1. Potassium Balance and Potassium Imbalance Pathophysiology Department, Tongji Medical College, HUST

2. Part Ⅰ

3. Potassium Balance Ⅰ Content and Distribution of Potassium in the Body Potassium in the Body Ⅱ Intake and Excretion of Potassium

4. Dietary K intake 70~100mmol/day ECF 2% Serum [K + ] round 4.5mmol/L K+K+ Skin trivial normally Colon 10% Kidneys > 80%  More ingested, more excreted  Less ingested, less excreted  Not ingested, excretion goes on Content, distribution, intake and excretion of K Excretion ICF [K + ] 160mmol/L 98% of the total body potassium Total body K content 31~57 mmol/Kg body weight

5. Ⅲ Maintenance of Potassium Homeostasis Ⅲ Maintenance of Potassium Homeostasis —Distribution of K + across the cell —Distribution of K + across the cell membrane and Regulation of renal membrane and Regulation of renal K + excretion K + excretion

6. Distribution of Potassium across the Cell Membrane The Na + /K + ATPase membrane pump and permeability of ion channels and permeability of ion channels

7. 1.Hormones — insulin, glucagon, catecholamines, thyroid hormone 2.Serum [K + ] 3.pH of ECF and plasma osmolality 4.Others — rate of cell breakdown, hypoxia, hypothermia, exercise Influencing Factors [K + ]↑ Na + Na + /K + - ATPase K+K+K+K+ K+K+K+K+ H+H+H+H+ Catecholamine Insulin

8. Regulation of Renal Potassium Excretion  Filtration, reabsorption and secretion of potassium of potassium The nephron and collecting tubule Cl - Na + /K + ATPase( Mg 2+ activated ) Na + /K + ATPase H + - K + ATPase

9. Regulation of Renal Potassium Excretion  Filtration, reabsorption and secretion of potassium  Secretion of potassium in the distal and collecting tubules principal cells, with Na + /K + ATPase membrane pump, for secretion of K +

10. lumen Principal Cell blood K+K+ Na + K+K+ Cl - K+K+ CO 2 HCO 3 - Cl - H+H+ K+K+ CO 2 Intercalated Cell

11. Regulation of Renal Potassium Excretion  Filtration, reabsorption and secretion of potassium  Secretion of potassium in the distal and collecting tubules  Reabsorption of K in the distal and collecting tubules, intercalated cells, with H + /K + -ATPase (proton pump) for reabsorption of K +

12. Regulation of Renal Potassium Excretion  Filtration, reabsorption and secretion of potassium  Secretion of potassium in the distal and collecting tubules  Reabsorption of K in the distal and collecting tubules intercalated cells, with H + /K + -ATPase (proton pump) for reabsorption of K +  Factors influencing excretion of K + by the distal and collecting tubules

13. Factors Influencing Excretion of K + by the Distal and Collecting Tubules  Aldosterone — activates Na + /K + ATPase, increase membrane permeability to K  [K + ] in the ECF  Flow rate of tubular fluid in the distal tubule  pH of ECF —↓pH inhibits Na + /K + ATPase

14. + lumenblood Principal Cell K+K+ Na + K+K+ Cl - K+K+ [K + ]↑ ② ③ CO 2 HCO 3 - Cl - H+H+ K+K+ CO 2 Intercalated Cell [H + ]↑ ① flow rate Factors Influencing Excretion of K + by the Distal and Collecting Tubules + + Ald + + + + + -

15. Maintenance of Potassium Homeostasis  Distribution of potassium across the cell membrane membrane  Regulation of renal potassium excretion  Excretion of K by the Colon also controlled by aldosterone by aldosterone

16. Function of Potassium in the Body Function of Potassium in the Body Ⅳ Function of Potassium in the Body  The part K + plays in metabolism  Maintenance of the resting membrane potential of excitable cells  Maintenance and regulation of osmotic pressure and acid-base balance both in ICF and ECF

