NSAID-LECTURE Non steroidal anti-inflammatory drugs

It will be helpful to read about analgesic

1. 1. Pt. 18 yrs, watches horror movie
all night. Develops headache.
2. Patient 60 yrs., with rheumatoid
arthritis. Develops pain over joints
3. Patient 40 yrs, suffers cancer pains
•Morphine ? Aspirin ? Steroids ?
1.Aspirin
2.Aspirin , Steroids
3.Morphine

2. What is the difference between them ?
•Aspirin: analgesic & antiinflammatory-
peripherally
•Morphine:only analgesic (centrally ) addicting
•Steroid : only antiinflammatory, pain relief
secondary to this effect
•Steroids :↓PG ,↓LT synthesis
•NSAIDs : ↓PG, ↑ LT synthesis

3. ANALGESICS
Non-Narcotics NarcoticsVisceral
Somatic pain Opioids Pain
NON-NSAIDs Pain
without inflammation
NSAIDs
Non steroidal anti-inflammatory drugs
Relief of pain associated with inflammation

4. Inflammation
Noxious Innocuous stimuli
Stimuli (Autoimmune Abs, Polln)
Injured cells
Migrating cells
AMINES LIPIDS PEPTIDES
5-HT
Histamine Prostaglandins BradikininIL-1
Inflammatory process triggered

5. NSAIDsare
Anti-inflammatory drugs
targeted against Specific mediator
( Prostaglandins )
↓
effective against that inflammation
triggered by that mediator ( PG ) only

6. Prostaglandins -PGE
2, PGF
2, PGI
2
20-C, unsaturated FA derivatives with
a cyclopentane ring
letter after PG refers to
substitutionsA,B…G,H
subscripts indicate
no. of double bonds

7. PGs:Autacoids
local hormones
do not circulate
Thromboxanes & Leukotrienes
related lipids derived from
same precursors of PGs

8. Cell membrane phopholipids
LOX-PathwayArachidonic acid Cox-Pathway
5-Lipoxygenase Peroxides Cycloxygenase
5-HPETE NSAIDS Inhibits
LEUKOTRIENES PG-G
2
PGI
2Prostacyclin
TxA
2Thromboxane PG H
2
PGI2
PGF2α

9. • NSAIDs Mechanism ?
•Inhibition of Cyclooxygenase (COX)
• 3Forms : COX 1 & COX 2 & COX 3 ?
• Cox 1 :involved in Physiological functions
“CONSTITUTIVE”
(-)leads to Adverse Effects
• COX 2: Operates during inflammation
“INFLAMMATORY”
(-) leads to Theraputic Effect
COX 3 : In brain, mediates fever & pain

10. Inhibition of Cyclooxygenase (COX)
3Forms : COX 1 & COX 2 & COX 3?
Cox 1 :involved in Physiological functions
“CONSTITUTIVE”
(-)leads to Adverse Effects
COX 2: Operates during inflammation
“INFLAMMATORY”
(-) leads to Therapeutic Effect
COX 3 : In brain, mediates fever & pain

11. What is the role of COX 2 ?
It is associated with :
1.Inflammation
2.Hyperalgia
3.Angiogenesis
4.Neuromodulation
5.Cancer
6.Alzheimer disease

12. •PREFERENTIAL INHIBITION OF
COX-2 OVER COX 1
1.CYTOPRPOTECTIVE PGs:
GIT –SIDE EFFECT avoided
2.PLATELET FUNCTION -PGs
BLEEDING –avoided
3.KIDNEY: COX-1 & COX 2 active
RENAL BLOOD FLOW COMPROMISED
Na
2 +
H
2O Retention & Edema (equally )

13. Newer classification
•NON SELECTIVE COX INHIBITORS
–A. REVERSIBLE INHIBITORS
–B. IRREVERSIBLE INHIBITORS
•PREFERNTIAL COX2 INHIBITORS
•HIGHLY SELECTIVE COX 2 INHIBITORS
•INHIBITOR OF COX 3 + COX 1 (WEAK)
•NSAID WITHOUT (-) OF PG SYNTHESIS

14. NON SELECTIVE COX INHIBITORS
I IRREVERSIBLE INHIBITORS
ASPIRIN & OTHER SALICYLATES –DIFLUNISAL
IiREVERSIBLE INHIBITORS
• PROPIONIC ACID DERIVATIVES
IBUPROFEN, FENOPROFEN , KETOPROFEN, FLURBIPROFEN
OXAPROZIN & NAPROXEN
2.INDOLE ACETIC ACID-DERIVATIVES
INDOMETHACIN, SULINDAC
3.OXICAM DERIVATIVES :
PIROXICAM

