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15
Inflammation,
arthritis
and
nonsteroidal anti-inflammatory
drugs
SYNOPSIS
A
third
of all
general practice consultations
are
for
musculoskeletal
complaints. Nonsteroidal
anti-inflammatory
drugs (NSAIDs)
are
widely
used,
and
their
gastrointestinal
effects
account
for an
estimated 1200
deaths
per
year
in the
UK. A
hitherto
unsuspected
inflammatory
component
is now
known
to
accompany
conditions
such
as
atherosclerosis.
As
understanding
of the
complex
mechanisms
underlying
the
inflammatory
process
increases,
new
ways
of
influencing
it are
developed,
as
witness
therapies directed
against
specific
cytokines,
and
COX-2
specific
NSAIDs
(COXIBs).
Inflammation
Arthritis
Nonsteroidal anti-inflammatory
drugs
Disease
modifying antirheumatic
drugs
Drug treatment
of
arthritis
Gout
Inflammation
The
clinical
features
of
inflammation have been
recognised since ancient times
as
swelling, redness,
pain
and
heat.
The
underlying mechanisms which
produce
these symptoms
are
complex, involving
COX: cyclo-oxygenase
COXIB:
COX-2
specific
NSAIDs
DMARD:
disease
modifying antirheumatic drug
FGF:
fibroblast
growth
factor
GM-CSF:
granulocyte macrophage-colony stimulating
factor
M-CSF
macrophage-colony stimulating factor
HPETE:
hydroperoxy-eicosatetraenoic
acid
IL:
interleukin
LT:
leukotriene
PG:
prostaglandin
TNF:
tumour
necrosis factor
TX:
thromboxane
many
different
cells
and
cell products,
and
only
a
general
account
of the
current understanding
of the
inflammatory
process
is
provided here.
A
normal
inflammatory
response
is
essential
to
fight
infections
and is
part
of the
repair mechanism
and
removal
of
debris following tissue damage. Inflammation
can
also cause disease,
due to
damage
of
healthy
tissue. This
may
occur
if the
response
is
over-
vigorous,
or
persists longer than
is
necessary.
Additionally,
we now
know that some conditions
have
a
previously unrecognised inflammatory com-
ponent,
e.g. atherosclerosis.
THE
INFLAMMATORY
RESPONSE
The
inflammatory response occurs
in
vascularised
tissues
in
response
to
injury;
it is
part
of the
innate
(nonspecific)
immune
response.
Inflammatory
re-
sponses require activation
of
leukocytes:
neutrophils,
279
15
INFLAMNATION,
ARTHRITIS
AN D
NSAIDS
eosinophils, basophils, mast cells, monocytes
and
lymphocytes, although
not all
cell
types need
be
involved
in an
inflammatory
episode.
The
cells
migrate
to the
area
of
tissue damage
from
the
circulation
and
become activated.
Inflammatory mediators
Activated
leukocytes
at a
site
of
inflammation release
compounds which enhance
the
inflammatory
res-
ponse.
The
account below
focuses
on
cytokines
and
eicosanoids
(arachidonic acid metabolites) because
of
their
therapeutic
implications. Nevertheless,
the
complexity
of the
response,
and its
involvement
of
other systems,
is
indicated
by the
range
of
mediators,
which include:
Complement products, especially
C3b and
C5-9
(the membrane attack complex);
kinins
and the
rela-
ted
proteins, bradykinin
and the
contact system
(coagulation
factors
XI and
XII, pre-kallikrein, high
molecular
weight kininogen); nitric oxide
and
vaso-
active
amines (histamine, serotonin
and
adenosine);
activated forms
of
oxygen;
platelet
activating
factor
(PAF);
proteinases (collagenses, gelatinases
and
proteoglycanase).
Cytokines
Cytokines
are
peptides that regulate cell growth,
differentiation
and
activation,
and
some have thera-
peutic
value:
•
Interleukins
produced
by a
variety
of
cells
including
T
cells, monocytes
and
macrophages.
Recombinant
interleukin-2 (aldesleukin)
is
used
to
treat metastatic renal cell carcinoma
and
malignant melanoma. Interleukin-1
may
play
a
part
in
conditions
such
as the
sepsis
syndrome
and
rheumatoid arthritis,
and
successful
blockade
of its
receptor
offers
a
therapeutic
approach
for
these conditions.
•
Cytotoxic
factors
include tumour necrosis
factor
(TNF)
which
is
similar
to
interleukin-1.
Biological
agents that block TNF, e.g.
etanercept,
infliximab
are
finding their place amongst drugs
that
modify
the
course
of
rheumatoid disease
(and
Crohn's
disease,
see p.
65).
•
Interferons
are so
named because they were
found
to
interfere with replication
of
live virus
in
tissue culture. Interferon
alfa
is
used
for a
variety
of
neoplastic conditions (see Table 30.3)
and for
chronic active
hepatitis.
•
Colony-stimulating
factors
have been developed
to
treat
neutropenic conditions,
e.g.filgrastim
(recombinant human granulocyte colony
stimulating
factor,
G-CSF)
and
molgramostim
(recombinant
human
granulocyte macrophage-
colony
stimulating
factor,
GM-CSF)
(see
Ch.
30).
Eicosanoids
Eicosanoids
(prostaglandins,
thromboxanes, leuko-
trienes,
lipoxins)
is the
name given
to a
group
of 20-
carbon
1
unsaturated
fatty
acids derived principally
from
arachidonic acid
in
cell
walls. They
are
short-
lived,
extremely potent
and
formed
in
almost every
tissue
in the
body. Eicosanoids
are
involved
in
most types
of
inflammation
and it is on
mani-
pulation
of
their biosynthesis that most present
anti-inflammatory
therapy
is
based. Their
bio-
synthetic
paths appear
in
Figure
15.1
and are
amplified
by the
following account.
