Non-steroidal

Anti-Inflammatory Drugs
(NSAIDs)
2018
Dr. Najat Mohammed Saeed (MSc, Ph.D)
Department of pharmacology
 Anti-inflammatory drugs

• Non-steroidal anti-inflammatory
drugs (NSAIDs)

• Steroidal anti-inflammatory drugs

(SAIDs)............ (Endocrine topic)
What are the non-steroidal
anti-inflammatory drugs?
NSAIDs
drugs that have:
1. Analgesic
2. Antipyretic
3. Anti-inflammatory effects.
1. Analgesic effect

Pain-killer
 2. Antipyretic effect

Drugs that relieves fever

 3. Anti-inflammatory effect

Most NSAIDs at higher doses are used for

treatment of rheumatic arthritis and other
inflammatory joints diseases.
NSAIDs
• Most NSAIDs are OTC (over the
counter)

• They do not produce physical

dependence

• They are also known as non-

narcotic or non-opioid analgesic
Mechanisms of action
of NSAID
 Pain

Fever
PGs
Inflammation

NSAIDs act by inhibition of PGs synthesis

 NSAIDS Pain

Fever
PGs
Inflammation

NSAIDs act by inhibition of PGs synthesis

Synthesis of prostaglandiens
COX
Arachidonic acid (PGs), (PGI2) (TXA2)

COX = Cyclooxygenase enzyme

PGs = Prostaglandiens
PGI2= Prostacycline
TXA2 = thromboxane 2
 COX
Arachidonic acid (PGs), (PGI2) (TXA2)

NSAIDs

NNSAIDs act by inhibition of PGs synthesis

SAIDs act by inhibition of PGs synthesis
 Membrane phospholipid
Stimulus

Phospholipase A2

Arachidonic acid
LOX COX

LTS PGS
Stimulus Membrane phospholipid

Phospholipase A2
SAIDs

Arachidonic acid
LOX
COX
LTS PGS
Types of (COX) enzymes
1. COX-1 (physiological role)

2. COX-2 (Pathological role)

3. COX-3 (CNS- Paracetamol)?

Differing roles of COX-1 and COX-2
enzymes
Arachidonic acid
COX1 COX2

PGs associated PGs associated

with physiological with pathological
roles roles
• GIT • Pain
• Renal function • Fever
• Platelet function • Inflammation
GIT function (roles of Cox-1) PGE2
and PGI2
Cytoprotective effect (Prevent peptic ulcer)
- HCL
- mucus
- Bicarbonate
- Blood supply

NSAIDs?
Renal Function (roles of Cox-1)

PGE2 and PGI2

- Renal vasodilator (RV)
- Regulate renal blood flow
- Increase salt & water excretion

NSAIDs ?
Classification of NSAIDs
A. Non-selective COX Inhibitors
((Classical NSAIDs)

B. Selective COX2 inhibitors

(Newer NSAIDs)
 A. Non-selective
COX Inhibitors

Arachidonic acid
COX1 COX2

PGs associated PGs associated

with physiological with pathological
roles roles
• GIT, Renal and • Pain, Fever
Platelet function • Inflammation

Inhibition of Cox1 by NSAIDs results in side effects

1. Salicylates:
a. Salicylates for systemic use:
- Aspirin (acetyl salicylic acid)
- Diflunisal

b. Salicylates for local use:

- Salicylic acid
- Methyl salicylate

2. Para-aminophenol:
- Paracetamol (acetaminophen)
- Phenacetin

3. Acetic acid derivatives:

- Indomethacin
- Diclofenac
4. Propionic acid derivative:
- Ibuprofen
- Naproxen
- Ketoprofen

5. Fenamic acids:
- Mefenamic acid
- Meclofenamic acid

6. Oxicams:
- Piroxicam
- Tenoxicam
 B. Selective
COX-2 inhibitors

Arachidonic acid
COX1 COX2

PGs associated PGs associated

with physiological with patological
roles roles
• GIT, renal & • Pain, Fever
platelet function • Inflammation
Inhibition of Cox2 by NSAIDs results in anti-inflammatory
effect
B. Selective COX-2 inhibitors
(Newer NSAIDs)
- Celecoxib
- Etoricoxib
- Meloxicam (preferential COX2
inhibitor)
A. Non- selective COX inhibitors
(Classical NSAIDs)

1. Salicylates

A. Salicylates for systemic use:

- Aspirin (Acetyl Salicylic Acid) (ASA)
- Sodium salicylate
- Diflunisal
26
B. Salicylates for local use

- Salicylic acid

- Methyl salicylate

27
Acetyl salicylic acid
It is OTC drug and have:
- Analgesic
- Antipyretic
- Anti-inflammatory
Mechanism of action

• It is inhibit the synthesis of PGs, TXs and PGI2.