17. Part Ⅱ

18. Potassium Imbalance ---abnormal changes in [K + ] in ECF

19. Hypokalemia Serum [K + ]<3.5mmol/L,may or may not be associated with K deficit

20. ECF 2% Dietary intake Serum [K + ] < 3.5mmol/L G.I losses---diarrhea, vomiting Renal losses---diuretics, some diseases of the kidney Losses from the skin---profuse sweating, burns Excessive losses ICF [K + ] may or may not be decreased Total body K content — decreased (K deficit) shifting — normal Crude cotton seed oil poisoning or Etiology and Pathogenesis

21. Ⅰ. Inadequate Intake Fasting, anorexia, inability to eat, prolonged IV alimentation without K supplementation, alcoholism Ⅱ. Excessive Losses 1.Gastrointestinal losses Diarrhea →extrusion of large amount of alkaline liquid stool with a high content of K→K depletion, acidosis, ECF volume contraction →↑secretion of aldosterone Vomiting →mainly increased renal excretion of K + due to metabolic alkalosis caused by loss of gastric acid, contraction of ECF volume

22. Etiology and Pathogenesis Ⅰ. Inadequate Intake Ⅱ. Excessive Losses 1.Gastrointestinal losses 2.Excessive renal losses (1)Diuretics→increased flow rate and delivery of Na +,Cl - and water to the distal tubule → increased Na + -K + exchange; volume contraction →increased aldosterone → renal K excretion↑

23. Regulation of Renal Potassium Excretion The nephron and collecting tubule Cl - Na + /K + ATPase( Mg 2+ activated ) Na + /K + ATPase H + - K + ATPase

24. Etiology and Pathogenesis Ⅰ. Inadequate Intake Ⅱ. Excessive Losses 1.Gastrointestinal losses 1.Gastrointestinal losses 2.Excessive renal losses 2.Excessive renal losses (1) Diuretics (1) Diuretics (2) Some diseases of the kidney (2) Some diseases of the kidney Renal tubular acidosis Renal tubular acidosis

25. Excessive Renal Losses (1) Diuretics (2) Some diseases of the kidney Renal tubular acidosis Renal tubular acidosis Diuretic recovery phase of acute renal failure Diuretic recovery phase of acute renal failure (3) Antibiotics (4) Excess of adrenocortical hormones Aldosteronism, Cushing’s syndrome Aldosteronism, Cushing’s syndrome (5) Magnesium deficiency Diuretic recovery phase of acute renal failure Diuretic recovery phase of acute renal failure

26. Regulation of Renal Potassium Excretion The nephron and collecting tubule Cl - Na + /K + ATPase( Mg 2+ activated ) Na + /K + ATPase H + - K + ATPase

27. A female patient, 42 years old, was admitted to the affiliated hospital of the Sichuan Med.College as an emergency case on April 4 1978, with a chief complaint of decreased food intake, nausea and frequent vomiting for 20 days. She had a history of diabetes mellitus for 3 years. Diagnosis: Diabetic ketoacidosis, which is a medical emergency. She was treated with insulin, with success. She was also found to have infection of the urinary tract as well as severe hypokalemia (the serum [K + ] was around 2mmol/L). Therefore she was given large doses of gentamycin for 33 days. KCl was also administered, both by mouth and IV instillation, in large doses, for 41 days. However, hypokalemia persisted (2.55mmol/L). Case Report

28. To the surprise of the doctor, the patient suddenly developed spastic rigidity of the limbs. It was until then, 41days after admission, the doctor examined the serum [Mg 2 + ], it was very low:0.2mmol/L!(The normal range of serum [Mg 2 + ] being 1.5~2.5mmol/L). IV MgSO 4 was immediately given, and also for several days, with complete success! The doses of KCl was reduced, however, the serum [K] rose to normal levels within 3 days! Serum [Mg 2 + ] also turned normal. No adverse reactions.( 《中华内科杂志》 1980 年 1 月 ) To the surprise of the doctor, the patient suddenly developed spastic rigidity of the limbs. It was until then, 41days after admission, the doctor examined the serum [Mg 2 + ], it was very low:0.2mmol/L!(The normal range of serum [Mg 2 + ] being 1.5~2.5mmol/L). IV MgSO 4 was immediately given, and also for several days, with complete success! The doses of KCl was reduced, however, the serum [K + ] rose to normal levels within 3 days! Serum [Mg 2 + ] also turned normal. No adverse reactions.( 《中华内科杂志》 1980 年 1 月 ) Questions :1. What is the cause or what are the causes of hypokalemia and hypomagnesemia in this patient? 2. Why did the doctor fail to diagnose hypomagnesemia earlier?

