Non-steroidal anti-inflammatory drugs (NSAIDs)

the topic contain nonsteroidal antiinflammatory drugs which include, mediatorsof inflammation, cox-1 and cox-2, classification of drugs, its pharmacological effect and adverse reaction of drug.

1. Nonsteroidal anti-inflammatory
drugs (NSAIDs)
Ravish Yadav

2. •Analgesic
•Antipyretic
•Anti-inflammatory (at higher
doses)
Nonsteroidal Anti-inflammatory
Drugs (NSAIDs)

3. THE INFLAMMATORY RESPONSE
1.The inflammatory response is a normal (desirable)
defense mechanism.
2.The side effects are undesirable.
3.Normal inflammatory response has an on/off
switch.
4.In chronic inflammation something has gone
wrong with the OFFswitch
5.Therefore we need drugs to control the
inflammatory reaction.

4. Complement system
histamine
serotonin
bradykinin -major contributors to symptoms of inflammation
leukotrienes -increase vascular permeability
 -increase mobilization of endogenous mediators of
inflammation
prostaglandins PGE
2
-promote edema and leukocyte infiltration
PGI
2
-increase vascular permeability, enhance
pain producing properties of bradykinin
Mediators of the inflammatory response

6. INFLAMMATORY SITE
Sensitized lymphocytes release soluble factors ( which
recruit & mobilize macrophages to the inflammed tissue.)
Additional activated macrophages produce enhanced levels
of enzymes and mediators
Thereby involving macrophages in the defense against
microorganisms and foreign antigens
BUTremember that the inflammatory cells have the
potential to destroy surrounding tissue.

7. Mediators of inflammation

8. 4 signs of inflammation
•Redness -due to local vessel dilatation
•Heat-due to local vessel dilatation
•Swelling–due to influx of plasma proteins and phagocytic cells into
the tissue spaces
•Pain –due to local release of enzymes and increased tissue pressure

9. Major pathways

10. Eicosanoids
Eicosanoids –a family of compounds that are the products of three
main pathways which use oxygen as a major cosubstrate.
The three pathways are:
•the cyclooxygenase pathway
•the lipoxygenase pathway
•the epoxygenase pathway.

11. COX 1 and COX 2
•The key enzyme in the cyclooxygenase pathwayis the enzyme
cyclooxygenase (COX).
•There are two forms of cyclooxygenase, COX1 (the predominant
form) and COX2.

12. COX-2
inhibitors
•Selective (coxibs)
•Preferential
Selective
COX-3
inhibitors
•Antipyretic
analgesics
Nonselective
(Aspirin-like)
COX-1/COX-2
inhibitors
NSAIDs
COX INHIBITORS

13. CLASSIFICATION

15. NSAIDs and prostaglandin (PG)synthesis inhibition

16. •In the developing fetus, the ductus arteriosus, also called the
ductus Botalli, is a blood vessel connecting the pulmonary
artery to the proximal descending aorta. It allows most of the
blood from the right ventricle to bypass the fetus's fluid-filled
non-functioning lungs. Upon closure at birth, it becomes the
ligamentum arteriosum.

17. MECHANISM OF ACTION
Non-steroidal anti-inflammatory drugs (NSAIDs)
•All NSAIDs inhibit the cyclooxygenase required for
conversion of arachidonic acid to endoperoxide
intermediate (PGG2 and PGH2).
•NSAIDs inhibit prostaglandin and thromboxane
synthesis, they are potent inhibitors of cyclooxygenase
and eliminate all prostaglandins and thromboxanes in
every cell they reach
•Recall that prostaglandins and thromboxanes play
crucial roles in: Pain, Inflammation, Fever , Excessive
blood clotting

18. Common Pharmacological Effects
to be covered below
•Analgesic (CNS and peripheral effect) may involve
non-PG related effects
•Antipyretic(CNS effect)
•Anti-inflammatory (except acetaminophen) due
mainly to PG inhibition.
Some shown to inhibit activation, aggregation, adhesion of
neutrophils & release of lysosomal enzymes
•Some are Uricosuric (increase the excretion of uric
acid in the urine)

19. Pharmacological Effects (cont’d)
•Diverse group of chemicals, but all inhibit cyclooxygenase.
•Resultant inhibition of PG synthesis is largely responsible for their
therapeutic effects.
•But, inhibition of PG synthase in gastric mucosa GIT damage
(dyspepsia, gastritis).

