Part 2: Non-steroidal anti-inflammatory drugs (NSAIDs)

Classification

■ Non-selective COX inhibitors (inhibit COX-1 and COX-2):

– Salicylic acid derivatives: aspirin, aloxiprine, aminosalicylic acid, diflunisal,

methyl salicylate, etc.
– Acetic acid derivatives:
– Carboxylic acetic acid: indomethacin, sulindac, etodolac.
– Phenyl acetic acid: diclofenac
– Propionic acid derivatives: iboprufen, ketoprofen, fenoprufen, naproxen.
– Fenamic acid derivatives: mefenamic acid, fulfenamic acid.
– Pyrazolone derivatives: phenylbutazone, azapropazone
– Oxicams: piroxicam, tinoxicam.

■ Selective COX-2 inhibitors: celecoxib, etoricoxib, meloxicam.

▌Acetylsalicylic acid (Aspirin)

Chemistry and pharmacokinetics

 Oral absorption is complete; most of absorption occurs from the stomach and
upper GIT.
 Widely distributed to all tissues including CNS.
 Metabolism of salicylates occurs by the hepatic microsomal enzymes.
– At low doses, elimination is done by the first-order process.
– At high doses, elimination is done by the zero-order process.
 Excretion is increased by alkalinization of urine (pH 8) because in alkaline urine,
most of aspirin is ionized and less re-absorbable.

Mechanism and pharmacological effects

Aspirin is non-selective and irreversible COX inhibitor leading to inhibition of both

PGs and TXs. This distinguishes it from other NSAIDs, which reversibly inhibit COX
enzyme.

Analgesic action: for mild to moderate intensity pain (not severe pain).

Mechanism:
– Peripheral effect: decrease PGs synthesis in the peripheral inflamed tissues.
– Central effect: decrease PGs synthesis in the subcortical sites (thalamus and
hypothalamus).

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Antipyretic effect:

Aspirin is antipyretic but NOT hypothermic agent i.e. it can lower elevated body
temperature but not normal body temperature.
Mechanism:
– Decrease PGE2 synthesis in the hypothalamus.
– Decrease the hypothalamic response to interleukin-1 (endogenous pyrogen).
– Cutaneous VD and increase sweating.

Anti-inflammatory, anti-immunological and anti-rheumatic effects:

Mechanism:
By inhibition of COX enzyme, it ↓ synthesis of PGs and TXs, and possibly other
inflammatory mediators leading to:
– Decrease inflammatory cell activation and chemotaxis.
– Decrease capillary permeability.
– Decrease hyaluronidase enzyme and inhibits spread of inflammation.
– Stabilize lysosomal membranes of inflammatory cells.

Respiratory effects:

– Low toxic doses: produce metabolic acidosis → compensatory

hyperventilation to wash excess CO2 → prolonged respiratory alkalosis.
– High toxic doses: produce metabolic acidosis together with inhibition of RC →
death from severe acidosis.

CVS effects:

– Therapeutic doses: no significant effect on the CVS.

– Toxic doses: inhibit VMC leading to circulatory failure.

GIT effects: salicylates can produce 2 types of gastric ulcer:

– Acute gastric ulcer: occurs as a result of acute ingestion of large doses of

salicylates. The pathogenesis is related to trapping of salicylate ions inside the
gastric mucosal cells leading to acute, painful gastric bleeding.

– Chronic gastric ulcer: occurs as a result of chronic ingestion of salicylates. The

pathogenesis is related to chronic inhibition of the protective PGE1, PGE2 and
PGI2 synthesis leading to chronic ulceration and chronic blood loss.

Hepatic effects: salicylates can produce 2 types of hepatic injury:

– Mild hepatic injury: it is dose-dependent, reversible and asymptomatic. There

may be mild increase in serum transaminases (SGOT and SGPT).

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 – Sevvere hepatic injury: “Reye’s
“ syyndrome”:: it is a
rare
e and fatal condition occurs if a aspirin is used
u to
conntrol fever of some viral infectio ons (e.g. chicken
c
poxx, influenzaa, etc.) in children below 12 2 years
old.. There is severe fa atty infiltra
ation of the liver,
panncreas, and kid
dney asssociated with
enccephalopatthy. The etiologyy is unk known.
Man nagement is supporttive.