• Aspirin irreversible inhibition of both COX-1

and COX-2 central & peripheral

• Other NSAIDs (e.g. diclofenac and ibuprofen..),

which are reversible inhibitors.
Inhibition of COX by Aspirin
 Aspirin (ASA)
Salicylic Acetyl group
Acid
(ASA) Deacetylation
by estrase to
Salicylic acid

SA
Acetylated
COX COX
(active) (inactive)

Acetyl group
Pharmacological effects
1. Analgesic action
• PGs sensitize the pain receptor to the action
of pain producing substance

• PGs Pain sensation

• Aspirin PGs Pain
sensation
• It is useful analgesic for treatment
mild pain (e.g. toothache, headach
and arithrits)

• It is not effective for visceral pain (e.g.

renal and myocardial infarction)
2. Antipyretic action
Bacterial infection Toxin IL1& other ILs

Induce COX-2 PGs disturb the heat

regulatory centre (hypothalamus) fever

Aspirin PGs Re-adjust

hypothalamic heat regulatory center (HRC)
• It has no effect on normal body temperature

• Salicylate in toxic dose may lead to

hyperthermia due to uncoupling of oxidative
phosphorylation

• deplete body ATP and increases body

temperature
3. Antinflammatory & antirheumatic action
a. Aspirin inhibit PG synthesis peripherally

b. It inhibit action of inflammatory mediator such

as bradykinin, histamine and cytokines

c. Aspirin also inhibit the migration of polymorphs

and macrophages to the site of inflammation
(inhibit the release of lymphokines from T cell)

d. Stabilization of lysosomal membrane

(inhibit the release of proteolytic enzymes)

e. It has ability to suppress Ag-Ab

reaction.
• It is the drug of choice in
treatment of:

• Rheumatic arthritis (RA)

• Rheumatic fever (RF)
• Other inflammatory joints
diseases.
 4. Antiplatelet effect

Inhibition of platelet COX1 enzyme &

TXA2 synthesis
 4. Effect on platelets
• PGI2 platelet aggregation
• TXA2 platelet aggregation

• Low dose of aspirin (75-100 mg) Irreversible

inhibition of platelet COX1 Inhibit TXA2
formation (selectively) with out effecting PGI2
in endothelial cell lining blood vessels.
 Aspirin (ASA)
Salicylic Acetyl group
Acid
(ASA) Deacetylation
by estrase to
Salicylic acid

SA
Acetylated
COX COX
(active) (inactive)

Serine residue Acetyl group

• The aspirin’s antiplatelet effect lasts 8-10 days
(prolongation of bleeding time).

• Aspirin used as prophylaxis against

thromboembolic disease, MI and CVA

• To prevent bleeding complication aspirin should be

withheld for one week before surgery.
 5. Effect on GIT
PGs Secretion of HCl
Secretion of mucus
Bicarbonate

cytoprotective effect
(prevent peptic ulcer)

Aspirin PGs formation epigastric

distress, nausea, vomiting, peptic ulcer and
gastrointestinal hemorrhage.
 RX
• Misoprostol
• Omeprazol
• H2 antihistamine

• Reduce the risk of gastric ulcer and use in

treatment of gastric damage induced by
NSAIDs.
 6. Hepatic and renal effects

• Large dose of aspirin hepatotoxicity and

nephrotoxicity

PGE2 and PGI2

- Renal vasodilator (RV)
- Regulate renal blood flow
- Increases Na & H2O excretion
• Inhibit PGE2 & PGI2 resulting in salt &
water retention, edema, hyperkalemia
& acute reduction of renal function.

• In patients with CHF, renal

insuffieciency and liver cirrhosis

• Interstitial nephritis occur with all

NSAIDs except aspirin (Aspirin week
inhibitor of renal cox)
 Reye’s syndrome
• Aspirin in some
children with viral
infection causes
encephalopathy
and hepatotoxicity.
 7. Uricosuric effects
• Low doses of aspirin uric acid excretion
[Link] uric acid in blood (contraindicate in gout
disease)

• Intermediate doses not alter uric acid

excretion.

