Dr. Yieldez Bassiouni
InflammationThe 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.
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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Inflammation
ProstaglandinsMediate pain, fever and headacheProduced via cyclooxygenase
pathwayCyclooxygenase pathway produce
prostaglandins, prostacyclines and thromboxanes
Thromboxanes causes vasodilation which lead to headache.
Mediators of inflammation
Cyclooxygenase enzymes make prostaglandins from acracadonic acid in the cell membrane
Leukotriensproduced via lipooxygenase pathway
components of the lipid-signalling pathway
have potential role in the inflammatory cascade as contributors to pain.
Antiinflammatory Drug ActionSteroidal antiinflammatory drugs decrease inflammation by inhibiting arachidonic acid formation.
Nonsteroidal antiinflammatory drugs decrease inflammation by inhibiting cyclooxygenase enzymes.
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NSAIDsNSAIDs 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 anti-inflammatory 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 GITPGs (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.
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. anti-thrombotic.
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 salicylateOther NSAIDs:
Propionic acid derivatives e.g. Ibuprofen and naproxen.
OxicamsAryl 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 - AspirinDuration of action ~ 4 hr.Orally Weak acid so, non-ionized in
stomach easily absorbed.
Pharmacological Actions of Salicylates
Analgesic actionSalicylates 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 bloodInhibits 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 actionSmall 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 effectsGastric 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).
SalicylismSalicylism: (occurs after repeated
administration of large doses of salicylates as in rheumatic fever and gout). Its symptoms are:
HeadacheMental confusion, Ringing in the earsVisual disturbancesSweating 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 NSAIDsIbuprofen: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 actingDiclofenac: (Voltaren)It is very potent used in:
Rheumatoid arthritis and osteoarthritisRenal 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.
ParacetamolIt 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.
ToxicitySkin 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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