Module 26 Flashcards
Some patients report a severe allergic reaction to aspirin consisting of angioedema and severe difficulty breathing. Is this likely to be a true allergic reaction? What mechanism appears to be responsible for most of these reactions? What other drugs should such a patient avoid? What questions should you ask the patient?
- Although true IgE-mediated allergies to aspirin can occur, by far the most common mechanism for these adverse reactions to aspirin is an inhibition of the production of prostaglandins leading to an increase in the production of leukotrienes.
○ It is the increase in leukotrienes that causes the adverse reaction.
○ This is because the limiting factor in the production of prostaglandins is the availability of arachidonic acid. Once there is a stimulus to release arachidonic acid, the other product of arachidonic acid metabolism is leukotrienes. What is not clear is why some patients are much more sensitive to this effect than others.- All nonselective COX inhibitors (nonsteroidal antiinflammatory drugs, NSAIDs) are likely to cause the same reaction. Therefore you should ask whether the patient has had reactions to other NSAIDs.
○ You should also find out if they have the classic triad associated with aspirin sensitivity; the other parts of the triad are nasal polyps and asthma, although certainly not all patients with aspirin sensitivity have this triad. NSAID reactions are more likely to be fatal in patients with asthma.
- All nonselective COX inhibitors (nonsteroidal antiinflammatory drugs, NSAIDs) are likely to cause the same reaction. Therefore you should ask whether the patient has had reactions to other NSAIDs.
How would you treat someone who is “allergic” to NSAIDs who also has severe arthritis?
- There are several options. Most, but not all patients will tolerate the COX-2 selective NSAIDS such as celecoxib (Celebrex). You can usually desensitize a patient to aspirin by starting at a very small dose and slowly increasing the dose. However, the patient must continue to take aspirin or they will lose the desensitization.
- Salicylate and acetaminophen are usually tolerated, but are not as effective, and some patients even react to these drugs.
- A leukotriene inhibitor such as montelukast can also prevent many of the symptoms, but it will not prevent a reaction in a patient with severe sensitivity.
Provide at least three mechanisms by which analgesics, such as aspirin, could cause complications during childbirth?
- Prostaglandins are involved in uterine contractions; therefore, aspirin can inhibit labor.
- Prostaglandins are involved in platelet aggregation, therefore aspirin can increase the risk of hemorrhage, which is a significant risk in childbirth.
- Prostaglandins are involved in keeping the ductus arteriosus open, and aspirin can cause premature closure.
Why is it a bad idea to take an NSAID for pain at the same time as low dose aspirin for the reduction in the risk of cardiovascular events?
- Aspirin works by acetylating a specific serine on cyclooxygenase, and this leads to irreversible inactivation of the enzyme. Aspirin is especially active in decreasing platelet aggregation.
- Other NSAIDs interact reversibly with cyclooxygenase and block access of aspirin to this serine; therefore, other NSAIDs partially block the antiplatelet activity of aspirin. In addition, other NSAIDs increase the risk of cardiovascular events because they have more of an effect on decreasing prostacyclin and other prostaglandins that decrease the risk of cardiovascular events
How might rofecoxib (Vioxx) increase the risk of MIs and stroke. What is the data with celecoxib (Celebrex)? How about other NSAIDs?
- COX-1 is constitutively expressed while COX-2 is inducible, and initially it was believed that COX-2 was only produced at sites of inflammation.
- However, it turned out that COX-2 is also constitutively expressed in the kidney and vascular endothelia. In the early clinical trial of rofecoxib the comparator drug was naproxen, and the risk of cardiovascular events was a little higher with rofecoxib than naproxen, but it was argued that naproxen is like aspirin and decreased cardiovascular risk.
- It appears that the risk associated with celecoxib is about the same as naproxen, presumably because it is selective for COX2, but not a pure COX2 inhibitor like rofecoxib, and inhibition of COX-1 mitigates some of the negative effects on the cardiovascular system.
Misoprostol is used to prevent NSAID-induced ulcers in patients with risk factors for this adverse reaction. Is it rational to use misoprostol in patients who use NSAID suppositories? What side-effect of misoprostol has led to another use for misoprostol?
- Much of the exposure to NSAIDs is through the blood rather than direct exposure in the gut. Therefore, even NSAID suppositories can increase the risk of a GI bleed higher up in the intestine, and it could be appropriate to use misoprostol if the patient was at high risk of a GI bleed. Misoprostol is used to induce uterine contractions in combination with other agents to induce an abortion.
What other conditions may respond to leukotriene antagonists?
- Leukotriene inhibitors such as montelukast have been tried for many indications other than asthma in which leukotrienes are believed to be involved. However, in most cases the results have been negative. They may have some efficacy in allergic rhinitis and exercise-induced bronchospasm.
Are all of the effects of prostaglandins proinflammatory?
- No, not all effects of prostaglandins are proinflammatory. The dominant prostaglandin is PGE2. It has multiple physiological effects. A major effect is vasodilatation at the site of inflammation leading to redness and edema. However, in other contexts it can be antiinflammatory with inhibition of T cell activation and proliferation.
- PGE2 can also have inhibitory effects on the innate immune cells, e.g. neutrophils, monocytes, and NK cells. In addition, it promotes the production of antiinflammatory Treg cells. To a large degree the effects depend on concentration and location. The reason that prostaglandins can have different effects in different organs is because there are 4 different PGE2 receptors that mediate different responses, and these receptors are present in different organs. It is more complicated than you might think.
What is latanoprost, and what side-effect may be used cosmetically?
Latanoprost is a PGF2a analog used in eye drops to treat glaucoma, but it was found to cause an increase in eyelash growth, which is considered desirable. It can also cause iris pigmentation.
