NSAIDs

Non steroidal anti-inflammatory drugs

1. Dr. Jannatul Ferdoush
Assistant Professor
Department of Pharmacology

2. Pain
Unpleasant sensory & emotional experience associated
with actual or potential tissue damage.
Component of pain:
Perception of pain- drugs act on this by increasing
threshold for pain
Emotional response

3. Component of regulation
Peripheral factor:
Tissue damage
↓
Release of certain factor bradykinin, PG
Brady kinin- pain producing subs.
PG- for inflammation PGE1 & PGI2 is responsible.
Bradikinin sensitize PG to produce pain.
For pain relief:
Antagonist of BK ( not available)
PG synthesis Blocker –NSAID-act by inhibiting
Cyclooxygenase or PG synthase.

4. Central regulation of pain
Pain R are distributed in pain pathway, hypothalamus,
limbic system, spinal cord.
Brain
Nociceptive pathway(spinal,
supraspinal-
thalamus, cortex)

Spinal cordglutamate,Subs P,
neurokinin, NO
BK,
5HT
PG
Afferent
nerve
(-) NSAID
Periphery
Opioids
stimulates
Descending
Inhibitory
Pathway
(Enchephalin,
5HT, NE)
Dorsal horn
Pain pathway
Tissue injury
We can block nociceptive pathway
Peripheral R
Ascendind pain pathway

5. Pain transmitted by Pain inhibited by
NO Opiates
Glutamate Enkaphalin
Subs P 5HT, GABA,NE

6. Classification of Analgesic
Based on – Peripherally acting
-Centrally acting
Peripheally acting :
NSAID or non narcotic analgesic (Block nociceptive
impulse)
e.g. Paracetamol, Diclofenac, Ibuprofen
Centrally acting:
Narcotic analgesic ( act on opioid R
act mainly on neuronal pathway -
Spinal, Supraspinal)

7. Choice of analgesic
Depends on:
Origin – visceral / somatic
Severity of pain (mild,moderate, severe)
Mild pain:
Headache, Myalgia
Non narcotic analgesic:
1)Paraceatamol, if not response –
2)antiinflammatory drug- ketoprofen, ibuprofen
3)Then diclofenac

8. If visceral pain :
opioid analgesic
Mild to moderate pain with an antiinflammatory
componant, generally chronic pain E.g. RA
Use: NSAID + low efficacy opioid
•Severe Pain:
If visceral (acute pain) MI , biliary colic etc.
Use: opioid analgesic- morphine ,pathedrine
Purely visceral with an antiinflammatory componant:
Gout, bone metastesis, post operative pain
Intolarable Pain:
High efficacy opioid analgesic + anxiolytic , sometimes
adjuvant drug.

9. Neuropathic pain
Neurological damage to the nervous system
Drug use which inhibit pain pathway.
e.g. 5HT agonist.

10. Narcotic:
Depress CNS
Produce sedation & drowsiness
Act by central mechanism
They also cause euphoria, physical dependence &
tolerance.
Non-narcotic:
Act chiefly peripherally
Relief somatic pain (muscle,joint, skin)
Do not produce physical dependence & tolerance

11. Adjuvant Medication
Usually not used for pain but rather for other
management.
They are not themselves analgesic, though they may
modify the perception or the concomitants of pain that
make it worse (anxiety, fear, depression), e.g.
psychotropic drugs, steroid, antidepressant.
They may modify underlying cases, e.g. spasm of
smooth or of voluntary muscle eg. Local
anasthetics,alpha 2 agonist

12. Mechanism of pain
Noxious stimuli(temp, mechanical , chemical)
↓
Stimulate sensory R (periphery)(1
st
order neuron)
↓
Transmitted to lateral spinothalamic tract or spinal cord
(2nd order neuron)
↓
Thalamus (interation)
↓
Sensory area of cortex( interpretetion)
( area no 1,2,3 Post cetral gyrus)