29. Excessive Renal Losses (1) Diuretics (2) Some diseases of the kidney Renal tubular acidosis Renal tubular acidosis Diuretic recovery phase of acute renal failure Diuretic recovery phase of acute renal failure (3) Antibiotics (4) Excess of adrenocortical hormones Aldosteronism, Cushing’s syndrome Aldosteronism, Cushing’s syndrome (5) Magnesium deficiency (6) Alkalosis

30. Etiology and Pathogenesis Ⅰ. Inadequate Intake Ⅱ. Excessive Losses 1. Gastrointestinal losses 2. Excessive renal losses 3. Excessive losses from the skin Profuse sweatings, burns or scalds

31. Etiology and Pathogenesis Ⅰ.Inadequate Intake Ⅱ.Excessive Losses Ⅲ.Shifting of K + from the ECF to ICF 1.Overdose of insulin 2.  -adrenergic agonist overdose Na + Na + /K + - ATPase K+K+K+K+ K+K+K+K+ H+H+H+H+ Albuterol Insulin

32. Etiology and Pathogenesis Ⅰ.Inadequate Intake Ⅱ.Excessive Losses Ⅲ.Shifting of K + from the ECF to ICF 1.Overdose of insulin 1.Overdose of insulin 2.  -adrenergic agonist overdose 2.  -adrenergic agonist overdose 3.Alkalosis 3.Alkalosis 4.Barium poisoning 4.Barium poisoning 5.Familial hypokalemic periodic paralysis 5.Familial hypokalemic periodic paralysis Na + Na + /K + - ATPase K+K+K+K+ K+K+K+K+ H+H+H+H+ Albuterol Insulin

33. Etiology and Pathogenesis Ⅰ.Inadequate Intake Ⅱ.Excessive Losses Ⅲ.Shifting of K + from the ECF to ICF Crude Cotton Seed Oil poisoning Crude Cotton Seed Oil poisoning

34. Effects on the Body — factors influencing the effects: the underlying diseases, the degree of hypokalemia and rapidity of its development, the ratio of [K + ] i / [K + ] e

35. Effects on Neuromuscular Excitability The Resting Membrane Potential (RMP) and Action Potential (AP) of a skeletal muscle cell in the normal state +35 0 -60 -90 Millivolts Milliseconds Threshold Nernst equation E m = -60lg[K + ] icf / [K + ] ecf (mv)

36. Acute Hypokalemia [K + ] i / [K + ] e ↑ RMP more negative than normal hyperdepolarization block, excitability↓ muscle weakness, flaccid paralysis, smooth muscle symptoms

37. -120 -90 -60 -30 0 30 NormalLow [K + ]High [K + ] TMP RMP Action potential (AP) The effects of serum K + concentration on cellular membrane excitability mv

38. ratio of [K + ] i to [K + ] e may be normal, RMP and excitability unchanged, interfering with cellular metabolism and vasodilation of muscles during exercise Chronic Hypokalemia

39. Effects on the Heart A Brief Review of the Bioelectric Phenomena of the Heart Phenomena of the Heart

40. a: effective refractory period; b: relative refractory period c: supranormal period RMP and AP of a Ventricular Muscle Cell of the Heart

41. 40 +20 0 -20 40 60 80 100 4 0 1 2 3 4 3 4 0 1 2 4 RMP max.diast.potential Atrial muscle Purkinje’s fiber The Membrane Potential of Atrial Muscle, and Purkinje’s Fiber

42. 1.Effects on excitability RMP<-90mv, excitability Ca 2 + inflow plateau, ERP shortened Phase 3, SNP prolonged AP prolonged

43. Effects of low serum [K + ] on the action potential of the myocardial cell of the myocardial cell normal low [K + ] e Threshold potential repolarization prolonged a.mus.v.mus.

