Nonsteroidal antiinflammatory drugs

NonsteroidalNonsteroidal AntiinflammatoryAntiinflammatoryDrugs Drugs (NSAIDs) (NSAIDs) Drugs Drugs (NSAIDs) (NSAIDs)

Inflamation

• Inflammation is a defense reaction caused by tissue damage or injury

• Can be elicited by numerous stimuli including:

• infectious agents

• antigen-antibody interaction• antigen-antibody interaction

• ischemia

• thermal and physical injury

Characterized by:

1. Redness (rubor): vasodilation of capillaries to increase blood flow

2. Heat (calor): vasodilation

3. Pain (dolor): Hyperalgesia, sensitization of nociceptors

4. Swelling (tumor): Increased vascular permeability (microvascular structural changes and escape of plasma proteins from the bloodstream)plasma proteins from the bloodstream)

5. Loss of function (functio laesa)

• Inflammatory cell transmigration through endothelium and accumulation at the site of injury

Mediators of Inflammation

1. Vasoactive amines (Histamine, Serotonin)

2. Platelet activating factor (PAF)

3. Complement system

4. Kinin system

5. Cytokines

6. Nitric oxide

7. Adhesion Molecules8. Arachidonic acid metabolites:

• Prostaglandins (PGs)• Thromboxane A2 (TXA2)• HETE (hydroxy-eicosatetraenoic acid)• Leukotrienes (LTs)

mediated by mediated by cyclooxygenasescyclooxygenases (COX)(COX)

ARACHIDONIC ACID (AA) METABOLITES

• Also known as eicosanoids.

• Variety of biologic processes, including inflammation and hemostasis - virtually every step of inflammation.

• short-range hormones that act locally at the site • short-range hormones that act locally at the site of generation and then decay spontaneously or are enzymatically destroyed

• Derived from : Leukocytes, mast cells, endothelial cells, and platelets

• Dietary linoleic acid

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ARACHIDONIC ACID METABOLITES

• Component of cell membrane phospholipids.

• AA is released from these phospholipids via cellular phospholipases – that have been activated by mechanical, chemical, or

physical stimuli, or by inflammatory mediators such physical stimuli, or by inflammatory mediators such as C5a.

• Metabolism proceeds along either of this two major enzymatic pathways• Cyclooxygenase : prostaglandins and thromboxanes -

AUTOCOIDS

• Lipoxygenase : leukotrienes and lipoxins


Cyclooxygenase Pathway

• Cyclooxygenase - a fatty acid enzyme present as COX-1 and COX-2,

• Metabolizes AA to following derivative– Prostaglandins (PGD2, PGE2 and PGF2-α)

– Thromboxane A2 (TXA2)– Thromboxane A2 (TXA2)

– Prostacyclin (PGI2)

– Resolvins

• Major anti-inflammatory drugs act by inhibiting activity of the enzyme COX – NSAIDs & COX-2 inhibitors


Two main forms of Two main forms of CyclooxygenasesCyclooxygenases (COX)(COX)

•• CyclooxygenaseCyclooxygenase--1 1 (COX(COX--11))

• Produces prostaglandins that mediate homeostatic functions

• Constitutively expressed

• Plays an important role in

•• CyclooxygenaseCyclooxygenase--2 2 (COX(COX--22))

• Produces prostaglandins that mediate inflammation, pain, and fever.

• Induced mainly in sites of • Plays an important role in

• Gastric mucosa

• Kidney

• Platelets

• Vascular endothelium

• Induced mainly in sites of inflammation by cytokines

Cyclooxygenase Pathway


Lipoxygenase Pathway

• Lipo-oxygenase - predominant enzyme in neutrophils.

• Acts on activated AA to form hydroperoxyeicosatetraenoic acid (5-HPETE).

• Further peroxidation forms following metabolites– 5-HETE (hydroxy compound) - intermediate

– Leukotrienes (LT)

– Lipoxins (LX)


Lipoxygenase Pathway



Mechanism of action of NSAIDsMechanism of action of NSAIDs

1. Antiinflammatory effect– due to the inhibition of the enzymes that produce

prostaglandin H synthase (cyclooxygenase, or COX), which converts arachidonic acid to prostaglandins, and to TXA2and prostacyclin.and prostacyclin.

– Aspirin irreversibly inactivates COX-1 and COX-2 by acetylation of a specific serine residue.

– This distinguishes it from other NSAIDs, which reversiblyinhibit COX-1 and COX-2.

2. Analgesic effect

A. The analgesic effect of NSAIDs is thought to be related to:

– the peripheral inhibition of prostaglandin production production

– may also be due to the inhibition of pain stimuli at a subcortical site.