15. 4.FENAMIC ACID DERIVATIVES
MEFENAMIC ACID, MECLOFENAMATE
ENFEMAMIC ACID, FLUFENAMIC ACID
5. PYRAZOLONES
PHENYLBUTAZONE,
OXYPHENBUTAZONE,
METAMIZOL,
PROPIPHENAZONE,
6. ARYL-ACETIC ACID DERIVATIVES
DICLOFENAC,
TOLMETIN,
KETOROLAC

16. PREFERNTIAL COX2
INHIBITORS
1. NIMESULIDE
2 MELOXICAM
3. NEBUMETONE

17. HIGHLY SELECTIVE COX 2
INHIBITORS
•1. CELECOXIB
•2. ETEROCOXIB
•VALDECOXIB & ROFECOXIB
•BANNED DUE TO CARDIAC
THROMBOTIC EVENTS

18. V.IINHIBITOR OF COX-3 (Good)
COX-1 ( POOR )&
NO COX-2 INHIBITION
PARACETAMOL, METAMIZOL
VI. NSAID WITH NO (-) OF PG
SYNTHESIS (Atypical NSAID)
NEFOPAM

19. COMMON FEATURES OF NSAIDS
•CHEMICALLY DISSIMILAR
•SHARE ANTIPYRETIC
ANALGESIC
ANTI-INFLAMMATORY ACTIONS
•PRIMARY MOA INHIBITION OF COX
ASA -IRREVERSIBLY
REST-REVERSIBLY
•ALL ARE ACID DERIVATIVES EXCEPT
NEBUMETONE A KETONE PRODRUG

20. •DO NOT INHIBIT LIPOXIGENASES
•SHARE COMMON SIDE EFFECTS
•ALL ARE EFFECTIVE IN
RA, SERO (-) SPONDYLOARTHROPATHIES,
OSTEOARTHRITIS, MUSCULOSKELETAL
SYNDROMES.
•ALL EFFECTIVE IN GOUT EXCEPT
TOLMETIN

21. •ALL UNDERGO ENTEROHEPATIC
CIRCULATION ( EHC )
GI irritation to EHC
•MOST OF THEM ARE HIGHLY
BOUND TO ALBUMIN MOSTLY
•ALL APPEAR IN SYNOVIAL FLUID
AFTER REPEATED DOSING
Short t½ stays longer
Long t½ to their t½

22. PHARMACOLOGICAL
ACTIONS

23. 1.ANTI –INFLAMMATORY
Cox-inhibition –PG synthesis

Inflammatory response
mediated by PG
USE:Arthritis (OA,RA) GOUT,
Rheumatic fever
* Does not arrest progress/ or induce
remission

24. 2. ANALGESIC (PERIPHERAL)
Nerve ending
PG-E2 –SENSITIZES BRADYKININ
PR HISTAMINE, ETC stimuli
MECHANICAL
ASA PAIN SENSATION PICKED UP
& CONDUCTED
USE:Treatment. Pain –of-low-Moderate intensity
Arising from integumental structures
Superior to opioids –Pain associated with inflammation

25. 3. ANTIPYRETIC
Infection HT-THERMO-Normal
Inflamm. R-CENTRE Temper,
Malignancy pgn
Allergy PGE2 >37°CHyperpyrexia
Hyper
sensitivity ASA Normal Tem.
WBCs
RESETS ‘THERMOSTAT’
Additional: Peripheral Heat Dissipation
Vaso-dilation Temp. ↑ Sweating

26. ANTI THROMBOTIC –
Only Aspirin ? Why low dose ?
•ASA-can acetylate and irreversibly
inhibit Cox-I on platelets.
(Others only 4-6 hrs)
•Low dose (60-80mg) enough to
inactive TXA
2
•High dose–PGI
2also will be
inactivated
4. EFFECT OF PLATELETS

27. TXA
2 (Platelets cannot synthesize new enzy.)
PGI2 synthesis recovers fast(endothelial cells
can synthesize new enzyme)
TXA
2–Proaggregatory
PGI
2 –Anti -aggregatory
USE:Prophylaxis –TIA, unstable angina, MI
coronary art.thrombosis

