17 Introduction to Potassium

17

Potassium is the final electrolyte which will be covered in this book. Some of the major differences between sodium and potassium are outlined below:

Introduction

Potassium…the final frontier.

K +

Na

Cl

HCO

BUN

glucose

Cr

K

Potassium is the ________ intracellular cation while sodium is the primary ___________ cation.

Disturbances in _______ concentration result in altered electrical ac-tivity which can affect the __________, muscles and nerves.

primary extracellular potassium heart

Medical Latin:

• Hypokalemia: low plasma potassium, K+ _{< 3.5 mEq/L.} • Eukalemia: normal plasma potassium, 3.5 < K+ _{< 5.0 mEq/L.} • Hyperkalemia: increased plasma potassium, K+ _{> 5.0 mEq/L.} • Kaluresis: loss of potassium in the urine.

Sodium

• Primary extracellular cation. • Alterations in sodium

concentra-tion affect the osmotic movement of water in and out of cells. Most clinical symptoms are related to cerebral edema or dehydration.

Potassium

• Primary intracellular cation. • Alterations in potassium

concen-tration result in electrical signals that interrupt normal cardiac rhythm, muscle activity and nerve conduction.

ATP AMP 3 Na+ 2 K+ K + K+ K+ K+

Introduction

The vast majority of the total body potassium is

intracellular.

When thinking about potassium physiology, two facts should always be considered:

• 99% of total body potassium is in cells.

• Small changes in plasma potassium can have dramatic clinical consequences.

Tight control over both the intracellular and extracellular potassium pools is necessary because the movement of only 1% of the intracellular potas-sium to the extracellular compartment can stop the heart.

Total body water for a 70 kg man is 42 liters. 14 liters is extracellular 28 liters is intracellular Total extracellular potassium is (14 L × 4 mEq/L).

56 mEq

3,920 mEq

The two central aspects of potassium physiology which must al-ways be considered are:

• The vast majority of potassium is ___________.

• Small changes in the extracellular _________ concentra-tion can have dramatic clinical consequences.

Movement of only ____ percent of the intracellular potassium pool to the extracellular compartment can stop the _______.

aaa intracellular potassium one heart intracellular compartment K+ _{=140 mEq/L} extracellular compartment K+ _{= 4 mEq/L}

Potassium balance

Potassium balance is maintained by the

cells and the kidney.

The immediate defense against a change in plasma potassium is intracellular ____________.

The long term control of plasma potassium is the responsibility of the _________. tightlyaaa buffering kidney K+ K+ K + Renal regulation long-term control

The body has both an immediate and a long-term strategy to regulate the plasma potassium concentration. Cellular buffering is the immediate de-fense against a change in plasma potassium, while the kidneys control long-term potassium balance.

Cells secrete potassium when plasma potassium falls; cells absorb sium when plasma potassium rises. The secretion and absorption of sium by cells is referred to as buffering. The kidneys affect long-term potas-sium balance through the excretion and resorption of potaspotas-sium.

Cellular control of potassium movement is influenced by: • catecholamines • insulin • plasma pH • cellular synthesis • cellular destruction • plasma potassium Renal potassium regulation is governed by:

• plasma potassium • aldosterone

• flow in the distal nephron

An understanding of these systems is necessary to comprehend the disor-ders which cause hypokalemia and hyperkalemia. The remainder of this chapter reviews the important concepts in intracellular and renal regula-tion of plasma potassium.

K+

K+

Intracellular buffering

The Na-K-ATPase pump is a membrane protein found on all cells. It is responsible for maintaining an intracellular environment which is high in potassium and low in sodium. The Na-K-ATPase pump is central to the ability of the intracellular compartment to buffer against changes in plasma potassium concentration.

Increased Na-K-ATPase activity lowers the plasma potassium concentra-tion, and decreased activity raises plasma potassium concentration. Na-K-ATPase activity is stimulated by:

• catecholamines • insulin

• increased plasma potassium

Potassium balance

Cells

Cellular distribution of potassium is

maintained by Na-K-ATPase activity.

