THE HYPERKALEMIC SYNDROMES

Transcription

1 THE HYPERKALEMIC SYNDROMES

2 K + BALANCE Cells (3400 meq) ECF (60 meq) External K Pump insulin catechols Na intake Leak K ph; osmolality membrane integrity distal Na + renal { delivery output aldosterone lumen voltage

3 TWO KINDS OF HYPERKALEMIC SYNDROMES Fiber Activation Threshold Disorder Skeletal muscle TTX - sensitive - 60 { periodic paralysis heart generally unaffected Myocardium TTX - insensitive - 75 { cardiac standstill rare skeletal muscle paralysis

4 RENAL HANDLING OF K + I. Complete proximal reabsorption II. Aldo-mediated principal cell secretion

5 THE CCD PRINCIPAL CELL Na amiloride K Cl 2K ATPase - 20 mv - 80 mv 0 mv K Cl 3Na Predominant in late DCT and CCT Aldosterone- responsive Sensitive to: amiloride triamterene spironolactone

6 ENaC Epithelial Na Channel Each α subunit : amiloride-sensitive Na channel β and γ subunits: surface delivery of ENaC Liddle's syndrome: β subunit mutation pseudohypoaldo I: α or β subunit mutation ARDS : α subunit mutation News in Physiol. Sci. 12:55, 1997

7 MAJOR CAUSES OF HYPERKALEMIA I. Diminished Renal Excretion Reduced GFR ATN ESRD Reduced Tubular Secretion Addison s disease DCT disease Principal cell disease Potassium - sparing diuretics II. Transcellular Shifts Acidosis Cell destruction HPP Diabetic hyperglycemia Insulin - dependence plus aldosterone lack Depolarizing muscle paralysis

8 DISTAL CONVOLUTED TUBULE DISEASE GORDON S S SYNDROME (PSEUDOHYPOALDOSTERONISM II) 2K Na 3Na Cl aldo Cl K WNK 1, 4 mutations activate thiazide-sensitive NaCl transporter shunt Cl permeability; paracellin-mediated Na avid Cl V M K, H secretion: CCT low renin hypertension responsive to diuretics, Na restriction

9 GORDON'S SYNDROME A DCT DISEASE WNK: with no lysine WNK I: NCC activity WNK IV: function unknown Yang et al. JCI 111:1039, 2003

10 HYPERKALEMIC RTA SYNDROMES PRINCIPAL CELL DISORDERS DISORDER PRINCIPAL DEFECT PRINCIPAL FEATURES Pseudohypoaldosteronism I Interstitial disease Closed Na + channel Hyporeninemic hypoaldosteronism K + ; Na + wasting; RTA K + ; Na + wasting; RTA

11 PRINCIPAL CELL DISEASES Na + CHANNEL BLOCKADE (PSEUDOHYPOALDOSTERONISM I) Na 2K 3Na K Cl aldo K Cl Na Channel Blockade: Prototype: amiloride Rx Na wasting V M K, H secretion Aldosterone unresponsive α or β subunit mutations in ENaC

12 PRINCIPAL CELL DISEASES HYPORENINEMIC HYPOALDOSTERONISM (GENERALIZED DISTAL NEPHRON DISEASE) Na 2K 3Na K aldo Cl K Interstitial renal disease renin, aldosterone Na wasting Cl V M K, H secretion low renin hypertension furosemide benefits

13 TREATMENT REGIMENS FOR HYPERKALEMIA K + REMOVAL KAYEXALATE: APPROXIMATELY 1 meq K / Gm RESIN HEMODIALYSIS: (30-50 meq / MINUTES) K + CLEARANCE: 200 ml / MINUTE (85 meq / HR) PERITONEAL DIALYSIS: K + CLEARANCE: ml / MINUTE K + ENTRY INTO CELLS ( meq / HR) ALKALINIZATION: 0.6 meq K + / 0.1 ph UNIT GLUCOSE AND INSULIN: 0.5 meq K + / 25 Gm GLUCOSE

14 CARDIAC PROTECTION IN HYPERKALEMIA Ca ++ SCREENING OF SURFACE POTENTIAL

15 TWO KINDS OF HYPERKALEMIC SYNDROMES Fiber Activation Threshold Disorder Skeletal muscle TTX - sensitive - 60 { periodic paralysis heart generally unaffected Myocardium TTX - insensitive - 75 { cardiac standstill rare skeletal muscle paralysis

16 HYPERKALEMIC PERIODIC PARALYSIS A SKELETAL MEMBRANE DISORDER TTX - sensitive Na + channel mutations Chromosome 17 mutation HPP } allelic variants paramyotonia Human form: : often with familial inbreeding Equine form: inbred quarter-horses HPP: episodic; may occur with normal K + levels paramyotonia: : cold-sensitive K-sensitive; acetazolamide-responsive

17 PROPERTIES OF SOME Na + CHANNELS TTX - SENSITIVE TTX - INSENSITIVE Primary location Brain, Muscle Heart Activation voltages (mv)

