Download NSAIDs

THE USE OF NON-STEROIDAL ANTIINFLAMMATORY DRUGS (NSAIDs) IN
PHARMACEUTICAL CARE
A RECEARCH PRESENTED BY
THE STUDENT : YOSRA ASHRAF EL-ALFY
ID # : 9760249
Project supervisor Dr.Rafiq R. A. Abou-Shaaban
JAN.2001
AJMAN UNIVERSITY OF SCIENCE & TECHNOLOGY
ABU-DHABI BRANCH
UAE
Research for this project was carried out by me during the period of
hospital Pharmacy training – l no.700315 (academic year 2000-2001)
Date:Jan.10th2000
Signed
1
ACKNOWLEDGMENT
ACKNOWLEDGMENT
Sincere gratitude were extended to project supervisor Dr.Asim Ahmed, for
the continuous follow up, constructive criticism, and valuable comments.
The author is indebted to Dr.Rafeeq Abushaaban from the pharmaceutics
department, to the support, encouragement and fruitful accompaniment
through out the training and presentation of this project.
The author wishes to express special gratitude and thanks to those
contributing in this revolutionary, distinctive and advanced Hospital
pharmacy training l ; namely Dr.Danna Sallam and the staff of New Medical
Center (NMC).
2
Project Title
The Use of Non-Steroidal Anti-Inflammatory Drugs
INDEX
Section l :
Page
GENERAL INTRODUCTION
1.1
Difenition of NSAIDS
p.6
1.2
Historical background
p.7
Section ll :
2.1 What is pain ?
p.9
2.2 What is inflammation ?
p.9
Section lll :Mechanism of action of NSAIDs:
p.11
**Action of NSAIDs
p.12
3.1 Analgesic effect
p.12
3.2 Antipyretic effect
p.12
3.3 Anti-inflammatory effect
p.12
3.4 Anticoagulent effect
p.12
Section lV :
3
Classification of NSAIDs
p.14
4.1 Classification according to mood of action
p.14
INDEX
4.2 classification according to chemical structure
p.15
Section V :
Adverse effect of NSAIDs
5.1 Adverse effect on GIT
p.17
5.1.1 NSAID-related gastric ulcers
p.17
5.1.2 Management of NSAID-related gastropathy
p.17
5.1.2.1 Ranatidine role in NSAID-related gastropathy
p.18
5.1.2.2 Misoprostol and NSAID-related gastropathy
p.18
5.2 Adverse effect on CVS
p.19
5.3 Adverse effects on liver
p.19
5.4 Febrile fever
p.19
5.5 Uric acid level
p.19
5.6 In pregnancy
p.19
5.7 Hypersensitivity reaction
p.20
Section Vl :
Role of NSAIDs in the treatment of :
6.1 Rheumatoid Artheritis
p.21
4
6.2 Osteoartheritis
p.23
INDEX
Section Vll :
NSAIDs pharmacokinetics & pharmacodynamics
p.24
Section Vlll :
DRUG DATA
p.25
Scetion lX :
NSAIDs Selection
p.38
Toxicty of NSAIDs
p.40
Section X:
Discussion
p.43
Section Xl :
Conclusion
p.44
** Key practice points
p.47
** Important events
p.48
REFERENCES :
Bibliography
p.49
5
GENERAL INTRODUCTION Section I
GENERAL INTRODUCTION
Definition of Non-Steroidal Anti-Inflammatory Drugs :
The antiinflammatory , antipyretic and analgesic drugs are heterogenous group of
compounds ,often chemically unrelated (although most of them are organic acids) which
share certain therapeutic actions and side effects . the prototype is aspirin ,so they are
called aspirin or salicylates-like drugs .
So these are salicylates & other agents that are also used to treat rheumatic disease share
the capacity to suppress the sings and symptoms of inflammation . Some of the drugs olso
exert antipyretic and analgesic effects , but it is their anti inflammatory properties that
make them useful in the management of disorders in which pain is related to the intensity
of the inflammatory process .
.All NSAIDs have analgesic effects but there maybe considerable variations in their antiinflammatory activity. They act at the site of injury rather than in the CNS where opioids
are principally act . They are aslo likely to produce sedation , respiratory depression or
mood changes .
--------------------------------------------------------------------**Discription :1. NSAIDs are the most widely used nonnarcotic analgesics .
2. They are available over the counter (OTC) .
6
GENERAL INTRODUCTION Section l
**Action :1. NSAIDs acts primarily on the peripheral nervous system to relieve pain
2. They also possess some central analgesic effect and were originally used to treat
inflammatory conditions such as rheumatoid arthritis .
**Indications :1.Management of mild to moderate pain (such as headache , tooth pain myalgia and
dysmenorrhea ) .
2.Reduction of fever .
3.Reduction of inflammation .
4 Reduction of platelet aggregation so it is used as a prophylactic/treatment of
myocardial infarction.
=================================
HISTORICAL BACKGROUND OF NSAIDs :
Quinine from cinchona bark is one of the oldest remedies for relief of mild pain and fever
. Willow bark was used in folk medicine for years for similar indications.There is a bark
of an english tree with a powerful astringent , and very effective in curing aguish and
intermitting disorders. In 1763, Reverend Edmund Stone, in a letter to the Royal Society ,
described his success in treating fever with a powder form of the Willow bark(salicin
7
chrystals isolated from willow bark). He had noted that the bitterness of Willow bark was
reminiscent of the taste of cinchona bark , the source of quinine .
GENERAL INTRODUCTION Section l
The active ingredient of Willow bark , Salicin , which on hydrolysis yields salicylic acid ,
was later found in other natural sources. Acetyl salicylic acid was synthesized in 1853,
but the drug was note used until 1899, when it is found to effective in arthritis. Because
of its greater efficacy and lower coast , aspirin rapidly replaces the natural products then
