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Disorders of Potassium Metabolism

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Content 1. Normal metabolism of Potassium

(1) Content and distribution

(2) Regulation of K+ balance

(3) Function of potassium

2. Hypokalemia 3. Hyperkalemia

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1. Normal metabolism of potassium (1) Content and distribution

  The adult body contains about 45 mmol/Kg of BW. About 98% of potassium is within the cells, [K +] i= 140~160 mmol/L. About 2% of K+ is in the ECF, [K +]e = 3.5~5.5 mmol/L. 75% of the intracellular K+ is in muscle cells.

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(2) Regulation of K+ balance

1) Equilibrium of K+ in ICF(98%) and ECF(2%) (Transcellular potassium)

2) Balance of intake and excretion

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1) Equilibrium of K+ in ICF and ECF (transcellular potassium movement)

Equilibrium means to keep

[K+]i= 140~160 mmol/L;

[K+]e = 3.5~5.5 mmol/L

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Mechanism to keep the equilibrium between ICF and ECF:

The basic mechanism to the balance is “leak and pump”.

(A) Functioning of Na+ -K+ pump

(B) Influence of leaking

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(A)Functioning of Na+ -K+ pump

“Pump” means the active transport of K+ from ECF to ICF against the concentration gradient of K+ with expending ATP. If the function of Na+-K+ pump is impaired (e.g. anoxia, acidosis), relative more K+ will move out of the cells by leaking, which will lead to high [K+]e. A) Insulin promotes the movement of K+ into the liver cells and skeletal muscle cells for glycogen synthesis via the Na+- K+ pump activation.

Na+- K+ pump activation K move from

ECF to ICF

【 K+ 】 e

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B) β -adrenergic agonists elevate Na+-K+ ATPase activity.

α -adrenergic agonists enhance K+ transport out of cells by reducing Na+ -K+ ATPase activity.

C) Aldosterone increases the activity of Na+ -K+ ATPase.

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D) A high [K+]e will stimulates Na+ -K+ATPase activity

E) Strenuous physical exercise can promote the K+ shift out of cells.

ATP depletion decrease the activity of Na+-K+ ATPase.  

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(B) Influence of leaking

“Leak” indicates the moving of K+ out of the cell according to the gradient of [K+ ] between ICF and ECF, without expending ATP.

Leaking leads to the tendency to reduce the [K+]i.

A) When the cell membrane is injured, the permeability of cell membrane to K+ is increased. More K+ move from cells into ECF.

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B) Acidosis induces K+ movement out of cells. (Alkalosis??)

A decrease 0.1 of pH elevates [K+]e about 0.6mmol/L.

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C) Increased osmolality of extracellular fluid draws water out of cells, increases the [K+]i and the gradient of [K+ ] between ICF and ECF, so more K+ out of cells.

(in hyperglycemia)

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2) Balance of intake and excretion

①Intake: The common foods, like lean meat, milk and fruits content a lot of potassium. The average diet contains 60~100 mmol of potassium per day, which is enough for the daily body requirement. 90% of potassium in food is absorbed in small intestine. The same amount of K+ as intake must be excreted.

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②Excretion

(A)Via kidney

About 90% or more potassium is eliminated from kidney.

The more K we eat, the more K is eliminated from kidneys. When the intake of potassium is decreased, the elimination from urine is decreased.

If no potassium intake, the kidneys will still secrete small amount of potassium .

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Potassium is freely filtered at the glomerulus. Almost all the potassium filtered is reabsorbed in proximal tubules via active transport (65%), and in loop of Henle via Na+-K+-2Cl- cotransporter(27%).

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Most of the potassium in the urine is secreted from distal tubules and collecting ducts by Na+-K+ exchange mechanism.

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Factors that affect the secretion of potassium in distal tubules and collecting ducts:

Increase of potassium concentration in ECF

Aldosterone

Na+--K+ pump

Secretion of K+

Acute acidosis Na+--K+ pump Secretion of K+

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(B)Via intestinal tract 10% of potassium in food is eliminated by feces. There are more loss of potassium with watery stool. The epithelial cells of colon excrete K+ as the same way as distal tubular cells (principal cells) controlled by aldosterone.

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(C) Via sweating

Generally speaking, the loss of K+ with sweat is neglectful (5~10 mmol/L). This kind of loss may be significant some time (in plenty of sweat).

