Non Steroidal Anti / Orthodontic Courses by Indian Dental Academy

ANTI-INFLAMMATORY
DRUGS ( NSAIDs)
NON STEROIDAL

INDIAN DENTAL ACADEMY

Leader in continuing dental education
www.indiandentalacademy.com

Pain is perfect misery, the worst of evils,
and excessive, overturns all patience.
John Milton (1608- 1674) Paradise Lost.
One of the greatest services doctors can do
their patients is to acquire skill in the
management of pain.
Pain management in dental patients is
individualized according to the quality of the
pain, its severity, cause and chronicity. Pain
arises when there is a noxious stimulus to the
tissues as the result of destruction or injury.
Such trauma can occur by means of a disease
process, formation of an abscess, or through
surgical intervention or extraction of a tooth.
Dental pain is best managed by selecting a
pharmacologic agent from one of the three
widely used groups.

Local anesthetic

Peripherally acting analgesics

Narcotic and opiates
Bark of willow tree was used in folk medicine
for years for mild pain and fever. Salicylic acid
was obtained by hydrolysis of the bitter
glycoside obtained from this plant. The active
ingredient of willow bark was salicin which on
hydrolysis yields salicylic acid which was later
found in other natural sources.

Acetylsalicylic acid was synthesized in 1853

1875 sodium salicylate was used in fever and
pain.

1899 it was found to be effective in arthritis and
was well tolerated.
NSAIDs are weak analgesics. They are also
called as non narcotic / non opoid analgesics or
aspirin type or antipyretic analgesics. They
have anti-inflammatory, antipyretic (reduce the
elevated body temperature). They have
uricosuric properties antiplatelet activity to
varying degrees. They do not depress the CNS,
do not produce physical dependence and have
no abuse liability. These drugs are chemically
diverse, but most are organic acids.
PROSTAGLANDINS
Prostaglandins are naturally occurring substances
composed of fatty acids found throughout body
tissues. Prostaglandins and Leukotrienes are
biologically active derivatives of 20 carbon atom,
poly unsaturated essential fatty acids that are
released from cell membrane phospholipids.
Prostanoic acid
IN 1930S human semen was found to
contract isolated uterine and other smooth
muscle strips and to cause fall in blood
pressure in animals. The active principle was
termed prostaglandin thinking it was derived
from prostrate.

BIOSYNTHESIS OF PROSTAGLANDINS
BENEFICIAL ACTION DUE TO PROSTAGLANDIN
SYNTHESIS INHIBITION.
Analgesia : prevention of pain nerve ending
sensitization
Antipyresis: reduces the elevated body
temperature
Anti-inflammatory
Anti-thrombotic
Closure of ductus arteriosus.
SHARED TOXICITIES DUE TO
PROSTAGLANDIN SYNTHESIS INHIBITION
Gastric mucosal damage
Bleeding : inhibition of platelet function
Limitation of renal blood flow : Na
+
and water
retention.
Delay / prolongation of labor
Asthma and anaphylactoid reaction in
susceptible individuals

PAIN is an unpleasant sensory and emotional
experience associated with actual or potential
tissue damage.
Pain is mainly a protective mechanism for the
body ; it occurs whenever any tissue are being
damaged , and it causes the individual to react
to remove the pain stimulus.
Pain has been classified into two major types:
fast pain and slow pain. Fast pain is felt
within about 0.1 second after a pain stimulus
is applied, whereas slow pain begins only
after 1 second or more and then increases
slowly over many second and sometimes
even minutes. The pain receptors in the skin
and other tissues are all free nerve endings.
They are widespread in the superficial layers of the
skin as well as in certain internal tissues, such as
the periosteum, the arterial walls, the joint
surfaces, and the falx and tentorium of the cranial
vault. Most other deep tissues are sparsely
supplied; still summate to cause the slow-chronic
aching type of pain in these areas are elicited by
multiple types of stimuli. They are classified as
mechanical, thermal, and chemical pain stimuli.
Fast pain is elicited by the mechanical and
thermal types of stimuli, whereas slow pain can
be elicited by all three types .
The fast-sharp pain signals they are transmitted
in the penpheral nerves to the spinal cord by
small type A fibers at velocities between 6 and
30 m/sec. On the other hand, the slow: chronic
type of pain is specially elicited by the chemical
type of pain stimuli but also at times by
persisting mechanical or thermal stimuli; this
slow-chronic pain is transmitted by C fibers at
velocities of between 0.5 and 2m/sec.
Because of this double system of pain
innervations, a sudden onset of painful
stimulus often gives a double pain sensation a
fast-sharp pain that is transmitted to the brain
by the A fiber pathway followed a second or
so later by a slow pain that is transmitted by
the C fiber pathway.

On entering the spinal cord from the dorsal
spinal roots, the pain fibers terminate on
neurons in the dorsal horns. On entering the
spinal cord the pain signals take two pathways
to the brain. Through the neospinothalamic
tract and through the paleospinothalamic tract.
The fast type A pain fibers transmit mainly
mechanical and acute thermal pain. They
terminate mainly in lamina I (laimina marginalis)
of the dorsal horn, and there excite the second
order neurons of the neospinothalamic tract
these give rise to long fibers that cross
immediately to the opposite side of the cord
through the anterior commissure and then pass
upward to the brain in the anterolateral
columns.
Few fibers of the neospinothalamic tract
terminate in the reticular areas of the brain
stem, but most pass all the way to the
thalamus, terminating in the ventrobasal
complex. A few also terminate in the posterior
nuclear group of the thalamus. From these
areas the signals are transmitted to other
basal areas of the brain and to the somatic
sensory cortex.
The paleospinothalamic pathway transmits pain
mainly carried in the peripheral slow-chronic
type C pain fibers; although it does transmit
some signals from type- A fibers as well. In
this pathway, the peripheral fibers terminate
almost entirely in laminas II and III of the dorsal
horn which together are called substantia
gelatinosa .Most of the signals then pass
through one or more additional short fiber
neurons within the dorsal horns themselves
before entering laminas V through VIII, also in
the dorsal horn.
Here the last neuron in the series gives rise to
long axons that mostly join the fibers from the fast
pathway, passing first through the anterior
commissure to the opposite side of the cord and
then upward to the brain in the same anterolateral
pathway. The slow-chronic paleospinothalamic
pathway terminates widely in the brainstem. Only
one-tenth to one fourth of the fibers passes all the
way to the thalamus.
Instead, they terminate principally in one of
three areas: (1) the reticular nuclei of the
medulla, pons, and mesencephalon; (2) the
tectal area of the mesencephalon deep to the
superior and inferior coliculli; or (3) the
periaqueductal gray region surrounding the
aqueduct of Sylvius

