced inflammation, pain, and
fever.
Therapeutic Applications
Heteroaryl acetic acid derivatives are primarily used for their anti-inflammatory, analgesic, and
antipyretic properties. Here are some of their main therapeutic applications:
Rheumatoid Arthritis
Osteoarthritis
Ankylosing Spondylitis
Acute Gouty Arthritis
Postoperative Pain
Dysmenorrhea
Musculoskeletal Pain
Bursitis and Tendinitis
Migraine
Indomethacin
p-Methoxy phenyl diazonium chloride is obtained by the diazotization of p-anisidine which on
reduction with sodium sulphite yields p-methoxy phenyl hydrazine. The resulting product
undergoes the Fischer-indole synthesis in the presence of methyl levulinate to form a hydrazone
which on intra-molecular rearrangement gives an enamine. This on cyclization loses a molecule
of ammonia and forms an intermediate compound. It is then hydrolysed to the corresponding acid
which is re-esterified via the anhydride to give the tert-butyl ester. Finally acy ylation with p-
chlorobenzoyl chloride followed by debutylation gives rise to the official compound.
1. Placement of other acidic functionalities instead of the carboxyl group decreases activity
and the amide derivatives are inactive.
2. Substituents of R1 useful for increasing anti-infl ammatory activity are ranked as C6 H4
CH2 > alkyl > H.
3. Acylation of the indole nitrogen with aryl/alkyl carboxylic acids results in the decrease of
activity.
4. Presence of substituents on the N-benzoyl derivatives in the p-position with F, Cl, CF3 , or
S-CH3 groups provide greatest activity.
5. X substituents activity are ranked as 5-OCH3 > N (CH3 )2 > CH3 > H.
6. The presence of indole ring nitrogen is not essential for activity because the corresponding
1-benzylidenylindene analogue (sulindac) is also active.
7. Alkyl groups especially methyl group at 2nd position is much active than aryl substituted
analogues.
8. Substitution of a methyl group at the α position of the acetic acid side chain leads to
equiactive analogues.
9. Anti-infl ammatory activity was displayed only by the dextrorotatory enantiomer with
similar absolute configuration; it has 25 times the activity of phenylbutazone.
References
Lectures by Dr. Mohsin Abbas Khan
Textbook of Medicinal Chemistry—V. Alagarsamy.
Medicinal Chemistry— Ashutosh Kar.
Medicinal Chemistry—D. Sri Ram