Hemattologic efffects:

– Antiplatelet acction: aspirrin inhibit p

platelet aggregation by:
– Irreverssible inhibition of COOX enzyme e → ↓ TXA2 → ↓ plateleet aggregattion.
– Irreverssible acetylation of pla
atelet cell membrane
m s → ↓ platellet adhesio
ons.
– Decrea ase plateleet ADP syn nthesis → decrease platelet accuumulation.

– Asp gh doses (> 6 gm /day) inhiibits hepatic prothrrombin (fa

pirin in hig actor II)
synthesis → prrolong blee
eding time
e.

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Renal e
effects:
– Anaalgesic neephropathyy: it is cchronic re
enal
Aspirin in a dose of 75-
failu
ure due to chronic abuse o of analgessics,
150mg is not thought to
which produc ce chronicc renal ischhemia duee to have a signnificant effe
ect on
deccrease syntthesis of reenal PGE2 and PGI2. plasma uraate levels - the
– Saltt and wateer retentionn: due to d
decrease RBF
R British Socciety for Rheu-
R
matology recommen nd it
andd increase aldosteron ne should be continued if re-
– Antaagonize diuretic
d efffect of d
diuretics and quired for cardiovas scular
antiihypertensive effects s of β-blocckers: due
e to prophylaxiss.
deccrease syntthesis of PGE
P 2.
– Uricc acid excrretion: smaall-to-mode
erate doses of
asppirin can ↓ uric
u acid ex xcretion andd thus con
ntraindicate
ed in patiennts with gouut.

Metabo
olic effectts:
– High doses cause
c oupling of oxidative phosphorrylation → tachycard
unco dia and
hyp
perpyrexia.

Uterus
s:
– Prolongation of pregnancy and
d delay of
labo
or due to inhibition of
o PGs nec cessary for
uterrine contra
action during labor. T
The use of
NSAAIDs after 20 weeks of pregna ancy is not
recoommended d.

Therap
peutic use
es of salicy
ylates

 As analgesicc and anttipyretic: in mild-to--

mooderate paiin e.g. hea
adache, art
rthritis, etc.
It should notn be used rou utinely as s
antipyretic be
ecause fevver may bee a norma al
pro
otective meechanism.
 As anti-inflam
mmatory and
a anti-rrheumatic
c:
in rheumatic c fever, rheumatoid
r d arthritis,
osteoarthritis, etc.
 As antithrom
mbotic: see box.

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  As keratolytic and counter-irritant:
– Salicylic acid has keratolytic action and is used for treatment of warts.
– Methylsalicylic acid is used as a counter-irritant for local rheumatic pain.

Adverse effects of salicylates

GIT: – Epigastric pain, nausea and vomiting.

– Acute and chronic gastric ulcers (why?).
Hepatic: – Mild reversible hepatic injury in adults.
– Severe hepatic injury in children: “Reye’s syndrome”.
Kidney: – Analgesic nephropathy (why?).
– Salt and water retention.
– ↓ the diuretic effect of loop diuretics and antihypertensive effects
of β-blockers (why?).
– Precipitation of acute gout in hyperurecemic patients.
Blood: – Increase bleeding tendency: (why?).
– Displacement of other drugs from plasma proteins.
Uterus: – Prolongation of pregnancy and delay of labor (why?).
Hypersensitivity – Bronchospasm (aspirin asthma) in patients with history of
reactions: asthma or allergic rhinitis due to accumulation of LTs.

Precautions and contraindications

 GIT disorders: peptic ulcer, gastritis, hemorrhagic pancreatitis, etc.

 Hemorrhagic disorders: hemophilia, thrombocytopenia, etc.
 Chronic renal diseases: aspirin may aggravate renal failure
 Chronic liver diseases: (those patients have bleeding tendency).
 Uncontrolled hypertension: risk of fatal bleeding.
 Gout: small-to moderate doses may inhibit uric acid excretion.
 Before surgery: aspirin must be stopped at least 7 days before surgery.
 Children <12 years old: fear of Reye’s syndrome.

Drug interactions

 Aspirin antagonizes the uricosuric effect of probenecid (see gout).

