NSAIDs

Non steroidal Anti- inflammatory drugs

Dr. Sohail Ahmad

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Inflammation

It is a non-specific manifestation of many diseases.

Acute

Chronic

Anti-inflammatory drugs are extensively used.

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Non steroidal Anti- inflammatory drugs

(NSAIDs) mainly produce their effects by

inhibiting the biosynthesis of

Prostanoids

Prostaglandins , Thromboxane A2

& Prostacyclin.

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Membrane phospholipids

Arachidonic acid

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Membrane phospholipids

Arachidonic acid

Leukotrienes Prostaglandins Thromboxane Prostacyclin

Prostanoids

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Membrane phospholipids

Arachidonic acid

Leukotienes Prostaglandins Thromboxane Prostacyclin

Prostanoids

COXLipoxygenase

Phospholipase

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Membrane phospholipids

Arachidonic acid

Leukotienes Prostaglandins Thromboxane Prostacyclin

Prostanoids

COXLipoxygenase

Phospholipase

NSAIDS

Cosrticosteroids

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Arachidonic acid is the primary precursor of prostanoids

Prostanoids are also called ‘Eicosanoids’

Arachidonic acid is a component of the phospholipids of cell membrane.

Free Arachidonic acid is released by cell damage mainly by the action of Phospholipase A2 enzyme.

Arachidonic acid undergoes 2 pathways, by the enzymes Cyclooxygenase & Lipooxygenase,

Biosynthesis of Prostanoids: 9

Membrane phospholipids

Arachidonic acid

Leukotienes Prostaglandins Thromboxane Prostacyclin

COXLipoxygenase NSAIDS

Phospholipase

Cosrticosteroids

Prostanoids

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Inhibition of cyclooxygenase enzyme & reduced biosynthesis of Prostanoids

(Prostaglandins Prostacyclin ,Thromboxane A2)

Aspirin & older non-selective NSAIDs reduce biosynthesis of Prostanoids by inhibiting both isoforms of the Cyclooxygenase (COX) enzyme

(COX-1& COX-2)

MOA of ASPIRIN / NSAIDs

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COX-1

It is responsible for the Physiologic production of

prostanoids.

It is “House keeping “enzyme that regulates the

normal cellular processes (via production of PGs)

such as

Gastric cytoprotection

Vascular homeostasis

Platelet aggregation

Kidney function.

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COX-2

It is constitutively expressed only in brain, kidney & bone

Its expression at other sites is increased in inflammation.

It is responsible for the elevated production of prostanoids

in inflammation & disease.

The selective COX-2 inhibitors have been synthesized.

Its expression is inhibited by Glucocorticoids

COX-3 more effects in CNS

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Aspirin is unique, it acetylates , & irreversibly inhibits the

enzymes, all other drugs produce reversible inhibition

There is ↓ PGs & Thromboxane synthesis throughout the body.

Release of PGs for inflammation as well as for homeostatic

function is disrupted (specially cytoprotection in gastric mucosa

& auto regulation of renal function)

Newer drugs, coxibs are COX2 selective inhibitors .

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PGG2

PGH2

Scheme for prostaglandin Biosynthesis

Stimulus

Disturbance of cell membrane

Phospholipids

Corticosteroids inhibit Phospholipase – A2

Arachidonic Acid

Aspirin & NSAIDs inhibit

CyclooxygenaseLipoxygenase

Endoperoxides

Prostacycline

Hydroperxides

TXA2 PGD2 PGF2αPGE2 Leukotrienes

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Classification of NSAIDs

A: Non-Selective COX Inhibitors.(Inhibitors of COX I & II)

1. Drugs with Analgesic & Marked Anti-inflammatory Effects:

a. Salicylic Acid Derivatives

Aspirin (Acetylsalicylic acid)

Diflunisal

Sodium Salicylate

Magnesium Choline salicylate

b. Pyrazolon Derivatives

Apazone, Phenylbutazone , Oxyphenbutazone

c. Acetic Acid Derivatives

Diclofenac , Tolmetin , ketorolac

Indomethacin , Etodolac , Sulindac

d. Oxicams ( Enolic acids): Piroxicam , Tenoxicam

e. Naphthylacetic Acid Prodrug: Nabumetone

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2. Drugs with Analgesic & Moderate Anti-inflammatory

Effect:

a. Propionic acid derivatives

Ibuprofen, Fenoprofen, Flurbiprofen , Ketoprofen , Naproxen,

oxaprozin , carprofen , Tiaprofen

b. Fenamates:

Mefenamic , Meclofenamic & Flufenamic acid

3. Drug with Analgesic & no Anti-inflammatory Effect:

Para aminophenol Derivative :

Acetaminophen

B: Selective COX Inhibitors.(Inhibitors of COX II only)

Celecoxib , Etoribcoxib , Meloxicam ,Nimesulide.