Glutamate, the neurotransmitter of the Type A
Fast Pain Fibers.
Type C pain fiber terminals entering the spinal
cord might secrete both glutamate transmitter
and substance P transmitter. The glutamate
transmitter acts instantaneously and lasts for
only a few milliseconds. On the other hand,
substance P is released much more slowly,
building up in concentration over a period of
seconds or even minutes
Prostaglandins particularly PGE and PGI
produce hyperalgesia associated with
inflammation. Prostaglandin alone induces
pain only in concentration that is unlikely to
occur physiologically. However they enhance
the potency of algesia (pain inducing)
substances by sensitizing the nerve endings
of of unmyelinated C fibers and small diameter
A fibers endings to other mediators such as
bradykinin and histamine Furthermore
bradykinin eliminates formation and release of
prostaglandins and a positive feed back of
sort.
FEVER which means a body temperature
above the usual range of normal can be caused
by abnormalities in the brain itself or by toxic
substances that affect the temperature
regulatory centers.

Body temperature between 99F (37.22C ) and
105F(40.57C) and onwards is called PYREXIA.

Rise of body temperature above 107F (41.66C)
is called HYPERPYREXIA. www.indiandentalacademy.com
Regulation of body temperature require a
delicate balance between production of heat
and loss of heat and the hypothalamus
regulates the set point at which body
temperature is maintained.

FEVER PRODUCTION
Many proteins, breakdown products of
proteins and certain other substances esp.
lipopolysaccharide toxins released from
bacterial cell membrane cause the set point of
the hypothalamic thermostat to rise.
Substances that cause this effect are called
pyrogens. The pyrogens can act directly on
the hypothalamic temperature regulating
centre to increase its set point. It can act
indirectly and may require several hours of
latency before causing their effect.
When bacteria or breakdown products of
bacteria are present in the tissues or the
blood, they are phagocytized by the blood
leukocytes, tissue macrophages and large
granular killer lymphocytes. All these cells in
turn digest the bacterial products and then
release into the body fluids the substance
interleukin1(cytokines) which induces the
formation of prostaglandin in vascular organs
in the preoptic hypothalamic area.
Prostaglandin (PGE
2
) produced acts on the
hypothalamus to elicit fever reaction.
When the set point of the hypothalamic
temperature regulating centre becomes
increased to a higher level than normal all the
mechanisms for raising the body temperature
are brought into play, including heat
conservation . The temperature is increased to
the new set point (higher level) and the body
temperature also approaches this level.

Anti-pyretic action of NSAIDs is central. In
fever the temperature regulating system
maintains temperature at a higher level
than normal. The stimulus for the shift to a
higher level is the action of endogenous
pyrogens such as interleukin 1 on neurons
of the thermoregulatory system in the
preoptic hypothalamus. NSAIDs it reduces
the effect of pyrogen.
NSAIDs reduces elevated temperature by
increased dissipation of heat caused by
vasodilatation of superficial blood vessels.
The antipyresis may be accompanied by
profuse sweating. NSAIDs block both the
pyrogen induced production of prostaglandin
and the central nervous system response to
interleukin 1 and so may reset the
temperature control in the hypothalamus
thereby facilitating heat dissipation.
Therapeutic doses of aspirin affect neither
normal body temperature nor an elevated
temperature associated with exercise, drugs
or hypothalamic lesions as there is no
pyrogen and no production of interleukin 1.

INFLAMMATION
Inflammation is defined as the local
response of living mammalian tissue to
injury due to any agent. It is a body defense
reaction in order to eliminate or limit the
spread of injurious agent. The word
inflammation means burning.
Signs of inflammation
Roman writer Celsus in 1st century AD
named the famous four cardinal signs of
inflammation.
Rubor (redness)
Tumor (swelling)
Calor (heat)
Dolor (pain)
Fifth sign function laesa (loss of function)
was later added by Virchow.
Types of inflammation
Acute and Chronic Inflammation.

Changes in acute inflammation
Vascular changes Cellular events
1.Haemodynamic changes 1. Exudation of leucocytes
2.Vascular Permeability 2. Phagoctosis
Chemical mediators of inflammation also
called as permeability factors or endogenous
mediators of increased vascular permeability
.These are a large and increasing number of
endogenous compounds which can enhance
vascular permeability. The substance acting
as a chemical mediator of inflammation may
be released from the cells, the plasma or
damaged tissue itself. They are broadly
classified into 2 groups.
Mediators released by cells
1. Vasoactive amines (histamine, 5-hydroxytryptamine)
2. Arachidonic acid metabolite
a. Metabolite via cyclo-oxygenase pathway
Prostaglandin, ThromboxaneA2, Prostcyclin
b. Metabolite via lipo-oxygenase pathway
5HETE, Leukotrienes
c.Metabolite via non-enzymatic pathway
Chemotatic lipid
3. Lysosomal components
4. Platelet activating factor.
5. Cytokines (interleukin I, tumor necrosis factor)
Mediators originating from plasma
The kinin system
The clotting system
The fibrinolytic system
The complement system. www.indiandentalacademy.com
NSAIDs reduce the synthesis of eicosonoid
mediators of inflammation; it also interferes
with chemical mediators of kallikerin system.
As a result inhibits granulocyte adherence to
damage vasculature, stabilizes lysosmes and
inhibits the migration of ploymorphonuclear
leukocytes and macrophages into the site of
inflammation.
CLASSIFICATION OF NSAIDs

A. Analgesic and anti-inflammatory

B. Analgesic but poor anti-inflammatory

1 Paraaminophenol
derivative
2 Pyrazolone derivatives
3 Benzoxazocine
derivative
1 Salicylates
2 Pyrazolone derivative

3 Indole derivatives
4 Propionic acid derivatives

5 Anthranilic acid derivative
6 Aryl-acetic acid derivatives

7 Oxicam derivatives
8 Pyrrolo-pyrrole derivative
9 Sulfonanilide derivative
10 Alkanones
SALICYLATES --- (Aspirin- protype)
(Aspirin, Salicylamide, Benorylate, Diflunisal)
The name aspirin was coined from
German word for the compound
acetylspirsaure (spirea, the genus of
plants from which it was obtained and
saure, the German word for acid)
Sodium salicylate
Aspirin Methyl salicylate
Apirin is acetylsalicylic acid. It is rapidly
converted in the body to salicylic acid which
is responsible for most of the actions. It is
one of the oldest analgesics anti-
inflammatory drugs and still is widely used.