• Large doses uric acid excretion

(uricosuria) it can be use for treatment of
gout disease.
 8. Effect on Acid/base balance
High dose act directly on respiratory center causing
hyperventilation & respiratory alkalosis

Toxic doses causing central respiratory paralysis &

respiratory acidosis

Metaboic acidosis due to accumulation of

salicylate metabolitis, also salicylate induce
disturbance carbohydrate metabolism results in
accumulation of lactate and pyruvate
salicylate metabolitis
Effect on Respiration
• Aspirin bronchial asthma

• Production of leukotriens (LT) which

bronchoconstraction bronchial asthma

• Contraindicated in asthmatic patients.

 Membrane phospholipid
Stimulus

Phospholipase A2 NSAIDs

Arachidonic acid

LOX COX1 & COX2

LTS PGS

Bronchoconstriction (Lt B4)

 9. Effect in uterus
• Aspirin PGs uterine relaxation.

in pregnant women
• Delay labor (prolonge gestation)
• Increase postpartum hemorrhage
• Intra-uterine closure of ductus arteriosus.
ductus arteriosus
-Aspirin cause intra-uterine closure of ductus
arteriosus (before birth)

-Aspirin facilitate closure

of a patent ductus
Arteriosus (after birth)

- Paracetamol is safest
analgesic antipyretic in
pregnant women.
Aspirin/ Pharmacokinetics
Aspirin/ Pharmacokinetics
• Salicylate is weak acid.

• Rapidly absorbed orally

• A peak plasma salicylate level within

1-2 hours.

• Bound to plasma protein (50-80%).

Metabolism:
Metabolisim by liver
mostly conjugation
with glucuronic acid
and glycin to
inactive metabolite

Little by oxidation
to active metabolite
 Excretion:
• Urine partly unchanged (free salicylic
acid), partly conjugated

• Alkalinization of the urine increases

the rate of excretion of free salicylate
and its water-soluble conjugates.

• Crosses the BBB and placental

barrier.
The plasma half life of aspirin (t1/2)
- Small dose
First order kinetics
(serum t1/2 = 3-4 hrs)
(constant t1/2).

- Large dose: Zero

order kinetics (serum
t1/2 = 15 hrs)
(increasing t1/2 with
increasing dose)
 Therapeutic uses of salicylates

- Antipyretic
- Analgesic
- Anti-inflammatory

They effective for relieving

mild pain but ineffective for
visceral pain.
1. Small dose (75-100 mg)
1. Prophylaxis against thromboembolic disease.

2. Reduce cancer colon.

3. Prophylaxis against Alzheimer’s disease.

4. Pregnant women
• Generally , aspirin is n’t recommended during
pregnancy unless presence certain medical
conditions:
• Pregnant women who have a high risk of
developing hypertension.

• Recurrent miscarriage associated with placenta

thrombosis

• Prevention of pre-eclampsia
2. Intermediated dose 325mg
1. Analgesic in mild to moderate pain (headache,
toothache and pain of muscles or joints.
(ineffective for visceral pain)

2. Dysmenorrhea (but may increase bleeding).

3. Common cold (treatment of fever, headache and

muscle pain).
 3. High dose (4-8g)
1. Analgesic and anti-inflammatory in:
-Rheumatic fever
- Rheumatoid arthritis and other
inflammatory joint diseases.

2. Uricosuric agent in chronic gout disease.

Local uses of salicylate
• Salicylic acid is applied topically as a
keratolytic agent
• Fungistatic (when combined with benzoic
acid).
• Salicylic acid is also used as wart remover.

• Methyl salicylate used as counterirritant.

It is employed for painful muscles or joints.
Side effects
1. GIT:
- Direct
- Indirect
- CTZ

- Reduced by taking drug with

food and a large volume of fluid.
 RX
• Misoprostol
• Omeprazol
• H2 antihistamine

• Reduce the risk of gastric ulcer and use in

treatment of gastric damage induced by
NSAIDs.
2. Hypersensitivity:
- Urticaria, bronchoconstriction and
angioedema
- (Epinephrine)

- LOX inhibitor (Zileuton) useful in

treatment of aspirin-induced
bronchial asthma.
 Membrane phospholipid
Stimulus

Phospholipase A2 NSAIDs

Arachidonic acid

LOX COX1 & COX2

LTS PGS
 Membrane phospholipid
Stimulus

Phospholipase A2 NSAIDs

Arachidonic acid

LOX COX1 & COX2

Zileuton
LTS PGS
3. Blood:
- Prolongation of bleeding time.