•
Arachidonic
acid
is
stored mainly
in
phospholipids
of
cell walls,
from
which
it is
mobilised largely
by the
action
of
phospholipase.
Glucocorticoids
prevent
the
formation
of
arachidonic acid
by
inducing
the
synthesis
of an
inhibitory
polypeptide called
lipocortin-1;
the
capacity
to
inhibit
the
subsequent formation
of
both
prostaglandins
and
leukotrienes, explains part
of
the
powerful
anti-inflammatory
effect
of
glucocorticoids
(for
other actions,
see p.
664).
•
Arachidonic acid
is
further
metabolised
by
cyclo-
oxygenase
(COX, also called
PGH
synthase),
which changes
the
linear
fatty
acids into
the
cyclical
structures
of the
prostaglandins.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
act
exert their
anti-inflammatory
effects
by
inhibiting COX.
•
COX
exists
as two
different
types, COX-1
and
COX-2.
The
isoform
COX-1
is
predominantly
constitutive
2
(although activity
is
increased
2^1-fold
by
inflammatory
stimuli);
it is
present
in
1
The
Greek word
for 20 is
eicosa,
hence
the
term eisocanoid.
2
Constantly
produced
by the
cell
regardless
of
growth
conditions.
280
15
Phospholipase
A
2
(inhibited
by
lipocortin-l
produced
in
response
to
glucorticoids)
ARACHIDONICACID
t
Prostaglandin
G/H
synthase
(cyclo-oxygenase)
(inhibited
by
NSAIDs)
ARACHIDONICACID
t
Lipoxygenase
ARACHIDONICACID
PROSTACYCLIN
THROMBOXANE
OTHER
Pgs
LEUKOTRIENES
(platelets) (endothelium) e.g PGE PGF
2
Fig. 15.1
Biosynthetic
path
of
eicosanoids (see
text
for
description).
Prostaglandins
are
found
in
virtually
all
tissues
of
the
body.
most
tissues,
especially stomach, platelets
and
kidneys. COX-2
is
inducible (10-20-fold)
by
inflammatory
stimuli
in
many cells including
macrophages, synoviocytes, chondrocytes,
fibroblasts
and
endothelial cells,
and
only
in low
concentration
in the
gastrointestinal mucosa.
Crucially,
NSAIDs
differ
in
their relative
inhibition
of the two
isoforms
of
COX,
recognition
of
which
has
lead
to the
development
of
selective
COX-2
inhibitors. Such
drugs have less adverse
effects,
especially
on the
gastrointestinal tract (see below).
•
Arachidonic acid
is
also metabolised
by
lipoxygenase
to
straight-chain hydroperoxy acids
and
then
to
leukotrienes
which cause increased
vascular
permeability, vasoconstriction,
bronchoconstriction,
as
well
as
chemotactic
activity
for
leucocytes (whence their name).
Inhibitors
of
lipoxygenase, e.g.
zileuton,
and
leukotriene receptor
antagonists,
e.g.
montelukast,
zafirlukast,
have
found
a
place
in the
therapy
of
asthma (see
p.
559).
•
Lipoxins
are
lipoxygenase-derived eicosanoids
that probably down-regulate inflammation
in the
INFLAMNATION
gastrointestinal
tract
and
other
organs
by
antagonising
effects
of
TNF-oc.
In
health,
PCs
have
a
number
of
important
physiological roles, namely:
•
protection
of
the
gastrointestinal tract
(PGE
2
and
PGI
2
)
•
renal homeostasis
(PGE
2
and
PGI
2
)
•
vascular homeostasis
(PGI
2
and
TXA
2
)
•
uterine function, embryo implantation
and
labour
(PGF
2
)
•
regulation
of
the
sleep-wake
cycle (PGD
2
)
•
body temperature
(PGE
2
).
Synthetic
analogues
of
prostaglandins
are
being
used
in
medicine, namely:
•
PGI
2
:
epoprostenol
(inhibits platelet aggregation,
used
for
extracorporeal circulation
and
primary
pulmonary hypertension).
•
PGE
r
-
alprostadil
(used
to
maintain
the
patency
of
the
ductus arteriosus
in
neonates with congenital
heart defects,
and for
erectile dysfunction
by
injection
into
the
corpus
cavernosum
of the
penis); misoprostol (used
for
prophylaxis
of
peptic ulcer associated with NSAIDs); gemeprost
(used
as
pessaries
to
soften
the
uterine cervix
and
dilate
the
cervical canal prior
to
vacuum
aspiration
for
termination
of
pregnancy).
•
PGE
2
:
dinoprostone
(used
as
cervical
and
vaginal
gel
to
induce labour
and for
late therapeutic
abortion).
•
PGF
2a
:
dinoprost
(termination
of
pregnancy).
CHRONIC
INFLAMMATORY DISEASE
In
many
diseases,
the
pathological process
is
chronic
inflammation;
some
of
these
are
shown
in
Table
15.1,
together with
the
predominant inflammatory
cell
infiltrates.
The
factors
which allow development
of a
chronic inflammatory state, while
not
fully
known,
are
thought
to
include
a
genetic predisposition
and
an
environmental trigger, perhaps
a
virus
or
other
infective
agent.
An
imbalance
of the
inflammatory
response
occurs
in
many
of
these
conditions,
because
proinflammatory mediators
are
present
in
excess. This
is a
feature
of
rheumatoid arthritis,
inflammatory
lung disease
(fibrosing
alveolitis)
and
inflammatory
bowel disease (Crohn's disease).