PHARMACOLOGICAL ACTIONS
-Analgesic, antipyretic, anti-inflammatory actions
Aspirin is a weaker analgesic than morphine type
drugs: aspirin 600 mg ~ codeine 60 mg. It relieves
inflammatory, tissue injury related, connective tissue
and integumental pain but is relatively ineffective in
severe visceral and ischemic pain. The analgesic
action is mainly due to obtunding of peripheral pain
receptors and prevention of PG mediated
sensitization of nerve endings. A central sub cortical
action raising threshold to pain perception also
contributes, but the morphine like action on psychic
processing or reaction component of the pain is
missing. No sedation, subjective effects, tolerance or
physical dependence is produced.
Aspirin resets the hypothalamic thermostat and
rapidly reduces fever by promoting heat loss
(sweating, cutaneous vasodilatation), but does not
decrease heat production.
Anti-inflammatory action is exerted at high doses (3-
6 g/day or 100 mg/kg/day). Signs of inflammation
like pain, tenderness, swelling, and vasodilatation
and leukocyte infiltration are suppressed. However,
the progression of the underlying disease in
rheumatoid arthritis, rheumatic fever and
osteoarthritis etc. is not affected.
2. Metabolic effects- These are significant only
at anti-inflammatory doses. Cellular metabolism is
increased, specially in skeletal muscles, due to
uncoupling of oxidative phosphorylation by
salicylates leads to conversion of a large part of
energy derived from oxidation into heat production.
Large doses of salicylates may lead to hyperpyrexia.
Increased protein catabolism leading to
aminoaciduria and a negative nitrogen balance.
Large doses of salicylates produce hyperglycemia
and gylcosuria in normal individuals this is due to
central sympathetic stimulus- release of adrenaline
and gluccocorticoids.
3. Respiration
Salicylates stimulate respiration as a result of direct
and indirect action. As a result of their action on the
mitochondria, at anti-inflammatory doses of salicylate
increase the consumption of oxygen primarily by the
skeletal muscles. This results in increased production
of CO
2
. Increased production of CO
2
production leads
to a direct stimulation of the respiratory centre
producing an increase in depth and to some extent in
the rate of respiration. With the entry of salicylates
into the brain, the medullary respiratory centre is
stimulated directly. In addition, it also stimulates the
chemoreceptors.
This produces an increase in the rate as well
as the depth of respiration leading to
hyperventilation. Hyperventilation is
prominent in salicylate poisoning. Further rise
in salicylate level causes respiratory
depression; death is due to respiratory failure
4. Acid-base and electrolyte balance
The respiratory alkalosis produced by the
anti-inflammatory doses is countered by the
excretion of alkaline urine containing
bicarbonate along with sodium and
potassium. This is termed the stage of
compensatory respiratory alkalosis.
Reduction in the bicarbonate and potassium
levels reduces the buffering capacity of the
extracellular fluids and a patient on aspirin
therapy is prone to develop acid-base
imbalance .
Hypokalemia as a result of urinary loss of
potassium is accompanied by water loss through
lungs due to hyperventilation through the skin via
augmented sweating and through urine as a result
of alkalosis .This may lead to dehydration and
hypernatremia. With acute doses of salicylates
hypokalemia is aggravated, the respiratory centre is
depressed. With CO
2
retention and excess CO
2

production continues leads to respiratory acidosis .
To this are added dissociated salicylic acid as well as
metabolic acids (lactic, pyruvic, acetoacetic) which
are produced in excess and metabolically derived
sulfuric and phosphoric acid which are retained due
to depression of renal function. These entire
combine to cause uncompensated metabolic acidosis
since plasma HCO3
-
is already low. Dehydration
occurs in poisoning due to increased water loss in
urine (to accompany Na
+
, K
+
and HC03
-
) increased
sweating and hyperventilation.
6. Gastrointestinal tract the ingestion of
salicylates may produce dyspepsia, nausea,
vomiting as a result of gastric irritation by the
released salicylic acid.
Aspirin (pKa 3.5) remains unionized and diffusible
in the acid gastric juice, but on entering the
mucosal cell (pH 7.1) it ionizes and becomes
indiffusible. This 'ion trapping' in the gastric
mucosal cell enhances gastric toxicity. Further local
absorption into the mucous cell causes inhibition of
prostaglandin synthesis , thus causing a loss of
protective effect on the stomach. Salicylates also
reduce the motility of the stomach and increases
the gastric emptying time. These effects increase
the period of contact of salicylates with the gastric
mucosa.
To avoid gastric irritation salicylate may be administered
- with plenty of water after food
- With milk
- With an alkali such as sodium bicarbonate
- As a soluble buffered aspirin
- With a prostaglandin analogue
Alkali induces the ionization of salicylates thereby
reducing their gastric absorption and local irritant effect.
As the ionized salicylate is more water soluble, it tends
to pass more quickly into the intestine and does not
adhere to the mucous membrane of the stomach.
7. Blood- Aspirin, even in small doses irreversibly
inhibits TXA
2
synthesis by platelets. Thus it
interferes with platelet aggregation and bleeding
time is prolonged to nearly twice the normal value.
This effect lasts for about a week (turnover time of
platelets). Long term use of large dose decreases
synthesis of clotting factors in liver and predisposes
to bleeding.
This can be detrimental in patients scheduled for
surgery. Bleeding time can be prolonged for a week.
Thus aspirin should not be used in presurgical dosing
for its analgesic effect. Recent evidence shows that a
dose of one aspirin daily can prevent myocardial
infarction and or cerebrovascular accident due to
clots initiated by the same mechanism.

