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CHAPTER II
LITERATURE REVIEW
2. 1 Definition
2. 1. 1 Definition of NSAIDs
Nonsteroidal anti-inflammatory drugs (NSAIDs) can be interpreted literally as
class of anti-inflammatory drugs that are not classified as steroids. Drugs
this type has various types of preparations and chemical formulations and in
particular
have a similarity with each other that is side effects and therapeutic effects
related to the mechanism of action of this preparation on the
enzyme cyclooxygenase
(COX). NSAIDs have been widely used in the medical world through their abilities
effectively reducing pain with mild to moderate intensity. NSAIDs
has an analgesic effect on pain originating from an integument rather than
originating
of the viscera, such as headaches, myalgia and abralgia. 1 The use of NSAIDs as
the analgesic is symptomatic so that when the symptom is gone, it is given
must be stopped. 4
2.1.2 Definition of enzymes Cyclooxygenase
The enzyme cyclooxygenase (COX), which was originally known as prostaglandin
H
synthase (PGHS), is the main enzyme involved in the oxidation of acid
arakidonik (AA) into prostaglandin G 2 (PGG 2) and prostaglandin H 2 (PGH 2).
Isoforms of COX enzymes are heme enzymes that have character-
specific characters and roles in various physiological processes in the human
body. 2
There are generally three types of isoforms of the COX enzyme, namely:
COX-1
o Considered as an enzyme constitutive (permanent enzyme) with
prostaglandin which has produced a very resourceful uses
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important in maintaining the body's homeostatic function. COX-1 by
sustainable expenditure in a high and regulated level
on cells and tissues such as endothelium, monocyte, platelets, tubules
collective kidney and seminal vesics. 2 Through a physiological stimulus,
COX-1 plays an important role in the stomach to reduce acid secretion
stomach, guarding renal blood flow, and streamline the process
platelet aggregation. 4 The primary structure of COX-1 consists of 602 amino
acids. 2
COX-2
o COX-2 is an indusible enzyme that is generally not observed in
most tissues, but will increase in inflammatory or
pathologic. 1 COX-2 produces a special type of prostaglandin
the effect leads to an inflammatory response, such as for example
swelling, redness, and pain. 4
COX-2 enzyme stimulated by
inflammatory mediators such as liposaccharide (LPS), interleukin-1
(IL-1), and tumor necrosis factor alpha (TNF-). Recent studies
indicates that this COX-2 continuous expression is involved
has a specific role in reproduction, renal physiology, resorption
bone, and neurotransmission. The COX-2 primary structure consists of 604
amino acid. 2
COX-3
o This enzyme is commonly present in the central nervous system and generally
inhibited by paracetamol (acetaminophen). 4
2.1.3 Definition of Prostaglandin
Prostaglandins (PG) is the end product of the metabolism of fatty acids are
produced
on the pathway physiology of COX enzymes. PG has long been known as a
mediator of physiology
and pathologies are important under various conditions. The conditions in it
there is a role of PG such as inflammation, pain, pyrexia, cancer, glaucoma,
dysfunction
sexual men, osteoporosis, cardiovascular disease, maternity, and asthma. 2 In
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in vitro evidence that prostaglandin E2 (PGE2) and prostacyclin (PGI2) in
the number of nanograms, causing erythema, vasodilation and increased blood
flow
local. 8
2. 2 NSAID Working Mechanism
When there is a cell damage or also an infection that can culminate
on cell damage, a special inflammatory process will occur. This process is initiated
by the human body as a form of protection, correction, and handling of
the damages that occurred. One of the initial mechanisms that occurs is
inlfamasi mediator release by leukocytes such as cytokines and eicosanoids. 5
Eicosanoid is a metabolite of the acid synthesized peripheral arakidonik
when there is inflammation. The effects of eicosanoids is the increase
an inflammatory process that is seen as a sign of redness, swelling, pain, and even
fever. Pain arises from the activation of sensory nerve fibers that culminate
on the pain sensation. Some inflammatory processes and infections will also be
followed by
the occurrence of fever (pyrexia) that occurs due to increased synthesis
prostaglandins in the thalamus as the thermoregulatory center in the central
nervous system. 5
Eicosanoids have various Subfamily such as thromboxane,
prostaglandin and leukotriene. Sub important class of eicosanoids is prostanoid
which includes various types of prostaglandins and thromboxane.