The
281
Plasminogen
(in
cell
wall)
15
INFLAMNATION,
ARTHRITIS
AND
NSAIDS
dominant cell types
and
some
of the key
pro-
inflammatory
cytokines
are
illustrated
in
Figure 15.2.
Once activated, macrophages
may
further
be
upregulated
by the
cytokines they release (IL8,
GM-
TABLE
1 5. 1
Diseases
with
a
chronic inflammatory
component
Inflammatory
disease
Acute
respiratory
distress
syndrome
Asthma
Atherosclerosis
Glomerulonephritis
Inflammatory
bowel
disease
Osteoarthritis
Psoriasis
Rheumatoid
arthritis
Sarcoidosis
Inflammatory
cell
infiltrate
Neutrophil
Eosinophil.T
cell,
monocyte,
basophil
T
cell, monocyte
Monocyte.T cell,
neutrophil
Monocyte,
neutrophil.T
cell,
eosinophil
Monocyte,
neutrophil
T
cell,
neutrophil
Monocyte,
neutrophil
T
cell,
monocyte
CSF,
M-CSF,
called
the
autocrine loop).
TNF-oc
and
IL-1
are
potent upregulators
of
several
cell
types
including fibroblasts
and T
cells.
TNF-a
may act
earlier
in the
hierarchy than other cytokines
and has
proven
to be an
important target
for
anticytokine
therapy
in
rheumatoid arthritis
and
Crohn's
disease
(see
later, anti-TNF therapy). Some small amounts
of
anti-inflammatory cytokines
may
also
be
present
(such
as
IL-10
and
interferon-y),
but
because
the
system
is not in
balance,
the end
result
is
inflammation.
Arthritis
The
most common types
of
arthritis
in the UK are
osteoarthritis
(UK
prevalence 23%)
and
rheumatoid
arthritis
(1%).
The
less
common
types
of
inflamma-
tory
arthritis
include: juvenile idiopathic arthritis;
spondylarthritis (ankylosing spondylitis, Reiter's
syndrome, psoriatic arthritis, arthritis associated with
inflammatory
bowel disease)
and
reactive arthritis
associated
with infection. Joint pains (arthralgia)
are
common
in
many other diseases,
for
example
the
connective
tissue
diseases (systemic lupus erythema-
tosus, scleroderma), endocrine conditions (hypo-
and
hyperthyroidism)
and
malignancies,
but in
these,
joint
inflammation
and
damage
do not
usually occur.
The
crystal associated
conditions,
gout
and
pseudo-
gout,
are
considered later
in
this chapter.
Drugs
have
an
important place
in the
therapy
of
all
forms
of
arthritis,
to
alleviate
symptoms,
to
modifying
the
course
of the
disease and,
in the
case
of
septic
arthritis,
to
cure. There follows
an
account
of
these
drugs.
Nonsteroidal anti-
inflammatory
drugs
(NSAIDs)
Fig. 15.2
The
main
cells
and
inflammatory cytokines
in
chronic
inflammatory
disease.
MODE
OF
ACTION
The
members
of
this class
of
drug, although struc-
turally
heterogeneous, possess
a
single common
mode
of
action which
is to
block
prostaglandin synthesis.
Various
NSAIDs have other actions that
may
con-
tribute
to
differences
between
the
drugs
and
these
282
NON
STEROIDAL
ANTI-INFLAMMATORY
DRUGS
(NSAIDS)
15
include:
the
inhibition
of
lipoxygenases
(diclofenac,
indomethacin); superoxide radical production
and
superoxide scavenging;
effects
on
neutrophil agg-
regation
and
adhesion, cytokine production
and
cartilage
metabolism. Nevertheless, their
key
action
of
inhibiting prostaglandin formation
is
reflected
in
the
range
of
effects,
beneficial
and
adverse, which
the
members exhibit. NSAIDs
may be
categorised
according
to
their
COX
specificity
as:
•
COX-2
selective
compounds, whose selectivity
for
inhibiting
COX-2
is at
least
5
times that
for
COX-
1. The
group includes
rofecoxib,
celecoxib,
meloxicam,
etodolac
and
nabumetone.
•
Non-COX-2
selective
compounds, which
comprise
all
other NSAIDs. These drugs inhibit
COX-1
as
much
as, or
even more than,
COX-2.
PHARMACOKINETICS
In
general, NSAIDs
are
absorbed almost completely
from
the
gastrointestinal tract, tend
not to
undergo
first-pass
(presystemic) elimination,
are
highly
bound
to
plasma albumin
and
have small volumes
of
distribution. Their t
1
/, values
in
plasma tend
to
group
into those that
are
short (1-5
h) or
long (10-60
h).
Differences
in
t
1
/^
are not
necessarily
reflected
pro-
portionately
in
duration
of
effect,
for
peak
and
trough
drug concentrations
at
their intended site
of
action
in
synovial
(joint)
fluid
at
steady-state dosing,
are
much
less
than
those
in
plasma.
The
vast majority
of
NSAIDs
are
weakly acidic drugs that localise
preferentially
in the
synovial tissue
of
inflamed
joints
(see
pH
partition hypothesis,
p.
97).
USES
The
wide range
of
recognised uses
is
expressed
below.
Some NSAIDs
are
available 'over
the
counter'
in the UK
(without
a
prescription),
an
acknowledgement
of
their general level
of
safety.
Analgesia: NSAIDs
are
effective
for
pain
of
mild
to
moderate intensity including musculoskeletal
and
postoperative pain,
and
osteo-
and
inflammatory
arthritis; they have
the
advantage
of not
causing
dependence, unlike opioids (but
see
analgesic
nephropathy, below).
