MUNI MED Consequences of K and Ca dysbalances on V and (m Jaromir Gumulec - Depolarisation, - electrical activation of muscle cells - Movement of Na, K, Ca CI across cardiac membranes - Repolarisation - Electrical deactivation 2 https://step1 .medbullets.com/cardiovascular/108015/myocardial-action-potential MUNI MED Potential changes - Movement of ions into and out of cells creates voltage difference across membrane - negative resting membrane potential - SA node -50 to -60 mV - AV node -60 to -70 mV - myocardial cells -80 to -90 mV - Driven by - Na/K ATPase contributes to the negative resting potential - The chemical gradient driving K+ out of the cell. - The electrical gradient pulling K+ back into the cell as the inside becomes more negative. - At equilibrium, K+ is the most permeable ion at rest (due to K+ leak channels). - If more negative (by decrease of extracel. K+) „hyperpolarisation" 3 MUNI MED Phases of action potential -During depolarisation: - cell inside becames less negative (more positively charged move to cell) - When threshold potential is reached, cardiac action potential is fired. - Treshold = temoraly disrupted membrane selectivity - Phases: - Phase 0: depolarisation: rapid Na+ entry to cell - Phase 1: early repolarisation: slow Ca enter to cell - Phase 2: plateau: slow Ca, Na enter to cell, - Phase 3: repolarisation: K out - Phase 4: return to resting membrane potential K* Na Ca" 'frak currents' MUNI MED QRS 0.2 0.4 0.6 Seconds In SA and AV: slow phase 0, lack of plateau - Slow inward current by slow Ca channels (block by verapamil slow heart rate https://www.semanticscholar.org/paper/Mechanisms-of-Excitation-and-Remodelin O%E2%80%99Connell/f5decafd0bebbaf2a80699c6a83de8ca389fd8e2/figure/0 g-of-the-in- MUNI MED mV < o o Cl $ O ■z. •< cc CQ LU 1Í 0 Purkyňova vlákna Pracovní myokard SA uzel -100 200 eflux IC repolarizace rychlý influx Ca2+ depolarizace 1? 0 li pomalý influx Na4 prepotenciál 400 AV uzel (nodální část) 600 —I- 800 ms eflux repolarizace pomalý influx CaJt depolarizace, zpomalení vedení 100 200 300 ms 100 200 300 ms m V l Pracovní myokard 0. -20. -40. -60- -80. -100- eflux rť"—- eflux časná repolarizace lí re polarizace S\ 0 depolarizace rychlý influx NaJ hlavní iniciace depolarizace 1 100 200 300 ms MUNI ED Goldbergová Gumulec Patfyz v obrazech - Stimulation of SA by sympathetic system - increases heart rate - Induce increased Ca2+ influx, which intreases contractile strength 7 Define footer - presentation title / department MUNI MED Potassium - Ratio of ICF to ECF K+ is major determinant of resting potential Q excitability - Shift to cells: Insulin (stimulate Na/Kpump), adrenaline, alkalosis Shift outa cells: insulin deficiency, aldosteron deficiency, some types of acidosis, cell lysis, insensive excercise - Block entry to cells: glucagon - Promote K excretion: Glukocorticoids, aldosterone - K is intracellular - difficult to measure -120 J-1 Normal K+ Low K+ High K+ Koeppen & $tanton: Gerne and Levy Physiology, 6th Edition, Copyright © 2006 by Mosby, an imprint of Elsevier, Inc. All rights reserved MUNI MED 30 _ 0 > E lij 1 -30 - CD o Cl CD c CO £ CD -60 -90 -■ Action potential i Normal threshold ■Resting Potasium - hypokalemia (simple) - more negative resting membrane potential (-90 to -100 mV): -decrease of excitability: |» weakness, smooth muscle atony, -delayed V repolarisation Q Risk of Dysrythmias - Q ECG decreased T, ST depression, U increase, - in severe hypokalemia peaked P, prolonged QT 9 MUNI MED Potasium - hypokalemia (detailed) - ECF hypokalemia can develop without losses of total body K+ - decrease of excitability: - (m skeletal muscle weakness, smooth muscle atony, cardiac dysrythmias,... - If: more negative resting membrane potential (-90 to -100 mV): hyperpolarised membrane require greater stimulus to trigger AP - V hypoK also delays (ventricular) repolarisation Q fail to conduct impulses efficiently Q Risk of Dysrythmias (sinus bradycardia, AVblock) - Repolarisation