MUNI MED Disorders of osmolarity and ionic balance 1 t—i—i—i—1-1-1—i—j—i—i—i—- 2 4 0 a Birin 6m. 1£m. 3/. 6y. 9y. 12y. 15y. Adult _ AGE Compartments of body water © PhysiologyWeb at www.physiologyweb.com • Extracellular fluid (ECF-approx. 1/3) • Plasma • InterstJtJum • Lymph has a composition corresponding to interstitial fluid • Transcelullar fluid (CSF, eye fluid, effusions in pathological conditions) • Primary urine actually acts as transcellular fluid as well Composition of ICF and ECF ICF: more proteins, K+, Mg2+, fosfáty (H2P04~/HP042~); Ca2+ is located in specialized compartments ECT: Na+, Ca2+, CI", HC03- (alkalic environment) plasma contains more proteins compared to interstitial and transcelullar fluid Same osmolarity (285-295 mosmol/l - a portion of proteins + phosphates in ICF is insoluble, as well as Mg2+ on the cationic side; in the ECF this concerns only a little amount of Ca2+ and proteins) 20Í - W. - 195 -H,COj CI' Car" HCO, A:: I:. Ciilnn:; Aninns Plij™ HCO," W,1 Parameter ECF Plasma CSF Na+(mEq/l) K+(mEq/l) Ca2+(mEq/1) kig2+(mEq/l) CI- (mEq/1) HCCy (mEq/1) Lh P^CmrnHg) PC02(mmHg) Glucose (mg/ml) Osmolality (mOsm kg"1 H20) Temperature (°C) 136-145 3.5-5 3.4 1.50-2.5 110-118 22-28 7.35-7.45 35 39.5 70-110 280-296 36.6-37.3 150 4.6 4.7 1.6 105.0 24.8 7.38-7.42 A-WB 75-100 A-WB 35-45 A-WB 70-110 280-296 37.0 147 2.9 (0.62) 2.3 (0.49) 2.2 (1.39) 120 (1.14) 25.1 7.4 42 50.2 64 289 37.7 -EdisseiuU'Fiji.j- litorsliul FljO lA-WB: Arterial whole blood; ECF (extracellular fluid ) and CSF (cerebrospinal flurd) values different from plasma are indicated in bold font. hlsroelijlsr F lud Agnati etal., 2017 Osmosis - water transfer in changing osmolarity Cell in hypotonic environment o o 0 o o o 0 o 0 o c o o o° • 280 . mmol/l c 6C * 0 O ( 260 mmol/l e c c D O e c o e o o e ° o o 8 o o o° ft c « . 260 . mmol/l 0 % H20 e c o t o c o °o r c • * J o c e o o o e ° c o 6 e ° Solute concentrations in ECF and ICF will reach balance through water influx ° o o o o o o Cell in hypertonic environment o c e o Solute concentrations in ECF and ICF will reach balance through water efflux o o o Extracellular solutes Intracellular solutes Osmolarity and osmolality • Osmolarity - concentration of osmotically active particles (per a unit of volume) • 1 mol of NaCI disociates into na 1 mol of Na+ and 1 mol of CI" and has thus the same osmolarity as 2 mols of glucose • Osmolality - similar, but calculated per a unit af mass • In practice, both values are similar in highly diluted water solutions • Osmotic pressure - n = R.T.I(c.i) • Estimation of overall body osmolarity based on plasma solutes: 2Na+ + 2 K+ + urea + glucose • i.e. double of plasma cations + neutral substances • the principle of elecroneutrality : CI" a and other anions are evened up by HC03" and vice versa, which has consequences for ABB, but not for osmolarity • natremia is therefore the main factor of plasma osmolarity Tonicity (effective osmolarity) • Osmolarity of solutes, which don't pass through a membrane and generate thus osmotic pressure (i.e. they are osmotically active) • Substances that passes membranes: • Blood gases - non-polar • Ethanol • Urea - polar, but has many channels (like water) • artificial phospholipid bilayer: 0=0,95 • most membranes and capillary wall: a<0,l • hematoencephalic barrier: o=0,5 (danger in rapid correction of uremia -> cerebral oedema) • Cells contain many osmotically active anions and they must expend energy for 3Na+/2K+ ATP-ase, which maintains the same tonicity at both sides of the membrane Regulation of osmolarity and circulating volume • RAAS (esp. angiotensin ll/lll and aldosterone) - increases circulating volume and maintains osmolarity Na+ and water), + vasoconstriction • ADH (V2 receptors) - decreases osmolarity by pure water reabsorption in kidney collecting ducts water), + vasoconstriction (high levels - shock) • Natriuretic peptides - decrease circulating volume (4^ Na+ and water), + vasodilation Natriuretic peptides ANP - stored in granules of atrial cardiomyocytes - „rapid reaction substance" in ^ venous