B. NSAIDs prevent the potentiating action of prostaglandins on endogenous mediators of peripheral nerve stimulation (e.g., bradykinin).

3. Antipyretic effect

– The antipyretic effect of NSAIDs is believed to be related to:

• inhibition of production of prostaglandins induced by interleukin-1 (IL-1) and interleukin-6 (IL-6) in the interleukin-1 (IL-1) and interleukin-6 (IL-6) in the hypothalamus

• the “resetting” of the thermoregulatory system, leading to vasodilatation and increased heat loss.

Therapeutic usesTherapeutic uses

1.1. InflammationInflammation– NSAIDs are first-line drugs used to arrest inflammation

and the accompanying pain of rheumatic and nonrheumatic diseases, including rheumatoid arthritis, juvenile arthritis, osteoarthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, psoriatic arthritis, ankylosing spondylitis, Reiter syndrome, and dysmenorrhea.

– Pain and inflammation of bursitis and tendonitis also respond to NSAIDs.

– NSAIDs:

• do not significantly reverse the progress of rheumatic disease

• they slow destruction of cartilage and bone

• allow patients increased mobility and use of their • allow patients increased mobility and use of their joints.

– Treatment of chronic inflammation requires use of these agents at doses well above those used for analgesia and antipyresis

– the incidence of adverse drug effects is increased.

– Drug selection is generally dictated by the patient's ability to tolerate the adverse effects, and the cost of the drugs.

– Antiinflammatory effects may develop only after several weeks of treatment.

2.2. AnalgesiaAnalgesia

• NSAIDs alleviate mild-to-moderate pain by:

– decreasing PGE- and PGF-mediated increases in pain – decreasing PGE- and PGF-mediated increases in pain receptor sensitivity.

• They are more effective against pain associated with integumental structures (pain of muscular and vascular

origin, arthritis, and bursitis) than with pain associated with the viscera.

3.3. AntipyresisAntipyresis

• NSAIDs reduce elevated body temperaturewith little effect on normal body temperature.temperature.

Classification• Non-selective COX inhibitors

– Salisylates : Aspirin

– Propionic Acid derivatives: ibuprofen, naproxen, ketoprefen

– Anthranilc acid derivative: mephanamic acid

– aryl-acetic acid derivative: Diclofenac, aceclofenac

– Oxicam derivatives : piroxicam, tenoxicam

– pyrolo-pyrolle derivative : ketorolac

– Indole derivative : indomethacin

– pyrozolone derivative: phenylbutazone, oxyphenbutazone

• Preferentical COX-2 inhibitors: Nimesulide, meloxicam, nabumetone

• Selective COX-2 inhibitors : Celecoxib, Etoricoxib, parecoxib

• Analgesic-antipyretics

– Paraminophenol : Paracetamol

– pyrozolone derivative: metamizol, propiphenazone

– Benzooxazocine derivative: nefopam

Salicylates

•• Aspirin (acetylsalicylic acid) Aspirin (acetylsalicylic acid)

•• NonacetylatedNonacetylated salicylatessalicylates::– sodium salicylate– sodium salicylate– magnesium salicylate– choline salicylate– sodium thiosalicylate– sulfasalazine– mesalamine– salsalate

Pharmacology

• Salicylates are weak organic acids; – aspirin has a pKa of 3.5.– These agents are rapidly

absorbed from the intestine as well as from intestine as well as from the stomach, where the low pH favors absorption.

– Salicylates are hydrolyzed rapidly by plasma and tissue esterases to acetic acid and the active metabolite salicylic acid.

Metabolism• Unmetabolizedsalicylates are excreted by the kidney.• If the urine pH is raised above 8, raised above 8, clearance is increased approximately fourfoldas a result of decreased reabsorption of the ionized salicylate from the tubules.

– Salicylates have a t1/2 of 3—6 hours after short-term administration.

– Long-term administration of

• high doses (to treat • high doses (to treat arthritis) or

• toxic overdose

– increases the t1/2 to 15—30 hours because the enzymes for glycineand glucuronideconjugation become saturated.

Therapeutic uses of Salicylates

• Salicylates are used to treat: – rheumatoid arthritis – juvenile arthritis– osteoarthritis– other inflammatory disorders

• 5-Amino salicylates (mesalamine, sulfasalazine) • 5-Amino salicylates (mesalamine, sulfasalazine) – can be used to treat Crohn's disease.

• Salicylic acid is used topically to treat: – plantar warts – fungal infections– Corns

• Aspirin– has significantly greater antithrombotic activity

than other NSAIDs

Adverse effectsAdverse effects1. Gastrointestinal effects

– most common adverse effects of high-dose aspirinuse (70% of patients): • nausea • vomiting • diarrhea or constipation • dyspepsia (impaired digestion)• dyspepsia (impaired digestion)• epigastric pain • bleeding, and ulceration (primarily gastric).