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ASPIRIN

Prototype Drug

The oldest member used.

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ASPIRINChemistry: Aspirin is Acetyl salicylic Acid.

Pharmacokinetics of Aspirin:

Absorption: Well from stomach & upper small intestine

Distribution: wide , crosses placental barrier

PPL: In 1-2hrs. t1/2: 15 min.

Metabolism: Rapid hydrolysis by Esterases in blood & tissues in to

Salicylate & Acetic Acid.

Salicylate is 80-90-% PPB

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Salicylate is metabolized in liver into:

1.Salicyluric acid (glycine conjugate)

2.Glucuronide conjugate

3. Gentisic acid

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MOA of ASPIRIN / NSAIDsAs Anti-inflammatory:

Aspirin irreversibly acetylates both isoforms of cyclooxygenase

enzyme , COX-1 & COX-2 & inactivates them. So it inhibits

biosynthesis of PGs which, primarily modulates those aspects of

inflammation in which PGs act as mediators.

Aspirin inhibits inflammation in Rheumatoid Arthritis but it neither

arrests the progress of disease nor it induces remission.

Other NSAIDs reversibly inhibit cyclooxygenase enzyme .

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As Analgesic:

1. Aspirin & Other NSAIDs inhibit cyclo-oxygenase enzyme ,

reduce production of PGs in injured tissue.

PGE2 is thought to sensitize the nerve ending

(pain receptors)to action of bradykinin , Histamine & other

mediators released by the inflammatory process.

So due to reduced production of PGE2 , they repress the sensation of pain.

2. Inhibit pain stimuli at subcortical sites --Thalamus & Hypothalamus.

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As Antipyretic:

Aspirin lowers raised body temperature , no effect on normal

temperature

Fever occurs when the set point of the thermoregulatory

center in anterior hypothalamus is elevated.

This may be due to PGE2 synthesis , stimulated by pyrogen such as

cytokine.

Cytokine is released from WBCs, activated by infection, malignancy

or inflammation.

Because of inhibition of PGE2 synthesis , the thermostat is reset

towards normal. & rapidly lowers body temperature by increasing

heat dissipation due to peripheral vasodilation & sweating.

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AS Antiplatelet:

TXA2 normally promotes platelet aggregation. prostacyclin –PGI 2

normally inhibit platelet aggregation.

In low doses Inhibit Platelet Aggregation due to irreversible

acetylation of COX-1 enzyme in platelets.

Low doses 81-100mg/ d inhibit TXA2 synthesis in platelets , higher

doses inhibit prostacyclin –PGI2 also.

Platelet aggregations is the first step in coagulation so it prevents

coagulation & prolongs bleeding time .

The action lasts for 3-8 days -- life span of platelets, because they

lack nuclei & can’t synthesize new enzyme.

Aspirin should be stopped 7-10 prior to operations, to avoid risk of

bleeding.

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Therapeutics Uses of Aspirin/ NSAIDS

1. Analgesic :

a. used alone in pain like.

: Headache, Myalgia, Arthralgia, Neuralgia

osteomyelitis, osteoarthritis. Toothache, Dysmenorhoea

b. With opioids – synergistic action

In pain of cancer metastases in bone

Post operative pain- requirement of opioids.

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2. Anti pyretic :↓ body temp in fever

Not effective in raised body temp. due to heat stroke or malignancy.

Does not lower normal body temp .

3. Acute rheumatic fever :Both for antipyretic & anti-inflammatoryeffects.

4. Rheumatoid Arthritis, Osteoarthritis:

To control symptoms.

No effect on progression of disease.

Does not induce remission.

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5. Anti Platelet :

Aspirin is used prophylactically :

For primary & secondary prevention (In Post myocardial

infarction & post stroke patients) of :

Transient ischemic attacks & stroke.

