Rational use of medicines
requires the patients to take medications that are appropriate to their
clinical needs, in doses that meet their own individual requirements, for an
adequate period of time, and at the lowest cost to them and their community1.
As stated by a famous humanitarian, A little simplification would be the first
step toward rational living.
Thus simplifying ,Rational use
of drugs require patients to take the Right medication, in the right dose, at
right time through the appropriate route.2 Failure to follow this
scheme has lead to medically inappropriate, un productive and unprofitable use
of pharmaceuticals world wide especially in the developed countries. This
misuse of drugs has resulted in wastage of resources as well as worldwide health
hazards. While; the non steroidal anti-inflammatory drugs (NSAIDs), now
constitute perhaps the most frequently prescribed class of medications.3
Although these are the
most widely prescribed medications in the united states for fever, arthritis
and a number of other inflammatory conditions to reduce pain and inflammation,
according to a research conducted on Un
necessary prescribing of NSAIDS in 1997 it was proved that they are
associated with a high incidence of side effects.4
In the last decades, epidemiologic studies
have revealed the risk of upper
gastrointestinal tract bleeding/perforation (UGIB) associated
with individual nonsteroidal anti-inflammatory drugs (NSAIDs).5
multicenter study revealed that Long-term NSAID use is associated with the
development of mucosal ulceration with an incidence of 20%.6
Many patients with Upper Gastro Intestinal Bleeding who are
taking NSAIDs present without dyspepsia but with hematemesis or melena as their
first symptom, owing to the analgesic effect of the NSAID.7
The use of over-the-counter (OTC) formulations NSAIDS is very
common. In this context, Data of 4164 consecutively diagnosed patients with
rheumatoid arthritis was collected on the GI risks of OTC doses of aspirin,
ibuprofen, naproxen, paracetamol, and no drug, from eight Arthritis,
Rheumatism, and Aging Medical Information System centers in North America. Serious
GI events such as bleeding, requiring hospitalization were reported in these
Serious side effects have been reported due to NSAIDS
especially in children..A large randomized controlled trial conducted by Lesko SM, Mitchell AA (1995) showed that
ibuprofen and acetaminophen were equivalent in their risk of adverse events .9
A 10 year old girl was
brought to the emergency of a local hospital in Rawalpindi, Pakistan with chief
complaints of epigastric pain (2 weeks), Bloody vomiting (a week) and fever (last
2 days). There was a sudden onset of pain after having meal .It was severe
enough to hamper child’s activity. Her mother was called to school and child
was brought to the Emergency.
The pain had been accompanied
by Hematemesis i.e. vomiting of blood since a week.
It was sudden in onset
and almost 2 tablespoons in volume. It was non projectile, bright red in color
associated with abdominal pain. No blood clots were seen. The child had intermittent,
low grade fever for the past 3 days. It was relieved by Ibuprofen. There were
no associated symptoms with fever such as rigors or chills, burning sensation
on stooping, acidity retrosternally etc.
examination showed temperature 101C, pulse 115/min, respiratory rate 22/min and
B.P.She weighed 40Kg.Her examination had revealed pallor, weight loss and anorexia.
She had flank pain in
the renal area and her CVS examination revealed palpitation and fatigue.CNS is
normal and intact.
There was no history of
constipation, diarrhea, malena, allergy and respiratory infection. While medical
history showed sub-vaginal delivery (SVD), mild anemia and pancytopenia.
medication history revealed frequent use of Ibuprofen (NSAID) for symptomatic
relief of fever since thirteen months.
The patient presented with
epigastric pain (2 weeks), bloody vomit (Hematemesis) (a week) and fever (last
2 days).The epigastric pain was sudden in onset after having meal and was
severe enough to hamper her activities. The vomit was non projectile, contained
blood and was almost 2 tablespoons in volume. Fever was mild intermittent and
relieved by ibuprofen.
Past medication history of the
patient showed frequent use of Ibuprofen for symptomatic relief of fever for
the past 13 months (91 weeks).
Ibuprofen is an oral, Nonsteroidal
Anti Inflammatory drug (NSAID) of the propionic acid chemical class. It
competitively inhibits both cyclooxygenase (COX) isoenzymes, COX-1 and COX-2,
by blocking arachidonate binding resulting in analgesic, antipyretic and anti
Cyclooxygenase 1 (COX-1) is
responsible for the physiologic production of prostanoids, that regulates the normal cellular processes such as gastric cytoprotection, vascular homeostasis, platelet aggregation and
kidney function.COX-2 cause’s elevated production of prostanoids in case of a disease
or at the site of inflammation.COX-2 is constitutively expressed in some tissues,
such as brain, kidney and bone. Its expression at other sites is increased
Since ibuprofen is a nonselective
COX inhibitor, it inhibits both of the COX enzymes resulting in wide range of
side effects. Focusing on the above mentioned case, as already described, COX-1
is responsible for the physiologic production of prostanoids that regulate
gastric cytoprotection i.e. Prostacyclin (PGI2) which inhibits gastric acid secretion,
whereas PGE2 and PGF2a stimulate synthesis of protective mucus in both the stomach
and small intestine .In the presence of Ibuprofen, these prostanoids are not
produced resulting in increased gastric acid secretion and diminished mucus
protection respectively. This results in epigastric distress, ulceration and
hemorrhage which increases with dose and duration and can occur at any time.10
This fact is supported
by Geis GS, Stead H, Wallermark C-B (1991)11 who reported the occurrence of mucosal lesions in
patients, with rheumatoid arthritis, due to chronic use of NSAIDS. It was
estimated that prevalence of NSAID induced gastric or duodenal ulcers, varies
between 14.6% and 43.9%.
and Bombardier (1990) estimated the absolute risk of gastric ulceration to be
The patient was prescribed ibuprofen 1 year back, when she had fever, by
a local physician. She had immediate relief and from then onwards when ever she
had fever in the past 13 months, she took ibuprofen for relief.
