classefication according to half live and cox ,uses ,side effect , uses in lactation renal and hepatic diseases

1. NONSTEROIDAL
ANTI-INFLAMMATORY
DRUGS
Dr TAREK M NASRALLAH
AL - AZHAR

3. NSAIDsLarge and chemically diverse group
of drugs with the following
properties:
Analgesic
Anti inflammatory
Antipyretic

4. 1) The decrease in vasodilator
prostaglandins (PGE2, PGI2) means
less vasodilatation and, indirectly,
less edema.
2) The inhibition of activity of
adhesion molecule.
(3) Accumulation of inflammatory cells
is also reduced

5.  decreased prostaglandin generation
means less sensitization of
nociceptive nerve endings to
inflammatory mediators such as
bradykinin and 5-hydroxytryptamine.
 Relief of headache is probably due to
decreased prostaglandin-mediated
vasodilatation

6.  This is partly due to a
decrease in the mediator
prostaglandin that is
responsible for elevating
the hypothalamic set-point
for temperature control in
fever.

7.  Prostaglandins were isolated from human
semen in 1936 by Ulf von Euler. He named
them Prostaglandins because he believed they
came from the prostate gland.
 The Swedish scientist received the Nobel Prize
in medicine in 1970 for this work.
 Since his work in this area it has been
determined that they exist and are synthesized
in almost every cell of the body.
 They are synthesized in the same cell on which
they act.

8. COXCOX ExpressionExpression FunctionFunction InhibitorsInhibitors
COX-1COX-1
constitutivelyconstitutively
throughout thethroughout the
bodybody
organ pain, plateletorgan pain, platelet
function, stomachfunction, stomach
protectionprotection
NSAIDsNSAIDs
including aspirinincluding aspirin
COX-2COX-2
Inducible andInducible and
constitutively inconstitutively in
brain, kidneybrain, kidney
Inducible:Inducible:
inflammation, pain,inflammation, pain,
feverfever
Constitutive: synapticConstitutive: synaptic
plasticityplasticity
NSAIDs, COX 2NSAIDs, COX 2
inhibitorsinhibitors
includingincluding
celecoxibcelecoxib
(Celobrex )(Celobrex )
COX-3COX-3
Constitutively, highConstitutively, high
in brain, heartin brain, heart
pain pathways, notpain pathways, not
inflammationinflammation
pathwayspathways
acetaminophenacetaminophen
some NSAIDssome NSAIDs

9. PHYSIOLOGIC
TEMPERATURE
CONTROL
BRONCHIAL TONE
CYTOPROTECTION
INTESTINAL
MOBILITY
MYOMETRIAL TONE
SEMEN VIABILITY
PATHOLOGIC
FEVER
ASTHMA
ULCERS
DIARRHEA
DYSMENORRHEA
INFLAMMATION
BONE EROSION
PAIN
ROLE OF PROSTAGLANDINS

10.  PGE2, PGI2
VASODILATION,
ACT SYNERGISTICALLY WITH OTHER
MEDIATORS
HISTAMINE, COMPLEMENT,
BRONCHODILATATION
INHIBITION OF PLATELET AGGREGATION
 TXA2
PROMOTION OF PLATLET AGGREGATION

11. COX-2
INDUCIBLE
INFLAMMATORY AND
NEOPLATIC SITES ALSO
PRESENT IN KIDNEY,
UTERUS. OVARY
BRAIN, SMALL INTESTINE

12. Act as :
1. Cytokine inhibitors ( IL-1, TNF, IL-8),
antibodies or antibody fragments. Antagonists
to various peptides that contribute to cytokine-
mediated responses (e.g., substance P,
bradykinin).
2. Inhibitors of cell adhesion molecules :
these include soluble fragments of receptors
to bind cell adhesion molecules and use of
antibodies, peptides, and carbohydrate
moieties to block cell adhesion molecules.

13. 3. phospholipase A2 inhibitors -
glucocorticoids but whose toxicity will
be less frequent and severe than that
of the steroids.
4. Inhibitors of lipoxygenase and
leukotriene receptors
5. Isoform specific inhibitors of
cyclooxygenase (meloxicam).