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(3) Function of potassium

1) Metabolism

2) Membrane potential

3) Regulation of pH

4) Osmotic pressure of ICF

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1) Metabolism

①K+ is required for the activity of some intracellular enzymes e.g. the enzyme for ATP production.

②K+ is involved in anabolism.

1 g of glycogen contents 0.33~0.45 mmol,

The K+ moves into cells with glucose, during the synthesis of glycogen.

1 g of protein needs 30 mmol of K+.

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2) Membrane potential [K+]iRMP= 59.5 lg ------------- [K+]e

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Minimal increase or decrease of [K+]e will lead to the change of membrane potential.

K+ is important for normal neuromuscular irritability.

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3) Regulation of pH

Exchange of K+ and H+ crossing the cell membrane is important for acid-base balance. When K+ moves out of the cells, H+ will move into the cells as an exchange for electrical neutral. More H+ will lead to acidosis. Changes of K+ concentration will lead to the changes of pH.

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4) Osmotic pressure

Potassium ion is the major intracellular cation, so K+ is important in the formation of osmotic pressure in the cell.

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2.Hypokalemia

(1) Concept

(2) Causes

(3) Effect on the body

(4) Principle of treatment

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(1) Concept

Hypokalemia indicates the [K+] in plasma is < 3.5 mmol/L.

If the hypokalemia is caused by the movement of K+ from ECF to ICF,

reduced [K+] ≠ K deficiency in the body.

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(2) Causes

1) Decreased intake

2) Excessive loss of K+

3) More moving of ECF K+ into cells

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1)Decreased intake

Since food is the main source of potassium in the body, fast, anorexia or inability to eat may cause hypokalemia. At the same time, there is still loss of potassium from kidneys (5~10 mmol/ day at least).

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2) Excessive loss of K+

①From gastrointestinal tract②Excessive renal loss

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①From gastrointestinal tract

The gastric and intestinal juices are rich in potassium.

--------------------------------- position 　 　 [K+] (mmol/L)

----------------------------------------------- Gastric juice

high acidity 　 　　　　　　　　　　　　 10　 　　 low acidity 　 　　　　 25

Bile 　 　 　　 　　　　　　　　　　　　　　　　　　　 10Juice in small intestine 20

Watery stool 　 　 40

---------------------------------------

Persistent vomiting, diarrhea, gastric suction and fistula are the common ways to lose potassium directly.

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②Excessive renal loss

Renal loss is the main way to lose potassium.

(A)Diuretics

A)increase urinary flow rate.

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The most common diuretics losing potassium are thiazines, frusemide and ethacrynic acid, which block the reabsorption of Na+ and Cl- in proximal tubule and Henle’s loop, then deliver more Na+ and Cl- to the distal tubules.

More K+ is exchanged with Na+ and the loss of potassium will increase.

B)increase Na+ delivery to the collecting duct.

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(B) Type I of Renal Tubular Acidosis(“classical”)

Hydrogen ion pump dysfunction leads the reduced hydrogen excretion in distal tubule, at the same time K+ reabsorption is reduced, so more K+ is excreted.

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(C) Hyperaldosteronism

Primary hyperaldosteronism is caused by adrenal tumors.

Secondary hyperaldosteronism is caused by markedly reduced effective arterial volume in congestive heart failure, liver cirrhosis and nephritic syndrome.

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Increased aldosterone secretion will increase the potassium loss from kidneys.

Administration of large amount of glucocorticoids can also produce hypokalemia.

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(D)Renal disease(pyelonephritis ) :tubular fluid flow (E) poorly reabsorbed anion in distal tubule

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3) More K+ moves into cell

①In alkalosis, H+ moves out of the cells, at the same time, K+ moves into the cells to maintain the electrochemical balance.

For each 0.1 unit increase of pH in ECF, the [K+] of serum decreases 0.7 mmol/L.

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② Some drugs

Insulin promotes the movement of K+ into the liver cells and skeletal muscle cells via the Na+- K+ pump activation for glycogen synthesis.

.

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③(Familiar) hypokalemia periodic paralysis is a rare disease, there is a acute shift of K+ from ECF to ICF, the [K+]e will reduce, which causes paralysis of the limb and trunk(Ca2+,K+,Na+).

