ANTI -INFLAMMATORY DRUGS 1

ANTI-INFLAMMATORY,
ANTIPYRETIC, AND
ANALGESIC AGENTS

FRANCIS M MALWAL. B.PHARM , M CLIN

01/28/2025
PHARM
 I. OVERVIEW
2

 Inflammation is a normal, protective response

to tissue injury caused by physical trauma,
noxious chemicals, or microbiologic agents.
 Inflammation is the body’s effort to
inactivate or destroy invading organisms,
remove irritants, and set the stage for tissue
repair.

ANTI -INFLAMMATORY DRUGS 01/28/2025

 Cont
3

 When healing is complete, the

inflammatory process usually subsides.
 Inappropriate activation of the immune
system can result in inflammation,
leading to immune mediated diseases
such as rheumatoid arthritis (RA).

ANTI -INFLAMMATORY DRUGS 01/28/2025

 Cont
4

 Normally, the immune system can

differentiate between self and non self.
 In RA, white blood cells (WBCs) view the
synovium (tissue that nourishes cartilage
and bone) as non self and initiate an
inflammatory attack.

ANTI -INFLAMMATORY DRUGS 01/28/2025

 Cont
5

 WBC activation leads to stimulation of T

lymphocytes, which recruit and activate
monocytes and macrophages.
 These cells secrete proinflammatory
cytokines, including tumor necrosis
factor (TNF)-α and interleukin (IL)-1, into
the synovial cavity
ANTI -INFLAMMATORY DRUGS 01/28/2025
 Pharmacotherapy
in the management of RA includes
10

 Anti-inflammatory and/or
immunosuppressive agents that
modulate/reduce the inflammatory
process, with the goals of reducing
inflammation and pain, and halting or
slowing disease progression.

ANTI -INFLAMMATORY DRUGS 01/28/2025

 CLASSES OUTLINE
11

 Nonsteroidal anti-inflammatory drugs

(NSAIDs)
 Celecoxib (cyclooxygenase-2 inhibitor),
 Acetaminophen, and
 Disease-modifying antirheumatic drugs
(DMARDs).
ANTI -INFLAMMATORY DRUGS 01/28/2025
 II. PROSTAGLANDINS
12

 Are produced in minute quantities by

virtually all tissues.
 They generally act locally on the tissues
in which they are synthesized,
 They are rapidly metabolized to inactive
products at their sites of action.

ANTI -INFLAMMATORY DRUGS 01/28/2025

 Cont
13

 Thromboxanes and leukotrienes are

related lipids that are synthesized from
the same precursors as the
prostaglandins.

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 A. Synthesis of
14
prostaglandins
 Arachidonic acid is the primary precursor
of the prostaglandins and related
compounds.
 Free arachidonic acid is released from
tissue phospholipids by the action of
phospholipase A2 via a process controlled
by hormones and other stimuli.
ANTI -INFLAMMATORY DRUGS 01/28/2025
 Cont
15

 There are two major pathways in the

synthesis of the eicosanoids from
arachidonic acid,

1. Cyclooxygenase and

2. Lipoxygenase.

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 Arachidonic acid metabolites and
inflammation
16

ANTI -INFLAMMATORY DRUGS 01/28/2025

 1.Cyclooxygenase
17
pathway:
 All eicosanoids : the prostaglandins,
thromboxanes, and prostacyclins).

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 1.1Cyclooxygenase-1 (COX-
18
1)
 Is responsible for the physiologic
production of prostanoids that:
 Regulates normal cellular processes, such
as gastric cytoprotection,
 Vascular homeostasis,

ANTI -INFLAMMATORY DRUGS 01/28/2025

 Cont
19

 Platelet aggregation,
 Reproductive and
 kidney functions

ANTI -INFLAMMATORY DRUGS 01/28/2025

 1.2 Cyclooxygenase-2 (COX-
20
2)
 causes the elevated production of
prostanoids that occurs in sites of
chronic disease and inflammation.
 COX-2 is constitutively expressed in
tissues such as the brain, kidney, and
bone.
 Its expression at other sites is increased
ANTI -INFLAMMATORY DRUGS 01/28/2025
 2. Lipoxygenase
21
pathway:
 Several lipoxygenases can act on
arachidonic acid to form leukotrienes.
 Antileukotriene drugs, such as zileuton,
zafirlukast, and montelukast, are
treatment options for asthma.