Prostanoid formed by the enzyme cyclooxygenase (COX) through the process of
oxygenation
fatty acid. One of the main types of thromboxane, which thromboxane A2 (TXA2)
commonly present in platelets and useful in the effectiveness of platelet
aggregation
which is important in controlling the wound and stopping the bleeding through
blood clots. Prostaglandins are important not only in the inflammatory process but
also in maintaining body homeostasis so it is important to remember
that inhibition of prostaglandin synthesis in some ways it is not good.
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There are various types of prostaglandins with different mechanisms of action
such as
for example PGI2 (prostacyclin), PGE2, PGD2 and PGF2 alpha. 4
During the inflammatory process, COX-1 mRNA and protein-protein activity are
not
experienced a moderate change in COX-2 that increased levels
also resulted in increased production of proinflammatory prostaglandins. Drugs
NSAIDs do not affect the process of tissue damage in a disease however
only prevent the symptoms arising from an increase in the production of
prostaglandins
this. 2
NSAIDs inhibit the enzyme cyclooxygenase (COX) so that the acid conversion
arachidonate to prostaglandins disturbed. Every drug inhibits
cyclooxygenase in different ways. NSAIDs that work as an insulator
COX will bind to the active part of the enzyme, on COX-1 and / or COX-2,
so this enzyme becomes malfunctioning and unable to alter the acid
arachidonic be inflammatory mediators prostaglandins (Figure 1). 1
Figure 1. Scheme of inflammatory mediator formation and its relationship with
working mechanism of NSAIDs. 5
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In addition to having anti-inflammatory effects, NSAIDs are also the top choice of
anti-
pain in daily medical practice. Anti-pain effects or also called analgesics
in NSAIDs is only effective against pain with low to moderate intensity,
such as headache, myalgia, arthralgia, dysmenorrhoea and also effective against
pain
which is associated with inflammation or tissue damage. The analgesic effect is
distant
weaker than opioate analgesic effects, but NSAIDs do not cause
addictive and do not cause adverse central side effects. When it happens
inflammation, pain may arise as a result of increased peripheral sensitization
resulting in a nociceptor response to a supposedly painless stimulus.
In particular, inflammation may also decrease the pain threshold of the noiseptor
polymodal. To induce an analgesic effect, NSAIDs work on the hypothalamus,
inhibit the formation of prostaglandins where inflammation occurs, and prevent
sensitization of pain receptors against mechanical or chemical stimuli. 4.5
Setting body temperature requires an accurate balance between forming
and heat loss. The body temperature control device is in the hypothalamus. On the
circumstances
This balance fever is disrupted but restored to normal by the drug
NSAIDs. Increased body temperature in pathological conditions begins the release
of a substance
endogenous pyrogens or cytokines eg IL1 which triggers the release of PG
redundant in the hypothalamic preoptic region then PGE2 later
cause fever. NSAID drugs suppress the effects of endogenous pyrogens by
inhibits PG synthesis. 10
The decrease in body temperature is associated with increased heat expenditure
due
widening of superficial veins. 7 Antipiresis may be accompanied by
formation of a lot of sweat. The fever that accompanies the infection is thought to
arise
due to two working mechanism, namely the formation of prostaglandins in the
fabric
central nervous system in response to pyrogenic bacteria and the presence of
interleukin-1 effects
in the hypothalamus. Aspirin and other NSAIDs inhibit both the pyrogens
induced by prostaglandin formation or central nervous system response
against interleukin-1 so that it can set back "thermostat" in the hypothalamus
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and facilitate the release of heat by way of vasodilation. 10 Chart on
the mechanism of action of NSAIDs as antipyretics in febrile states can be seen in
Figure 2.