④ Barium poisoning: Barium ions can block K+ channels in SMC membrane.

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(3) Alterations of metabolism and function following hypokalemia

1) Effect on neuromuscular irritability

2) Effect on the heart

3) Effect on the acid-base balance

4) Effect on the kidney

5) Effect on metabolism

 

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1) Effect on neuromuscular irritability

Basic concepts Resting membrane potential

(RMP) is determined by the ratio of the intracellular to extracellular [K+] ([K +]i∕[K +]e). The interior of the cell is negative to the outside of the cell.

Threshold membrane potential (TMP) is the critical membrane potential at which there will be a rapid depolarization.

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Depolarization When stimuli apply to cells, the membrane permeability to sodium is increased, the positive Na+ rush into the cells because of the gradient.

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Repolarization: When the

depolarization reach a certain

value, the membrane potential is

rapidly reversed because the

membrane permeability to k+ is

increased and the permeability to

Na+ is decreased.

At this stage, k+ diffuses out

of the cells, the membrane

potential returns to resting level

(negative level).

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Action potential: This transient reversal of polarity is called action potential.

High Neuromuscular irritability (high excitability) means easy to start AP.

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Excitability is determined by the distance between the RMP and TMP. The less distance (difference) , the higher of excitability(easy to start AP).

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(a) Decrease the neuromuscular irritability.

The difference between [K+]i and

[K+]e is increased.

The negative value of RMP is

increased (hyperpolarization). The

difference between resting and

threshold potential is increased.

A greater stimulus is needed to

produce an action potential (not easy to

start AP).

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(b) manifestations

① Effect on skeletal muscles The effects of hypokalemia depend on partly the

decrease speed of serum [k+]. The rapidly decreased serum [k+] leads to skeletal

muscle weakness, flabbiness (soft), and flaccid (soft) paralysis.

The most severe problem of muscular paralysis is ??

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In chronic potassium depletion, the k+ in ICF

moves to ECF, both intracellular and extracellular [k+]

are decreased, the ratio of [k+]i to [k+]e is not

obviously changed, the resting potential is not

changed. The neuromuscular irritability is not changed

obviously.

Chronic potassium depletion may lead to the

muscle atrophy ( thin and weakness of the muscle) ,

which is mainly caused by disturbance of protein

metabolism.

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② Effect on SMC Decreased neuromuscular irritability also affects

the smooth muscle of gastrointestinal tract, which causes:

decreased intestinal motility,

abdominal distension,

anorexia,

nausea

constipation.

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2) Effect on heart

Basic concepts

Action potential of myocardial cell Phase 0 is the rapid inward sodium current via sodium channel. Phase 0 is the stage of depolarization. Phase 1 is related to the outward of K+ current.

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Phase 2 is the plateau of the AP. At this stage, the k+ moves to ECF and the Ca+ moves into the myocardial cell.

Phase 3 is the

function of the outward potassium current (repolarization).

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Phase 4 is the stage of spontaneous depolarization with slow outward potassium current and slow inward sodium current. The inward sodium current is a little greater than the outward potassium current.(a slope)

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(a)Effects on myocardiac cells Increased① excitability in Purkinje cell

The potassium permeability of myocardiac cell is reduced in hypokalemia. Less K+ moves outside the cell, the RMP is less negative. The difference between RMP and TMP is reduced. Smaller stimulus may produce the AP.Note:Other cardic cell excitability reduced.

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②The conductivity of Purkinje cell is reduced.

The rate of

depolarization and

repolarization is reduced

in hypokalemia, because

the RMP is near the

TMP.

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③ The contractibility of myocardiac cell is increased.

K+ in ECF can inhibit the inward flow of calcium ions, this inhibiting effect is reduced in hypokalemia.

Na+-K+ pump activity is inhibited, [Na+]i increase, Na+/Ca2+exchange

More Ca 2+ within myocardiac cell will increase the contractibility.

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④ The autorhythmicity is increased(purkinje cell)

In phase 4, the potassium permeability in hypokalemia is reduced, the outward potassium current is decreased and inward sodium current is relatively increased.

The speed of spontaneous depolarization is increased. (Slope rise steeply)

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Summary of the effect of hypokalemia on the myocardiac cells

The excitability is increased.

