Pharmacology- 2, 2024-2025, Prof. Dr.

Marwa Safar

Non Steroidal Anti-inflammatory Drugs (NSAIDS)

Inflammation: 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. When
healing is complete, the inflammatory process usually subsides. However, inappropriate
activation of the immune system can result in inflammation and immune-mediated
diseases such as rheumatoid arthritis (RA).
Chemoattraction (chemotaxis) of inflammatory cells → release of inflammatory mediators
e.g. tumor necrosis factor (TNF)-α and interleukin (IL)-1capable of killing microorganisms.

Eicosanoids
Phospholipids

Corticosteroids (by (-) Phospholipase A2

lipocortin)
Nonsteroidal anti- Arachidonic acid
inflammatory drugs
(NSAIDs) (-) (-) Zileuton
Cyclooxygenase 5-lipoxygenase
Leukotrienes (LT)
Cyclic endoperoxides
LTB4, LTC4, LTD4, ,LTE4
These are the main mediators of
PGI2 synthase PG synthase TX synthase bronchial asthma

PGI2 PGE2 & TXA2

(Prostacyclin) PGF2 (Thromboxane A2)
Platelet aggregation

Eicosanoids with ring structures (prostaglandins, thromboxanes, and prostacyclin) are

synthesized via the cyclooxygenase pathway.

PGs are the main inflammatory mediator:

Prostaglandins 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 are
rapidly metabolized to inactive products at their sites of action. Therefore, prostaglandins do
not circulate in the blood in significant concentrations.

 Effects of other inflammatory mediators

 PGs synthesis sensitivity of sensory nerve endings to nociceptive
by COX-enzymes stimuli→ amplify generation of pain impulses

V.D.,  vascular permeability (edema), swelling,

Inhibit COX enzymes &  PGs synthesis pain

NSAIDs

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 Pharmacology- 2, 2024-2025, Prof. Dr. Marwa Safar

Cyclo-oxygenase enzyme (COX-I & COX-II)

COX-I COX-II

• Constitutive. • Mostly inducible “induced in response to

• Responsible for the physiologic inflammatory stimuli”, functions in
production of prostanoids, inflammatory conditions.
• House-keeping Enzyme: Functions under • Causes the elevated production of
physiological conditions regulates prostanoids in sites of chronic disease
normal tissue functions as: and inflammation.
1. Gastric cytoprotection: • Constitutively expressed in tissues such
prostacyclin (PGI2) inhibits as the brain, kidney, and bone.
gastric acid secretion, and
PGE2 and PGF2α stimulate
synthesis of protective mucus
in both the stomach and small
intestine.
2. Platelet aggregation (catalyzes
formation of TXA2)
3. Kidney function: Regulates
blood flow in the kidneys.
4. Vascular homeostasis

Classification of COX inhibitors

Non selective COX inhibitors (inhibit COX1 and COX2)
Selective COX2 inhibitors

Non-steroidal anti-inflammatory drugs (NSAIDS)

‾ Antipyretic
‾ Analgesic Inhibit COX enzymes &  PGs synthesis
‾ Anti-inflammatory.

Classification of NSAIDS

1. Salicylates (Aspirin, Diflunisal)

2. Propionic acid derivatives (ibuprofen, fenoprofen, flurbiprofen, ketoprofen,
naproxen)
3. Oxicams (Piroxicam, Meloxicam)
4. Carboxylic Acetic acid derivatives (Indomethacin, Sulindac, Acetic acid
Etodolac) derivatives
5. Phenylacetic acid derivatives (Diclofenac)
6. Fenamates (Mefenamic acid, meclofenamate)
7. Selective Cox2 inhibitors (Celecoxib,Etoricoxib)

Uses: treatment of osteoarthritis, gout, RA, and common conditions requiring analgesia (for
example, headache, arthralgia, myalgia, and dysmenorrhea). Combinations of opioids and
NSAIDs may be effective in treating pain caused by malignancy. Indeed, the addition of
NSAIDs may lead to an opioid-sparing effect, allowing for lower doses of opioids to be
utilized.

