K Edited and presented by Laith Sorour

Physiology

Potassium (K+) is the major intracellular cation, approximately 98% of total body K+ stores are intracellular at a concentration of 140-150 mmol/l, and only 2% in the extracellular fluid, where it ranges between 3.5 and 5 mmol/l (normal serum conc.).

• Major Functions:

- Na/K ATPase (which is basically in every cell)

- Heart Conduction

- Important factor in maintaining the resting membrane potential

- Osmolarity

increased distal tubular urine flow rate and Na+ delivery (thiazides and loop diuretics) And other anions and met. alkalosis hypomagnesemia

activates epithelial sodium channels in cortical collecting duct, causing Na+ reabsorption and K+ excretion

K+ excretion = urine flow rate x urine [K+]

• potassium excretion is regulated at the distal tubule

The resting potential is influenced by both the ratio of intracellular and extracellular potassium ions across the cell membrane and the activation of membrane sodium channels that leads to passive diffusion of extracellular sodium into the cells. The latter is the primary process in generating an action potential. Potassium ions tends to leave the cells to equalize the osmotic gradient, which results in a voltage of -90 mV (resting membrane potential). An increased extracellular potassium concentration decreases the gradient, leading to a reduced voltage. This brings the membrane potential closer to the threshold that triggers an action potential. Persistent depolarization eventually inactivates sodium channels, which ultimately reduces the net membrane excitability. • ↑ Extracellular K+ concentration → ↓ resting membrane potential (less

negative than -90 mV) → ↑ excitability

• ↓ Extracellular K+ concentration → ↑ resting membrane potential (more negative than -90 mV) → ↓ excitability

Hyperkalemia

• K level >5 meg\L

• Symptoms usually occur if serum potassium levels are > 7.0 mEq/L or they change rapidly.

• Cardiac arrhythmias (e.g., atrioventricular block, ventricular fibrillation)

• Muscle weakness, paralysis, paresthesia

• ↓ Deep tendon reflexes; While a reduced resting potential initially increases membrane excitability, persistent depolarization eventually inactivates sodium channels and leads to a reduced total membrane excitability.

• Nausea, vomiting, diarrhea

Etiology

• Potassium excess • Reduced excretion: acute and chronic kidney disease; GFR < 20ml/min/1.73 m2 • Endocrine causes: hypocortisolism, hypoaldosteronism decreases excretion • Drugs: potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers, NSAIDs, and trimethoprim-

sulfamethoxazole (Blocks Epithelial Na channels) • GI absorption: increased intake of high-potassium foods (e.g., fresh fruits, dried fruits and legumes, vegetables, nuts,

seeds, bran products, milk, and dairy products) • Type IV renal tubular acidosis (Low aldosterone, aldosterone resistance, seen in DM) • Release from cells: myolysis, tumor lysis, hemolysis

• Extracellular shift • Acidosis → ↑ extracellular H+ → inhibition of the Na+/H+ antiporter → ↓ intracellular Na+ → ↓ sodium gradient inhibits

the Na+/K+-ATPase → ↑ extracellular K+ concentration • Hyperkalemia → ↑ extracellular K+ concentration → ↑ potassium gradient stimulates the Na+/K+-ATPase → ↑ extracellular Na+ → ↑

sodium gradient stimulates the Na+/H+ antiporter → ↑ extracellular H+ → acidosis • Exception: In renal tubular acidosis, findings include hypokalemia and metabolic acidosis.