ANTI -INFLAMMATORY DRUGS 01/28/2025

 Cont
25

 Prostaglandins are also among the

chemical mediators that are released in
allergic and inflammatory processes.
 Therefore, they find use for a number of
disorders.

ANTI -INFLAMMATORY DRUGS 01/28/2025

 II. NONSTEROIDAL ANTI-
INFLAMMATORY DRUGS
28

 Derivatives of salicylic acid (aspirin )

 Propionic acid (ibuprofen ,fenoprofen ,
ketoprofen
 Acetic acid (diclofenac )
 indomethacin
 Enolic acid such meloxicam,
 piroxicam
 fenamates (mefenamic )

ANTI -INFLAMMATORY DRUGS 01/28/2025

 I.Aspirin
29

 Aspirin can be thought of as a traditional

NSAID, but it exhibits antiinflammatory
activity only at relatively high doses that are
rarely used.
 It has gained much more usage at lower doses
for the prevention of cardiovascular events
such as stroke and myocardial infarction (MI).

ANTI -INFLAMMATORY DRUGS 01/28/2025

 Cont
30

 Aspirin is often differentiated from other

NSAIDs, since it is an irreversible
inhibitor of cyclooxygenase activity.

ANTI -INFLAMMATORY DRUGS 01/28/2025

 A.Anti-inflammatory
31
actions:
 Cyclooxygenase inhibition diminishes the
formation of prostaglandins and, thus,
modulates aspects of inflammation in which
prostaglandins act as mediators.
 NSAIDs inhibit inflammation in arthritis, but
they neither arrest the progression of the
disease nor induce remission.
ANTI -INFLAMMATORY DRUGS 01/28/2025
 B.Analgesic action
32

 PGE2 is thought to sensitize nerve

endings to the action of bradykinin,
histamine, and other chemical mediators
released locally by the inflammatory
process.
 Thus, by decreasing PGE2 synthesis, the
sensation of pain can be decreased.
ANTI -INFLAMMATORY DRUGS 01/28/2025
 C.Antipyretic action:
33

 The NSAIDs lower body temperature in

patients with fever by impeding PGE2
synthesis and release.

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 Cont
34

 This rapidly lowers the body temperature

of febrile patients by increasing heat
dissipation as a result of peripheral
vasodilation and sweating.
 NSAIDs have no effect on normal body
temperature.

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 Therapeutic uses:
35

 Anti-inflammatory and analgesic uses:

 Antipyretic uses:
 Cardiovascular applications:

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 Adverse events
36

 Because of the associated adverse

events, it is preferable to use NSAIDs at
the lowest effective dose for the shortest
duration possible.
 Gastrointestinal:
 Increased risk of bleeding (antiplatelet
effect): TXA.ANTI -INFLAMMATORY DRUGS 01/28/2025
 II.Celecoxib

38

 Celecoxib a selective COX-2 inhibitor, is

significantly more selective for inhibition
of COX-2 than COX-1.
 Unlike the inhibition of COX-1 by aspirin
(which is rapid and irreversible), the
inhibition of COX-2 is reversible.

ANTI -INFLAMMATORY DRUGS 01/28/2025

 Therapeutic uses:
39

 Celecoxib is approved for the treatment

of RA, osteoarthritis, and acute mild to
moderate pain.
 Celecoxib has similar efficacy to NSAIDs
in the treatment of pain.

ANTI -INFLAMMATORY DRUGS 01/28/2025

 Adverse effects:
40

 Headache, dyspepsia, diarrhea, and

abdominal
 pain are the most common adverse effects.
 Celecoxib, when used without concomitant
aspirin therapy, is associated with less GI
bleeding and dyspepsia than other NSAIDs.