return BNP - mainly ventricular cardiomyocytes (and brain), no storage, long elimination halftime - chronic heart failure (marker) CNP - vascular endothelium - only vasodilation, no natriuretic effects Urodilatin - alternative (longer) transcript of the ANP gene, paracrine action in the kidneys Internal Izatlon.1 clearance of peptides ;;tp Biological actions GTP eGMP Biologies! action?. Antidiuretic hormone Chemical Structures of Oxytocin and Vasopressin • Produced in nucleus supraopticus (SON) and nucleus paraventricularis (PVN) together with oxytocin, released from posterior pituitary (both hormones also act as neurotransmitters linked to social behaviour) • Hypothalamic "osmostat" and ADH • reacts to 1% deviation from baseline • ADH production is supressed by • lowering of osmolarity, alcohol, cold environment • Osmotic and volume balance is regulated mostly using the V2 receptors V2R OTR Oxytocin Via vascular smooth muscle,platelet, liver, brainstem ft Ig Cvasoconstriction, platelet agregation, glycogenosis AVP Vlb anterior pituitary gland, hypothalamus > V2 collecting duct (kidney), heart, pancreas water retention, stimulation of insulin synthesis Diabetes insipidus (DI) (a) central DI • damage of >85%ADH-neurons of PVN and SON posterior pituitary = i ADH (b) renal DI • caused by mutations in genes for ADH-receptors (V2) or aquaporin-2 = t ADH • diuresis up to 201/day (ii urine osmolarity/1 plasma osmolarity) • hypernatremia (Na >145mmol/l) • sensation of thirst and fluid intake may compensate D • But low fluid intake or low thirst sensation (hypodipsia, adipsia) dehydration threatens konc, ADH ' žízeň " PKA-CREB^^--------. 5'AMP \5^7 N CREB-j^--^--- AC VI ( Vasopressin Poly cystin 1 ligand unlB*'..--r pitu(l»ry Euvolemic/hypervolemic cancer patients have a high intracelular volume, while extracelular volume may be normal or mildly increased because of „syndrome of inappropriate antidiuretic hormone (SIADH)". ADH promotes water uptake in the distal tubule by binding V2 receptor. Mechanism of thirst is suppressed by low osmolarity (in lab. animals, this stops the water intake, humans tend to spontaneously continue drinking even in low osmolarity). SIA DH often develops in the tumours of lungs, pleura, brain or thymus (e.g. 10% to 45% of patients suffering from small-cell lung carcinoma have symptoms of SIADH. Iatrogenic causes: cytostatic drugs Hyper- and hypovolemia • Hypervolemia • systemic edema • pulmonary edema • hypertension • Hypovolemia • loss of skin turgor • hypotension, shock • renal failure (prerenal; urea:kreatinin > 100:1 Tonicity disorders and CNS • similarly to other cells, neurons and glia swell in hypotonic solution (danger of cerebral edema) and shrink in hypertonic solution (danger of demyelination) • in chronic conditions, neurons are able to compensate a difference in osmolariyty (tonicity) by the retention or increased removal of osmotically active solutes • following the rapid osmolarity correction (NaCI, loop diuretics), water may be transferred in opposite direction, which threatens by opposite disorder HCO3 RVI So'uto gar Cell shrinkage Organic Ositiot/tes RVD Solute loss Organic Osmolytes cr Organic Gsmoiytes (VSQAQ ~4P Normal cell volume Cell swelling loo Tdpid let^ydraS^n Disorders of volume and tonicity - causes • Hypoosmolar hyperhydration • Psychogenic polydipsia, SIADH, glucose solutions -> Glc metabolizsation • Isoosmolar hyperhydration • Heart failure, kidney failure, iatrogenic - isotonic ion solutions • Hyperosmolar hyperhydration • Kidney faliure, hyperaldosteronism, high NaCI intake • Hypoosmolar dehydration • Addison disease, overdose by loop diuretics, lack of NaCI in food • Isoosmolar dehydration • Bleeding, burns, ascites, severe (secretion) diarrhea • Hyperosmolar dehydration • Low water intake, diabetes insipidus, diabetes mellitus, osmotic diuretics (manitol), diarrhea Disorders of volume and tonicity © (Polydipsia) INSUFFICIENT RENAL H,0 EXCRETION Hypoproteinemi a ILO RETENTION Massive Na intake g SIADH © INSUFFICIENT RENAL HP EXCRETION SIADH g Failing heart