NONSTEROIDAL ANTIINFLAMMATORY DRUGS AND ANTIPYRETICANALGESICS

Overview
These drugs are a group of chemically dissimilar agents that have antipyretic, analgesic and antiinflammatory effects.
The structure of this kind of drug differs from that of steroidal anti-inflammatory drugs.

Phospholipids
Phospholipase

Arachidonic Acid
5-lipoxygenase cyclooxygenase

5-HPTE
peroxidase

PGG 2 LTC4 PGH2

LTB4

TXA 2 PGI2 PGE2 PGF2 PGD2

 PGE2 : Vasodilatation, pain sensitization, gastric cytoprotection [mucous/HCO3 secretion], fever PGF2 : Bronchoconstriction, uterine contraction PGI2 : Inhibition of platelet aggregation, gastric cytoprotection TXA2 : Platelet aggregation

Anti-inflammatory action
NSAIDs only inhibit the symptoms of inflammation
But they neither arrest the progress of the disease nor do they induce remission

Anti-inflammatory action
The decrease in vasodilator prostaglandins (PGE2, PGI2) means less vasodilatation and, indirectly, less odema. The inhibition of activity of adhesion molecule. Accumulation of inflammatory cells is also reduced.

Mechanism of action
The principal pharmacological effect of NSAIDs is due to their ability to inhibit prostaglandin synthesis by blocking the cyclooxygenase(COX) activity of COX-1 and COX-2. NSAIDs - acetylation of COX

(reversible or irreversible)
COX-1: constitutive enzyme: is involved in tissue homeostasis. COX-2: inducible enzyme: is responsible for the production of the prostanoid mediators of inflammation.

NSAIDs
Prostaglandins pGE2 pGF2 Inflammatory factors

+
Symptoms of inflammation Red, swelling, Heating, Pain

Bradykinin Histamine 5-HT

block prostaglandins production

Sites of action: peripheral tissue

Antipyretic action
Normal temperature: slightly affected

Elevated temperature: reduced

The higher temperature, the more potent Mechanism of antipyretic action: Blocks pyrogen-induced prostaglandin production in thermoregulatory center (CNS)

 Heat production and heat dissipation. In

fever associated with an infection, increased oxidative processes enhance heat production .
Aspirin causes cutaneous vasodilation, prompts perspiration, and enhance heat dissipation.

Prostaglandins pGE2

Pyrogen

thermoregulatory center set point heat production Heat dissipation

NSAIDs
Antipyretic Mechanism

Block prostaglandins production Sites of action: Central Nervous System

Fever

Analgesic action
Pain may arise from: Musculature, dental work , vascular , postpartum conditions, arthritis , bursitis Sites of action: Peripherally - sites of inflammation subcortical sites

NSAIDs
Prostaglandins
pGE2 pGF2

factors

+
Nerve ending of pain

Bradrkinin histamine

block prostaglandins production

Sites of action: peripheral tissue

Pain

CLASSIFICATION
Nonselective COX inhibitors (traditional NSAIDs)
1) Salicylates : Aspirin 2) Propionic acid derivatives : Ibuprofen Naproxen Ketoprofen Flurbiprofen 3) Anthranilic acid derivatives: Mephenamic acid 4) Aryl- acetic acid derivatives: Diclofenac Aceclofenac 5) Oxicam derivatives: Piroxicam Tenoxicam 6) Pyrrolo- pyrrole derivatives: Ketorolac 7) Indole derivatives: Indomethacin 8) Pyrazolone derivatives: Phenylbutazone Oxyphenbutazone

 Preferential COX-2 inhibitors Nimesulide Meloxicam Nabumetone Selective COX-2 inhibitors Celecoxib Etoricoxib Parecoxib Analgesic- antipyretics with poor antiinflammatory action 1) Paraaminophenol derivative: Paracetamol (Acetaminophen) 2) Pyrazolone derivatives: Metamizol ( Dipyrone) Propiphenazone 3) Benzoxacine derivatives: Nefopam

Salicylates: Aspirin
Analgesic Effect Aspirin is most effective in reducing pain of mild to moderate intensity (headache, toothache, dysmenorrhea, arthralgia, etc). It is not effective for severe visceral pain, e.g. myocardial infarction or renal or biliary colic. It acts peripherally through its effects on inflammation but probably also inhibits pain stimuli at a subcortical site.