28. ADR 1:↑Bleeding time :
C I –in ulcer
dose of anti coagulants
stop ASA 1 wk prior to surgery
5.TOCOLYTIC
Threatened abortion,
Preeclampic Toxemia
( PET ↑ed by TxA
2 )

29. 6. In cancer :NSAIDS-Chronic use
incidence of colorectal cancer
(Cox-2-inhibition)
7. Alzheimer’s disease
Inhibits inflammatory events &
components
→ severity of disease
8. Closure of patent ductus arteriosus
PGE2 –Keeps D.Art.-Open
↑ (-)
ASA →Closure

30. 9. Use Of Salicylates For External Applications
TOPICAL SALICYLIC ACID –
Treatment ofCorns, Calluses
Epidermophytosis
Methyl Salicylate→Cutaneous counter
(oil of wintergreen) irritant in liniments

31. 10. GIT :Actions –contributes to ADR
NSAIDS PGI
2 PGE
2 & PGF
2
↑ HCl (-) (+)
Mucus HCl Mucus secretion
 secretion stomach & Int.
ADR Hence
Protect mucosal layer

32. ADR 2 :
1. Epigastric distress
2. Ulceration
3. Hemorrhage
Rx with misoprostol: PGE
1analog
Enteric coated ASA / Buffered ASA
Only marginally help

33. 11. RENAL EFFECTS
Use :Bartter’s syndrome
Loss of H
2O, Na, K,Cl -in urine→
↑ Reninhyperreninemia
NSAIDs (-) PGE
2& PGI
2–reversal
Retention of Na, H
2O & K
ADR-3: Edema, Hyperkalemia

34. 12. RESPIRATORY ACTIONS
a.Therapeutic dose :
↑alveolar ventilation
(uncouple oxid.PO4ln. →↑Co
2&
↑ respiration )
b. High dose :
Hyper ventilation & Res. alkalosis
(direct stimulation of Res. Centre )

35. C. Toxic dose :
Respiratory paralysis →
Resp. acidosis
(due to continued Co
2production)
↑ Res→ Res. alkalosis→ Resp.
Acidosis
↑ DOSE → → → ↓
uncompensated metabolic acidosis
ADR –4

36. 13. METABOLIC PROCESSES
Toxic dose :uncouples oxidative
phosphorylation
Energy
↑Tem Heat ATP production
↑↑ASAdose normal
ADR-5

37. 14. HYPERSENSITIVITY
ADR 6 :
↑↑Lipoxygenase pathway.
Allergy –urticaria,
broncho constriction,
angioneural edema

38. ADR 7 -Reye’s syndrome:
Associated with viral infection
•Fatal fulminating hepatitis with
cerebral edema
•Common in children with ASA use
(Give Paracetamol instead of ASA)

39. ADR 8-URATE EXCRETION (DOSE RELATED)
LOW DOSE →↓Urate Excretion
< 2G / D
HIGH DOSE→↑ urate Excretion
>5G/D (-) s R.T Reabsorption

40. SALICYLATES DOSE DEP. EFFECTS
1.Mild, chronic toxicity : SALICYLISM
2.Acute symptoms
Mild :N,V, headache, mental confusion,
dizziness
Severe :salicylate toxicity intoxication
Restlessness, delirium, hallucination,
convulsions, hyperpyrexia, hyperglycemia
Lethal:Respiratory failure, Vasomotor
collapse , Death

42. TREATMENT:
1.Measure serum salicylate conc. & pH.
2.Mild :Symtomatic treatment
↑ urinary pH →↑ Excretion
3. Serious:
IV fluids, dialysis (Hemo/ peritoneal)
correction of acid-base and electrolyte
balance
* diflunical –no salicylates

43. Drug interaction with NSAIDs
•NSAIDS ↓ THE THERAPEUTIC EFFECT OF :
Diuretics, BBs, ACEIs.,
↑ the ADR of anticoagulants, OHAs,
Corticosteroids, cyclosporine
(-) metabolism OACs, SUs., Phenitoin,
valproate
•EXCRETION OF NSAIDS ↓ BY
Digoxin, Li, AGs,, Methotrexate

44. ASA dose
•Analgesic & antipyretic : < 1G /day
•Antithrombotic dose : < 100 mg / day
•Antiinflammatory dose : 3-5 G / day

