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COX INHIBITORS

Nonsteroidal anti-inflammatory drugs
Nonopioid analgesics

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Management of pain is one of clinical medicine's greatest challenges.

Pain is an unpleasant sensation that can be either acute or chronic and that is a consequence of complex neurochemical processes in the peripheral and (CNS).

Pain is subjective ,and the clinician must rely on patients perception and description.

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Alleviation of pain depends on its type:

Headaches or mild to moderate arthritic pain NSAIDs are effective.

for severe or chronic malignant pain, opioids are usually the drugs of choice.

Neuropathic pain responds best to amitriptyline , Gabapentin.

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Analgesics

NSAIDs

(Non-opioid analgesics)

(Non -narcotic analgesics)

Mild to moderate pain

Opioid analgesics

(narcotic analgesics)

Morphine

Moderate to severe pain

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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).

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Common Pharmacological Effects

Analgesic (CNS and peripheral effect) may involve non-PG related effects

Antipyretic (CNS effect)

Anti-inflammatory (except acetaminophen) due mainly to PG inhibition.

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Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Different:
chemical families
pharmacokinetics and potency
selectivity to COX I and II

Common:
mechanism of action

(cyclooxygenase inhibition)

therapeutic indications
adverse effects

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A normal inflammatory response is essential to fight infections“Response 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.

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Inflammatory mediators

Activated leukocytes at a site of inflammation release compounds which enhance the inflammatory response mainly cytokines and eicosanoids (prostaglandins, thromboxanes, leukotrienes).

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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

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(+)

Phospholipase A₂

Phospholipids

Arachidonic acid

5-lipoxygenase

Leucotrienes

Cyclooxygenase (COX)

Endoperoxides

PGs

TxA₂

Inflammatory stimulus

Ex

In

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Cell Membrane Phospholipids

Arachidonic Acid

Phospholipase A₂

Cyclooxygenae

Lipoxygenas

Others

NSAIDs

Steroids

Prostaglandins

Thromboxanes

Prostacyclins

Isoprostanes

Cyt. P450

products

Leukotrienes

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Mechanism of action

They act by inhibiting the cyclooxygenase enzymes that catalyze prostaglandin synthesis.

This leads to decreased prostaglandin synthesis with both beneficial and unwanted effects.

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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

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COX-2 (inducible) is

induced in inflammatory cells by pathological stimulus.

COX-3 (in brain).

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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

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NSAIDs inhibit the COX enzyme, which exists in two forms

Arachidonic acid

COX-1�(constitutive)

COX-2�(induced by inflammatory stimuli)

Non-selective NSAIDs

Gastrointestinal cytoprotection
Platelet activity

Inflammation
Pain
Fever

Prostaglandins

×

COX-2 selective NSAIDs

Vane & Botting 1995

3. NSAIDs inhibit the COX enzyme, which exists in two forms

NSAID-mediated inhibition of prostaglandin synthesis is the central mechanism behind both the therapeutic and toxic activity of these drugs. Prostaglandins are synthesised through the action of the COX enzyme on the cell membrane constituent, arachidonic acid.² COX exists in two forms; the COX-1 isoform is constitutively expressed in most tissues and is believed to have a ‘housekeeping’ role, producing prostaglandins that regulate normal cell activity. The COX-2 isoform is virtually undetectable in most tissues under normal physiological conditions, but can be induced in the presence of inflammation, tissue damage or malignant transformation.²^–⁴ Prostaglandins produced by COX-2 are thought to be mediators of pain, inflammation and fever,²^–⁴ and the anti-inflammatory effects of NSAIDs appear to be largely attributable to inhibition of COX-2.²^–⁴ The cardioprotective effects of NSAIDs stem from inhibiting the COX-1-mediated synthesis of thromboxanes by platelets. Aspirin has the most pronounced anti-thrombotic effect of all NSAIDs as it irreversibly inhibits COX-1 in platelets.⁵

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NSAIDs are heterogeneous group having anti-inflammatory, analgesic and antipyretic effects, they include:

Prototype NSAIDs: acetylsalicylic acid(aspirin).

Non-selective NSAIDs: ibuprofen, diclofenac, naproxen.

selective COX-2 inhibitors: celecoxib

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Benefical actions of NSAIDs due

to prostanoid synthesis inhibition

Analgesia

2. Antipyretic

3. Antiinflammatory action

4. Anthithrombotic action (Aspirin)

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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

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they should be avoided in:

Peptic ulcer. why?????

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they should be avoided in Bronchial asthma.
Why???
as inhibition of prostaglandin synthesis can cause a shift toward leukotriene production and, therefore, increase the risk of exacerbations of asthma.