Anti-inflammatory action:
this
is
utilised
in all
types
of
arthritis, musculoskeletal conditions
and
pericarditis.
Antipyretic action: cytokine-induced
PG
synthesis
in the
hypothalamus
is
blocked, thus reducing
fever.
Antiplatelet function: aspirin
is
indicated
for the
treatment
and/or
prevention
of
myocardial
infarc-
tion, transient ischaemic attacks
and
embolic strokes.
Prolongation
of
gestation
and
labour: inhibition
of
PG
synthesis
by the
uterus during labour
by
indomethacin will prolong labour.
Patency
of the
ductus arteriosus:
as PGs
maintain
the
patency, indomethacin given
to a
new-born
child
with
a
patent ductus
can
result
in
closure,
avoiding
the
alternative
of
surgical ligation.
Primary
dysmenorrhoea:
mefanamic acid
is
used
to
reduce
the
production
of PGs by the
uterus
which cause uterine hypercontractility
and
pain.
Further
areas
of
potential
benefit
from
NSAIDs
are
being explored, including
the
prevention
of
Alzheimer's dementia
and
colorectal carcinoma.
ADVERSE
REACTIONS
Gastrointestinal
effects
Gastric
and
intestinal mucosal damage
is the
com-
monest adverse
effect
of
NSAIDs.
The
physiological
function
of
mucosal prostaglandins
is
cytoprotective,
by
inhibiting acid secretion,
by
promoting
the
secretion
of
mucus
and by
strengthening resistance
of
the
mucosal barrier
to
back-diffusion
of
acid
from
the
gastric lumen into
the
submucosal tissues
where
it
causes damage. Inhibition
of
prostaglandin
biosynthesis removes this protection. Indigestion,
gastro-oesophageal reflux,
erosions,
peptic
ulcer,
gastrointestinal haemorrhage
and
perforation,
and
small
and
large bowel ulceration occur.
In the UK an
estimated
12 000
peptic ulcer
complications
and
1200 deaths
per
year
are
attributable
to
NSAID use.
3
Toxicity
relates
to
anti-
3
Hawkey
C J
1996 Scandinavian Journal
of
Gastroenterology
(Suppl.)
220: 124-127,221:
23-24.
283
15
INFLAMMATION,
ARTHRITIS
AND
NSAIDS
inflammatory
efficacy.
A
meta-analysis
of 12
con-
trolled epidemiological studies ranked common
NSAIDs
according
to
their propensity
for
causing
gastrointestinal complications.
4
Azapropazone,
pir-
oxicam,
ketoprofen
and
indomethacin were asso-
ciated
with
high
risk
(and
azapropazone
was
9.2
times more likely than low-dose ibuprofen
to
cause
such adverse
effects).
Clinical
trial evidence
in
general appears
to
support
the
theory that COX-2 selective inhibitors
are as
effective
as, but
have
fewer
adverse
effects
than, non-COX-2 selective compounds;
for
example
meloxicam
is
better tolerated than diclofenac
or
piroxicam.
5
'
6
The
relative risk
of
serious
gastro-
intestinal
effects
(bleeding peptic ulcers)
due to
rofecoxib
(COX-2
selective)
was
0.51
compared with
conventional NSAIDs.
7
COX-2
selective drugs
are
yet
associated with significant
dyspeptic
symptoms
(indigestion, heartburn),
and
these
effects
may
result
from
inhibition
of the
(protective) constitutively
expressed
COX-2
in the
stomach.
In
practice,
a
minority
of
patients
are
intolerant
of
all
NSAIDs. They
may
benefit
from
the co-
administration
of a
proton pump inhibitor,
a H
2
-
receptor
blocker
or the
prostaglandin analogue,
misoprostol.
To
address
this
problem, some NSAIDs
are
presented
in
combination with misoprostol,
e.g.
diclofenac
with misoprostol (Arthrotec)
and
nap-
roxen
with misoprostol (Napratec). Some patients
experience abdominal pain
and
diarrhoea
from
the
misoprostol component.
Ulceration
and
stricture
of the
small bowel
may
also
be
caused
by
NSAIDs,
and in
some patients there
is
occult blood loss, diarrhoea
and
malabsorption,
i.e.
a
clinical syndrome indistinguishable
from
Crohn's
disease.
Renal
effects
Renal
blood
flow
is
reduced because
the
synthesis
of
vasodilator renal prostaglandins
is
inhibited;
the
4
Henry
D et al
1996 British Medical Journal
312:1563.
5
Hawkey
C J et al
1998 British Journal
of
Rheumatology
37:
937.
6
Dequeker
J et al
1998
British Journal
of
Rheumatology
37:
946.
7
Langman
M J et al
1999 Journal
of the
American Medical
Association
282: 1929.
result
is
sodium
and
fluid
retention
and
arterial
blood pressure
may
rise. Renal
failure
may
occur
when glomerular
filtration
is
dependent
on the
vasodilator
action
of
prostaglandins,
e.g.
in the
elderly,
those with pre-existing renal disease, hepatic
cirrhosis, cardiac failure,
or on
diuretic therapy
sufficient
to
reduce intravascular volume.
Analgesic
nephropathy. Mixtures
of
NSAIDs
(rather
than single agents) taken repeatedly cause
grave
and
often
irreversible renal damage, notably
chronic
interstitial nephritis, renal papillary necrosis
and
acute renal
failure;
these
effects
appear
to be due
at
least
in
part
to
ischaemia through inhibition
of
formation
of
locally produced vasodilator
pro-
staglandins.