45. ASA : low dose -1
st
order kinetics
high dose –Zero order kinetics

46. •ASA poor water solubility :less Abs.
Microfining, addition of alkali :↑Abs
•Deacetylated in :
Gut, Plasma & tissues to SSA
•Hepatic conjugation with
glycine (major)and Gluc. Acid (lesser)
•Good placental entry
•Toxic doses: t ½ > 30 H

47. Preferential COX 2 inhibitors

48. •NIMESULIDE :addl. MOA (-) of
TNF αrelease, PAF synthesis, Superoxides
formation, metaloproteinase activity in
cartilage
•ADR:FULMINATING HEPATIC FAILURE
PAEDIATRIC PREPS. –BANNED
•MELOXICUM
LONG ACTING,< ADR
•NEBUMETONE KETONE PRODRUG
ANTIPYRETIC ACTION > ASA, ADR< ASA
•ETODOLAC: < GIT ADR

49. Highly Selective COX Inhibitors
•CELECOXIB, ETEROCOXIB ( long t ½ ),
•NO ANTIPLATELET ACTION
•CONCEERN OVER NO COX -1 (-)
•MAY NOT COVER WIDE RANGE OF INFLMN.
•Ulcer & H .pylori induce COX 2: protection
•JUXTAGLOMERULAR COX 2 : CONSTITUTIVE
Na & water retention
Selective COX 2 (-) → ↓ PGI2 without (-)
platelet TxA2 → ↑ stroke & heart attack
•VALEDEOXCIB & ROFECOXIB BANNED RECENTLY

50. SPECIFIC USES
•Ankylosing spondylitis :Indomethacin
•Gout:Naproxen
•Patent ductus arteriosus :Indomethacin
•RA :Oxaprozin
•Dysmenorrhoea :Mefenamic acid
•Post op. analgegiaexcept Obst. :Ketorolac
•Topical gel:Diclofenac, Piroxicum, Naproxen,
Nimesulide
•Eye Drops :Ketorolac, Fluribiprofen, Diclofenac
•Antithrombotic :low dose aspirin

51. NSAID SPECIFIC ADR
•INDOMETHACIN :Contra indicated in
PREGNANCY, EPILEPSY,
PSYCHIATRIC ILLNESS
•NIMESULIDE : CI in infants
•DICLOFENAC :caution –Hepatotoxicity
•ASPRIN :CHILDREN ( VIRAL INFECTION)

52. PARACETAMOL
•Safe, widely used, alternative to ASA
•No anti inflammatory action
•No prolongation of BT
•No GIT irritation / bleeding
•No renal / CVS effects
•Potent anti pyretic = ASA
•Potent analgesic = ASA

53. MOA :
•COX 3 : INHIBITION-Marked
•COX 2 : INHIBITION -NIL
•COX 1 : INHIBITION-Poor
•COX 3 : Abundant in brain
mediates fever & pain
COX 1 : also mediates INFLMN, butparacetamol not
active in the pr. of superoxide
SO, ONLY ANALGESIC & ANTIPYRETIC AND NO
ANTIINFLAMMATORY ACTION.

54. Metabolism:
Paracetamol →N-acetyl benzo quinonone imine
↓ ↓ minor path way
Sulp. & gluc. Acidglutathione conjugation
Inactive metabolite
•Toxic dose. > 150 mg /kg
•Fatal dose > 250 mg/ kg
•Plasma transaminases increased
•Prothrombin time increased
•Bilirubin conc. increased
•Cenrilobular hepatic necrosis & renal tubular
necrosis
Chronic alcoholics & children are more prone

56. N-ACETYL CYSTEINE
•DETOXIFIES NABQI
•REPLENISH GSH STORES
•ALSO CONJUGATES DIRECTLY AS
GSH SUBSTITUTE
•PROTECTS AGAINST EXTRA
HEPATIC INJURY
•ANTIOXIDANT
•ANTI INFLAMMATORY

57. NEFOPAM
Cyclic analog of orphenadrine
Analgesic potency :> NSAIDS < OPIODS
•No resp..depression
•No gastric irritation
•No dependance
Use:Acute / post operative pain,cancer pain

58. MOA : No PG synthesis (-)
•Uptake inhibitor of 5HT, DA, NE
•Anti muscarinic (ADR )
•Sympathomimetic (Avoid in MI)
ADR :
•Convulsions, cerebral edema
CONTRAINDICATIONS:
•Glaucoma / Epilepsy
•USE :Post Op., Cancer, dental pain