- Dr.

Rashmi Mahajan
Learning Objectives
• At the end of this interactive session:

• 2nd year MBBS students should be able to classify NSAIDs.

• 2nd year MBBS students should be able to explain mechanism of action of NSAIDs.

• 2nd year MBBS students should be able to describe pharmacological effects of NSAIDs.

• 2nd year MBBS students should be able to identify clinical uses

• 2nd year MBBS students should be able to recognize adverse effects, drug interactions
and contraindications
 CLASS OUTLINE
1. Clinical case 6. Drug interactions
2. NSAIDs classification 7. Aspirin
3. Mechanism of action 8. Acetaminophen
4. Therapeutic Uses 9. Selective COX-2 inhibitors
5. Adverse effects 10. Other NSAIDs
 CLINICAL CASE
• A 64-year-old man who suffered a myocardial infarction 2 years
earlier is taking 80 mg of aspirin each day on the recommendation of
his family physician. His doctor has advised him that this will reduce
his chances of another myocardial infarction or stroke.
a. What is the mechanism of aspirin’s cardioprotective effect in this
patient?
b. What are the hazards of daily aspirin therapy?
c. What concomitantly administered drugs might impair the
cardioprotective effects of aspirin?
ANTI-INFLAMMATORY CORTICOSTEROIDs

ANALGESIC OPIOIDs

ANTI-PYRETIC

ANTI-PLATELET
Difference between Opioid & Non-Opioid
analgesics
OPIOIDS NON-OPIOID ANALGESICS

Stronger Analgesics Weaker analgesics (except for

inflammatory pain)

Depress CNS Do not depress CNS

Causes physical dependence No dependence

Mainly CNS action Action - Primarily peripheral

(also in CNS)
 Differences between NSAIDs and Steroids
Feature NSAIDs Corticosteroids (Steroids)

Inhibit phospholipase A2 → ↓ Prostaglandins +

Mechanism of action Inhibit COX enzymes → ↓ Prostaglandins
Leukotrienes

Level of action Peripheral (inflammation site) Central + peripheral (gene-level action)

Anti-inflammatory effect Moderate Very strong

Analgesic effect Good (mild–moderate pain) Indirect (via anti-inflammatory action)

Antipyretic effect Present Minimal/absent

Immunosuppression No Strong immunosuppressive action

Onset of action Faster Slower (genomic effects)

Common uses Pain, fever, arthritis, dysmenorrhea Autoimmune diseases, asthma, severe inflammation

Cushingoid features, hyperglycemia, osteoporosis,

Adverse effects GI ulcer, renal damage, platelet inhibition
infections

Examples Ibuprofen, Diclofenac, Aspirin Prednisolone, Dexamethasone, Hydrocortisone

 INFLAMMATION
• Immune system’s protective response to an injurious stimulus
• Inflammation may be exaggerated & sustained → hypersensitivity,
autoimmune diseases & chronic inflammation
Components of acute Mediators of inflammation
inflammation
Local vasodilation Histamine
Increased capillary permeability 5HT & Kinin
Infiltration of leukocytes & Leukotriene
phagocytic cells PAF
Tissue degeneration & fibrosis PGs (PGE2, PGI2,PGD2)
Cytokines, chemokines
 PAIN
• Nociceptors – Peripheral terminals of primary afferent fibre that sense pain &
they get stimulated by heat, acids or pressure
• Tissue injury → Inflammation → increased sensitivity of nociceptors & potentiate
pain perception
PGs in Pain
Peripheral sensitization Central sensitization
Reduction in the threshold to stimulate Increase in excitability of spinal dorsal horn
nociceptors neurons → Hyperalgesia & Allodynia
(disinhibition of glycinergic pathway)
Mediated by PGE2 & PGI2 Centrally acting PGE2; Other - PGI2, PGD2 &
PGF2α
NSAIDs – Reversal of peripheral sensitization Both COX-1 and COX-2 are expressed in the
spinal cord under basal conditions
 FEVER
Fever (Hypothalamic set point elevated)
Injurious stimuli, inflammation

Increase cytokines – IL-1, TNF (endogenous pyrogens)