in use and has remained one of the most widely employed remedies for 100 years.
---------------------------------------------
8
Section ll
WHAT IS MENT BY INFLAMMATION & PAIN ?
***PAIN :It is defined as unpleasant sensory and emotional experience associated with
actual or potential tissue damage .
Aetiology & Neurophysiology :
The majority of tissues and organs are innervated by special sensory receptors called
(Nociceptors) connected to primary afferent nerve fibres which terminates in the dorsal
horn of the spinal cord grey matter . Peripheral mechanisms of inflammatory pain include
the sensitization of nociceptors by PG , particularly PGE2 and prostacyclin . These will
increase the pain response to other chemical mediators such as histamine and bradykinin
which are released in response to cell damage in order to create the characteristic sings of
inflammation : rubon (erythema) , tumor (swelling) , and dolor (pain) .
***INFLAMMATION :Inflammation is divided into three phases:
(1) ACUTE INFLAMMATION : Is the initiate response to tissue injury . It is
mediated by the release of autacoids and usually precedes the development of the
immune system response .
9
Section ll
(2) IMMUNE RESPONSE : Occures when the immunologic cells are activated as a
response to foreign organisms or antigenic substances liberated during the acute or
chronic inflammation . This response involves ph agocytosing or neutralizing the foreign
bodies.
(3)CHRONIC INFLAMMATION : Involves the release of a number of mediators like in
case of rheumatoid arthritis in which chronic inflammation result in pain and destruction
of bone and cartilage that can lead to sever disability and in which systemic changes
occure that can result in shortening of life .
PHOSPHOLIPASE
ARACHIDONIC
ACID
CYCLO-OXYGENASE
PROSTACYCLIN
INJURY
PG
VASODILATATION
LIPO-OXYGENASE
HISTAMINE
SEROTONIN
KININS
COMPLEMENT
LEUKOTRIENES
INCREASED VASCULAR PERMEABILITY
PAIN
EDEMA
EWELLING
10
Section lll
MECHANISM OF ACTION OF NSAIDs :(1) They act by reversible competitive inhibition of the enzyme cyclo-oxygenase
(cox1 & cox2) which is responsible for prostaglandine formation (PG are released
in almost all forms of tissue damage to sensitize the pain receptors to different
stimuli such as chemical mediators , heat and mechanical stimuli) . So due to
inhibition of PG biosynthesis they will prevent the presence of PG in tissue
disruption thus preventing pain sensation .
(2)Certain NSAIDs also may inhibit lipoxygenase enzymes or phospholipase C or may
modulate T-cell function leading to suppression of inflammation.
(3) NSAIDs might have central mechanism that augments the peripheral effect
acting within supra-spinal or spinal level.
(4) They inhibit Thromboxane A2 (TXA2) formation leading to decrease
possibility of thrombus formation .
11
Section lll
Actions of theNSAIDs:*** ANALGESIA :
NSAIDs are very potent analgesics for symptoms of
superfacial pain like headache , toothache , myalgia and dysmenorrhea in their
intermediate dose (aspirin dose of 300 mg ) .
*** ANTIPYRETIC EFFECT :
They decrease body temperature only in case of fever which is usually
caused by vira or bacterial infections , as the virus or bacteria will induce pyrogenic
materials which will increase prostaglandine synthesis in the hypothalamus thus
increasing body temperature . This antipyretic effect is reached by intermediate doses .
*** ANTI-INFLAMMATORY EFFECT :
These analgesics are effective in the treatment of different types of
inflmmation such as rheumatoid arthritis , osteoarthritis and rheumatic fever .This effect
achieved at a high doses ( aspirin dose is 1.5-2 g three times daily ) .
*** PLATELETE AGGREGATION :
This is done by the inhibition of TXA2 and this will hence prevent
platelete aggregation .ti is considersd as atherapeutic effect in case of M.I and as a side
effect as it increases the chance of bleeding (haemorrhage) which is dangerous in case of
hemophilic patient (absence of coagulation factors ) or in case of taking anticoagulants
like warfarin and heparin .
12
Section lll
13
Section lV
Classification of NSAIDs :
**** According to mood of action :
**Cyclooxygenase isoforms :
Prostaglandin H2 synthase enzyme complex (PGHS) exhibit two distinct enzyme
activities:
-
Cyclooxygenase-which converts arachidonic to prostaglandin G2 (PGG2).
-
Peroxidase-which converts PGG2 to PGH2.
Cyclooxygenase which is also referred to as Pgsynthase is encoded by different genes
producing two isoforms known as cyclooxygenase- (cox-1) & cyclooxygenase-2 (cox-2).
((1))—Cyclooxygenase-1 :
COX-1 is present in many cells and tissues generating PGs-prostanoids
e.g : prostacyclin which regulate important physiologic processes such as gastrointestinal
cytoprotection , vascular hhomeostasis , platelet function and maintaining renal integrity .
PGs produced by COX-1 serve as major cyto-protective substances to the gastric mucosa,
inhibitinggastric acid secretion and reducing pepsin content , to addition to increasing
mucous and bicarbonate production and maintaining mucosal blood flow . PGs affect
renal function by regulation perfusion pressure , distribution of renal blood flow , water
metabolism and tubular iron transport leading to diuresis . the characteristic gastri , renal