Figure 2. The mechanism of action of NSAIDs as an antipyretic on pathological
fever. 10
As an antipyretic, NSAIDs will decrease body temperature only during fever. Drug
this does not affect body temperature if the body temperature rises by factors such
as exercise
or increased ambient temperature. Although most of the drugs are NSAIDs
show in vitro antipyretic effect, not all are useful as antipyretics
because it is toxic when used regularly or too long. It's related
with the hypothesis that COX exists in the central brain, especially COX-3 where
only
can be inhibited by paracetamol and some other NSAID drugs. 4
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2. 3 Classification of NSAIDs
NSAIDs are initially grouped by their chemical structure. Classification
which is now commonly used is grouping by selectivity
obstacles to the discovery of two forms of the enzyme cyclooxygenase -1 (COX-1)
and
cycloocygenase-2 (COX-2) as follows: 1.4
A.
Non-selective COX inhibitors (traditional NSAIDs)
Salicylate: aspirin
Propionic acid derivatives: ibuprofen, naproxen, ketoprofen, flurbiprofen
anthranilic acid derivatives: mefenamic acid
aryl-acetic acid derivatives: diclofenac, akeklofenak
Oxicam derivatives: piroxicam, tenoxicam
pyrrolo-Pyrrole Derivatives: ketorolac
Derivatives indole: indomethacin
Derivatives pyrazolone: phenylbutazone, oxyphenbutazone
B.
Preferential COX-2 inhibitors: nimesulide, meloxicam, nabumetone
C.
Selective COX-2 inhibitors: celecoxib, rofecoxib, etoricoxib, lumiracoxib,
parecoxib, valdecoxib
D.
Analgesic-antipyretic with low anti-inflammatory effect
Derivatives paraaminophenol: paracetamol (acetaminophen)
Derivatives pyrazolone: metamizole (dipyrone), propiphenazone
Derivatives benzoxazocine: nefopam
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Meanwhile, according to its half-life, NSAIDs can be divided into: 4
a. NSAIDs with short half-lives (3-5 hours): aspirin, flufenamic acid, acid
meclofenamate, mefenamic acid, niflumat acid, perrofenamat acid,
diclofenac, indomethacin, carprofen, ibuprofen, and ketoprofen.
b. NSAIDs with moderate half-life (5-9 hours): fenbufen and piroprofen.
c. NSAIDs with middle half-life (approx 12 hours), ie, diflunisal and
naproksen.
d. NSAIDs with a long half-life (24-45 hours): piroxicam and tenoxicam.
e. NSAIDs with very long half-lives (more than 60 hours): phenylbutazone
and oxifenbutazone
2. 4 Side Effects of NSAIDs
2.4.1 Side Effects of NSAIDs on Gastrointestinal
In the use of NSAIDs, the most common complaints arise from use
drugs are the reactions that affect the digestive tract, especially dyspepsia and
upper gastrointestinal bleeding. Gastrointestinal disorders resulting from
the use of NSAIDs shows varying severity ranges, from
from asymptomatic mucosal damage, pain-like complaints
abdomen, heartburn and dyspepsia, until gastrointestinal complications that are
as serious as the formation of ulcers or gastrointestinal bleeding that require
hospital treatment. 9 Estimated incidence of gastrointestinal complications
caused by the use of NSAIDs varies greatly. In general, at least
10-20% of patients taking NSAIDs will experience dyspepsia. In the patient
rheumatoid arthritis receiving NSAID therapy within 6 months,
about 5-15% of patients will discontinue use of NSAIDs due to complaints
dyspepsia. The mortality rate in patients treated in hospital due to experience
gastrointestinal bleeding due to NSAID use ranges from 5% to 10%. 3
In humans, COX-1 is continuously expressed along channels
gastrointestinal. Prostaglandins such as PGE2 and PG12, manufactured by
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COX-1, is known to have a cytoprotective effect on the gastrointestinal mucosa
with
how to reduce gastric acid secretion by parietal cells in the stomach, increase
mucosal blood flow, and stimulates mucus expenditure. Traditional NSAIDs
has a working mechanism that inhibits COX, in which case the side effects on
gastrointestinal due to gastroprotective PG inhibition
produced by the pathway of physiology COX-1. 1
It is quite helpful in the provision of NSAIDs is the availability of preparations
selective COX-2 inhibitors developed and used to reduce
toxicity of the gastrointestinal tract. 1 Selective COX-2 inhibitors developed into a