relies on K efflux: - Reduced extracellular K+ slows K+ efflux during repolarization. Q prolongation of the action potential duration, and delayed V repolarization. Q ECG decreased T, ST depression, U increase, in severe peaked P, prolonged QT. D arrytmias Re-entry, EAD MUNI 11 Na K ATPase X K efflux - in hypokalemia, the decreased extracellular potassium does reduce the activity of the Na+/K+ pump (Na7K+-ATPase). However, this reduction in pump activity does not fully counteract the effects of slower K+ efflux during repolarization Delayed rectifier K+ channels (l_Kr and l_Ks) are the primary drivers of repolarization in cardiac myocytes during Phase 3 of the action potential. - The Na+/K+ pump, while affected by hypokalemia, plays a much smaller role in repolarization dynamics compared to these K+ channels. iPhast? 1 . Phaseo .tffect 'we Refractory Periaf?\ \ ;Phase 4 Na' Ca Ca . ■ r Na leak currents' Potassium - Hyperkalemia - increased Cl neuromuscular irritability - Mild: more rapid repolarisation (smaller distance of Em and Et) Q narrow, taller T, short QT - Severe: delayed V conduction Q preventing repolarisation Q ST depression, PR prolongation, QRS widening, - prolonged hypopolarization/partial depolarisation Q voltage-gated sodium channels (Na+ channels) become inactivated □ cardiac arrest. For these channels to reset and become available for the next action potential, the membrane potential must be sufficiently negative during resting conditions - Excitability determined by KECF/K|CF Q manifestation in acute disorders, gradient normalises in chronical ones! - Long-term increases in KECF results in shift of K to ICF Q KECF/K|CF normalised 12 MUNI MED Potassium and acidosis - Acute acidosis: - H+ accumulate in ICF.(unless anion portion of acid - acetoacetate, lactate - entered cells), imbalance occur, to maintain balance, K leaves cells Q hyperkalemia - Acute alkalosis 13 MUNI MED -co 'u c CD O Q. E ■-o mV +30 1 -90 1 -120 ' TEZKA HYPOKALEMIE < 2,5 mmol/L o — -30 ' -60 1 MIRNA HYPOKALEMIE < 3,5 mmol/L IE NORMOKALEMIE 3,5 - 5,1 mmol/L MÍRNÁ HYPERKALEMIE 5,5 - 6,5 mmol/L Te STREDNETEZKA HYPERKALEMIE TEZKA HYPERKALEMIE 6,5-7,5 mmol/L snazší depolarizace snazší repolarizace vyšší excitabilita obtížnější repolarizace nižší excitabilita snazší depolarizace snazší repolarizace vyšší excitabilita obtížnější otevírání Na kanálů ji - - 44E -E„ prodlouženi • ™ t : -: -i I i excitabilita obtížnější repolarizace snížená excitabilita > 7 mmol/L TTT Em E > E p m žádná excitabilita 1 neutečení Na kanálů neschopnost depolarizace žádná excitabilita co c -i dl c deprese ST prodloužení PQ rozšířeni QRS oploštění T zvýraznění U m V -100 Em fibrilace komor arytmie (komorové extrasystoly) junkční až idioventrikulární rytmus sinusová bradykardie arytmie 1 svalového tonu zácpa únava -50 není substrát pro Na-K pumpu (selhává perm eabilita \ membrány pro K'} 1 10 100 Kalémie m M J\--/ r v V v v úzké hrotnaté T zkrácení QT fibrilace komor idioventrikulární rytmus riziko re-entry tachy prodloužení PQ ... až vymizeni P rozšíření QRS deprese ST ... až sinusové vlny izoelektrická linie fibrilace komor arytmie (komorové extrasystoly) riziko re-sntry tacby junkční až idioventrikulární rytmus zástava srdce v diastole Goldbergová Gumulec Patfyz v obrazech ED Calcium - Ca2+ x HPO4- = constant - Serum free Ca pH-affected - Acidosis: ionized Ca increases ( H+ binds to albumin QCa released (competition with albumin) - Effect on £§ initiation of action potential - primarily in excitable membranes of neurons and £ -Effecton - # muscle contraction - Duration of action potential (repolarisation) 15 Normal Low High High Low (K+) (K+) (Ca+t) (Ca--) MUNI McCance Pathophysiology . . _ _ Calcium: Hypocalcemia (simple) - Increase of £l neuromuscular excitablity -weaker V contraction - prolonged QT 16 MUNI MED Calcium: Hypocalcemia (detailed) - D Increase of % neuromuscular excitablity, because - Ca+ stabilize the voltage-gated sodium