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NON STEROIDAL
ANTIINFLAMMATORY
DRUGS ( NSAIDs)
INDIAN DENTAL ACADEMY
Leader in continuing dental education
www.indiandenta...
“Pain is perfect misery, the worst of
evils,

and

excessive,

overturns

all

patience”.
John Milton (1608- 1674) Paradis...
One of the greatest services doctors can do
their

patients

is

to

acquire

skill

in

the

management of pain.
Pain

ma...
Dental pain is best managed by selecting a
pharmacologic agent from one of the three
widely used groups.
Local anesthetic
...
Bark of willow tree was used in folk medicine
for years for mild pain and fever. Salicylic acid
was obtained by hydrolysis...
NSAIDs are weak analgesics. They are also
called as non narcotic / non opoid analgesics or
aspirin type or antipyretic ana...
PROSTAGLANDINS
Prostaglandins are naturally occurring substances
composed of fatty acids found throughout body
tissues. Pr...
IN 1930’S human semen was found to
contract isolated uterine and other smooth
muscle strips and to cause fall in blood
pre...
BIOSYNTHESIS OF PROSTAGLANDINS

www.indiandentalacademy.com
BENEFICIAL ACTION DUE TO
PROSTAGLANDIN SYNTHESIS INHIBITION.
Analgesia : prevention of pain nerve ending
sensitization
Ant...
SHARED TOXICITIES DUE TO
PROSTAGLANDIN SYNTHESIS INHIBITION
Gastric mucosal damage
Bleeding : inhibition of platelet funct...
PAIN – is an unpleasant sensory and emotional
experience associated with actual or potential
tissue damage.
Pain is mainly...
Pain has been classified into two major types:
fast pain and slow pain. Fast pain is felt
within about 0.1 second after a ...
They are widespread in the superficial layers of the
skin as well as in certain internal tissues, such as
the periosteum,
...
The fast-sharp pain signals they are transmitted
in the penpheral nerves to the spinal cord by
small type Aδ fibers at vel...
Because of this double system of
innervations,

a

sudden

onset

of

pain
painful

stimulus often gives a double pain sen...
On entering the spinal cord from the dorsal
spinal roots, the pain fibers terminate on
neurons in the dorsal horns. On ent...
www.indiandentalacademy.com
The fast type Aδ pain fibers transmit mainly
mechanical and acute thermal pain. They
terminate mainly in lamina I (laimina...
Few fibers of the neospinothalamic tract
terminate in the reticular areas of the brain
stem, but most pass all the way to ...
The paleospinothalamic pathway transmits pain
mainly carried in the peripheral slow-chronic
type C pain fibers; although i...
Here the last neuron in the series gives rise to
long axons that mostly join the fibers from the fast
pathway,

passing

f...
Instead, they terminate principally in one of
three areas: (1) the reticular nuclei of the
medulla, pons, and mesencephalo...
Glutamate, the neurotransmitter of the Type Aδ
Fast Pain Fibers.
Type C pain fiber terminals entering the spinal
cord migh...
Prostaglandins particularly PGE and PGI
produce
hyperalgesia
associated
with
inflammation. Prostaglandin alone induces
pai...
FEVER which means a body temperature
above the usual range of normal can be caused
by abnormalities in the brain itself or...
Regulation of body temperature require a
delicate balance between production of
heat and loss of heat and the
hypothalamus...
FEVER PRODUCTION

www.indiandentalacademy.com
Many proteins, breakdown products of
proteins and certain other substances esp.
lipopolysaccharide toxins released from
ba...
When bacteria or breakdown products of
bacteria are present in the tissues or the
blood, they are phagocytized by the bloo...
When

the

set

temperature

point

of

regulating

the

hypothalamic

centre

becomes

increased to a higher level than n...
Anti-pyretic action of NSAIDs is central. In
fever the temperature regulating system
maintains temperature at a higher lev...
NSAIDs reduces elevated temperature by
increased dissipation of heat caused by
vasodilatation of superficial blood vessels...
Therapeutic doses of aspirin affect neither
normal body temperature nor an elevated
temperature associated with exercise, ...
INFLAMMATION
Inflammation is defined as the local
response of living mammalian tissue to
injury due to any agent. It is a ...
Signs of inflammation—
Roman writer Celsus in 1st century AD
named the famous four cardinal signs of
inflammation.
Rubor (...
Types of inflammation
Acute and Chronic Inflammation.