13. Nonsteroidal anti-inflammatory drugs
(NSAIDs)
Chemical classification –
Para-amino phenol derivatives :
Paracetamol (acetaminophen)
Salicylic acids :
Aspirin, Diflunisal, Benorilate
Acetic acids :
Indomethacin, Sulindac, Diclofenac sodium,
Etodolac, Ketorolac
Fenamic acid :
Mefenamic acid, Meclofenamic acid

14. Propionic acids :
Ibuprofen, Ketoprofen, Fenoprofen, Naproxen,
Flurbiprofen, Oxaprozin
Enolic acids :
Piroxicam, Meloxicam, Nabumetone

15. NSAIDs may be categorized according
to their COX specificity as:
COX-2 selective
compounds-
Celecoxib
Etorocoxib
NON-selective –
all other
NSAIDs.
These drugs inhibit
COX-1 as much, or
even more than,
COX-2.

16. According to potency of anti-inflammatory effect:
Strong anti-inflammatory drug:
Indomethacin
Piroxicam
Aspirin
Diclofenac
Tenoxicum
Moderate anti-inflammatory drug:
Naproxen
Ketoprofen
Ibuprofen
Weak anti-inflammatory drug:
Paracetamol is not a NSAID.

17. Most of the NSAIDs have three major types of effect:
Anti-inflammatory effects:
In acute inflammation
PGE2 & PGI2 generated by local tissue & PGD2 released by
mast cell
↓
These are powerful vasodilator and potentiate other
inflammatory Vessodilatator ( Histamine and bradykinin)
↓
the combined dilator action on precapillary arterioles cause
redness & ↑ blood flow in the areas of inflammation.
↓
Blocks PG synthesis and thereby suppress pain, swelling, ↑
blood flow associated with inflammation

18. NSAIDs have some general properties in common:
All but one of the NSAIDs are weak organic acids as
given; the exception, nabumetone, is a ketone pro-drug
that is metabolized to the acidic active drug.
Most of the NSAIDs are highly metabolized, some by
phase I followed by phase II mechanisms & others by
direct glucoronidation (phase II) alone
Metabolism proceeds, in large part, by way of P450
enzymes in the liver
Pharmacokinetics of NSAIDs

19. Renal excretion is the most important route for final
elimination
Nearly all undergo varying degrees of biliary excretion
& reabsorption (enterohepatic circulation)
Most of the NSAIDs are highly protein bound (~98%),
usually to albumin
All NSAIDs can be found in synovial fluid after
repeated dosing

20. Analgesic action
Trauma
↓
Pain
↓
Tissue damage
↓
Liberation of chemical sustance bradykinin & prosglandin.
↓
Bradykinin sensitize pain R to PG.
↓
NSAID blocks PG synthesis
↓
Relieve of pain

21. Antipyretic effect
Normal body temperature regulates a center of
hypothalamus .

Inflammatory reaction  bacterial endotoxin  release of a
pyrogen-IL-1 from macrophage   stimulate the
generation of PGE2 in hypothalamus  Disturbance of this
hypothalamic ‘thermostate’  leads to the set point of body
temperature being raised  causes the elevation of the
set-point for temperature fever
So, NSAID  inhibit PGE
2
production & release in the
hypothalamus  antipyretic effect

22. Anti-platelet action
Low dose Aspirin

23. Primary dysmennorhea:
Mefenamic acid is used to reduce the production of PGs by the
uterus which cause uterine hypercontractility & pain.
Patency of the ductus arteriosus:
As PGs maintain the patency, indomethacin given to a new-
born child with a patent ductus arteriosus can result in closure,
avoiding the alternative of surgical ligation

24. Unwanted effects of NSAIDs

25. Unwanted effects of NSAIDs
Renal effect:
Prolong high dose of NSAID
↓
↓PGI2
↓
No renal Vessodilatation
↓
Renal ischemia
↓
↓GFR
↓
Na & water retention
↓
HTN, HF aggravates.

26. NSAID induce gastric ulcer:
Aspirin which is acidic drug remains unionized in gastric
acidic environment.
So, drug enters into cell by simple diffusion
In cell pH is high, the drug become ionized & trapped &
cannot diffuse back. So an ion trapping occur and this
may cause gastric erosion, ulceration.