channels - With fewer calcium ions stabilizing the sodium channels Q Na ch destabilisatoin Q Hypopolarisation Q smaller stimulus needed Q Partial depolarisation of nerves and muscles - Paresthesias, spasms, hyperreflexias - Lower ECF Ca Q lower Ca influx to ICF through L channels Q - Q Weaker Ca efflux from sarcoplasmatic reticle Q weaker V contraction - D Prolonged repolarization (less Ca2+ is available to balance K+ efflux during plateau Q longer action potential Q prolonged V depolarisation Q prolonged QT - Specific to cardiac muscle, where calcium influx is directly responsible for contraction strength and the plateau phase of the action potential. MUNI MED Feature Skeletal Muscle Cardiac Muscle Source of calcium for contraction Mostly from the sarcoplasmic reticulum (SR) From both extracellular calcium and SR Role of extracellular calcium Minimal, primarily stabilizes membrane potential Essential for triggering calcium-induced calcium release (via ryanodine receptors (RyR2) Effect of hypocalcemia No effect on contraction strength, but increases excitability Weakens contraction and prolongs repolarization (QT) In 18 Hypocalcemia affects membrane excitability, not the intracellular calcium release machinery MUNI MED Calcium: hypercalcemia (simple) -stronger V contractility - Shortening QT, depression of T -In decreased excitability QFatigue, weakness, letargy, anorexia, constipation, nausea 19 MUNI MED Calcium: hypercalcemia (detailed) - In V ECF Ca increased Q greater influx of Ca ro cells (L channels) - Plato phase acceleration Q increased calcium-induced calcium release (CICR) (from SR) Q stronger V contractility - Hypercalcemia increases the rate of calcium reuptake by the sarcoplasmic reticulum +exchanger. Q faster repolarisation + shorter plateau Q Shortening QT, depression of T - In t contraction strength is not directly dependent on ECF Ca - (contraction relies on intracellular calcium released from the SR) - Elevated ECF Ca increases the stabilization of voltage-gated sodium channels, making them harder to activate Q Treshold becomes more positive (hyperpolarisation) Q decreased excitability - Fatigue, weakness, letargy, anorexia, constipation, nausea MUNI Effect Cardiac Muscle Skeletal Muscle Increased ECF Ca2+ CICR Enhanced CICR —> stronger contraction (positive inotropy) Little to no effect on CICR, as calcium entry plays a minimal role in skeletal muscle contraction. Effect on Plateau Phase Faster calcium uptake/release —► shortened QT interval and faster repolarization. N/A (no plateau phase in skeletal muscle action potentials). Reduced Excitability (Hyperpolarization) Stabilized Na+ channels —> reduced excitability, slower AP conduction (arrhythmias possible). Stabilized Na+ channels —> reduced excitability, leading to fatigue and weakness. Overall Contractility Increased strength of contraction (positive inotropy). No significant increase; reduced excitability dominates, causing weakness. MUNI MED N) N) pnend. |olv„rd hough nu, Jw>p ^ HKtors contributinn .„ ,1,, j , l,?L^ *«lopmM, „f hypokalemia ° have inad I (SAwwd'byJM diets, food iusecu "om the cell into ,heECF """"inniiied. but Ihe mourn age tubes, fistulae, excessive ingestion if black licorice, andlaxa-Hve'overuje'can all result in hypokalemia. Normally, only 5 to 10 mEq of potassium and approximately JOOml. of water are excreted in the stool each day. With diarrhea, fluid and electrolyte losses can be voluminous, with several liters of fluid and 100 ,"200 mEq of K+ lost per day. Vomiting ™» gastric suction frequently is associated with V deplehon. The occurs in part because of the K* lost ,l > However, the low principally is caused by rcn«j S**tr'^fl for volume depletion and metabolic alkalosis C°I1,I,*W* secondary (o lasses of sodium, chloride, and loss of fluid and sodium stimulates the secretion1^'11 which in turn results : m»y occur ln p„ ,e . ™ ■ * dlciary deficiency of K* rich fruits ad vcKcablc ttH >"•*<<■: ofpolassium- "ty, or lack of ,„C" ™il br W ""is. food insecu. ^dividual, with ""'^ ^ I™""*)- " i"t°l« generally CT7 J*""8 diS°r*rs- A K* causes of K- depleHoT " ^ «*» ™^T*P — -» bo*. ™ shifts fron, fh t t t rr" 'yP? ' »n. to m,u„a,n the p,Ll ac fbl"'^1^hyd™8" ECF hvdroi.,„ „ , bi" balance. In alkalosis, sis and K° ^ T 'he '° co"«' ulkalo- insulin promotes cellular uptakeofK.,a„d insuiin adminislra-n°,kea„nf ?T "-iE i'0,"SiUm *** P-'-'arlyw," he eva, . 