According to British National Formulary
13, the dose for children under 12 years is 20 mg/kg of body weight in divided doses per day.
As she weighed 40Kg, her total daily dose becomes 800mg in divided doses.
Depicting irrational use, she took more then the required dose, according to
her mother two 400 mg tablets at a time for fever .Thus by taking double dose each time ,the serum level for the drug increased then
the required leading to exaggerated
effect. Use of adult dosage form by the child also depicts irrational
prescribing by the physician.
So as the child consumed
ibuprofen for a long period, she developed ulceration leading to hemorrhage
which presented as Hematemesis.
Blood CP of the child revealed mild anemia representing continuous blood loss
Lindblad R,Rödjer S (1991) suggested that patients
on prolonged therapy should undergo regular blood monitoring as ibuprofen
causes iron deficiency anemia and pancytopenia.14
According to Autret-Leca E, Bensouda-Grimaldi L, Maurage C, Jonville-Bera AP (2007) ,Regional Centre of Pharmacovigilance, France; NSAIDS, when used in children
for pain or fever relief, are associated with serious Gastro Intestinal complications
which increase with the length of exposure and dose.15
So lowest effective dose should
be given for the shortest period of time to limit these adverse effects.
Irrational use of OTC
drugs is a major problem of present day medical practice. All NSAIDs can cause
gastrointestinal discomfort and rarely serious but potentially fatal
gastrointestinal effects such as ulcers, bleeding and perforation, which may
increase with dose or duration of use but can, occur at any time without warning.
So it is the responsibility of the health care professionals to optimize and
help rationalize the use of these OTC drugs by the consumer.
1 medicines/areas/rational use. Department of Essential Medicines and Pharmaceutical Policies (EMP),
World Health Organization Head quarters , 20 Avenue Appia 1211, Geneva 27,Switzerland.
Richard Manasse ,Kasey K. Thompson, American Society of
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facilities. American Society of Health-System
Pharmacists,7272 Wisconsin Avenue,Bethesda,MD,20814,attn
3 Baum C, Kennedy DL, Forbes MB,1985.
Utilization of nonsteroidal anti-inflammatory drugs. Arthritis Rheum., (Vol ,28
, pg 686-92). PMID:4004978
4 Tamblyn R, Berkson L, Dauphinee WD, Gayton D, Grad R, Huang A, Isaac L, McLeod P, Snell L.McGill
University, Montreal, Quebec, Canada ( Sep 15,1997). Unnecessary prescribing of
NSAIDs and the management of NSAID-related gastropathy in medical practice. Ann Intern Med.vol 127, pg 429-38. PMID:9312999
5 Hernandez-Diaz S, Rodriguez
2000. Association between nonsteroidal anti-inflammatory drugs and upper
gastrointestinal tract bleeding/perforation: An overview of epidemiologic
studies published in the 1990s. Arch Intern
Med ,vol160, pg 2093-2099. PMID:10904451
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Division of Immunology and Rheumatology, Stanford University School of
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a view from the ARAMIS database. Arthritis, Rheumatism, and Aging Medical
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SM, Mitchell AA. An assessment of the safety of pediatric
ibuprofen. A practitioner-based randomized clinical trial. The Journal Of
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A. Harvey, Michelle
A Clark, Richard
A. Rey, Karen Whalen.Lippincott's Illustrated Reviews: Pharmacology, .Lippincott Williams
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11 Geis GS, Stead
H, Wallermark C-B, et al. Prevalence of mucosal lesions in the stomach and
duodenum due to chronic use of NSAIDs in patients with rheumatoid arthritis or
osteoarthritis and interim report on prevention by misoprostol of diclofenac
associated lesions. J Rheumatol 1991, vol 18(Suppl 28), pg 11-14. PMID:1903808
12 Gabriel SE, Bombardier C. NSAID induced
ulcers. An emerging pandemic? J Rheumatol 1990, vol 17, pg 1-4. PMID:2179547
Medical Association, Pharmaceutical
Society of Great Britain, Joint
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severe pancytopenia caused by ibuprofen.Department of Medicine, Ostra Hospital,
Gothenburg University, Sweden. J Intern Med. 1991 , vol Mar229(3), pg 281-3. PMID:2007846
15 Autret-Leca E, Bensouda-Grimaldi
L, Maurage C, Jonville-Bera AP. CHRU of Tours,
Regional Centre of Pharmacovigilance, Department of Pharmacology, Hôpital
Bretonneau, 2 boulevard Tonnellé, 37044 Tours Cedex 9, France. Upper gastrointestinal
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