14. 6. Reduction of superoxide radicals,
7. Induction of apoptosis,
8. Inhibition of adhesion molecule expression,
9. Decrease of nitric oxide synthase,
10. Modification of lymphocyte activity,
11.Alteration of cellular membrane functions

15.  NSAIDs can be classified based on their
chemical structure or mechanism of action.
 Older NSAIDs were known long before their
mechanism of action was elucidated and
were for this reason classified by chemical
structure or origin.
 Newer substances are more often
classified by mechanism of action

17.  Ibuprofen
 Dexibuprofen
 Naproxen
 Fenoprofen
 Ketoprofen
 Dexketoprofen
 Flurbiprofen
 Oxaprozin
 Loxoprofen

18.  Indomethacin
 Tolmetin
 Sulindac
 Etodolac
 Ketorolac
 Diclofenac Safety alert by FDA
 Nabumetone drug itself is non-acidic but the active,
principal metabolite has a carboxylic acid group

19.  Lysine clonixinate
 Piroxicam
 Meloxicam
 Tenoxicam
 Droxicam
 Lornoxicam
 Isoxicam
 Natural
 Hyperforin
 Figwort

20.  Mefenamic acid
 Meclofenamic acid
 Flufenamic acid
 Tolfenamic acid

21.  (Celecoxib (FDA alert
 )Rofecoxib (withdrawn from market
 (Valdecoxib (withdrawn from market
 Parecoxib FDA withdrawn, licenced in the EU
 Lumiracoxib TGA cancelled registration
 Etoricoxib FDA withdrawn, licenced in the EU
 Firocoxib used in dogs and horses

22.  (Nimesulide (systemic preparations are
banned by several countries for the
potential risk of hepatotoxicity
 Others
 Licofelone acts by inhibiting LOX
(lipooxygenase) & COX and hence known as
5-LOX/COX inhibitor
 Lysine clonixinate

23.  • Analgesic, no anti inflammatory‐
effect.
 • Can replace morphine in mild to
moderate postsurgical pain.
 • IM, IV.
 • Similar toxicities. Renal toxicity
common with chronic use.

24.  Peak Cp 30-60
 Dose <65 years: 20 mg (orally), then 10 mg every 4-6 hours
 not to exceed 40 mg/24 hours
 >65 years 10 mg every 4-6 hours not to exceed 40 mg/24 hours
 Commonly given parenterally (60 mg IM followed by 30 mg every
6 hours, or 30 mg IV every 6 hours
 Potent analgesic, poor anti inflammatory
 Protein binding 99%
 Metabolites glucuronide conjugate (90%)
 t1/2 4-6 hours

25.  Analogue of indomethacin and similar
profile; anti-inflammatory mainly with
analgesic and antipyretic activity and
uricosuric action.
 It is used for RA, OA and as a post-operative
analgesic.
 It may cause GI ulceration and hemorrhage
at high doses. This drug is well absorbed

26.  Peak Cp 1 hour
 Dose 200-400 mg 3-4 times/day
 Some COX-2 selectivity
 Protein binding 99%
 Metabolites Hepatic metabolites
 T 1/2 7 hours

27.  • Half life of 45 hrs. Once daily dosing.‐ ‐
Delay onset of action.
 • High doses inhibits PMN migration,
decrease oxygen radical production, inhibits
lymphocyte function.
 • Used in osteoarthritis, ankylosing
spondylitis and rheumatoid arthritis.
 • Adverse effects: GI symptoms, dizziness,
tinnitus, headache, rash. Peptic ulcer (9.5
higher).