The conductivity is reduced.

The autorhythmcity is increased.

The contractibility is increased.

All the alters make it easy to produce ectopic beats (arrhythmia) from Purkinje fiber and ventricular muscle.

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Electrocardiogram (ECG)

The P wave reflects depolarization of atrial muscle and represents the original impulse passes through the atrium. The QRS complex represents depolarization of the ventricular muscle mass, and reflects the speed of conduction throughout the ventricle.

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The S-T segment represents the period between the end of depolarization of ventricular muscle and the beginning of repolarization of ventricle. The S-T segment corresponds to the plateau (phase 2) of AP.

The T wave represents the major portion of repolarization after ventricular contraction. T wave corresponds to the phase 3 of AP.

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Broad and flat T wave　 appears because the potassium permeability in hypokalemia is reduced, the rate of repolarization is reduced. The phase 3 is prolonged. Prolonged P-R interval and Q-T interval are

caused by reduced conductivity.

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Suppressive S-T segment is related to the short phase 2 due to accelerated inward flow of calcium.

Widening QRS complex is caused by reduced conductivity.

Prominent U wave can be often seen in hypokalemia, but it is hard to explain the mechanism(phase 3 of purkinje cell).

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3) Effect on the acid-base balance

  Hypokalemia leads to metabolic alkalosis.

When [K+]e of ECF reduce caused by other reasons except alkalosis, the K+ of ICF moves out of the cells, at the same time, H+

moves into the cells for electric neutrality.

Then the [H+] in ECF will be reduced, which is called metabolic alkalosis.

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There are two kinds of ion exchange in renal tubules: K+ -- Na+ H+ -- Na+ ,. In hypokalemia, the K+-Na+ exchange is reduced, the H+--Na+ exchange will increase, so the excretion of H+ from kidneys is increased, which leads to acidic urine.

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Usually in alkalosis, the elimination of H+ is reduced from kidneys, and the urine should be alkaline.

But in the alkalosis caused by hypokalemia, the urine is acidic, it is unusual, so it is called unusual aciduria.

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4) Effect on the kidney failure to urine concentration:

The volume of urine is increased and the specific gravity will reduce.

distal tubule and collectin duct damage:the renal tubular cells can not produce sufficient cAMP (cycle adenosine monophosphate), which is necessary for ADH to work, so the tubules lose the concentrating ability to urine.

Dysfunction of sodium reabsorption in ascending thick of loop of Henle

Thirst may occur in patients with hypokalemia.

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5) Effect on metabolism

(a) Negative balance of protein synthesis (b) Decreased energy production because of the low

enzyme activity. Low ATP leads to cerebral dysfunction, lethargy

(being tired), drowsiness (feeling sleepy), apathy (uninterested), confusion.

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4. Principle of treatment

 1) Etiological treatment is to correct the underlying diseases. 2) Replacement of potassium salts slowly after urination (no oliguria). Oral potassium chloride is better than intravenous administration. We must pay attention to the rate of intravenous administration and the potassium concentration of potassium chloride solution. The major problem of replacement of potassium is to prevent hyperkalemia.

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3. Hyperkalemia(1) Concept

Serum [K+]>5.5mmol/L is defined as hyperkalemia.

If the increase of serum [K+] is caused by the movement of potassium from ICF to ECF, the hyperkalemia does not mean potassium excess.

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(2) Causes

1) Decrease of renal excretion potassium

2) Increased potassium intake

3) Increased movement of potassium from

cells to ECF

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1) Decrease of renal excretion potassium

(a) GFR decrease:

oliguria and anuria

Normally 90% of potassium is excreted from kidneys.

The serum [K+] increases 0.7 mmol/L per day if the patient is anuria without K intake, and 10 days later, the patient with anuria will die from hyperkalemia.

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(b)Absence of aldosterone: Addison’s disease, hypoaldosteronism, renal tubule acidosis -IV

(c) Some diuretics (e.g. spironolactone, an antagonist of aldosterone): inhibit the sodium reabsorption and the secretion of K is reduced.

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2) Increased potassium intake

①Eat more if oliguria.②Too rapid intravenous administration of KCl leads to

a severe incident, which is fatal. Before the intravenous infusion of KCl , we

must make sure that the renal function is good enough to eliminate potassium.