• Hyperosmolality • Insulin deficiency (manifests with hyperglycemia) • Release from cells: rhabdomyolysis, tumor lysis syndrome, hemolysis • Drugs

• Beta-blockers • Succinylcholine: (esp. when given with preexisting burns and/or muscle trauma) • Digoxin: inhibits the Na+/K+-ATPase → ↑ extracellular K+ concentration

• Pseudohyperkalemia: due to the release of potassium from red blood cell lysis • Blood drawn from the side of IV infusion or a central line without

previous flushing

• Prolonged use of a tourniquet

• Fist clenching during blood withdrawal

• Delayed sample analysis

Diagnostic

• Laboratory evaluation • Serum potassium levels (always confirm abnormal serum potassium levels with a repeat blood draw) • Creatinine, GFR to assess renal function • In normal renal function: aldosterone level to rule out Addison disease • Arterial blood gas (ABG): influence of pH on the potassium homeostasis

• Metabolic acidosis: hyperkalemia • Metabolic alkalosis: hypokalemia

• ECG changes

• ECG changes and cardiotoxicity (do not correlate well with serum *K+])

• peaked and narrow T waves

• decreased amplitude and eventual loss of P waves

• prolonged PR interval

• widening of QRS and eventual merging with T wave (sine-wave pattern)

• AV block

• ventricular fibrillation, asystole

Management

• FIRST OF ALL ECG & ABC

• Hx, Px, Meds, KFT

• If no changes consider lab error and repeat sample w\o tourniquet

• Then if

• Potassium level ≤ 6.5 mEq/L and no signs of cardiotoxicity: decrease intake/absorption (slow-acting option) Discontinue drugs that increase serum potassium

• Avoid high-potassium foods

• Cation-exchange resins (e.g., sodium polystyrene sulfonate): bind potassium in the gut via the exchange of Na+ for K+ (The onset of action is several hours after administration)

• Adverse effect (rare): intestinal necrosis

• Patiromer

• Loop diuretics: promote excretion of potassium and lower total body potassium stores

• Intravenous, non potassium containing fluids: normal saline, dextrose 5% in water

• Potassium level > 6.5 mEq/L or cardiotoxicity or 6 with ECG changes: IV therapy for cardio protection and to induce elimination/intracellular shift (rapid-acting option)

• IV Calcium gluconate 100 mg over 10 min:

should be administered first; While hyperkalemia elevates the resting membrane potential, calcium increases the threshold potential, which stabilizes the cardiac cell membrane by restoring a normal gradient between the resting membrane and threshold potentials. Calcium does not decrease the serum potassium concentration. It is used in medical emergencies and must be avoided in patients on digitalis.

• Insulin, preferably short-acting insulin, in combination with glucose;

Insulin decreases serum potassium levels by stimulating the Na+/K+-ATPase pump (skeletal muscles), which moves potassium into the cell. Glucose should be given simultaneously in order to avoid hypoglycemia (25 g; 50 mL of 50% solution when Glucose<250 mg\dL ) Effective up to 6 hours

• Beta-2-adrenergic agonists;

inhaled Albuterol has been shown to decrease serum potassium levels by 0.3 to 0.6 mEq/L within 30 minutes; the decrease lasts for at least 2 hours; Stimulates the Na+/K+-ATPase pump

• Sodium bicarbonate: in acidemic patients (controversial)

• Forced diuresis (loop diuretics with normal saline solution)

• Renal failure\ oligouric kidney dz or ineffective initial treatment or Severe Hemodialysis: most effective and definitive treatment option

• You may use binders but some studies say meh

For Chronic Hyperkalemia

Limit Potassium intake

Thiazide or loop diuretics

In hypoaldosteronism :

Fludrocortisone will normalize Potassium but it may cause HTN and edema .

Patiromer (Veltassa)

Newer oral K binder

Hypokalemia

• Serum potassium level < 3.5 mEq/L

• It can be divided into disorder of :

1. Internal balance (shifting between intracellular and extracellular ) .

2. External balance (decrease K intake and increased output ).

Etiology

• Potassium loss (External) • Renal loss

• Endocrine causes: hyperaldosteronism, hypercortisolism (alkalosis) • Drugs: diuretics, glucocorticoids, licorice (Blocks 11B-HSD, aldosterone-like), SAME • Hypomagnesemia

• (1) Since magnesium serves as a cofactor in Na+/K+-ATPases, hypomagnesemia disrupts the Na+/K+-ATPase in the basolateral membrane of the cells of the proximal convoluted tubule and loop of Henle, leading to decreased Na+ reabsorption. This causes increased luminal sodium that, distally, leads to increased sodium reabsorption and potassium secretion by the principal cell; and

• (2) Apical ROMK channels in principal cells are inhibited by intracellular magnesium. With low levels of magnesium available, the ROMK channels are not inhibited, so K+ secretion increases.