Changes in acute inflammation—
Vascular changes

Cellular events

1...
www.indiandentalacademy.com
Chemical mediators of inflammation also
called

as

permeability

endogenous

mediators

factors
of

or

increased

vascul...
Mediators released by cells

1. Vasoactive amines (histamine, 5hydroxytryptamine)
2. Arachidonic acid metabolite
a. Metabo...
NSAIDs reduce the synthesis of eicosonoid
mediators of inflammation; it also interferes
with chemical mediators of kallike...
CLASSIFICATION OF NSAIDs
A. Analgesic and anti-inflammatory

1

Salicylates

2

Pyrazolone derivative

3

Indole derivativ...
SALICYLATES --- (Aspirin- protype)
(Aspirin, Salicylamide, Benorylate, Diflunisal)

The name aspirin was coined from
Germa...
Apirin is acetylsalicylic acid . It is rapidly
converted in the body to salicylic acid
which is responsible for most of th...
PHARMACOLOGICAL ACTIONS

-Analgesic, antipyretic, anti-inflammatory actions
Aspirin is a weaker analgesic than morphine ty...
Aspirin resets the hypothalamic thermostat and
rapidly reduces fever by promoting heat loss
(sweating, cutaneous vasodilat...
2. Metabolic effects- These are significant
only at anti-inflammatory doses. Cellular metabolism
is increased, specially i...
Large doses of salicylates produce hyperglycemia
and gylcosuria in normal individuals this is due to
central sympathetic s...
3. Respiration
Salicylates stimulate respiration as a result of direct
and indirect action. As a result of their action on...
This produces an increase in the rate as well
as

the

depth

of

respiration

leading

to

hyperventilation. Hyperventila...
4. Acid-base and electrolyte balance
The respiratory alkalosis produced by the
anti-inflammatory doses is countered by the...
Hypokalemia as a result of urinary loss of
potassium is accompanied by water loss through
lungs due to hyperventilation th...
To this are added dissociated salicylic acid as well
as metabolic acids (lactic, pyruvic, acetoacetic)
which are produced ...
6. Gastrointestinal tract the ingestion
of salicylates may produce dyspepsia, nausea,
vomiting as a result of gastric irri...
Aspirin (pKa 3.5) remains unionized and diffusible
in the acid gastric juice, but on entering the
mucosal cell (pH 7.1) it...
To avoid gastric irritation salicylate may be administered
- with plenty of water after food
- With milk
- With an alkali ...
7.

Blood-

Aspirin,

even

in

small

doses

irreversibly inhibits TXA2 synthesis by platelets.
Thus it interferes with p...
This can be detrimental in patients scheduled for
surgery. Bleeding time can be prolonged for a week.
Thus aspirin should ...
8. Uricosuric effects- Urate present in the
glomerular infiltrate is reabsorbed by the proximal
tubules of the kidney and ...
6. CVS -Aspirin has no deleterious effect in
therapeutic doses. Larger doses increase cardiac
output to meet increased per...
Pharmacokinetics-

Salicylates are absorbed from the stomach and
largely from the upper part of the small intestine.

www....
On

oral

therapeutic

administration
dose,

concentrations

are

of

a

appreciable
found

single
plasma

within

30

min...
Both salicylate and salicylic acid are absorbed
from intact skin, esp. when applied with
alcohol, petrolatum, lard or lano...
After

absorption,

salicylate
mainly

is

approx.

bound

albumin.