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Aspirin

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Examples<non- selective>

Aspirin (acetyl salicylic acid)

Salicylic acid can be used locally as keratolytic agent for treatment of corns

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MOA of Aspirin

ONLY NSAID THAT BLOCKS THE COX ENZYME IRRERVERSIBLY

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Therapeutic uses of Aspirin

Antipyretic
Analgesic ; mild-moderate pain…
Anti platelet effect 🡪 inhibit platelet aggregation & its main clinical importance as prophylaxis; in MI, stroke

Low doses of aspirin (81-325mg/day) irreversibly inhibits TXA2 production in platelets by acetylation of COX.

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Therapeutic uses of Aspirin

Anti-inflammatory…treatment of Rhumatoid arthritis, osteoarithritis
Colon cancer – Chronic use decreases incidence of colorectal cancer.

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Pharmacological/Physiological Effects� Platelets

ARACHIDONIC ACID

Platelet

TXA₂

Endothelial

PGI₂

Vasoconstriction

Platelet Aggregation

Vasodilation

Anti-Platelet Aggregation

COX -1

COX -2

ASPIRIN

_

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Adverse effects of Aspirin and other NSAIDs

1. Gastrointestinal effects of aspirin.

PGs inhibits acid secretion &stimulates mucous secretion in stomach and intestine.

Aspirin inhibits these PGs epigastric distress, ulceration,heamorrhage

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Gastrointestinal effects of aspirin

Aspirin should be taken with food and plenty of fluid, mesoprostol, PPI and to less extent H2 blockers may be needed

Buffered aspirin, enteric-coatings

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Adverse effects of Aspirin and other NSAIDs

2. Action of aspirin and NSAIDs on the Kidney

PGE2 & PGI2 maintain renal blood flow, particularly in the presence of circulating vasoconstrictors.
Decreased synthesis of these PGs🡪Na &water retention,edema.
Interstetial nephritis can occur with all NSAIDs.

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Adverse effects of Aspirin and other NSAIDs

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REYE’S SYNDROME

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3. Aspirin causes rare Reye's syndrome in children with viral infection

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Aspirin Toxicity - Salicylism

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

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Aspirin Toxicity - Treatment

Decrease absorption - activated charcoal, emetics, gastric lavage

Enhance excretion - alkalinize urine, forced diuresis, hemodialysis

Supportive measures - fluids, decrease temperature, bicarbonate, electrolytes, glucose, etc…

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Other NSAIDs

Diclofenac sodium: (voltaren)
Oral ,IM,ED. Gel , supp.
One of the Least irritants to the GI tract mucosa.
high conc. in synovial fluid.

Ibuprofen:
oral (pink capsule)
Fewer side-effects(GIT effects)

Naproxen:
is indicated for juvenile and rheumatoid arthritis.

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Diclofenac

Oral ,IM,ophthalmic preparation. gel

Piroxicam
nonselective COX-1/COX-2 inhibitor that at has long half-life permits once-daily dosing.

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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

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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	(+)	(+)

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Coxibs are selective COX-2 inhibitors. They exert

antiinflammatory, analgesic and antipyretic action

with low ulcerogenic potential.

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Selective COX-2 Inhibitors

Celecoxib: less GI side effect.

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OUT OF DATE

Many severe side effects

Thromboses (< PGI₂; > TxA₂)

Bextra^® (Valdecoxib): Pfizer (penalty!)

OUT OF DATE

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ACETAMINOPHEN

“Paracetamol”

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Acetaminophen (Paracetamol

Inhibits PGs synthesis in the CNS🡪 (antipyretic and analgesic).
lacks platelet-inhibiting properties

Less effect on COX in peripheral tissues (weak antiinflammatory) and not an NSAID.

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Given orally, parentrally & rectally

Oral normal dose = 0.5 to 1 g every 4 to 6 hr.

Max daily dose = 4 g.

Therapeutic uses:
Substitute analgesic & antipyretic effect of aspirin in those patients with gastric problems & those who do not require the anti-inflammatory action of aspirin.

It is drug of choice, for children with viral infection

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Adverse effects

With normal therapeutic doses, acetaminophen is virtually free of any significant adverse effects.

Hepatic necrosis: Acetaminophen-Induced hepatotoxicity
very serious and potentially life-threatening condition.
With large doses of acetaminophen.
toxic doses (10-15 g )~ (about 10 or 20 tab) in one dose .

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paracetamol poisoning

Acute paracetamol poisoning occurs specially in small children who have low hepatic glucoronide conjugating ability.
.
N-acetyl-p-benzoquinoneimine (NABQI) is a highly reactive metabolite of paracetamol which detoxified by conjugation with glutathione

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paracetamol poisoning

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

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Treatment

activated charcoal, given orally or through the tube to prevent GI absorption,

acetylcysteine (by i.v. infusion).

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Question

An 8-year-old girl has a fever and muscle aches from a presumptive viral infection. Which one of the following drugs would be most appropriate to treat her symptoms?

A. Acetaminophen.

B. Aspirin.

C. Celecoxib.

D. Codeine.

E. Indomethacin.