Applied Science Private University

Pharmacy Institute
Clinical Pharmacy and Therapeutics Department

Pharmacology III (906410)

Anti-inflammatory, Antipyretic, and

Analgesic Agents
Chapter 40

Dr. Luai Hasoun

MSc. Samar Khater
1st semester 2023/2024
Amman-Jordan
Objectives

▪ To be able to discuss the pathophysiology of

inflammation, and gout.

▪ To be able to discuss the mechanisms

underlying drug actions, therapeutic uses,
adverse effects, precautions and
contraindications for anti-inflammatory,
antipyretic, and analgesic Agents

Anti-inflammatory, Antipyretic, and Analgesic Agents 2

Contents

❑ Overview
❑ Prostaglandins
❑ Nonsteroidal anti-inflammatory drugs
▪ Aspirin & other NSAIDs
▪ Mechanism of action
▪ Therapeutic uses
▪ Pharmacokinetics
▪ Adverse events
▪ Celecoxib
❑ Acetaminophen
❑ Gout

Anti-inflammatory, Antipyretic, and Analgesic Agents 3

I. Overview

Inflammation: is a normal, protective response to tissue injury.

It is caused by:
physical trauma, noxious chemicals, or microbiologic agents.
▪ Why Inflammation occurs in our body:
1) To inactivate or destroy invading organisms
2) Remove irritants
3) Set the stage for tissue repair

✓ 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, Antipyretic, and Analgesic Agents 4

I. Overview
✓ Normally, the immune system can differentiate between self and non-self.

✓ In RA ( Rheumatoid arthritis), white blood cells (WBCs) view the synovium

(tissue that nourishes cartilage and bone) as non-self and initiate an
inflammatory attack.
✓ WBC activation leads to stimulation of T lymphocytes, which activate
monocytes and macrophages.

✓ These cells secrete

proinflammatory cytokines,
including tumour necrosis factor
(TNF)-α and interleukin (IL)-1,
into the synovial cavity.

Anti-inflammatory, Antipyretic, and Analgesic Agents 5

I. Overview
✓ The release of cytokines then causes:
1) ↑ cellular infiltration into the endothelium due to release of
histamines, kinins, and vasodilatory PGs

2) ↑ production of C-reactive protein by hepatocytes

3) ↑ production and release of proteolytic enzymes by chondrocytes,

leading to degradation of cartilage and joint space narrowing

4) ↑ osteoclast activity (osteoclasts regulate bone breakdown), resulting in

focal bone erosions and bone demineralization around joints

5) systemic manifestations in certain organs such as the heart

✓ In addition to T-lymphocyte activation, B lymphocytes are also involved

and produce RF (Rheumatiod factor an inflammatory marker) and other
autoantibodies with the purpose of maintaining inflammation.

Anti-inflammatory, Antipyretic, and Analgesic Agents 6

I. Overview
✓ These defensive reactions cause:
• progressive tissue injury
• resulting in joint damage and erosions
• functional disability
• significant pain
• reduction in quality of life.

✓ Pharmacotherapy in the management of RA includes:

✓ anti-inflammatory and/or
✓ immunosuppressive agents that modulate/reduce the
inflammatory process, Disease-Modifying Antirheumatic
Drugs (DMRDs)
✓ with the goals of reducing inflammation and pain, and
halting or slowing disease progression.

Anti-inflammatory, Antipyretic, and Analgesic Agents 7

II. Prostaglandins
✓ The NSAIDs act by ↓ the synthesis of PGs.
✓ Thus, an understanding of NSAIDs requires comprehension of the
actions and biosynthesis of PGs—unsaturated fatty acid derivatives
containing 20 carbons that include a cyclic ring structure. [These
compounds are sometimes referred to as eicosanoids; “eicosa” refers
to the 20 carbon atoms.]

A. Role of prostaglandins as local mediators:

✓ PGs and related compounds are produced in minute quantities by
virtually all tissues.

✓ They generally act locally on the tissues in which they are synthesized,
and they are rapidly metabolized to inactive products at their sites of
action → PGs do not circulate in the blood in significant
concentrations.

✓ TXs and LTs are related lipids that are synthesized from the same
precursors as the PGs.
Anti-inflammatory, Antipyretic, and Analgesic Agents 8
II. Prostaglandins
B. Synthesis of prostaglandins:

✓ Arachidonic acid (AA) is the primary precursor of the PGs and related
compounds.