It

to
is

80%

plasma
rapidly

of

the

proteins

di...
Salicylates are mainly metabolized in the liver
and excreted in the urine in the form of
conjugate with glycine and glucur...
Adverse Effects—
Side effects that occur at analgesic dose (0.3-1.5
g/day) are nausea, vomiting, epigastric distress,
incr...
Hypersensitivity
and
idiosyncrasy
though
infrequent, these can be serious. Reactions
include rashes, fixed drug eruption, ...
GIT – the commonest side effects of salicylates
and other NSAIDs are dyspepsia, nausea,
vomiting and heartburn. Therapeuti...
Haemopoietic system -salicylates in large
doses reduce the plasma prothrombin level by
interfering with the action of vita...
Reyes syndrome- This serious and often fatal
complication occur a few days after viral infection,
especially influenza and...
Pregnancy and infants- When taken during
term, aspirin by inhibiting prostaglandin synthesis in
the uterus may delay the o...
Anti-inflammatory

doses

(3-6

g/day)

produce the syndrome called salicylism
diziness,

tinnitus,

vertigo,

reversible
...
Salicylism-

prolonged

administration

of

salicylates may produce a condition of mild
salicylate

intoxication

termed

...
Acute salicylate poisoning – may be due to
overzealous therapy in infants or an accidental
ingestion by children and adult...
Manifestations
areVomiting,
dehydration
electrolyte
imbalance,
acidotic
breathing,
restlessness,
delirium,
hallucinations,...
Precaution and contraindication-Aspirin is contraindicated in patients who
are sensitive to it and in peptic ulcer,
bleedi...
-Aspirin should be stopped 1 week before
elective surgery.
- Given during pregnancy it may be
responsible for low birth we...
Uses-As analgesic
-As antipyretic
-Acute rheumatic fever
-Rheumatoid arthritis
-Osteoarthritis
-Postmyocardial infarction ...
PYRAZOLONES –
These are-Aminopyrine and antipyrine
-Phenylbutazone and Oxyphenbutazone
-Other drugs like Phenyldimethyl py...
Antipyrine
(phenazone)
and
amidopyrine
(aminopyrine) were introduced in 1884 as
antipyretics and analgesics. Their use was...
Phenylbutazone It inhibits COX and is more
potent anti-inflammatory than the usually tolerated
doses of aspirin; somewhat ...
Pharmacokinetics

Phenylbutazone
is
completely absorbed orally. Absorption from i.m.
sites is slower and it causes local t...
Adverse effects- More toxic than aspirin.
Nausea, vomiting, epigastric distress and peptic
ulceration are common. Diarrhea...
Uses -Because of risk of fatal agranulocytosis and
other serious reactions, phenyl-butazone and
oxyphenbutazone have-been ...
INDOLE DERIVATIVES
(Indomethacin, Sulindac )

Indomethacin it is a potent anti-inflammatory
drug, comparable to phenylbuta...
Pharmacokinetics Indomethacin is well
absorbed orally; rectal absorption is slow but
dependable. It is 90% bound to plasma...
Adverse effects - A high incidence (upto, 50%)
of gastrointestinal and CNS side effects are
produced.
Marked gastric irrit...
Uses - it is indicated in rheumatoid arthritis not
controlled by aspirin. It is particularly
efficacious in ankylosing spo...
PROPIONIC ACID DERIVATIVES
( Ibuprofen, Naproxen, Ketoprofen, Fenoprofen,
Flurbiprofen )

Ibuprofen was the first member o...
Pharmacokinetics - All are well absorbed
orally, highly bound to plasma proteins (90-99%),
but displacement interactions a...
Adverse effects- Ibuprofen and all its congeners
are better tolerated than aspirin. Side effects are
milder and their inci...
CNS side effects include headache, dizziness,
blurring of vision, tinnitus and depression.
Rashes, itching and other hyper...
Uses
Ibuprofen is used as a simple analgesic and
antipyretic in the
same way as low dose of
aspirin.
It
is
particularly
ef...
ANTHRANILIC ACID DERIVATIVE
(Mephenamic acid)