8. Uricosuric effects- Urate present in the
glomerular infiltrate is reabsorbed by the proximal
tubules of the kidney and the main excretion of
urate in urine occur due to its secretion by the
distal tubule. Salicylates exhibit biphasic action on
the excretion of urate. In small doses (1-2g per
day) salicylate interferes with urate secretion by
the distal tubule, thereby elevating the plasma
urate level. The high doses of salicylates (over 5g
per day) inhibit the reabsorption of urate by
proximal tubule which can cause uricosuria.
6. CVS -Aspirin has no deleterious effect in
therapeutic doses. Larger doses increase cardiac
output to meet increased peripheral O
2
demand and
cause direct vasodilatation. Toxic doses depress
vasomotor centre: BP may fall. Because of increased
cardiac work and Na
+
water retention, CHF may be
precipitated in patients with low cardiac reserve.
Pharmacokinetics-
Salicylates are absorbed from the stomach and
largely from the upper part of the small intestine.
On oral administration of a single
therapeutic dose, appreciable plasma
concentrations are found within 30 minutes,
peak plasma level is achieved within 2 hrs
and approximately 50% of the dose is
eliminated in urine within 24hrs. The plasma
half-life ranges from 2-8 hrs. Factors such as
particle size, pH of the GIT, solubility of the
salicylate preparation, presence of food in
the stomach modify the absorption.
Both salicylate and salicylic acid are absorbed
from intact skin, esp. when applied with
alcohol, petrolatum, lard or lanolin base and
systemic poisoning in children has been
reported following such local application.
Aspirin is rapidly deacetylated in the gut wall,
liver plasma and other tissues to release
salicylic acid which is a major circulating and
active form.

After absorption, approx. 80% of the
salicylate is bound to plasma proteins mainly
albumin. It is rapidly distributed through
most of the tissues and achieves a significant
concentration in the saliva, milk, spinal,
sensorial and peritoneal fluids and in the
erythrocytes.
Salicylates are mainly metabolized in the liver
and excreted in the urine in the form of
conjugate with glycine and glucuronic acid. A
small portion is oxidized to gentisic acid and
excreted in the urine. High salicylate
concentrations are observed in the liver, heart
and muscle while brain contains relatively
smaller amounts.

Adverse Effects

Side effects that occur at analgesic dose (0.3-1.5
g/day) are nausea, vomiting, epigastric distress,
increased occult blood loss in stools. The most
important adverse effect of aspirin is gastric
mucosal damage and peptic ulceration.

Hypersensitivity and idiosyncrasy though
infrequent, these can be serious. Reactions
include rashes, fixed drug eruption, urticaria,
rhinorrhoea, angioedema, asthma and
anaphylactoid reaction. Salicylates induced
angioedema and anaphylaxis like reaction
respond to adrenaline .Aspirin can induce
idiosyncratic mild haemolysis in individuals with
glucose 6 phosphate dehydorgenase deficiency
(G6PD).

GIT the commonest side effects of salicylates
and other NSAIDs are dyspepsia, nausea,
vomiting and heartburn. Therapeutic doses of
aspirin may irritate gastric mucosa and increases
the blood loss in majority of persons without
obvious symptoms. A nonacetylated salicylate may
be less irritating, should be avoided in patients
with a history of ulcers and should not be used
with alcohol or other agents that promote ulcer
formation. Risk is greater in elderly and debilitated
patients, esophageal injury may also occur.
Haemopoietic system -salicylates in large
doses reduce the plasma prothrombin level by
interfering with the action of vitamin k in the
liver.
Kidney- in normal people, aspirin has little
effect on the kidney. However if there is an
underlying circulatory problem such as
congestive heart failure, aspirin decreases
renal blood flow. This can precipitate acute
renal failure. Aspirin also enhances sodium
and water retention which can increase edema
formation in some patients.
Reyes syndrome- This serious and often fatal
complication occur a few days after viral infection,
especially influenza and varicella, in children
below12 years. There occur anicteric liver
dysfunction due to hepatic mitochondrial injury
and a consequent metabolic encephalopathy.
Therefore aspirin should be avoided in children
under the age of 12 years.
Pregnancy and infants- When taken during
term, aspirin by inhibiting prostaglandin synthesis in
the uterus may delay the onset of labor and may
cause greater blood loss at delivery. They cause
premature closure of the ductus arteriosus with
resultant serious pulmonary hypertension in the
newborn. Salicylate readily crosses the placental
barrier and may prove toxic to the newborn as the
ability of the newborn to detoxify and excrete
salicylate is poor.
Anti-inflammatory doses (3-6 g/day)
produce the syndrome called salicylism
diziness, tinnitus, vertigo, reversible
impairment of hearing and vision, excitement
and mental confusion, hyperventilation and
electrolyte imbalance.
Salicylism- prolonged administration of
salicylates may produce a condition of mild
salicylate intoxication termed salicylism. The
syndrome usually develops when the plasma
salicylate level exceed 25mg% and characterized
by headache, dizziness, vertigo, tinnitus, difficulty
in hearing, and dizziness of vision, drowsiness
,lethargy, mental confusion, nausea and vomiting.
The signs and symptoms of salicylism are
reversible on cessation of therapy.
Acute salicylate poisoning may be due to
overzealous therapy in infants or an accidental
ingestion by children and adults. A serum salicylate
level of 50 mg% indicates mild toxicity, level above
75mg%, are potentially fatal.
Manifestations are- Vomiting, dehydration
electrolyte imbalance, acidotic breathing,
restlessness, delirium, hallucinations,
hyperpyrexia, convulsions, coma and death due
to respiratory failure cardiovascular collapse.
Treatment is symptomatic and supportive. Most
important is external cooling and iv fluid with Na+,
K+, HCO3
-
] and glucose: according to need
determined by repeated monitoring, Gastric
lavage to remove unabsorbed drug; forced
alkaline diuresis or haemodialysis to remove
absorbed drug is indicated in severe cases. Blood
transfusion and vit K should be given if bleeding
occurs.
Precaution and contraindication-
-Aspirin is contraindicated in patients who
are sensitive to it and in peptic ulcer,
bleeding tendencies, in children suffering
from chicken pox or influenza. Due to risk of
Reyes syndrome pediatric formulations of
aspirin are prohibited.
- In chronic liver disease: cases of hepatic
necrosis.
- It should be avoided in diabetics, in those
with low cardiac reserve or frank CHF and in
juvenile rheumatoid arthritis.
-Aspirin should be stopped 1 week before
elective surgery.
- Given during pregnancy it may be
responsible for low birth weight babies.
Delayed or prolonged labor, greater
postpartum blood loss and premature closure
of ductus arteriosus are possible if aspirin is
taken at or near term.
-It should be avoided by breast feeding
mothers.
-Avoid high doses in G-6-PD deficient
individuals-haemolysis can occur.