The
condition
is
most common
in
people
who
take high doses over years,
e.g.
for
severe
chronic
rheumatism
and
patients with personality
disorder. Whilst analgesic nephropathy appears
to
be
associated with long-term abuse
of
NSAID
mixtures,
the
strong evidence that phenacetin
was
particularly
responsible
has
rendered this drug
obsolete.
8
Cutaneous effects
Urticaria,
severe rhinitis
and
asthma occur
in
susceptible individuals,
e.g.
with nasal polyposis,
who are
exposed
to
NSAIDs, notably aspirin;
the
8
During
the
influenza pandemic
of
1918
a
physician
to a big
factory
in a
Swedish town prescribed
an
antipyretic powder
containing phenacetin, phenazone (both NSAIDs)
and
caffeine.
Survivors
of the
epidemic thought they
felt
fitter
and
reinvigorated during convalescence
if
they took
the
powder
and
they continued
to
take
it
after
recovery.
Consumption increased
and
many
families
'could
not
think
of
beginning
the day
without
a
powder. Attractively
wrapped packages
of
powder were
often
given
as
birthday
presents'.
Deaths
from
renal
insufficiency
rose
in the
'phenacetin
town',
but not in a
similar Swedish town,
and in
the
decade
of
1952-61
they were more than
3
times
as
many.
An
investigation
was
resisted
by the
factory
workers
to the
extent
that there
was an
organised burning
of a
questionnaire
on
powder-taking.
It was
eventually
discovered that most
of
those
who
used
the
powders
did so,
not
for
pain,
but to
maintain
a
high working pace,
from
'habit',
or to
counter fatigue
(an
effect
probably
due to the
caffeine).
Eventually
the
rising death rate brought home
to
the
consumers
the
gravity
of the
matter,
something
that
has
yet to be
achieved
for
tobacco smoking
or
alcohol drinking
(Grimlund
K
1964 Acta Medica Scandinavica
174:
suppl.
405).
284
15
mechanism
may
involve inhibition
of
synthesis
of
bronchodilator prostaglandins, notably
PGE2
(see
Pseudoallergic
reactions,
p.
146). Other
effects
on the
skin include photosensitivity, erythema multiforme,
urticaria,
and
toxic epidermal necrolysis.
Other
general
effects
include cholestasis, hepato-
cellular
toxicity, thrombocytopenia, neutropenia,
red
cell
aplasia,
and
haemolytic anaemia. Ovulation
may be
reduced
or
delayed (reversibly).
An
account
of
adverse reactions that probably
relate
to
individual chemical classes
of
NSAID
is
given later.
INTERACTIONS
NSAIDs
give scope
for
interaction,
by
differing
pharmacodynamic
and
pharmacokinetic mecha-
nisms,
with:
•
ACE
inhibitors
and
angiotensin
II
antagonists:
there
is
risk
of
renal impairment
and
hyper-
kalaemia.
•
Quinolone antimicrobials: convulsions
may
occur
if
NSAIDs
are
co-administered.
•
Anticoagulant
(warfarin)
and
antiplatelet agents
(ticlopidine, clopidogrel): reduced platelet
adhesiveness
and GI
tract
damage
by
NSAIDs
increase
risk
of
alimentary
bleeding
(notably
with azapropazone). Phenylbutazone,
and
probably azapropazone, inhibit
the
metabolism
of
warfarin, increasing
its
effect.
•
Antidiabetics: azapropazone
and
phenylbutazone inhibit
the
metabolism
of
sulphonylurea hypoglycaemics, increasing their
intensity
and
duration
of
action.
•
Antiepileptics: azapropazone
and
phenylbutazone inhibit
the
metabolism
of
phenytoin
and
sodium valproate, increasing
their
risk
of
toxicity.
•
Antifungal:
fluconazole
raises
the
plasma
concentration
of, and
thus risk
of
toxicity
from,
celecoxib.
•
Antihypertensives: their
effect
is
lessened
due to
sodium retention
by
inhibition
of
renal
prostaglandin formation.
•
Antivirals: ritonavir
may
raise plasma
concentration
of
piroxicam; NSAIDs
may
increase haematological toxicity
from
zidovudine.
I N Dl VI
DUAL
NSAIDS
•
Ciclosporin: nephrotoxic
effect
is
aggravated
by
NSAIDs.
•
Cytotoxics: renal tubular excretion
of
methotrexate
is
reduced
by
competition with NSAIDs, with risk
of
methotrexate toxicity (low-dose methotrexate
given weekly avoids this hazard).
•
Diuretics: NSAIDs cause sodium retention
and
reduce
diuretic
and
antihypertensive
efficacy;
risk
of
hyperkalaemia with potassium-sparing
diuretics; increased nephrotoxicity risk (with
indomethacin, ketorolac).
•
Lithium: NSAIDs delay
the
excretion
of
lithium
by
the
kidney
and may
cause lithium
toxicity.
Individual NSAIDs
The
currently available NSAIDs exhibit
a
variety
of
molecular
structures
and it is
usual
to
classify
these
drugs
by
their chemical class. Clinical trials
in
rheumatoid arthritis
and
osteoarthritis, however,
rarely
find
substantial
differences
in
response
to
average
doses
of
NSAIDs whatever their structure,
and
this
no
doubt
reflects
their common mode
of
action.
Some
60% of
patients will respond
to any
NSAID
and
many
of the
remainder will respond
to a
drug
from
another group.
A
structural
classification
is
nevertheless
used
here
as it
provides
a
logical
framework;
furthermore,
specific
toxicity
profiles
tend also
to
relate
to
chemical group
(see
below).
