Altitude Sickness, Part 5

[gregw822]

Busy days.

This final part of the series is about Diamox, the primary drug for treating acute mountain sickness. Its chemical name is acetazolamide. In addition to AMS, Diamox is used to treat glaucoma, epilepsy, cranial hypertension and heart failure. Here is the chemical structure of acetazolamide/Diamox, C4H6N4O3S2. (carbon = black, hydrogen = white, nitrogen = blue, oxygen = red and sulfur = yellow.

Diamox.jpg

Among other things, Diamox affects the bicarbonate equilibrium described in Parts 1 and 2:
CO2 + H20 ⇄ H2CO3 ⇄ H3O+ + HCO3-

This reaction is much too slow on its own to support life. In fact every biochemical reaction is catalyzed by something. A catalyst is a substance that makes a reaction go faster by changing the path the chemicals follow going from starting materials to products (aka the mechanism, of the reaction.) By analogy, a catalyst is a bit like following a lower-altitude route to cross a high ridge. You start and end at the same place, but you follow an easier path on route. Catalysis is a focus area of chemical research in both academics and industry. Almost all biochemical reactions are catalyzed by enzyme proteins. The enzyme that catalyzes the bicarbonate equilibrium is carbonic anhydrase (CA), and its ribbon structure is shown here:

CA + Diamox.jpg

The structure includes helix segments (green), and a new feature of protein structure: the sheet, (tan). A short sheet strand can be seen at the top of the structure. These segments are marked with arrowheads that show the directional flow of the protein chain. Non-specific sections of protein chain (gray) lead into and out of each sheet strand. In the middle of the protein, a large sheet structure is formed by alignment of several strands. The helix and the sheet are the dominant structural forms of most proteins.

The sheet strands of CA form a cavity in the protein where the bicarbonate buffer reaction takes place. This area is the active site of CA. A zinc ion (Zn2+), represented here by a purple sphere is held in the active site by three amino acid side chains. In fact, the three side chains are of the same type as the side chain used to hold heme in hemoglobin. (They're all histidines, if you know your amino acids.)

Here is a surface representation of CA that shows the active site cavity. The green patch is a molecule occupying the active site, and you can just see trace of the zinc ion, in blue, deep in the cleft. I'm not sure what the pink spot represents. Could be a water molecule or an amino acid chain. (This is not my structure, I took this one from the internet. https://pdb101.rcsb.org/motm/49.) I did make all the other structures shown in this series.)

49-CarbonicAnhydrase-1cnw.jpg

The zinc ion in CA is also bonded to a water molecule. The Zn2+ ion activates the water molecule, enabling its reaction with carbon dioxide. Briefly, CO2 and H2O enter the active site. The protein holds CO2 molecule very weakly, but in just the right position to undergo attack by the zinc-activated water molecule. Th zinc ion is the actual catalyst for the reaction. In the very instant the two partners align, the reaction is over. Carbonic anhydrase is one of the most efficient enzymes ever discovered. All enzymes work equally well going in either direction. In other words, CA catalyzes the release of CO2 and H2O just as efficiently as it created them in the first place. Which direction the enzyme works depends on what the cell needs in order to maintain equilibrium.

And now we jump back to Diamox. Look at the first model of carbonic anhydrase, the ribbon structure. A Diamox molecule can be seen in the active site of the enzyme. In fact, Diamox binds very tightly to the active site of the CA, and in doing so blocks the access of the carbon dioxide and water molecules required for the buffer reaction. The CA enzyme cannot do its job when Diamox is in the active site. Diamox is an inhibitor of carbonic anhydrase.

Not all CA proteins are occupied by Diamox. That would quickly be fatal. However, enough of the enzyme is inhibited to to cause a significant disruption in the bicarbonate buffer reaction. Here it is, one more time:

CO2 + H2O ⇄ H2CO3 ⇄ H3O+ + HCO3-

As described in Part 2, hyperventilation due to rapid breathing in thin air depletes carbon dioxide from the blood. The bicarbonate reaction shifts to the left, trying to regain equilibrium by making CO2. The shift in the buffer reaction now depletes carbonic acid from the blood, thereby lowering the acidity of the blood. There is a corresponding increase in pH and the basicity of the blood, which results in the condition of alkalosis and the onset of acute mountain sickness.

The traditional explanation for the action of Diamox focusses on the kidneys, which recycle bicarbonate into the bloodstream. With the CA enzyme inhibited by Diamox, the kidneys excrete rather than recycle bicarbonate ion. This increases the basicity of urine, with a corresponding increase in acidity in the blood. An increase in blood acidity ameliorates alkalosis, decreasing the symptoms of AMS. Unfortunately, this is an incomplete story.

There is ample evidence in the literature for much greater complexity in the action of Diamox. The bicarbonate equilibrium is involved in more biochemistry than just controlling the pH of blood. Diamox appears to increase cerebral blood flow and to cause general increases in ventilation by stimulating metabolic acidosis. I think part of the issue here is that carbonic anhydrase is a ubiquitous enzyme. It is found throughout the body in several structural forms, all of which have slightly different chemistry.

This may be an unsatisfying ending to the series, but it is a fitting place to stop. We know Diamox is an effective treatment for altitude sickness, and we know in general how it works. However, biochemistry is rarely simple, and there is much research still to be done.

Thanks for reading along.

[bobby49]

Gregw822, I've been reading your posts with great interest. I tend to agree with you about Diamox as a carbonic anhydrase inhibitor. I've had a prescription for Diamox on three high altitude trips, but I've only actually consumed it on one of those.

In my opinion, the average backpacker has very little interest in the biochemical mechanisms. When I've tried to explain some of this to backpackers, their eyes glaze over. I found it much easier to tell them that Diamox affects their water balance, and I leave it at that. Sometimes I mention that it is not an O2 thing, it is a CO2 thing.

Larry Penberthy (Mister MSR) was chasing his related theories on this about fifty years ago, and you see where that got him.

[gregw822]

Few people in general have much interest in this stuff, or any other kind of science for that matter. Nevertheless, for those who do, I enjoy the challenge of writing simplified explanations of complex systems.

[bobby49]

You should write a book for Amazon: Altitude Sickness For Dummies.

[bobby49]

I took my first high altitude trek to Mount Everest Base Camp in 1983. I had no special medication with me, but others did, and these were drugs related to Diamox. I noticed and started studying up on Diamox. In 1996, I was going on a climb in Argentina, so I asked my physician for a prescription for Diamox. He had no idea what I was talking about, so I handed him a printed article on the subject. He looked it up online and saw what I was talking about, so he gave me the prescription. That worked out well at high altitude. In 1997, I was going back to Nepal, so I asked my physician for a prescription. He sent me to the travel clinic, and they gave me the prescription. In 2000, I was going to Kilimanjaro, so I got another prescription for it. As it turned out, I felt fine and never started taking the stuff. However, the local porters got to 18,000 feet and became sick as dogs, so the head guide asked me if I had any of "those pills." I admitted that I had the pills, but they were for me. The guide pleaded, so I set out 50% of my pills for the guide to take for his porters. I explained that I was not going to supply the pills to them, but if the guide needed to, it would be his responsibility. Everybody made it down OK, including one person with early HAPE symptoms who had not taken any Diamox.