and thrombogenic side effects of NSAIDs are believed to arise from inhibition of COX-1
Section lV
14
((2))—Cyclooxygenase-2 :
COX-2 up-regulation is regarded as the mechanism by which cellular PG levels are
elevated in inflammation. COX-2 is found in the synovial cells and chondrocytes which
are located in the joints . Also COX-2 is found in the cartilage breakdown that occurs in
rheumatic disease. Selective COX-2 inhibitor are of great importance as they act on PGs
at inflammation site , but not at the GIT or kidney sites where COX-1 acts.
NSAID type
Extentof inhibition of COX1and COX-2
Indomethacin &
Inhibited COX-1 much more strongly than COX-2
piroxicam
Ibuprofen
Difference was smaller than for indomethacin
Diclofenac & naproxen
Inhibited COX-1 and COX-2 equally.
Nabumetone
Inhibited COX-2 more strongly and have little effect on COX-1.
***Classification of NSAIDs according to different chemical classes :
NSAIDs are usually classified according their chemical structure under the category of
acidic and non-acidic . Most NSAIDs are organic acids , and can be classified into two
families which are carboxylic acids and enolic acids.
(!) Carboxylic acids : represent the majority of NSAIDs :1 . Propionic acid derivatives :
e.g : Ibuprofen ---- Fen profen ---- Naproxen ---- Ketoprofen ---- Flurbiprofen .
2
.Hetero Cyclic acid derivatives :
Section lV
15
e.g : Indomethacin ---- Sulindac ---- Diclofenac.
3 . Fenamates :
e.g : Mefenamic acid ---- Meclofenac .
4 Acetic acid group :
e.g : Nabumetone.
(2) Enolic acids :
1 . Oxicam :
e.g : piroxicam ---- Tenoxicam .
2 . Pyrazolone derivatives :
e.g : Phenyl butazone (withdrawn due to liver and blood toxicity ) .
(3) Selective COX-2 blocker :
eg : Meloxicam.
(4) this is in addition to :
1. Salicylic acid derivatives:
e.g: acetyl salicylic acid (aspirin) ---- Diflunisol.
2. Para aminophenol group :
e.g : paracetamol ( acts as antipyretic and analgesic only due to acting only centrally ).
Section V
16
Major NSAIDs side effects :(1). GIT :
Prostaglandine is a cytoprotective agent which by decreasing the acid secretion
and increase mucous secretion which protects from the direct contact between the
stomach and acid thus preventing ulcer . So NSAIDs will remove the mucousal protection
leading to ulcer formation . So NSAIDs are also contraindicated in infants even in
antipyretic or analgesic dose .
* (intermediate dose will cause gastritis while antiinflammatory dose will induce peptic
ulcer ).
* It is necessary to give H2-blocker together with NSAIDs therapy like ranatidine.
 when gastritis occure it may lead to gastric bleeding which will cause microcytic
anaemia due to iron deficiency .
5.1.1 NSAID-RELATED GASTRIC ULCERS:
NSAID use is associated with the occurrence of gastric ulcers. Between 89%-95% of
peptic ulcer-related serious upper GIT events may be attributed to NSAIDs use ,
Helicobacter pylori infection and cigarette smoking.
5.1.2 MANAGEMENT OF NSAID-RELATED GASTROPATHY :
Drugs with prolonged acid suppression may be very effective in preventing NSAIDrelated gastric ulcers , as for example a dose of 20mg of mesoprostol is given daily
provide effective prophylactic therapy in patient at risk of developing NSAID-related
peptic ulcer or dyspeptic symptoms.
Section V
17
5.1.2.1 RANATIDINE ROLE IN NSAIDs-RELATED GASTROPATHY :
Ranatidine is significantly promotes healing rates in rheumatoid anthritis (RA) patients
with deudenal ulcer in which NSAIDs therapy is discontinued. Low oral dose Ranatidine
(150-mg bid) shows effectiveness in the treatment of both NSAIDs-related dyspeptic
symptoms and mucosal lesions with or without peptic ulcer in rheumatoid arthritis and
osteoarthritis (OA) patient who continues the use of NSAIDs . High dose Ranatidine is
effective for the prevention of recurrent gastric ulcer in RA patients taking NSAIDs .
5.1.3.2 MISOPROSTOL & NSAIDs-RELATED GASTROPATHY :
Misoprostol has long-term efficacy in preventing NSAIDs-induced gastroduodenal ulcers
in rheumatic patients. Misoprostol reduces serious GIT complications (e.g: bleeding ,
perforation and gastric outlet obstruction ) by 40% in elderly patient with RA receiving
NSAIDs. And this effect will continue for 3 months only.Although misoprostol provides
safe , effective prophylactic approach but it does not prevent a new mucosal lesion
induced by diclofenac and does not accelerate the healing of biopsy sites. Despite that
misoprostol decreases the frequency of declofenac-related epigastric discomfort, but is
associated with increased gas bloating and flatulence as adverse effect.
Section V
18
(2) . CVS :
In the normal doses NSAIDs have no effect on the CVS , but in high or toxic
doses they can produce shock due to inhibition of the vasomotor center .
(3) . Liver :
They have no effect on normal liver , but they are dangerous in case of having
hepatic disorders like hepatitis because NSAIDs aredepending on the liver in their
metabolism as they will get congugated with glycine present in the liver and then they get
excreted .
(4). Febrile Fever :
NSAIDs may cause Reyes Syndrome in children with high fever . It is a leathal
condition as it may cause hepatitis and encephalitis .
(5) . Uric Acid :
NSAIDs in law doses will inhibit the uric acid excretion so it is contraindicated
in Gout & Hyperuricemia .But in case of very high doses they can cause increase in uric