8 "rb"ll>,Jr«"; *»*. For this reason, it is crucial to evaluate potassium status i„ emergency settings when treating a person will, diabetes who presents with severe hyperglycemia and/or diabetic ketoacidosis (DKA). Failure tt do so before administering IV insulin can result in life-threatening hypokalemia. Treating DKA typically requires administration or supplemental potassium simultaneously with IV insulin and rehydration therapy. With DKA, the overall insulin deficit results in potassium shifts from the ICF to the ECF, due to lack of insulin action on the Na*-K* ATPasepump. A normal serum potassium level usually is maintained; however, potassium excretion through the kidney continues, resulting in a deficit of total body potassium. The deficit becomes clinically evident when insulin treatment and rehydration therapy arc initiated. Accordingly, in the treatment of hyperglycemia with or without DKA, the standard of care is potassium supplementation with close monitoring. Treatment of pernicious anemia with vitamin Bu or folate also may precipitate hypokalemia if the formation of new red blood cells causes enough K* uptake to effect an extracellular decrease in K* concentration. Familial hypokalemic periodic paralysis is a rare genetically transmitted disease that causes K* to shift into the intracellular space with episodes of extreme muscle weakness. Losses of K* from body stores are most commonly caused by •gastrointestinal and renal disorders. Diarrhea, intestinal drain . ...___.■___rLl__L li^An/ii Qiirl lava allossofK*. """'^O Renal losses of K* are related to increased sec the distal tubule. Predisposing factors include the ^^"i, ics, excessive aldosterone secretion, an increased d**^*^ flow rate, and a low plasma magnesium concent ^ ^ diuretics inhibit the reabsorptiori of sodium chlf?'*0"-Si, ing in increased urine production. With enhanced fl^' '*v* tion, the increased flow through the distal tubule al ^ % potassium excretion. If sodium loss is severe, the c ° ^^^"^ aldosterone secretion (which causes secondary h rorusm) may further deplete K+ stores. Primary hvT^'^ ronism with excessive secretion of aldosterone Irorn adenoma also causes K' wasting Many kidney tW Ihc kidney's ability to conserve audiuni. The rieaeav,! ""^ reabsorptioii produces a diuretic clfect. .As a increased flow through the distal tubule promote the*"'1' ^ of-K*. Magnesium deficiency increases loop of Henk i^T*S*, potassium secretion, causing secondary hypokalemia " s-T* medications, including amphotericin B, gentamicm cillin. cause hypokalemia by increasing the rate of L. ? excretion. Rare hereditary defects in renal potassium trs (Earner and Giteiman syndromes) also can result in hvrjTi! mia (Table 3.9). Clinical Manifestations. Mild losses of K* are 14.^1 asymptomatic. With severe hypokalemia (<2.5 mEqi'L), ntnj! muscular excitability decreases, causing skeletal musclt ness, smooth muscle atony, cardiac dysrhythmias, ghet* intolerance, and impaired urinary concentrating ability. Symptoms occur in proportion to the rate of potassnm; depletion. The body can accommodate slow losses of potassium Decreases in the ECF potassium concentration may facilitat; TABLE 3,9 Causes of Potassium Alterations Hypokalemia <3.5 mEq/L Decreased intake, starvation or eating disorders. inadequate (eplacemeni Increased renal loss, renal concentrating defect, closing diuretics. hyperaidosteroni5m. vomiting, diarrhea, use of specific medical ions Shift from ECF 10 ICF metabolic alkalosis, insulin administration, gene