Mephenamic acid an analgesic, antipyretic and
anti-inflammatory drug, known...
Pharmacokinetics- Oral absorption is
slow but almost complete. It is highly bound
to

plasma

proteins

displacement

inte...
Adverse

effects-

Diarrhea

is

the

most

important dose related side effect. Epigastric
distress is complained, but gut...
Uses Mephenamic acid is indicated primarily
as analgesic in muscle, joint and soft tissue
pain where strong anti-inflammat...
ARYL-ACETIC ACID DERIVATIVES
(DiclofenacE, Tolmetin )
Diclofenac

sodium

a

newer

analgesic-

antipyretic-anti-inflammat...
Pharmacokinetics
It is well absorbed orally, 99% protein bound,
metabolized and excreted both in urine and
bile. The plasm...
Adverse effects - are generally mild: epigastric
pain, nausea, headache, dizziness, and rashes.
Gastric

ulceration

and

...
Uses - Its indications are similar to those of
ibuprofen - rheumatoid and osteoarthritis,
bursitis,

ankylosing

dysmenorr...
OXICAM DERIVATIVES
(Piroxicam, Tenoxicam, Meloxicam )

Piroxicam It is a novel long acting potent NSAID
with anti-inflamma...
Pharmacokinetics

it

completely absorbed:
bound;

largely

is

rapidly

and

99% plasma protein

metabolized

in

liver

...
Adverse effects Common side effects are
heart burn, nausea and anorexia, but it is better
tolerated

and

less

ulcerogeni...
Uses It is suitable for use as short term
analgesic

as

well

as

long

term

anti-

inflammatory drug - rheumatoid and o...
PYRROLO-PYRROLE DERIVATIVE
(Ketorolac)

Ketorolac A novel NSAID with potent analgesic
and modest anti-inflammatory activit...
Pharmacokinetics Ketorolac is rapidly absorbed after oral and
i.m. administration. It is highly plasma protein
bound and 6...
Adverse effects Nausea, abdominal pain,
dyspepsia, ulceration, loose stools, drowsiness,
headache, dizziness, nervousness,...
Uses

Ketorolac

is

frequently

used

in

postoperative and acute musculoskeletal pain:
15-30 mg i.m. every 4-6 hours (ma...
SULFONANILIDE DERIVATIVE
(Nimesulide )

Nimesulide- this newer NSAID is a relatively
weak inhibitor of PG synthesis (may b...
The

analgesic,

antipyretic

and

anti-

inflammatory activity of nimesulide has been
rated comparable to other NSAIDs. I...
Pharmacokinetics Nimesulide is almost completely absorbed
orally,

99%

plasma

protein

bound,

extensively metabolized a...
Adverse

effects

of
nimesulide
are
gastrointestinal
(epigastralgia,
heart
burn,
nausea, loose motions), dermatological (r...
PARA-AMINO PHENOL DERIVATIVES
(Paracetamol )

Phenacetin was introduced in 1887. It was
extensively used but is now banned...
Anti-inflammatory component. Analgesic action
of aspirin and paracetamol is additive.
Paracetamol is a good and promptly a...
Subjective

effects:

Phenacetin

probably

produces a sense of relaxation and well being
in some people. In the early par...
In contrast to aspirin, paracetamol does not
stimulate respiration or affect acid-base, nor
increase cellular metabolism. ...
Pharmacokinetics

Paracetamol

is

well

absorbed orally, only about 1/3 is protein
bound in plasma and uniformly distribu...
Adverse effects in isolated antipyretic doses
paracetamol are safe and well tolerated.
Nausea and rashes occur occasionall...
Paracetamol poisoning it occurs specially in
small children who have low glucuronide
conjugating ability. If a large dose ...
Fulminating hepatic failure and death are
likely if the plasma levels are above the line
joining 200 µg/ml at 4 hours and ...
Mechanism of toxicity N-acetyl-benzoquinoneimine is a highly reactive arylating minor
metabolite of paracetamol which is d...
Paracetamol is not recommended in premature
infants (2 kg) for fear of hepatotoxicity.
Treatment-If

the

patient

is

bro...
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. Alte...
Uses Paracetamol is one of the most commonly
used over the counter' analgesic for headache,
musculoskeletal pain, dysmenor...
BENZOXAZOCINE DERIVATIVE
(Nefopam)