Uses-
-As analgesic
-As antipyretic
-Acute rheumatic fever
-Rheumatoid arthritis
-Osteoarthritis
-Postmyocardial infarction and post stroke
patients
PYRAZOLONES
These are-
-Aminopyrine and antipyrine
-Phenylbutazone and Oxyphenbutazone
-Other drugs like Phenyldimethyl pyrazolone
(analgin)
Antipyrine (phenazone) and amidopyrine
(aminopyrine) were introduced in 1884 as
antipyretics and analgesics. Their use was
associated with high incidence of
agranulocytosis: are banned in many countries.
Phenylbutazone was introduced in 1949 and
soon its active metabolite oxyphenbutazone was
also marketed. These two are potent anti-
inflammatory drugs. Two other pyrazolones
available in India - metamizol and
propiphenazone are primarily used as analgesic
and antipyretic.
Phenylbutazone It inhibits COX and is more
potent anti-inflammatory than the usually tolerated
doses of aspirin; somewhat comparable to
corticosteroids. The analgesic and antipyretic
action is poorer and slower in onset. It is
uricosuric by virtue of a metabolite which inhibits
renal tubular reabsorption of uric acid.
Phenylbutazone causes definite retention of Na +
and water by direct action on renal tubules,
edema, and expansion of plasma volume occur
after 1-2 weeks of use: CHF may be precipitated.
Pharmacokinetics Phenylbutazone is
completely absorbed orally. Absorption from i.m.
sites is slower and it causes local tissue damage:
this route is not recommended. It is 98% bound to
plasma: proteins: completely metabolized in liver
by hydroxylation and glucuronidation. The plasma
t1/2 is 60 hours; even then divided daily doses are
given to minimize gastric irritation.
Adverse effects- More toxic than aspirin.
Nausea, vomiting, epigastric distress and peptic
ulceration are common. Diarrhea and a variety of
CNS side effects are reported. Edema is the major
limitation of use for more than 1-2 weeks.
Hypersensitivity: rashes, serum sickness, hepatitis
and stomatits. .
Bone marrow depression, agranulocytosis and
Stevens-Johnson syndrome are serious dangers.
Goiter and hypothyroidism have occurred on long
term use.
Uses -Because of risk of fatal agranulocytosis and
other serious reactions, phenylbutazone and
oxyphenbutazone have-been banned in some
countries. With the availability of safer NSAIDs,
these drugs should be used only in severe cases
not responding to other drugs. Rheumatoid arthritis
and ankylosing spondylitis: for short period (1-2
weeks) during an acute exacerbation.
Rheumatic fever: cases not responding to aspirin.
Acute gout: to suppress the attack. It is nearly as
effective as colchicines and better tolerated.
Though uricosuric, it is not recommended for long
term therapy of chronic gout.
INDOLE DERIVATIVES
(Indomethacin, Sulindac )
Indomethacin it is a potent anti-inflammatory
drug, comparable to phenylbutazone. In addition, it
is a potent and promptly acting antipyretic.
Analgesic action is better than phenylbutazone,
but it relieves only inflammatory or tissue injury
related pain. It is a highly potent inhibitor of PG
synthesis and suppresses neutrophil motility. In
toxic doses it uncouples oxidative phosphorylation
(like aspirin). www.indiandentalacademy.com
Pharmacokinetics Indomethacin is well
absorbed orally; rectal absorption is slow but
dependable. It is 90% bound to plasma
proteins partly metabolized in liver to inactive
products and excreted by kidney. Plasma t1/2
is 2-5 hours.
Adverse effects - A high incidence (upto, 50%)
of gastrointestinal and CNS side effects are
produced.
Marked gastric irritation, nausea, anorexia,
gastric bleeding and diarrhea.
Frontal headache (very common), dizziness,
ataxia, mental confusion, hallucination.
Depression and psychosis.
Leukopenia, rashes and other hypersensitivity
reactions are also reported.
Increased risk of bleeding due to decreased
platelet agreeability.
It is contraindicated in machinery operators,
drivers, psychiatric patients, epileptics, kidney
disease. pregnant women and in children.
Uses - it is indicated in rheumatoid arthritis not
controlled by aspirin. It is particularly
efficacious in ankylosing spondylitis, acute
exacerbations of destructive arthropathies and
psoriatic arthritis.
It acts rapidly in acute gout. Malignancy
associated fever refractory to other antipyretics
may respond to indomethacin. It has been the
most common drug used for medical closure of
patent ductus arteriosus three 12 hourly doses
of 0.1-0.2 mg/kg achieves closure in majority of
cases.
PROPIONIC ACID DERIVATIVES
( Ibuprofen, Naproxen, Ketoprofen, Fenoprofen,
Flurbiprofen )
Ibuprofen was the first member of this class to
be introduced in 1969 as a better tolerated
alternative to aspirin.
The analgesic, antipyretic and anti-
inflammatory efficacy is rated somewhat lower
than high dose of aspirin. All inhibit PG
synthesis, naproxen being most potent; but
their in vitro potency for this action does not
closely parallel in vivo anti-inflammatory
potency. They inhibit platelet aggregation and
prolong bleeding time.
Pharmacokinetics - All are well absorbed
orally, highly bound to plasma proteins (90-99%),
but displacement interactions are not clinically
significant dose of oral anticoagulants and oral
hypoglycemic need not be altered. Because they
inhibit platelet function, use with anticoagulants
should, nevertheless, be avoided. All propionic
acid derivatives enter brain, synovial fluid and
cross placenta. They are largely metabolized in
liver by hydroxylation and glucuronide
conjugation and excreted in urine as well as bile. www.indiandentalacademy.com
Adverse effects- Ibuprofen and all its congeners
are better tolerated than aspirin. Side effects are
milder and their incidence is lower.
Gastric discomfort, nausea and vomiting, though
less than aspirin or indomethacin, are still the
most common side effects. However, even some
peptic ulcer patients are able to tolerate these
drugs. Gastric erosion and occult blood loss are
rare.
CNS side effects include headache, dizziness,
blurring of vision, tinnitus and depression.
Rashes, itching and other hypersensitivity
phenomena are infrequent. However, these
drugs also precipitate aspirin induced asthma.
Fluid retention is less marked than that with
phenylbutazone.
They are not to be prescribed to pregnant
women and should be avoided in peptic ulcer
patient.