mutations in K" transport Hyperkalemia >5 0 mEq/L__; Loss Excess dietary or intravenous intake Decreased renal loss, oliguric renal disease, K*-Sparing diuretics, liypoaldosteronisrn LShift from ICF to ECF: some types of metabolic acidosis, massive cell injury or death____^ ECF, Extracellular fluid; ICF, intracelluiar fluid; K: potassium. Cellular CHAPTER 3 The Cellular ElMmNnM* a -—---- ronrr>*n1- n"'di end EUttrotwtem. Acid, .net Bases v from the intracellular spacr and into the ^t***'""1 emotes the return of the potassium con-^ ^P djU*1111' Lward a more normal status, reducing ncu-lcF on f!f!,dif"1 lS Villi iituie and severe potassium loss, o*Pilar sTmpl0" musculBT excitability are more profound. "■""■Tntf* Wiefl initially occurs in the larger muscles feS S** WCs"nd Ultimo1? *«Kts the diaphragm, com-Pfcstf*1'^ With severe losses, paralysis and respira-ES ■**J r. Loss of smooth muscle tone may result |fS>" nwV ^trointeslinal manifestations such as consti-|fln«ri«|V 0 , intention, anorexia, nausea, vomiting, and >"1 inte*1"1 ■ ,;c nf the intestinal muscles). Table 3.10 ^^^^^ofK-aheraUons. O153 511,11 II il- .rfhVP^letma are related to changes in cardi*c f • As ,]W BCF potassium concentration .-.k* eXCi'a& Y< ___^rtrtt^nrinl hminiR mure ncora. r. membrane potential bt ^,'^SS",, from -90 to -100 millivolts): A U* i'<-^membrane requires a greater stimulus to tri^e* hrrxrP01"1 I IHiK 31tr5' ("otassiurn also contributes to the „, actio" P016" haje Qf (he action potential, hypokalemia delays f^^^lariiJlion' Consequently, hypokalemia may result in various dysrhythmias, including sinus bradycardia wrioventTieTilaT block, and paroxysmal atrial tachycardia. The characteristic changes in the dectrrxardios-ram (tCG) relied rfrlayeJ wnlricuW r.fwiariijiw,, yviib flowed conduction and pacemaker activity. The impliUifW ot the i wave decrraw*. the amplitude of the U wave increases, and the SI- segment is depressed (Hg. 3.q) In •evere Males of hypokalemia. P waves' P«k, the QT interval is prolonged, and T-wave ,-.. .-i -..ms may be seen. Hypokalemia enhances the therapeutic effect of disjl-lalis by slowing the Na'-K' pump and excessively intreasing intracellulu calcium and sodium concentrations. The risk ol digitalis toxicity is increased. Concurrent alterations in pkumn cdJcium coinrenrrdrion also contribute to changes in neuromuscular excitability associated with hypokalemia Increases in ECF calcium concentration tend to make the threshold potential (E) less negative. The result is decreased membrane excitability and potentiation of hyperpo-laniiation, amplifying the neuromuscular effects of hypokale mia (see Fig. 3.8C). A wide range of metabolic dysfunctions may result from potassium deficiency. Carbohydrate metabolism i* affected. Hypokalemia depresses insulin secretion and alters hepatic and skeletal muscle glycogen synthesis, Renal function is impaired Postural hypotension Dysrhythmias ECG changes (Battened T waves. U waves. ST depiession, peaked P waw, prolonged QT interval) Weak, irregular pulse rate Ventricular fibrillation Lethargy Fatigue Confusion Paresthesias Decreased tendon reflexes Nausea and vomiting Decreased motility Distention Decreased bowel sounds Dysrlivthfrias ECG changes(peaked T waves, prolonged F^irnerval.aDieirtP wave with widened DPS corncaex) Bradycardia Heal block Cardiac arrest Anxiety Tingling Numbness Nausea and vomrung Early Diarrhea Early. Colicky pain Sköeteiand trnooth rnjstie Inability fo concentrate urine Oliguria Water loss Kidney da Thirst Kidney damage Weakness Flaccid paralysis Respiratory arrest Constipation Bladder dysfunction tarty hyperactive muscles and reflexes SLats weakness and flaccid paralysis fCG. Electro JULIA L. ROGERS : UI.MIA.S I. l!.K,V-HEK> Well, McCance is very concise in terms of channel mechanisms - and this is totally enough! MUNI ED JJNPTI The Cell PoWips/a (increased lh|™* Cmaus,nS Polywa (increased unne). r potassium into the DKA, are often accompanied by hyperkalei may result secondary to digitalis toxicity High inhibit the Na*-K* ATPase transport pump, J, to remain outside Ihe cell. I tiJ.i hypokalemia is can result from disor-from shifts of extracel- Decreased renalfunction is Mm ionly ■Btpifl <30ml./h) "»ciaied recti ng these have "Placing Iom pota^siu^ " Z! 