acid excretion .
(6) . Pregnancy :
We can give it in law doses in normal pregnancy , but it is contraindicated before
labour because NSAIDs will inhibit PG availability which is important to increase uterine
contractions , so they may inhibit labour .And also it is dangerous to have bleeding before
labour
Section V
19
(7) . Hypersensitivity Reactions :
NSAIDs causes hypersensitivity reaction due to enhancing the formation of
leukotriens . It can be mild that produce bronchospasm and skin rash or it can be sever
that induce anaphylactic shock .
Section Vl
20
ROLE OF NSAIDs IN THE TREATMENT OF
**RHEUMATIC ARTHRITIS
**OSTEOARTHRITIS
NSAIDs are considered as the center piece of pharmaco-therapy for most rheumatic
disorders. They are used primarily in the treatment of rheumatic and chronic arthritic
conditions and certain soft tissue disorders associated with pain and inflammation. The
dominant mechanism of action for most if not all NSAIDs, is inhibition of PG synthesis
in the synovial compartment.The concentration in the synovial fluid (SF) is an important
determination of clinical response to NSAIDs. The pharmacokinetic pattern of NSAIDs
in the SF rely on their plasma elimination t1/2 . It has been suggested that , NSAIDs
therapy may contribute to cartilage deterioration in patients with rheumatic disease.
(1)---RHEUMATOID ARTHRITIS :
RA is an autoimmune , common chronic inflammatory disease characterized by pain,
swelling , and prolonged morning stiffness in multiple symptomatic joints. RA involve
inflammation of the synovial membrane and mononuclear cell infiltration. Rheumatoid
synovial tissues release large quantities of PGs , mainly PGE2 and PGF2 alpha ,
prostacyclin , and thromboxane , that are important mediators of inflammation. Chronic
joint inflammation commonly results in progressive joint destruction , deformity and loss
of function. This disease severity increases by age and specially in females.
Section Vl
21
The standard therapeutic approach for the treatment of RA is patient education, rest,
exercise, and NSAIDs. The use of NSAIDs in RA is mainly for symptomatic treatment as
they reduces inflammation and associated pain and improve function. NSAIDs may affect
RA by causing significant reduction in blood levels of rheumatoid factor and C-reactive
protein (CRP).
DRUGS USED IN THE TREATMENT OF RA
FIRST LINE TREATMENT:
Analgesics
NSAIDs
SECOND LINE TREATMENT:
Antimalarials
Gold (parenteral and oral)
Penicillamine
Salphasalazine
THIRD LINE TREATMENT:
Azathioprine
Methotrexate
Cyclophosphamide
OTHER AGENTS:
Corticosteroids (oral or parenteral)
Section Vl
22
(2)----OSTEOARTHRITIS :
OA is a multifactorial disease , defined as a condition of slow degeneration of joints
tissue (synovial joints) characterized by cartilage loss accompanied by changes to the
underline bone. OA is relatively pain free but with loss cartilage and joint movement. The
final phase of OA seems to reflect a failure of the reparative process, resulting in
degradation of the matrix, cell death (necrosis and apoptotic), and total loss of cartilage
integrity(chondrophy).OA can be due to trauma, surgery to a joint, genetic
predisposition(generalized OA),abnormal metabolism or various rare metabolic disorders
(secondary OA),or due unknown reason (primary OA) which is common in post
menopausal women.
OA is the most common indication for NSAIDs. Traditionally NSAIDs are the first line
treatment which is symptomatic and not curative. They provide effective pain relieve and
improve function by maintaining mobility and reducing disability.
23
Section Vll
NSAIDs PHARMACOKINETICS & PHARMACODYNAMICS
All NSAIDs apper to be absorbed completely , have negligible first-pass hepatic
metabolism , are tightly bound to albumin >98% (except piroxicam) , and have small
volume of distribution. NSAIDs pharmacokinetic may be significantly altered in elderly
and in patient with renal hypoalbuminaemia (more than gm%) and hepatic diseases , for
example patient with low levels of serum albumin (eg: cirrhosis or active RA) may have
higher drug free concentrations. NSAIDs are highly metabolized in the liver (except
nabumetone only 40% metabolized) , resulting either in inactivation or activation. Some
NSAIDs (eg: naproxen ) reverts back after metabolism to active parent form. Variability
in the clinical effects of various NSAIDs is attributed to differences in pharmacokinetics
and mechanism of action. Consequently expect differences in clinical response and toxic
effects among NSAIDs.
PHARMACOKINETIC PARAMETERS OF NSAIDs
DRUG
Tmax (h)
Vd (L/kg)
%renal
excretion
T1/2 (h)
Diclofenac
1–2
0.12
1.1
<1
Indomethacin
1–2
0.12
4.6
<15
Ibuprofen
0.5 – 1.5
2.1
1
Ketoprofen
0.5 – 2
0.11
1.8
<1
Nabumetone
3-6
0.11
26
1
Piroxicam
2
0.12
38
10
Phenylbutazone
2
0.17
50 – 100
1
Aspirin
1-2
0.15
0.25
<2
24
Section Vlll
DRUG DATA
PROPIONIC ACID DERIVATIBES :
IBUPROFEN :
INDICATIONS:
RA---- other musculoskeletal disorders---- mild to moderate pain including
dysmenorrhoea---- postoperative analgesia---- migraine---- fever and pain in children.
It has fewer side effects than other NSAIDs but its antiinflammatory property is weaker.
DOSE:
Initial doses of (1.2 – 2.4 g) is needed for RA daily,and maintenance dose of (1.6 –1.2 g).
PHARMACOKINETIC & PHARMACODYNAMIC:

It is extensively metabolized in the liver, and little is excreted unchanged.

Pharmacokinetic is influenced by age and renal impairment.

It increases serum creatinine.
SIDE EFFECTS:

Gastrointestinal irritation and bleeding, aseptic meningitis , fluid retention,
agranulocytosis, aplastic anaemia, acute renal failure and nephrotic syndrome.
INTERACTIONS:

The use of ibuprofen concomitantly with aspirin may decrease the total antiinflammatory effect
.Contraindications:

It is unsuitable for asthma and conditions where inflammation is prominent such
as acute gout.Also in case of nasal polyps,and angioedema
25
Section Vlll
KETOPROFEN:
INDICATIONS:

In rheumatic diseases, musculoskeletal disorders, after orthopaedic surgery, acute
gout and dysmenorrhea.
PHARMACOKINETIC & PHARMACODYNAMIC:

It is metabolized completely in the liver, rapidly absorbed but its t1/2 is short,
99% is bounded to plasma protein .
SIDE EFFECTS:

The major side effects is on the CNS and GIT.
INTERACTIONS:

Administration of probenecid elevates ketoprofen levels and prolongs its plasma
t1/2.
DOSE:

For RA: 100 – 200 mg in 2 – 3 divided doses daily or 100mg suppositories at bed
time. For pain & dysmenorrhoea: 50mg 3 times daily

Deep I.M into gluteal muscle 50 – 100mg every 4 hrs.
CONTRAINDICATIONS: As Ibuprofen.
FENOPROFEN:
INDICATIONS:

ALL AS IBUPROFEN
DOSE:

300 – 600mg 3- 4 times daily with food.
26
Section Vlll
SIDE EFFECTS:
Upper respiratory infection, nasopharyngitis and cystitis
FLURBIPROFEN :

The same as ibuprofen + for sore throat.
CONTAINDICATIONS: As Ibuprofen
DOSE:

By mouth or rectum 150 – 200mg daily in divided doses and can be increased in
acute cases to 300mg daily.

For dysmenorrhoea: initially 100mg then 50 – 100mg every 4 – 6
hrs.(max.300mg).
FENBUFEN :
INDICATIONS: As Ibuprofen.
SIDE EFFECTS:

Erythena multiform and Stevens-Johnson syndrome and interstitial lung disorders
follow rashes.
27
Section Vlll
HETEROCYCLIC ACID
INDOMETHACIN
INDICATIONS:

Pain and moderate to sever inflammation in rheumatic disease and other acute
musculoskeletal disorder ,acute gout, dysmenorrhoea, and closure of ductus
arteriosus.
SIDE EFFECTS:
GIT ulceration and bleeding, blood disorders (thrompocytopenia), hypertension,
hyperglycemia, peripheral neuropathy, intestinal strictures, blurred vision, confusion,
convulsions, insomnia, drowsiness, frontal lobe headache and corneal deposites.
CAUTIONS:

Avoid rectal administration in case of having proctitis and haemorrhoid.

Upon prolonged therapy epilepsy, parkinsonism and psychatric disturbances may
occure.

blood and ophthalmic examination must be done.
DOSE:

For rheumatic disease (by mouth): 50 – 200mg daily in divided doses with food .

For acute gout: 150 – 200mg daily in divided doses.

For dysmenorrhoea: up to 75mg
28

Supposetories: 100mg at night and in the morning if required.
Section Vlll
NAPROXEN :

THE SAME AS IBUPROFEN BUT WITH MORE SELECTIVITY TO COX-1.
Indications:

Used also for tendenitis and bursitis.
NOTES:

Trough concentrations >50 are associated with response to RA.

Greater than 99.7% is bounded to protein , saturation with increased dose with :
uremia, liver cirrhosis, and in elderly and decreased in RA and hypoalbuminemia.
29
Section Vlll
ENOLIC ACID DERIVATIVES
OXICAM :
TENOXICAM :

It has a rapide onset of analgesic effect with a reliable 24 hr anti-inflammatory
action.
INDICATIONS:

RA, OA, ankylosing spondylitis , extraarticular inflammation and acute gout.
DASING:

20mg daily is the usual dose in all indications due its long t1/2 of 72 hrs.
HIGH RISK PATIENT:
It is well tolerated by high risk patient, i.e; elderly, those with hepatic, renal or heart
failure and they do not need dose adjustment due to unchanged pharmacokinetic
parameters and there is no accumulation beyond the expected steady state plasma level.
INTERACTIONS:

It is not to be taken with acetylsalicylic acid, other NSAIDs or potassium-sparing
diuretics.
PHARMACOKINETIC & PHARMACODYNAMIC:
The long t1/2 of 72 hrs results in constant plasma levels and avoids the effects of peaks in
concentration. It penetrates rapidly into the synovial fluid, giving a rapid onset of action.
30
It has high bioavailability (tablet100% , suppositories80%) , rapid absorption
(1.3hrs) and a small distribution volume ensure rapid analgesia. It is poorly distributed in
Section Vlll
fatty tissues, CNS and skin because it is highly bounded to protein with poorly lipophelic
property. It differs from all NSAIDs in that it is not excreted in an unaltered form in the
bile it is metabolized completely to form inactive metabolite in which 2/3 are excreted via
the kidney and 1/3 in the bile. It causes a minor decrease in creatinine clearance in
patient with pre-existing renal impairment.
NOTES:

It has a greater COX-2 selectivity than nabumetan and less mucosal damage than
piroxicam.
PIROXICAM:
INDICATIONS:(as Tenoxicam)
 RA,OA and ankylosing spondylitis.
SIDE EFFECTS:

Rectal irritation and occasional bleeding.
PHARMACOKINETIC &PHARMACODYNAMIC: As Tenoxicam.
DOSE:
For RA:Initial dose is 20mg daily and maintenance dose is 10 – 30 mg daily(by mouth or
rectum),for acute musculoskeletal disorder: 40mg for 2 days & then 20mg daily for 1-2
weeks, for acute gout 40mg or deep I.M injection.
31
NOTES:

