NONSTEROIDAL ANTI-

INFLAMMATORY DRUGS

Presented by: Msc. Ardita Emiri

E-mail: [Link]@[Link]
Learning 1 PROSTAGLANDIN (PG) AND THROMBOXANE
(TX) SYNTHESIS, COX-1 AND COX-2

objectives 2 MECHANISM OF ACTION OF

NSAIDS: EFFECTS ON COX-1 AND
COX-2
NON-SELECTIVE AND SELECTIVE
3 COX-2 INHIBITORS

4 PHARMACOLOGICAL ACTIONS,
CLINICAL USES AND ADVERSE
EFFECTS OF NSAIDS
 INFLAMMATION
Inflammation is a defense reaction caused by
tissue damage or Injury

• Can be elicited by numerous stimuli

including:
o infectious agents
o antigen-antibody interaction
o ischemia
o thermal and physical injury
 INFLAMMATION
Characterized by:

Redness (rubor): vasodilation of

capillaries to increase blood flow

Heat (calor): vasodilation

Pain (dolor): Hyperalgesia, sensitization of nociceptors

Swelling (tumor): Increased vascular permeability

(microvascular structural changes and escape of
plasma proteins from the bloodstream)

Loss of function (functio laesa)

Inflammatory cell transmigration through

endothelium and accumulation at the site of injury
 Mediators of inflammation

 Vasoactive amines • Serotonin – actions similar to histamine.

(mast cells and platelets) Found in platelets.

• Histamine – abundant in granules of Released after platelet aggregation, or under

mast cells (very abundant around blood the influence of platelet activating factor
vessels) (PAF).
 Mediators of inflammation
 Cytokines:  Kinin system
• Interleukin (IL)-1, (IL)-2,
• Tumor Necrosis Factor (TNF), • Vasoactive peptides called kinins are generated by
granulocyte/macrophage colony stimulating proteases called kallikrein
factor (GM-CSF). • Most important product is bradykinin
• Coagulation pathway
 Mediators of inflammation
 Platelet activating factor (PAF)  Nitric oxide: made by NO synthase (NOS) both constitutive
and Inducible; induced in macrophages by TNF- or IFN-
Potent vasodilator; Involved in the pathogenesis of septic
shock

 Complement system
 Mediators of inflammation
 Adhesion Molecules

Arachidonic acid metabolites:

• Prostaglandins (PGs),
• Thromboxane A2 (TXA2),
• HETE
• Leukotrienes (LTs)
 Cyclooxygenases(COX)
Two main forms of Cyclooxygenases (COX)

Cyclooxygenase-1 (COX-1) Cyclooxygenase-2 (COX-2)

Produces prostaglandins that mediate Produces prostaglandins that mediate

homeostatic functions inflammation, pain, and fever.

Constitutively expressed • Induced mainly in sites of

inflammation by cytokines
Plays an important role in
• Gastric mucosa • Constitutive expression in brain
• Kidney and kidney
• Platelets
• Vascular endothelium
 Prostaglandins synthesis
Prostaglandins (PGs) are products of long-chain fatty
acids.

Arachidonic acid - The precursor for the biosynthesis of

all

The enzyme involved - cyclooxygenase (COX).

The main PGs in humans:

• prostaglandin E₂ (PGE₂)
• prostaglandin F₂ (PGF₂)
• prostacyclin (PGI₂).
 Analgesics
Analgesics are drugs that relieve pain without significantly altering
consciousness. They relieve pain without affecting its cause.
 Nonsteroidal Anti-inflammatory
Drugs (NSAIDs):
Group of chemically diverse agents Mechanism of Action

Vary in: •Inhibit cyclooxygenase (COX) enzymes

• Antipyretic • COX catalyzes the first step in prostanoid
• Analgesic biosynthesis
• Anti-inflammatory activity •↓ Prostaglandin synthesis therapeutic & adverse
effects

COX Selectivity and Clinical Implications

•COX-1 inhibition:
• Associated with cardiovascular protection
• Linked to most adverse effects

•COX-2 inhibition:
• Responsible for anti-inflammatory and analgesic effects
 Classification
1. Nonselective cyclooxygenase (COX) inhibitors
• Salicylates: Aspirin
• Propionic acid derivatives: Ibuprofen, ketoprofen,
naproxen, flurbiprofen.
• Acetic acid derivatives: Diclofenac, aceclofenac.
• Fenamic acid derivatives: Mefenamic acid.
• Pyrrolo–pyrrole derivatives: Ketorolac, etodolac
• Oxicam derivatives: Piroxicam, tenoxicam.
• Indole derivatives: Indomethacin

2. Preferential COX-2 inhibitors:

Nimesulide, meloxicam, nabumetone

3. Highly selective COX-2 inhibitors:

Etoricoxib, parecoxib, lumiracoxib.

