Download NSAIDs not 4 322

Dr. Yieldez Bassiouni
Inflammation
 The inflammatory process is a normal
response to injury.
 Inflammation is considered the first
step in the process of healing.
 Inflammation can become exaggerated,
which leads to further tissue damage.
Inflammation
 When tissues are damaged, substances like
histamine, bradykinin, PGs, 5HT are
released that produce vasodilation and
increased permeability of the capillary walls
 Leukocytes migrate to the area to destroy
harmful substances introduced by the
injury.
 Redness, swelling (edema), warmth, pain,
and loss of function.
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Mediators of inflammation
Prostaglandins
 Mediate pain, fever and headache
 Produced via cyclooxygenase pathway
 Cyclooxygenase pathway produce
prostaglandins, prostacyclines and
thromboxanes
 Thromboxanes causes vasodilation which
lead to headache.
Cyclooxygenase enzymes make prostaglandins from acracadonic acid
in the cell membrane
Leukotriens
produced via lipooxygenase
pathway
components of the lipid-signalling
pathway
 have potential role in the
inflammatory cascade as
contributors to pain.
Antiinflammatory Drug Action
 Steroidal antiinflammatory drugs
decrease inflammation by inhibiting
arachidonic acid formation.
 Nonsteroidal antiinflammatory drugs
decrease inflammation by inhibiting
cyclooxygenase enzymes.
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NSAIDs
 NSAIDs are group of drugs that share in
common the capacity to induce:
 Analgesic effect.
 Antipyretic effect.
 Anti-inflammatory effect.
 Paracetamol is an analgesic and
antipyretic drug with no antiinflammatory activity. It is not included
in NSAIDs.
ANALGESIC
Drug that relieve pain.
ANTIPYRETIC
Drug that lower
the elevated body
temperature to
normal.
MOA OF NSAIDS
PGs have protective effect on GIT
 PGs (generated via COX-1)
1) inhibit stomach acid secretion,
2) stimulate mucus and HCO3- secretion,
vasodilation and therefore,
3) are cytoprotective for the gastric mucosa.
 Therefore, NSAIDs with COX-1 inhibitory
activity will produce gastric irritation
Cyclo-oxygenase (COX)
 Exists in the tissue as constitutive isoform
(COX-1).
 At site of inflammation, cytokines stim the
induction of the 2nd isoform (COX-2).
 Inhibition of COX-1 is responsible for their
GIT toxicity.
 Inhibition of COX-1 exerted antiplatelet
activity
 Inhibition of COX-2 is responsible for the
antiinflammatory effect of NSAIDs.
COX (cont’d)
 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.
THERAPEUTIC USES
 Fever (non-specific).
 Analgesic (headache, toothache, myalgia and
arthralgia).
 Common cold (lowers fever and relieves
headache and muscle aches).
 Rheumatoid arthritis .
 Acute rheumatic fever
 Reducing the risk of myocardial infarction.
Aspirin in low dose (75- 150 mg/ day or lower)
inhibits platelet aggregation i.e. antithrombotic.
CLASSIFICATION OF NSAIDS
Non-selective COX
inhibitors
Selective COX-2 inhibitors
Classification of NSAIDs:
 Non-selective COX inhibitors:
 These NSAIDs inhibit the constitutive COX-
1 and the inducible COX-2 so are liable to be
associated with GIT upset and renal
impairment on long term use. This group is
further classified according to chemical
structure into:
Salicylates e.g. acetyl salicylic acid,
sodium salicylate
Other NSAIDs:
 Propionic acid derivatives e.g.
Ibuprofen and naproxen.
 Oxicams
 Aryl acetic acid derivatives e.g.
Diclofenac.
 Indole derivatives e.g.
Indomethacin and sulindac.
Selective COX-2 inhibitors:
 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.
Mechanism of action of NSAIDs:
 Acetyl salicylic acid, the prototype of
NSAIDs induces irreversible inhibition of
both COX-1 and COX-2 enzymes. This
inhibit conversion of arachidonic acid to PG
and TXA2.
 Other NSAIDs cause competitive
reversible inhibition of COX enzymes.
 Celecoxib is a selective COX-2 inhibitor.
The Salicylates - Aspirin
 Duration of action ~ 4 hr.
 Orally
 Weak acid so, non-ionized in stomach 
easily absorbed.