✓ AA is present as a component of the phospholipids of cell membranes.

Free AA is released from tissue phospholipids by the action of
phospholipase A2 (PLA-2) via a process controlled by hormones and
other stimuli.

✓ There are two major pathways in the synthesis of the eicosanoids from
AA:
▪ the cyclooxygenase pathway
▪ the lipoxygenase pathway

Anti-inflammatory, Antipyretic, and Analgesic Agents 9

II. Prostaglandins

B. 1. Cyclooxygenase pathway:

✓ All eicosanoids with ring structures (PGs, TXs, and PCs) are synthesized
via the cyclooxygenase pathway.

✓ Cyclooxygenase-1 (COX-1) is responsible for the physiologic production

of prostanoids
✓ COX-1 is a constitutive enzyme that regulates normal cellular processes,
such as:
✓ gastric cytoprotection,
✓ vascular homeostasis,
✓ platelet aggregation, and
✓ reproductive and
✓ kidney functions.
✓ cyclooxygenase-2 (COX-2) causes the elevated production of
prostanoids that occurs in sites of chronic disease and inflammation.

Anti-inflammatory, Antipyretic, and Analgesic Agents 10

II. Prostaglandins

B. 1. Cyclooxygenase pathway:

✓ COX-2 is constitutively expressed in tissues such as the brain, kidney,

and bone.
✓ Its expression at other sites is increased during states of chronic
inflammation.

✓ Differences in binding site shape have permitted the development of

selective COX-2 inhibitors (Figure 36.2).

✓ Another distinguishing characteristic of COX-2 is that its expression is

induced by inflammatory mediators like TNF-α and IL-1
✓ but can also be pharmacologically inhibited by glucocorticoids (Figure
36.3), which may contribute to the significant anti-inflammatory effects
of these drugs.

Anti-inflammatory, Antipyretic, and Analgesic Agents 11

Chapter 40 Structural differences in active sites of COX-1 & COX-2
• Figure 40.2

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Chapter 40 Figure 40.3
Synthesis of PGs & LTs

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II. Prostaglandins

2. Lipoxygenase pathway:

✓ Alternatively, several lipoxygenases can act on AA to form LTs (Figure

36.3).

✓ Antileukotriene drugs, such as zileuton, zafirlukast, and montelukast,

are treatment options for asthma.

Anti-inflammatory, Antipyretic, and Analgesic Agents 14

II. Prostaglandins

C. Actions of prostaglandins
✓ Many of the actions of PGs are mediated by their binding to a wide
variety of distinct cell membrane receptors that operate via G-coupled
proteins.
✓ PGs and their metabolites, produced endogenously in tissues, act as
local signals that fine-tune the response of a specific cell type.
✓ Their functions vary widely, depending on the tissue and the specific
enzymes within the pathway that are available at that particular site
✓ For example, the release of thromboxane A2 (TXA2) from platelets
during tissue injury triggers the recruitment of new platelets for
aggregation, as well as local vasoconstriction.
✓ However, prostacyclin (PGI2), produced by endothelial cells, has
opposite effects, inhibiting platelet aggregation and producing
vasodilation.
✓ The net effect on platelets and blood vessels depends on the balance of
these two prostanoids.

Anti-inflammatory, Antipyretic, and Analgesic Agents 15

II. Prostaglandins

D. Therapeutic uses of prostaglandin

✓ PGs have a major role in modulating pain, inflammation, and fever.

✓ They also control many physiological functions, such as acid secretion

and mucus production in GIT, uterine contractions, and renal blood
flow.

✓ PGs are also among the chemical mediators that are released in allergic
and inflammatory processes.
✓ This leads to many therapeutic applications for prostaglandins

Anti-inflammatory, Antipyretic, and Analgesic Agents 16

17
II. Prostaglandins: PGE1 analogues

1. Alprostadil

✓ It is a PGE1 analogue that is naturally (seminal vesicles, cavernous

tissues, placenta, ductus arteriosus of the fetus).