Uses
Ibuprofen is used as a simple analgesic and
antipyretic in the same way as low dose of
aspirin. It is particularly effective in
dysmenorrhoea in which the action is clearly due
to PG synthesis inhibition.
Ibuprofen and its congeners are widely used in
rheumatoid arthritis, osteoarthritis and other
musculoskeletal disorders, specially where pain is
more prominent than inflammation.
They are indicated in soft tissue injuries, fractures,
vasectomy, tooth extraction, postpartum and
postoperatively: suppress swelling and
inflammation.
ANTHRANILIC ACID DERIVATIVE
(Mephenamic acid)
Mephenamic acid an analgesic, antipyretic and
anti-inflammatory drug, known from 1950s, but
has not gained popularity because of lower
efficacy. It inhibits PG synthesis and
antagonizes certain actions of PGs as well.
Mephenamic acid exerts peripheral as well as
central analgesic action.
Pharmacokinetics- Oral absorption is
slow but almost complete. It is highly bound
to plasma proteins displacement
interactions can occur; partly metabolized
and excreted in urine as well as bile. Plasma
tl/2 is 2-4 hours.
Adverse effects- Diarrhea is the most
important dose related side effect. Epigastric
distress is complained, but gut bleeding is
not significant.
Skin rashes, dizziness and other CNS
manifestations have occurred. Hemolytic
anemia is rare but serious complication.
Uses Mephenamic acid is indicated primarily
as analgesic in muscle, joint and soft tissue
pain where strong anti-inflammatory action is
not needed. It is quite effective in
dysmenorrhoea. It may be useful in some cases
of rheumatoid and osteoarthritis but has no
distinct advantage
ARYL-ACETIC ACID DERIVATIVES
(DiclofenacE, Tolmetin )
Diclofenac sodium a newer analgesic-
antipyretic-anti-inflammatory drug, similar in
efficacy to naproxen. It inhibits PG synthesis
and has short lasting anti platelet action;
Neutrophil chemotaxis and superoxide
production at the inflammatory site are
reduced.
Pharmacokinetics
It is well absorbed orally, 99% protein bound,
metabolized and excreted both in urine and
bile. The plasma t1/2 is 2 hours. However, it
has good tissue penetrability and
concentration in synovial fluid is maintained
for 3 times longer period than in plasma,
exerting extended therapeutic action in joints.
Adverse effects - are generally mild: epigastric
pain, nausea, headache, dizziness, and rashes.
Gastric ulceration and bleeding are less
common. Reversible elevation of serum amino-
transferases can occur; kidney damage is rare.
Uses - Its indications are similar to those of
ibuprofen - rheumatoid and osteoarthritis,
bursitis, ankylosing spondylitis,
dysmenorrhoea, post-traumatic and
postoperative inflammatory conditions -
affords quick relief of pain and wound edema.
OXICAM DERIVATIVES
(Piroxicam, Tenoxicam, Meloxicam )
Piroxicam It is a novel long acting potent NSAID
with anti-inflammatory potency similar to
indomethacin and good analgesic-antipyretic
action. It is a reversible inhibitor of
cyclooxygenase; lowers PG, concentration in
synovial fluid and inhibits platelet aggregation-
prolonging bleeding time. In addition, it
decreases the production of IgM rheumatoid
factor. Chemotaxis of leukocytes and ratio of T-
helper to T-suppressor lymphocytes are
reduced. Thus, it can inhibit inflammation in
diverse ways.
Pharmacokinetics it is rapidly and
completely absorbed: 99% plasma protein
bound; largely metabolized in liver by
hydroxylation and glucuronide conjugation;
excreted in urine and bile; enterohepatic
cycling occurs. Plasma t1/2 is long-nearly 2
days. Steady state concentrations are achieved
in a week. Single daily administration is
sufficient.
Adverse effects Common side effects are
heart burn, nausea and anorexia, but it is better
tolerated and less ulcerogenic than
indomethacin or phenylbutazone; causes less
faecal blood loss than aspirin. Rashes and
pruritus are seen in < 1% patients. Edema and
reversible azotemia have been observed.
Uses It is suitable for use as short term
analgesic as well as long term anti-
inflammatory drug - rheumatoid and osteo-
arthritis, ankylosing spondylitis, acute gout,
musculoskeletal injuries, dentistry, episiotomy,
dysmenorrhoea etc. Its efficacy is comparable
to high dose aspirin or indomethacin.
PYRROLO-PYRROLE DERIVATIVE
(Ketorolac)
Ketorolac A novel NSAID with potent analgesic
and modest anti-inflammatory activity. In
postoperative pain it has equaled the efficacy of
morphine, but does not interact with opioid
receptors and is free of respiratory depressant,
dependence producing, hypotensive and
constipating side effects. It inhibits PG
synthesis and is believed to relieve pain by a
peripheral mechanism. In short lasting pain, it
has compared favorably with aspirin. Platelet
aggregation is inhibited for short periods.
Pharmacokinetics -
Ketorolac is rapidly absorbed after oral and
i.m. administration. It is highly plasma
protein bound and 60% excreted unchanged
in urine. Major metabolic pathway is
glucuronidation; plasma t1/2 is 5-7 hours.
Adverse effects Nausea, abdominal pain,
dyspepsia, ulceration, loose stools, drowsiness,
headache, dizziness, nervousness, pruritus, pain
at injection site, rise in serumtransaminase and
fluid retention have been noted. .
No significant drug interactions have been
reported and it has been used concurrently with
morphine. However, it should not be given to
patients on anticoagulants.
Its safety in ulcer patients, in cardiac, renal and
hepatic disease, children, elderly and pregnant
women has not been established.
Uses Ketorolac is frequently used in
postoperative and acute musculoskeletal pain:
15-30 mg i.m. every 4-6 hours (max. 120
mg/day). It may also be used for renal colic,
migraine and pain due to bony metastasis.
Orally it is used in a dose of 10-20 mg 6 hourly
for short term management of moderate pain.
Continuous use for more than 5 days is not at
present recommended. It should not be used for
preanaesthetic medication or for obstetric
analgesia www.indiandentalacademy.com
SULFONANILIDE DERIVATIVE
(Nimesulide )
Nimesulide- this newer NSAID is a relatively
weak inhibitor of PG synthesis (may be somewhat
selective for COX-2); appears to exert its effects by
other mechanisms like reduced generation of
superoxide by neutrophils, inhibition of PAF
synthesis and TNF release, free radical
scavanging, inhibition of metalloproteinase activity
in cartilage. www.indiandentalacademy.com
The analgesic, antipyretic and anti-
inflammatory activity of nimesulide has been
rated comparable to other NSAIDs. It has been
used primarily for short lasting painful
inflammatory conditions like sports injuries,
sinusitis and other ear-nose-throat disorders,
dental surgery, bursitis, low backache,
dysmenorrhoea; postoperative pain and
osteoarthritis.
Pharmacokinetics -
Nimesulide is almost completely absorbed
orally, 99% plasma protein bound,
extensively metabolized and excreted mainly
in urine with a t1/2 of 2-5 hours.
Adverse effects of nimesulide are
gastrointestinal (epigastralgia, heart burn,
nausea, loose motions), dermatological (rash,
pruritus) and central (dizziness). Claims of better
gastric tolerability than other NSAIDs have not
been substantiated. There is also no proof that
renal complications associated with NSAID use
are missing with nimesulide. However, most
asthmatics and those who develop
bronchospasm or intolerance to aspirin and other
NSAIDs do not cross react with nimesulide. Its
specific usefulness appears to be only in such
patients.
PARA-AMINO PHENOL DERIVATIVES
(Paracetamol )
Phenacetin was introduced in 1887. It was
extensively used but is now banned in many
countries, including India, because it was
implicated in analgesic abuse nephropathy.
Paracetamol (acetaminophen) the
deethylated active metabolite of phenacetin, was
also introduced in the last century but has come
into common use only since 1950.
The central analgesic action of paracetamol is
like aspirin, i.e. it raises pain threshold, but has
weak peripheral
Anti-inflammatory component. Analgesic action
of aspirin and paracetamol is additive.
Paracetamol is a good and promptly acting
antipyretic.
Paracetamol has negligible anti-inflammatory
action. It is a poor inhibitor of PG synthesis in
peripheral tissues, but more active on COX in
brain. One explanation offered for the
discrepancy between its analgesic-antipyretic
and anti-inflammatory actions is its poor ability
to inhibit COX in the presence of peroxides
which are generated at sites of inflammation.
Subjective effects: Phenacetin probably
produces a sense of relaxation and well being
in some people. In the early part of present
century it was widely abused by factory
workers in the industrializing Europe. It was
claimed to reduce tension, fatigue and to
increase work capacity: was considered habit
forming, but not producing physical
dependence though discontinuation did
produce mild symptoms. Paracetamol has not
shown such a pattern of abuse. www.indiandentalacademy.com
In contrast to aspirin, paracetamol does not
stimulate respiration or affect acid-base, nor
increase cellular metabolism. It has no effect
on CVS. Gastric irritation is insignificant -
mucosal erosion and bleeding occur rarely
only in overdose. It. does not affect function
or clotting factors and is not uricosuric.
Pharmacokinetics Paracetamol is well
absorbed orally, only about 1/3 is protein
bound in plasma and uniformly distributed in
the body. It is conjugated with glucuronic acid
and is excreted rapidly in urine. Plasma tl/2 is
2-3 hours. Effects after an oral dose last 3-
5hrs.
Adverse effects in isolated antipyretic doses
paracetamol are safe and well tolerated.
Nausea and rashes occur occasionally.
Analgesic nephropathy occurs after years of
heavy ingestion of analgesics; such
individuals have some personality defect. It
manifests as papillary necrosis, tubular
atrophy followed by renal fibrosis. Urine
concentrating ability is lost and the kidneys
shrink. Because phenacetin was commonly
abused, it was primarily implicated and has
gone into disrepute, though other analgesics
are also liable to produce similar effects.
Paracetamol poisoning it occurs specially in
small children who have low glucuronide
conjugating ability. If a large dose (> 150 mg/kg
or> 10 g in an adult) is taken serious toxicity can
occur. Fatality is common with> 250 mg/kg.
Early manifestations are just nausea, vomiting,
abdominal pain and liver tenderness impairment
of consciousness. After 12-18 hours
centrilobular hepatic necrosis occurs which may
be accompanied by renal tubular necrosis and
hypoglycemia that may progress to coma.
Jaundice starts after 2 days. Further course
depends on the dose taken.
Fulminating hepatic failure and death are
likely if the plasma levels are above the line
joining 200 g/ml at 4 hours and 30 g/ml at
15 hours. If the levels are lower-recovery with
supportive treatment is the rule.