20. ADVERSE EFFECTS OF NSAID’S
Renal papillary necrosisis a disorder of the kidneys in which all or part of the renal papillae die. The renal papillae are
the areas where the openings of the collecting ducts enter the kidney, and where the urine flows into the ureters.
Nasal polypsare soft, painless, noncancerous growths on the lining of your nasalpassages or sinuses. They hang down
like teardrops or grapes. They result from chronic inflammation due to asthma, recurring infection, allergies, drug
sensitivity or certain immune disorders

21. Common Adverse Effects
•Platelet Dysfunction
•Gastritis and peptic ulceration with bleeding
(inhibition of PG + other effects)
•Acute Renal Failure in susceptible
•Sodium+ water retention and edema
•Analgesic nephropathy
•Prolongation of gestation and inhibition of labor.
•Hypersenstivity (not immunologic but due to PG
inhibition)
•GIT bleeding and perforation

22. NSAID
↑ Leukocyte-Endothelial
Interactions
Capillary
Obstruction
Ischemic
Cell Injury
Proteases +
Oxygen Radicals
Endo/Epithelial
Cell Injury
Mucosal Ulceration
Loss of PGI
2induced inhibition of LTB
4mediated
endothelial adhesion and activation of neutrophils

23. Cyclo-oxygenase(COX)
•Exists in the tissue as constitutive isoform (COX-1).
•At site of inflammation, cytokines stim the induction of the 2
nd
isoform
(COX-2).
•Inhibition of COX-2 is thought to be due to the anti-inflammatory actions
of NSAIDs.
•Inhibition of COX-1 is responsible for their GIT toxicity.
•Most currently used NSAIDs are somewhat selective for COX-1, but
selective COX-2 inhibitors are available.

24. COX (cont’d)
•Celecoxib, etoricoxib, valdecoxib –selective COX-2 inhibitors.
•Have similar efficacies to that of the non-selective inhibitors, but the
GIT side effects are decr by ~50%.
•But, no cardioprotection and there is actually increased MI.

26. The Salicylates-Aspirin
•Duration of action ~ 4 hr.
•Orally taken.
•Weak acid (pK
a~ 3.5); so, non-ionized in stomach easily absorbed.
•Hydrolyzed by esterases in tissues and blood to salicylate (active) and
acetic acid.
•Most salicylate is converted in liver to H
2O-sol conjugates that are
rapidly excreted by kidneys.

27. The Salicylates -Aspirin
•Effect on Respiration: triphasic
1.Low doses: uncoupling phosphorylation → ↑
CO
2 → stimulates respiration.
2.Direct stimulation of respiratory center →
Hyperventilation → resp. alkalosis → renal
compensation
3.Depression of respiratory center and
cardiovascular center → ↓ BP, respiratory
acidosis, no compensation + metabolic acidosis
also

28. Aspirin
•GI system
1.Dose dependent hepatitis
2.Reye’s syndrome (an extremely rare but serious illness that can affect the brain
and liver, occurs most commonly in kids recovering from a viral infection.)
•Metabolic
1.Uncoupling of Oxidative Phosphorylation
2.Hyperglycemia and depletion of muscle and
hepatic glycogen
•Endocrine: corticosteroids, thyroid

29. Cardiovascular
• Platelets: Inhibition of platelet COX-1-derived TxA
2
with the net effect of increasing bleeding time
(inhibition of platelet aggregation)
• Endothelial COX-2 derived PGI
2can inhibit platelet
aggregation (inhibition augments aggregation by
TxA
2).
Aspirin (acetylsalicylic acid) covalently modifies and,
irreversibly inhibits platelet COX. The enzyme is
inhibited for the lifetime of the platelet (~8 -11 days).
Effect achieved at very low dose.
• Basis of therapeutic efficacy in stroke and MI (reduces
mortality and prevents recurrent events).

