pharmacology of NSAIDs

1. NonSteroidalAntiInflammatoryDrugs
(NSAIDs)
Girmay F.
girmaytg@yahoo.com 1

2. Presentation outline
 Introduction
 Mechanism of Action
 Pharmacokinetics
 Clinical Effects
 Drug interaction
 Diclofenac
 Ketorolac
 Aspirin(Acetyl Salicyclic Acid) 2

3. Introduction
 A heterogeneous class of drugs grouped together by
their common Anti-inflammatory , Analgesic and Anti-
pyretic properties.
 Used for Rx of
 Mild-to moderate pain
 Chronic inflammation
 Post –op pain where they have an opioid sparing effect.
3

4.  Most are organic acids.
 conventional NSAIDs can be grouped according to their chemical
structure
4

5. Mechanisms of Action
 Inhibition of the enzyme cyclooxygenase.
 Reduce the production of :
 Prostaglandin synthesis (PGH2, PGE2, PGF2).
 Leukotrienes, prostacyclins.
 Thromboxanes .
5

6. 6

7. Prostaglandins (PGs) : PGE2,PGD2,PGF2
o present in all organs and are synthesised in most cells of
the body.
o Act locally producing many diverse effects via GPC
membrane receptors.
oThey have a variety of effects on Glandular secretions, Renal
function , Peripheral blood vessels and Smooth muscles.
7

8.  Involved in the modulation of pain both at peripheral and
central sites.
 PGs sensitize primary nerve endings in the periphery to the
algesic action of agents (such as bradykinin, histamine and
serotonin) produced as part of the inflammatory response to
tissue injury.
8

9.  Spinal and Supra spinal analgesic effects are due to
modulation of the spinal actions of NMDA and
Substance P.
 NSAIDs may also have direct inhibitory effects on
neutrophils activation and function in inflamed tissues.
9

10. Mechanism of action antipyretic:
1. Inhibition of production of prostaglandins induced by
interlukin-1 (IL-1) and interlukin-6 (IL-6) in the
hypothalamus
2. the resetting of the thermoregulatory system, leading to
vasodilatation and increased heat loss.
10

11.  The COX enzyme has two distinct isoforms
termed COX-1 and COX-2.
 These two enzymes are coded for by two genes
and expressed differentially in various tissues.
11

12.  COX-1:
 being “constitutive” .
 is expressed continuously in many tissues, for example
kidneys, stomach, lung liver and platelets.
 It is involved in various protective homeostatic
Mechanisms, for example Renal blood flow, Gastric
mucosal integrity and platelet aggregation. 12

13.  COX-2:
 being “inducible”, such that it is not normally present in
any appreciable quantity in tissues.
 its production is induced in sites of inflammation and
tissue injury by cytokines (e.g. interleukin-1) and tumor
necrosis factor alpha.
13

14.  Conventional NSAIDs inhibit both enzymes; inhibition
of COX-1 accounting for most of the unwanted side
effects of NSAIDs and inhibition of COX-2 accounting
for the therapeutic effects.
 In theory the ‘perfect’ NSAID would therefore only
inhibit COX-2, leaving COX-1 to continue with normal
homeostatic processes.
14

15.  Selective COX2
Inhibitor( coxibs)
 Celecoxib
 Etoricoxib
 parecoxib.
 Rofecoxib
15

16. 16

17.  effective against pain associated with integumental
structures (pain of muscular and vascular origin, arthritis,
and bursitis) than with pain associated with the viscera.
 Have an opioid -sparing effect after abdominal,
thoracic and orthopaedic surgery.
 less sedation, improved respiratory function, less urinary
retention
17

18. Pharmacokinetics
 NSAIDs are weak organic acids(pKa=3-5)
 Rapidly absorbed in the acid environment of the
stomach.
 Low first-pass metabolism and a high oral bio-
availability.
 Exception: Diclofenac has a high hepatic metabolism
resulting in a bio availability of 60%. 18

19.  highly protein-bound and have the potential to displace
other drugs from plasma proteins so potentiating the
effects these drugs (oral anti coagulants ,anti convulsants
,lithium and oral hypoglycemic agents).
 In general , NSAIDs are eliminated by Hepatic
Biotransformation followed by Renal excretion
19

20. Clinicaleffects/Sideeffects
1. Gastrointestinal tract
 PGE2 have a ‘Gastro-protective effect’
 a decrease in gastric acid production
 an increase in production of the protective gastric mucosal barrier
and an increase in local gastric mucosal blood flow.
 NSAIDs : Decrease prostaglandin production and may also cause
damage to the gastric mucosa by a direct contact physiochemical
effect. 20

