MEDICINAL CHEMISTRY-MEDICINAL CHEMISTRY-IIIIII

introductionWed. 2/ 5/ 1432H

Prof.Prof. Dr. Wafaa ZagharyDr. Wafaa Zaghary wzaghary@ksu.edu.sa

PHC 426

Different ‘types’ of pain, not just different degrees of pain

Multiple chemical mediators of pain

Optimal therapy matches the Optimal therapy matches the analgesic(s) with the type(s) of painanalgesic(s) with the type(s) of pain

Different ‘types’ of pain, not just different degrees of pain

Multiple chemical mediators of pain

Optimal therapy matches the Optimal therapy matches the analgesic(s) with the type(s) of painanalgesic(s) with the type(s) of pain

NSAIDs(non steroidal anti-inflammatory drugs)

Nonsteroidal Anti-Inflammatory Drug

A therapeutic agent which relieves pain and fever by inhibiting the inflammatory response.

These drugs are available over the counter and by prescription.

Some common examples include aspirin, ibuprofen, Celebrex, and less commonly acetaminophen (Tylenol).

Benefits of NSAIDs

Decrease pain and inflammation associated with rheumatic diseases.

Some studies show that Cox-2 inhibition may play a role in the modulation of intestinal polyps and colorectal cancer.

Other studies show that Cox-2 inhibition may prevent Alzheimer’s disease.

NSAID use

NSAIDs are available OTC

NSAIDs can be toxic on their own

People who take NSAIDs (elderly people) often take many drugs which can lead to dangerous interactions

NSAIDs are metabolized by multiple hepatic pathways

Common Side Effects

Common side effects to ALL NSAIDs are:Abdominal painDiarrheaNauseaFluid retention

These side effects occur in about 30% of all people taking NSAIDs.

Adverse effects

NephrotoxicBleeding problemsIncrease blood pressure

FDA requires medication guide be dispensed with every NSAID prescription – www.fda.gov/cder/drug/infopage/COX2/NSAIDmedguide.pdf

FDA fact: >70,000 hospitalizations per year and 10,000-20,000 deaths per year can be associated with NSAID use

Possible Side Effects

Cox-1 inhibitors GI ulceration, perforation,

toxicity Kidney failure Congestive heart failure

Cox-2 inhibitors GI problems May delay ulcer healing Increased risk of CV

disease Kidney failure* Increased risk factors include

being male, advanced age, and history of ulcers.

Startling Statistic

N Engl J Med 1999;340:1888-1899

20,197

16,685 16,500

10,503

5,338 4,441

0

5,000

10,000

15,000

20,000

25,000

Leukemia AIDS NSAIDsToxicity

MultipleMyeloma

Asthma CervicalCancer

# o

f D

eath

s p

er

Year

Categories of NSAIDsThere are two major categories for non-steroidal anti-inflammatory drugs

The first is non-selective anti-inflammatory drugs.

The second is selective anti-inflammatory drugs, COX-2 inhibitors.

The Inflammatory ResponseThe body’s response to a stimuli which causes pain and/or tissue damage.

Physiologically capillaries become “leaky” through vasodilation.

The response is initiated by the chemical messengers prostaglandins.

Biosynthesis of Prostaglandins

The goal is to inhibit the biosynthesis of prostaglandins in order to relieve the symptoms caused by the inflammatory response.

Prostaglandins are synthesized from arachidonic acid in a pathway mediated by the Cyclooxygenase enzymes.

FitzGerald, G. A. et al. N Engl J Med 2001;345:433-442

Production and Actions of Prostaglandins and Thromboxane

COX Expression Function Inhibitors

COX-1constitutively throughout the body

organ pain, platelet function, stomach

protection

NSAIDs

including aspirin

COX-2Inducible and constitutively in

brain, kidney

Inducible:  inflammation, pain, feverConstitutive:  synaptic

plasticity

NSAIDs, COX 2 inhibitors including celecoxib

(Celobrex )

COX-3Constitutively, high

in brain, heart

pain pathways, not inflammation pathways

acetaminophen some NSAIDs

Cox-1 vs. Cox-2 inhibitors

Selective COX-II Inhibitors

Anti-inflammatory with less adverse effects, especially GI events.Potential toxicities: kidney and platelets - ? increased risk of thrombotic events Role in Cancer preventionRole in Alzheimer’s disease

ASPIRIN Major Actions

Antipyretic action

Block the production of PGE2 to reset the hypothalamic temperature set point

ASPIRIN Major Actions

Antiplatelet/antithrombotic

Decreases platelet production of TXA2

by COX-1 to limit platelet aggregation and vasoconstrictiion

ASPIRIN/ NSAIDs ADVERSE GI EFFECTSBLEEDING

ULCERATION

OBSTRUCTION

Textbooks:

Williams, D.A. and Lemeke, T.L., Foye’s Principle of Medicinal Chemistry, Lippincott Williams & Wilkins, Philadelphia, PA., 5th Edition, 2002.

References

1. Tramer MR, et al. quantitative estimation of rare adverse events which follow a biological progression: a new model applied to chronic NSAID use. Pain. 2000 Mar;85(1-2):169-82.

2. DeBisschop M. What are the risks of long-term NSAIDs and COX-2 inhibitors? J of Family Practice. 2003 Mar;52(3):199-200.

3. Deviere J. Do selective cyclo-oxygenase inhibitors eliminate the adverse events associated with nonsteroidal anti-inflammatory drug therapy?

4. Oviedo JA, Wolfe MM. Clinical potential of cyclo-oxygenase-2 inhibitors. Biodrugs. 2001;15(9):563-72.

5. Hernandez-Diaz S, Rodriguez LA. Association between nonsteroidal anti-inflammatory drugs and upper gastrointestinal tract bleeding/perforation: an overview of epidemiologic studies published in the 1990’s. Arch Internal Medicine. 2000 Jul 24;160(14):2093-9.

References

6. Hawkey CJ. Non-steroidal anti-inflammatory drug gastropathy: causes and treatment. Scandinavian Journal of Gastroenterology 1996; vol. 220: 124-7.

7. Wolfe MM, Liechenstein DO, Sigh G. Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. N Engl J Med1999;340:1888-1899

8. FDA and International Guidelines on Efficacy and Safety of

Cox-2 Inhibitors