NSAIDs.pptx

8/22/2019 NSAIDs.pptx

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Nonsteroidal Anti-

inflammatory Drugs (NSAIDs) Common therapeutic indications

Common adverse effects

Different pharmacokinetics and potency

Different chemical families

Common mechanism of action (cyclooxygenase

inhibition) Different selectivities to COX I and II

Similarities more striking than Differences


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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.

Some shown to inhibit activation, aggregation,adhesion of neutrophils & release of lysosomal enzymes

Some are Uricosuric


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Common Adverse Effects

Platelet Dysfunction

Gastritis and peptic ulceration with bleeding

(inhibition of PG + other effects) Acute Renal Failure in susceptible

Sodium+ water retention and edema

Analgesic nephropathy

Prolongation of gestation and inhibition oflabor.

Hypersenstivity (not immunologic but due toPG inhibition)


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NSAID

Leukocyte-Endothelial

Interactions

Capillary

Obstruction

IschemicCell Injury

Proteases +

Oxygen Radicals

Endo/EpithelialCell Injury

Mucosal Ulceration

Loss of PGI2 induced inhibition of LTB4 mediated

endothelial adhesion and activation of neutrophils


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The Salicylates - Aspirin

Effect on Respiration: triphasic

1. Low doses: uncoupling phosphorylation

CO2 stimulates respiration.2. Direct stimulation of respiratory center

Hyperventilation resp. alkalosis renalcompensation

3. Depression of respiratory center andcardiovascular center BP, respiratoryacidosis, no compensation + metabolicacidosis also


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GI system

1. Dose dependent hepatitis

2. Reyes syndrome Metabolic

1. Uncoupling of Oxid. Phosphorylation

2. Hyperglycemia and depletion of muscle andhepatic glycogen

Endocrine: corticosteroids, thyroid

Aspirin


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Antipyretic, analgesic

Anti-inflammatory: rheumatic fever,

rheumatoid arthritis, other rheumatologicaldiseases. High dose needed (5-8 g/day)

Prophylaxis of diseases due to platelet

aggregation (CAD, post-op DVT)

Pre-eclampsia and hypertension of pregnancy

(?excess TXA2)

Aspirin - Therapeutic Uses


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Generation of Lipoxins by Aspirin


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Role of Lipoxins in Anti-inflammatory effects of Aspirin


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Effect of NSAIDs on Platelet-Endothelial Interactions
http://jpet.aspetjournals.org/content/vol300/issue2/images/large/pt0222074003.jpeg


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Use of Aspirin in Unstable Angina


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Use of Aspirin in Unstable Angina


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Headache - timmitus - dizzinesshearingimpairmentdim vision

Confusion and drowziness Sweating and hyperventilation

Nausea, vomiting

Marked acid-base disturbances

Hyperpyrexia

Dehydration

Cardiovascular and respiratory collapse, coma

convulsions and death

Aspirin Toxicity - Salicylism


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Decrease absorption - activated charcoal,

emetics, gastric lavage

Enhance excretion - alkalinize urine,

forced diuresis, hemodialysis

Supportive measures - fluids, decrease

temperature, bicarbonate, electrolytes,glucose, etc

Aspirin Toxicity - Treatment


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Other NSAIDs

Phenylbutazone: additional uricosuric effect.Aplastic anemia.

Indomethacin: Common ADRs. CNS mostcommon: halucinations, depression, seizures

Propionic acids: better tolerated. Differ inpharmacokinetics

Acetaminophen: differes in effects and ADRsfrom rest. Main toxicity: hepatitis due to toxicintermediate which depletes glutathione. Treatwith N-acetylcysteine.


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Attempts to

Decrease

Toxicity of

NSAIDs

Nitroaspirins


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Selective COX-II Inhibitors

Anti-inflammatory with less adverseeffects, especially GI events.

Potential toxicities: kidney andplatelets - ? increased risk ofthrombotic events

Role in Cancer prevention

Role in Alzheimers disease


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VIGOR - Summary of GI Endpoints

p < 0.001. * p = 0.005.

0

1

2

3

4

5

Confirmed ClinicalUpper GI Events

ConfirmedComplicated

Upper GI Events

All ClinicalGI Bleeding

RR: 0.46(0.33, 0.64)

RR: 0.43*(0.24, 0.78)

RR: 0.38

(0.25, 0.57)

Rate

sper100Patient-Years

RofecoxibNaproxen

( ) = 95% CI.

Source: Bombardier, et al.N Engl J Med. 2000.


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Patients with Events (Rates per 100 Patient-Years)

Event CategoryRofecoxibN=4047

NaproxenN=4029

Relative Risk(95% CI)

ConfirmedCV events

45 (1.7) 19 (0.7) 0.42(0.25, 0.72)

Cardiacevents

28 (1.0) 10 (0.4) 0.36(0.17, 0.74)

Cerebrovascularevents

11 (0.4) 8 (0.3) 0.73(0.29, 1.80)

Peripheralvascular events

6 (0.2) 1 (0.04) 0.17(0.00, 1.37)

VIGOR - Confirmed Thrombotic

Cardiovascular Events

Source: Data on file, MSD


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Effect of Celecoxib & Rofecoxib onPGIM

* p


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0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Months of Follow-up

0 2 4 6 8 10 12 14

C

umulativeIncidence%

Rofecoxib (OA)

Investigator-Reported Thrombotic

Cardiovascular Events in the VIGOR Study

Compared with Phase IIb/III OA Study

Rofecoxib (VIGOR)

Naproxen (VIGOR)

FDA files

Ibuprofen, Diclofenac,

Nabumetone (OA)


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Treatment of Gout

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