2. Second phase
Induction of COX-2 → PGE2 → crosses BBB &
1. Initial Phase
act on thermosensitive neurons → trigger
- Ceramide release in
hypothalamus to increase body temperature
anterior hypothalamus
- Increase heat generation
- Decrease heat loss
MECHANISM OF ACTION
COX or Prostaglandin endoperoxidase
synthase enzyme
Homodimer
• Allosteric monomer
• Catalytic monomer (two
active sites)
1. Cyclo-oxygenase site
(AA → PGG2)
2. Peroxidase site
(PGG2 → PGH2)
COX - 1 COX - 2

Narrow substrate side

substrate pocket
channel
Feature COX-1 COX-2

Expression Constitutive (always present) Inducible (during inflammation)

Physiological role “Housekeeping” functions Inflammation & injury response

Main sites Stomach, platelets, kidneys Inflamed tissues, macrophages, endothelium

Prostaglandins produced Protective prostaglandins Pro-inflammatory prostaglandins

Gastric mucosal protection, platelet aggregation, renal

Functions Pain, fever, inflammation
blood flow

Platelet function Produces thromboxane A₂ → platelet aggregation Minimal role

Effect of inhibition GI ulcer, bleeding, renal side effects Anti-inflammatory, analgesic, antipyretic effects

Drug selectivity Inhibited by non-selective NSAIDs Selectively inhibited by COX-2 inhibitors

Examples of drugs Aspirin, Ibuprofen (non-selective) Celecoxib, Etoricoxib

 COX - Inhibition

Irreversible COX inhibition Reversible COX inhibition Selective COX-2 inhibition

ASPIRIN tNSAIDs Celecoxib & other coxibs

Duration of effect – turnover Duration of effect depend Etoricoxib > Rofecoxib >
rate of COX in different tissue on time course of drug Celecoxib
disposition
 PHARMACOKINETIC
Absorption
• Rapidly absorbed following oral ingestion
• Antacids and Foods – may delay absorption (PPI – No change) but it is given
with food to reduce gastric irritation

Distribution
• High plasma protein binding (Albumin) – conc. dependent & saturable
• Widely distributed – synovial fluid (Ibuprofen, Naproxen & Piroxicam,
Indomethacin, Tolmetin)
• Most NSAIDs – central analgesic effect. Celecoxib – lipophilic – cross BBB
• Topical preparation – Diclofenac – detectable conc. in synovial fluid via
dermal absorption & systemic circulation
Elimination
• Hepatic biotransormation & Renal elimination
• Ibuprofen, diclofenac, and acetaminophen have a t1/2 of 1 to 4 h
• Piroxicam has a t1/2 of about 50 h
 THERAPEUTIC USES

Fetal circulatory
Inflammation Pain Fever
system

Cardio Systemic Niacin Bartter

protection mastocytosis tolerability syndrome

Cancer
Preeclampsia
chemoprotection
1. Inflammation – muculoskeletal disorders eg – RA, OA, Gout,
Ankylosing spondylitis

2. Pain – Low to Moderate intensity

• NSAIDs + Opioids – reduce AE of Opioid & need less dose
• Effective in inflammation causing peripheral & central sensistization. Eg –
Post-op pain, Arthritic pain
(NOT effective in hollow viscera pain, except Menstrual pain)
• First line therapy in Migraine. Combined with Triptans (Naproxen +
Sumatriptan)

3. Fever – Reduce fever by increase in dissipation of heat by

cutaneous vasodilation
 3. Cardioprotection - ASPIRIN
• Irreversible acetylation of
platelet COX
• Permanent & complete
suppression of TxA2
• Reduce vascular events in
high risk patient (Eg. MI)

• Other tNSAIDs – reversible

COX inhibition – NOT
cardioprotective

• ASPIRIN + other tNSAIDs -

Cardioprotection lost
5. Fetal circulatory system – to close inappropriate ductus arteriosus.
Eg. Indomethacin, Ibuprofen