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 Pharmacology- 2, 2024-2025, Prof. Dr. Marwa Safar

Aspirin (Acetyl Salicylic acid) Prototype; Bark of willow tree

Pharmacodynamics:
MOA:
 CYCLO-OXYGENASE (COX) enzyme
Salicylates inhibit central & peripheral COX enzyme by irreversible acetylation (covalent
bond) PGs (centrally & peripherally).
N.B. Other NSAIDs are reversible (competitive) inhibitors of COX.

Pharmacological actions:

1. Analgesics
➢ Centrally: by  the sensitization of pain receptors to mechanical & chemical stimuli.
➢ Peripherally: by  synthesis of inflammatory mediators as PGs.
N.B. PGE2 sensitizes nerve endings to histamine & bradykinin & other mediators released
locally during inflammation.  PGE2 →  sensation of pain.
Salicylates are more effective in pain associated with inflammation than opioids.

2. Anti-pyretic
a.  synthesis of PGE2  readjustment of set point of the thermoregulatory center in the
hypothalamus.
N.B. Synthesis of PGE2 is induced by pyrogens such as cytokines which are released from
WBCs during inflammation, infection.
b. Peripheral vasodilation (COX independent mechanism; increase NO) & sweating → heat dissipation
N.B. NSAIDs have no effect on normal body temperature.

3. CVS:
➢ Low doses (75-162 mg—commonly 81 mg)  TXA2→ platelet aggregation 
risk of ischemic heart attack (myocardial infarction) & stroke.

N.B.
❖ The antiplatelet effects persist for the life of the platelet
❖ NSAIDs other than aspirin are not utilized for their antiplatelet effect but can still prolong
bleeding time, especially when combined with anticoagulants.
❖ Concomitant use of NSAIDs and aspirin can prevent aspirin from binding to
cyclooxygenase. Patients who take aspirin for cardioprotection should avoid
concomitant NSAID use if possible or take aspirin at least 30 minutes prior to the
NSAID.

4. GIT:
➢ PGI2  inhibit HCl secretion
➢ PGE2 & PGF2α  mucus secretion (protective)
➢ Salicylates  PGI2, PGE2 & PGF2a  HCl (ulcer)

Doses:
➢ Dose needed to prevent platelet aggregation (75-160 mg, used for prevention of
myocardial infarction and stroke)  analgesic antipyretic dose < anti-inflammatory dose
(very high, rarely used).
N.B. The antiplatelet effects persist for the life of the platelet (3 to 7 days) and new
platelets need to be generated.
➢ Over dose can be antagonized by alkalinization of urine using NaCO 3.

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 Pharmacology- 2, 2024-2025, Prof. Dr. Marwa Safar

Adverse effects:

1. GI:  gastric acid secretion +  Protective gastric mucosa  ulcer & risk of GI
bleeding (NSAIDs should be taken with food and fluids) + Patients at risk of GIT
upsets should use concomitantly antiulcer drug: proton pump inhibitor or
Misoprostol)

N.B. Prostacyclin (PGI2) inhibits gastric acid secretion, and PGE2 and PGF2α stimulate
synthesis of protective mucus in both the stomach and small intestine.

2. Blood:  platelet aggregation  bleeding time so not given one week prior to
surgery.

3. Kidney: NSAIDs prevent the synthesis of PGE2 and PGI2, prostaglandins that are
responsible for maintaining renal blood flow.
 synthesis of prostaglandins → renal impairment (retention of sodium and water and may
cause edema). Patients with a history of kidney disease are at high risk.

4. Aspirin should be avoided in patients less than 20 years old with viral infections, such as
varicella (chickenpox) or influenza, to prevent Reye’s syndrome (a syndrome that can cause
fulminating hepatitis with cerebral edema, often leading to death).

5. Inhibition of PG synthesis cause the shift towards leukotriene production → Exacerbate

asthma.

6. Some people are allergic to aspirin and experience hypersensitivity reactions. Symptoms
of true allergy include urticaria, bronchoconstriction, and angioedema (swelling underneath
the skin). Fatal anaphylactic shock is rare. Patients with severe hypersensitivity to aspirin
should avoid using NSAIDs.