• These gastrointestinal effects are thought to be due to: 1.a direct chemical effect on gastric cells or 2.a decrease in the production and cytoprotective

activity of prostaglandins, which leads to gastric tissue susceptibility to damage by hydrochloric acid.

Adverse effectsAdverse effects

– The gastrointestinal effects may contraindicate aspirin use in patients with an active ulcer.

– Aspirin may be taken with prostaglandins to reduce gastric damage.

– Decrease gastric irritation by:– Decrease gastric irritation by:• Substitution of enteric-coated or timed-release

preparations, or • the use of nonacetylated salicylates, may

decrease gastric irritation.

Adverse effectsAdverse effects2. Hypersensitivity (intolerance)• Hypersensitivity is relatively uncommon with the use of aspirin (0.3% of

patients); hypersensitivity results in: – rash – bronchospasm– rhinitis – Edema, or – an anaphylactic reaction with shock, which may be life threatening.

• The incidence of intolerance is highest in patients with asthma, nasal • The incidence of intolerance is highest in patients with asthma, nasal polyps, recurrent rhinitis, or urticaria.

• Aspirin should be avoided in such patients.• Cross-hypersensitivity may exist:

– to other NSAIDs– to the yellow dye tartrazine, which is used in many pharmaceutical

preparations.• Hypersensitivity is not associated with:

– sodium salicylate or – magnesium salicylate.


• The use of aspirin and other salicylates to control fever during viral infections (influenza and chickenpox) in children and adolescents is associated with an increased incidence of Reye's syndrome, an illness characterized by vomiting, hepatic disturbances, and encephalopathy that has a 35% mortality rate.

• Acetaminophen is recommended as a substitute for children • Acetaminophen is recommended as a substitute for children with fever of unknown etiology.

• Miscellaneous adverse effects and contraindications– May decrease the glomerular filtration rate, particularly in patients

with renal insufficiency.– Occasionally produce mild hepatitis– Prolong bleeding time.


• Aspirin irreversibly inhibits platelet COX-1 and COX-2 and, thereby, TXA2 production, suppressing platelet adhesion and aggregation.

• The use of salicylates is contraindicated in patients with bleeding disordersbleeding disorders

• Salicylates are not recommended during pregnancy; they may induce: – postpartum hemorrhage– premature closure of the fetal ductus arteriosus.

Drug interactionsDrug interactions

Aspirin Toxicity Aspirin Toxicity

• In adults, salicylism (tinnitus, hearing loss, vertigo) occurs as initial sign of toxicity after aspirin or salicylate overdose or poisoning.

• In children, the common signs of toxicity include hyperventilation and acidosis, with accompanying lethargy and hyperventilation.

• Treatment of Aspirin ToxicityAspirin Toxicity includes: • Treatment of Aspirin ToxicityAspirin Toxicity includes: 1. correction of acid—base disturbances 2. replacement of electrolytes and fluids 3. cooling 4. alkalinization of urine with bicarbonate to reduce

salicylate reabsorption5. forced diuresis, hemodialysis6. gastric lavage or emesis

Other Other nonsteroidalnonsteroidal antiinflammatoryantiinflammatory drugsdrugs

– NSAIDs are absorbed rapidly after oral administration. – These agents are extensively bound to plasma proteins,

especially albumin. – They cause drug interactions due to the displacement of

other agents, particularly anticoagulants, from serum albumin; these interactions are similar to those seen with albumin; these interactions are similar to those seen with aspirin.

• NSAIDs are

• metabolized in the liver

• excreted by the kidney

• The half-lives: #1 -45 h

# most: 10 -20 h

• These agents commonly produce: – gastrointestinal disturbances – cross-sensitivity with aspirin

• Non-dose-related acute renal failure and nephroticsyndrome:syndrome:– in combination with ACE inhibitors

– More nephrotoxic:

» Indomethacin

» Meclofenamate

» Tolmetin

» phenylbutazone

AntiinflammatoryAntipyresisAnalgesiaPrototypeChemical Class

+++++++++AspirinSalicylates

Marginal++++++AcetaminophenPara-aminophenols

+++++++++++IndomethacinIndoles

+++++++++Tolmentin, mefenamic acid

Pyrrol acetic acids

+++++++++++Ibuprofen, naproxen

Propionic acids

++++++++++Phenylbutazone, piroxicam

Enolic acids

+++++++NabumetoneAlkanones

+++++++++++CelecoxibSulfonamide

PropionicPropionic acid derivativesacid derivatives

(Ibuprofen, Fenoprofen, ketoprofen , naproxen)(Ibuprofen, Fenoprofen, ketoprofen , naproxen)

– There is no reported interaction of ibuprofen or ketoprofen with anticoagulants.

