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By the end of the lecture, students will be ableto:

- Name the non steroidal anti-inflammatory

drugs (NSAIDs) and other antipyretic agents- Describe the mechanisms of action of aspirin- Explain the clinical uses of aspirin- Describe the toxicities of aspirin

- Describe the mode of action of otherNSAIDs, their clinical uses and toxicities- Describe the mode of action ofacetaminophen, its clinical uses and toxicity

Antipyretic Drugs

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Mechanism of Action of NSAIDsDecrease prostaglandin, prostacyclin and thromboxane

synthesis throughout the body

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Cycloxygenases

COX

Constitutive

Cytoprotective

PGsStomach Kidney

Inducible

Inflammatory

PGsFever Pain

Inflammation

COX-1 COX-2

PainFever

COX-3

CNS

Platelets

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Non steroidal anti-inflammatory drugs (NSAIDs)

1) Salicylates as Aspirin, Diflunisal & Methyl salicylate

2) Heteroaryl acetic acids as Diclofenac3) Acetic acids:Etodolac, Sulindac, Indomethacin

Inhibit both COX-1 & COX-2

COX-1constitutivepresent in GIT(Hcl, mucus), Kidney(Regulate the hemodynamics), Platelets (Control aggregation)

4) Propionic acid derivatives (profens) as, Ibuprufen ,Ketoprofen, Naproxen.

5) Pyrazolidine derivatives asPhenylbutazone

6) Oxicams asPiroxicam

7) Fenamates:Mefenamic acid

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COX-2 InhibitorsCelecoxib

N.BMeloxicamis preferentially selective

COX 2 inhibitor

Antipyretic analgesic

Acetaminophen

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- Anti-inflammatory

- Analgesics- Antipyretics

Common actions of NSAIDs

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The major difference between NSAIDs

1. Aspirin acetylates the enzyme, so it irreversibly

inhibits COX while other NSAIDs inhibition isreversible

2. Aspirin effect results in longer duration of its

antiplatelet inhibition3. Vary in their potency as anti-inflammatory :

* Moderate effectiveness as Ibuprufen & Naproxen

* Greater effectiveness as Indomethacin

4. Celecoxib is COX-2 selective inhibitors

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ASPIRIN

Pharmacokinetics-Hydrolyzed to acetic acid and salicylate by esterase.-At therapeutic dose 600mg,elimination in accordance to

first order kinetics, half life is 3 to 5 hours.

-With higher dose half life increases up to 20 to 24 hours

in accordance to zero order kinetics.

Mechanism of action

Irreversible non-selective COX inhibitor

Eff f A i i

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Effects of Aspirin:PGs synthesizesit:) Analgesic1

* Centrally pain threshold esp. in thalamus

* Peripherally anti-inflammatory effect) Antipyretic:2

synthesis of PGs

* Peripheral VD heat loss by radiation

* Sweating heat loss by evaporation

) Effect on platelets:3Inhibition of thromboxane synthesis results in reduced plateletaggregation

) Immunological effects :4

inhibits antigen/antibody reaction through Cortisol release

5) Gastrointestinal effects:Inhibits PGI2 , PGE2 & PGF2

Resulting in increased gastric acid secretion and diminished

mucus protection Causing epigastric distress, ulceration and/or hemorrhage

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rheumatic-inflammatory & anti-Anti)6

1- PGs synthesis E2& I2 VD

2. Salicylate inhibits Kallekrein enzyme synthesis of bradykinin pain & VD

3. Salicylate inhibits Hyaluronidaze enzyme capillary Permeability swelling &

edema

4.Fibrinolysin & tissue damaging enzymes

5. Migrationof polymorphs & macrophages

to inflammatory sites.6. Stabilization of Lysosomes release of

proteolytic enzymes

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Clinical Uses of Aspirin

1. Anti-inflammatory: arthritis

2. Antipyretic.

3. Analgesic: headache, dysmenorrheapostoperative, dental pain.

4. platelet aggregation

5.incidence of colon cancer whentaken chronically.

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Toxicity of Aspirin

1) GIT: Epigastric distress, nausea, vomiting &

GI bleeding2) Nephrotoxcity

3) Respiration:

-Precipitates asthmatic attack in asthmatic patient due to

shift of arachidoinc acid to form leukotrienes or due Ag-

Ab reaction

-In toxic doses aspirin causes respiratory depression

4) Blood:

-Hypoprothrombinemia in chronic usecaution in patienton warfarin therapy

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Phenylbutazone & indomethacin may cause

aplastic anemia and agranulocytosis in chronic

use

5) Salicylism: inLarge dose for Long time in the formof Tinnitus, blurring of vision & irritability

(Reversible after stopping salicylates).

6) Reye's syndrome: occurs in some children withviral infection (e.g. Influenza or Chicken pox) Encephalopathy & Hepatotoxicity

7) Allergy Rash, urticaria, angio-edema8) Idiosyncrasy Hemolysis

9) Teratogenicity

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COX-2 Selective NSAIDs (coxib)Celecoxib

* No effect on platelets function.* Have reducedrisk ofGIT effects, including

gastric ulcers and GIT bleeding NOT recommended in renal patient as COX-2 is

constitutively present in kidney

Increased risk ofcardiovascular adverseeffects

May cause hypersensitivity in patients

allergic to sulphonamides

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Acetaminophen (Paracetamol)** More selective against COX-3

* It is an analgesic antipyretic*Lacksanti-inflammatory and antiplatelet effects

*Safe during pregnancy, in patient with

peptic ulcer, bronchial asthma, bleedingtendency & children with viral infection

*Overdose or in severe liver impairment thedrug is hepatotoxic, acetylcysteine is theantidote