K Balance Flashcards
What is the clinical relevance of K homeostasis?
- Abnormal plasma [K+] is the most common electrolyte disorder encountered in medicine.
- Both a surplus and a deficit of extracellular K predispose patients to potentially life-threatening arrhythmias.
• How does high and low plasma K affect the Heart?
o Cardiac function declines both with an increase and a decrease in extracellular [K+].
• How does high and low K affect the Neuromuscular Junction and Respiration?
o both high and low plasma [K+] can lead to muscle weakness and paralysis, which can lead to respiratory failure.
• How does high and low plasma K affect Smooth muscles and GI mobility?
o Changes in [K+] also affect the enteric nervous system and smooth muscles and thereby alter GI motility.
• Does High Plasma K cause vasodilation or constriction? Low?
o In the vasculature low plasma [K+] causes vasoconstriction, while high plasma [K+] results in vasodilation.
• Why is the brain relatively protected from plasma K levels?
o CNS manifestations of K disturbances are relatively rare.
o Even minor changes in extracellular [K+] can cause major disruptions in neuronal function, and therefore the brain is sheltered from changes in plasma [K+] by the blood-brain barrier, glial cells and the cerebrospinal fluid.
Since the typical dietary intake exceeds the K content of the ECF (~70 mmole), even a typical meal could result in life-threatening hyperkalemia if all the ingested K were to remain in the ECF. Why does this not happen?
- The typical dietary intake of K is 80-120 mmole/day. K balance is achieved by regulating both renal as well as colonic K excretion, but excretion of the ingested K takes time.
- The body precisely regulates the distribution of K between the ECF and ICF through internal K balance.
Why do K levels have little effect on Na/K-ATPase?
- Uneven distribution of K is generated by the Na/K-ATPase.
- Factors that affect internal K balance alter the activity of this enzyme.
- Surprisingly, extracellular [K+] per se has relatively small direct influence, because the activity of Na/K-ATPase since the external K site is already saturated.
Why do Na levels effect the Na/K-ATPase?
- The KM of Na/K-ATPase for intracellular Na is right around the typical intracellular [Na], and thus changes in intracellular [Na] exert a large kinetic effect.
- Changes in the activity of Na-coupled transporters (such as the ubiquitous Na/H exchanger) that alter intracellular [Na], have a large influence on Na/K-ATPase activity, and consequently, on transmembrane K distribution.
What creates the Resting Membrane Potential?
- The Na/K-ATPase is an electrogenic pump: it exports 3 Na ions in exchange for 2 K ions and hence makes the cell’s interior slightly negative.
- Nevertheless, direct contribution of the pump to the resting membrane potential (RPM) is relatively modest, even though it is its ultimate source.
- The main cause of the RPM is the diffusion of K+ out of the cell downhill its chemical gradient, which was generated by the pump.
- Changes in extracellular K+ alter this driving force and thus the RPM.
What are factors that affect internal K balance?
- Insulin
- Exercise and catecholamines
- Acid-Base balance
- Plasma Osmolality
How does Insulin affect internal K balance?
The hormone that has the largest effect on K distribution is insulin.
It increases K uptake into the cell by several mechanisms and therefore causes hypokalemia.
• Directly stimulates the activity of the Na/K-ATPase.
• Insulin also increases glucose uptake, which is converted to glucose-6-phosphate.
o The latter event requires uptake of phosphate, which occurs in co-transport with Na, resulting in an increase of intracellular [Na], thereby stimulating Na/K-ATPase turnover.
• Insulin activates the Na/H exchanger, and the resulting Na influx further stimulates Na/K-ATPase activity.
What are some clinical examples of the effect insulin has on K distribution?
• When patients with diabetes mellitus are given insulin, plasma [K] may fall precipitously.
• Re-feeding with a carbohydrate-rich meal following a period of starvation may result in fatal hypokalemia.
o This was part of the mechanism that resulted in the sudden death in many inmates after their liberation from concentration camps after World War II.
• The robust effect of insulin plus glucose on plasma [K] can correct hyperkalemia
How do exercise and muscle activity affect Internal K homeostasis? (Note catecholamines will help balance this. They are coming up)
- Exercise has a complex effect on internal K homeostasis.
- During the action potential, Na enters and K leaves the muscle cell.
- The increase in intracellular [Na] facilitates the reuptake of the lost K by stimulating Na/K-ATPase.
- However, significantly more K is lost than can be regained by “feeding” the Na/K-ATPase with Na+ that entered the cell during the period of increased conductance.
- Several Na entry mechanisms are however also stimulated including Na/Ca and Na/H exchangers but are still insufficient to prevent a net K efflux.
- Some of this extra K accumulates in the T-tubules, but significant amounts escape into the circulation
- The local rise in [K] serves important roles (it dilates local blood vessels and also contributes to fatigue), but systemic changes in plasma [K] are undesirable and are minimized by dual adrenergic regulation of Na/K-ATPase.
What is the effect of Epi via β2-receptors on Na/K-ATPase?
What is the effect of Norepi via α-receptors on Na/K-ATPase?