Unstable angina

Coronary artery thrombosis & Myocardial infarction.

To prevent Thrombosis after coronary artery bypass grafting.

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6. In Bartter’s syndrome:

There is defect in tubular transport of K---Hypokalemia----PG

synthesis stimulated---Increased Renin---

Hyperaldosteronism.

Aspirin prevents this secondary Hyperaldosteronism due to

inhibition of PG synthesis .

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7.Chemoprophylaxis of cancer of colon .50% decrease with

frequent use of aspirin

8.Closure of PDA . As PGs keep patency of Ductus arteriosus.

9. Diarrhea after Radiation & Cholera in which PGs are implicated.

10.Prophylaxis of Cataract: some studies indicate decrease in

incidence of cataract with frequent use of aspirin.

11. With Niacin to improve compliance because Aspirin ↓ flushing,

which is an A/E of Niacin due to PGs.

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Dosage of Aspirin:

3 therapeutic dose ranges:

1. Low range<300mg/d(81, 100mg) as single dose --to↓ Platelet

Aggregation

2. Intermediate dose :300-2400mg/d as 3 divided doses) Analgesic,

Antipyretic.

3. High dose : 2400- 4000mg/d– as 3 divided doses --for Anti-

Inflammatory effect.

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Adverse Effects of Aspirin

At therapeutic doses

1. Gastric Intolerance:

The most common & serious is gastritis, Gastric

ulceration or Exacerbation of Peptic ulcersymptoms.

Dyspepsia & Heart burn , Abdominal Pain .

Nausea & Vomiting, Hematemesis

Fecal blood loss

Iron deficiency Anemia

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To decrease gastric intolerance:

Aspirin may be given with Misoprostol.

Addition of Proton pump inhibitors with Aspirin.

H2 Blockers, if aspirin has been stopped

Use of Special Prep. Of Aspirin: only marginally

effective Aloxiprin (Enteric coated aspirin)

Buffered Aspirin

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2. Impaired hemostasis:

↓ Platelet Aggregation & Hypoprothrobinaemia:

3. Allergic / Hyper sensitivity Reactions:

Skin rashes, Rhinitis, Bronchial asthma

4. Hyperuricemia:

Retention of uric acid at low doses<2.5 g/d ,

(although at high doses> 3.6/d –increases uric acid excretion).

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5. Decreased renal function:

Normally PGE2 & PGI2are responsible for maintaining renal flow specially in presence of circulating vasoconstrictors.

Inhibition of PGs synthesis may produce:

Retention of Sodium & water

Edema

Hyperkalemia.

Interstitial nephritis with other NSAIDs , but not Aspirin

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6.Effects on Respiration:

In high doses– stimulation of Respiratory Center—hyperventilation–

respiratory alkalosis—compensated by kidney------ compensated

respiratory alkalosis

In toxic doses respiratory depression & a combination of

uncompensated respiratory & metabolic acidosis .

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7. Effects on CNS:

In large doses: Salicylism--- Vomiting ,tinnitus,

↓ hearing ,vertigo.

In Toxic Doses :Stimulation of CNS including convulsions ,followed by

depression.

Repiratory depression

Cardiotoxicity

Hyperpyrexia because salicylates uncouple the oxidative

phosphorylation. The energy normally used for production of ATP

is dissipated as heat .

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8. ↑ Risk of Reye’s syndrome:

Aspirin & other salicylates given in viral infection in young children

have been associated with an ↑ incidence of Reye’s syndrome.

In Reye’s syndrome there is fulminating hepatitis ,with cerebral edema which may be fatal.

So Acetaminophen or Ibuprofen should be used instead of Aspirin.

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In pregnancy & during lactation:

Avoid in pregnancy & lactation

Aspirin & salicylates cross placental barrier & are secreted in breast

milk.

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10. Drug Interactions:

Corticosteroids ,other NSAIDs: ↑ GIT A/E.

With ACE inhibitors. ↓ Antihypertensive effect

With Warfarin or Heparin : ↑ GIT bleed.

With Probenecid & sufinpyrazone:

Aspirin antagonizes uricosuric action of Probenecid &

sufinpyrazone , as it inhibits tubular secretion of uric acid (in low

doses—< 2g/d). So C/I in Gout in low doses.