6. Systemic mastocytosis –
• Abnormal accumulation and activation of mast cells (bone marrow, liver,
spleen, skin, and GIT)
• Increase release of PGD2 → Flushing, Vasodilation & Hypotension
• Rx – Aspirin & Ketorolac (can cause mast cell degranulation)
• Histamine receptor blockade considered before NSAID therapy
7. Niacin Tolerability – facial flushing A/E via PGD2
• Rx – Aspirin
8. Bartter syndrome – (hyper PGE syndrome)
• Mutation in Na+-K+-2Cl- co-transporter
• Hypokalemic, hypochloremic metabolic alkalosis
• Rx – Aspirin + K+ repletion + Spironolactone
9. Cancer chemoprevention
• COX-2 promotes angiogenesis, cell proliferation & inhibit apoptosis
• Aspirin & COX-2 inhibitors
10. Preeclampsia – HTN & proteinuria during pregnancy
• Platelet activation through endothelial inflammation and renal dysregulation
of blood pressure
• Rx – Low dose aspirin
In paediatric age group
• Kawasaki disease-High dose aspirin in acute phase followed by low
dose anti platelet therapy in subacute phase
• Safest NSAIDs: Paracetamol, Ibuprofen, Naproxen
ADVERSE
EFFECTS
GIT
• Most common ADR with NSAIDs
• Abdominal pain, Nausea, Diarrhea, Dyspepsia
• Gastric erosion/ Ulcer Risk increased with –
• [Link] infection
• GI hemorrhage – Anemia • Heavy alcohol consumption
• Perforation/ Obstruction • Concurrent use of warfarin &
glucocorticoid
• Aspirin + tNSAIDs
• Multiple NSAIDs
• High dose of single NSAID
• Age > 70 years
• Past h/o ulcer
• PGI2 & PGE2 – cytoprotective
• Ion trapping
• Increased LOX product – Ulcerogenic

Rx – PGE1 analogue (Misoprostol)

- DOC - PPI
CVS
• Increased risk of MI, stroke, thrombosis with COX-2 inhibitors & older
tNSAIDs – Diclofenac, Meloxicam & Nimesulide
• Black box warning – for CVS risk & Cx following CABG

Mechanism -
• Depression of COX-2 dependent prostanoid formation in vasculature & kidney
(decrease PGI2 & PGE2)
• Risk factor – patient at high risk of CVS disease or thrombotic events. Eg – RA
• Factors affecting – dose, t1/2, degree of COX-2 selectivity, potency & Rx duration
• Lowest dose prescribed for shortest duration
 In CCF, CKD, Hypovolemia & other states where
RAAS activated → PG – local vasodilation as
compensation
Renal NSAIDs inhibit –
1. PG induced vasodilation
2. PG induced reabsorption of Cl-
3. PG induced action ADH
l/t Salt & water retention → HTN, Volume
overload
Promotes reabsorption of K+ due to decreased of
Na+ at distal tubular site → hyperkalemia

Analgesic Nephropathy
Depression of afferent and medullary renal blood
flow by inhibition of vasodilator PGs → ischemic
episodes and acute kidney injury including acute
tubular necrosis (Phenacetin)
4. Pregnancy & Lactation –
• Hours before parturition – increase in PGE2 & PGF2α
• NSAID – particulary Indomethacin – Rx of pre-term labor (off-label
use) → can cause early closure of ductus arteriosus & impair fetal
circulation
• COX-2 NSAIDs – Oligohydramnios
• NSAID & Aspirin in late pregnancy – Increase chance of Post partum
hemorrhage
5. Hypersensitivity
To aspirin (d/t LT) & NSAID – Vasomotor rhinitis, urticarial, flushing,
hypotension, shock, bronchial constriction
Aspirin intolerance Cx to therapy any other NSAIDs d/t cross-sensitivity
(rare with Acetaminophen)