an effective anti-inflammatory agent that has gastrointestinal side effects
lower thanks to its ability to selectively inhibit COX-2 without
impact on COX-1. 2 Celecoxib and refecoxib that specifically inhibit
COX-2 shows minimal side effects on the gastrointestinal tract
diclofenac, naproxen and ibufrofen. However, this effect is meaningful only on
short-term use for less than six months. 12
Thus, the use of NSAIDs in patients with a history of the disease or
certain gastrointestinal conditions, such as patients with a history of gastritis or
peptic ulcer, should be avoided. 1 It should be noted that the choice of drug
also affect the frequency and intensity of gastrointestinal disturbances
inflicted. Ibuprofen is an NSAID drug with a risk of channel interference
the lowest digestibility. Diclofenac, naproxen, and indomethacin have risks
the same gastrointestinal disorders but higher than ibuprofen. Ketoprofen and
piroxicam has the highest risk of causing gastrointestinal disorders. 3 On
long-term use of diclofenac is still safer than
celecoxib. 1
2.4.2 Side Effects of NSAIDs on Kidney Function
Continuous use of NSAIDs will also have an impact on physiological function
kidney. This is related to the effect of decreased blood flow in the kidneys
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by long-term use of NSAIDs. PG12 and PGE2 will physiologically
triggering vasodilatation thus improving renal blood flow as well as maintaining
rate
kidney glomerular filtration. Inhibition of prostaglandin by NSAID will trigger
vasoconstriction of the kidney, decreases renal blood flow, so eventually it will
interferes with the kidney function itself. 11
Some types of prostaglandin (PG) has functions in regulating vascular tone
and maintain normal blood flow, in other words also play a role in
maintain renal physiological function. Research on animals with kidney disease,
patients
congestive heart disease, liver cirrhosis, and renal insufficiency show that
PGE2 is specifically responsible for maintaining normal function
kidney. In humans, COX-1 is continuously produced in the kidney vasculature,
collective ducts, and the loop of Henle; whereas COX-2 is expressed
sustained in macula densa, epithelial cells that coat the loop of the part Henle
ascending and medial interstitial cells of the renal papillary. COX-2 enzyme has a
role
in normal kidney development and proven in cases where deficiency
COX-2 in experimental mice will lead to severe nephropathy. 8
The use of NSAIDs is also reported to trigger sodium retention so that at
will eventually increase blood pressure. Studies show that
Sodium retention due to NSAIDs in healthy or elderly individuals is associated
with
the presence of COX-2 inhibition, while decreased renal filtration rates were
associated with
the inhibition of COX-1. Recent studies indicate that compared
with selective COX-2 inhibitors, the use of refecoxib is associated with
increased risk of kidney disease and arrhythmias. 2
2.4.3 Side Effects of NSAIDs on Cardiovascular
In recent decades, studies have reported an increase
incidence of myocardial infarction and other thrombotic diseases during a
treatment
using selective COX-2 inhibitors as well as non-selective NSAIDs. 10 terms
the study of molecular pharmacology is known that COX-2 is needed deeply
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maintain heart health. In the study of Shinmura et al concluded that COX
-2 is cardioprotective protein, so if the activity of COX-2 is inhibited will
resulting in an increase in cardiovascular events. Besides the obstacles
against COX activity will decrease the production of vasodilator prostaglandin
so there is no mediator capable of overcoming the effects of vasoconstrictors
catecholamines, which consequently will increase the patient's blood pressure. 1
Further studies conclusively show that COX-2 inhibitors
shown to interfere with the natural balance between
prothrombotic thromboxane A2
(TXA2) and antithrombotic prostacyclin (PGI2), which could increase
the possibility of a thrombotic cardiovascular problem. On the moon
April 2005, the United States Food and Drug Association (FDA)
unequivocally concluded that the drugs increase the risk of coxibs group