Summary
data
on
NSAIDs licenced
in the UK are
given
in
Table
15.2.
ADVERSE
EFFECTS
A
general account
of the
unwanted
effects
of
NSAIDs
is
given
on
page
283.
In
addition, adverse reactions
that
feature
within particular chemical classes
of
NSAID
appear below, together with comments
on
some individual drugs.
Paracetamol:
see
below.
Salicylic
acids:
see
aspirin, below.
Acetic
acids.
Indomethacin
may
cause prominent
salt
and
fluid
retention. Headache
is
common,
often
similar
to
migraine,
and is
attributed
to
cerebral
oedema;
it can be
limited
by
starting
at a low
dose
285
15
NFLAMNATION
,
ARTHRITIS
AN D
NSAIDS
TABLE
15.2
Nonsteroidal anti-inflammatory
drugs
licenced
in the UK
Chemical
class
Para-amino phenol
Salicylic
acids
Acetic
acids
Fenamic
acid
Propionic
acids
Enolic
acids
Non-acid drugs
Generic name
paracetamol
aspirin
diflusinal
benorilate
indometacin
acemetacin
sulindac
diclofenac
sodium
etodolac
ketorolac
mefanamic
acid
ibuprofen
fenbufen
fenoprofen
flurbiprofen
ketoprofen
naproxen
tiaprofenic
acid
piroxicam
meloxicam
tenoxicam
azapropazone
phenylbutazone
nabumetone
celecoxib
aceclofenac
rofecoxib
Compound
acetaminophen
acetylsalicylic
acid
salicylate
salicylate-paracetamol
ester
indole
indole
indene
phenylacetic
acid
pyranocarboxyate
ketorolac
trometerol
fenamate
propionic
acid
propionic
acid
propionic
acid
propionic
acid
propionic
acid
propionic
acid
propionic
acid
oxicam
oxicam
oxicam
benzotriazine
pyrazone
napthylalkanone
coxib
phenylacetoxyacetic
acid
coxib
Half-life
(t'/
2
)
2h
15
min
7-1 5 h
4h
3h
8h
2h
7h
5h
3h
2h
lOh
3h
4h
1
h
I4h
2h
45
h
20
h
72
h
I8h
72
h
22
h
lOh
4h
I7h
Usual
adult
dose
1
gqid
300-900
mg
q.d.s.
maximum
4 g
daily
500-1
000 mg
daily
in
1
or 2
doses
1.
5 g
q.d.s.
initially
50-75
mg
daily
as
1 or 2
doses,
maximum
200 mg
daily
60
mg
b.d.
or
t.d.s.
200 mg
b.d.
75- 1 50 mg
daily
in 2
divided
doses
600
mg
o.d.
500
mg
t.i.d.
1.
6-2.4
g
daily
in
divided
doses
300
mg in
a.m.
and
600
mg
nocte,
or
450
mg
b.d.
300-600
mg
t.d.s.
or
q.d.s.,
maximum
3 g
daily
1
50-200
mg
daily
in
divided
doses,
maximum
300 mg
daily
1
00-200
mg in 1-4
divided
doses
250-500
mg
b.d.
600
mg in 2-3
divided
doses
20
mg
o.d.
7.5-15
mg
o.d.
20
mg
o.d.
1.2
g
daily
in 2 or 4
divided
doses
1
g
nocte, additional
500 mg — 1 g
o.d.
if
necessary
200-400
mg
daily
in
divided
doses
lOOmgb.d.
1
2.5-25
mg
o.d.
and
increasing slowly. Vomiting, dizziness
and
ataxia
occur.
Allergic reactions occur
and
there
is
cross-
reactivity
with aspirin. Indomethacin
may
aggravate
pre-existing renal disease. Drugs
of
this group
are
best avoided where there
is
gastroduodenal, renal
or
central
nervous system disease
or in the
presence
of
infection.
Unusually among
the
NSAIDs, adverse
effects
of
sulindac
on the
kidney
may be
less likely
as
the
active (sulphide) metabolite
of
sulindac appears
not to
inhibit renal prostaglandin synthesis.
Fenamic acid.
The
principal adverse
effects
of
mefenamic
acid
are
diarrhoea, upper abdominal
dis-
comfort,
peptic ulcer
and
haemolytic anaemia.
Elderly
patients
who
take mefenamic acid
may
develop nonoliguric renal
failure
especially
if
they
become
dehydrated,
e.g.
by
diarrhoea;
the
drug
should
be
avoided
or
used with close supervision
in
the
elderly.
Propionic acids.
The
main advantage
of the
286
15
members
of
this group
is a
lower incidence
of
adverse
effects
particularly
in the
gastrointestinal tract,
and
especially
with ibuprofen
at low
dose. Nevertheless
epigastric discomfort, activation
of
peptic ulcer
and
bleeding
may
occur. Other
effects
include headaches,
dizziness,
fever
and
rashes.
Enolic
acids. Note
the
generally long t
l
/
2
of
each
member
of
this group,
and in
consequence
the
anticipated
time
to
reach steady state
in
plasma
(5 x
t
l
/
2
).
Adverse
effects
are
those
to be
expected with
NSAIDs
in
general, gastrointestinal
and
central
nervous system complaints being
the
commonest.
Toxic
reactions
are
relatively frequent
with
aza-
propazone
which should
be
used only
in
rheumatoid
arthritis, ankylosing spondylitis
and
acute gout when
other drugs have
failed.
Phenylbutazone
is
also
relatively
toxic
(gastrointestinal, hepatic, renal, bone
marrow);
it is
rarely indicated except
in
ankylosing
spondylitis under specialist supervision.
Nonacidic
drugs.