2 K+ ATP AMP 3 Na+ K+ K+ potassium 140 mEq/L sodium 4 mEq/L sodium 140 mEq/L potassium 4 mEq/L

The ________ pump moves potassium into the cell and sodium out of the cell. It is responsible for maintaining low _______ and high ________concentrations within the cell.

Increased Na-K-ATPase activity ________ (lowers/raises) plas-ma potassium concentration.

Na-K-ATPase activity is stimulated by ________, catechola-mines and increased plasma ___________.

Na-K-ATPase sodium potassium lowers insulin potassium

Potassium balance

Cells

Activation of beta-2 receptors

in-creases Na-K-ATPase activity.

2 K+ ATP AMP 3 Na+ K+ K+ ß-2 receptor catecholamines

Catecholamines, via beta-2 receptors, stimulate Na-K-ATPase activity which increases the uptake of potassium into cells. The beta-2 receptors influence potassium levels in three situations:

• Stress (physiologic or emotional) increases release of endogenous epinephrine. Epinephrine binds to beta-2 receptors and can tran-siently drop plasma potassium.

• Beta-agonists are primarily used in the treatment of bronchoc-onstriction (e.g., asthma). Beta-agonists like albuterol are inhaled in order to open constricted bronchioles. A side effect of beta-agonists is a transient lowering of serum potassium.

• Beta-blockers are life-saving medications used in the treatment of hypertension and angina. The inhibition of beta activity through the use of these medications can blunt the ability of cells to absorb potassium,potentially increasing plasma potassium.

_____________ can bind to ß2-receptors and activate the

Na-K-ATPase pump.

Stress and beta-agonists can ___________ (lower/raise) plasma tassium, while beta-blockers can _________ (lower/raise) plasma po-tassium.

Catecholamines

lower raise

Think: Beta Bottoms Banana

Potassium balance

Cells

Insulin stimulates Na-K-ATPase

activity, lowering plasma potassium.

The primary action of insulin is to facilitate the movement of glucose from the blood into cells. Insulin also affects the movement of potassium into cells. This dual action of insulin is adaptive because it compensates for both the glucose and potassium ingested in meals.

2 K+

ATP

AMP

Insulin _________ Na-K-ATPase activity, driving K+

into ______. Insulin causes the _______ of glucose and potassium into cells.

stimulates; cells movement

Think: INsulin causes both glucose and potassium to go INto cells.

K

+

K

+

The intracellular compartment buffers changes in both potassium and hydrogen concentration. Increased plasma hydrogen (↓ pH) causes cells to absorb hydrogen and secrete potassium. Decreased plasma hydrogen con-centration (↑ pH) causes cells to secrete hydrogen and absorb potassium. The movement of hydrogen and potassium are linked to maintain electro-neutrality.

The effect of pH on plasma potassium varies depending on the type of acid-base disorder. For example, plasma potassium does not change in res-piratory acidosis and changes only minimally in lactic acidosis and ketoaci-dosis.

Below are various mnemonics to remember the relationship between pH and potassium. Pick one and commit it to memory:

Potassium balance

Cells

Changes in pH affect the movement

of potassium into and out of cells.

Think: potassium and pH always move in opposite directions.

pH causes potassium pH causes potassium

Think: potassium and hydrogen concentration walk together.

hydrogen causes potassium hydrogen causes potassium

Alkalosis

Low plasma hydrogen concentration causes the cellular release of hydrogen and the resorp-tion of potassium.

Acidosis

High plasma hydrogen concentration causes the cellular uptake of hydrogen and the excre-tion of potassium.

Think: aLKalosis

Low K+

A drop in pH means the hydrogen concentration is _________ (decreased/increased).