the onset of cardiovascular problems. The basis of this statement is that of PG12
is a potent vasodilator and inhibitor of platelet aggregation produced
by COX-2 in places where an inflammation occurs. Therefore,
the use of COX-2 inhibitors, which leads to inhibition of PG12 formation, would
increases the risk of developing cardiovascular disease such as infarction
myocardial. However, celecoxib is still allowed to be marketed on a regular basis
medical, but is accompanied by the warning category of black (black box
warning) the
indicating a risk of cardiovascular problems. Furthermore,
The FDA also even suggests to other NSAID manufacturers in general
to include warning labels that possible cardiovascular problems
into a common side effect that can occur in any type of drug inside
class of NSAIDs. 2 In connection with its effect on cardiovascular, use
NSAIDs in patients with hemophilia and who are treated with anti-inflammatory
drugs
coagulant should be avoided. Besides the use in patients with the condition
of overload
fluid or heart failure should be avoided, given the effects of sodium retention
and water and the possibility of causing edema in the use of NSAIDs. 1
A study states that the use of NSAIDs for 15-30 days will
increases the risk of atrial fibrillation when compared with individuals
which does not consume NSAIDs. It is estimated that this is related to
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working menkanisme NSAIDs inhibit the enzyme cyclooxigenase
expressed in the kidneys. This enzyme inhibition may eventually cause
increased blood pressure due to fluid retention, increased vascular resistance
blood peripheral, and weaken the work effect of diuretic and antihypertensive
drugs. 8
2.5 Examples of NSAIDs
2.5.1 Paracetamol
Pharmacodynamic Paracetamol
Paracetamol is an NSAID class of acetaminophen and is an NSAID
which has no anti-inflammatory effect. Paracetamol is hepatotoxic
sehinggai should be combined with glutlhation for antioxidant effects. Effect
hepatotoxicity will occur after long-term use is due
paracetamol to form reactive which can damage the liver cells. as an antidote
paracetamol poisoning can be given n-acetylcystein and metionine. Need
also note the possibility of the emergence of allergic reactions are quite frequent
happening to cause Steven Johnson syndrome. 13
Paracetamol in its working mechanism does not interfere with platelet function and
it does not
affect the level of uric acid in plasma and excretion. Therefore,
paracetamol may be a substitute drug for analgesic and antipyretic effects
aspirin and other NSAIDs if they are contraindicated in
patient. Paracetamol is also the primary choice of atypical agents in pediatric
patients
to reduce the risk of Reye's syndrome. 14
Farmakinetik Paracetamol
The dose of paracetamol for adults is 3-4 grams per day divided by 3-4
dose. The dose of paracetamol for pediatric patients is 60mg / kgBW / day divided
in 3-4 doses. Further paracetamol dosage formulations can be seen in Table 1.
The maximum dose of paracetamol for adults is 4g / day and 80mg / kgBW / day
for pediatrics. 17
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The metabolism of paracetamol requires liver enzymes, especially through the
process
glucuronidation conjugation. Paracetamol is metabolized by cytochrome P450
enzymes
and then will produce a toxic metabolite N-acetyl-p-benzoquinoneimine
(NABQI) which will be eliminated through conjugation of glutathione (GSH).
This conjugation will change NABQI be mercapturic the conjugate acid
then it can be excreted through the kidneys. However, when paracetamol is
consumed
orally in large quantities, especially in alcoholic patients, will occur
NABQI toxic metabolite accumulation. This buildup will deplete the availability
Gluthatione so metabolite finally able to interact with proteins in the kidney
and liver that will trigger hepatic cell death. Thus, it can be said
that liver necrosis is an effect of paracetamol overdose. About 10 grams
(20 tablets) of paracetamol or 150 mg / kgBW taken together
deadly impact, for example in cases of attempted suicide. 14
Table 1. Paracetamol dosage formulation. 17
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Figure 3. Examples of drugs containing paracetamol are sold freely.