6. Aspirin resistance – All forms of Rx failure with aspirin

7. Reye’s Syndrome
Acute onset encephalopathy,
liver dysfunction, fatty
infiltration of liver

Aspirin & other salicylates

Cx <12 years
Drug Interactions
Drug Mechanism Effect
ACE Inhibitors NSAID – Block PG induced ACE inhibitors effectiveness
vasodilation reduced
Hyperkalemia Severe bradycardia &
syncope
Corticosteroid, SSRI Increase GI complication
Warfarin + Aspirin Complete suppression of Bleeding
platelet
At PPB site – Warfarin, Displace these drugs Toxicity
Sulfonylurea, Methotrexate
Lithium Piroxicam – decrease renal Toxicity
excretion of Li
Sulindac – Inc. renal Rx failure
excretion of Li
Aspirin + tNSAIDs Increase GI A/E
Aspirin + Ibuprofen Impede access site for Prevent cardioprotection
aspirin
Individual NSAIDs
 Aspirin & Other Salicylates

• Includes: Aspirin, diflunisal, salsalate, mesalamine, sulfasalazine

• Salicylic acid highly GI irritant → used only topically
• Aspirin = acetylated derivative of salicylic acid
• Widely used: cardioprotection (low dose), analgesic, antipyretic, anti-
inflammatory
• Toxicity → risk of fatal poisoning (especially children)
Mechanism of Action
• Aspirin → irreversible COX inhibition via acetylation
• ↓ Prostaglandins + ↓ Thromboxane A₂ (antiplatelet effect - Platelet
acetylation occurs presystemically as platelets pass through gut
capillaries)
• Other salicylates → weak reversible COX inhibition
• Also ↓ COX-2 expression (transcriptional level)
Aspirin – Absorption & Distribution
• Rapid oral absorption (stomach + upper small intestine)
• Peak plasma level ~1 hour
• ↑ pH → ↑ solubility → ↑ absorption
• Food delays absorption; rectal → slow & variable
• Enteric coating → ↓ bioavailability (~50%)
• Wide distribution (pH-dependent); crosses placenta & CSF
• 80–90% protein bound (↓ binding at high dose)
Metabolism & Excretion
• Aspirin → rapidly deacetylated → salicylic acid
• Metabolites: salicyluric acid, glucuronides
• Renal excretion (free + metabolites)
• Urinary pH dependent elimination
• Alkaline urine (pH 8) → ↑ clearance (~4×)
• t½: Aspirin ~20 min; Salicylate 2–12 h
• High dose → prolonged t½ (up to 30 h)
Clinical PK & Monitoring
• Dose-dependent (nonlinear) kinetics → toxicity risk
• Hypoalbuminemia → ↑ free drug → ↑ toxicity
• Drug interactions (protein binding displacement)
• Renal disease → ↑ salicylate levels
• Hemodialysis effective in overdose
• Therapeutic level: 150–300 μg/mL (anti-inflammatory)
Urinary Alkalinization & Ion Trapping (Aspirin Overdose)

• Salicylate = weak acid (HA ⇌ H⁺ + A⁻)

• In acidic urine → more unionized (HA) → reabsorbed
• In alkaline urine → more ionized (A⁻) → trapped in lumen
• Ionized form cannot diffuse back → ↑ renal excretion
• Urinary alkalinization (NaHCO₃) → treatment of overdose
• Clearance ↑ up to 4× at urine pH ~8
• Also reduces CNS toxicity (↓ drug entry into brain)
 Ion Trapping in Gastric Mucosa → Aspirin Toxicity

• Aspirin = weak acid (HA form in acidic stomach)

• Non-ionized (HA) → diffuses into gastric mucosal cells
• Inside cells (higher pH) → converts to ionized (A⁻)
• Ionized form gets trapped intracellularly
• Leads to local accumulation → mucosal injury
• COX-1 inhibition → ↓ protective prostaglandins
• Result: gastritis, erosion, ulcer, bleeding
 Aspirin & Salicylates – Therapeutic Uses
Systemic Uses
• Analgesic–antipyretic: 325–1000 mg q4– Local / GI Uses
6h • Mesalamine → IBD (ulcerative colitis)
• Anti-inflammatory (rare): 4–8 g/day (e.g.,
rheumatic fever) • Forms: oral (colon-targeted), enema,
suppository
• Max dose: 4 g/day • Sulfasalazine, olsalazine → RA,
• Used less now → safer NSAIDs preferred ankylosing spondylitis

