COX INHIBITORS

Nonsteroidal anti-inflammatory drugs Nonopioid analgesics

Nonsteroidal Anti-Inflammatory Drugs

NSAIDs means.. Non Steroidal Anti Inflammatory Drugs Usually referred to as NSAIDs to distinguish them from Corticosteroids (which treat inflammation effectively)

The term NSAIDs does not fully describe the pharmacologic actions of these agents (analgesic, antipyretic, and anti-inflammatory.

Most of these drugs have 3 major types effect:

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

Inflammatory stimulus (+)

Phospholipase A2

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.

 Inflammation is triggered by release of chemical mediators as Prostaglandins (PGs), Leukotrienes

II. PLATELETS
TXA2 stimulates platelet aggregation PGI2 inhibits platelet aggregation
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Cyclooxygenase (COX) is found

bound to the endoplasmatic reticulum. It exists in 3 isoforms:

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).

NSAIDs inhibit the COX enzyme, which exists in two forms

Arachidonic acid

COX-1 (constitutive)

COX-2 (induced by inflammatory stimuli) COX-2 selective NSAIDs

Prostaglandins

Non-selective NSAIDs

Prostaglandins

Gastrointestinal cytoprotection Platelet activity

Inflammation Pain Fever

Vane & Botting 1995

COX INHIBITORS
NSAIDs
Nonselective COX-1/COX-2 inhibitors

COX-2 inhibitors
Selective (coxibs)

Selective COX-3 inhibitors

Antipyretic analgesics

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

Benefical actions of NSAIDs due to prostanoid synthesis inhibition

1.Analgesia
2. Antipyretic 3. Antiinflammatory action

4. Anthithrombotic action (Aspirin)

5. Closure of ductus arteriosus(Indomethacin)

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

Vasoconstriction Platelet Aggregation

Vasodilation Anti-Platelet Aggregation

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

LARGE DOSE Inhibit reabsorption Uricosuric action

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6.Decrease % of radiation induced diarrhea. 7.Colonic and rectal cancer

Contraindications
1. Peptic ulcer 2. Bronchial asthmawhy?
Cell Membrane Phospholipids

NSAIDS

Phospholipase A2

Arachidonic Acid Cyclooxygenase I&II Leucotriens

Bronchospasm

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3.Viral infection in children Because it cause rare Reye's syndrome

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

??? Serious and fatal complications ???

So aspirin to be avoided, paracetamol is preferred.

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Aspirin Toxicity - Salicylism

Headache , tinnitus , dizziness , hearing impairment , dim vision Confusion and drowsiness Sweating and hyperventilation Nausea, vomiting Marked acid-base disturbances Hyperpyrexia Dehydration Cardiovascular and respiratory collapse, coma convulsions and death

 Therapeutic doses of asprin:

Relief pain & antipyretic effect 300-600mg/day every 4-6hrs Suppress inflammation larger Dose may be needed

Indomethacin Used :1. to close ductus arteriosus in newborn 2. Management of pretermlabour.

S/Es: A high incidence (up to 50%) of GI and frontal headache & other CNS side effects is produced:

Ibuprofen Least GI toxicity among NSAIDs

 Diclofenac-sodium Available as tablets, injections, creams, eye drops

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

Comparatively acton between COX inhibitors

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.

 Selective COX II inhibitors

E.g. Celecoxib Exert antiinflammatory, analgesic and antipyretic action with low ulcerogenic potential

Used in rheumatoid arthritis

Less GIT toxicity

 Bextra

(Valdecoxib): Pfizer (penalty!)

Many severe side effects

Thromboses (< PGI2; > TxA2)

COX-2 Inhibitors & Cardiovascular System

In clinical studies, COX-2 inhibitors decreased systemic prostacyclin (PGI2) production in healthy volunteers. Specific COX-2 inhibitors that do not inhibit platelet COX-1 might unfavorably alter the thromboxane (TxA2)prostacyclin balance by inhibiting COX-2 dependent synthesis of vasoprotective prostacyclin in endothelial cells risk of cardiovascular complication ?

 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

Basic & Clinical Pharmacology 10th Ed. (2007)

paracetamol
to hepatotoxic metabolites (NABQI etc.)
(GSH glutathione; SG glutathione moiety)
Daily dose > 7.5 g:

hepatotoxicity and nephrotoxicity

NABQI

NB: Acetylcysteine and GSH contain SH groups.