ANTI -INFLAMMATORY DRUGS 01/28/2025

 Cont
41

 However, this benefit is lost when aspirin

is added to celecoxib therapy.
 Patients who are at high risk of ulcers
and require aspirin for cardiovascular
prevention should avoid the use of
celecoxib.

ANTI -INFLAMMATORY DRUGS 01/28/2025

 Cont
42

 Celecoxib should be used with caution in

patients who are allergic to
sulfonamides.

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 III.ACETAMINOPHEN

43

 Acetaminophen (N-acetyl-p-aminophenol or
APAP) inhibits prostaglandin synthesis in the CNS.
 This explains its antipyretic and analgesic
properties.
 Acetaminophen has less effect on
cyclooxygenase in peripheral tissues (due to
peripheral inactivation)

ANTI -INFLAMMATORY DRUGS 01/28/2025

 Therapeutic uses

45

 Acetaminophen is a suitable substitute for

the analgesic and antipyretic effects of
NSAIDs for those patients with gastric
complaints/ risks, in those whom a
prolongation of bleeding time is not desirable,
as well as those who do not require the anti-
inflammatory action of NSAIDs.

ANTI -INFLAMMATORY DRUGS 01/28/2025

 Cont
46

 Acetaminophen is the
analgesic/antipyretic of choice for
children with viral infections or
chickenpox (due to the risk of Reye
syndrome with aspirin)

ANTI -INFLAMMATORY DRUGS 01/28/2025

 Adverse effects

47

 At normal therapeutic doses,

acetaminophen is virtually free of
significant adverse effects.

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48 THE END OF NSAID
DISEASE-MODIFYING
ANTIRHEUMATIC DRUGS

ANTI -INFLAMMATORY DRUGS 01/28/2025

 DISEASE-MODIFYING
ANTIRHEUMATIC DRUGS
49

 DMARDs are used in the treatment of RA

and have been shown to:
 slow the course of the disease
 induce remission
 prevent further destruction of the joints
and involved tissues.
ANTI -INFLAMMATORY DRUGS 01/28/2025
 Cont
50

 When a patient is diagnosed with RA,

DMARDs should be started within 3
months to help stop the progression of
the disease at the earlier stages.
 NSAIDs or corticosteroids may also be
used for relief of symptoms if needed.

ANTI -INFLAMMATORY DRUGS 01/28/2025

 A.Choice of drug
51

 No one DMARD is efficacious and safe in

every patient, and trials of several different
drugs may be necessary.
 Monotherapy may be initiated with any of
the DMARDs (methotrexate, leflunomide,
hydroxychloroquine, or sulfasalazine) for
patients with low disease activity.
ANTI -INFLAMMATORY DRUGS 01/28/2025
 Cont
52

 For patients with moderate to high

disease activity or inadequate response
to monotherapy, combination DMARD
therapy (usually methotrexate based) or
use of anti-TNF drugs (adalimumab,
certolizumab, etanercept, golimumab,
and infliximab) may be needed.
ANTI -INFLAMMATORY DRUGS 01/28/2025
53

 For patients with more established

disease, use of other biologic therapies
(for example, abatacept, rituximab) can
be considered.
 Most of these agents are
contraindicated for use in pregnant
women.
ANTI -INFLAMMATORY DRUGS 01/28/2025
 B. Methotrexate
54

 Methotrexate used alone or in combination

therapy, has become a mainstay of treatment in
patients with rheumatoid or psoriatic arthritis.
 Methotrexate is a folic acid antagonist that
inhibits cytokine production and purine
nucleotide biosynthesis, leading to
immunosuppressive and anti-inflammatory
effects.
ANTI -INFLAMMATORY DRUGS 01/28/2025
 Cont
55

 Response to methotrexate occurs within 3 to

6 weeks of starting treatment; it can also
slow the appearance of new erosions within
involved joints.
 The other DMARDs can be added to
methotrexate therapy if there is partial or no
response to maximum doses of methotrexate.