Nefopam It is a recently introduced nonopioid
analgesic which does, not inhibit PG syn...
Celecoxib
This

selective

COX-2

inhibitor

has

become

available in India in 2000. It exerts potent antiinflammatory, a...
Though tolerability of celecoxib is better than
older NSAIDs, still abdominal pain, dyspepsia
and mild diarrhea are the mo...
Rofecoxib
It is a COX-2 selective inhibitor. Rofecoxib has
been found to be as effective as other NSAIDs in
osteoarthritis...
Pedal

edema

and

rise

in

BP

occurs

occasionally. Rofecoxib is well absorbed
orally, 87% plasma protein bound, extens...
Valdecoxib
Recently marketed selective COX-2 inhibitor
having similar efficacy and tolerability profile
as Rofecoxib. The ...
Name

Available as

Dose / Frequency

Salicylates
(Aspirin)

300, 350 mg tab

300-350 mg t.i.d

Ibuprofen (Brufen)

200, 4...
Choice of Nonsteroidal anti-inflammatory
drug
NSAIDs have their own spectrum of adverse
effects.

They

differ

quantitati...
The nature of problem (acute/chronic; pain:
inflammation
ratio,
severity)
along
with
consideration of risk factors in an i...
4.

Exacerbation

of

rheumatoid

arthritis,

ankylosing spondylitis, acute gout, acute
rheu-matic

fever

-

high

dose

...
The Propionic acid derivatives and other newer
drugs - diclofenac, piroxicam are, in general,
better tolerated. Due to ris...
References –
1. Manual of dental therapeutics
Raymond F. Zambite ,James J Sciubber (1993)

2.Medical Pharmacology
Clark, B...
6. Essential pathology for dental students
Harsh Mohan

7.Pharmacology and pharmacotherapeutics
R. S. Satoskar

8. Textboo...
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Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy

  1. 1. NON STEROIDAL ANTIINFLAMMATORY DRUGS ( NSAIDs) INDIAN DENTAL ACADEMY Leader in continuing dental education www.indiandentalacademy.com www.indiandentalacademy.com
  2. 2. “Pain is perfect misery, the worst of evils, and excessive, overturns all patience”. John Milton (1608- 1674) Paradise Lost. www.indiandentalacademy.com
  3. 3. 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. www.indiandentalacademy.com
  4. 4. 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 www.indiandentalacademy.com
  5. 5. 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 www.indiandentalacademy.com was well tolerated.
  6. 6. NSAIDs are weak analgesics. They are also called as non narcotic / non opoid analgesics or aspirin type or antipyretic analgesics. They have anti-inflammatory, elevated body antipyretic (reduce temperature). They the 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. www.indiandentalacademy.com
  7. 7. 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 www.indiandentalacademy.com
  8. 8. IN 1930’S 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. www.indiandentalacademy.com
  9. 9. BIOSYNTHESIS OF PROSTAGLANDINS www.indiandentalacademy.com
  10. 10. BENEFICIAL ACTION DUE TO PROSTAGLANDIN SYNTHESIS INHIBITION. Analgesia : prevention of pain nerve ending sensitization Antipyresis: reduces the elevated body temperature Anti-inflammatory Anti-thrombotic www.indiandentalacademy.com Closure of ductus arteriosus.
  11. 11. 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 www.indiandentalacademy.com
  12. 12. 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. www.indiandentalacademy.com
  13. 13. 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. www.indiandentalacademy.com
  14. 14. 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 www.indiandentalacademy.com elicited by all three types .
  15. 15. The fast-sharp pain signals they are transmitted in the penpheral nerves to the spinal cord by small type Aδ 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. www.indiandentalacademy.com
  16. 16. Because of this double system of innervations, a sudden onset of pain painful stimulus often gives a double pain sensation a fast-sharp pain that is transmitted to the brain by the Aδ fiber pathway followed a second or so later by a slow pain that is transmitted by the C fiber pathway. www.indiandentalacademy.com
  17. 17. 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. www.indiandentalacademy.com
  18. 18. www.indiandentalacademy.com
  19. 19. The fast type Aδ 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. www.indiandentalacademy.com
  20. 20. 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. www.indiandentalacademy.com
  21. 21. 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 δ 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. www.indiandentalacademy.com
  22. 22. 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. www.indiandentalacademy.com
  23. 23. 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 www.indiandentalacademy.com
  24. 24. Glutamate, the neurotransmitter of the Type Aδ 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 con-centration over a period of seconds or even minutes www.indiandentalacademy.com
  25. 25. 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 Aδ fibers endings to other mediators such as bradykinin and histamine Furthermore bradykinin eliminates formation and release of prostaglandins and a positive feed back of www.indiandentalacademy.com sort.
  26. 26. 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 99ºF (37.22ºC ) and 105ºF(40.57ºC) and onwards is called PYREXIA. Rise of body temperature above 107ºF (41.66ºC) www.indiandentalacademy.com is called HYPERPYREXIA.
  27. 27. 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. www.indiandentalacademy.com
  28. 28. FEVER PRODUCTION www.indiandentalacademy.com
  29. 29. 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. www.indiandentalacademy.com
  30. 30. 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) formation of which prostaglandin induces in the vascular organs in the preoptic hypothalamic area. Prostaglandin (PGE 2 ) produced acts on the www.indiandentalacademy.com hypothalamus to elicit fever reaction.
  31. 31. When the set temperature point of regulating the hypothalamic 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. www.indiandentalacademy.com
  32. 32. 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. www.indiandentalacademy.com
  33. 33. 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. www.indiandentalacademy.com
  34. 34. 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. www.indiandentalacademy.com
  35. 35. 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. www.indiandentalacademy.com
  36. 36. 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. www.indiandentalacademy.com
  37. 37. 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 www.indiandentalacademy.com
  38. 38. www.indiandentalacademy.com
  39. 39. Chemical mediators of inflammation also called as permeability endogenous mediators factors of or increased vascular permeability .These are a large and increasing compounds number which can of endogenous enhance vascular permeability. The substance acting as a chemical mediator of inflammation may be released from the cells , the plasma or www.indiandentalacademy.com damaged tissue itself. They are broadly
  40. 40. Mediators released by cells 1. Vasoactive amines (histamine, 5hydroxytryptamine) 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 The The The kinin system clotting system fibrinolytic system www.indiandentalacademy.com complement system.
  41. 41. 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. www.indiandentalacademy.com
  42. 42. CLASSIFICATION OF NSAIDs A. Analgesic and anti-inflammatory 1 Salicylates 2 Pyrazolone derivative 3 Indole derivatives 4 B. Analgesic but poor anti-inflammatory Propionic acid derivatives 1 2 5 Anthranilic acid derivative 6 Aryl-acetic acid derivatives 7 3 Benzoxazocine derivative Pyrrolo-pyrrole derivative 9 Pyrazolone derivatives Oxicam derivatives 8 Paraaminophenol derivative Sulfonanilide derivative 10 Alkanones www.indiandentalacademy.com
  43. 43. 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) www.indiandentalacademy.com
  44. 44. 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. Sodium salicylate Aspirin www.indiandentalacademy.com Methyl salicylate
  45. 45. 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 www.indiandentalacademy.com physical dependence is produced.