7. PGE2 and PGI2 are natriuretic as well as vasodilators, and NSAIDs consequently cause
salt and water retention, antagonize the effects of diuretics and antihypertensives and
exacerbate heart failure.

8. Salicylate is excreted into the urine and can decrease uric acid excretion. Therefore,
aspirin should be avoided in gout.

Drug interactions: Salicylate is roughly 80% to 90% plasma protein bound (albumin) and
can be displaced from protein-binding sites, resulting in increased concentration of free
salicylate. Alternatively, aspirin can displace other highly protein-bound drugs, such as
warfarin, phenytoin, or valproic acid, resulting in higher free concentrations of these agents.

Diflunisal
Salicylic acid derivative but Not metabolized to salicylates.
3-4 fold more potent than aspirin as analgesic, anti-inflammatory.
Doesn’t cross BBB, so no antipyretic effect.
Doesn’t cross placenta.

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 Pharmacology- 2, 2024-2025, Prof. Dr. Marwa Safar

2. Propionic acid derivatives

e.g. Ibuprofen, Ketoprofen, Naproxen & Fenprofen
1. Analgesic, antipyretic & anti-inflammatory.
2. Treatment of rheumatoid arthritis (RA) & osteoarthritis (OA).
3. GI effects less than aspirin, but cause dose dependent gastric irritation, long term use
causes ulcer.
4. Renal failure by long term use or even short term use with no adequate fluid
(dehydration).

3. Phenylacetic acid derivatives e.g. Diclofenac

Similar to propionic acid derivatives.
Adverse effects: Hepatitis

4. Oxicams derivatives (enolic acid derivatives)

e.g. Piroxicam & Meloxicam
1. Acute arthritis and osteoarthritis
2. Meloxicam is somewhat selective COX-2 inhibitors (but not as celecoxib), Loses
selectively at high doses.
3. Piroxicam has long t1/2 so can be taken once daily.

5. Acetic acid derivatives:

e.g. Indomethacin, Sulindac (prodrug), Etodolac, Nabumetone (prodrug), Ketrolac
1. Potent Anti-inflammatory.
2. Reversible COX inhibition.
3. Adverse effects limit the use to acute arthritis, osteoarthritis, acute gout.
Remark:
Ketorolac can be taken I.V. It is used for postoperative pain, severe pain, for a short time.

5- COX-2 selective NSAIDS:

-Coxibs eg. Celecoxib, Rofecoxib
MOA: Selective COX-2 inhibitor (Reversible)
Pharmacological actions:
➢ Doesn’t inhibit platelet aggregation  No  in bleeding time (Platelets contain only
COX-1 isoenzyme).
➢ Reduced GIT side effects.
Uses: Rheumatoid arthritis & Osteoarthritis.

Adverse effects: Although COX-2-selective drugs may have reduced gastric toxicity, but they may
increase the incidence of cardiovascular thrombotic events e.g. myocardial infarction and stroke due
to reduced synthesis of PGI2 (Prostacyclin) mediated by COX-2. SHOULD BE USED IN PATIENTS
WITH NO CV RISK FACTORS

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 Pharmacology- 2, 2024-2025, Prof. Dr. Marwa Safar

Acetaminophen=Paracetamol=N-acetyl P-aminophenol (APAP)

MOA: inhibits PGs in the CNS (inhibits COX3 in brain→ lacks anti-inflammatory activity).

Pharmacological actions:
1. Antipyretic, Analgesic
2. NO anti-inflammatory (weak peripheral COX inhibition due to peripheral inactivation, not
active in presence of peroxides generated at site of inflammation).
3. NO effect on platelet aggregation nor bleeding time.
4. Substitutes aspirin in patients with GI-problems.

Uses:
- Fever and the relief of pain.
- Drug of choice in children with viral infections or chickenpox (avoid Reye’s disease).