ANTI -INFLAMMATORY DRUGS 01/28/2025

 Cont
56

 The most common side effects observed

after methotrexate treatment of RA are
mucosal ulceration and nausea.
 Cytopenias (particularly depression of the
WBC count), cirrhosis of the liver, and an
acute pneumonia-like syndrome may
occur with chronic administration.
ANTI -INFLAMMATORY DRUGS 01/28/2025
 Cont
57

 Taking leucovorin (folinic acid) once daily

after methotrexate reduces the severity
of adverse effects.
 Periodic liver enzyme tests, complete
blood counts, and monitoring for signs of
infection are recommended.

ANTI -INFLAMMATORY DRUGS 01/28/2025

 C. Hydroxychloroquine
58

 Hydroxychloroquine is used for early, mild

RA, often combined with methotrexate.
 This agent is also used in the treatment of
lupus and malaria.
 Its mechanism of action in autoimmune
disorders is unknown, and onset of effects
takes 6 weeks to 6 months.
ANTI -INFLAMMATORY DRUGS 01/28/2025
 Cont
59

 Hydroxychloroquine has less effects on

the liver and immune system than other
DMARDs.
 it may cause ocular toxicity, including
irreversible retinal damage and corneal
deposits.
 It may also cause CNS disturbances, GI
ANTI -INFLAMMATORY DRUGS 01/28/2025
 C. Leflunomide

60

 Leflunomide is an immunomodulatory agent

that preferentially causes cell arrest of the
autoimmune lymphocytes through its action
on dihydroorotate dehydrogenase (DHODH).
 Activated proliferating lymphocytes require
constant DNA synthesis to proliferate.

ANTI -INFLAMMATORY DRUGS 01/28/2025

 Mechanism of action
61

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 Cont
62

 Pyrimidines and purines are the building

blocks of DNA, and DHODH is necessary
for pyrimidine synthesis.
 After biotransformation, leflunomide
becomes a reversible inhibitor of
DHODH.

ANTI -INFLAMMATORY DRUGS 01/28/2025

63

 Leflunomide is approved for the

treatment of RA.
 It can be used as monotherapy or in
combination with methotrexate.
 The most common adverse effects are
headache, diarrhea, and nausea.

ANTI -INFLAMMATORY DRUGS 01/28/2025

 Cont
64

 Other untoward effects are weight loss,

allergic reactions, including a flu-like
syndrome, skin rash, alopecia, and
hypokalemia.
 Monitoring parameters include signs of
infection, complete blood counts, and
liver enzymes.
ANTI -INFLAMMATORY DRUGS 01/28/2025
 E. Sulfasalazine

65

 Sulfasalazine is also used for early, mild

RA in combination with methotrexate
and/or hydroxychloroquine.
 Onsetof activity is 1 to 3 months, and it
is associated with leukopenia.
 Its mechanism of action in treating RA is
unclear. ANTI -INFLAMMATORY DRUGS 01/28/2025
 F. Glucocorticoids

66

 Glucocorticoids are potent anti-inflammatory

drugs that are commonly used in patients
with RA to provide symptomatic relief and
bridge the time until DMARDs are effective.
 Timely dose reductions and cessation are
necessary to avoid adverse effects
associated with long-term use.
ANTI -INFLAMMATORY DRUGS 01/28/2025
 VI. BIOLOGIC THERAPIES IN
RHEUMATOID ARTHRITIS
67

 IL-1 and TNF-α are proinflammatory cytokines

involved in the pathogenesisof RA.
 When secreted by synovial macrophages, IL-1
and TNF-α stimulate synovial cells to proliferate
and synthesize collagenase, thereby degrading
cartilage, stimulating bone resorption, and
inhibiting proteoglycan synthesis.