21. 21

22. 22

23.  Aspirin, acts in a non-competitive manner by
irreversibly inactivating COX. Platelets cannot synthesis
proteins de novo, and are therefore unable to produce
“new” COX enzyme, thereby rendering them ineffective
for their lifespan of up to ten days.
 It is for this reason that aspirin must be discontinued for
(1-2 weeks) prior to elective surgery. 23

24.  PGI2, produced by normal endothelium,
 inhibit platelet aggregation, antithrombotic properties of intact
blood vessels.
 vasodilatation of vascular beds exception the pulmonary
vasculature where they cause vasoconstriction.
 PGI2 is COX-2 dependent, higher risk of cardiovascular
side effects seen with some COX-2 selective NSAIDs.
24

25.  A small increase in MI risk is associated with the long-term
use of certain NSAIDs (e.g. Diclofenac), others confer no
increased risk (ibuprofen) or perhaps even slightly
reduce the risk (Naproxen).
 The greatest risk appears to be with the long-term use of
COX-2 inhibitors, this has been shown to be associated with
25

26. 3. Renal:
 In patients with heart failure, chronic renal failure and/or
Hypovolaemia, renal blood flow is much more dependent
on prostaglandin-induced vasodilatation .
 NSAID induced reduction in prostaglandin levels can
precipitate acute renal failure.
26

27.  prostaglandins normally inhibiting ADH hormone
production leads to excretion sodium and water.
 NSAIDS increase retention with the risk of oedema
and/or hypertension.
 All NSAIDs are contraindicated in patients with heart
failure and renal failure.
27

28. 4. Obstetrics
 PGs are important for initiating labour .
 NSAID usage can lead to prolonged labour and a NSAID
(commonly rectal Indometacin) is sometimes used as a
tocolytic in premature labour.
 potentially serious side effects including fetal oligiuria,
and premature closure of the ductus arteriosus.
28

29.  NSAID-induced closure in utero can lead to pulmonary
hypertension and myocardial infarction.
 It may increase the risk if miscarriage. The effect seems
to be greatest if NSAIDs are used for more than a week
and around the time of conception.
29

30. 5.Respiratorysystem:
 Bronchospasm in susceptible individuals. ’Aspirin-
induced asthma ‘ affects between 10 and 20% of adults
with asthma, and bronchospasm can be severe and fatal.
 Hyper sensitivity reactions ,urticaria ,rashes and angio-
oedema have been reported.
30

31.  These Rxns are due to COX inhibition w/c increase
arachidonic acid levels and increases metabolism via
lipoxygenase pathway to form of leukotrienes.
31

32. Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000) 32

33. Summery Common Adverse Effects
Gastritis and peptic ulceration with bleeding (inhibition
of PG + other effects)
 GIT bleeding and perforation
o Platelet Dysfunction
 Acute Renal Failure in susceptible
 Sodium+ water retention and edema
 Analgesic nephropathy
 Prolongation of gestation and inhibition of labor.
 Hypersensitivity (not immunologic but due to PG
inhibition)
33

34. Drug interactions
 can interact with other drugs in various ways.
 Firstly, as a result of their potential effect on renal function the
plasma levels of other drugs may be affected (e.g. lithium).
 NSAIDs may compound the effects of another drug. For example,
patients taking an NSAID and Warfarin are at greater risk of
severe hemorrhage
 an elevated INR which may occur in patients taking warfarin
and a concomitant NSAID.
34

35. 35

36. DICLOFENAC
KETOROLAC
ASPIRIN(ASA)
36

37. DICLOFENAC
 A phenylacetic acid derivatives.
 Potent anti inflammatory and analgesic properties.
 It has a great affinity for COX than other NSAIDs.
 Potent inhibitors of PGs synthesis.
 A central analgesic action is mediated by endogenous
opioids .
 Higher therapeutic ratio than most NSAIDs. 37

38.  Indication:
 mild to moderate pain.
 For relief of signs and symptoms of osteoarthritis,
rheumatoid arthritis and
 For acute or long-term use in the relief of signs and
symptoms of ankylosing spondylitis.
38

39. Pharmacokinetics
 Absorption
 Diclofenac is 100% absorbed after oral administration
compared to IV administration as measured by urine
recovery.
 Due to first-pass metabolism, only about 50% of the
absorbed dose is systemically available
39

40.  Distribution
 More than 99% bound to human serum proteins,
primarily to albumin.
 Serum protein binding is constant over the
concentration range (0.15 to 105 mcg/mL) achieved
with recommended doses.
40

41.  Excretion: eliminated via metabolism and subsequent
urinary and biliary excretion of the glucuronides and the
sulfate conjugates of the metabolites.
 Little or no free unchanged diclofenac is excreted in the
urine
 65% of the dose is excreted in the urine and approximately
35% in the bile as conjugates. 41