COXIBs
are
associated with
fewer
gastrointestinal adverse
effects,
but
otherwise
the
general
profile
of
adverse reactions
to
NSAIDs
applies.
The
possibility that
COXIBs
may be
asso-
ciated
with
increased risk
of
thrombotic cardio-
vascular
events
is the
subject
of
pharmacovigilance
studies.
More
extensive accounts
of
paracetamol
and
aspirin
are
given below, because
of the
importance
and
widespread
use of
these drugs.
PARACETAMOL
(ACETAMINOPHEN)
(PANADOL)
This
popular domestic analgesic
and
antipyretic
for
adults
and
children
can be
bought over
the
counter
in
the UK. It is a
major
metabolite
of the now
obsolete
phenacetin (see
p.
284).
Its
analgesic
efficacy
is
equal
to
that
of
aspirin
but in
therapeutic
doses
it has
only
weak
anti-inflammatory
effects
(for
this
reason
it is
sometimes deemed
not to be an
NSAID). Para-
cetamol
inhibits prostaglandin synthesis
in the
brain
but
hardly
at all in the
periphery;
it
does
not
affect
platelet
function.
Paracetamol
is
effective
in
mild
to
moderate pain such
as
that
of
headache
or
dysmenorrhoea
and it is
also
useful
in
patients
who
should avoid aspirin because
of
gastric intolerance,
a
bleeding tendency
or
allergy,
or
because they
are
aged
< 12
years.
N D I VI
DUAL
NSAIDS
Pharmacokinetics. Paracetamol
(i
l
/
2
2h) is
well
absorbed
from
the
alimentary tract
and is
inactivated
in
the
liver principally
by
conjugation
as
glucuronide
and
sulphate. Minor metabolites
of
paracetamol
are
also
formed
of
which
one
oxidation product,
N-
acetyl-p-benzoquinoneimine
(NABQI),
is
highly
reactive
chemically. This substance
is
normally
rendered harmless
by
conjugation
with
glutathione.
But
the
supply
of
hepatic glutathione
is
limited
and if
the
amount
of
NABQI
formed
is
greater than
the
glutathione available, then
the
excess metabolite
oxidises thiol (SH-) groups
of key
enzymes, which
causes
cell
death. This explains
why a
normally
safe
drug
can,
in
overdose, give rise
to
hepatic
and
renal
tubular
necrosis
(the
kidneys also contain drug
oxidising enzymes).
Dose.
The
oral dose
is 0.5 to 1 g
every
4 to 6 h,
maximum
daily
dose
4 g.
Adverse
effects.
Paracetamol
is
usually well-
tolerated
by the
stomach because inhibition
of
prostaglandin synthesis
in the
periphery
is
weak;
allergic
reactions
and
skin rash sometimes occur.
Heavy,
long-term daily
use may
predispose
to
chronic renal disease.
Acute
overdose.
Severe hepatocellular damage
and
renal tubular necrosis
can
result
from
taking
150
mg/kg
(about
10 or 20
tablets)
in one
dose,
which
is
only
2.5
times
the
recommended maximum
daily
clinical dose. Patients specially
at
risk
are:
•
those whose enzymes
are
induced
as a
result
of
taking
drugs
or
alcohol
for
their livers
and
kidneys
form
more
NABQI
and
•
those
who are
malnourished (chronic alcohol
abuse, eating disorder,
HIV
infection)
to the
extent that their livers
and
kidneys
are
depleted
of
glutathione
to
conjugate
with
NABQI
(see
above).
The INR
(prothrombin time)
is
preferred
to
plasma bilirubin
and
hepatic enzymes
as a
monitor
of
liver
damage,
and
renal impairment
is
better
assessed
by
plasma creatinine than urea (which
is
metabolised
by the
liver).
The
clinical
signs
(jaundice,
abdominal
pain, hepatic tenderness)
do not
become apparent
for
24^18
h and
liver
failure,
when
it
occurs, does
so
between
2 and 7
days
after
the
overdose.
It is
vital
287
15
NFLAMMATION, ARTHRITIS
AND
NSAIDS
that this delay
be
remembered
for
lives
can be
saved
only
by
effective
anticipatory action (see below).
The
plasma concentration
of
paracetamol
is of
predictive
value;
if it
lies above
a
semilogarithmic graph joining
points between
200
mg/1 (1.32
mmol/1)
at 4 h
after
ingestion
to 50
mg/1 (0.33
mmol/1)
at 12 h,
then
serious hepatic damage
is
likely.
Patients
who are
enzyme induced
or
malnourished
(see
above)
are
regarded
as
being
at
risk
at 50% of
these plasma
concentrations (plasma concentrations measured
earlier
than
4 h are
unreliable because
of
incomplete
absorption).
The
general principles
for
limiting drug absorption
apply
(Ch.
9) if the
patient
is
seen
within
4 h.
Activated
charcoal
by
mouth
is
effective
but the
decision
to use it
must take into account
its
capacity
to
bind
an
oral antidote (methionine).
Specific
therapy
is
directed
at
replenishing
the
store
of
liver
glutathione which combines with
and so
dim-
inishes
the
amount
of
toxic metabolite available
to
do
harm. Glutathione
itself
cannot
be
used
as it
penetrates cells poorly
but
N-acetylcysteine (NAC)
(Parvolex)
and
methionine
are
effective
as
they
are
precursors
for the
synthesis
of
glutathione.
NAC is
more
effective
because
its
conversion into glutathione
requires
fewer
enzymes; also,
it is
administered
by
i.v.
infusion
which
is an
advantage
if the
patient
is
vomiting. Methionine alone
may be
used
to
initiate
treatment when
facilities
for
infusing
NAC are not
immediately available.