Other Systemic Salicylates Topical Uses

• Diflunisal → potent analgesic (OA, • Salicylic acid → keratolytic (warts,
musculoskeletal pain) corns, dermatitis)
• Less antipyretic, ↓ GI & antiplatelet • Methyl salicylate → liniments for
effects muscle pain
• Salsalate, Mg salicylate → alternatives
 Adverse effects
Respiratory & Acid–Base Effects
• ↑ O₂ consumption, ↑ CO₂ production (uncoupling of oxidative
phosphorylation)
• Direct stimulation of respiratory center (medulla)
• → Hyperventilation → ↓ PCO₂ → respiratory alkalosis
• Compensation → ↑ renal HCO₃⁻ loss → metabolic acidosis
• Early: respiratory alkalosis
• Late toxicity: mixed metabolic + respiratory acidosis
• Severe → respiratory depression → death
GI, Renal & Cardiovascular Effects
• GI: epigastric pain, ulcer, painless bleeding
• Chronic blood loss → iron deficiency anemia
• Renal: ↓ function (CHF, CKD, hypovolemia)
• Analgesic nephropathy (with combinations)
• High dose → Na⁺ + water retention → edema
• ↑ cardiac workload → CHF, pulmonary edema
• Noncardiogenic pulmonary edema (elderly)
Hepatic, Uric Acid & Hematologic Effects
• Hepatic: ↑ transaminases (>150 µg/mL levels)
• Usually reversible; avoid in liver disease
• Uric acid (dose-dependent dual effect): Aspirin blocks action of uricosurics (e.g.,
• Low dose → ↓ excretion (OAT)→ ↑ uric acid probenecid)
• High dose → uricosuric (URAT1) (rarely used) Even small doses →
reduce efficacy of gout treatment
• Hematologic:
• Irreversible platelet inhibition → bleeding
• Stop ≥1 week before surgery
• Hemolysis in G6PD deficiency
CNS, Ototoxicity & Special Situations
• CNS: headache, dizziness, confusion → coma (high dose)
• Salicylism: tinnitus, hearing loss
• Ototoxicity → reversible after stopping (Inc. labyrinthine pressure
resolve in 2 -3 days after stoppage)
• Pregnancy: ↓ birth weight, ductus arteriosus closure
• Children: Reye syndrome risk
• Topical (methyl salicylate) → systemic toxicity possible
 • Active metabolite of phenacetin
• Widely used OTC analgesic & antipyretic
ACETAMINOPHEN • Max dose: 4 g/day (↓ to 2 g in alcoholics)
• MOA -
• 50% inhibition of both COX1 &2
• Poor ability to inhibit COX in presence of
peroxide – NO anti-inflammatory activity
• Toxic metabolite -
• NAPQI formation (N-acetyl-parabenzoquinone
imine)
• Rx – As analgesic & antipyretic
• A/E –
• Rash & allergic reaction (drug fever)
• Liver damage on high dose
 Overdosage of acetaminophen
• Acute ADR of overdosage of acetaminophen - fatal hepatic necrosis
• Conditions of CYP induction (e.g., chronic heavy alcohol consumption)
or GSH depletion (e.g., fasting or malnutrition) increase the
susceptibility to hepatic injury
• In acetaminophen overdose - hepatocellular levels of GSH become
depleted
• The highly reactive NAPQI metabolite binds covalently to cell
macromolecules, leading to dysfunction of enzymatic systems and
structural and metabolic disarray.
• Depletion of intracellular GSH - hepatocytes highly susceptible to
oxidative stress and apoptosis. Renal tubular necrosis and
hypoglycemic coma also may occur.
Clinical picture
• 12- 36 h – Plasma transaminases elevated
• First 2 days – Symptoms develop (gastric distress - e.g., nausea,
abdominal pain, anorexia)
• 2 to 4 days - Clinical indications of hepatic damage manifest, right
subcostal pain, tender hepatomegaly, jaundice, and coagulopathy
• 3 to 4 days - Liver enzyme abnormalities typically peak and may be
accompanied by hepatic encephalopathy
• Toxic level - plasma concentrations of acetaminophen > 300 μg/mL at 4 h
or 45 μg/mL at 15 h after the ingestion of the drug
• Initial management - Activated charcoal, within 4 h of ingestion
• N-acetylcysteine (NAC) - antidote for acetaminophen overdose
• NAC - detoxify NAPQI.
• Repletes GSH stores
• Conjugate directly with NAPQI by serving as a GSH substitute.
• Supprotve care -
• Management of hepatic and renal failure, if they occur, and intubation if the patient
becomes obtunded.
• Hypoglycemia can result from liver failure, and plasma glucose should be monitored
closely.
• Fulminant hepatic failure is an indication for liver transplantation.
 Acetic acid derivatives
Adverse Effects / Notes
Drug Key Features ADME Highlights Therapeutic Uses
t½: 1–2 h; high protein
RA, OA, AS, GI toxicity (~20%); ↑ CV
Most used NSAID binding; first-pass
dysmenorrhea, risk (MI); hepatotoxicity
Diclofenac (Europe); relatively metabolism (~50%);
migraine; topical & (monitor LFTs); edema,
COX-2 selective accumulates in synovial
ophthalmic forms rash
fluid
Very potent (≈20× t½ ~2.5 h; High ADR rate (35–50%);
RA, OA, gout; PDA
aspirin); nonselective enterohepatic severe GI, CNS
Indomethacin closure in neonates
COX inhibitor; inhibits circulation; synovial = (headache, psychosis);
neutrophil motility plasma levels hematologic toxicity