27. Drug interactions of NSAIDs
 NSAID + Warfarin: ­ the risk of hemorrhage.
NSAID + Antidiabetics: Azapropazone & phenylbutazone
inhibit the metabolism of sulfonylurea hypoglycemics, ­ their
toxicity
Aspirin + phenytoin, valproic acid: ­ the plasma conc. of
phenytoin, valproic acid

28. Antihypertensives: Their effect is lessened due to sodium
retention by inhibition of renal PG formation
Diuretics: NSAIDs causes Na
+
retention & reduce diuretic &
antihypertensive efficacy
Lithium: NSAIDs delay the excretion of lithium by the kidney
& may cause lithium toxicity
ACEI & angiotensin II antagonists: there is a risk of renal
impairment & hyperkalemia

29. Caution & contraindications
In the elderly, allergic disorders, during pregnancy & breast
feeding, & coagulative defects.
In patients with renal, hepatic or cardiac disease.

30. •In patient with bronchial asthma –
•NSAIDs or aspirin block the COX-1enzyme →↓
TXA2 & PGE
2
→ overproduction of leukotrienes &
produces the severe asthma and allergy-like effects.
Over expression of both the LT R & the LTC
4

synthase

enzyme in respiratory tissue from patients
with aspirin-induced asthma, cause ↑ response to
LT & ↑ production of LT.

31. Paracetamol
Acetaminophen inhibits PG synthesis in the CNS.
This explains its antipyretic & analgesic properties.
Acetaminophen has less effect on COX in peripheral
tissues,
which accounts for its weak anti-inflammatory

32. Inactivated in the liver principally by conjugation as
glucoronide & sulphate.
Minor metabolites of paracetamol are also formed N-
acetyl-p-benzoquinoneimine (NABQI), is highly reactive
chemically.
This substance is normally rendered harmless by
conjugation with glutathione.

33. •At normal doses of paracetamol, the NABQI reacts with the
sulfhydryl group of glutathione, forming a nontoxic substance.
•But the supply of hepatic glutathione is limited & In overdose,
•NABQI formed is greater than the glutathione available,
then the toxic metabolite accumulates & reacts with
nucleophilic constituents in the cell.
•The excess metabolite oxidises thiol (SH-) groups of key
enzymes, which causes cell death.
•Cause hepatic & renal tubular necrosis.

34. Paracetamol poisoning
Treatment –
Gastric lavage followed by oral activated charcoal if
ingested within 1 hour
liver damage can be prevented by giving agents that
increase glutathione formation in the liver
(acetylcysteine intravenously, or methionine orally)
If more than 12 hours of ingestion of a large dose, the
antidotes, which themselves can cause adverse
effects (nausea, allergic reactions), are less likely to be
useful

35. Aspirin (acetylsalicylic acid) is the prototype of traditional
NSAIDs
The bark of the willow tree (Salix) contains salicin from
which salicylic acid is derived; it was used for fevers in the
18
th
century as a cheap substitute for imported cinchona
(quinine) bark
Rarely used as an anti-inflammatory medication; it has
been replaced by ibuprofen & naproxen
Effective, available as OTC & safe .
Aspirin

36. Aspirin is a weak organic acid
 Irreversibly acetylates (& thus inactivates) COX, so
preventing the formation of products including thromboxane,
prostacyclin & other PGs
The other NSAIDs, including salicylate, are all reversible
inhibitors of COX.
Aspirin is rapidly deacetylated (hydrolysed) by esterases in
the plasma, producing salicylate
Has anti-inflammatory, anti-pyretic & analgesic effects but
additionally exerts important effects on respiration,
intermediary metabolism & acid-base balance
Mode of action of aspirin

37. Actions of aspirin:
Aspirin has 3 major therapeutic actions –
They reduce -
Inflammation (anti-inflammation)
Pain (analgesia)
Fever (antipyrexia)

38. Anti-inflammatory action:
Nonselective inhibitor of both COX isomers.
irreversibly inhibits COX activity
¯
¯ the formation of PGs &, thus, modulates those aspects
of inflammation in which PGs act as mediators.
Antiplatelet action:
Low doses (75mg daily) of aspirin can irreversibly inhibit TXA
2

production in platelets without markedly affecting PGI
2

production in the endothelial cells of the blood vessel.
 As a result of the ¯ in TXA
2
, platelet aggregation (the 1
st
step in
thrombus formation) is reduced, producing an anticoagulant
effect with a prolonged bleeding time.