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Displacement of PPB drugs:

As aspirin is 90-95 % PPB Aspirin can displace many drugs from

PPB sites , ie Warfarin , Phenytoin , Valproic acid ,

Sulfonylureas, Methotrexate , Indomathacin , Naproxen ,

Ketoprofen, Fenoprofen & Bilirubin ----Increased level of free

drugs/ Bilirubin– toxicity.

Aspirin ↓ diuretic action of Fursemide, Thiazides,

Spironolactone.

Aspirin blocks the active transport of Penicillin from CSF to

blood.

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Contraindications / Precautions: Peptic ulcer.

Hemophilia.

Aspirin hypersensitivity

Children with a viral illness.

Chronic liver disease.

Aspirin should be stopped one week before elective surgery.

Avoid high doses in G-6-PD deficient.

Avoid in pregnancy & lactation

Consider drug interactions.

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Management of Aspirin/Salicylate Overdose

toxicity/Poisoning

Aspirin/Salicylate poisoning is a medical emergency, & death may result.

There is no antidote.

Management begins with rapid assessment, followed by

A(airway),B(breathing), C(circulation), D(decontamination) approach.

Gastric Lavage , Activated Charcoal to prevent further absorption, specially if enteric coated tablets have been used

Measurement of serum salicylate level & pH

Correct fluid, electrolyte & acid base balance.

Maintain high urine out put.

Keep airway patent.

Lower body temperature by cold sponging.

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Vit. K I/V to correct hypopthrombinemia.

Diazepam I/V for convulsions.

Promote excretion by NaHCO3 I/V to alkalinize

urine, maintain pH at 8.o.

Hemodialysis /Peritoneal dialysis in severe

acidosis & coma.

Ventilatory assistance in severe cases.

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Topically used salicylates:

Methyl salicylate: As counter irritant

Salicylic acid :Topically on skin for corns ,warts

Salfasalazine , Mesalamine --- suppository & rectal

suspension enema in Inflammatory bowel disease.

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Therapeutic uses:

1. Mild to moderate pain like Aspirin

2. Antipyretic

Preferred to Aspirin

In children with viral infections

In pt. with Peptic ulcer, Hemophilia

Pt. allergic to Aspirin.

Concomitantly with Probenecid & sulfinpyrazone in patients of

gout.

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Pharmacokinetics of Acetoaminophen

Rapid absorption from GIT.

Significant First pass metabolism in gut wall & liver.

When given in doses up to 0.5-4g/d:

90-95% metabolized to inactive glucuronide & sulphate conjugates

which are excreted in urine.

5-10 % hydroxylated to form N- Acetyl=p benzoquinoneimine

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N- Acetyl-p benzoquinoneimine is a highly reactive

metabolite which reacts with sulhydral groups.

Normally it reacts with sulhydral group Of Glutathion & forms

a non-toxic substance.

At doses above 4g/d Glutathion reserves are depleted & it can

produce toxicity– Hepatic necrosis & Renal tubular necrosis.

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Toxicity: At therapeutic doses

Rash & Allergic reactions.

Drug fever.

Mild increase in hepatic enzymes.

With over dosage:

Doses above 4g may be toxic.

15g may be fatal due to metabolite N-Acetylbenzoiminoquinone which

produces:

Hepatic necrosis--- potentially fatal

Renal tubular necrosis---may occur

Hypoglycemic coma --may occur

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Management of Acetoaminophen toxicity:

It constitutes a medical emergency, early diagnosis & treatment is required.

Activated Charcoal to prevent further absorption.

Correct fluid, electrolyte & acid base balance

Antidote--N-Acetylsysteine by I/V infusion.

It provide SH-groups to neutralize the toxic metabolite.

It is life saving if given within 10 hrs of overdose.

Avoid in severe hepatic impairment.

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Prevention of toxicity:

Base line & periodic estimation of hepatic enzymes

should be undertaken in patients on high dose

acetoaminophen.

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B: Selective COX-2 Inhibitors (Coxibs)

Prototype—Celecoxib : A Sulfonamide

MOA: Celecoxib is 10-20 times more selective in inhibiting COX-2 than COX-

1.

COX-2

It is constitutively expressed only in brain, kidney & bone .

Its expression at other sites is increased in inflammation.

It is responsible for the elevated production of prostanoids in inflammation &

disease.

It has larger & more flexible substrate channel than COX-I .

& a large space where the Celecoxib binds..