2.5.2 Mefenamic Acid
Pharmacodynamic Acid Mefenamat
The mefenamic acid is known as anti-inflammatory, analgesic, and active
antipyretic on
animal studies. The mechanism of action of mefenamic acid, the same as other
NSAID drugs
that is generally associated with inhibition of prostaglandin synthesis. Acid
mefenamat interacts with oral anti coagulant drugs such as warfarin, asetosal
(aspirin), diuretics, methotrexate and insulin. Giving these drugs together
with mefenamic acid should be avoided. 12
Pharmacokinetics of Mefenamatic Acid
Recommended dose of mefenamic acid for handling acute pain at
adults and children over the age of 14 years is 500mg as a dose
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an initial resumption of 250mg per 6 hours if required, with no use exceeding
1 week. To reduce unwanted gastrointestinal side effects,
oral administration should coincide with food. 18 Mefenamic acid very
quickly absorbed after oral administration. In twice 500 mg oral dose
studied, showing an area of absorption of 30.5 mcg / hr / mL. Based on 1 gr
single oral dosage, plasma peak levels can be achieved from 10 to 20 mcg /
mL3. The plasma peak level starts from 2 to 4 hours and half-life elimination
approx 2 hours. 11
Figure 4. Examples of drugs containing free-sized mefenamic acid.
2.5.3 Ibuprofen
Pharmacodynamics Ibuprofen
Ibuprofen is only effective against pain with low to moderate intensity, and
effective against pain related to inflammation or tissue damage. Effect
the analgesic is much weaker than the opioate analgesic effect, but it is not
addictive and do not cause central side effects
dis advantageous. Ibuprofen is an NSAID with the least side effects
than all other NSAIDs. Side effects on gastrointestinal as well
reported as the lowest because of the half-life of ibuprofen
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low. To produce an analgesic effect, ibuprofen works on the hypothalamus,
inhibit the formation of prostaglandins place of occurrence of inflammation, and
prevent
sensitization of pain receptors against mechanical or chemical stimuli. 12
Ibuprofen will lower body temperature only in a state of fever. The fever
accompanying infection is thought to arise as a result of two mechanisms of action,
ie formation
prostaglandins in the central nervous system in response to bacterial pyrogens
and the presence of interleukin-1 effects in the hypothalamus. Ibuprofen inhibits
both pyrogen
induced by prostaglandin formation or central nervous system response
against interleukin-1 so that it can set back "thermostat" in the hypothalamus
and facilitate the release of heat by way of vasodilation. 12
Ibuprofen can be used in musculoskeletal treatment such as arthritis
rheumatoid, osteoarthritis, and ankylosing spondylitis. However, ibuprofen only
alleviate pain and inflammatory symptoms associated with the disease
symptomatic, does not stop, repair, or prevent tissue damage
in musculoskeletal disorders. 11.12
Pharmacokinetics Ibuprofen
As an anti-inflammatory, the inflammatory effect of ibuprofen is achieved when
the use
at doses of 1200-2400 mg / day. Fast absorption of ibuprofen through the stomach
and levels
maximum in plasma is achieved after 1-2 hours. Half time in plasma is about
2 hours. Nearly most (90%) ibuprofen is bound to plasma proteins. Onset
ibuprofen work is felt after about 30 minutes. The duration of ibuprofen ranges
from
6-8 hours. The absorption of ibuprofen if given orally reaches 85%. Metabolites
primarily the result of hydroxylation and carboxylation metabolized in the liver.
Ibuprofen excretion is fast and complete. Approximately 90% of the dose
absorbed will be excreted through the urine as a metabolite or conjugate (1% as
drug free), some also excreted through the feces. Ibuprofen will enter the room
synovial with slow. Concentrations of ibuprofen will accumulate higher in space
synovial than in plasma. 13
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The available combination preparation is a combination of ibuprofen with
paracetamol; ibuprofen with paracetamol and caffeine; and ibuprofen with
Vitamin B6 and B12 B6. Low-dose Ibuprofen (200 mg and 400 mg) are numerous
available. Ibuprofen has a dose-dependent duration of about 4-8 hours, which is
more
longer than recommended from half-life. 13 As an analgesic and antipyretic doses
ibuprofen for adults is 1200-1800 mg / day divided in 3-4 doses, whereas
for paediatrics over 3 months is 30 mg / kg / day divided into 3
dose. For the treatment of rheumatoid arthritis (RA), the maximum dose for an
adult
recommended is up to 3200mg / day and 40mg / kgBB / day for paediatrics. 17
Further dosage formulations of ibuprofen can be seen in Table 2. Total
consumption
the maximum ibuprofen for an adult is 800 milligrams per dose or 3200
mg per day (4 maximum doses). 17 Dose Ibuprofen 5-10 mg / kg with intervals
giving 4-6 hours, reducing fever 15% faster than paracetamol
dose of 10-15 mg / kgBW. 13
Table 2. Formulation of ibuprofen dosage. 17
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Figure 5. Examples of over-the-counter medicines containing ibuprofen.