- Epinephrine, via β2-receptors stimulates Na/K-ATPase and thus promotes hypokalemia
- Norepinephrine via α-receptors inhibits Na/K-ATPase activity and thereby promotes hyperkalemia
Thought Question: How would ß-receptor agonists (used in asthma) affect plasma K? How do ß-blockers affect plasma K?
- ß-agonists are prone to develop dangerous hypokalemia.
- ß-agonists can be used to treat hyperkalemia, although they are less effective than insulin plus glucose.
- ß-blockers increase plasma K
How do the opposing effects of catecholamines on muscle K come into play during different phases of physical activity?
- Exercise results in a release of K from muscle cells.
- The body anticipates the resulting hyperkalemia and releases epinephrine at the onset of exercise with stimulates Na/K and decreases plasma K
- After the cessation of exercise, the mechanisms that stimulate K uptake cannot be turned off immediately. This could cause a rebound hypokalemia.
- Increased norepinephrine levels inhibits Na/K and increases plasma K.
Thought question: How does voluntary exercise pose similar risks as non-selective B-blockers to people predisposed with K balance problems?
- Increase plasma [K] associated with voluntary exercise tend to be larger the effects of epinephrine to decrease plasma K, thus some patients who have K balance problems are vulnerable to developing cardiac arrhythmias with exercise.
- Patients taking nonselective ß-blockers are at increased risk of Hyperkalemia
What are the repercussions that catecholamines have on internal K during a heart attack?
• The epinephrine surge associated with the stress of a myocardial infarction lowers plasma [K] and is thought to contribute to the development of life-threatening arrhythmias.
How does Acid-base balance affect K balance? Long Version
- Hypokalemia leads to lower cellular K and results in intracellular acidosis, while K loading alkalinizes the cells. (Details follow)
- Extra- and intra-cellular pH has a complex effect on transmembrane K distribution, which depends on the type of the acid-base disturbance.
- Although mechanistically not quite correct, the easiest way to conceptualize this effect is to postulate that H+ ions enter cells in exchange for K+ maintain electroneutrality.
- K+ movement is not required if an acid crosses the membrane in its undissociated form, like organic acids do, or if acidosis is of the respiratory type (since CO2 can also freely move through the cell membrane).
- Thus, a K shift occurs predominantly during the gain or loss or HCl. Due to this apparent H+/K+ exchange, cellular K depletion results in intracellular acidosis while K loading alkalinizes the cells.
How does Acid-base balance affect K balance? Short Version
• Hypokalemia leads to lower cellular K and results in intracellular acidosis
K loading alkalinizes the cells.
How do changes in Plasma Osmolality affect K balance?
- In hyperosmolality, cell shrinkage increases intracellular K concentration, and some K leaks out to increase plasma [K].
- In hypo-osmolality, cell swelling decreases intracellular K concetration, and some K enters the cell, decreasing plasma K
Thought Question: how would Type I Diabetes affect plasma K before and after an insulin injections? (Hint: glucose can be an osmole under certain circumstances)
- In the absence of insulin, glucose becomes an effective osmole and its accumulation in the ECF results in an increase in effective osmolality, which exacerbates the hyperkalemia due to the lack of insulin-stimulated K uptake (see above).
- The reverse process takes place after insulin injection: as glucose permeability is restored, the plasma becomes hypotonic, and this may exaggerate the direct hypokalemic effect of insulin.
What is External K balance?
- Under normal conditions the main mechanism for achieving external K balance is by regulating renal K excretion.
- K excretion via the GI track is also regulated but is quantitatively less important, as only ~10% of K is excreted via the colon.
- Regulation of K balance via the colon, however, becomes critical when renal function is compromised, such as in patients on dialysis.
K transport in the kidney bi-directional both reabsorption and excretion. Na transport in the kidney is unidirectional, just reabsorption. Why is K excretion different than Na excretion?
In a nutshell, K has always been plentiful, whereas Na has not.
Explain K transport in the proximal tubule.
- K is reabsorbed in this segment at a rate comparable to that of Na, i.e. ~2/3 of filtered load. K reabsorption is passive, paracellular and is mediated by solvent drag and by the lumen-positive voltage in the second half of the PT.
- K reabsorption changes in parallel with fluid reabsorption and, in general, is affected by the same factors that govern PT fluid reabsorption.
Explain K transport in the Loop of Henle.
- In the thin ascending limb of the loop a significant amount of K is secreted into the tubular fluid.
- This process is passive and is driven by the high [K] in the medullary interstitium.
- On the other hand, ~20% of the filtered K, along with the amount secreted by the thin limb, is reabsorbed in the thick ascending limb.
- Reabsorption of K in the TAL establishes a cortico-papillary gradient for K through a process analogous to the countercurrent multiplication of Na.
K secretion in the thin limb and reabsorption in the thick limb may seem counterproductive. Why is this necessary?
• K accumulation in the medullary interstitium is necessary to minimize K back-leak from the medullary collecting duct where [K] may increase to >200 mM on a high K diet (see below).
