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The term NSAIDs does not fully describe the pharmacologic actions of these agents (analgesic, antipyretic, and anti-inflammatory.
1. Analgesic: reduction of pain 2. Anti-Inflammatory: modification of inflammatory reaction 3. Antipyretic effect: of a raised temperature
The clinical features of inflammation have been recognized since ancient times as swelling, redness, pain and heat.
The underlying mechanisms which produce these symptoms are complex, involving many different cells and cell products.
A normal inflammatory response is essential to fight infectionsResponse of the body to injurious stimuli
and is part of the repair mechanism and removal of debris following tissue damage. Inflammation can also cause disease, due to damage of healthy tissue.
Inflammatory mediators Activated leukocytes at a site of inflammation release compounds which enhance the inflammatory response mainly cytokines and eicosanoids (arachidonic acid metabolites). But the complexity of the response is indicated by the range of many mediators:
Eicosanoids (prostaglandins,
thromboxanes, leukotrienes) derived principally from arachidonic acid in cell Walls and formed in almost every tissue in the body. Eicosanoids are involved in most types of inflammation and it is on manipulation of their biosynthesis that most present antiinflammatory therapy is based.
Ex
Phospholipids
In
Arachidonic acid
Cyclooxygenase (COX) 5-lipoxygenase Leucotrienes Endoperoxides PGs TxA2
Prostaglandins
Prostaglandins are a group of lipid like compounds that exhibit a wide range of pharmacologic activities. Appear to be hormones that regulate cell function under normal and pathological conditions.
II. PLATELETS
TXA2 stimulates platelet aggregation PGI2 inhibits platelet aggregation
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COX-1 (constitutive) acts in physiological conditions. Maintains the normal (house keeping function
COX-2 (inducible) is induced in inflammatory cells by pathological stimulus. COX-3 (in brain).
COX-1 (constitutive)
Prostaglandins
Non-selective NSAIDs
Prostaglandins
COX INHIBITORS
NSAIDs
Nonselective COX-1/COX-2 inhibitors
COX-2 inhibitors
Selective (coxibs)
Preferential
Most NSAIDs in currently use are inhibitors of the 2 enzymes The anti-inflammatory action of NSAIDs is mainly related to their inhibition of COX II & their unwanted effect (mainly GIT S/Es) are largely a result of their inhibition of COX I
Shared toxicities of NSAIDs due to prostanoid synthesis inhibition 1. Gastric mucosal damage 2. Bleeding 3. Limitation of renal blood flow 4.Sodium+ water retention and edema formation 5.Analgesic nephropathy 6. Delay / prolongation of labour 7. Asthma and anaphylactoid reactions
Examples<non- selective>
Aspirin (ASA) & other salicylates
Salicylic acid can be used locally as keratolytic agent for treatment of corns ONLY NSAID THAT BLOCKS THE COX ENZYME IRRERVERSIBLY
Uses: 1.As anti-inflammatory effects (e.g. rheumatoid arthritis) 2.For analgesia in painful condition
3.To lower temperature (but Paracetamol is preferred) 4.Anti platelet effect inhibit platelet aggregation & its main clinical importance as prophylaxis; in MI, stroke
Inhibition of TXA2 by Aspirin at LOWER DOSES (75-150 mg) reduce platelet aggregation.
Pharmacological/Physiological Effects
Platelets
ARACHIDONIC ACID
COX -1
COX -2
Platelet TXA2
ASPIRIN
Endothelial PGI2
5. On uric acid
Uric acid excretion occurs because of tubular secretion.
SMALL DOSE Interfere with urate secretion Elevate urate level Blocks the action of uricosuric drugs
Contraindications
1. Peptic ulcer 2. Bronchial asthmawhy?
Cell Membrane Phospholipids
NSAIDS
Phospholipase A2
Bronchospasm
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REYES SYNDROME
Children < 12 years develops viral infection (influenza & vericella)
Administered aspirin
liver dysfunction due to.. Hepatic mitochondrial fatty infiltration of the injury liver
Metabolic encephalopathy
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Piroxicam nonselective COX-1/COX-2 inhibitor that at has long half-life permits once-daily dosing.
Meloxicam has been shown to preferentially inhibit COX-2 over COX-1,It is not as selective as the other coxibs and may be considered preferentially" selective rather than highly selective. The drug has been approved for treatment of osteoarthritis and rheumatoid arthritis. It is associated with fewer clinical GI symptoms
COX-1/COX-2 inhibitors
COX-2 inhibitors
1. Analgesic action
2. Antipyretic action 3. Antiinflammatory action 4. Gastric mucosal damage 5. Renal salt/water retention
(+)
(+) (+) (+) (+) (+) (+)
(+)
(+) (+) (+) (+)
Coxibs are selective COX-2 inhibitors. They exert antiinflammatory, analgesic and antipyretic action with low ulcerogenic potential.
Bextra
Paracetamol Called acetaminophen Used as analgesic, antipyretic agents It does not affect uric acid levels lacks platelet-inhibiting properties Has relatively weak anti-inflammatory activity Given orally, by injection, as suppositories
Therapeutic uses: Substitute analgesic & antipyretic effect of aspirin in those patients with gastric problems & those who do not require the antiinflammatory action of aspirin. It is drug of choice, for children with viral infection
Acute paracetamol poisoning occurs specially in small children who have low hepatic glucoronide conjugating ability. If a large dose (> 150 mg/kg or > 10 g in adult) is taken, serious toxicity can occur. Lethal dose is 250 mg/kg. N-acetyl-p-benzoquinoneimine (NABQI) is a highly reactive metabolite of paracetamol which detoxified by conjugation with glutathione
When a very large doses paracetamol are taken, glucuroconjugation capacity is saturated, more NABQI is formed, hepatic glutathione is depleted and NABQI binds covalently to proteins in liver cells (and renal tubules) causing necrosis
Treatment
activated charcoal, given orally or through the tube to prevent GI absorption, acetylcysteine (by i.v. infusion).
Metabolism of
paracetamol
to hepatotoxic metabolites (NABQI etc.)
(GSH glutathione; SG glutathione moiety)
Daily dose > 7.5 g:
NABQI