Very potent analgesic; Short acting; multiple Acute pain (≤5 days) Severe GI, renal, bleeding
Ketorolac weak anti- routes ; postoperative; risk; limit duration; avoid
inflammatory (IV/IM/oral/intranasal) ophthalmic use in CKD, CABG
 Enterohepatic cycling; Less toxicity than
Prodrug → active
Sulindac less potent than RA, OA, gout, AS indomethacin; GI (~20%),
sulfide metabolite
indomethacin rash

Duration: 6–8 h;
Partial COX-2 RA, OA, mild- Better tolerated; mild GI,
Etodolac sustained-release
selectivity moderate pain CNS effects (~5%)
available

Reduced absorption GI (~15%), less severe CNS

Tolmetin Comparable to aspirin RA, OA, JRA
with food effects

Prodrug → active
metabolite (6-MNA GI upset (diarrhea), rash,
Nabumetone Long acting RA, OA
6-methoxy-2- dizziness
naphthylacetic acid )
 Propionic acid derivatives
Adverse Effects / Notes
Drug Key Features ADME Highlights Therapeutic Uses

Rapid absorption; t½
Most commonly used ~2 h; high protein Better tolerated; GI (5–
Ibuprofen Pain, fever, RA, OA;
NSAID (U.S.); good binding; hepatic 15%); rash, edema; rare
PDA closure (IV)
safety profile metabolism → renal thrombocytopenia
excretion

Longer acting; may GI (1–10%); relatively

t½: 9–25 h (long);
Naproxen have better analgesia RA, OA, AS, gout, lower CV risk
~99% protein bound;
& morning stiffness dysmenorrhea (controversial) ; CNS
hepatic metabolism
relief effects
 Adverse Effects / Notes
Drug Key Features ADME Highlights Therapeutic Uses

Similar NSAID GI/CNS

Flurbiprofen Potent NSAID Good oral absorption RA, OA, pain
effects

GI upset; rash; CNS

Fenoprofen Moderate potency Hepatic metabolism RA, OA, pain
effects

Rapid absorption; GI effects;