Mechanism of toxicity N-acetyl-benzoquinone-
imine is a highly reactive arylating minor
metabolite of paracetamol which is detoxified
by conjugation with glutathione. When a very
large dose of paracetamol is taken,
glucuronidation capacity is saturated, more of
minor metabolite is formed- hepatic glutathione
is depleted and this metabolite binds to proteins
in liver cells (and renal tubules) causing
necrosis. Toxicity thus shows a threshold effect
manifesting only when glutathione is depleted
to a critical point. In chronic alcoholics even 5-6
g/day taken for a few days can result in
hepatotoxicity.
Paracetamol is not recommended in premature
infants (2 kg) for fear of hepatotoxicity.
Treatment-If the patient is brought early,
vomiting should be induced or gastric lavage
done. Activated charcoal is given orally or
through the tube to prevent further absorption.
Other supportive measures, as needed, should
be taken.
N-acetylcysteine 150 mg/kg should be infused
i.v. over 15 min, followed by the same dose i.v.
over the next 20 hours. Alternatively, 75 mg/kg
may be given orally every 4-6 hours for 2-3
days. It replenishes the glutathione stores of
liver and prevents binding of the toxic
metabolite to other cellular constituents.
Ingestion-treatment interval is critical;
earlier the better. It is practically ineffective if
started 16 hours or more after paracetamol
ingestion.