✓ It is used to treat erectile dysfunction

✓ PGE1 maintains the patency of the ductus arteriosus during pregnancy.
The ductus closes soon after delivery to allow normal blood circulation
between the lungs and the heart.
✓ Alprostadil keeps the ductus arteriosus open in neonates with
congenital heart conditions until surgery is possible (Infusion of the
drug maintains the ductus open as it naturally occurs during pregnancy,
allowing time until surgical correction is possible).

Anti-inflammatory, Antipyretic, and Analgesic Agents 18

II. Prostaglandins PGE1 analogues

2. Lubiprostone

✓ It is a PGE1 derivative

✓ It is indicated for the treatment of:

chronic idiopathic constipation, opioid-induced constipation, and irritable
bowel syndrome with constipation.

✓ MOA: It stimulates Chloride-channels in the luminal cells of the intestinal

epithelium, thereby ↑ intestinal fluid secretion.

✓ SEs: Nausea and diarrhea (Figure 36.4).

✓ Nausea can be decreased if taken with food.

Anti-inflammatory, Antipyretic, and Analgesic Agents 19

Chapter 40 Some adverse reactions to lubiprostone
Figure 40.5

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II. Prostaglandins PGE1 analogues
3. Misoprostol
✓ It is a PGE1 analog

✓ It is used to protect the mucosal lining of the stomach during chronic

NSAID treatment. ( ↓ HCl secretion, has a GI cytoprotective effect).

✓ There is a combination product containing diclofenac and misoprostol.

✓ Misoprostol is also used off-label* in obstetric settings for:

✓ labor induction, since it ↑ uterine contractions.
✓ Misoprostol has the potential risk to induce abortion in pregnant
women. Therefore, the drug is CI during pregnancy.

✓ Its use is limited by common SE: diarrhea and abdominal pain.

*Off-label: the use of drug to treat a condition for which it has not
received approval by a regulatory agency.

Anti-inflammatory, Antipyretic, and Analgesic Agents 21

 Prostaglandin E2 analogs:
• Dinoprostone is a synthetic analog of PGE2
• Uses:
• Labor induction
• An abortifacient
• Route of administration: via the vagina ( as a gel or a
removable insert)
• Actions:
• Relaxation of cervical smooth muscles
• Induction of uterine contractions
• Common A/E: fever, chills, N/V, diarrhea and headache

22
II. Prostaglandins
4. Prostaglandin F2α analogs

✓ Bimatoprost, latanoprost, tafluprost, and travoprost are PGF2α analogs

✓ They are indicated for the treatment of open-angle glaucoma. By

binding to PG receptors, they ↑ uveoscleral outflow, ↓ IOP

✓ They are administered as ophthalmic solutions 1x/day and are as

effective as timolol or better in ↓ IOP

✓ Bimatoprost ↑ eyelash prominence, length, and darkness and is

approved for the treatment of eyelash hypotrichosis.

✓ Ocular reactions include blurred vision, iris color change (↑ brown

pigmentation), ↑ number and pigment of eyelashes, ocular irritation,
and foreign body sensation.

Anti-inflammatory, Antipyretic, and Analgesic Agents 23

II. Prostaglandins
5. Prostacyclin (PGI2) analogs

✓ Epoprostenol, the pharmaceutical form of naturally occurring

prostacyclin,
✓ and the synthetic analogs of prostacyclin iloprost and treprostinil are
potent pulmonary vasodilators
✓ used for the treatment of pulmonary arterial hypertension.

✓ These drugs mimic the effects of prostacyclin in endothelial cells,

producing a significant ↓ in pulmonary arterial resistance with a
subsequent ↑ in cardiac index and oxygen delivery.

✓ These agents all have a short half-life.

✓ Epoprostenol and treprostinil are administered as a continuous IV

infusion,
✓ and treprostinil may also be administered orally or via inhalation or SC
infusion.
Anti-inflammatory, Antipyretic, and Analgesic Agents 24
II. Prostaglandins
5. Prostacyclin (PGI2) analogs

✓ Inhaled iloprost requires frequent dosing due to the short half-life

(Figure 36.5).

✓ Dizziness, headache, flushing, and fainting are the most common

adverse effects (Figure 36.6).

✓ Bronchospasm and cough can also occur after inhalation of iloprost.

Anti-inflammatory, Antipyretic, and Analgesic Agents 25

Chapter 40 Administration and fate of iloprost
Figure 40.6

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Chapter 40 Some adverse reactions to iloprost
Figure 40.7

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