28.  • Short half life (1 2 hrs), high 1st pass‐
metabolism accumulates in synovial fluid after oral
administration
 • GI S/E : in about 20% pt. Severe effects like GI
distress, GI bleeding, gastric ulceration less
frequent than other NSAIDs and similar to
celecoxib.
 • High doses impairs renal function. Elevates liver
enzymes.
 • CI : children, pregnant women and nursing
mothers

29.  Most potent inhibitor of prostaglandin synthesis (COX 1)‐
May also inhibit phospholipase A ,C
 • Orally absorbed, highly bound to plasma proteins, half ‐
life 2hrs.
 • Metabolized in liver, excreted in bile and urine.
 • A/E : GI, severe migraine (20 25%), dizziness,‐
confusion and depression, risk of fluid retention,
hyperkalemia and blood dyscrasias.
 • Contraindicated in pregnancy and in patients with
psychosis.
 •Uses : Treatment of patent ductus arteriosus in
premature babies.

30.  GOOD ABSORPTION
 HEPATIC METABOLISM
 HIGHLY PROTEIN BOUND
 BOTH ENTEROHEPATIC AND RENAL
EXCRETION
 VARIABLE HALF LIFES

31. SHORT HALF LIFE-MORE RAPID EFFECT AND
CLEARANCE
 IBUPROFEN,DICLOFENAC,INDOMETHACIN,
LONGER HALF LIFE-SLOWER ONSET AND SLOWER
CLEARANCE
NAPROSYN, CELOCOXIB, ROFECOXIB
NABUMETONE, PIROXICAM

32.  ANTI-HYPERTENSIVE RX
 PHENYTOIN
 ANTI-COAGULANTS
 METHOTREXATE

33. Rapid absorption;
– the majority of absorption takes place in the
stomach and the upper portion of the small intestine;
– absorption is reduced when taken at night;
– the majority binds with plasma proteins;

34.  The pharmacological effect comes from
the drug in its free state (unbound);
 – Metabolism is predominantly hepatic
and is faster in children;
 – Excretion is renal;
 – elimination is faster in children than
in adults, requiring more frequent
doses.

35. 
Max: dose/dayMax: dose/day IntervalInterval
AspirinAspirin 65 – 325 mg65 – 325 mg
Max: 3600mgMax: 3600mg
4 - 64 - 6 Available as rectal, liquid, and sustained-release forms. Do not use inAvailable as rectal, liquid, and sustained-release forms. Do not use in
children <12 yearschildren <12 years
old with suspected viral infection, due to potential of Reye’sold with suspected viral infection, due to potential of Reye’s
syndrome. Causes irreversiblesyndrome. Causes irreversible
inhibition of platelet aggregation. Anti-inflammatory effects start atinhibition of platelet aggregation. Anti-inflammatory effects start at
3600mg/day.3600mg/day.
AcetaminophenAcetaminophen 65 – 325 mg65 – 325 mg
Max: 4000mgMax: 4000mg
4 - 64 - 6
ER:8ER:8
No peripheral anti-inflammatory or antiplatelet properties. Available asNo peripheral anti-inflammatory or antiplatelet properties. Available as
rectal, liquid, andrectal, liquid, and
sustained-release formssustained-release forms
FenoprofenFenoprofen 100 - 300 mg100 - 300 mg
Max: 3200mgMax: 3200mg
6 – 86 – 8
IbuprofenIbuprofen 200 - 400 mg200 - 400 mg
Max: 3200mgMax: 3200mg
6 – 86 – 8 May inhibit anti-platelet effect of aspirin if administeredMay inhibit anti-platelet effect of aspirin if administered
concomitantly. Take aspirin 30concomitantly. Take aspirin 30
minutes before ibuprofen or take ibuprofen 8 hours afterminutes before ibuprofen or take ibuprofen 8 hours after
aspirin.Lowest incidence of GI side effects. Weaker anti-inflammatoryaspirin.Lowest incidence of GI side effects. Weaker anti-inflammatory
propertiesproperties
FlurbiprofenFlurbiprofen 100 mg100 mg
Max: 300mgMax: 300mg
6 - 126 - 12
Ketoprofen,Ketoprofen,
Ketoprofen SRKetoprofen SR
50 – 100 mg50 – 100 mg
Max: 300mgMax: 300mg
6 – 86 – 8
SR: 24SR: 24
High risk of GI side effects.High risk of GI side effects.
NaproxenNaproxen 250 – 500 mg250 – 500 mg
Max: 1500mgMax: 1500mg
1212
MeloxicamMeloxicam 7.5 – 15 mg7.5 – 15 mg
Max: 15mgMax: 15mg
2424
PiroxicamPiroxicam 10 – 20 mg10 – 20 mg 2424 High risk of GI side effects. Doses> 20mg daily associatedHigh risk of GI side effects. Doses> 20mg daily associated