4. Analgesic—antipyretics with poor anti-inflammatory

effect: Paracetamol, nefopam.
 Pharmacokinetics

Protein Binding

NSAIDs: Absorption and Elimination •~98% protein-bound, mostly to albumin

Bioavailability
Renal excretion: primary • Most are racemic mixtures
• Well absorbed orally elimination route (e.g., ibuprofen)
• Food has minimal effect on • Some are single enantiomers
bioavailability Also undergo: (e.g., naproxen)
• Others are achiral (e.g., diclofenac)
• Biliary excretion
Metabolism of NSAIDs
• Reabsorption →
Metabolized via:
enterohepatic circulation NSAIDs in Synovial Fluid
Detected in synovial fluid after repeated
• Phase I → Phase II (conjugation)
The degree of lower dosing
• Or direct glucuronidation
gastrointestinal (GI) tract •Short half-life drugs stay longer than
(Phase II)
irritation → correlated to expected
•Involves CYP3A and CYP2C enzymes
enterohepatic circulation •Long half-life drugs clear proportionally
(liver)
to half-life
 Pharmacological actions of aspirin and
other NSAIDs

Aspirin (acetylsalicylic acid) is the prototype drug.

The other nonselective NSAIDs vary mainly in their potency, analgesic,

antiinflammatory effects and duration of action.

Analgesic effect

• NSAIDs are mainly used for relieving musculoskeletal pain,

dysmenorrhoea and pain associated with inflammation or tissue
FIGURE 1. Analgesic mechanism of
damage. acetaminophen. Acetaminophen is
metabolized to p-aminophenol, which easily
crosses the blood-brain barrier and is
• Analgesic effect is mainly due to peripheral inhibition of PG converted to AM404 by FAAH. AM404 mainly
[Link] also increase pain threshold by acting at subcortical acts on both the brain and spinal cord via
COX, anandamide, CB1, TRPV1, opioid, and
site. 5-HT3 receptors. AM404, N-acylphenolamine;
FAAH, fatty acid amide hydrolase; COX,
cyclooxygenase; CB1, cannabinoid 1; TRPV1,
• These drugs relieve pain without causing sedation, tolerance or drug transient receptor potential vanilloid 1

dependence.
 Pharmacological actions of aspirin and
other NSAIDs

Antipyretic effect

• The thermoregulatory centre is situated in the hypothalamus.

Fever occurs when there is a disturbance in hypothalamic
thermostat.

• NSAIDs reset the hypothalamic thermostat and reduce the

elevated body temperature during fever.

• They promote heat loss by causing cutaneous vasodilatation

and sweating. They do not affect normal body temperature.

• The antipyretic effect is mainly due to inhibition of PGs in the

hypothalamus.
 Pharmacological actions of aspirin and
other NSAIDs

Antiinflammatory effect

• Antiinflammatory effect is seen at high doses (aspirin: 4–6 g/day in

divided doses). Drugs produce only symptomatic relief.

• Suppress signs and symptoms of inflammation such as pain,

tenderness, swelling, vasodilatation and leukocyte infiltration
but do not affect the progression of underlying disease.

• The antiinflammatory action of NSAIDs → mainly due to inhibition

of PG synthesis at the site of injury.

• Also affect other mediators of inflammation (bradykinin,

histamine, serotonin, etc.) → inhibit granulocyte adherence to
the damaged vasculature.

• NSAIDs also cause modulation of T-cell function, stabilization

of lysosomal membrane and inhibition of chemotaxis.
 Pharmacological actions of aspirin and
other NSAIDs

Antiplatelet (antithrombotic) effect

Aspirin in low doses (50–325 mg/day)

→ irreversibly inhibits platelet TXA2 synthesis and

produces antiplatelet effect (lasts for 8–10 days, i.e.
the life-time of platelets)

Aspirin in high doses (2–3 g/day)

→ inhibits both PGI2 and TXA2 synthesis

→ beneficial effect of PGI2 is lost.