'Spaf Tremmen, involves the anocbtcd^ IT '° "*'ont "or""l Wi and been cordeda"dba" ""'»'•"^ On, «rracting 1 Id vTn^l™ '°" Sh°Uld f*™"" T should ^«co^d^f!?™^ W»<™- i-dividno.' "nal function, ,^ ZT "T ,"Ch f°°ds' With rJ'LZn icrrl , rCl,rren' ™'h h>T»™6neSer„ia is refractory ,„ rrealmenl uniil magnesium levels are copied. Hyperkalemia Palhcphysiolog,. Hyperkalemia is defined as » ECF potas- ^""•"•rvlS ions of serum K* concentration. The Severn is a function of the amounl of K* intake t^^*6 mEq/L) causes delayed cardiac conduction pt ^ ^"JStefe***0* of heart muscle. There is a decrease' US* tion velocity, depressed ST segment, prolonged PR *" and widening of the QRS complex (loss of atrial (see Fig. 3.9). Brady dysrhythmias and delayed condurS are common in hyperkalemia; severe hyperkalemia ventricular fibrillation or audiac-arrest. Changes in the ratio of intracellular to extracellular K* con centration contribute to the clinical presentation of hypericalt ^.mia (see Table 3.9). If extracellular K1 concentration increases without a significant change in intracellular K+ concentratm, the resting membrane potential becomes more positive (t^ changes from -90 to -80 millivolts) and the cell membraneB _ hy popularized (the inside of the eel! becomes less negatrnn partially depolarized increased excitability)) (see Fig. IMl With mild elevations in extracellular K* concentration, ihcci more rapidly repolarizes and becomes more irritable (peaked L waves). An action potential then is initiated more rapidly because the distance between the resting membrane potra tial and the threshold potential has been decreased. H'rtfc more severe hyperkalemia, the resting membrane potential approaches or exceeds the threshold potential (wideQRSmcrj ing with T wave). In this case the cell is not able to repolaiiw and therefore does not respond to excitation stimuli/me most serious consequence is cardiac arrest. Like the effects of hypokalemia, the neuromuscular effects the ECF of hyperkalemia are related to the rate of increase in potassium concentration and the presence of othercontriW hypokalemia may develop if Ihe excreted K< is not replaced. ing factors, such as acidosis and calcium balaraflBP In states vtJcUostM hv-dT^fW-rmrr-srrit^^ increases in ECF potassium concentration result in eJ^l^elU^n^Z, the-anion portion-of the ,„,o the cell because the tendency .to "-^•T-jS ,Jl"f enters cells- therefore hyperkalemia and acidosis often of intracellular/ex.racellular potassium "oce^rafio— Z^JtL. **ZL££F°*T Of ^ — elevahonsofe^racellularK-concentratlonaffectneur^ ouemlyX"/." defied which occur with conditions such as lar irritability because this ra„o ,s disrupted. CHAPTEB 3 Tha Callul,, Envi.onm.nl; Fluid. ,r,d BMmM„ Acid, and Base, inlluences the HireshuM potential, ,1 (jtitaBAration can augment, or over-^'"ili E^^hyperkalemia. With hypocalcemia the M*to .j becomes more negative, enhancing ihe lid* 1 jd po,en'cts 0f hyperkalemia. Hypercalcemia causes ^te*tl0tlsCul»rC ua| to become less negative, counteract-l(n .Mid P°tCr (r](a|emia on resting membrane potential show a Tteatment. Hyperkalemia ' clinical settings (e.g., renal c ' ""'^j fi^lencV, Addison disease, u common disease, massive of potassium some types of metabolic acidosis). How E"^*Bte* °'evolve often is a function of the underly-FUr ^^'^ECG will identify conduction abnormalities or Eibytlu0**; of hyperkalemia includes both treating the ^ sun»Ben,e es and correcting excessive potassium con-_nmt>ulin6 " ^i.