• Type I and II renal tubular acidosis and other defects (Liddle, Bartter, Gitelman) (Alkalosis)

• Gastrointestinal loss: vomiting (Hypochloremic Alkalosis), diarrhea, laxatives (e.g., in bowel preparation prior to medical procedures) (Metabolic Acidosis)

• Decreases Intake: Only in very severe def. diet

• Intracellular shift (Internal)

*Total K is normal but there is problem with distribution

• Alkalosis → ↓ extracellular H+ → stimulation of the Na+/H+ antiporter (transfers H+ out of the cells in exchange for Na+) → ↑ intracellular Na+ → ↑ sodium gradient stimulates the Na+/K+-ATPase (transfers K+ into the cells in exchange for Na+) → ↓ extracellular K+ concentration • Hypokalemia → ↓ extracellular K+ concentration → ↓ potassium gradient inhibits the Na+/K+-ATPase → ↓

extracellular Na+ → ↓ sodium gradient inhibits the Na+/H+ antiporter → ↓ extracellular H+ → alkalosis • Exception: In renal tubular, acidosis findings include hypokalemia and metabolic acidosis!

• Hypoosmolality

• Drugs • Insulin: stimulation of the Na+/K+-ATPase pump, which moves potassium into the cell; An excess of insulin causes

increased Na+/K+-ATPase activity with K+ accumulating intracellularly. • Beta-2-adrenergic agonists: beta-2 receptor-mediated stimulation of the Na+/K+-ATPase pump • Soluble barium intake; Block k exit from cells, Can produce sever hypokalemia with level below 2 meq/ l

• Increases Cell Production after repletion with B12, Folate, and in High turnover like leukemias

• Hypomagnesemia can lead to refractory hypokalemia!

Clinical features

• Symptoms usually occur if serum potassium levels are < 3.0 mEq/L or they change rapidly.

• Cardiac arrhythmias (e.g., premature atrial and ventricular complexes, ventricular fibrillation)

• Muscle weakness, paralysis

• Muscle cramps and spasms and in severe Rhabdomyolysis

• ↓ Deep tendon reflexes

• Nausea, vomiting, constipation, ileus

• Fatigue

• Polyuria; Hypokalemia leads to ADH resistance

• In patients treated with digoxin: symptoms of digoxin toxicity; Digoxin inhibits the Na+/K+-ATPase pump by competing with potassium for the same binding site. Therefore, decreased serum potassium concentration “results in digoxin having a greater effect and increases the risk of toxicity.

Diagnostics

• Laboratory evaluation • Serum potassium levels (always confirm abnormal serum potassium levels with a repeat blood

draw) • Urinary potassium level (either 24 collection or spot K-Cr)

• > 20 mEq/L: renal loss • < 20 mEq/L: extrarenal loss

• Arterial blood gas (ABG): influence of pH on the potassium homeostasis • Metabolic alkalosis: hypokalemia • Metabolic acidosis: hyperkalemia

• ECG changes • Presence of U waves: small waveform following the T wave that is often absent and becomes

more pronounced in the context of hypokalemia or bradycardia • Possibly TU fusion; premature atrial and ventricular complexes • ST depression • T-wave flattening • V.tach & V.fib

Management

• Determine the cause by Hx and Labs

• Differentiate btw external and internal balance (Gold Standard is 24 hour K urine collection, alternative is spot urine K-Cr ratio; <13 is external)

• Treat the underlying cause or adjust an existing treatment; correct possible hypomagnesemia • If diuretic-induced (e.g., loop or thiazide diuretics):

• Discontinue the diuretic or reduce the dose and combine with potassium-sparing diuretic spironolactone, ACE inhibitors, or beta blockers.