Aspirin should be withdrawn 1 week prior to

elective surgery because of the risk of bleeding.
 Pharmacological actions of aspirin
and other NSAIDs

Acid–base and electrolyte balance:

In therapeutic doses
→ salicylates cause respiratory alkalosis,
(high pH + low CO₂) which
is compensated by excretion of alkaline urine
(compensated respiratory alkalosis).

In toxic doses
→ the respiratory centre is depressed and can lead to
respiratory acidosis.

Later, there is uncompensated metabolic acidosis.

 Pharmacological actions of aspirin
and other NSAIDs

Gastrointestinal tract (GIT):

Aspirin irritates the gastric mucosa and produces
nausea, vomiting and dyspepsia.

The salicylic acid formed from aspirin also

contributes to these effects.

Aspirin also stimulates chemoreceptor trigger zone

(CTZ) and produces vomiting.
 Pharmacological actions of aspirin
and other NSAIDs

Cardiovascular system (CVS):

Urate excretion:

Prolonged use of aspirin and other NSAIDs Salicylates, in therapeutic doses

→ sodium and water retention. → inhibit urate secretion into the renal tubules
and increase plasma urate levels.
May precipitate congestive cardiac failure
(CCF) in patients with low cardiac reserve. In high doses, salicylates
→ inhibit the reabsorption of uric acid in renal
May also decrease the effect of tubules and produce uricosuric effect
antihypertensive drugs.
 Clinical uses of NSAIDs

1. As analgesic: 3. Rheumatoid arthritis:

In painful conditions like toothache, headache, NSAIDs → first group of drugs to be used.
backache, bodyache, muscle pain,
temporomandibular and other joint pain, bursitis, They have analgesic and antiinflammatory
neuralgias, dysmenorrhoea, etc. effects and can produce only symptomatic
relief, but they do not alter the progression of
disease.
2. As antipyretic:
To reduce elevated body temperature in fever 4. Acute rheumatic fever:
paracetamol is preferred because:
Aspirin → preferred drug.
a. Gastrointestinal symptoms are rare.
Reduces fever, relieves swelling and joint pain,
b. It does not cause Reye’s syndrome in does not affect the normal course of the disease.
children.
 Clinical uses of NSAIDs
5. Osteoarthritis:
7. Other uses:
In mild cases, paracetamol is used.
In severe cases of osteoarthritis, other NSAIDs are more a. Medical closure of patent ductus arteriosus
effective than paracetamol. (Indomethacin is preferred)

Topical agents like methyl salicylate, diclofenac gel, b. Colon and rectal cancer: Regular use of
capsaicin cream, etc. can also be used. aspirin is reported to reduce the risk of cancer.

c. Aspirin is reported to reduce the risk and

6. Thromboembolic disorders: retard the onset of Alzheimer’s disease.
The antiplatelet effect of low-dose aspirin is made use of in
the prophylactic treatment of various thromboembolic d. To control radiation-induced diarrhoea.
disorders, such as:

a. Transient ischaemic attacks (TIA) e. To control pruritus and flushing associated

b. Myocardial infarction (MI) with the use of nicotinic acid.
(i) to reduce incidence of recurrent MI
(ii) to decrease mortality in post-MI patients
NSAIDs and Their Important Features
 Adverse effects

1. GIT: 2. Hypersensitivity:

Nausea, vomiting, dyspepsia, epigastric pain, Relatively more common with aspirin.
acute gastritis, ulceration and GI bleeding
The manifestations:
Ulcerogenic effect → major drawback of
NSAIDs, prevented/minimized by taking: skin rashes, urticaria, rhinitis, bronchospasm,
angioneurotic oedema and rarely anaphylactoid
a. NSAIDs after food. reaction.

b. proton pump inhibitors/H2-blockers/misoprostol

Bronchospasm (aspirin-induced asthma) → due to
with NSAIDs. increased production of leukotrienes.
c. buffered aspirin (preparation of aspirin with
Incidence of hypersensitivity → high in patients with
antacid). asthma, nasal polyps, recurrent rhinitis or urticaria.
d. selective COX-2 inhibitors.
Aspirin should be avoided in such patients
 Adverse effects
5. Reye’s syndrome:
3. In people with G6PD deficiency →
administration of salicylates may cause Use of salicylates in children with viral infection
haemolytic anaemia → cause hepatic damage with fatty infiltration
and encephalopathy

