Mode of action of potassium binders

Hello everyone, my name is Joost Beusekamp and I'm a medical doctor at the University Medical Center Groningen at the department of cardiology. Welcome to this three-way course on potassium binding. Today, I will discuss the essentials to know about the mode of action. For this subject I have nothing to declare.

Let's start with hyperkalaemia in the acute phase in the inpatient setting. The first immediate step is to stabilize the membrane of the myocardium, to protect the myocardium from the negative effects of severe hyperkalaemia. This can be done by using calcium gluconate. In the minutes hereafter you want a shift of the excess potassium into the cell. And you want a fast, but temporary redistribution of the potassium, to avoid immediate consequences of the severe hyperkalaemia. This can be done by using an infusion of insulin and glucose. Or you can use a beta 2-adrenergic receptor agonist, as salbutamol. If a metabolic acidosis is the cause of the hyperkalaemia, you can also use sodium bicarbonate. Next, in the hours to come, you want to remove the excess potassium from the body, to restore the total balance of potassium within the body. Herefore, you can use Sodium Polystyrene Sulfonate (SPS), you can use loop diuretics, and dialysis has a place in here as well.

But how do we manage potassium levels on the long term? We have several options for long-term potassium management or hyperkalaemia management, but they all have their downsides. First of all, I want to discuss RAASi reduction. These agents have proven to elevate serum potassium levels and therefore downtitrating, or even discontinuing these drugs will lower the serum potassium levels in these patients. However, these are life-saving agents, so downtitrating or discontinuing these drugs will worsen the outcomes of your patient population. Another possibility is a dietary restriction of potassium. However, as we all know, when it comes to a diet, this comes along with a poor compliance. And this has several reasons, for instance a patient could already be on another diet. Potassium is a common ingredient in many foods and a patient might already be on a healthy diet, for instance the DASH diet to lower their sodium intake, but they also actively increase their potassium intake, and therefore, you might give them a restriction in eating their healthy foods. Lastly, we have the Sodium Polystyrene Sulfonate, also known as SPS. Even though this drug was already approved in the late 1950s, there's only limited data on this drug from clinical trials. And there's precaution because this drug uses sodium as a counter exchanger for potassium. And therefore you can induce a state of a sodium overload. And lastly, but mostly feared are the serious Gastrointestinal Adverse Events (GIAEs), as colonic necrosis or fecal impaction.

Then we come to the three therapeutic agents we have for long-term hyperkalaemia management; for long-term potassium management. We have Sodium Polystyrene Sulfonate, also known as SPS. We have the Sodium Zirconium Cyclosilicate (ZS-9). And lastly, we will discuss the effects of Patiromer.

First of all, the agent from the late 1950s, Sodium Polystyrene Sulfonate, SPS. This is a non-specific, sodium-based potassium exchanger. When this comes into a solvent it starts to swell, and this swelling allows the potassium to be exchanged for the reactive group. In the case of SPS this is sodium and in the case of CPS this reactive group is calcium. However, unfortunately, this agent is not exclusively selected for potassium. So, it might exchange calcium or magnesium for the sodium as well. This agent is not absorbed into the system and therefore, it's fully eliminated through the feces. Earlier, in vitro studies have shown that one gram of SPS is able to bind three milliequivalents of potassium. However, the in vivo models have shown that one gram of SPS only binds one third of the in vitro capacity and only binds one milliequivalent of potassium. And this might have to do with the competition with the other ions, as calcium or magnesium. This drug can be administered one to four times daily as an oral powder, and then it's a dosage of fifteen grams. We also have the enema and this has a dosage of 30 to 50 grams and same as for the oral powder, this can be administered one to four times daily. The adverse events are mostly related to the gastrointestinal tract. For instance, patients can suffer from gastric irritation, constipation, or even diarrhoea. You can also overcorrect the serum potassium levels and therefore induce a state of hypokalaemia, hypomagnesaemia or, because the reactive agent is sodium induce a state of a sodium overload. And as already mentioned, the intestinal necrosis is the mostly feared adverse event. Since it's a drug we've already known for over 60 years, we know every drug-drug interaction there is and they are listed in the slide as well. The clinical efficacy of this drug starts within one to two hours and it maintains for at least up to ten hours with a lowering effect of one milliequivalent of potassium per liter. Of course, this lowering effect is dose dependent.

Then we come to the Sodium Zirconium Cyclosilicate, SZC or ZS-9. This is an inorganic, non-absorbable sodium-potassium exchanger, and this selectively traps potassium ions moving through the gastrointestinal tract. This compound consists of micropores as shown in the figure below, and these have a specific diameter, specific for potassium. Therefore, you won't see any capture of sodium, calcium or magnesium. Since it's a non-absorbable compound, the drug will not be systemically absorbed, and therefore eliminated entirely through the feces. The dose is five or ten grams and it can be administered up to three times daily. From the clinical trials, no serious adverse events have been listed, but patients have complained from gastrointestinal disturbances, such as diarrhoea or constipation. Same as for the SPS, you can overcorrect the serum potassium level and induce a state of hypokalaemia. This drug hasn't shown data for administering the drug for longer than 4 weeks, and therefore, we don't know the long-term safety and efficacy of the drug. And also no clinically meaningful interactions have been identified, yet. This drug starts to work within one hour, so that's rather fast. The drug maintains for up to four weeks, and lowers the potassium level for around one milliequivalent per liter.

And then we come to patiromer. This is a non-absorbable, calcium-based potassium exchanger. It's a polymer with a high capacity of exchanging calcium for potassium, so it doesn't use sodium. The primary side of action is the distal colon and this is where the highest concentration of free potassium is seen and therefore, it enhances faecal excretion of potassium. It is a tasteless powder that should be mixed. And as mentioned, it is free of sodium, so it doesn't induce a state of sodium overload. For instance, in patients vulnerable for sodium overload, such as heart failure patients. It is not metabolized or systemically absorbed. And, same as for the other drugs, it is a dose-dependent drug. Different from the other drugs, it is a drug that only should be administered one time daily. No serious adverse events have been listed so far, except for gastrointestinal disturbances, such as diarrhoea or constipation. It also can induce a state of hypomagnesaemia, or overcorrected serum potassium levels, and induce hypokalaemia. This drug binds to several drugs, including cardiovascular drugs. Therefore this drug should be taken three hours apart from other oral drugs. This is possible, due to the fact that this drug should only be administered one time daily. The clinical effect starts within seven hours and it maintains for up to four weeks. And same as for the other compounds, it lowers the serum potassium levels, with around one per liter. The data from the clinical trials will be discussed in another lecture.

To sum up, what are the differences and the conclusion of these three compounds? We have discussed SPS, which only has a limited selectivity for potassium, and it has known serious adverse events. Lastly, no real data are available from clinical trials. And we have the SZC, which has the fastest mode of action. However, it uses sodium as an exchanger for potassium, and therefore, it can induce a state of sodium overload. Lastly, we have discussed patiromer. This uses calcium instead of sodium, and therefore, this might be the desirable option in patients with heart failure. Additionally, this is a drug which only should be dosed one time a day. The data from the clinical trials for patiromer and SZC will be discussed in another lecture. So, this was what I wanted to discuss with you today on potassium binding agents. I hope you have learned more about our essentials of the mode of their action. Thank you for your attention.