18 THE GREAT HODGKIN-HUXLEY HUXLEY CONTRIBUTION Membrane potential Ionic fluxes Gating of channels Other stimuli Other transport mechanisms CLASSICAL CYCLE OF ELECTRICAL EXCITATION

19

20

21

22

23

24

25

26

27 CATION CHANNEL KINETICS

28 Na + CHANNEL INACTIVATION: KEY FEATURES 1. INACTIVATION IS NOT, STRICTLY, VOLTAGE - DEPENDENT 2. ACTIVATION GATES MUST OPEN BEFORE INACTIVATION GATES CLOSE 3. THE SEEMING VOLTAGE-DEPENDENCE OF INACTIVATION RELATES TO THE VOLTAGE- DEPENDENCE OF ACTIVATION GATE OPENING

29 VOLTAGE-GATED CATION CHANNELS Ptáček Am. J. Med. 104:58, 1998

30 SODIUM CHANNEL ACTIVITY: NORMAL RESTING OUT IN ACTIVATION V M = - 90 V M ~ + 20 LOW P Na HIGH P Na REPOLARIZATION INACTIVATION V M ~ - 70 LOW P Na V M ~ LOW - 50 P Na

31 HYPERKALEMIC PERIODIC PARALYSIS A SKELETAL MEMBRANE DISORDER TTX - sensitive Na + channel mutations Chromosome 17 mutation HPP } allelic variants paramyotonia Human form: : often with familial inbreeding Equine form: inbred quarter-horses HPP: episodic; may occur with normal K + levels paramyotonia: : cold-sensitive K-sensitive; acetazolamide-responsive

32 THE MAGNIFICENT FLAWED THOROUGHBRED Scientific American May, 1991

33 Pillars of the STUD BOOK James Weatherby, 1791 Godolphin Arabian 1725 Darley Arabian 1688 Byerley Turk 1690

34

35 THE GREAT RACES Scientific American May, 1991

36 QUARTER HORSES 1. Sprint races ~ 0.25 miles 2. Primarily aerobic 3. Selective in-breeding: very muscular 4. Continued in-breeding: HPP Laryngeal neuropathy Yearling osteoarthritis

37 THE HYPP INDEX HORSE

38

39

40

41 SODIUM CHANNEL ACTIVITY: HPP RESTING OUT IN ACTIVATION V M = - 90 V M + 20 LOW P Na HIGH P Na HPP : TTX - SENSITIVE MUSCLE FIBERS 1. FAILURE OF INACTIVATION GATES TO CLOSE 2. PERSISTENT TTX - SENSITIVE i Na

42 Na + CHANNEL DEFECT IN HPP

43 TWO KINDS OF HYPERKALEMIC SYNDROMES Fiber Activation Threshold Disorder Skeletal muscle TTX - sensitive - 60 { periodic paralysis heart generally unaffected Myocardium TTX - insensitive - 75 { cardiac standstill rare skeletal muscle paralysis

44

45 PARTIAL DEPOLARIZATION INACTIVATES CARDIAC ACTION POTENTIAL TSIEN & HESS, 1986

46 THE CARDIAC ACTION POTENTIALS GATING Ca ++ Na + Na + Ca ++ Na + Na + TSIEN & HESS, 1986

47 SODIUM CHANNEL ACTIVITY: HYPERKALEMIA RESTING OUT IN ACTIVATION V M = - 70 LOW P Na CARDIOTOXICITY V M LOW - 20 P Na 1. K + DEPOLARIZES V M 2. ACTIVATION GATES PARTIALLY OPEN 3. INACTIVATION GATES CLOSED 4. i Na BLOCKED

48 Na + CHANNELS SKELTAL MUSCLE TTX SENSITIVE CHANNEL LOW ACTIVATION VOLTAGE CARDIAC INSENSITIVE HIGH VOLTAGE

49 SODIUM CHANNEL ACTIVITY: NORMAL RESTING OUT IN ACTIVATION V M = - 90 V M ~ + 20 LOW P Na HIGH P Na REPOLARIZATION INACTIVATION V M ~ - 70 LOW P Na V M ~ LOW - 50 P Na

50 SODIUM CHANNEL ACTIVITY: HPP RESTING OUT IN ACTIVATION V M = - 90 LOW P Na V M + 20 HIGH P Na HPP : TTX - SENSITIVE MUSCLE FIBERS 1. FAILURE OF INACTIVATION GATES TO CLOSE 2. PERSISTENT TTX - SENSITIVE i Na

51 SODIUM CHANNEL ACTIVITY: HYPERKALEMIA RESTING OUT IN ACTIVATION V M = - 70 LOW P Na CARDIOTOXICITY V M LOW - 20 P Na 1. K + DEPOLARIZES V M 2. ACTIVATION GATES PARTIALLY OPEN 3. INACTIVATION GATES CLOSED 4. i Na BLOCKED