Different strokes – Common painkillers and their mechanisms

We find a lot of over-the-counter (OTC) painkillers like aspirin, acetaminophen, ibuprofen. All these drugs though relieve pain and control fever, act in different ways and have different properties.  I thought it would be interesting to look at how these drugs act and the differences between the drugs.

First, I ran a query for aspirin, acetaminophen and ibuprofen in Distilbio to look at what I could find. Aspirin and Ibuprofen are categorized as NSAIDs (Non-steroidal anti-inflammatory drug) whereas acetaminophen is not an NSAID. I also ran a query to check if there are any common targets between these drugs.

Query: aspirin > protein > acetaminophen
                         > ibuprofen

The results are as below:

I have tabulated the results for easy comparison.

Drug	Aspirin (Acetylsalicylic acid)	Ibuprofen	Acetaminophen (Paracetamol)
Brands	Ecotrin, Bayer Aspirin	Advil, Brufen, Motrin	Tylenol, Calpol, Panadol
Structure
Target	PGH1, PGH2	PGH1, PGH2	PGH1, PGH2
Indications	Pain, fever, inflammation or prevention of heart disease/stroke	Pain, fever or inflammation	Pain or fever
Side Effects	Stomach upset, ulcer, bleeding	Stomach upset, ulcer, bleeding	Usually well tolerated
Precautions	Bleeding; Not considered safe for children	Bleeding	Heavy drinkers are prone to liver damage because it limits the livers capacity to metabolize the drug
Pregnancy/Lactation	Relatively safe in intermittent dosages during 1st and 2nd trimester; Avoid during 3rd trimester Detected in breast milk	Avoid during pregnancy No info on lactation	Relatively safe in all trimesters of pregnancy Detected in breast milk but adverse effects not reported in infants

All the drugs target the enzymes PGH1 and PGH2, also known as the COX enzymes. Apart from that CP3A4, a Cytochrome P540 family protein is also shown. This is a protein required for the metabolism of the drugs. The question that immediately arises is – though these drugs target the same proteins why do they have different properties? These drugs also target other proteins apart from the COX enzymes. Click the links for the other protein targets – Aspirin-targets, Ibuprofen-targets, Acetaminophen-targets.

Lets first see what do PGH1 (COX1) and PGH2 (COX2) do. I ran a query in distilbio for the proteins PGH1 and PGH2. These proteins/enzymes catalyze the crucial step in the conversion of arachidonic acid to prostaglandins.

So what are prostaglandins and what do they do? Prostaglandins are secreted by the body’s immune system to fight infections. They are also present around wounds and cuts causing pain and inflammation. They also signal to the hypothalamus (controls the body temperature) in the brain to increase the temperature of the body during infections. Prostaglandins are also present in the stomach and protect the mucous lining of the stomach. They are also present in blood platelets and help the platelets stick together to initiate blood clotting in wounds.

Let us look at the mechanism of action of the drugs to see if it will help us understand the differences between the drugs.

Aspirin is an irreversible inhibitor of COX2 and stops the production of prostaglandins, therefore reducing inflammation, fever and pain. But aspirin also targets COX1 and hence inhibits the formation of prostaglandins in the stomach lining leading to its side-effect of stomach irritation/gastrointestinal bleeding/ulcers. The anti-platelet effect of aspirin does not allow the platelets to stick together and therefore reduces clots in arteries and could prevent heart attacks. Aspirin and its variants have many other benefits and uses. That could be topic for a whole other post.

Ibuprofen is an inhibitor of COX enzymes, similar to aspirin and therefore is an effective analgesic, anti-pyretic and anti-inflammatory agent. It also causes stomach irritation by affecting the stomach lining. But since it is a reversible inhibitor it does not have any anti-platelet effect like aspirin and reportedly blocks the irreversible effect of anti-platelet activity of aspirin if taken together. Therefore it is advisable not to take ibuprofen along with aspirin.

Acetaminophen also known as paracetamol, one of the most popular analgesic and anti-pyretic medication has been considered to be a COX inhibitor but not an NSAID. Though discovered ~100 years ago and in use for ~50 years, the exact mechanism of action of this drug is still unclear. As can be seen in the above image, Acetaminophen indirectly blocks COX and this is in-effective in the presence of peroxides, which are high in areas of inflammation and platelets. Therefore, Acetaminophen is not an effective anti-inflammatory or anti-platelet agent. I also looked at a few research articles in Pubmed to find more information on the mechanism of action of Acetaminophen. Different theories prevail regarding the mechanism of action of this drug.

1. It has been suggested that acetaminophen inhibits COX enzymes selectively in the central and/or peripheral nervous systems and has limited effects in the gastro-intestinal tract or at the site of inflammation. Hence its usage is not associated with gastric side-effects or anti-inflammatory benefits. (6)
2. Reports of acetaminophen inhibiting a third form of COX, COX3 have also been suggested, but this theory has been rejected since this form is not found in humans or is not clinically relevant. (5,6)
3. It has also been suggested that acetaminophen has no affinity for the active site of the COX enzyme but instead blocks the activity by reducing the active oxidized form of the enzyme to an inactive form in the presence of low concentrations of peroxide/free radicals. If the peroxide concentration increases such as at site of inflammation, the drug is overwhelmed and will not be able to inhibit COX. Therefore it is in-effective as an anti-inflammatory agent. (6)
4. Another theory suggests that acetaminophen may be a COX2 selective inhibitor and therefore the gastric and anti-platelet effects like other NSAIDs are not seen. (7)
5. A recent mechanism suggested is that acetaminophen activates a protein called TRPA1, found on the surface of nerve cells that reduces transmission of information from pain-sensing nerves to the brain and therefore alleviates pain. (8,9)

As seen from the queries and results above, there are a lot of similarities and differences between these drugs and it is important to choose wisely the right drug for the drug kind of pain or indication.

References:

1. Should I take tylenol, advil or aspirin. (http://www.scq.ubc.ca/should-i-take-tylenol-advil-or-aspirin/)
2. Differences Between Aspirin vs Tylenol vs Advil. (http://kathrynvercillo.hubpages.com/hub/Differences-Between-Aspirin–Tylenol-and-Advil)
3. Drugs.com (www.drugs.com)
4. From experience to design – The science behind Aspirin. (http://www.creatingtechnology.org/biomed/aspirin.htm)
5. Mechanism of action of acetaminophen: is there a cyclooxygenase 3? (PMID: 11113024)
6. Cellular mechanisms of acetaminophen: role of cyclo-oxygenase. (PMID: 15705740)
7. Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man. (PMID: 17884974)
8. Paracetamol: new vistas of an old drug. (PMID: 17227290)
9. TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Δ(9)-tetrahydrocannabiorcol. (PMID: 22109525)