ANTI -INFLAMMATORY DRUGS 01/28/2025

68

 The TNF-α inhibitors:

 Adalimumab,
 Certolizumab,
 etanercept,
 golimumab, and
 infliximab)

ANTI -INFLAMMATORY DRUGS 01/28/2025

 Cont
69

 Have been shown to decrease signs and

symptoms of RA, reduce progression of
structural damage, and improve physical
function.
 Clinical response can be seen within 2
weeks of therapy.

ANTI -INFLAMMATORY DRUGS 01/28/2025

70

 If a patient has failed therapy with one

TNF-α inhibitor, a trial with a different
TNF-α inhibitor or a non-TNF biologic
therapy (abatacept, rituximab,
tocilizumab,is appropriate.

ANTI -INFLAMMATORY DRUGS 01/28/2025

71

 TNF-α inhibitors can be administered

with any of the other drugs for RA,
except for the non-TNF biologic therapies
(due to increased risk of infection).

ANTI -INFLAMMATORY DRUGS 01/28/2025

 Cont
72

 Patients receiving TNF-α inhibitors are at

increased risk for infections (tuberculosis
and sepsis), fungal opportunistic
infections, and pancytopenia.
 Live vaccinations should not be
administered while on TNF-α inhibitor
therapy.
ANTI -INFLAMMATORY DRUGS 01/28/2025
73

 Should be used very cautiously in those

with heart failure, as they can cause
and/or worsen preexisting heart failure.
 An increased risk of lymphoma and other
cancers has been observed with the use
of TNF-α inhibitors.

ANTI -INFLAMMATORY DRUGS 01/28/2025

 VII. DRUGS USED FOR THE
74
TREATMENT OF GOUT

ANTI -INFLAMMATORY DRUGS 01/28/2025

 VII. DRUGS USED FOR THE
TREATMENT OF GOUT
75

 Gout is a metabolic disorder

characterized by high levels of uric acid
in the blood (hyperuricemia).
 Hyperuricemia can lead to deposition of
sodium urate crystals in tissues,
especially the joints and kidney.

ANTI -INFLAMMATORY DRUGS 01/28/2025

76

 Hyperuricemia does not always lead to

gout, but gout is always preceded by
hyperuricemia.
 The deposition of urate crystals initiates
an inflammatory process involving the
infiltration of granulocytes that
phagocytize the urate crystals.
ANTI -INFLAMMATORY DRUGS 01/28/2025
 Cont
77

 The cause of hyperuricemia is an

imbalance between overproduction of
uric acid and/or the inability of the
patient to excrete it via renal
elimination.

ANTI -INFLAMMATORY DRUGS 01/28/2025

 Cont
78

 Most therapeutic strategies for gout

involve lowering the uric acid level below
the saturation point (6 mg/dL), thus
preventing the deposition of urate
crystals.

ANTI -INFLAMMATORY DRUGS 01/28/2025

 A. Treatment of acute gout
79

 Acute gout attacks can result from

 excessive alcohol consumption,
 a diet rich in purines, and
 Kidney disease.

ANTI -INFLAMMATORY DRUGS 01/28/2025

 Cont
80

 NSAIDs, corticosteroids, or colchicine are

effective alternatives for the management
of acute gouty arthritis.
 Indomethacin is considered the classic
NSAID of choice.
 all NSAIDs are likely to be effective in
decreasing pain and inflammation.
ANTI -INFLAMMATORY DRUGS 01/28/2025
 Cont
81

 Intraarticular administration of
corticosteroids (when only one or two
joints are affected) is also appropriate in
the acute setting,
 Systemic corticosteroid therapy for more
widespread joint involvement.

ANTI -INFLAMMATORY DRUGS 01/28/2025

 Cont
82

 Patients are candidates for prophylactic

urate-lowering therapy if they have more
than two attacks per year or they have
chronic kidney disease, kidney stones, or
tophi.

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 B.Treatment of chronic gout
83

 Urate-lowering therapy for chronic gout aims to

reduce the frequency of attacks and
complications of gout.
 treatment strategies include the use of
xanthine oxidase inhibitors to reduce the
synthesis of uric acid or
 use of uricosuric drugs to increase its excretion.