Its expression is inhibited by Glucocorticoids

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MOA of Celecoxib--- conti

Arachidonic acid is the primary precursor of Prostaglandins, is a component of the phospholipids of cell membrane.

Free Arachidonic acid is released by cell damage mainly by the action of Phospholipase A2 enzyme.

Arachidonic acid is converted to prostaglandins at site of inflammation by Cyclo-oxygenase-2 (COX 2) enzyme.

It reduces PG synthesis by selectively inhibiting COX-2 enzyme induced at sites of inflammation without affecting the actions of COX-1--- gastric cytoprotection & platelet aggregation

Inhibition of COX-2 enzyme is time dependent & reversible.

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PGG2

PGH2

Scheme for prostaglandin Biosynthesis

Stimulus

Disturbance of cell membrane

Phospholipids

Corticosteroids inhibit Phospholipase – A2

Arachidonic Acid

Lipoxygenase Cyclooxygenase

Aspirin & NSAIDs inhibit

Endoperoxides

Prostacycline

Hydroperxides

TXA2 PGD2 PGF2αPGE2 Leukotrienes

X

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Pharmacologic Effects :

Analgesic

Antipyretic

Anti-inflammatory effects

No inhibition of platelet aggregation. Does not

prolong bleeding time.

No inhibition of protective gastric PGs--- No gastric

irritation.

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PhK:

Long half life: 11 hrs– Once or twice daily dose.

Metabolized by CYP2C9.

Excreted in feces & urine.

Can inhibit CYP2D6

Dose adjustment in hepatic dysfunction

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Therapeutic uses:

Specially useful in osteoarithritis & Rheumatoid Arthritis.

Useful in Dysmenorrhea, acute gouty arthritis, acute musculoskeletal pain & ankylosing spondylitis

Also used in Primary familial adenomatus polyposis.

Useful in patients undergoing bone repair / operation.

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A/E:

Potential for increasing thrombotic events– --------Myocardial

infarction & stroke, specially in cases of Rheumatoid Arthritis Who are

at risk of myocardial infarction.

Selective COX-2 inhibitors depress PGI2 formation by endothelial cells,

without concomitant inhibition of platelets TXA2. PGI2 restrains the effects

of TXA2 on CVS, so selective COX-2 inhibitors increase the risk of

thrombosis.

Renal toxicities similar to non selective NSAIDs: depressed renal

function, edema , Hypertension.

Less GIT A/E (mediated by inhibition of COX-1)

Skin rash---because it is a Sulfonamide

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D/I:

Inhibitors of CYP2C9-- Fluconazole , Fluvastatin ,& Zafirlukast may increase the serum levels of Celecoxib

Celecoxib can inhibit CYP2D6--- may increase the serum levels of Beta blockers , Antidepressants & Antipsychotic drugs

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C/I:

Sulfonamide allergy

Anaphylactoid reaction with Aspirin.

Hepatic dysfunction.

Severe renal insufficiency

Severe heart disease

Volume depletion

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Meloxicam: Related to Piroxicam. Preferentially selective COX-2 inhibitor.

Etoricoxib: Resembles diclofenac

Monitoring of hepatic functions required.

Long half life: 22 hrs

Nimesulide: new compound less gastric irritation.

Valdecoxib & Rofecoxib

Withdrawn due to. higher risk of incidence of Cardiovascular thrombotic events----Myocardial Infarction & stroke.

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Pyrazolone Derivatives

Phenylbutazone: Obsolete --- Agranulocytosis

Apazone / Azopropazone: less risk of agranulocytosis

These are now rarely used.

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Acetic Acid Derivatives

Phenylacetic acid derivative: Diclofenac , Tolmetin , ketorolacIndomethacin , Etodolac , Sulnidac

Diclofenac: Very commonly used NSAID.

MOA: Non-selective COX inhibitor.

Good anti- inflammatory.

More potent than Indomethacin & Naproxen.

Accumulates in synovial fluid .

Drug & its metabolites are eliminated via kidney.

t1/2 --- 1.1 hrs

A/E: Nephrotoxic– Impaired renal blood flow & GF, fluid retention and

edema

Less Gastric irritation

↑ Liver enzymes

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Uses & dosage forms Diclofenac is used for long term use in Rheumatoid arthritis ,Osteoarthritis , &

Ankylosing spondylitis.