In acidosis, extracellular pH is partly stabilized by movement of excess _________ into cells; potassium moves out of cells in order to maintain ________________.

increased

hydrogen electroneutrality

Potassium balance

Cells

Cell destruction and cell

construc-tion can dramatically affect plasma potassium concentraconstruc-tion.

The intracellular compartment contains 99% of the body’s potassium and ⅔ of total body water. Because of this, changes in cell number can alter the plasma potassium concentration. This is seen in two clinical settings:

• Massive cell destruction. Both chemotherapy and trauma can cause large-scale cell destruction and the release of intracellular potassium, causing hyperkalemia.

• Cell production. The treatment of severe megaloblastic ane-mia with folic acid or vitamin B-12 decreases plasma potassium as it is used to create the intracellular environment for the new red blood cells.

140 mEq/L K+ K+ K + K + 140 mEq/L

Cell destruction Cell synthesis

Because the majority of the body’s potassium is found in _____, changes in cell number can alter plasma _________.

Cell destruction with ____________ or trauma releases potassium, causing ___________.

Acute increases in cell number are uncommon but can occur dur-ing the treatment of megaloblastic anemia with _______ or B-12.

cells potassium chemotherapy hyperkalemia

Potassium balance

Kidney

Long-term potassium control is

ac-complished by the resorption and selective secretion of potassium.

The kidney balances potassium intake with potassium excretion so that K+in = K+out. This is done through coordinated potassium handling in the

proxi-mal tubule, the loop of Henle and the distal nephron.

Potassium, like all electrolytes, is freely filtered at the glomerulus. Ini-tially, the tubular fluid has the same concentration of potassium as does plasma.

In the proximal tubule, bulk resorption of potassium occurs without re-gard for the potassium status of the body. The loop of Henle resorbs potas-sium due to the activity of the Na-K-2Cl pump in the thick ascending limb. Working together, the proximal tubule and the loop of Henle resorb about 90% of filtered potassium.

The primary site of potassium regulation is the collecting tubule. The study of renal potassium excretion can be focused almost exclusively on the activity of the collecting tubule.

The proximal tubule resorbs potassium.

The loop of Henle resorbs potassium.

The collecting tubule secretes potassium.

Potassium is resorbed in the _________ tubule and the ______ __ _______.

Potassium is _________ by the distal nephron.

The most important part of the nephron in potassium regula-tion is the _______ ________. proximal loop of Henle secreted distal nephron K+ K + K+ K + K+ K+ K+

Na+ K+ 3 Na+ ATP 2 K+ AMP K+ K+_{= 140 mEq/L} Na+= 4 mEq/L principle cell tubular lumen high potassium low potassium low sodium

Potassium balance

Kidney

Secretion of potassium in the

dis-tal nephron is a four-step process.

The positively charged po-tassium flows down both concentration and electrical gradients into the tubule.

Potassium secretion in the distal nephron is a multistep process which culminates in potassium flowing down electrical and chemical (concentra-tion) gradients into the tubular fluid:

Step one: the Na-K-ATPase pump maintains a low concentration

of sodium and a high concentration of potassium in the cells.

Step two: the low intracellular sodium concentration allows sodium

to flow down its concentration gradient into the tubular cells. The flow of sodium into the tubular cell is the rate-limiting step in potas-sium secretion.

Step three: the movement of positively charged sodium into the

tubular cell without an associated anion creates an electrical gra-dient between the tubule and the tubular cells. The tubular lumen is negatively charged.

Step four: potassium passively flows down both electrical and

chemical (concentration) gradients into the tubular fluid.

In the cell, the Na-K-ATPase pump keeps the potassium concentration high and the sodium concentration low. Sodium flows down its con-centration gradient into the tubular cell through sodium channels.

The movement of the posi-tively charged sodium ions makes the tubular fluid nega-tively charged (electronega-tive).

The ___________ of potassium in the distal nephron depends on establishing favorable electrical and __________ gradients.

excretion chemical

1

2

3

4

Potassium balance

Kidney

Potassium handling in the distal

nephron is affected by four factors.