39. •The acetylation of COX is irreversible. Because platelets lack
nuclei, they cannot synthesize new enzyme, & the lack of TXA
2

persists for the lifetime of the platelet (3-7 days). This contrasts
with the endothelial cells, which have nuclei &, therefore, can
produce new COX.
Respiratory action:
 At therapeutic doses, aspirin ­ alveolar ventilation.
Salicylates  uncouple oxidative phosphorylation  elevated
CO
2
 ­ respiration.
 Higher doses work directly on the respiratory center in the
medulla, resulting in hyperventilation & respiratory alkalosis that
is usually compensated by the kidney (­ bicarbonate excretion).
 At toxic levels, central respiratory paralysis occurs, &
respiratory acidosis ensures due to continued production of CO
2

40. GIT effects:
PGI
2
inhibits gastric acid secretion.
PGE
2
& PGF
2α
stimulate synthesis of protective mucus in
both the stomach & small intestine.
Aspirin (-) PG synthesis → ­ gastric acid secretion & ¯
mucus protection
Actions on the kidney:
COX inhibitors prevent the synthesis of PGE
2
& PGI
2
– PGs
maintain renal blood flow, particularly in the presence of
circulating vasoconstrictors.
¯synthesis of PGs can result in retention of sodium & water
& may cause edema & hyperkalemia in some patients.

41. Aspirin in high dose reduces renal tubular reabsorption of
urate
 Low dose (< 2g/d) inhibit urate secretion, causing urate
retention
Dosage of aspirin:
75-300 mg/d are used routinely to prevent
thromboembolic vascular occlusion;
Low doses (75mg or 100mg) are to be prescribed
following bypass surgery & post MI
300 mg as immediately after the diagnosis of IHD. Aspirin
decrease the mortality after MI;
300-900 mg every 4-6 hourly when necessary for
analgesia

42. Salicylates, especially methyl salicylates, are absorbed through
intact skin.
 Aspirin has a
P
Ka of 3.5. After oral administration, in the
stomach aspirin is un-ionised & thus lipid-soluble & diffusible.

 In gastric epithelial cells (
P
H 7.4) it will ionise, become less
diffusible & so harms, the gastric mucosa.
 In the body aspirin is metabolised to salicylic acid (
P
ka 3.0),
which at
P
H 7.4 is highly ionised & thus remain in the ECF.
salicylic acid in the plasma are filtered by the glomeruli & pass
into the tubular fluid, which is generally more acidic than plasma
& causes a proportion of salicylic acid to become un-ionised &
lipid-soluble so diffuses back into the tubular cells.
P/K of aspirin

43. At normal low dosages (650 mg/d), aspirin (half-life 15
minutes) is hydrolysed to salicylate & acetic acid by esterases
in tissues & blood.
Salicylate is converted by the liver to water-soluble
conjugates (glycine conjugation) that are rapidly cleared by
the kidney, resulting in elimination with first-order kinetics & a
serum half-life of 3.5 hours.
At anti-inflammatory dosages (> 4g/d), the hepatic metabolic
pathway becomes saturated, & zero-order kinetics are
observed, with the drug having a half-life of 15 hours or more
Salicylate is an organic anion & in addition to undergoing
glomerular filtration, is secreted by the proximal renal tubule

44. Alkalinising the urine with sodium bicarbonate causes more
salicylic acid to become ionised & lipid-insoluble so that it
remains in the tubular fluid, & is eliminated in the urine
Most absorption of aspirin, however, occurs in the ileum
because of the extensive surface area of the microvilli
Rectal absorption of salicylates is slow & unreliable, but it is a
useful route for administration to children with vomiting.
Salicylates (except diflunisal) cross both BBB & the placenta.