• Rehydrate with normal saline in the case of volume depletion and contraction alkalosis.

• Repletion • Intake of high-potassium foods • Potassium chloride (KCl)

• Preferred route of administration: oral in mild (3-3.5) • In severe hypokalemia (< 2.5 mEq/L): IV

• Oral or IV Magnesium for patients with hypomagnesemia to prevent ongoing K loss

• IV potassium may cause local irritation and lead to cardiac arrhythmias. Therefore, it should always be administered slowly (max. rate of 10-20 mEq/hour Via peripheral line\\40 meg\L via central line with close monitoring )!

Kalemic Periodic Paralysis

Periodic paralyses comprises a group of muscle diseases that are characterized by weakness (proximal, symmetric, flaccid paralysis) with a simultaneous drop or rise in potassium levels. Autosomal-dominant inheritance with complete penetrance

Pathophysiology Symptoms are triggered by hypo- or hyperkalemia: Periodic paralysis may be associated with hyperkalemia or hypokalemia.

Hyperkalemic periodic paralysis Hyperkalemic periodic paralysis is caused by a genetic defect affecting the voltage-gated sodium channel → sodium channels remain open → membrane repolarization is impaired

Hypokalemic periodic paralysis Change in membrane permeability to potassium → extracellular potassium deficiency and intracellular sodium deficiency → refractory muscle tissue Hypokalemic periodic paralysis may be caused by a genetic defect affecting one or all of the following three ion channels: 1. Calcium channel (most common defect; 70% of cases) 2. Voltage-gated sodium channel (less common) 3. Inward rectifier potassium channel (rare defect) 4. Acquired disease occur with hyperthyroid PT

Clinical features • Hypokalemic periodic paralysis

• Proximal, symmetric, flaccid paralysis and areflexia; Symptoms appear early in the morning hours and in the evening.

• Paralysis may last for hours to days and may involve respiratory muscles.

• Triggers: a carbohydrate-rich meal, a rise in insulin levels , hyperthyroidism

• Hyperkalemic periodic paralysis

• Hyperkalemic periodic paralysis is generally less severe than the hypokalemic form; respiratory muscles are spared while facial and pharyngeal muscles are often involved.

• Paralysis may last for minutes to hours

• Triggers: small fluctuations in potassium levels, exposure to cold, physical exertion

• Diagnostics • Neurological examination: flaccid paralysis, areflexia

• EMG: low-amplitude muscle potentials

• EKG: U-wave in the case of hypokalemia, peaked T-wave in the case of hyperkalemia

• Laboratory findings: serum potassium levels < 3.5 mmol/L (hypokalemia) or > 5.5 mmol/L (hyperkalemia)

• Treatment • During a spell of periodic paralysis:

• Hypokalemic periodic paralysis: potassium chloride, acetazolamide (an episode of hypokalemic periodic paralysis can be lethal!)

• Hyperkalemic periodic paralysis: calcium gluconate

Quick Summary

• Potassium disorders may take the form of hyperkalemia (high serum potassium) or hypokalemia (low serum potassium).

• The most common cause of hyperkalemia is decreased kidney function. It may also be caused by endocrinological disturbances (e.g., hypoaldosteronism, hypocortisolism) or drugs such as potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), and digoxin.

• Low serum potassium levels, on the other hand, can be caused by gastrointestinal losses (e.g., due to vomiting, diarrhea) or drugs such as non-potassium-sparing diuretics and laxatives. To determine the cause of a potassium disorder, it is essential to review the patient's medications and test for aldosterone and cortisol disturbances.

• Acute changes in serum potassium are very dangerous, as they influence the resting membrane potential and thus the electrical excitability of cells. These changes can lead to malignant cardiac arrhythmias. The management of hypokalemia and hyperkalemia includes dietary changes, medications, and, in the case of hyperkalemia, dialysis. The potassium serum concentration should be monitored closely until it is corrected.