-ne the extracellular potassium concentra p& no-1 EeW1" Adrnin's,rall0and^,in^stratlon 0f gjucose and insulin for those jjcrtion, or a ^ ceuu|ar entry of potassium. Renin-^ diabet"jdosiet0ne system inhibitor therapy and use of Lotensin- jum hinders optimize therapy. Buffered solutions jetton >,orn""'Jw°th a variety of methods; the treatment rt the cause and severity of the problem, be administered to restore membrane jiti 8luC°"*scruril potassium levels are dangerously high, biliiyira |uCOSe, which readily stimulates insulin removes potassium in cases siurn level. Dialysis effectively renaldysfunction. Calcium and Phosphate The total body content of calcium is approximately 1200 g. Most calcium (99%) is located in bone as hydroxyapatite (in inorganic compound that contributes to bone rigidity), ,nd the remainder is in the plasma and body cells. The total fraction of calcium circulating in the blood is small (9.0 to 10.5 mg/dL), and approximately 50% is bound to plasma proteins, primarily albumin. Approximately 40% is in the free or ionized form (5.5 to 5.6mgydL)- Ionized calcium has the most important physiologic functions. Approximately 20% of ingested calcium is absorbed in the small intestine, primarily in the duodenum. Calcium (Ca2+) is a necessary ion for many fundamental metabolic and cellular processes. In bound form, it is the major cation associated with the structure of bones and teeth. The ionized form serves as an enzymatic cofactor for blond clotting and is required for hormone secretion and the function of cell receptors. Plasma membrane stability, permeability, and repair are directly related to calcium ions, as is the transmission of nerve Impulses and the contraction of muscles. Calcium metabolism "linked to phosphate and magnesium metabolism. pJosphaie (HPO,) is found primarily in bone (85%), with jailer amounts found within the intracellular and extracel-^ spaces. In the plasma, phosphate exists in phospholipids -Phosphate esters and as inorganic phosphate, which is the iortl?er, torm, Jht iinrmjl serurn k-vt-k h.uc range from 2Tin 4.5 mg/dL and may be as high as 6.0 to 7.0 mg/ dL in infants and young children. Intracellular phosphate has many metabolic form*, including the high-energy tfroc-tures creatine phosphate and adenosine In phosphate (.fifV). Phosphate acts as an intracellular int' «rtracel\ular anion buffer in the regulation of acid-base balance; in the form of ATP, It provides energy far muscle contraction. Calcium and phosphate concent rations are rigidly controlled. They are related by the product of calcium and phosphate (HPO.,) concentrations, which is a constant IK) lCai+) X HPO; = K],1hus, if the concentration of one ion increases or decreases, that of the other normally increases or decreases. Calcium and phosphate balance is regulated by three hormones; parathyroid hormone (EXH}. vitamin -D, and cakilu-nin. Acting together, these substances determine the amount of dietary calcium and phosphate absorbed from the intestine, the deposition and absorption of calcium and phosphate from bone, and the renal reabsorption and excretion of calcium and phosphate by the kidney. The parathyroid glands secrete PTH in response to lew-levels of scrum calcium (The specific actions of PTH in relation to calcium and phosphate are described in Chapter 21.) Parathyroid hormone (PTH) controls levels of ionized calcium and phosphate in the blood and other ECFs. Renal regulation of calcium and phosphate balance requires PTH. PTH stimulates reabsorplioti of calcium aloug the distal rcbulr of the nephron and inhibits phosphate reabsonpiion by the proximal tubule of the nephron. The net result is an increase in serum calcium concentration and increased urinary excretion of phosphate. Fig. 3.10 summarizes hormonal regulation of calcium. Another compound important to calcium and phosphate regulation is vitamin D. Vitamin D (cholecakiferol) is a fat-soluble steroid ingested in food or synthesized in the skin in the presence of ultraviolet light. Several steps of activation arc required before vitamin D can act on target tissues. The hist step occurs in the liver; final