It is reported to cause about 12 times more GIT adverse effects than ibuprofen.
CONTRAINDICATIONS: As Tenoxicam
Section Vlll
PYRAZOLONE
PHENYLBUTAZONE
INDICATION:

RA, ankylosing spondylitis, acute gout and musculoskeletal disorders.
CAUTIONS:

Blood counts before and during the treatment must be done specially in elderly
and breast feeding
SIDE EFFECTS:

Agranulocytosis , aplastic anaemia, Stevens-Johnson-syndrome, toxic epidermal
necrolysis, pulmonary toxicity, thrombocytopenia, parotitis, stomatitis, goitre,
pancreatitis, hepatitis, nephritis and visual disturbance.
DOSE:

Initially 200mg 2-3 times daily for 2 days with or after food then reduced to 100mg 2-4
times daily
CONTRAINDICATIONS:

In CVS diseases, renal and hepatic impairment, pregnancy, history of peptic
ulceration, inflammatory bowel disease, porphyria, thyroid disease.
32
Section Vlll
ACETIC ACID DERIVATIVES
NABUMETONE :
Nabumetone is a prodrug. It is given as a ketone and converted to an acetic acid
derivative in the body. Its half- life of more than 24hrs, permits once daily dosing.
Otherwise, its properties are very similar to those of other NSAIDs.
----------------------------------------------------------------------------------
FENAMATES
MEFENAMIC ACID
INDICATIONS:
*Used for its analgesic effect.
PHARMACOKINETICS & PHARMACODYNAMICS:
*It has a short t1/2 and reaches the peak plasma level in 30 – 60 min.
*It is excreted in the urine .
CONTRAINDICATIONS
*It should be not taken for longer than 1 week and never in children.
*It is also contraindicated in pregnancy.
INTERACTIONS:

This drug inhances the effect of oral anticoagulants.
33
Section Vlll
OTHER ADDITIONAL GROUPS
(1)SALICYLIC ACID DERIVATIVES:
ASPIRIN:
INDICATIONS:

It is mainly used as a prophylactic from myocardial infarction.
SIDE EFFECTS;

It increases the chance of bleeding.

It can cause gastritis.

Causes hyperuricemia due to inhibition of uric acid excretion.
CONTRAINDICATIONS:

Patient with peptic ulcer.

Patient with hepatitis (metabolized by glycine congugation in the liver).

In children (causes Hayes Syndrom which causes hepatitis and encephalitis).

In labor because it inhibits PG which leads to uterine relaxation,and also causes
increase in bleeding chance.

In patient with hypersensitivity reactions (allergy to aspirin).
34

Patient with hemophilia.
INTERACTIONS:

It increases the chance of bleeding in the presence of Warfarin and Heparin.
Section Vlll
ASPIRIN TOXICITY:

Toxicity is usually lethal due serious change in the blood pH.

High Doses:
Will increase the energy utilization by the skeletal muscles(increase phosphorylation)thus
increasing CO2 causing a respiratory stimulation (increase rate & depth of respiration)
which leads to increase CO2 elimination .So in case of high dose if the patient took any
drug which can block the respiratory center (like barbiturates) it’ll immediately lead to
acidoses.

Higher Doses:
It will cause stronger stimulation to the respiratory center leading to alkalosis which will
stimulate the kidney to excrete bicarbonateto compensate alkalosis.

Very High Doses:
It’ll depress the respiratory centers leading to CO2 accumulation (acidoses) which is a
noncompensated respiratory acidoses.Also this high dose will inhibit the excretion of
other acids obtained from metabolism (lactic and pyruvic acids).This will lead to
metabolic acidoses thus coma and death.
**Treatment of aspirin toxicity :
35

In coma state we have to aid respiration by artificial respiration .

Gastric aspiration and lavage(by charcoal to prevent further absorption).

Give sod.bicarbonate(I.V) to increase the pH and aspirin excretion.
Section Vlll
PARA-AMINOPHENOL DERIVATIVES
PARACETAMOL
INDICATIONS:

It has only antipyretic and analgesic effects because it lacks the peripheral action.

It is used in all cases when aspirin is contraindicated because it lacks the
peripheral action which leads to the aspirin side effects.

Used in cases of:bleeding disorder, asthma, pregnancy, fever in children, gout, and
hepatitis.
PHARMACOKINETICS & PHARMACODYNAMICS:
Paracetamol is metabolized by a minor pathway which uses sulfuhydryl group as a
congugator and converted to acetaminophen sulfate and glucuronide.. It is taken orally
and its rate of absorption depends on gastric emptying .The peak plasma conc is reached
in 30 – 60 min. It is slightly bond to plasma protein. Its t1/2 is 2 – 3 hrs.and unaffected by
renal function.
DOSES:
Acute pain and fever is managed by 325 – 500 mg 4 times daily.
ADVERSE EFFECTS:
36

Mild increase in the hepatic enzymes.

Nephritis and papillary necrosis

15g is tethal.

Heamolytic anaemia.
Section Vlll
Contraindications:
In patient with hepatic diseases.
PARACETAMOL TOXICITY:

In case of over dose the drug will utilize all the sulfuhydryl group available then
uses the hepatocyte S-H group resulting in liver cirrhosis.

Ti is very essential to treat the patient immediately with acetyl systeine.
NOTE: when the patient reached the coma stage the treaetment will be with no use.
37
Section lX
NSAID selection

Choosing a particular NSAID is typically based on efficacy, safety,
availability, cost, and dosing schedule. At equipotent doses, the different NSAIDs are
similarly effective across patient populations. However, the responsiveness of
individual patients to specific NSAIDs differs. The lack of a patient's response to one
NSAID does not mean response to another. The determinants of individual
responsiveness to specific NSAIDs may involve variations in absorption and
bioavailability of the drugs, and the patient's compliance with the prescribed regimen.