Because it is in charge of fine-tuning the excretion of potassium, the dis-tal nephron is under tight control from various inputs. The primary factors which affect potassium excretion are:

mineralocorticoid activity plasma potassium

distal flow

nonresorbable anions in the distal nephron

K+ K+ K + K + K+ K + K + K+ Plasma potassium Distal flow K + K+ K+ Nonresorbable anions A -HCO3 Mineralocorticoid activity ALDOSTERONE

The excretion of potassium in the _______ nephron is regulated by ________ different factors.

The factors which affect potassium excretion include

________________ activity, plasma potassium concentration, dis-tal flow and nonresorbable ________ in the disdis-tal nephron.

distal four

mineralocorticoid anions

Potassium balance

Kidney

Aldosterone is one of the

prima-ry factors which regulates potassium excretion.

In addition to its central role in volume regulation, aldosterone is an im-portant factor in potassium regulation. Increases in plasma potassium as small as 0.1 mEq/L will cause a measurable increase in aldosterone release. Aldosterone stimulates the production of the following proteins in order to increase potassium excretion:

Na-K-ATPase pump. Increased Na-K-ATPase activity keeps the

intracellular sodium concentration low and the intracellular potas-sium concentration high.

Sodium channels. The addition of sodium channels allows more

sodium to enter the tubular cell. This increases the electrical gradi-ent across the tubular wall which enhances excretion of potassium.

Potassium channels. The addition of potassium channels

facili-tates the movement of potassium down its chemical and electrical gradient into the tubule lumen.

Increased aldosterone activity ________ (decreases/increases) potassium excretion.

increases

Aldosterone increases the number of potassium chan-nels which facilitate the ex-cretion of potassium. Aldosterone increases the number of Na-K-ATPase pumps in the basolateral membrane.

Aldosterone increases the number of sodium channels which facilitates increased sodium resorption.

Increased sodium resorption due to aldosterone increases the electrical gradient for po-tassium secretion.

1

2

3

4

Na+ K+ 3 Na+ ATP 2 K+ AMP K+ K+= 140 mEq/L Na+= 4 mEq/L principle cell

Potassium balance

Kidney

Increased plasma potassium

stim-ulates the excretion of potassium independent of aldosterone.

Increased plasma ___________ stimulates the excretion of potas-sium in the distal ____________.

Elevated plasma potassium stimulates the production of Na-K-ATPase pumps and __________ channels.

potassium nephron sodium

1

2

3

4

and electrical gradients into the tubule.

Increased plasma potassium concentration increases the number of Na-K-ATPase pumps.

Increased plasma potassium concentration increases the number of sodium channels which facilitates sodium re-sorption.

Increased sodium resorption increases the electrical gradi-ent for potassium secretion.

Increased plasma potassium directly stimulates the secretion of potas-sium into the tubule. This effect of potaspotas-sium is independent of aldosterone. Increased plasma potassium increases Na-K-ATPase activity and the num-ber of sodium channels. Plasma potassium’s effect on potassium excretion is weaker than aldosterone’s effect on potassium excretion.

Potassium balance

Kidney

Increased flow in the distal

neph-ron leads to increased potassium excretion.

When the flow rate in the distal nephron is increased, it enhances both the chemical and electrical gradients for potassium secretion. Increased distal flow refers to the increased delivery of water and sodium to the distal neph-ron.

Increased distal flow enhances the chemical gradient by quickly washing away any secreted potassium. This prevents the accumulation of potassium in the tubule which would decrease the chemical gradient.

Increased delivery of sodium to the distal nephron increases sodium re-sorption and enhances the electrical gradient, favoring potassium excre-tion.

Increased flow in the distal nephron enhances ________ of potassi-um and can lead to ________.

