Lecture 8- Non-steroidal Anti-inflammatory Drugs (NSAIDs)

Question 1

NSAIDs

Answer 1

-provide symptomatic relief from pain + swelling in chronic joint disease; osteo + rheumatoid arthritis
-treat symptoms of acute inflammatory conditions; sports injuries, fractures + sprains
-provide relief from postoperative, dental + menstrual pain

-ineffective in treating the underlining inflammatory conditions; rheumatoid arthritis

Question 2

NSAIDs

Answer 2

-actions very similar to aspirin
3 main therapeutic effects of NSAIDS;

• an anti-inflammatory effect; modification of the inflammatory reaction
• an analgesic effect; reduction of certain types of inflammatory pain
• antipyretic effect; lowering of body temp when raised in disease (fever)- bacterial invasion- prostaglandin E2= released to a part of the brain to increase body temp to make environment comfortable for microbe

-increase in temp= cells/enzymes denature

-modification= modify any process that are responsible for acute inflammation

Question 3

Basic mechanism of action of NSAIDs

Answer 3

-effects of NSAIDs are related to;

*inhibiton of the fatty acid cyclooxygenase enzyme (COX) -> inhibition of the production of prostaglandins + thromboxanes

Question 4

Cyclooxygenases

Answer 4

2 known isoforms;
- cox-1
- cox-2
^both closely related + catalyse the same reaction
-expressions and roles are different

Question 5

COX-1

Answer 5

-constitutive enzyme in most tissues; including blood platelets
-involved in tissue homeostasis
-responsible for the production of prostaglandins involved in gastric cytoprotection

Question 6

COX-2

Answer 6

-induced in inflammatory cells when activated
-responsible for the production of prostanoid mediators of inflammation

Question 7

Cyclooxygenase inhibitors

Answer 7

-inhibitors of both isoenzymes - vary in the degree to which they inhibit each isoform
-anti-inflammatory action of the NSAID= related to their inhibiton of COX-2
-unwanted effects; those affecting the GIT= result of inhibition of COX-1

Question 8

Pharmacological actions of NSAIDs

Answer 8

3 major actions- reduce inflammation, pain + fever
-not equally potent in each of these actions

*anti-inflammatory actions- NSAIDs modulates aspects of inflammation in which prostaglandins act as mediators; including vasodilation, oedema + pain

-they suppress the pain, swelling + increased blood flow associated with inflammation; however have little/ or no action on the progress of the disease

-ineffective on aspects of inflammation such as; leucocyte migration, lysosomal enzyme release + toxic oxygen radical production = contribute to tissue damage in chronic inflammatory conditions; RA

Question 9

Pharmacological actions of NSAIDs

Answer 9

*analgesic action- NSAIDs are effective against mild/moderate pain especially that arise from inflammation/tissue damage

-peripheral action due to decreased production of the prostaglandins that sensitise nociceptors to inflammatory mediators; bradykinin

*antipyretic action- normal body temp is regulated by a centre in the hypothalamus that controls the balance between heat loss + heat production

-fever= result of disturbance to this ‘set point’. NSAIDs = reset the thermostat= operation of temp-regulating mechanisms to reduce temp

Question 10

Mechanism of action of NSAIDs

Answer 10

COX-2= binding site is characterised by a ‘side pocket’ that can accommodate the bulky groups; methylsufonyl moiety of the prototype COX-2 inhibitor-> impede its access to the COX-1 site

*flurbiprofen= can enter the active site of either enzyme

Question 11

Side affects of NSAIDs

Answer 11

1. Gastrointestinal disturbances;
   -from inhibition of gastric COX-1= responsible for the synthesis of the prostaglandins-> inhibit acid secretion + protect the mucosa
   -gastric discomfort
   -dyspepsia
   -diarrhoea
   -nausea + vomiting
   -gastric bleeding + ulceration
2. Skin reactions (mild erythematous, urticarial + photosensitivity reactions)
3. Adverse renal effects
4. Less common/unwanted effects; CNS, bone marrow disturbances + liver disorders

Question 12

Aspirin in the prevention of cardiovascular disorders

Answer 12

-through the antiplatelet action of low-dose aspirin

-alters the balance between TXA2= promotes aggregation and PGI2 which inhibits it

-after administration of aspirin; TXA2 synthesis does NOT record until the affected cohort of platelets is replaced in 7-10 days