Module 45

Question 1

What is the mechanism of action of aspirin? salicylate? and acetaminophen?

Answer 1

• Aspirin inhibits COX by acetylation of a serine at the active site of the enzyme; in the case of COX-1 it is serine 530, and in the case of COX-2 it is serine 516. This inhibition is irreversible. It is not clear exactly how salicylate works; it cannot acetylate cyclooxygenase, but it does weakly inhibit COX.
  
  • Despite its use for more than a century, the mechanism of acetaminophen is unknown. At one time it was thought to inhibit a new cyclooxygenase, COX-3, but this enzyme appears to be specific to dogs. The most interesting hypothesis is that it produces a cannabinoid. Specifically, acetaminophen is hydrolyzed to p-aminophenol. This gets to the brain where it forms a conjugate with arachidonic acid, which is similar to the endogenous cannabinoid, anandamide.
    ○ It has also been proposed that the analgesic effect of acetaminophen involves scavenging free radicals, that it indirectly affects serotonin receptors in neurons involved in pain, and that it inhibits nitric oxide synthase.
    Acetaminophen also appears to act at the peroxide site of COX and that may be part of its mechanism of action. The story of acetaminophen is ongoing

Question 2

What is the rationale, other than to decrease side-effects, for the use of low dose aspirin (30 mg/day) for prophylaxis against myocardial infarctions and strokes, and what is the evidence that it is superior to normal dose aspirin?

Answer 2

• Inhibition of cyclooxygenase has both positive and negative effects relative to cardiovascular events.
  
  • Inhibition decreases thromboxane synthesis in platelets, and this decreases platelet aggregation, which decreases the risk of cardiovascular events. However, it also inhibits prostacyclin synthesis in vascular endothelial cells, which increases the risk of clotting and tips the balance toward vasoconstriction.
  • Therefore, it would be good if it were possible to inhibit cyclooxygenase in platelets without inhibiting it in the vascular endothelium.
    ○ To some degree this can be accomplished by giving a very small dose. Clearance of aspirin by the liver is high, but saturable; therefore, with a small dose, very little reaches the systemic circulation, and there is very little inhibition of prostacyclin synthesis in the vascular endothelium. However, there are platelets in the portal circulation that are exposed to aspirin before the portal blood reaches the liver. The inhibition of cyclooxygenase by aspirin is irreversible, and platelets have no nucleus and cannot make more cyclooxygenase. With repeated dosing most of the platelets will be exposed to aspirin in the portal circulation.
    ○ Therefore, this strategy improves the balance between prostacyclin and thromboxane synthesis. This is the theory, but there is no good clinical data to demonstrate that it really works. However, this strategy does still decrease the risk of cardiovascular events with a lower risk of bleeding than giving a full dose of aspirin. It is an example of why it is important to think through the pharmacokinetics of a drug and the site of action.

Question 3

What are the two types of cyclooxygenase, and what is the relevance of the subtypes to the development of safer NSAIDs?

Answer 3

the two types of cyclooxygenase are COX-1 and COX-2.
- COX-1 is the key enzyme involved in prostaglandin synthesis.
○ It is a constitutive enzyme present in many organs and is important for things such as intestinal integrity. It is also present at sites of inflammation
- In contrast, COX-2 is not expressed in most cells, but it is induced by inflammation. Therefore, it was hoped that selective COX-2 inhibitors would selectively decrease inflammation and not have the side-effects associated with COX-1 inhibitors.
○ However, COX-2 is constitutively expressed in the kidney and vascular endothelium, and the potent and very selective COX-2 inhibitor, rofecoxib (Vioxx) caused a significant increase in cardiovascular events and was voluntarily withdrawn.

Question 4

Why is it not recommended to start allopurinol during an acute gout attack?

Answer 4

• The recommendation is to wait at least 2 weeks after an acute attack of gout before starting allopurinol because allopurinol can exacerbate an acute attack.
  ○ However, clear evidence for this is lacking. A recent retrospective study found a small initial increase in flares of gout if allopurinol was started during an attack, but they also achieved target serum urate levels faster, and if the acute attacks were treated with adequate antiinflammatory therapy the small increase in the number of flares may not be important.
  In a prospective study, it was found that starting low doses of allopurinol during an attack of gout did not lead to prolongation of the acute attack; however, it was a small study (17 patients treated with placebo and 14 on allopurinol.) In short, the optimal time to start allopurinol therapy is open to debate

Question 5

A patient is on azathioprine 50 mg po daily for several years for rheumatoid arthritis. He starts allopurinol 100 mg po daily for gout. A couple weeks later, he feels unwell, has a fever, and notices petechiae on his legs and feet. Blood work at his doctor’s office shows low white blood cell and platelet count. Give a potential explanation for why this happened.

Answer 5

• Azathioprine is a prodrug that is nonenzymatically converted to 6-mercaptopurine. 6-mercaptopurine is further converted to thioguanine and its nucleosides, which are responsible for most of the therapeutic activity and toxicity.
  
  • Allopurinol inhibits one of the enzymes involved in mercaptopurine metabolism; specifically, xanthine oxidase. In addition, allopurinol also increases another metabolite of mercaptopurine, thioxanthine, which inhibits thiopurine methyl transferase, another enzyme involved in mercaptopurine inactivation.
  • Therefore, allopurinol decreases the inactivation of 6-mercaptopurine and increases its toxicity. However, this interaction has been used to increase the effectiveness of 6-mercaptopurine and azathioprine for conditions such as inflammatory bowel disease, although the dose of these drugs must be decreased when combined with allopurinol. There are many metabolites, and it gets rather complicated.

Question 6

What effect do NSAIDs have on the risk of colon cancer?

Answer 6

• NSAIDs decrease the risk of colon cancer. This may be useful in patients who are at high risk, but for the general population, the decrease in colon cancer risk is outweighed by the risk of gastrointestinal bleeds and other NSAID side-effects.
  
  • the exact mechanism is not known, but cyclooxygenase is often over expressed in cancers, and this may promote immune tolerance and keep the immune system from destroying the tumor.
    NSAIDs may decrease the risk of other cancers such as prostate cancer. It was hoped that the COX-2 selective NSAIDs would have the same benefit without the risks associated with the nonselective agents; however, there is less data for the COX-2 inhibitors, and even the COX-2 selective agents can have serious side-effects.

Question 7

What is the evidence that therapeutic touch is effective in relieving pain or improve healing?

Answer 7

• Practitioners of therapeutic touch claim to be able to feel and manipulate human energy fields, and in doing so, relieve pain and speed healing. The effectiveness of therapeutic touch is very implausible. Despite the lack of plausibility and clear evidence that practitioners cannot detect ‘human energy fields” Cochrane did a review, and of course found no evidence of efficacy. However, the practice continues.