Metabolism:
1. Significant 1st pass effect.
2. Could be metabolized by microsomal enzymes to NAPQI, N-acetyl paraaminobenzo
quinoneimine (combine with SH group in enzymes and other biomolecules 
hepatotoxicity due to SH depletion)
N.B. Normally acetaminophen is safe because liver produces glutathione (SH group
make detoxification). Overdose is treated by NAC (N-acetylcysteine: SH donor).

N.B. Acetaminophen should be avoided in patients with hepatic impairment.

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 Pharmacology- 2, 2024-2025, Prof. Dr. Marwa Safar

Drugs Used for the Treatment of Gout

• 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.
• The deposition of urate crystals initiates an inflammatory process involving the
infiltration of granulocytes that phagocytize the urate crystals.

Symptoms: pain, swelling, tenderness, and redness in the affected joints (for example,
big toe, knees, ankles, wrists, or elbows).

Pathophysiology: imbalance between overproduction of uric acid and/or the inability to

excrete uric acid renally.

Treatment of acute gout

▪ Acute gout attacks can result from a number of conditions, including excessive alcohol
consumption, a diet rich in purines, and kidney disease.
▪ NSAIDs, corticosteroids, and colchicine are effective agents for the management of
acute gouty arthritis.
▪ Indomethacin is considered the classic NSAID of choice, although all NSAIDs are likely
to be effective in decreasing pain and inflammation.
▪ Intra-articular administration of corticosteroids (when only one or two joints are affected)
is also appropriate in the acute setting, or systemic corticosteroids for more widespread
joint involvement.

Colchicine
A plant alkaloid, used to relieve pain in acute attacks of gout.
Mechanism of action: Binds to tubulin, a microtubular protein, causing its depolymerization.
This disrupts cellular functions, such as the mobility of neutrophils, thus decreasing their
migration into the inflamed joint.
Adverse effects: nausea, vomiting, abdominal pain, and diarrhea. Chronic administration
may lead to myopathy, neutropenia, aplastic anemia (bone marrow depression), and
alopecia.

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 Pharmacology- 2, 2024-2025, Prof. Dr. Marwa Safar

Treatment of chronic gout

Urate-lowering therapy for chronic gout aims to reduce the frequency of attacks and
complications of gout.
Treatment strategies either reduce the synthesis of uric acid or increase its excretion
(uricosuric drugs).

Allopurinol (Zyloric®)

A purine analog
Mechanism of action: xanthine oxidase inhibitor, it reduces the production of uric
acid by competitively inhibiting the last two steps in uric acid biosynthesis that are
catalyzed by xanthine oxidase.

The primary metabolite alloxanthine (oxypurinol) is also a xanthine oxidase inhibitor with
a half-life of 15 to 18 hours. Thus, effective inhibition of xanthine oxidase can be
maintained with once-daily dosing.

The drug and its active metabolite are excreted in the urine. Dose adjustment
is needed in renal impairment.

Adverse effects: Hypersensitivity reactions, especially skin rashes.

Febuxostat (Feburic®)

- Oral xanthine oxidase inhibitor structurally unrelated to allopurinol.

- The risk for rash and hypersensitivity reactions are less than allopurinol.
- Febuxostat does not have the same degree of renal elimination as allopurinol thus
requires less adjustment in those with reduced renal function.
- Febuxostat should be used with caution in patients with a history of heart disease or
stroke, as this agent may be associated with a greater risk of these events as
compared to allopurinol.

Probenecid

- Uricosuric drug.
- Weak organic acid
- Promotes renal clearance of uric acid by inhibiting proximal tubular reabsorption of
uric acid.
- Avoided in low creatinine clearance.
- Adverse effects: nausea, vomiting, and dermatologic reactions.

Pegloticase
- recombinant form of the enzyme urate oxidase or uricase.
- Converts uric acid to allantoin, a water-soluble nontoxic metabolite that is excreted
primarily by the kidneys.
- Indicated for patients with gout who fail treatment with standard therapies.
- IV infusion every 2 weeks.
- Infusion-related reactions and anaphylaxis may occur, and patients should be pre-
medicated with antihistamines and corticosteroids.

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Pharmacology- 2, 2024-2025, Prof. Dr. Marwa Safar