It productively utilizes the energy of the proton gradient across the inner mitochondrial membrane created by oxidation-powered pumps to drive ATP formation at an approximate rate of 3 protons to 1 ATP. If the ATP is not used up quickly, then its concentration slows the action of ATP synthases, which slow the movement of protons out of the intermembrane space. This buildup of protons will eventually be enough that the free energy needed to transfer a proton into the intermembrane space from the electron transport chain will not be sufficient to overcome the concentration gradient.
Electron transport is slowed, and working backwards, the chain reaction slows respiration rates in general. Thus there is a direct association between respiration rate and physiological energy need. Interestingly, there is an exception to this tight coupling of the electron transport chain and formation of ATP.
The purpose of brown fat aka brown adipose tissue , which is most often found in newborn and hibernating mammals, is to generate non-shivering non-movement-based heat to keep the animal warm. This is accomplished by uncoupling the electron transport chain from the ATP synthesis. This uncoupling is a hormonally controlled process based on the presence of a mitochondrial proton channel called thermogenin.
To understand salicylate toxicity, we need to have a cursory understanding of uncoupling. And to do that you have to go back a bit, to biology class. You may recall that one of the main roles of the mitochondria is to synthesize ATP.
It does this by creating a kind of battery inside your cells. Look at the diagram below. It is important to note that for the current to flow it must go somewhere. The main role of oxygen is to be the final electron acceptor in this process.
It completes the circuit. The whole reason we breathe is so that this little electron has a final home , oxygen. But I digress. We use it to pump protons across a membrane. And what does moving protons across a membrane have to do with anything?
Stay with me, we are almost done. Mitochondria are kind of weird. They have both an outer membrane and an inner membrane. Between those two orange in the picture above is the inner membrane space. This is where the protons end up. Think about it. When you move positive charges across a divide you end up with positive and negative relatively speaking charges separated across a potential space.
Like I said above, this is like a battery, at least conceptually. And like a battery, this charge separation represents potential energy which can be used to power things. In the case of the mitochondria, this energy is used to make ATP the fuel all energy-dependent reactions run on.
When it all works as designed, the process is said to be coupled. That is, electron flow is coupled to ATP formation. So, what do uncouplers do? They uncouple electron flow from ATP formation. Salicylate is a great example of an uncoupler. It works by grabbing protons and shuttling them back across the inner mitochondrial membrane.
It can also open up pores in the membrane but the effect is the same, it shorts out the battery. This causes less ATP formation. In response, it revs up the engine sending more and more electrons through the system.
This results in big increases in metabolism, glycolysis, the TCA cycle, and all those processes that feed into this. So, what happens clinically when you rev up a system without producing more work?
You get heat. This is why patients who overdose on uncouplers can get profoundly hyperthermic. Lots of energy is consumed, but no work is produced — the engine overheats. Clinically this is also one of the ways that aspirin contributes to death. The lack of ATP targets the brain and the heart they are so needy causing the famous life-threatening dyad of a really bad aspirin overdose — cerebral and pulmonary edema.
So I promised I would talk about keeping pH normal and why that is important. First, it is important to mention why salicylate causes acidosis. OK, move on. To be fair we do know a lot about this, but it is complicated. Steve Curry and Meghan Spyres do a great job discussing this in their chapter on salicylate. The simple version is that under a normal state the hydrogen ions produced when ATP is consumed are balanced by the hydrogen ions used when ATP is made. As long as your metabolic demands are met, you are fine.
But as I said above, at high concentrations salicylate is an uncoupler, so you are consuming energy faster than you can make it. This is one of the ways uncouplers cause metabolic acidosis. Acidosis is a really bad thing in large salicylate overdoses. In a salicylate overdose, we do. This has to do with the dissociation constant of salicylate first mitochondria and now pharmacokinetics. The dissociation constant is the pH at which half of the molecules in a solution are ionized and half are non-ionized.
Things that are ionized, or charged, have a harder time crossing biologic membranes than those that are uncharged, or non-ionized. This means at a normal serum pH of 7. And that is a good thing because only unbound, non-ionized salicylate crosses membranes. Another way of saying this is so long as you keep the pH normal, most salicylate will stay out of the brain and heart. This means that even small changes in pH can have profound changes to the amount of ionized salicylate.
If you drop serum pH from 7. So what does this all mean? It means to keep salicylate out of the heart and brain, where it causes its problems, you need to keep pH normal or even better, alkaline. To make a drip, most of us toxicologists will use three amps of sodium bicarb in 1L of D5W and run a drip at 1. On a side note, if you can also alkalize the urine then you get the added benefit of excreting more salicylate in the urine.
Quick tip : to alkalinize the urine you must keep patients from getting hypokalemic 6 , cause the kidney will preferentially hold on to potassium and dump a proton, preventing the alkalinization. Another way to maintain arterial pH is to breathe. As you likely recall, salicylates cause patients to hyperventilate. This causes the classic mixed acid-base disorder of respiratory alkalosis with metabolic acidosis test tip: an ABG on a test with a low PCO2 and bicarb is probably a salicylate overdose.
Why do salicylates cause people to breath deeper hyperpnea and faster hyperventilation? We know It is not from cyclooxygenase inhibition. It helps to keep your serum pH normal to alkaline. Why would you do that? Because the patient is sick. As I have already discussed, at high concentrations salicylates uncouple oxidative phosphorylation. This means less ATP being formed in your brain. We intubate them. This is important, and the whole point of this post.
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