 Aspirin antagonizes the diuretic effect of diuretics and the antihypertensive effect
of antihypertensives (e.g. β-blockers, ACEIs) by inhibition of PGs synthesis.
 Aspirin can displace anticoagulants (heparin and warfarin), and other drugs from
plasma proteins leading to increase their plasma concentrations.
 Antacids decrease absorption of aspirin.

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▌Acute aspirin toxicity

Aspirin toxicity is dose-dependent and effects are determined by plasma drug levels

Manifestations:
– Tachypnea (hyperventilation) is the earliest sign of aspirin toxicity.
– Tinnitus, vomiting, hematemesis.
– Metabolic acidosis.
– Hyperthermia, hypoglycemia, dehydration, and coma.

Treatment:
– Repeated gastric lavage with activated charcoal.
– i.v. fluids and sodium bicarbonate to correct dehydration and acidosis.
– Vit K 10 mg i.m. or slowly i.v. to control hemorrhage.
– Alkalinization of urine: to enhance salicylate excretion.
– Hemodialysis in severe cases (when blood levels > 100 mg/dl).

█ OTHER NSAIDS

Diclofenac
– One of the most widely used NSAIDs.
– Generally, it is less gastric irritant than other NSAIDs but more nephrotoxic. A
dose of 150 mg/day can impair renal blood flow and GFR.
– It is often combined with PGE analogue misoprostol to decrease gastric
ulceration.
– Topical gel is available for local rheumatic pain and osteoarthritis of the knee and
hands.

Sulindac and ketorolac

– Both have minimal effect on platelet aggregation.
– Sulindac is a prodrug and has long t½.
– Ketorolac is a potent analgesic but it can cause severe GIT bleeding.

Ibuprofen, fenoprofen, ketoprofen

– They have no reported interactions with oral anticoagulants
– Ibuprofen is a good alternative to aspirin in children with flu fevers.
– Fenoprofen has been reported to induce nephrotoxic syndrome
– Long-term use of ibuprofen is associated with an increased incidence of
hypertension in women.

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 Indom
methacin
– It iss a very po
otent COX inhibitor b
but
relaatively moore toxic than oth her
NSA AIDs.
– It iss approved
d to speed the closu ure
of patent ductus
d arrteriosus in
prem mature infants (othherwise it is
not used in children);
c itt inhibits tthe
prod duction of PGs wh hich preve ent
clossure of the
e ductus.

Piroxic
cam
– It haas long t½
½ (~ 45 hours).
– Likee aspirin and indomethaccin,
bleeeding and d ulceratio
on are mo ore
likely with piro
oxicam thaan with oth
her
NSA AIDs.

▌Sele
ective CO
OX-2 inhibitors:
Celeco
oxib, etoric
coxib, me
eloxicam

Selectivve COX-2 inhibitors

s are newe er
forms of NSAIDss that dire ectly targe
et
COX-2 enzyme e respon nsible fo or
mation and
inflamm d pain. Celecoxib iis
approxximately 30
0 times more
m potennt
at inhhibiting COX-2 tha an COX-1 1.
Meloxiccam is slightly
s se
elective foor
COX-2 than COX X-1 enzyme e.
Seleectivity forr COX-2 re educes th he
risk of peptic ulc ceration bu ut does no ot
seem tto affect other
o adveerse-effectts
of NSA AIDs (espec cially the risk
r of renaal
failure).. Selectivve COX-2 2 inhibitorrs
may also incrrease the e risk o of
cardiov vascular accidents
a s (myocard d-
ial infa
arction, thrrombosis and a strokee)
due to relative in ncrease in TXA2 and platelet ag ggregation
n (TXA2 is fformed by COX-1
where PGI2 is formed by b COX-2 ). Rofeco oxib (Vioxxx®) and valdecoxib b were
withdraawn from the t market in 2004 an nd 2005 re
espectively
y because of these potential
p
adverse e effects.

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 Non-selective COX inhibitors Selective COX-2 inhibitors

Mechanism: They inhibit COX-1 (non- They inhibit COX-2

inducible) and COX-2 (inducible) enzyme only
(inducible) enzymes
Pharmacological
Both classes have equal analgesic and antipyretic effects
effects:
Gastric side effects: Frequent Less frequent
Renal side effects: Frequent Frequent
Thrombotic Decreased Increased
complications: (due to decreased platelet (due to increased platelet
aggregation) aggregation)

Hypersensitivity Frequent Less frequent

reactions:

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