Uses Paracetamol is one of the most commonly
used over the counter' analgesic for headache,
musculoskeletal pain, dysmenorrhoea etc. where
anti-inflammatory action is not required. It is one
of the best drugs to be used as antipyretic.
Dose to dose it is equally efficacious as aspirin for
noninflammatory conditions, It is much safer than
aspirin in terms of gastric irritation, ulceration and
bleeding (can be given to ulcer patients), does not
prolong bleeding time. Hypersensitivity reactions
are rare; no metabolic effects or acid-base
disturbances; can be used in patients in whom
aspirin is contraindicated. It does not have
significant drug interactions. Thus, it may be
preferred over aspirin for most minor conditions.
BENZOXAZOCINE DERIVATIVE
(Nefopam)
Nefopam It is a recently introduced nonopioid
analgesic which does, not inhibit PG synthesis. In
traumatic and postoperative pain, it acts rapidly
with an efficacy approaching morphine, yet has no
opioid actions. Favorable results have been
obtained in short lasting musculoskeletal pain not
responding to other nonopioid analgesics.
Nefopam produces anticholinergic (dry mouth,
urinary retention, blurred vision and
sympathomimetic (tachycardia, nervousness) side
effects, and nausea is often dose
Limiting. It is contraindicated in epileptics
Celecoxib
This selective COX-2 inhibitor has become
available in India in 2000. It exerts potent anti-
inflammatory, analgesic and antipyretic actions
with low ulcerogenic potential. Comparative trials
in rheumatoid arthritis have found it to be as
effective as naproxen or diclofenac, without
affecting COX-I activity in gastroduodenal mucosa
even at maximal therapeutic dose. Platelet
aggregation in response to collagen exposure
remained intact in celecoxib recipients. www.indiandentalacademy.com
Though tolerability of celecoxib is better than
older NSAIDs, still abdominal pain, dyspepsia
and mild diarrhea are the most common side
effects.
Celecoxib is slowly absorbed, 97% plasma
protein bound and metabolized primarily by
CYP 2C9 with mean t1/2 of 11 hrs. It is
approved for use in osteo- and rheumatoid
arthritis in a dose of 100-200 mg B D.
Rofecoxib
It is a COX-2 selective inhibitor. Rofecoxib has
been found to be as effective as other NSAIDs in
osteoarthritis, rheumatoid arthritis as well as in
dysmenorrhoea, dental, postoperative and acute
musculoskeletal pain at a dose of 12.5-25 mg
once daily. Occurrence of peptic ulcer is rare
and incidence of ulcer bleeds over 1 year of use
has been found to be significantly lower than
with other NSAIDs .Rofecoxib has no effect on
TXA
2
production by platelets. Side effects are
mild g.i. complaints, headache and dizziness.
Pedal edema and rise in BP occurs
occasionally. Rofecoxib is well absorbed
orally, 87% plasma protein bound, extensively
metabolized and has an average t1/2 of 17
hours. It should be avoided in presence of
severe hepatic/renal disease and in those
receiving rifampin, warfarin, methotrexate.

Valdecoxib
Recently marketed selective COX-2 inhibitor
having similar efficacy and tolerability profile
as Rofecoxib. The plasma t1/2 is 8-11 hours.
In osteoarthritis and rheumatoid arthritis it is
recommended in a dose of 10 mg once daily,
while for primary dysmenorrhoea or post-
operative pain upto 20 mg twIce daily may be
used.
Name Available as Dose / Frequency
Salicylates
(Aspirin)
300, 350 mg tab 300-350 mg t.i.d
Ibuprofen (Brufen) 200, 400mg tab 400-600mg t.i.d
Naproxen
(Naprosyn)
250mg tab 250-500mg b.i.d
Diclofenac
(voveran)
50mg tab 50mg b.i.d
Piroxicam (pirox)

10-20mg capsules

10-20mg o.d

Paracetamol
(Crocin)
300, 500mg 300-500mg t.i.d
Indomethacin
(Indocid)

25mg

25-50mg t.id

Choice of Nonsteroidal anti-inflammatory
drug
NSAIDs have their own spectrum of adverse
effects. They differ quantitatively among
themselves in producing different side effects and
there are large inter-individual differences. At
present NSAIDs is a bewildering array of strongly
promoted drugs. No single drug is superior to all
others for every patient. Choice of drug is
inescapably empirical. .
The nature of problem (acute/chronic; pain:
inflammation ratio, severity) along with
consideration of risk factors in an individual
patient directs the initial selection.
1. Mild to moderate pain with little inflammation -
paracetamol or low dose ibuprofen.
2. Acute musculoskeletal, osteoarthritis, injury
associated inflammation - a propionicacid
derivative, diclofenac or piroxicam.
3. Postoperative or other acute but short lasting
painful conditions with minimal inflammation -
ketorolac, nefopam.
4. Exacerbation of rheumatoid arthritis,
ankylosing spondylitis, acute gout, acute
rheumatic fever - high dose aspirin,
indomethacin, naproxen, piroxicam.
5. Patients with history of asthma or
anaphylactoid reactions to aspirin/other
NSAIDs-nimesulide.
6. Combination of two or more NSAIDs is not
superior to single agents. If at all used,
combination therapy should be limited to
short periods. www.indiandentalacademy.com
The Propionic acid derivatives and other newer
drugs - diclofenac, piroxicam are, in general,
better tolerated. Due to risk of Reye's
syndrome, aspirin should not be used in
children without medical advice. During
pregnancy lower dose of aspirin is probably the
safest but it should be discontinued near term.
The possibility of drug interactions should be
considered in patients receiving prolonged
therapy with other drugs (e.g. hypertensives,
diabetics, ischemic heart disease patients etc.
References
1. Manual of dental therapeutics
Raymond F. Zambite ,James J Sciubber (1993)
2.Medical Pharmacology
Clark, Barter, John (1992)
3.Essentials of medical pharmacology
K D Tripathi (1999)
4.Concise medical pharmacology
Chaudhuri
5.Medical physiology
Guyton Hall
6. Essential pathology for dental students
Harsh Mohan
7.Pharmacology and pharmacotherapeutics
R. S. Satoskar
8. Textbook of dental pharmacology and
therapeutics
John G Walton, John W. Thompson

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