Intravenous solution containing potassium should never be started until urine has been assessed.

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3) Increased movement of potassium from ICF to ECF

(a) Acidosis: (b)Cell destruction: tissue trauma, burn,

rhabdomyolysis, lysis of tumor cells by cytotoxic agents ,hemolysis.

(c) Hypoxia: sodium retention in cell,acidosis and cell necrosis

(4)Hyperkalemia periodic paralysis:αsubunit of voltage gated sodium channel

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(3) Effect on the body

1) Effect on the neuromuscular irritability

2) Effect on the heart

3) Effect on acid-base balance

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1) Effect on the neuromuscular irritability

In mild hyperkalemia (<7mmol/L), the neuromuscular irritability is increased.

In severe hyperkalemia (>7mmol/L), the neuromuscular irritability is decreased.

(Biphasic)

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In hyperkalemia, the RMP is less negative (partial depolarization), the difference between the RMP and TMP is decreased, which means that a smaller stimulus will evoke an action potential (AP).

The excitability ( irritability) of skeletal muscles is increased at first.

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manifestation of skeletal muscle :stabbing pain and abnormal sensation ( too sensitive for pain) at first ( with mild hyperkalemia) 。

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In severe stage, the RMP< or = TMPNa+ channel will not open. The excitability is decreased to disappear.The excitability ( irritability) of skeletal muscles is then decreased at last. (Biphasic) then weakness and paralysis in severe stage.

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The excitability ( irritability) of smooth muscles of GI tract is increased at first, then decreased at last. (Biphasic)

It may be manifested at first by diarrhea, intestinal colic ( abdominal pain) and abnormal sensitivity (paresthesia), then abdominal distension.

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2) Effect on the heart

(a) A gradual increase of serum [K ] produces biphasic sequences of excitability of myocardiac cells. An initial increase of excitability is followed by a decrease. ( same as the effect on skeletal and smooth muscle)

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(b)The conductivity of myocardiac cell is reduced.

The difference between the RMP and TMP is decreased,

The rate of depolarization is reduced in hyperkalemia, because the RMP is near the TMP.

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(c) The autorhythmicity is decreased, because the membrane permeability to potassium is increased, the outward potassium current is increased and the inward sodium current is relatively decreased.

Sinoatrial node is not sensitive to hyperkalemia.The autorhythmicity decreasing focused on Purkinje cell.

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(d) The contractivity is reduced due to decreased intracellular calcium, because the high [K+]e inhibits the inward flow of calcium and Na+-Ca2+ exchange increase due to the Na+-K+ pump activation.

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(f) Changes of ECG

T wave is peaked and tent-shaped because phase 3 is accelerated due to rapid outward of potassium (Potassium permeability of membrane of myocardiac cells is increased.)

P wave is prolonged and eventual disappear due to the decreased conductivity and excitability in atrium.

QRS complex is widened due to the decreased conductivity in ventricle.

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3) Effect on acid-base balance

(a) extracellular acidosis

When [K+] of ECF is increased in hyperkalemia, the K+ of ECF moves into the cells, at the same time the H+ in ICF moves into the ECF for electric neutrality. Then the [H+] in ECF will be increased.

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(b) unusual alkalinuria.

There are two kinds of ion exchange, K+-Na+ and H+-Na+ , in renal tubules.

In hyperkalemia, the K+--Na+ exchange is increased, the H+--Na+ exchange will decrease, so the excretion of H+ from kidneys is reduced, which leads to basic (alkaline) urine.

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(4) Principle of treatment

1) Complete restriction of exogenous

potassium intake.

2) Control of the underlying disease

(etiologic treatment)

3) Transport of the serum K+ into cells (a) Administration of insulin and glucose to transport the potassium from ECF into the cells.

(b) Bicarbonate infusion (alkaline solution) can drive the potassium into the cells.

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4) Increase the elimination of potassium

(a) A sodium polystyrene sulfonate resin is

used to remove potassium from colon.

(b) Peritoneal dialysis

(c) Hemodialysis

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(5)Protection of cardiac cells A increased [Ca2+] may raise the threshold potential, which may reestablish the difference between the resting and threshold potential and restores the excitability.

A increased Na+ will increase the inward sodium current in phase 0 (depolarization) to increase the excitability of heart muscle.