42.  Metabolism:
 Five diclofenac metabolites have been identified in human
plasma and urine. The metabolites include
 4'-hydroxy-, 5-hydroxy, 3'-hydroxy-, 4',5-dihydroxy- and 3'-
hydroxy-4'-methoxy Diclofenac.
 Diclofenac metabolites undergo further glucuronidation
and sulfation followed by biliary excretion.
42

43.  Dose:
 Paediatric ; PO/PR:1mg/kg tds, maximum
3mg/kg/day(>1yr).
 Adult : PO/PR: 25-50mg tds(or 100mg 18-hourly)
 Maximum 150 mg/day
 Onset of action: 30 minutes.
 Duration of action: up to 8 hours. 43

44.  Cautions C/I :
 Hypersensitivity to aspirin
 Asthma
 Severe renal impairment
 Peptic ulceration
44

45. KETOROLAC
 A pyrrole acetic acid derivatives
 More effective as analgesic than as anti inflammatory
and anti pyretic drug.
 The trimethamine salt possesses sufficient water
solubility to allow it to be given IV or IM injection
 Dose:10-30mg
45

46. ASPIRIN(ASA)
 Derivative of salicylic acid
 Weak organic acids , Pka of 3.5
 Rapid absorption in the stomach mainly in the unionized
form.
 Salicylate anion trapping can occur in the alkaline env’t of
the stomach and absorption may occur in the small
intestine . 46

47. MOA: Irreversible, non-selective COX inhibitor(causes
acetylation of COX) .
 Low dose- analgesic-antipyretics,300-600mg,6-8 hourly
 inhibition of PGs in the periphery and has some central
action.
 Standard anti inflammatory agent, Most potent
 High dose-anti inflammatory(3to 6g). 47

48.  Pharmacokinetics:
 Rapidly absorbed from the stomach and upper GI.
 Peak plasma level within 2hrs.
 Hydrolyzed by plasmaesterasein blood ,liver and tissue to:
Acetic acid and salicylates .
 Salicylates are mainly metabolized in the liver to salicyluric acid and
glucuronides . there fore Readily excreted by the kidney.
48

49. Clinical application
A. Anti inflammatory Action:
• Aspirin irreversibly inactivates COX-1 and COX-2 by
acetylation of a specific serine residue.
 prevent PG(PGE and PGF) synthesis.
 Inhibits migration PMNL and Macrophages into sites
of inflammation.
 Inhibits granulocytes adhesion. 49

50.  used to treat:
 rheumatoid arthritis ,Rheumatic fever ,juvenile
arthritis , osteoarthritis and other inflammatory
disorders.
B. Cardio protective; Low dose aspirin (75mg/day)
has been shown to reduce the risk of TIA secondary to
MI.
50

51. C.Prevention of pre- eclampsia
D. As analgesic : 300 to 600 mg during 6 to 8 h for
headache, backache, pulled muscle, toothache, neuralgias.
 Aspirin is a weaker analgesic than morphine-type drugs
 Aspirin 600 mg < Codeine 60 mg < 6 mg Morphine
51

52. Side effects
 Platelet dysfunction
 GI problems
 Acute Renal Failure in susceptible ,Sodium+ water
retention and edema.
 Hypersensitivity reaction ,aspirin induced asthma in
susceptible individuals.
52

53. C/I andCautions
 should not be given to children under 15 years unless
specifically indicated, e.g. for juvenile arthritis (paracetamol
is preferred).
 Reyes syndrome
 liver dysfunction and Encephalopathy following an acute
viral illness which has a mortality rate of 20-40%.
53

54.  C/I
 in patients with bleeding disorders
 Salicylates are not recommended during pregnancy;
they may induce:
 postpartum hemorrhage
 premature closure of the fetal ductus arteriosus.
54

55. Salicylism
o Chronic ingestion of large dose of aspirin /Over dose
(toxicity) when the amount of aspirin ingested is >150-
175mg/kg.
 Characterized by ;
o Tinnitus , dizziness, ,deafness, sweating and Hyperthermia .
o CNS stimulation – agitation, confusion and convulsion
o CNS depression –stupor, coma. 55

56.  Effect on Respiration: triphasic
1. Low doses: uncoupling phosphorylation → ↑ CO2 →
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
56

57. Treatment of Aspirin Toxicity
1. Correction of acid—base disturbances
2. Replacement of electrolytes and fluids
3. Cooling
4. Alkalinization of urine with bicarbonate to reduce salicylate
reabsorption
5. Forced diuresis, hemodialysis
6. Gastric lavage or emesis
57

58. NSAID Therapy Guidelines
 The lowest dose for the shortest duration
of therapy that accomplishes the therapeutic goal should be
used
 Most NSAIDs are not used in children, however
ibuprofen is an exception
58

59. 59