Williamson L1

Question 1

Why has life expectancy increased?

Answer 1

Until 1900s, main reason was due to reduction in infant mortality. Since there have been reductions in premature deaths from infections.

Question 2

What is inflammation?

Answer 2

A common response of the body to a wide range of challenges like tissue damage, infection etc.

Question 3

What are the different processes involved in inflammation?

Answer 3

• Increased blood flow (to bring leukocytes to affected tissue and wash out causative agents and dead cells)
• Accumulation of leukocytes in damaged tissue (ie they stick)
• Increased permeability of endothelial cells lining blood vessels – blood leaks out into surrounding tissue

Question 4

What are the general effects of inflammation?

Answer 4

Vasodilation – blood vessels get wider (relaxed). Therefore the tissue heats up.
Oedema – fancy medical word for swelling – due to leaking of blood into tissue.
Erythema – fancy medical word for tissue going red

Question 5

What signal is used to stimulate oedema and vasodilation?

Answer 5

Prostaglandins.

Question 6

What signals are prostaglandins

Answer 6

Autocrine (made by same cell that receives the signal, ie the cell turns itself on) or paracrine (made by one cell and received by a neighbouring cell).

Question 7

Why are prostaglandins NOT endocrine?

Answer 7

They do not originate from endocrine glands but from a wide range of cells.

Question 8

How are prostaglandins produced?

Answer 8

They are produced by the oxidation of fatty acids (usually arachidonic acid) by an enzyme called cyclooxygenase (COX). This converts arachidonic acid into prostaglandin H2 which can be further converted in particular to thromboxane and prostacyclin.

Question 9

What are the two main types of prostaglandins?

Answer 9

• Prostacyclin (prostaglandin I2). This is a vasodilator. It is made by endothelial cells and inhibits the aggregation of platelets. It therefore stimulates inflammation and the migration of leukocytes into the tissue.
• Thromboxanes - these are made by activated platelets and have the opposite effect: they are vasoconstrictors and promote platelet aggregation.

Question 10

What is blood clotting?

Answer 10

Essential response to tissue damage. But needs to be very tightly regulated, to prevent unwanted blood clots (thrombosis) on the one hand and bleeding on the other.

Question 11

What occurs in blood clotting?

Answer 11

Damaged tissue leads to activation of platelets causing conformational changes from round into tissue factors. The activated platelets stick to the damaged tissue to form a plug.
They also release various signals, one of which is thromboxane A2, which further activate other platelets.
At the same time, the damaged tissue causes changes to proteins circulating in blood, which ultimately activate prothrombin to thrombin, and thus convert fibrinogen to fibrin.

Question 12

What inhibits blood clotting?

Answer 12

This is inhibited by various factors released by endothelial cells, among which is prostacyclin I2, which inhibits platelet activation.

Question 13

What are NSAIDS?

Answer 13

Non steroidal anti inflammatories.

Question 14

How do NSAIDS work?

Answer 14

Inhibit cyclooxygenase (COX, prostaglandin-endoperoxidase synthase (PTGS).
COX leads to both prostaglandins (inflammatory) and thromboxanes (anti-inflammatory) but in normal tissue mainly to prostaglandins, so inhibiting COX reduces inflammation.
Also reduce fever and headaches (antipyretic and analgesic).

Question 15

How was aspirin discovered?

Answer 15

Extracts of willow bark have been used to reduce inflammation for thousands of years. The active ingredient is salicylic acid. In 1897, Hoffmann synthesised acetyl salicylate (aspirin).

Question 16

How does aspirin work?

Answer 16

In 1971 it was shown that aspirin works by inhibiting COX, by irreversibly acetylating it. Reduction of thromboxane synthesis reduces clotting, and hence low doses of aspirin are also used to reduce the risk of heart attacks. It has also been suggested in the treatment of Alzheimer’s. However, aspirin leads to gastric bleeding, because prostaglandins protect the stomach lining.

Question 17

What did Rous Sarcoma virus show in terms of COX genes?

Answer 17

There are two different genes for COX, COX-1 and COX-2. Most NSAIDs inhibit both.

Question 18

What are the characteristics of COX2?

Answer 18

COX-2 is mainly found in inflamed tissues. Therefore a COX-2 inhibitor should reduce inflammation but not cause gastric irritation (mainly a consequence of COX-1). Produced locally by blood vessels when there is an infection or cut.

Question 19

How do COX1 and COX2 differ in prostacyclin and thromboxane synthesis?

Answer 19

COX-2 seems to be important for making prostacylins but less important for thromboxanes. Therefore if you inhibit COX-2 you might reduce inflammation but increase the risk of thrombosis (because you are not inhibiting thromboxanes derived from COX-1 stimulation).

Question 20

What drugs arised as COX2 inhibitors?

Answer 20

Called ‘coxibs’ eg etoricoxib (Merck), celecoxib (Pfizer), valdecoxib (Bextra) and rofecoxib (Merck), which has the brand name Vioxx.
The market leader was Vioxx, which was approved in 1999 and made $2.5bn in 2003, making it a blockbuster (annual sales greater than $1bn). It was used for osteoarthritis, acute pain, and severe period pain.

Question 21

What was the risk with vioxx?

Answer 21

It emerged that clinical trials from 2001 onwards showed an increased risk of heart attacks with high doses. Small trials in 1999-2001 showed a 3- to 8-fold increased cardiovascular risk.
Meta-analysis showed that of 21432 patients studied up to the end of 2001, 64 had heart attacks. Comparison to controls suggests that the risk of heart attack is 2.24x greater with Vioxx.

Question 22

How much money has Merck used to deal with Vioxx problems?

Answer 22

Merck have set aside about $6bn to deal with legal claims. (They also contributed $21m to a legal report that claimed that Merck management had acted in good faith, and if there was a problem it was with the sales team).