45. GIT: Epigastric distress, nausea, vomiting
Blood: prolonged bleeding time due to (-) platelet
aggregation. Should not be taken for at least one week
prior to surgery.
Allergy: severe rhinitis, urticaria, angioedema, asthma or
shock. Those who already suffer from urticaria, nasal
polyps or asthma are more susceptible
Adverse effects of aspirin

46. Salicylism:
occurs with repeated ingestion of large doses of salicylate.
It is a syndrome consisting of tinnitus (a high-pitched buzzing
noise in the ears), vertigo, ¯ hearing, dizziness, headache &
confusion.
Sometimes also nausea & vomiting
Reye’s syndrome: Rare disorder in children.
It is a combination of liver disorder & encephalopathy (CNS
disturbances) that can follow an acute viral illness & has a 20-
40% mortality.
Should not be given to children under 12 years unless
specially indicated, e.g. for juvenile arthritis, should be avoided
in those up to & including 15 years (paracetamol is preferred)

47. Respiratory alkalosis develops:
Salicylates uncouple oxidative phosphorylation (mainly in the
skeletal muscle) → ­ O
2
consumption & ­ production of CO
2
.
This stimulates respiration, which is also stimulated by a direct
action on the respiratory center.
The resulting hyperventilation causes a respiratory alkalosis that
is normally compensated by renal mechanisms involving ­
HCO
3
-
excretion
The blood pH thus rises, & renal loss of HCO
3
-
is accompanied
by Na
+
& K
+
as well as water; dehydration & hypokalemia result
Salicylate poisoning

48. Metabolic acidosis :
Accumulation of lactic & pyruvic acids due to interference
with TCA cycle enzymes
stimulation of lipid metabolism causing ­ production of
ketone bodies.
Late toxic respiratory depression may also cause CO
2

retention
Salicylate poisoning
-More serious in children than in adults.
-The acid-base disturbance seen in children is usually a
metabolic acidosis whereas that in adults is a respiratory
alkalosis

49. Treatment:
Activated charcoal: adsorbs salicylate & prevents its
absorption from the alimentary tract; gastric lavage or
the use of an emetic is no longer recommended
Correction of dehydration: alkalosis or mixed
alkalosis/acidosis need no specific treatment.
Metabolic acidosis is treated with sodium bicarbonate,
which alkalinises the urine & accelerates the removal of
Salicylate in the urine
Hemodialysis: may be necessary, either if renal failure
develops or the plasma salicylate concentration exceeds
900 mg/l

50. COX-2 selective inhibitors, or coxibs, were
developed in an attempt to inhibit PG synthesis by
the COX-2 isoenzyme induced at sites of
inflammation without affecting the action of the
constitutively active “house-keeping” COX-1
isoenzyme found in the GIT, kidneys, & platelet
COX-2 selective NSAIDs

51. COX-2 inhibitors have analgesic, antipyretic, & anti-
inflammatory effects similar to those of nonselective
NSAIDs but with an approximate halving of GI adverse
effects
These selective agents also have no significant effects on
platelets
The COX-2 inhibitors (like the traditional NSAIDs) may
cause renal insufficiency .
Clinical data have suggested a higher incidence of
cardiovascular thrombotic events associated with COX-2
inhibitors such as rofecoxib & valdecoxib, resulting in their
withdrawal from the market

52. Celecoxib is useful for long term use in chronic arthritis. It
has minimal side effects
Etorocoxib is indicated for symptomatic relief of osteoarthritis
& acute gout
Nimesulide, a relatively selective COX-2 inhibitor is useful in
mild to moderate arthritis, somatic pain & fever
Aceclofenac has a chondroprotective property, which may be
useful for long term management of osteoarthritis. It is also
effective in rheumatoid arthritis & alkylosing spondylitis. It is
well tolerated, thus suitable for the elderly

53. COX I & COX II

55. T
h
a
n
k y o
u