– Fenoprofen has been reported to induce nephrotoxic syndrome.

– Long-term use of ibuprofen is associated with an increased incidence of hypertension in women.

Sulindac, Sulindac, tolmetintolmetin, Ketorolac, Ketorolac

Sulindac:Sulindac:• is a prodrug that is oxidized to a sulfone and then to the active

sulfide• has a relatively long t1/2 (16 h) because of enterohepatic cycling.

Tolmetin:Tolmetin:• has minimal effect on platelet aggregation; • it is associated with a higher incidence of anaphylaxis than other • it is associated with a higher incidence of anaphylaxis than other

NSAIDs. • Tolmetin has a relatively short t1/2 (1 h).

Ketorolac:Ketorolac:• is a potent analgesic with moderate antiinflammatory activity • can be administered:

– intravenously or – topically in an ophthalmic solution.

IndomethacinIndomethacin

Use: As anti-inflammatory

Treatment of • Ankylosing spondylitis• Reiter syndrome• Reiter syndrome• Acute gouty arthritis.

to speed the closure of patent ductus arteriosus in premature infants (otherwise, it is not used in children);

• it inhibits the production of prostaglandins that prevent closure of the ductus.

– Indomethacin is not recommended as a simple analgesic or antipyretic because of the potential for severe adverse effects.

– Bleeding, ulceration– Headache– Headache

– Occasional:Tinnitus, dizziness, or confusion

PiroxicamPiroxicam

– Piroxicam is an oxicam derivative of enolic acid.

– Piroxicam has t1/2 of 45 hours.

– Like aspirin and indomethacin, bleeding and ulcerationare more likely with piroxicam than with other NSAIDs.

Meclofenamate, mefenamic acidMeclofenamate, mefenamic acid

– t1/2 of 2 hours.

– A relatively high incidence of gastrointestinal disturbances is associated with these agents.

NabumetoneNabumetone

– Compared with NSAIDs, nabumetone is associated with reduced:

• inhibition of platelet function

• incidence of gastrointestinal bleeding.

– Nabumetone inhibits COX-2 more than COX-1.

Other NSAIDS include flurbiprofenflurbiprofen, , diclofenacdiclofenac, , and and etodolacetodolac..

Flurbiprofen is also available for topical ophthalmic use.

COXCOX--2 2 Selective agentsSelective agents

–– Celecoxib [Celebrex]Celecoxib [Celebrex]–– Rofecoxib [Vioxx] Rofecoxib [Vioxx] –– Valdecoxib [Bextra] Valdecoxib [Bextra]

– that inhibit COX-2 more than COX-1 have been developed and approved for use. and approved for use.

– The rationale behind development of these drugs was that:

A. inhibition of COX-2 would reduce the inflammatory response and pain

B. not inhibit the cytoprotective action of prostaglandins in the stomach, which is largely mediated by COX-1.

–– Rofecoxib and valdecoxib Rofecoxib and valdecoxib have been removed from the market due to a doubling in the incidence of heart attack and stroke

–– CelecoxibCelecoxib remains on the market and is approved for: – Osteoarthritis and rheumatoid arthritis– Osteoarthritis and rheumatoid arthritis– Pain including bone pain, dental pain, and headache – Ankylosing spondylitis.

NonopioidNonopioid analgesics and antipyreticsanalgesics and antipyretics

–– Aspirin, NSAIDsAspirin, NSAIDs, and , and acetaminophen (acetaminophen (ParacetamolParacetamol):):

– are useful for the treatment of mild-to-moderate pain associated with integumental structures, including pain of muscles and joints, postpartum pain, and headache.

– These agents have: • antipyretic activity• have antiinflammatory activity at higher doses except

for acetaminophen

AcetaminophenAcetaminophen ((ParacetamolParacetamol):):

– does not displace other drugs from plasma proteins

– it causes minimal gastric irritation

– has little effect on platelet adhesion and aggregation

– Acetaminophen has no significant antiinflammatory activity.

– Acetaminophen is administered orally and is rapidly absorbed.

– It is metabolized by hepatic microsomal enzymes to sulfate and glucuronide.

– Acetaminophen is a substitute for aspirin to treat mild-to-moderate pain for selected patients who are:

• intolerant to aspirin • have a history of peptic ulcer or hemophilia • are using anticoagulants or a uricosuric drug to manage

gout • are at risk for Reye's syndrome.

Health & Medicine

Nonsteroidal antiinflammatory drugs