4. Reye’s syndrome:
- Aspirin in some children with viral
infection causes encephalopathy
and hepatotoxicity

- Rx Paracetamol instead of Aspirin

Toxicity of aspirin
1. Acute aspirin toxicity (sever) (15-30 gm)
- Fever (hyperpyrexia)
- Dehydration
- Hypoprothrombinemia
- Tremors, convulsions,
hallucination and coma.
- Metabolic and respiratory acidosis

Death from aspirin over dose is caused

by respiratory and renal failure.
 Treatment of acute toxicity
• Gastric lavage with sodium bicarbonate
• Correction of dehydration by Plenty of IV fluids
• Increase urine excretion: alkalinization of urine
with NaHCO3
• Vitamin K administration + fresh blood
transfusion
• Cooling (ice bags)
• Hemodialysis may be needed in sever cases
2. Chronic aspirin toxicity (Salicylism)

Salicylism: large dose for long time lead to

-Headache
- Mental confusion
- Vertigo, ringing in ears (tinnitus)
- Blurring vision
- Sweating
- GIT irritation
Contraindication
1. Allergy to salicylates
2. Bleeding tendency
3. Peptic ulcer
4. Bronchial asthma
5. Virus infection in children because of the risk
of Reye’s syndrome.
6. Small doses in patient with gout.
Drug interactions of salicylates
1. Displace drug from plasma protins e.g. oral
anticoagulants and oral hypoglycemics

2. Ammonium chloride enhances toxicity (acid)

3. NSAID, corticosteroids and alcohol increase

ulcerogenic effect of salicylates

4. Phenobarbitone increase the metabolism of

salicylates

5. Antagonize the action of antihypertensive agent

ACEI and diuretic
2. Diflunisal
• Anti-inflammatory drug (osteoarthritis)

• It is more potent than aspirin( 3-4

times)

• It is has no antipyretic effects

• Less side effect

• All salicylates except diflunisal cross

BBB & placenta.
 2. Para-aminophenol derivatives

1. Paracetamol = acetaminophen
Paracetamol
A commonly used analgesic
antipyretic instead of aspirin
in cases of:
• Peptic or gastric ulcers
• Bleeding tendency
• Allergy to aspirin
• Viral infections in children
• Pregnancy.
• Bronchil asthma
• Gout
 Mechanism of action
• It inhibits central but NOT peripheral COX.

• It inhibit COX-3 enzyme in CNS with weak

peripheral effect.
 Pharmacological action:
1. Analgesic, antipyretic effect similar to aspirin
(central action)

2. It has No significant anti-inflammatory action

(no peripheral action)

3. It has no effect on platelet aggregation

4. No gastric irritation (used by patients with peptic
ulcer)
5. No bronchospasm (used by patients with
bronchial asthma)

6. It has no effect on uric acid levels (used by

patients with goat disease)
Pharmacokinetics
• It absored orally

Metabolism:
• 95% Conjugation with glucuronic acid &
sulfate Inactive metabolite

• 5% Cytochrom P450 (NABQ)

N-acetyl-p-benzoiminoquinone (Toxic
metabolite)
Conjugation with Glutathion-SH Non
toxic
Toxic metabolite (NABQ) is normally detoxificated
by glutathione

Large doses of paracetamol

Depletion of glutathione-SH

Accumulation of NABQ

Hepatotoxicity and nephrotoxicity

 Adverse effects and toxicity (toxic dose
10g in adult and 4g in children)
• In therapeutic doses are usually well tolerated.

• Skin rash and other allergic reactions occur

occasionally.

• Excessive use of paracetamol cause fatal

Hepatotoxicity and nephrotoxicity.

• Toxicity from paracetamol is not from the drug itself

but from its metabolites (NABQ).
 Treatment of acute toxicity
• Antidote N-acetylcysteine (neutralize the toxic
metabolites).

• The antidote N-acetylcysteine (rich in SH) acts as

glutathione substitute, binding the toxic metabolite
as it is being produced

• A liver transplant may be required for patients with

hepatic failure.
3- Acetic acid derivatives:
a. Indomethacin
- Is a potent non-selective COX inhibitor
it inhibits both central and peripheral COX.

- It is a powerful anti-inflammatory agent.

- Must not be used as an analgesic or

antipyretic (side effects).
Pharmacokinetics
• Rapidly and almost completely absorbed from GIT
after oral ingestion.