ANTI -INFLAMMATORY DRUGS 01/28/2025

84

 Xanthine oxidase inhibitors (allopurinol,

febuxostat) are first-line urate-lowering
agents.
 Uricosuric agents (probenecid) may be
used in patients who are intolerant to
xanthine oxidase inhibitors or fail to
achieve adequate response with those
ANTI -INFLAMMATORY DRUGS 01/28/2025
 Cont
85

 Medications for the prevention of an

acute gout attack (low-dose colchicine,
NSAIDs, or corticosteroids) should be
initiated with urate-lowering therapy and
continued for at least 6 months.

ANTI -INFLAMMATORY DRUGS 01/28/2025

 C. Colchicine
86

 Colchicine, a plant alkaloid, is used for

the treatment of acute gouty attacks.
 It is neither a uricosuric nor an analgesic
agent, although it relieves pain in acute
attacks of gout.

ANTI -INFLAMMATORY DRUGS 01/28/2025

 Cont
87

 Colchicine binds to tubulin, a

microtubular protein, causing its
depolymerization.
 This disrupts cellular functions, such as
the mobility of granulocytes, thus
decreasing their migration into the
affected area.
ANTI -INFLAMMATORY DRUGS 01/28/2025
 Cont
88

 colchicine blocks cell division by binding

to mitotic spindles.
 Therapeutic uses: Gout and prophylactic
agent to prevent acute attacks of gout in
patients initiating urate-lowering
therapy.

ANTI -INFLAMMATORY DRUGS 01/28/2025

 Cont
89

 ADR: Acute include: diarrhea and GI

pain.
 Long use hematuria, alopecia,
myelosupression, gastritis and
peripheral neuropathy.

ANTI -INFLAMMATORY DRUGS 01/28/2025

 Cont
90

 ADR: Acute include: diarrhea and GI

pain.
 Long use hematuria, alopecia,
myelosupression, gastritis and
peripheral neuropathy.

ANTI -INFLAMMATORY DRUGS 01/28/2025

 D. Allopurinol

91

 Allopurinol, a xanthine oxidase inhibitor,

is a purine analog.
 It reduces the production of uric acid by
competitively inhibiting the last two
steps in uric acid biosynthesis that are
catalyzed by xanthine oxidase.

ANTI -INFLAMMATORY DRUGS 01/28/2025

92

ANTI -INFLAMMATORY DRUGS 01/28/2025

 I. Therapeutic uses
93

 Treatment of gout and hyperuricemia

secondary to other conditions, such as
that associated with certain
malignancies or in renal disease.
 Skin rashes are the most common
adverse reaction, peripheral
neuropathy , stone formation.
ANTI -INFLAMMATORY DRUGS 01/28/2025
 E. Probenecid
94

 These drugs (e.g. sulfinpyrazone,

probenecid) have been largely
superseded by allopurinol, but are useful
for patients who require prophylactic
therapy and who have severe adverse
reactions to allopurinol.
 Uricosuric drugs inhibit active transport
of organic acids by renal tubules.

ANTI -INFLAMMATORY DRUGS 01/28/2025

95

 Their main effect on the handling of uric

acid by the kidney is to prevent the
reabsorption of filtered uric acid by the
proximal tubule, thus greatly increasing
excretion.
 Probenecid can precipitate an acute
attack of gout.

ANTI -INFLAMMATORY DRUGS 01/28/2025

96

 Sulfinpyrazone is a weak NSAID in its

own right, and a flare of gout is less
likely to occur when using it.
 Unlike other NSAIDs, there is also
evidence that it has a clinically useful
antiplatelet action.

ANTI -INFLAMMATORY DRUGS 01/28/2025

97

 The patient should drink enough water

to have a urine output of 2L/day during
the first month of treatment and a
sodium bicarbonate or potassium citrate
mixture should be given to keep the
urinary pH above 7.0 to avoid
precipitation of uric acid stones.
 Other adverse effects include rashes and
gastro-intestinal upset

ANTI -INFLAMMATORY DRUGS 01/28/2025