Salicylates → contraindicated in children with

viral infection.
4. Prolonged use of salicylates

→interferes with action of vitamin K in the

liver

→ decreased synthesis of clotting factors

(hypoprothrombinaemia)

→ predisposes to bleeding (can be treated by

administration of vitamin K).
6. Pregnancy: 7. Analgesic nephropathy:

These drugs inhibit PG synthesis, thereby: Slowly progressive renal failure may
• delay onset of labour occur on chronic use of high doses of
• increase chances of postpartum NSAIDs.
haemorrhage.
Renal failure is usually reversible on
• In the newborn, inhibition of PG stoppage of therapy but rarely, NSAIDs
synthesis results in premature closure of may cause irreversible renal damage.
the ductus arteriosus.
 Nonselective cyclooxygenase (COX)
inhibitors
ASPIRIN
Used as a cardiovascular drug because of its ability to provide
a prolonged inhibition of platelet COX-1 and hence reduce
aggregation.

Uses include:
• colonic and rectal cancer: aspirin (and COX-2 inhibitors)
may reduce some types of colorectal cancer
• Alzheimer’s disease: this was suggested on the basis of
epidemiological evidence
• radiation-induced diarrhoea

Unwanted effects

May produce both local and systemic toxic effects.

Specific unwanted effects:

• Salicylism,
• Reye’s syndrome
 Analgesic—antipyretics with poor
anti-inflammatory effect
PARACETAMOL
• Excellent analgesic and antipyretic activity
(inhibition of CNS prostaglandin synthesis)

• Weak anti-inflammatory activity

• No gastric or platelet side effects

Pharmacokinetic aspects
Given orally and is well absorbed, with peak
plasma concentrations reached in 30–60 min.

Paracetamol is inactivated in the liver, being conjugated to give

the glucuronide or sulfate.

Unwanted effects
With therapeutic doses, side effects are few and uncommon,
although allergic skin reactions sometimes occur.
 Selective COX-2 Inhibitors (‘ Coxibs’)

Use of coxibs to patients for whom

treatment with conventional NSAIDs would
cause serious gastrointestinal issues

Celecoxib and etoricoxib

Used in symptomatic relief in the treatment

of osteoarthritis and rheumatoid arthritis
and some other conditions.

Common unwanted effects may include

headache, dizziness, skin rashes and
peripheral oedema caused by fluid
Retention

Because of the potential role of COX-2 in

the healing of ulcers, patients with pre-
existing disease should avoid the
drugs, if possible.
 NSAIDs of choice
Some guidelines are:

5. Paediatric patients—only
1. Mild-to-moderate pain with little paracetamol, aspirin, ibuprofen and
inflammation— paracetamol or low-dose naproxen have been adequately
ibuprofen. evaluated in children— should be
preferred in them.
2. Acute but short-lasting pain—ketorolac, a Due to risk of Reye’s syndrome,
propionic acid derivative, diclofenac or aspirin should be avoided unless viral
nimesulide. infection can be ruled out.

3. Gastric intolerance to conventional

NSAIDs or predisposed patients— etoricoxib
or paracetamol. 6. Pregnancy—paracetamol is the
safest; low dose aspirin is probably
4. Patients with history of asthma or the second best.
anaphylactoid reaction to aspirin/other
NSAIDs—nimesulide, COX-2 inhibitor.
 NSAIDs of choice
Some guidelines are:

7. Hypertensive, diabetic, ischaemic heart disease, epileptic

and other patients receiving long-term regular medication—
possibility of drug interaction with NSAIDs should be considered
and the physician consulted.

8. Patients with risk factors for cardiovascular diseases,

stroke—avoid etoricoxib/ celecoxib; ibuprofen or low-dose
aspirin may be used.
 References

1. Ritter, J. M., Flower, R. J.,Henderson, G., Loke, Y. K.,

MacEwan, D., Robinson, E., & Fullerton, J. (2023). Chapter 26.
E-book: Rang & dale's pharmacology E-book (10th ed.).
Elsevier Health Sciences.

2. Lerchenfeldt, S. (2020). Chapter 6 (pp. 160–169). In BRS

pharmacology (7th ed.). Wolters Kluwer.

3. Tripathi, K. D. (2008). Chapter 13. In Essentials of medical

pharmacology (6th ed.). Jaypee Brothers Medical Publishers.

4. Basic& Clinical Pharmacology 14th Edition, Chapter 36.

Thank You