  46. 46. 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 (36 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. www.indiandentalacademy.com
  47. 47. 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 www.indiandentalacademy.com to aminoaciduria and a negative nitrogen balance.
  48. 48. Large doses of salicylates produce hyperglycemia and gylcosuria in normal individuals this is due to central sympathetic stimulus- release of adrenaline and gluccocorticoids. www.indiandentalacademy.com
  49. 49. 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 CO2. Increased production of CO2 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 www.indiandentalacademy.com chemoreceptors.
  50. 50. 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 www.indiandentalacademy.com
  51. 51. 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 . www.indiandentalacademy.com
  52. 52. 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 CO2 retention and excess CO2 production continues leads to respiratory acidosis . www.indiandentalacademy.com
  53. 53. 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. www.indiandentalacademy.com
  54. 54. 6. Gastrointestinal tract the ingestion of salicylates may produce dyspepsia, nausea, vomiting as a result of gastric irritation by the released salicylic acid. www.indiandentalacademy.com
  55. 55. 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 www.indiandentalacademy.com with the gastric mucosa.
  56. 56. 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. www.indiandentalacademy.com
  57. 57. 7. Blood- Aspirin, even in small doses irreversibly inhibits TXA2 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. www.indiandentalacademy.com
  58. 58. 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. www.indiandentalacademy.com
  59. 59. 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. www.indiandentalacademy.com
  60. 60. 6. CVS -Aspirin has no deleterious effect in therapeutic doses. Larger doses increase cardiac output to meet increased peripheral O2 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. www.indiandentalacademy.com
  61. 61. Pharmacokinetics- Salicylates are absorbed from the stomach and largely from the upper part of the small intestine. www.indiandentalacademy.com
  62. 62. On oral therapeutic administration dose, concentrations are of a appreciable found single plasma 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, www.indiandentalacademy.com presence of food in the stomach modify the
  63. 63. 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. www.indiandentalacademy.com
  64. 64. After absorption, salicylate mainly is approx. bound albumin. It to is 80% plasma rapidly of the proteins distributed through most of the tissues and achieves a significant concentration in the saliva, milk, spinal, sensorial and peritoneal fluids and in the erythrocytes. www.indiandentalacademy.com
  65. 65. 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. www.indiandentalacademy.com
  66. 66. 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. www.indiandentalacademy.com
  67. 67. 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). www.indiandentalacademy.com
  68. 68. 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 www.indiandentalacademy.com occur.
  69. 69. 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 www.indiandentalacademy.com formation in some patients.
  70. 70. 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. www.indiandentalacademy.com
  71. 71. 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. www.indiandentalacademy.com
  72. 72. 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. www.indiandentalacademy.com
  73. 73. 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. www.indiandentalacademy.com
  74. 74. 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. www.indiandentalacademy.com
  75. 75. Manifestations areVomiting, 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. www.indiandentalacademy.com
  76. 76. 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 Reye’s 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. www.indiandentalacademy.com
  77. 77. -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. www.indiandentalacademy.com
  78. 78. Uses-As analgesic -As antipyretic -Acute rheumatic fever -Rheumatoid arthritis -Osteoarthritis -Postmyocardial infarction and post stroke patients www.indiandentalacademy.com
  79. 79. PYRAZOLONES – These are-Aminopyrine and antipyrine -Phenylbutazone and Oxyphenbutazone -Other drugs like Phenyldimethyl pyrazolone (analgin) www.indiandentalacademy.com
  80. 80. 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 antiinflammatory drugs. Two other pyrazolones available in India metamizol and propiphenazone are primarily used as analgesic and antipyretic. www.indiandentalacademy.com
  81. 81. 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. www.indiandentalacademy.com
  82. 82. 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. www.indiandentalacademy.com
  83. 83. 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. www.indiandentalacademy.com
  84. 84. Uses -Because of risk of fatal agranulocytosis and other serious reactions, phenyl-butazone 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. www.indiandentalacademy.com
  85. 85. 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
  86. 86. 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. www.indiandentalacademy.com
  87. 87. 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 www.indiandentalacademy.com disease. pregnant women and in children.
  88. 88. 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 www.indiandentalacademy.com cases.
  89. 89. 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 antiinflammatory 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. www.indiandentalacademy.com
  90. 90. 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 www.indiandentalacademy.com conjugation and excreted in urine as well as bile.
  91. 91. 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. www.indiandentalacademy.com
  92. 92. 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. www.indiandentalacademy.com
  93. 93. 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 www.indiandentalacademy.com inflammation.
  94. 94. 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 www.indiandentalacademy.com central analgesic action.
  95. 95. 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. www.indiandentalacademy.com