Also for short term treatment of Dysmenorhea, post operative pain, acute musculoskeletal disorders.

Oral tablets , capsules, intramuscular Injection

Also available in combination with misoprostol & omeprazole.

Prevention of postoperative ophthalmic inflammation after intraocular lens implantation & strabismus surgery: 1% Eye drops

Solar keratoses: 3% gel

Choice for analgesia with nausea -- rectal suppository.

Oral mouthwash.

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Etodolac:

10 times more selective Cox-2 inhibitor.

Good for post-operative relief after coronary artery bypass operation.

Less gastric intolerance.

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Indomethacin: Indole derivative.

Potent non selective COX inhibitor.

May also inhibit Phospholipase- A2 & C.

↓ neutrophils migration also ↓ T & B cell proliferation.

Th. Uses:

Gout, ankylosing spondylitis, PDA.

Conjunctival & gingival inflammation.

Postlaminectomy syndrome-- epidural inj.

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A/E of Indomethacin:

More GIT A/E & Pancrentitis

Headache, Dizziness confusion & Depression.

Rare: Thrombocytopenia , Aplstic anemia.

Psychosis with hallucination

Hepatic abnormalities.

Renal papillary necrosis.

Tolmetin: Ineffective in gout

A/E: Thrombocytopenia.

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Ketorolac:

Mainly Analgesic.Not anti-inflammatory

Can replace Morphine in post surgical pain .

More Nephrotoxic on chronic use

Sulnidac: Sulfoxide prodrug, undergoes, EHC.

DOA: 12-16 hrs.

Suppresses familial polyposis, ↓ incidence of cancer colon , breast & prostate.

A/E: Serious

Stevens Johnsons syndrome

Nephrotic syndrome

Agranulocytosis

Hepatic toxicity.

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Oxicams ( Enolic acids) : Piroxicam ,Tenoxicam

Piroxicam (Feldene): Oxicam derivative.

MOA: Non-selective Cox inhibitors

Inhibition of chemotaxis migration of polys & macrophages , Inhibits lymphocyte function.

↓ O2 radical production.

Long t ½ - once daily dosage.

Metabolized in liver-

A/E: peptic ulcer & bleeding (at higher dose > 20 mg/d ) 9.5 times higher

than other NSAIDs.

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Naphthylacetic Acid Prodrug:

Nabumetone : Non-acid NSAID.

Active metabolite has t ½ > 24hrs--- once daily

A/E: Pseudoporphyria & photosensitivity.

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Drugs with Analgesic & mild to moderate

anti-inflammatory effect

Propionic acid derivatives:

Ibuprofen – prototype

MOA: Like Aspirin– Non-selective COX inhibitor & also inhibits leukocyte

migration.

Good anti- inflammatory.

2400 mg = 4 g of aspirin. t ½ : 2 hrs

More effective in closure of PDA

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Preparations & Uses Oral tablet, liquid , I/V : For Anti-rheumatoid effects

For closure of PDA in pre-term infants.

Topical cream for Osteoarthritis , liquid gel for post surgical dental pain.

A/E: Like other NSAIDs

Less Gastric irritation

Nephrotoxic —Ac. renal failure , Interstitial nephritis. Nephroticsyndrome.

Aseptic meningitis in SLE patients

Interaction with anticoagulant uncommon.

Rare agranulocytosis & aplastic anaemia

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Flurbiprofen: Non-selective COX inhibitors & also inhibits TNF-α& Nitric

oxide synthesis.

Given orally. Other preparation also available

Topical ophthalmic prep.– for inhibition of intraoperative miosis.

I/V for periopretive analgesia.

Lozenges for sore throat.

Additional A/E: cogwheel rigidity , ataxia , tremor & myoclonus.

Fenoprofen: A/E--interstitial nephritis

Ketoprofen: Also inhibits lipo-oxygenase, not superior to other NSAIDs.

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Naproxen: More Toxic, rare allergic pneumonitis, vasculitis, pseudoporphyria.

Oxaprozin: t ½: 50-60hrs. Has uricosuric effect

b. Fenamates

Mefenamic, Meclofenamic & Flufenamic acid:

Inhibit both COX & Phospholipase A2.

Have no advantages over other NSAIDs.

A/E: Severe diarrhea , inflammation of bowel , Hemolytic anemia.

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