Try to use as possible as you can NSAIDs with more COX-2 inhibition in
elderly.

NSAID-related toxicities, particularly those involving the GItract, has become
central in selecting an NSAID. Two newer NSAIDs -- nabumetone and etodolac -have been heralded as safer thanolder NSAIDs, perhaps because of their relatively
selective COX-2 effects.

The traditional use of specific NSAIDs for certain indications (eg,
indomethacin
38
for gout, aspirin for RA) often guides physicians' selections. Patient
characteristics may also prompt consideration of a particular NSAID. For instance,
nonacetylated salicylates are relatively safer in patients with a history of asthma, nasal
polyps, or aspirin sensitivity.

Acetaminophen, along with non-drug therapies, can be used effectively for many
patients with back pain, various bone and joint disorders or other types of
non-cancerous pain in the eldly
Section lX

Pharmacologic properties of the various NSAIDs may influence prescribing
practices. NSAIDs with short half-lives are better suited for treating acute
musculoskeletal pain (eg, athletic injuries, gouty attacks) because of their typically more
rapid onset of action, whereas NSAIDs with longer half-lives are more appropriate for use
in RA or other chronic conditions. The more convenient dosing regimens also tend to
enhance compliance. Nevertheless, once-daily NSAID formulations should be used with
caution in the elderly and in patients with hepatic or renal impairment.
39
Section lX
Toxicity of NSAIDs
Gastrointestinal

Dyspepsia, nausea, and, less frequently, vomiting may disrupt NSAID treatment.

Nonacetylated salicylatestend to cause less dyspepsia than do other NSAIDs,
perhaps because of theabsence of the acetyl group.
Renal

All available NSAIDs can induce nephrotoxic effects, which are both
prostaglandin
and non-prostaglandin mediated. Prostaglandins play a central role in renal
hemodynamics and glomerular filtration, as well as in the metabolism of sodium,
potassium, and water.

Patients at highest risk for NSAID-related renal failure are those who depend on
intrarenal production of prostaglandins for normal renal function. These include
40

Persons with normal renal function can safely take a 1- to 2-week course of
NSAIDs. Even persons over the age of 60 years who have mild renal insufficiency
(mean creatinine clearance, 50 to 60 mL per minute) can tolerate a 2-week course of
naproxen 750 mg per day without renal patients with clinically significant congestive
heart failure, cirrhosis with or without ascites, or intrinsic renal diseases such as
nephrotic syndrome. If treatment with NSAIDs is essential, use nonacetylated
salicylates at the lowest possible dose for the shortest duration. Nonacetylated
salicylates, as weak inhibitors of prostaglandin synthesis, may offer a theoretical
advantage over traditional NSAIDs.
Section lX

close monitoring is necessary in NSAID users over the age of 60 who have
preexisting renal or hepatic disease or congestive heart failure or who are taking
diuretics concomitantly. Measure electrolytes and blood urea nitrogen and serum
creatinine at baseline and again between the first and second weeks of treatment.

advised to take acetaminophen rather than aspirin or NSAIDs for painful
syndromes.
Hepatic
NSAIDs cause serum transaminase elevations; the particular NSAID chosen, as well as
the duration of therapy and total daily dose, can affect the risk. Diclofenac has been
reported to cause clinical hepatitis and has been linked to several cases of hepatic death.
sulindac, ascompared with other NSAIDs, significantly increased the risk of acute
41
liverinjury. However, the liver injury associated with sulindac and the otherNSAIDs was
generally mild and reversible.
 NSAID-related liver dysfunction is disease specific. For example,naproxenrelated liver function abnormalities are more common in patients with OA than in
those withRA.
Central Nervous System

Tinnitus is common in patients taking high-dose salicylates.
Hematologic

The antiplatelet effects of NSAIDs are well recognized and are used to advantage
Section lX
in patients with coronary artery disease. HoweverNonacetylated salicylates are a safer
choice in these patients. Doses of nonacetylated salicylates should remain within
recommended ranges to avoid any possible inhibition of platelet COX, which may
occur at the highest dose levels.

In patients about to undergo surgery, withhold NSAIDs preoperatively for a
duration equaling 4 to 5 half-lives. Since aspirin irreversibly inhibits platelet
COX and since platelets lack the "machinery" to produce new COX
42
Section X
DISCUSSION
( About GIT Problems )

Incidence. Fewer than half of NSAID users with GI symptoms have
gastricerosions or ulcers. This lack of an association between symptoms and
endoscopically recognizable pathology makes it difficult to identify patients who
should undergo diagnostic studies and ulcer treatment/prophylaxis. Although the
proportion of NSAID users who experience serious GI side effects (eg,
bleeding,perforation,) is low -- only 1% to 2% in the first year of treatment[11] – the
absolute number of users who experience such events is large because of the
widespread use of these drugs.
43

An analysis of 16 studies showed that NSAID users were 3 times more likely
than nonusers to experience adverse GI effects. In persons over the age of 60,the
relative risk for NSAID-induced ulcers was 5.5. A univariate analysis of 2,400
patients with RA showed that NSAID users were 7 times more likely than nonusers to
be hospitalized because of adverse GI effects. Elderly patients with NSAID-induced
ulcers tend to present with anemia, hemorrhage, or perforation rather than with
abdominal pain. This may explain why the elderly, as compared with their younger
counterparts, more frequently require emergency surgical intervention for NSAIDinduced gastropathy and have a higher mortality rate.