 Antipyretic Effects: Aspirin reduces elevated temperature, whereas normal body temperature is not affected. Aspirins antipyretic effect is mediated by cyclooxygenase-2 (COX-2) inhibition in the central nervous system. The fall in temperature is related to increased dissipation of heat caused by vasodilation of superficial blood vessels and may be accompanied by profuse sweating.

 Anti-inflammatory Effects: The anti-inflammatory property of aspirin in high dosage is responsible for treatment various kinds of inflammation including acute rheumatic fever, rheumatoid and other types of arthritis. It has been advocated as a diagnostic test when acute rheumatic fever is suspected

 Effect on platelets
Low doses of aspirin can inhibit platelet aggregation and produce a slightly prolonged bleeding time by irreversible inhibition of platelet COX. Low doses of aspirin can irreversibly inhibit the production of TXA2 in platelets without markedly interfering with PGI2 production in endothelial cells. In general, Aspirin should be stopped 1 week prior to surgery to avoid bleeding complication. Aspirin has been shown to decrease the incidence of transient isochemic attacks, unstable angina, coronary artery thrombosis with myocardial infarction, and thrombosis after coronary artery bypass grafting.

ADVERSE EFFECTS
1. Gastrointestinal tract This effect can be decreased with suitable buffering(taking Aspirin with meals ). The gastritis that occurs with Aspirin may be due to irritation of gastric mucosa by the undissolved tablet, or to inhibition of production of protective prostaglandins. Therefore, aspirin should be avoided by individuals with peptic ulcer disease.

 2.Blood Aspirin increases bleeding time,decreases platelet adhesiveness,,and ,at large doses,may cause hypoprothrombinaemia. 3.hepatotoxicity 4.Hypersensitivity: Aspirin asthma 5.Salicylate intoxication 6. Reyes syndrome

 Ibuprofen is a simple derivative of Arylpropionic acid. In doses of about 2400 mg daily,ibuprofen is equivalent to 4 g of aspirin in anti-inflammatory effect.Oral ibuprofen is often prescribed in lower doses(<2400mg/d),at which it has analagesic but not anti-inflammatory efficacy. It is used for treatment of rheumatoid arthritis and other inflammatory joint conditions It is available over the counter in lower dosage under several trade names.

Propionic acid derivatives: Ibuprofen

Indole derivative: Indomethacin

Indomethacin is an indole derivative. It enjoys the usual indications for use in rheumatic conditions and is particularly popular for gout and ankylosing spondylitis. In addition,it has been used to treat patient ductus arteriosus. It is one of the most potent COX inhibitors, and has more adverse effects.

Pyrazolone derivative: Phenylbutazone

Phenylbutazone,a pyrazolone derivative rapidly gained favor after its introduction in 1949 for the treatment of rheumatic syndromes But its toxicities,particularly the hematologic effects (including aplastic anemia),have resulted in its withdrawal from many markets Rarely used today

Selective COX-2 inhibitors

Celecoxib is a selective COX-2 inhibitor, having slight action on COX-1 in therapeutic dosage. The incidence of gastric toxicity is much lower with it than with non-selective COX inhibitors. It is used for treatment of osteoarthritis and rheumatoid arthritis.

Paraaminophenol derivative: Acetaminophen

Acetaminophen is the active metabolite of phenacetin responsible for its analgesics effect. It is a weak prostaglandin inhibitor in peripheral tissues and possesses no significant antiinflammatory effects. Acetaminophen is one of the most important drugs used for the treatment of mild to moderate pain when an anti-inflammatory effect is not necessary. Phenacetin is more toxic and has no rational indications

Anti pyretic

analg esic

Antiinflammatory

Side action

Acetaminophen ++

++

Indomethacin
sulindac tolmetin diclofenac Ibuprofen meloxicam Phenylbutazone ketorolac +++ + + + ++ +++

++++
++++ ++ ++ + +++

++++
++ ++ ++ + ---+++

cox2 i.m

Over-the-Counter Anti-inflammatory Drugs NSAIDs that can be purchased over-the-counter include: ibuprofen, naproxen sodium, aspirin Ibuprofen is also available as a prescription at doses higher than the over-the-counter medications.

Prescription Anti-inflammatory Drugs The following NSAIDs are available only with a doctor's prescription: Celecoxib, Sulindac Oxaprozin Salsalate Diflunisal indomethacin piroxicam piroxicam