36. Meclofenamate sodiumMeclofenamate sodium 50 – 100 mg50 – 100 mg
Max: 400mgMax: 400mg
6 - 86 - 8
Mefenamic acidMefenamic acid 250 mg250 mg
Max: 1000mgMax: 1000mg
66 Therapy not recommended for > 1Therapy not recommended for > 1
weekweek
CelecoxibCelecoxib 100 – 200 mg100 – 200 mg
Max: 400mgMax: 400mg
12 - 2412 - 24 Adjust dose in renal impairmentAdjust dose in renal impairment
DiclofenacDiclofenac 50 mg – 100 mg50 mg – 100 mg
Max: 200mgMax: 200mg
8 - 128 - 12
XR: 24XR: 24
Published case studies have shown anPublished case studies have shown an
increased risk of cardiovascularincreased risk of cardiovascular
events.events.
Misoprostol is contraindicated inMisoprostol is contraindicated in
pregnancypregnancy
EtodolacEtodolac 200 – 400 mg200 – 400 mg
XR: 1000mgXR: 1000mg
Max: 1200mgMax: 1200mg
8 - 128 - 12
XR: 24XR: 24
IndomethacinIndomethacin 25 mg25 mg
SR: 75mgSR: 75mg
Max:200mg;150mgMax:200mg;150mg
SRSR
8 - 128 - 12
SR:12-24SR:12-24
KetorolacKetorolac 10 mg10 mg
Max: 40mgMax: 40mg
4 - 64 - 6 Limit treatment to 5 days. MayLimit treatment to 5 days. May
precipitate renal failureprecipitate renal failure
TolmetinTolmetin 400 mg400 mg
Max:1800mgMax:1800mg
6 - 86 - 8 High risk of GI side effectsHigh risk of GI side effects

37.  GASTROINTESTINAL
 RENAL
 HEMATOLOGIC
 CNS
 HEPATIC
 SKIN
 ALLERGIC

38. ENDOSCOPIC ULCERS
GASTRIC 15-30%
DUODENAL 10%
COMPLICATIONS
PERFORATIONS, BLEEDING
MORTALITY 7500 PER YEAR
OVERALL RISK 1/1000

39.  OLDER AGE
 STEROIDS
 RA
 HIGHER DOSE NSAID
 Previous adverse reaction to NSAIDs or other
drugs
 The use of other medicines that may
exacerbate any

40.  selective serotonin reuptake inhibitors
(SSRIs)
 Liver disease
 Chronic kidney disease (CKD)
 Smoking
 Excessive alcohol consumption

41.  SYMPTOMS SIMILAR TO
NONSELECTIVE NSAIDS
 ULCERATIONS MUCH LESS THAN
NONSELECTIVE
 RISK OF BLEEDING AND
PERFORATIONS LESS
 EFFECTS ON COLONIC POLYPS AND
CANCER

42.  Celecoxib includes a boxed warning, highlighting the
potential for increased risk of cardiovascular events and
the well described, serious, potential life-threatening
gastrointestinal bleeding associated with their use.
 The fact that it now carries exactly
the same warning for gastrointestinal
risk as the older nonselective NSAIDs
is quite
 Remarkable, new drugs—were supposedly less risky to
the gastrointestinal tract than the older nonselective
agents

43.  Paracetamol is generally better tolerated
than NSAIDs in people at increased risk of
gastrointestinal adverse effects.
 Diclofenac and COX-2 inhibitors appear to be
the least likely NSAIDs to cause upper
gastrointestinal perforation, obstruction or
bleeds,
 while the risk is likely to be increased for
patients taking ibuprofen and naproxen.