• Metabolized in liver, highly bound to plasma

proteins (90%).

• Concentrated in synovial fluid.

• Excreted in urine, bile and feces

• Undergoes enterohepatic circulation
Adverse effects
1. GIT side effects

2. CNS disturbance

3. Hypersensitivity reaction
(rash, urticaria and asthma)
Therapeutic Uses
1. A potent anti-inflammatory drug used in
treatment of rheumatoid arthritis.

2. Very effective in treatment of acute gout.

3. To close patent ductus arteriosus in neonates.

4. Tocolytic agent to suppress uterine contraction

in women with preterm labour.
 Contraindications
Indomethacin should not be used in
• Pregnant women (teratogenic effect)
• Psychiatric disorders
• Epilepsy
• Parkinsonism
• Renal disease
• Ulcerative lesions of the stomach or intestines
Diclofenac

• It has analgesic, antipyretic and anti-

inflammatory activities.

• It is more potent than indomethacin.

Pharmacokinetics
• Diclofenac is rapidly and completely absorbed
after oral administration and it is highly bound to
plasma proteins (99%).

• Accumulates in synovial fluid after oral

administration..

• Metabolized in liver to hydroxydiclofenac; the

metabolites are excreted in the urine (65%) and
bile (35%).
Adverse effects
1. Gastrointestinal distress, occult
gastrointestinal bleeding, gastric
ulceration.

2. Diclofenac at dosage of 150 mg/day

appears to impair RBF & GFR

3. Skin rashes and allergic reaction.

4. Fluid retention and edema.

Therapeutic Uses

1. Use in treatment of rheumatoid arthritis,

osteoarthritis

2. Postoperative pain e.g. Prevention of

postoperative ophthalmic inflammation

3. Dysmenorrhea
4. Propionic acid derivative:
Ibuprofen

• It has analgesic, antipyretic and

inflammatory action
Pharmacokinetics
• Ibuprofen is rapidly absorbed after oral
administration and is extensively (99%)
bound to plasma proteins.

• Ibuprofen metabolized in liver, and more

than 90% of an ingested dose is excreted
in urine as metabolites.
Therapeutic Uses
• Rheumatoid arthritis
• Osteoarthritis
• Dysmenorrhea
• Postsurgical dental pain.
• Closing patent ductus arteriosus in
preterm infants
Adverse effects
• Gastrointestinal side effects (epigastric pain,
nausea, heartburn). The drug may be given with
The drug may be given with milk or food to
minimize gastrointestinal side effects

• The incidence of these side effects is less with

ibuprofen than aspirin or indomethacin.

• Rash, tinnitus, dizziness, headache, blurred

vision and fluid retention.
2. Naproxen
• It is approximately 20 times more potent than
aspirin.

• It half life =14 hrs.

• It is effective in treatment of acute attack of

gout.
5. Fenamic acids:
• Mefenamic acid

• They have analgesic, antipyretic and

anti-inflammatory activity

• They are used for treatment of

dysmonorrhea, rheumatoid arthritis and
osteoarthritis.
VI. Oxicams:
Piroxicam
• Piroxicam is an effective analgesic, antipyretic
and anti-inflammatory.

• It is used for treatment of rheumatoid arthritis,

osteoarthritis and postoperative pain.

• Long half life, which permits the administration of

a single daily dose.

• Main side effects: It can cause GI irritation

2. Selective COX-2 inhibitors (New
NSAIDs)

Mechanism of action
They inhibit PG synthesis by COX-2
enzymes induced at site of
inflammation without affecting the
action of COX-1 enzymes
Beneficial effects:
• They have analgesic, antipyretic and anti-
inflammatory with less risk of gastric
ulceration.

• They decrease progression of Alzhiemer

disease.

• They decrease the risk of colorectal cancer.

- Celecoxib
- Etoricoxib
- Meloxicam
They are withdrawn
- Rofecoxib from market because
- Valdecoxib of high risk of heart
attack and stroke
Celecoxib
• They are effective as other NSAIDs in the
treatment of rheumatoid arthritis and
osteoarthritis with fewer gastrointestinal side
effects.

• It does not affect platelet aggregation at usual

doses.

• Other adverse effects are similar to those of

other NSAIDs.
Etoricoxib
• It is a second generation COX-2 selective
inhibitor (highly selective).

Meloxicam
• It is related to piroxicam
• Preferentially selective