Ketoprofen Potent NSAID RA, OA, pain
high protein binding photosensitivity

Long t½ → once GI effects; better

Oxaprozin Slow elimination RA, OA
daily dosing compliance
 Fenamates & Enolic acid (Oxicams)
Drug/Class Key Features ADME Highlights Therapeutic Uses Adverse Effects / Notes
Fenamates
Diarrhea (may be severe) ,
(Mefenamic Anthranilic acid
Usual NSAID PK; Short-term pain, steatorrhea; ↑ LFTs (~5%);
acid, derivatives; no
hepatic dysmenorrhea, rare autoimmune hemolytic
Meclofenamate major advantage
metabolism RA, OA anemia; avoid in children &
, Flufenamic over other NSAIDs
pregnancy
acid)
Longest t½ (~50 h);
nonselective COX Complete
RA, OA;
inhibitor; additional absorption; ↑ GI toxicity & severe skin
Piroxicam sometimes gout
anti-inflammatory enterohepatic reactions; ~20% ADR; not first-
(Oxicam) (not for acute
effects (↓ cycling; steady line
pain)
neutrophils, state: 7–12 days
cytokines)
COX-2 selective Less GI toxicity vs piroxicam (at
Meloxicam Once-daily dosing
(partial); better GI RA, OA, JRA low dose); advantage lost at
(Oxicam) (7.5–15 mg)
safety at low dose higher dose
COX-2 Selective NSAIDs
• Selectively inhibit COX-2 (inflammation), spare COX-1 (gastric protection)
• Structure fits COX-2 hydrophobic pocket

Drugs
• Available: Celecoxib (U.S.), Etoricoxib (other countries)
• Withdrawn: Rofecoxib, Valdecoxib, Lumiracoxib

Advantages
• ↓ GI ulceration vs nonselective NSAIDs
• Similar efficacy (no superiority)
Major Limitation
• ↓ PGI₂ (vasodilator, anti-platelet)
• TXA₂ unaffected → prothrombotic state
• → ↑ risk of MI, stroke, hypertension

Clinical Rule
• Avoid in CV / cerebrovascular disease
• Use lowest dose, shortest duration
Celecoxib
• t½ ~11 h → once/twice daily
• Metabolism: CYP2C9 (inhibits CYP2D6)
• Dose:
• OA → 200 mg/day
• RA → 100–200 mg BD
• Uses: OA, RA, JRA, AS, dysmenorrhea, acute pain
Adverse Effects
• ↑ MI & stroke risk (dose dependent)
• Renal: edema, hypertension
• GI advantage lost if combined with aspirin
• ↓ bone healing (chronic use)
Etoricoxib
• t½: 20–26 h (long acting)
• Uses: OA, RA, gout, dysmenorrhea
• Not available in U.S.

Key Points
• ↑ CV risk similar to other COX-2 inhibitors
• Hepatic impairment → accumulation
 COX-2 inhibitors
↓ PGI₂ but not TXA₂
→ thrombosis risk
 Triple whammy effect → AKI

NSAID + ACEi/ARB + Diuretic

1. Diuretic – Reduce GFR

2. NSAIDs – Constrict afferent
arterioles
3. ACEi/ARBs – Dilate efferent
arterioles
Q1. Which NSAID has the least anti-inflammatory efficacy?

Q2. Which NSAID permanently inactivates TxA2 synthesis by platelets?

Q3. Diclofenac has a t1/2 in plasma of 1 to 2 hours, yet its therapeutic

effects in treating rheumatoid arthritis last for much longer. This
prolongation of therapeutic effect is due to -
a. irreversible inhibition of COX-1 and COX-2.
b. its relative selectivity or COX-2.
c. its accumulation in synovial fluid.
d. the formation of a long-lived active metabolite.
e. CNS effects unrelated to inhibition o prostaglandin synthesis
Q4. The cardiovascular risk associated with celecoxib results from
a. inhibition of prostaglandin production in the gastric epithelium.
b. inhibition of platelet thromboxane production.
c. effects on myocardial ion channels.
d. inhibition of prostaglandin in the kidney.
e. enhanced prostacyclin production by vascular endothelium.

Answer is d. Inhibition of PG production in the kidney, which increases the likelihood of

hypertension and edema, occurs with celecoxib, as well as nonselective COX inhibitors. The lack of
an effect on COX-1 production in platelets and the inhibition of prostacyclin synthesis by COX-2 in
vascular endothelium increase the risk of thrombosis resulting in myocardial infarction and ischemic
stroke.
Newer Analgesic
• FDA approved in Jan 2025
• SUZETRIGINE oral tablet
• MOA – block sodium channels in pain sensing nerves
• Rx - Moderate to severe acute pain
THANK YOU