  96. 96. Adverse effects- Diarrhea is the most important dose related side effect. Epigastric distress is complained, but gut bleeding is not significant. Skin rashes, manifestations dizziness have and occurred. other Hemolytic anemia is rare but serious complication. www.indiandentalacademy.com CNS
  97. 97. 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 www.indiandentalacademy.com
  98. 98. 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. www.indiandentalacademy.com
  99. 99. 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. www.indiandentalacademy.com
  100. 100. Adverse effects - are generally mild: epigastric pain, nausea, headache, dizziness, and rashes. Gastric ulceration and bleeding are less common. Reversible elevation of serum aminotransferases can occur; kidney damage is rare. www.indiandentalacademy.com
  101. 101. Uses - Its indications are similar to those of ibuprofen - rheumatoid and osteoarthritis, bursitis, ankylosing dysmenorrhoea, postoperative spondylitis, post-traumatic inflammatory and conditions affords quick relief of pain and wound edema. www.indiandentalacademy.com -
  102. 102. 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 aggregationprolonging bleeding time. In addition, it decreases the production of IgM rheumatoid factor. Chemotaxis of leukocytes and ratio of Thelper to T-suppressor lymphocytes are reduced. Thus, it can inhibit inflammation in diverse ways. www.indiandentalacademy.com
  103. 103. Pharmacokinetics it completely absorbed: bound; largely is rapidly and 99% plasma protein 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. www.indiandentalacademy.com
  104. 104. 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. www.indiandentalacademy.com
  105. 105. Uses It is suitable for use as short term analgesic as well as long term anti- inflammatory drug - rheumatoid and osteoarthritis, ankylosing spondylitis, acute gout, musculoskeletal injuries, dentistry, episiotomy, dysmenorrhoea etc. Its efficacy is comparable indomethacin. to high dose www.indiandentalacademy.com aspirin or
  106. 106. 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 www.indiandentalacademy.com aggregation is inhibited for short periods.
  107. 107. 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. www.indiandentalacademy.com
  108. 108. 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. www.indiandentalacademy.com
  109. 109. 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 analgesia medication or www.indiandentalacademy.com for obstetric
  110. 110. 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 TNFα release, free radical scavanging, inhibition of metalloproteinase activity in cartilage. www.indiandentalacademy.com
  111. 111. 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, dysmenorrhoea; bursitis, low postoperative osteoarthritis. www.indiandentalacademy.com backache, pain and
  112. 112. 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. www.indiandentalacademy.com
  113. 113. 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. www.indiandentalacademy.com
  114. 114. 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 www.indiandentalacademy.com weak peripheral
  115. 115. 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 www.indiandentalacademy.com which are generated at sites of inflammation.
  116. 116. 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 dependence not though producing physical discontinuation did produce mild symptoms. Paracetamol has not www.indiandentalacademy.com shown such a pattern of abuse.
  117. 117. 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. www.indiandentalacademy.com
  118. 118. 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 35hrs. www.indiandentalacademy.com
  119. 119. 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 www.indiandentalacademy.com are also liable to produce similar effects.
  120. 120. 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 www.indiandentalacademy.com depends on the dose taken.
  121. 121. Fulminating hepatic failure and death are likely if the plasma levels are above the line joining 200 µg/ml at 4 hours and 30 µg/ml at 15 hours. If the levels are lower-recovery with supportive treatment is the rule. www.indiandentalacademy.com
  122. 122. Mechanism of toxicity N-acetyl-benzoquinoneimine 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. www.indiandentalacademy.com
  123. 123. 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. www.indiandentalacademy.com
  124. 124. 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. www.indiandentalacademy.com
  125. 125. 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 www.indiandentalacademy.com preferred over aspirin for most minor conditions.
  126. 126. 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 www.indiandentalacademy.com Limiting. It is contraindicated in epileptics
  127. 127. Celecoxib This selective COX-2 inhibitor has become available in India in 2000. It exerts potent antiinflammatory, 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 www.indiandentalacademy.com celecoxib recipients.
  128. 128. 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. www.indiandentalacademy.com
  129. 129. 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 TXA2 production by platelets. Side effects are www.indiandentalacademy.com mild g.i. complaints, headache and dizziness.
  130. 130. 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. www.indiandentalacademy.com
  131. 131. 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 postoperative pain upto 20 mg twIce daily may be used. www.indiandentalacademy.com
  132. 132. 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 www.indiandentalacademy.com
  133. 133. 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 www.indiandentalacademy.com inescapably empirical. .
  134. 134. 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 www.indiandentalacademy.com ketorolac, nefopam.
  135. 135. 4. Exacerbation of rheumatoid arthritis, ankylosing spondylitis, acute gout, acute rheu-matic fever - high dose aspirin, indomethacin, naproxen, piroxicam. 5. Patients anaphylactoid with history reactions of to asthma or 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
  136. 136. 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 . www.indiandentalacademy.com
  137. 137. 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 www.indiandentalacademy.com
  138. 138. 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 www.indiandentalacademy.com
  139. 139. www.indiandentalacademy.com

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