The
earlier
such therapy
is
instituted
the
better
and it
should
be
started
if:
• a
patient
is
estimated
to
have taken
> 150
mg/kg,
without waiting
for the
measurement
of the
plasma concentration
•
plasma concentration indicates
the
likelihood
of
liver
damage
(above)
•
there
is any
uncertainty about
the
amount taken
or
its
timing.
NAC
is
administered
i.v.
150
mg/kg
in
dextrose
5%
(200
ml)
over
15
min;
then
50
mg/kg
in
dextrose
5%
(500
ml)
over
4 h;
then
100
mg/kg
in
dextrose
5%
(1000
ml)
over
16 h, to a
total
of
about
300
mg/kg
in
20
h.
While
it is
most
effective
if
administered within
8 h of the
overdose, evidence shows that treatment
continuing
up to 72 h yet
provides
benefit.
The
INR and
serum creatinine should
be
measured daily.
If the INR
exceeds
2
there
is
risk
of
infection
and
gastric bleeding,
and an
antimicrobial
plus
either
sucralfate
or a
histamine
H
2
receptor
antagonist
should
be
given prophylactically.
The
patient
should
be
kept well hydrated
and in
fluid
balance;
falling
urine output, indicative
of
acute
renal
tubular necrosis, will necessitate measures
to
improve urine
flow
(see Chapter 23).
A
paracetamol-methionine
combination (co-methi-
amol; Pameton)
has
been marketed,
the
methionine
content
ensuring
that hepatic glutathione concen-
trations
are
maintained when
the
drug
is
used
in
therapeutic
(and
over-)
dose.
But the
problem
of
ensuring that this
is
used
by the
people most likely
to
benefit
from
such prophylaxis
has not
been
solved since paracetamol
is on
direct sale
to the
public
and
this proprietary preparation
is
more
expensive than generic paracetamol.
A
more simple
measure, reduction
of the
pack-size
in
which
paracetamol
is
sold
to the
public, appears
to
have
reduced
the use of
paracetamol
as a
means
of
deliberate self-harm.
9
ASPIRIN
(ACETYLSALICYLIC
ACID)
Aspirin (acetylsalicylic
acid)
was
introduced
in
1899;
it is by far the
commonest
form
in
which
salicylate
is
taken.
The
bark
of the
willow tree
(Salix)
contains salicin
from
which salicylic acid
is
derived;
it was
used
for
fevers
in the
18th
century
as
a
cheap substitute
for
imported cinchona (quinine)
bark.
Mode
of
action. Acetylsalicylic acid
is
unique
among NSAIDs
in
that
it
also irreversibly inhibits
COX
by
acylating
the
active site
of the
enzyme,
so
preventing
the
formation
of
products including
thromboxane, prostacyclin
and
other prostaglandins,
until more
COX is
synthesised. Acetylsalicylic acid
is
rapidly hydrolysed
to
salicylic acid
in the
plasma.
Salicylic
acid also
has an
anti-inflammatory action
but
additionally exerts important
effects
on
respi-
ration, intermediary metabolism
and
acid-base
balance,
and it is
highly irritant
to the
stomach.
The
anti-inflammatory,
analgesic
and
antipyretic
actions
of
aspirin
are
those
of
NSAIDs
in
general
1
Hawton
K et al
2001
British
Medical Journal 322: 1203.
288
[...]... 57-62 Parkin J, Cohen B 2001 An overview of the immune system Lancet 357:1777-1789 Seymour H E, Worsley A, Smith J M, Thomas S H L 2001 Anti-TNF agents for rheumatoid arthritis British Journal of ClinicalPharmacology 51: 201-208 Sneader W 2000 The discovery of aspirin: a reappraisal British Medical Journal 321:1591 Walker-Bone K et al 2000 Medical management of osteoarthritis British Medical Journal... multidisciplinary approach with physiotherapy, occupational therapy and adjustment on the part of the patient all being important SYMPTOMATICTREATMENT NSAIDs provide much symptomatic relief and improve clinical indicators of disease activity such as joint swelling, but do not improve its outcome, i.e joint destruction The current strategy for treating rheumatoid arthritis is to start treatment with specific... inhibits pyrimidine synthesis and prevents T-cell proliferation, which is thought to be important in the pathogenesis of rheumatoid arthritis The onset of action is faster than other DMARDs, providing clinical benefit in 4-6 weeks As the drug is retained in the body for 2 years, elimination therapy with either cholestyramine or activated charcoal may be necessary if a change to another DMARD is planned... pericarditis), complete bed rest is advised and a corticosteroid should be used instead of aspirin since the latter may precipitate cardiac failure Prednisolone should be given in a dose sufficient to suppress clinical and laboratory (ESR, plasma viscosity, C-reactive protein) signs of inflammation; 10-15 mg/d is usually adequate in adults, and specific therapy for cardiac failure may also be necessary Neither... depression may also cause CO2 retention Adults who have taken a single large quantity usually develop a respiratory alkalosis Metabolic acidosis suggests severe poisoning Often, a mixed picture is seen clinically In children under 4 years, severe metabolic acidosis is more likely than respiratory alkalosis, especially if the drug has been ingested over many hours (mistaken for sweets) Treatment Serial . L
2001
Anti-TNF agents
for
rheumatoid arthritis.
British
Journal
of
Clinical Pharmacology
51:
201-208
Sneader
W
2000
The
discovery
of
aspirin:
. times more likely than low-dose ibuprofen
to
cause
such adverse
effects).
Clinical
trial evidence
in
general appears
to
support
the
theory that