.Few data suggest an increased risk for peptic ulcer disease in NSAID users who
smoke or who have a modest alcohol intake.
Section X

The presence of infection Helicobacter pylori does not appear to increase the
risk for NSAID-induced peptic ulcer disease; however, patients may complain of
more GI distress if they are on NSAIDs and are infected with H pylori.

Misoprostol -- a syntheticprostaglandin analog -- and omeprazole -- a proton-
pump inhibitor -- have beenshown to heal NSAID-induced ulcers. However,
misoprostol is not as effective asfamotidine -- a histamine H2 antagonist -- or
omeprazole in relievingNSAID-induced dyspepsia.

Usual doses of H2 antagonists, taken concomitantly with NSAIDs, have been
shown to prevent duodenal, but not gastric, ulcers and their complications. High-dose
44
famotidine and omeprazole have been shown to decrease the incidence of both gastric
and duodenal ulcers, but not ulcer-related complications.
Section Xl
CONCLUSION
** Differences in anti-inflammatory activity between different NSAIDs are small , but
there is considerable variation in individual patient tolerance and response. The main
difference between NSAIDs are in the incidence and type of side effects.
** Before treatment is started the prescriber should weigh efficacy against possible side
effects. And also NSAIDs vary in their selectivity for inhibiting different types of cyclooxygenase.
The range of activities of NSAIDs against COX-1 compared with COX-2 explains the
variations in the side effects of NSAIDs at their anti-inflammatory doses. NSAIDs which
45
have the highest potency against COX-2 and a better COX-2/COX-1 activity ratio will
have potent anti0inflammatory activity with fewer side effects in stomach and kidney.
** Parenteral administration of NSAIDs for the short term relief of acute pain compared
to the oral rout of administration may increase compliance , act more rapidly by reashing
peak concentrations more quickly, and may increase tolerability by avoidance of direct
contact of the drug with the gastric mucosa.
** Patient treated with NSAID-therapy show an asymptomatic , reversible impairment
of renal function characterized by reduction of creatinine clearance and corresponding
rises in plasma creatinine level, urea and potassium.
Section Xl
** NSAIDs are contraindicated in patient with history of hypersensitivity to aspirin and
patient having these diseases:

Asthma.

Angioedema.

Urticaria.

Rhinitis.

Peptic ulcer.
** Azapropazone is always associated with high risk of upper G.I.T side effects.
46
** Nephrotoxicity is vary from drug to another
** Sulindac is the only NSAID that it spares renal PG synthesis.
Section Xl
Key Practice Points :
Avoid using NSAIDs in patients with platelet defects (eg, von Willibrand disease)
or thrombocytopenia (platelet count less than 50,000/mm).

NSAIDs should not be used in chronic bases.

NSAIDs were to be prescribed in the lowest possible doses, and to be
administered with food.

Simultaneous use of oral and topical NSAIDs shpuld be avoided as possible.

In patients about to undergo surgery, withhold NSAIDs preoperativley for a
duration equaling 4 to 5 half-lives.

Avoid using NSAIDs in pregnant women, as the safety of these drugs has not
been well studied.
47

Combination NSAID therapy cannot be rationalized, given the toxicity and the
lack of improved efficacy.

Analysis showed a clinically significant rise in blood pressure in NSAID-treated
patients.
So,check blood pressure at baseline and within 1 to 2 weeks of starting NSAID
treatment in hypertensive patients.

Some evidence suggests that NSAIDs interfere with b blockers, angiotensin
converting enzyme inhibitors,and loop and thiazide diuretics in the management of
hypertension.
Section Xl
IMPORTANT EVENTS :

Bromfenac, an NSAID usedpredominantly as an analgesic, was recently approved
for short-term use only(less than 10 days). Shortly after being approved, bromfenac
was withdrawn fromthe market because of severe liver injury in 1 out of every 10,000
to 20,000patients who took it for longer than 10 days. At least 4 patients diedand
8required liver transplantation.

Central nervous system side effects associated with NSAIDs ( include aseptic
meningitis, psychosis, and cognitive dysfunction), are more prevalent in elderly patients
than in younger ones, particularly in association with indomethacin. Thus, prescribe
indomethacin and other NSAIDs judiciously in the elderly and monitor their mental status
periodically.

patients should stop aspirin at least 1 week before a planned surgical procedure
48

Enteric-coated formulations of aspirin may prevent some symptoms of local
gastric
irritation, but they are unpredictably absorbed and are more expensive than
traditional aspirin tablets.
References
REFERENCES
Bibliography:

CLINICAL PHARMACY & THERAPEUTICS
Roger Waiker – Clive Edward.

THE MANAGEMENT OF ACUTE PAIN
Gilbert Park & Barbara Fulton.

PHARMACOLOGY
Leonard s. Jacob.

THE PHARMACOLOGICAL BASES OF THERAPEUTICS
Alfred Goodman Gilman.
49

LIPPEN COTTS

BASIC & CLINICAL PHARMACOLOGY
Bertram G. Katzung.

ESSENTIALS OF HUMAN ANATOMY & PHYSIOLOGY
Elaine N. Marieb

BRITISH NATIONAL

CLINICAL DRUG DATA

THE MERCK MANUAL

OTHER MEDICAL JOURNALS:
(BNF)
** Drugs(reprint)….Focus on Tenoxicam
References
** Drug Safety(reprint)….Tenoxicam and renal function
** Scandinavian journal of Rheumatology(selective
cyclooxygenase inhibition : promise for future NSAID therapy)
** British journal of Rheumatology (studies in Meloxicam)
** Voltaren journal (diclofenac).
** Geigy Pharmaceuticals (product information).
** Documenta CIBA-GEIGY (An international forum for the
doctor).
** Product information on Tilcotil (Tenoxicam).
50


51