30. Additional Cardiovascular Considerations
• Blood vessels/smooth muscle
COX-2 derived PGI
2can antagonize catecholamine-and angiotensin II-
induced vasoconstriction (NSAIDs can elevate bp).
• Atherosclerosis
Inhibition of COX-2 can destabilize atherosclerotic plaques (due to its
anti-inflammatory actions)

31. Renal
•COX-1 and COX-2 –generated PGs (TxA
2, PGF
2, PGI
2
(glom), PGE
2(medulla), powerful vasodilators) can
both incr and decr Na
+
retention (natriuresis
predominates), usually in response to changes in
tubular Cl
-
, extracellular tonicity or low bp.
•NSAIDs tend to promote Na
+
retention and can
therefore increase bp. Can counteracteffects of many
anti-hypertensives (diuretics, ACE inhibitors and -AR
antagonists). •
•PGs have minimal impact on normal renal blood flow,
but become important in the compromised kidney.
Patients (particularly elderly and volume depleted) are
at risk of renal ischemia with NSAIDs.

32. Gastrointestinal
•PGs (generated via COX-1)
1) inhibit stomach acid secretion,
2) stimulate mucus and HCO
3
-
secretion, vasodilation
and therefore,
3) are cytoprotective for the gastric mucosa.
•Therefore, NSAIDs with COX-1 inhibitory activity will
produce opposite effects, leading to:
•Gastric distress, gastric bleeding, sudden acute
hemorrhage (effects are dose-dependent)

33. Gestation
PGs (generated from COX-2) are involved in the
initiation and progression of labor and delivery.
Therefore, inhibition of their production by NSAIDs
can prolong gestation.
Respiratory system
High doses (salicylates) cause partial uncoupling of
oxidative phosphorylation with increased CO
2
production (COX-independent effects). Increase in
plasma CO
2hyperventilation. Even higher doses
cause depression of respiration.
Other uses of NSAIDs (mechanisms less understood) -
Decreased risk of fatal colon carcinoma

34. Aspirin -Therapeutic Uses
•Antipyretic, analgesic
•Anti-inflammatory: rheumatic fever, rheumatoid
arthritis (joint dis), other rheumatological
diseases. High dose needed (5-8 g/day).
•But many pts cannot tolerate these doses (GIT); so,
proprionic acid derivatives, ibuprofen, naproxen
tried first.
•Prophylaxis of diseases due to platelet aggregation
(CAD, post-op DVT)
•Pre-eclampsia (a condition in pregnancy characterized by high blood pressure, sometimes with fluid
retention and proteinuria) and hypertension of pregnancy

35. Aspirin Toxicity -Salicylism
•Headache -tinnitus -dizziness –hearing
impairment –dim vision
•Confusion and drowziness
•Sweating and hyperventilation
•Nausea, vomiting
•Marked acid-base disturbances
•Hyperpyrexia
•Dehydration
•Cardiovascular and respiratory collapse, coma
convulsions and death

36. Aspirin Toxicity -Treatment
•Decrease absorption -activated charcoal, emetics, gastric lavage
•Enhance excretion–ion trapping (alkalinize urine), forced diuresis,
hemodialysis
•Supportive measures -fluids, decrease temperature, bicarbonate,
electrolytes, glucose, etc…

37. Acetaminophen
•Paracetemol (tylenol)–no significant anti-inflammatory effect, but
used for its mild analgesic effect.
•Well-absorbed and without GIT irritation.
•Serious disadvantage: at high doses, severe hepatotoxicity results.

38. Mechanisms of Action
•Analgesia –both centrally and peripherally.
-assoc with anti-inflammatory actions.
-results from inhibition of PG synthesis in inflamed tissues.
-[PGs little pain relief themselves, but potentiate the pain caused by
other mediators of inflammation (e.g., histamine, bradykinin).

39. Mechanisms of Action
•Anti-inflammatory action –PGs in inflammation vasodilation and incr
vasc permeability.
-Inhibition of PGs by NSAIDs attenuates, not abolish, inflammation
(NSAIDs do not inhibit mediators of inflammation).
-Very modest relief from pain, stiffness, swelling for RA often
prescribed for their anti-inflammatory actions.

