Drugs

Some notes on the COX enzymes. There are two types of COX - COX1 and COX2.

COX 1 - constitutively expressed in all cells of the body, especially in the GI tract. This is why we will talk about how COX 1 selective inhibitors have a tendency to cause GI side effects.

COX 2 is inducible, which means that it tends to be expressed in situations of inflammation and inflammatory disease. Additionally, it is not going to be expressed everywhere, but it is constitutively expressed in the kidney. This will be important for when we discuss how COX2 contributes to CV issues.

Some notes on the prostaglandins (in this lecture, lipoxins and leukotrienes are not going to be discussed significantly). There are largely 3 classes of prostaglandins: prostacyclins (which contribute to vascular dilation and decreased platelet aggregation - generally restrict thrombus formation), thromboxanes (which are opposite to prostacyclins in that they cause vasoconstriction and platelet aggregation), and finally PGD/PGE which cause vasodilation and increased vascular permeability (though we don’t talk about that one as much in this lecture).

ASPIRIN

This drug is going to be used in cases of inflammation and pain and even fever, however there are better antipyretics (such as Tylenol). Aspirin is interesting in that it is more COX 1 selective, even though it does have SOME COX2 activity, but it will also bind IRREVERSIBLY to the COX enzyme. This means that it will take the COX enzyme completely out of business. The effect of this is is that there is a greater amount of vasodilation that is occurring, because the thromboxanes are not going to be produced to a significant degree and that the prostacyclins are, which are vasodilatory. In addition, because the COX inhibitor will actually go into the platelet (which is anucleated and does not have the ability to recreate its machinery), it means that those platelets are no longer able to actually create those thromboxanes that it lost because the COX1 is IRREVERSIBLY bound.

Basically: we are sparing the prostacyclins, and we are hammering down the thromboxanes (COX1 blocking specific). This means that it is well indicated for patients who want to avoid thrombosis/prevent clotting.

The main side effect is that it can produce GERD and GI ulcers, because prostaglandins will regulate the mucus and bicarbonate in the GI system. It is contraindicated in children, because there is a chance that they can develop Reye syndrome. It should also be avoided in patients with hemophilia.

INDOMETHACIN

This drug has the same indications as above: pain, inflammation, but another indication is a patent ductus arteriosus. Why? Prostacyclins and other prostaglandins will actually allow for the patent ductus arteriosus to remain open.

So, this means that when we administer a COX inhibitor like Indomethacin, we are limiting the amount of prostaglandins that are produced and we would be able to get the PDA closed.

Indomethacin is different from aspiring because it will bind reversibly to the COX 1 and COX 2 enzyme.

The only contraindication worth knowing is that it should NOT be taken if there is a patient that is on Lithium for bipolar disorder. This is because the drug-drug interaction can cause an accumulation of lithium by the kidneys, which can be fatal.

Ibuprofen (Advil) and Naproxen (Aleve) are both similar to aspiring in that they are indicated for pain and inflammation. It will also bind reversibly though to COX 1 and some COX2. They can both be used as antipyretics and ibuprofen can also be used for PDA.

Celecoxib is an important NSAID to know about because this is an example of a selective COX2 inhibitor. This is different from the other ones, which have been COX1. What are the ramifications of being a COX2 inhibitor?

Well, there are two things that COX2 does as wild type. First, it is being constitutively expressed on the kidneys and we need COX2 for both sodium excretion (and therefore water excretion) as well as for renin release. In addition, COX2 is important because it will shift the balance towards preferred thromboxanes and away from prostacyclin. This promotes more clots (from thromboxanes) and less clear vessels (from lack of prostacyclins), which makes a patient at higher risk of CV issues such as thrombosis. Also note, platelets do not have COX2 and platelets are the ones that are going to be releasing thromboxanes, so they will continue to make them since they are not being inhibited by anything.

COX Enzymes Overview

  • COX-1:

    • Constitutively expressed in all cells, especially the GI tract.

    • Selective inhibitors can cause GI side effects.

  • COX-2:

    • Inducible, expressed during inflammation.

    • Constitutively expressed in the kidneys; linked to cardiovascular issues.

Prostaglandins Classes

  1. Prostacyclins: Vascular dilation, decreased platelet aggregation.

  2. Thromboxanes: Vasoconstriction, increased platelet aggregation.

  3. PGD/PGE: Vasodilation, increased vascular permeability.

Key NSAIDs

  • Aspirin:

    • COX-1 selective, irreversible binding.

    • Indicated for inflammation, pain, and thrombosis prevention.

    • Side effects: GERD, GI ulcers; contraindicated in children (Reye syndrome).

  • Indomethacin:

    • Reversible binding; used for pain and to close patent ductus arteriosus.

    • Contraindicated with lithium.

  • Ibuprofen/Naproxen:

    • Reversible binding; used for pain, inflammation, and antipyretic.

  • Celecoxib:

    • Selective COX-2 inhibitor; higher risk of cardiovascular issues due to thromboxane production.