Increased flow to the distal nephron causes potassium excretion by _____ mechanisms:

• Increased sodium resorption increases the _______ gradient. • Increased flow prevents the accumulation of potassium in

the tubule and maintains a ____________ gradient in favor of potassium excretion. secretion hypokalemia two electrical chemical K+ K + K+ K + K+ K+

Increased delivery of sodium increases sodium resorption to enhance the electrical gradient. Increased flow of fluid quickly washes away

se-creted potassium to maintain the concentration gradient.

Potassium balance

Kidney

Increased nonresorbable anions

in the tubular fluid enhance potassium excretion.

Cl– Cl – Cl– Cl– K+ K+ HCO3 HCO3 Na+ Na+ A

-Increased nonresorbable anions in the distal nephron increase the elec-trical gradient for the secretion of potassium.

Normally, the tubule fluid is negatively charged and attracts the posi-tively charged potassium. The negative charge is created by the resorption of sodium without chloride by the tubular cell. As the movement of sodium causes the tubule fluid to become more electronegative, some of this nega-tive charge is lost as chloride slips between the tubule cells and is resorbed. If the predominant anion in the tubules is not chloride, but rather a nonre-sorbable anion, none of the negative charge is lost. If none of the negative charge is lost, the tubule will attract more potassium.

Normally, the movement of chloride decreas-es the electrical gradient and reducdecreas-es potas-sium secretion.

Nonresorbable anions (including bicarbonate) in the tubular fluid increase the electrical gradient, drawing potassium into the tubule.

Renal loss of ___________ can be accelerated by nonresorbable __________ in the tubular fluid.

Chloride normally disrupts the electrical _____________ by moving from the negative ___________ to the positive interstitium.

The electrical gradient normally draws _________ into the tubule.

potassium anions gradient tubule potassium

Cellular redistribution is

con-trolled by the Na-K-ATPase pumps in the cell membrane. The Na-K-ATPase pump maintains a high con-centration of potassium and a low concentration of sodium inside of cells. Factors which influence Na-K-ATPase affect the movement of po-tassium in and out of cells.

Potassium is the primary intracel-lular ion. 99% of total body potassium is located in cells. Movement of 1% of the cellular potassium to the extra-cellular compartment can cause car-diac arrhythmias.

Summary

Introduction to potassium.

To accomplish this tight control, the body employs two systems for po-tassium regulation: intracellular buffering and renal excretion.

ATP AMP

K+

The important factors which influ-ence the Na-K-ATPase pump are beta-2 receptor activity, insulin and pH.

Epinephrine and beta-2 selective drugs (e.g., albuterol) stimulate the Na-K-ATPase pumps and can lower plasma potassium. Beta-blockers (e.g., metoprolol, propranolol) have the opposite effect.

ATP AMP

K+

ß-2

Insulin stimulates the Na-K-ATPase pumps and causes movement of po-tassium into cells.

When plasma hydrogen increases (pH decreases), potassium is drawn out of cells; when plasma hydrogen decreases (pH increases) potassium is driven into cells.

H

Cell lysis releases potassium into the plasma and can cause hyperkale-mia.

Summary

Introduction to potassium.

140 mEq/L 140 mEq/L K+ K+ K + K +

Sudden increases in cell production cause the new cells to absorb extra-cellular potassium, lowering the plasma potassium.

Renal potassium excretion is

regulated by aldosterone, plasma po-tassium concentration, and increased distal flow.

Aldosterone is the primary hormone involved in potassium homeostasis. In the distal nephron, aldosterone in-creases the production of Na-K-AT-Pase pumps, sodium channels and potassium channels. These all facili-tate the excretion of potassium.

Plasma potassium concentration is an important factor in the kidney’s handling of potassium. Increased lev-els stimulate potassium excretion while low levels trigger potassium retention.

Increased distal flow increases the excretion of potassium. The increased delivery of fluid maintains the con-centration gradient in favor of potas-sium secretion. Increased delivery of sodium increases the resorption of sodium which maintains the electri-cal gradient in favor of potassium secretion.