40. Mechanisms of Action
•Antipyretic actions –Fever, heat stroke, incr T°are hypothalamic
problems.
-So, NSAIDs do not decr body T°.
-Fever release of endog pyrogens (e.g., interleukin-1) released from
leucocytes acts directly on the thermoregulatory centers in
hypothalamus incr body T°.
-This is assoc with incr in brain PGs (pyrogenic).
-Aspirin prevents the T°-rising effects of interleukin-1 by preventing the
incr in brain PGs.

41. Mechanism of Action on the Active Site of COX
•Possess a long channel (COX-2 channel is widerthan
in COX-1).
•Non-selective NSAIDs enter channel (but not aspirin).
•Block channels by binding with H-bonds to an arg half
of the way in.
•This reversibly inhibits the COX by preventing
arachidonic acid from gaining access.
•Aspirin acetylates COX (at ser530) and is, therefore,
irreversible.
•Selective COX-2 inhibitors generally more bulky
molecules -can enter and block the channel of COX-2,
but not that of COX-1.

42. •Paracetamol–reducing cytoplasmic peroxide:
•Recall: peroxide is necessary to activate heme enzyme to the Fe.
•Acute inflammation: paracetamol is not very effective bec
neutrophiles and monocytes produce much H
2O
2and lipid peroxide,
which overcome the actions of the drug.

43. Selective COX-2 Inhibitors
(Coxibs)
•Anti-inflammatory with less adverse
effects, especially GI events.
•Potential toxicities: kidney and platelets -
? increased risk of thrombotic events.
•Assoc with MI and strokebecause they do
not inhibit platelet aggregation. Thus,..
should not be given to patients with CV
disease

45. Other NSAIDs
•Phenylbutazone: additional uricosuric effect. Aplastic
anemia.
•Indomethacin: Common adverse rxns: gastric
bleeding, ulceration, CNS most common:
hallucinations, depression, seizures, headaches,
dizziness.
•Proprionic acids: better tolerated. Differ in
pharmacokinetics; ibuprofen, fenbufen, naproxen
widely used for inflammatory joint disease and few
side-effects.
•Acetaminophen: differs in effects and adverse rxn
from rest. Main toxicity: hepatitis due to toxic
intermediate which depletes glutathione. Treat with
N-acetylcysteine.

46. Mechanism of paracetamol toxicity
N-acetyl-p-benzoquinoneimine (NABQI) 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 the minor metabolite is formed-
hepatic glutathione is depleted and this metabolite binds covalently
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.
ln chronic alcoholics even 5-6 g/day taken for a few days can result in
hepatotoxicity because alcoholism induces CYP2E1that metabolises
paracetamol to NABQI.
Paracetamol is not recommended in premature infants (< 2kg) for
fear of hepatotoxicity.
Treatment : specific: N-acetylcysteine( MUCOMIX,ANTIFEN 200 mg/mlinj in 2, 5 ml
amps)150 mg/kg should be infused i.v. over 15 min, followed by the same .e i v. over
the next 20 hours.

49. Glucocorticoids
-inhibit phagocytosis
-inhibit synthesis of IL-1, TNF, PGs LTs.
-inhibit antigen processing by macrophages
-stabilizes lysosomal membranes
-inhibits accumulation of neutrophils and monocytes at
inflammation site.
-inhibit phospholipase A
2
.

50. Glucocorticoids
•examples:prednisone
dexamethasone
Side effects:
osteoporosis
impaired wound healing
edema, hypertension, congestive heart failure
CNS effects (euphoria -psychosis)
Cushingoid Syndrome
Glucocorticoids

52. Prostaglandin
Biosynthesis,
Function, and
Pharmacologic
Inhibition.

53. Control of vascular tone and platelet activation by thromboxanes and prostacyclins

54. Lipoxins –Anti-inflammatory Mediators
•During inflammation, cells die by apoptosis.
•Lipoxins signal macrophages to clean up.
•During the acute inflammatory process, cytokines (e.g., IFN-γ and IL-
1β) can induce the expression of anti-inflammatory mediators
(lipoxins and IL-4), which promote the resolution phase of
inflammation.

55. Generation of Lipoxins by Aspirin

56. Role of Lipoxins in Anti-inflammatory effects of Aspirin

57. Effect of NSAID’s on Platelet-Endothelial Interactions