44.  Advise patients to take NSAIDs with
milk or food so the stomach is not
empty and irritation is reduced.
 A Cochrane review found that both PPIs
and histamine-2 receptor antagonists,
e.g. ranitidine, were effective at
preventing chronic NSAID-related
gastric and duodenal ulcers.

45.  If a patient develops
gastrointestinal symptoms during
NSAID treatment another type of
NSAID can be trialed, an alternative
class of analgesic trialed, or a PPI
prescribed

47.  Blood concentrations of NSAIDs after
applying topical products are typically less
than 5% of those reached by using oral
NSAIDs
 Approximately six or seven patients out of
ten will experience successful pain control
with topical NSAIDs.
 However, a large proportion of this effect is
because sprain-type injuries tend to improve
without treatment

48.  TRANSAMINITIS
 HEPATITIS

49.  IMPAIRED PLATELET
AGGREGATION
 PROLONGED BLEEDING TIME
 ANTI-COAGULATION RX

50.  NO EFFECT ON WBC OR HB
 NO EFFECT ON PLATELET
AGGREGATION
o PLATELETS EXPRESS ONLY COX-1
o NEED TO USE LOW DOSE ASP. FOR
CARDIAC
o CAN BE USED WITH COUMADIN BUT
COUMADIN DOSE MAY NEED
ADJUSTMENT

51.  HEADACHE
 CONFUSION
 DIZZINESS
 MOOD ALTERATION,
DEPRESSION
 ASEPTIC MENINGITIS

52.  COX-2 PREDOMINANT ISOFORM
IN NEOCORTEX, HIPPOCAMPUS
 STUDIES IN ALZHEIMER’S ttt. IN
PROGRESS

53.  All medicines which block COX-2 are
potentially nephrotoxic because they
can reduce blood flow to the kidney by
preventing prostaglandin-mediated
vasodilation
 This is particularly true in
patients who are dehydrated.

54.  In New Zealand over 40% of all renal
adverse reactions reported to the
Centre for Adverse Reactions
Monitoring (CARM) were associated
with diclofenac
 serum creatinine and potassium should
be measured after one to two weeks of
treatment and then monitored regularly

55.  NSAID nephrotoxicity can be exacerbated by
ACE inhibitors or Angiotensin II receptor
blockers (ARBs) as these medicines impair
the regulation of blood flow leaving the
kidney.
 Renal function can be compromised even
further if a patient is also taking a diuretic
can result in hyponatremia or hyperkalemia,
cardiac failure

56.  DECREASED RBF: DECREASED RENAL PG
 RISK FACTORS: VOLUME DEPLETION
RENAL, LIVER DISEASE
VASCULAR DISEASE→
 EDEMA, HBP, INCREASED CREATININE
 NEPHROTIC SYNDROME: INTERSTITIAL NEPHRITIS
 ELECTROLYTE IMBALANCE: K+
 ↑↑ BP
 PAPILLARY NECROSIS
 STONES

57. FIBROSIS,INFLAMMATION,PAPILLARY
CHANGES
 CLINICAL STUDIES
EDEMA-RESOLVES WITH DRUG
WITHDRAWAL.

58.  - In healthy hydrated individuals, renal PGs
do not play a major role in sodium and water
homeostasis
 - Under certain conditions of localized
circulatory stress associated with elevated
levels of angiotensin II and catecholamines
resulting in decreased renal perfusion, renal
blood flow is dependent upon prostaglandin
synthesis

59.  NSAID-induced inhibition of PG synthesis can result
in significant decreases in renal blood flow and
GFR, leading to acute renal failure in kidney
function-compromised individuals
 - Patients at most risk include those with
 congestive heart failure,
 volume depletion, chronic renal disease,
 liver disease and
 patients receiving diuretics

61.  URTICARIA
 ANAPHALAXIS
 BRONCHOSPASM
 NASAL POLYPS, ASTHMA

62.  The reaction is due to COX-1 inhibition
and is not mediated by IgE, therefore it
is not a true allergy.
 NSAIDs can be routinely prescribed to
patients with asthma who have no
previous history of NSAID-associated
symptoms