activation is in the kidney. Ihe renal activation of vitamin D begins when the serum calcium level T Renal activation of vitamin D 1 intestina', absorption ot calcium i t Renal teabscxpiion of calcium \ and " excretion o! phosphate I T Bona resorption of calcium | Fig. 3.10 Hotmonal Regulation ot Calcium Balance. PTH, Parathyroid hormone. MUNI MED JÜÜE/Th.cil Lfít_v Ýftf íílv n,J, decreases and s ™i°n ollou-cate " , ' "eti J"">»Pta min D ,- ■caJcitrio]) then d 1>.:J1,C PTH then acts to J£, decrease in the tontemration of ionized calciu nan«rend excretion of % juratory alkalosis causes symptoms of hyB0^J*e&W F!l Il!^ls- 7be c°mW- ^ the change in pH enhances protein bindC secretion causes : change in pH ť dum. Hypoalbui protein binding lowers total serum ">. loop-Jiuretics) H^mragnesemia^S-OnnEq/Ll o!i(junc renal disease; also excessive intake of tnagnesiutn-containing anocids. 3*enal insirfficiencY Increased neuronkiKulai ewitatnlir/. iinrjlinrj. iiln»p— ■ IpaHitularfv in feei, and facial musclesl miewinal cramping, fiycaeclne tntmem. With elevated serum calcium occurs°c en-a redproca^ decrease in serum phosphate values in, „ 11KlSc dia!tIosti' procedures to identify the contribut-SPIlMlogiccondition are required. Treatment is rehted to the severity of symptoms and the underlying disease. When renal function is normal, oral phosphate administration is effective. When acute illness and high ciikiun 1 levels are present, treatment options include IV administration of large amounts of normal saline to enhance renal excretion of calcium, administration of bisphosphonatesj in the absence of renal dysfunction, and administration of calcitonin. Bisphosphonates and denosumab are used for malignancy-associated hypercalcemia, and cinacalcet is approved for the reduction of hypercalcemia associated with parathyroid carcinoma.15 Ultimately, the underlying pathologic condition must be treated. Hvpophosphatemia Pathophysiology. Hypophosphatemia is, a serum phosphate level less than Z.OmgML and is usually an indication of phosphate deficiency. In some conditions, total body phosphate concentration is normal, but serum concentrations are low. The most common causes are intestinal malabsorption and increased renal excretion of phosphate- Inadequate absorption is associated with vitamin D deficiency, use of magnesium- and UNI ED Excitation-Contraction Coupling E-C coupling refers to the entire process by which an electrical signal (excitation) is translated into a mechanical contraction of the muscle. 1. Excitation: An action potential travels along the muscle cell membrane (sarcolemma) and into the T-tubules. 3. Calcium Release: •Cardiac muscle: CICR occurs—calcium entry via DHPR triggers calcium release from the sarcoplasmic reticulum (SR) through ryanodine receptors (RyR2). •Skeletal muscle: Calcium release is directly triggered by mechanical coupling between DHPR and RyR1 on the SR membrane, independent of extracellular calcium influx. 2. Trigger Signal: •In cardiac and skeletal muscle, this signal opens L-type calcium channels in the T-tubule membrane. 4. Contraction: The released calcium binds to troponin C, initiating the interaction of actin and myosin, leading to muscle contraction. 26 MUNI MED Calcium-Induced Calcium Release CICR is a specific mechanism where calcium influx through L-type calcium channels acts as a trigger to release more calcium from the sarcoplasmic reticulum via ryanodine receptors. •Occurs in: •Cardiac muscle: CICR is the main mechanism by which calcium is released from the SR. The calcium entering the cell during the action potential (via L-type channels) amplifies calcium release from the SR. •Smooth muscle: CICR also plays a role in smooth muscle contraction, depending on the specific tissue. •Does not occur in skeletal muscle: In skeletal muscle, calcium release from the SR is mechanically coupled to L type Ca channels, without requiring calcium entry from the extracellular space. MUNI MED