Pharmacological Actions of Salicylates
Analgesic action
 Salicylates act on subcortical level to
produce their analgesic action:
 By raising the threshold to painful stimuli.
 Through its anti-inflammatory action
because inflamed tissue will stimulate the
pain receptors.
Antipyretic action
 Salicylates lower the elevated body
temperature to normal by:
 Inhibiting prostaglandin synthesis
(centrally).
 Acting on heat regulating center in the
hypothalamus promoting loss of heat by:
 Vasodilatation of cutaneous blood vessels
stimulating radiation.
 Increasing sweating and evaporation.
Anti-inflammatory and anti-rheumatic
action
 Relieves muscular pain.
 Relieves joint pain and swelling.
 through decreasing the synthesis of
prostaglandins.
On the G.I.T.
 Salicylates irritate gastric mucosa leading
to nausea and vomiting.
 Central due to stimulation of CTZ.
 Peripheral due to irritation of gastric
mucosa by the released salicylic acid.
 Higher doses may cause: Gastric ulceration,
and bleeding.
Effect on the blood
 Inhibits platelet aggregation secondary to
inhibition of platelet COX and reduces
production of TXA2 (a platelet aggregating
factor) with prolongation of bleeding time.
 Large doses lead to hypoprothrombinaemia
and prolongation of coagulation time.
 This effect is reversed by vitamin K.
Uricosuric action
 Small doses: (less than 5 g /day) depress
uric acid secretion by proximal tubules
causing uric acid retention.
 Large doses: (greater than 5 g/day)
inhibit the renal reabsorption by proximal
tubules, increasing uric acid excretion,
decreasing its plasma level thus producing
uricosuric action.
 This effect is enhanced if the urine is
made alkaline.
Side effects
 Gastric irritation, N&V , gastric
ulceration, bleeding
 Hypersensitivity; Bronchoconstriction,
Urticaria.
 Mechanism: by inhibiting COX enzyme,
therefore arachidonic acid will be acted upon
by lipo-oxygenase enzyme increasing
leukotrienes (powerful bronchoconstrictor).
Salicylism
 Salicylism: (occurs after repeated administration
of large doses of salicylates as in rheumatic fever
and gout). Its symptoms are:





Headache
Mental confusion, Ringing in the ears
Visual disturbances
Sweating
Nausea, vomiting and diarrhea
 Disappear after stoppage of the drug
Contraindications of Salicylates:
 Patients with peptic ulcer.
 Patients having hypersensitivity reactions to
salicylates.
 Bleeding tendency.
 Patients taking anti-coagulants.
 Gout: in small dose.
 Viral infections in children
Other NSAIDs
Ibuprofen:
 Effective and better tolerated (less side effects).
 First choice in inflammatory joint diseases.
Naproxen:
 Related to ibuprofen. More potent. Moderate risk of side
effects, longer acting
Diclofenac: (Voltaren)
 It is very potent used in:
 Rheumatoid arthritis and osteoarthritis
 Renal colic and postoperative pain
Indomethacin (Indocid)
 Potent, but due to its serious side effects, its use is limited
Selective COX-2 Inhibitors
Celecoxib:
 It is a selective COX-2 inhibitor that
spares COX-1, thus it does not inhibit
synthesis of protective PGs in the gut.
Hence, its anti-inflammatory effect is
associated with less GI adverse effects.
Paracetamol
 It is an analgesic-antipyretic with no anti-
inflammatory action.
 It effectively inhibits PG synthesis in the
CNS resulting in analgesic and antipyretic
effects but it is a weak PG inhibitor in
peripheral tissue.
 It has no anti-inflammatory effect.
 A commonly used analgesic antipyretic
instead of aspirin in cases of:
 Peptic or gastric ulcers.
 Bleeding tendency.
 Allergy to salicylates.
 Viral infections in children (to avoid
Reye syndrome).
 Pregnancy.
 Reye syndrome is sudden (acute) brain
damage and liver function problems of
unknown cause.
 The syndrome has occurred in children
who have been given aspirin when they
have chicken pox or the flu. Reye
syndrome has become very uncommon
since aspirin is no longer
recommended for routine use in
children.
Toxicity
 Skin rash.
 Liver damage (with over dosage).
 NB. In case of acute paracetamol poisoning,
N-acetyl cysteine is a specific antidote and
should be given as early as possible (it
contains -SH group)
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