63.  People who have had a
hypersensitivity reaction to a NSAID
should avoid all non-selective
NSAIDs as the reaction is likely to
be a class effect

64.  COX-2 INDUCED BY LH PRIOR TO
OVULATION
 COX-2 INDUCED AT DELIVERY
o INHIBITORS MIGHT BE OF VALUE IN
PREVENTING PRETERM DELIVERY

65. DECREASE IN COLON CANCER
DECREASE NUMBER AND SIZE OF
ADENOMAS IN PTS WITH HX OF
FAMILIAL ADENOMAS
COX-2 INHIBITORS APPROVED IN
FAMILIAL POLYPOSIS

66.  INDUCTION OF COX-2 IN RODENT AND
HUMAN COLORECTAL ADENOMAS AND
CARCINOMAS
 COX-2 INHIBITION-REGRESSION OF
NEOPLASTIC POLYPS AND PREVENTION OF
THEIR DEVELOPMENT
 ROLE OF COX-2 INHIBITORS IN CANCER
PREVENTION IN PROGRESS

69.  Drug, infant and maternal factors
are considered when assessing the
risks and benefits of prescribing to
breastfeeding women

70.  The decision to use pharmacological
therapy in breastfeeding women must
balance the benefits of therapy for the
mother and continuing breastfeeding
for the mother and infant against the
potential risk of drug exposure to the
infant

71.  The maternal plasma concentration of a drug
 most medicines enter human milk by passive
diffusion
 Drugs with long half-lives are more likely to
accumulate in human milk
 Exposure of the infant to a drug can be reduced
by avoiding breastfeeding at the time the drug
reaches its maximum concentration in the plasma
and by using drugs with shorter half-lives

72.  Drugs with high molecular weights (e.g. heparins,
interferons and insulin) are less likely to pass into
breast milk
 Highly lipid soluble drugs penetrate into breast
milk in higher concentrations than those that are
not
 Drugs which are highly protein bound (e.g.
warfarin) have low levels in breast milk.

73.  Breast milk is more acidic than plasma, therefore drugs
with a high pH (e.g. barbiturates) may concentrate more
in breast milk.
 Drugs with a low oral bioavailability (e.g. omeprazole) do
not enter the infant’s bloodstream via breast milk
 One of the more popular methods for assessing
infant risk is to estimate the Relative Infant
Dose (RID),
 Many sources now suggest that medications with an RID
of <10% are generally considered safe for breastfeeding
full term infants

74.  The most important infant factors to consider are the age
and maturity of the infant.
 Adverse events associated with drug exposure via
lactation occur most often in infants < 2 months and
rarely in infants > 6 months
 Infants can be categorised as
 low (age 6-18 months),
 moderate (full-term infants age 2 weeks – 6 months) or
 High risk (premature, newborn or infants with medical
conditions such as renal impairment)

75.  include the severity of the condition being
treated and the risk to the mother of not
receiving medication
 mothers are advised to breastfeed first, and
then take their medicine, thereby decreasing
the likelihood of overexposing the infant to
the medicine

76.  Preparations containing paracetamol are
suitable for use by breastfeeding mothers
up to the maximum dose of two tablets four
times a day
 Paracetamol may also be included in cold
remedies and it is important not to take
double the ingredient by accident

77.  Products containing ibuprofen are also
safe for a breastfeeding mother to take
 Paracetamol and ibuprofen can be
taken together (to their maximum daily
dose of 8 paracetamol + 3 ibuprofen
400milligrammes) for the relief of
severe pain.

78.  Non - steroidal anti-inflammatory drugs
are generally safe to be taken during
breastfeeding as they transfer in small
amounts into breastmilk e.g. Diclofenac,
 Naproxen longer half-life than
diclofenac but amount secreted into
breastmilk is small

79.  Indomethacin (Indocid®) should be avoided
if possible as there is one report of
convulsions in a neonate exposed to this
drug through breastmilk (Hale 2016).
 Mefenamic acid (Ponstan®) is frequently
given to reduce period pain and transfers
into breastmilk in small amounts (BNF
2017)

80.  There is less information on the transfer of the
Cox 2 anti-inflammatories e.g. Celecoxib
(Celebrex®).
 They can be avoided by taking a combination of
traditional NSAID with a proton pump inhibitor e.g.
omeprazole, a combination of which is safe in
breastfeeding.
 However it appears that the amount of celecoxib
passing through breastmilk is too small to be
harmful.