44. 2. Effects on autorhythmicity K channel conductance of the cell membrane of the fast response autonomic cells acceleration of spontaneous diastolic depolarization, autorhythmicity

45. The Membrane Potential of Purkinje’s Fiber 3 4 0 1 2 4 max.diast.potential normal hypokalemia

46. 3. Effects on conductivity Amplitude and rapidity of phase 0 depolarization smaller than normal conductivity

47. Cardiac arrhythmias due to increased excitability, shortened ERP, prolonged SNP, increased autorhythmicity and decreased conductivity

48. The conducting system of the heart

49. a: effective refractory period; b: relative refractory period c: supranormal period RMP and AP of a Ventricular Muscle Cell of the Heart

50. conductivity and cardiac arrhythmias —— reentry of excitation

51. Schematic diagram showing reentry of excitation in a Purkinje’s fiber-ventricular muscle circuit (1) normal (2) conduction slowed down (3) monodirectional block stalk ventricular muscle stalk branch A branch B ventricular muscle conduction slowed down monodirectional block + (4) Ventricular premature excitation resulted from reentry of excitation action potential monodirectional block reentry of excitation ECG

52. 4.Effects on contractility increased in acute hypokalemia, decreased in chronic hypokalemia

53. Effects on the Kidney functional and mosphological changes

54. Effects on Metabolism carbohydrate metabolism, protein metabolism, acid-base balance

55. Effects on the Nervous System documented symptoms, contradictory reports

56. Principles of Prevention and Treatment Ⅰ. Measures against the causes Ⅱ. Replacement therapy with potassium 1.Oral replacement: 40~120mmol of K/day 2.IV instillation: KCl≤40mmol/L, ≤10mmol of K/h Never inject! Never inject! Monitor serum [K + ] and ECG

57. Hyperkalemia serum [K + ]>5.5mmol/L, serum [K + ]>5.5mmol/L, a medical emergency a medical emergency

58. Etiology and Pathogenesis  Inadequate excretion of K Renal failure, hypoaldosteronism, K sparing diuretics  Redistribution of K in the body tissue injury, acidosis, insulin deficiency, familial hyperkalemic periodic paralysis  Increased intake of K—rapid IV K administration

59. Effects on the Body Ⅰ. Effects on neuromuscular excitability In mild to moderate hyperkalemia the ratio of [K + ] i to [K + ] e RMP less negative than normal, excitability abnormal sensibility (paresthesia), diarrhea Severe hyperkalemia, RMP decreased to level of TMP, depolarization block muscle weakness, paralysis, dizziness, coma

60. Ⅰ. Effects on neuromuscular excitability Ⅱ. Effects on the heart 1.Effects on excitability In mild to moderate cases, excitability, phase 0 upstroke smaller and slower; Phase 2 plateau prolonged, phase 3 repolarization shortened In severe cases, no AP can be induced cardiac arrest Effects on the Body

61. Ⅰ. Effects on neuromuscular excitability Ⅱ. Effects on the heart 1.Effects on excitability 2. Effects on autorhythmicity K channel conductance, autorhythmicity

62. Ⅰ. Effects on neuromuscular excitability Ⅱ. Effects on the heart 1.Effects on excitability 2. Effects on autorhythmicity 3.Effects on conductivity a smaller and slower phase 0 upstroke conductivity Effects on the Body

63. Ⅰ. Effects on neuromuscular excitability Ⅱ. Effects on the heart 1.Effects on excitability 2. Effects on autorhythmicity 3.Effects on conductivity 4.Effects on contractility high serum [K + ] inflow of [Ca 2+ ] contractility Effects on the Body

64. Ⅰ. Effects on neuromuscular excitability Ⅱ. Effects on the heart Ⅲ. Effects on acid-base balance  ECF [K + ] secretion of insulin and aldosterone ECF [K + ] shifted into cells while [H + ] move out  ECF [K + ] Na + -K + exchange in renal distal tubules and secretion of H +  ECF [K + ] renal NH 4 production, acid retention metabolic acidosis Effects on the Body Effects on Acid-Base Balance

65. Principles of Prevention and Treatment Restriction of K intake, control of underlying diseases, insulin + glucose, use of Ca 2+ and Na + to counteract K, bicarbonate infusion, ion-exchange resin, dialysis