2.5.4 Diclofenac Sodium
Pharmacodynamic Sodium Diclofenac
Sodium Diclofenac works by blocking enzymes that cyclooxigenase
prostaglandin formation is inhibited. This NSAID is the type that can
accumulates in the synovial so that it is used for the treatment of all types of
arthritis. Drug
this is contraindicated in patients with hypertension, heart failure, and
renal disease due to these patients require a restriction condition
sodium. 11
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Pharmacokinetics Sodium Diclofenac
The recommended initial dosage of diclofenac sodium is 75-150 mg / day. For
Long-term treatment, the recommended dose is 75-100 mg / day. Oral dosage
this is divided in 2 or 3 doses per day. 19 Sodium diclofenac can be absorbed
fast and complete and the amount absorbed does not decrease when given together
with food. The peak drug levels are achieved in -1 hours. Bond protein
ranging from 99.7% with a half-life of 1-2 hours. Administration of recurrent doses
of sodium
diclofenac does not cause any accumulation. Elimination and its expression
primarily
through urine. In addition to the oral dosage form, diclofenac sodium is also
available
in the form of injection, suppository, patch paste, and cream. 13.11
Figure 6. Examples of drugs containing free-selling diclofenac sodium.
2.5.5 Meloxicam
Pharmacodynamics Meloxicam
Meloxicam is used to treat pain, swelling and pain
caused by inflammation of osteoarthritis and rheumatoid arthritis. Work
mechanism
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of meloxicam is cyclooxigenase enzyme inhibition (COX). Side effects
the most common is the induction of peptic ulcer or peptic ulcer
sometimes accompanied by anemia secondary to chronic gastrointestinal bleeding.
The mechanism of gastric irritation is localized irritation
causing back diffusion of stomach acid into the mucosa and causing damage
network. 12
Meloxicam Pharmacokinetics
For the treatment of osteoarthritis, the recommended dose of meloxicam is 7.5 mg /
day and if necessary can be increased up to 15 mg / day. For handling
rheumatoid arthritis, the recommended dose is 15 mg / day and can be reduced to
7.5 mg / day when the desired therapeutic response has been obtained. Maximum
dose on
of adult patients is 0.25 mg / kgBW / day. 20 Distribution of meloxicam is bound to
proteins
human plasma (especially albumin) in the therapeutic dose range. Faction inside
binding proteins does not depend on the concentration of the drug, during the
concentration range
clinically relevant, but decreased in patients with kidney disease.
Its oral biovaibility is 89% with the maximum concentration obtained in 4-5
hour. The concentration of meloxicam in synovial fluid after a single oral dose,
ranges
between 40% to 50% of what is in plasma. Fraction free in the liquid
synovial is 2.5 times higher than in plasma, because of the content
albumin is low in synovial fluid compared with plasma. Meloxicam
metabolized up to four active biological metabolites and excreted in the urine
and faeces. The half-life of meloxicam elimination is about 20 hours. This is
reflected
of total plasma clearance, ie 7-8 ml / min. 12
Meloxicam is well absorbed in oral administration; and absorption unchanged /
influenced by food. However, meloxicam may irritate the mucosa
stomach so it is better if consumed with food to mengutangi
gastrointestinal side effects. 13
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Figure 7. Examples of drugs containing meloxicam sold in Indonesia.
23
Original Indonesian text:
Gambar 6. Contoh obat-obatan mengandung natrium diklofenak yang dijual bebas.
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