81.  If a patient is likely to benefit from NSAID
treatment naproxen or ibuprofen are
recommended first-line, at the lowest
effective dose, for the shortest possible
time.
 Patients taking NSAIDs who are at increased
risk of complications require regular
monitoring

82.  Teratogenicity of drug treatment is a great
concern for doctors and patients alike.
 First trimester use of NSAIDs has been
studied prospectively in the large American
Collaborative Perinatal Project. Data from
this project including> 50 000 mother child
pairs on aspirin [7] and some other NSAIDs
[8] did not show an increased risk of
congenital malformations.

84.  Prescribe long-term NASIDs
with caution to people with an
elevated cardiovascular risk,
particularly if they have had a
previous cardiovascular event

85.  All non-selective NSAIDs and COX-2
inhibitors are associated with
increased cardiovascular risk
 except naproxen up to 1000 mg per
day or
 Ibuprofen up to 1200 mg per day.

86.  This increased risk begins within the first
week of treatment
 A study of over 83 000 patients with prior
myocardial infarction found that NSAID use
increased the risk of recurrent myocardial
infarction or death by 1.45 times during the
first seven days of treatment
 .

87.  The greatest risk was associated with
diclofenac which increased the risk of
myocardial infarction and/or death by
3.26 times at day one to seven of
treatment
 Diclofenac at doses of ≥ 150 mg per
day is associated with an increased risk
of cardiovascular events .

88.  Diclofenac use is
contraindicated in patients who
have had a myocardial infarction
in the previous 12 months.

89.  A Meta-Analysis of Randomized Clinical Trials
7,462 patients exposed to celecoxib 200 to800
mg/day for 1,268 patient-years compared with
4,057 patients treated with placebo for 585
patient-years
 • 19,773 patients treated with celecoxib 200 to
800 mg/day for 5,651 patient-years compared
with 13,990 patients treated with nonselective
NSAIDs (diclofenac, ibuprofen, naproxen,
ketoprofen, and loxoprofen) for 4,386 patient-
years

90.  Celecoxib compared with placebo is not
associated with an increased risk for
cardiovascular events for duration of use
from 12 to 52 weeks.
 • Celecoxib compared with nonselective
NSAIDs is not associated with increased
cardiovascular endpoints.

92.  Ibuprofen is generally the preferred NSAID for
use in children.
 Naproxen is not indicated for the short-term
treatment of pain and fever in children, but
may be prescribed for rheumatoid arthritis in
children aged over five years.
 Diclofenac is the only other NSAID available for
the treatment of pain and inflammation in
children aged under 12 years,

93.  Paracetamol (children aged over one month, 15
mg/kg per dose, every four hours, up to four
times daily, maximum 1 g per dose and 4 g per
day) or
 ibuprofen (children aged under 12 years, 20
mg/kg in divided doses, to a maximum of 500 mg
per day in children under 30 kg)
 Are both indicated for the treatment of pain and
fever in children.

94.  Mild fevers (<38°C) do not need to be treated
 Paracetamol or ibuprofen should not be given for the
sole purpose of reducing body temperature
 Medicines for fever should only be prescribed for as long
as the child is in discomfort. .
 If discomfort is not alleviated before the next dose is
due, then switching ,e.g. changing from paracetamol to
ibuprofen, may be considered.

95.  Do not give paracetamol and ibuprofen at the same
time
 Paracetamol and ibuprofen do not prevent febrile
convulsions and should not be prescribed specifically
for this reason
 Advise parents of the need for children with fever to
receive regular fluids.
 Small quantities of water offered frequently are best,
or breast milk if the child is being breast fed

96.  The lowest dose for the shortest
duration of therapy that
accomplishes the therapeutic goal
should be used