INSUFFICIENT RENAL Na EXCRETION d " * Failing kidney (4-GFR) -1 NSAIDs' f T Mineralocorticoids © © ADH O^ ERCOMPEN-SATION LOSS OF Na MAINLY LOSS OF ISOTONIC FLUIDS I * Blood, plasma. m Renal losses m Osmotic diuresis Saluretics 4, Mineralocorticoids Diabetesjnsigklus^ © LOSS OF HYPOTONIC FLUIDS Sweat, vomits, diarrhoe n 3 M m G o i iE —I (inability to drink ion Plasma [mmol/l] ICT [mmol/l] Na+ 140 10 K+ 4,5 140 Ca2+* Mg2+* 1 8 ci- H2P04/HP042- * 1 40 HCO3- • * involves both ionized and bound form Examples of membrane transporters A and B are examples of membrone channels allowing the diffusion of X and Y along with their electrochemical gradients. C is an ionic pump exchanging solutes X a Y in opposite direction (which makes X an intracellular and Y an extracellular solute). D corresponds with secondary active exchanger (antiporter) changing Y ions for Z, which are thus transferred against their electrochemical gradient (a condition for this is a sufficient gradient of Y). Finally, E is a cotransporter, where Y and Z, which are transferred along with their electrochemical gradient, are accompanied by X, which goes against its gradient. This is also driven by the ionic pump creating a gradient of Y. In practice, X may be represented e.g. by potassium, Y by sodium and Z by chlorine or calcium The most abundant intracellular cation (98% intracellular) Most willingly passes cellular membrane Concentration gradient is maintained by Na+/K+ ATPase The extra/intracellular distribution is regulated by hormones (insulin, adrenaline, aldosterone) and pH (see further) Its total body content depends mainly on renal functions Both hyper- and hypokalemia are frequent conditions in clinical practice and both are proarrhythmogenic • Transcellular exchange of K+/H+, or eventually the K+ + HC03~ symport, act as a kind of buffer system allowing the binding/release of H+ ions, while maintaining electroneutrality • In practice, higher H+ in the circulation is linked to K+ transfer from the cells and vice versa • Analogically, e.g. hypokalemia in hyperaldosteronism may lead into metabolic alkalosis • Attention in rapid correction of ABB disorders - e.g. in chronic respiratory acidosis, kidneys compensate hyperkalemia by increased K+ excretion; following the correction, hypokalemia may occur due to K+ transfer inside cells (and posthypercapnic alkalosis with HC03~ excretion) Potassium and the membrane potential • Positively charged, intracellular ion: f concentration -> lowering of membrane polarity (more than corresponds with its change in ECF - analogy of a small and a large basin connected by a hose) • Various functionally different K+ channels • By various mechanisms, potassium increases the permeability of K+ channels • direct binding • competion with Mg2+ that closes the K+ channels • changes in expression and translocation Cardiomyocyte membrane potential Effect on sodium channels • Mild hyperkalemia - easier excitation • Severe hyperkalemia - block of a portion of Na+ channel • Slower conduction • Finally the threshold voltage „runs away" from baseline voltage and the depolarization is no longer possible • Mild hypokalemia - hyperpolarization • Severe hypokalemia - lack of substrate for the Na/K ATP-ase -> lower polarity, easier excitation Potassium - main effects on ECG • Hyperkalemia • Peaked T wave (dif. dg. hyperacute phase of Ml) • Wide QRS (may merge into sinusoid wave with T) • Widening, flattening and event, disappearing of the P wave (but sinus rhythm remains for a long time) • Higher excitability at the beginning, then lower, diastolic arrest in the end (heart is depolarized compared to the normal state) • risk of re-entry (^ differences in conduction velocities) • Hypokalemia • Flat, wide T-wave • Pathologic U wave (delayed repolarization), lengthening of QT (QU) interval • EAD, torsades de pointes • Sometimes, peaked P is present • 1s risk of re-entry (1s differences in refraktory periods) • First lower excitability (hyperpolarization), then higher Changes of ECG in hyper-/hypokalemia Periodic muscle paralysis in hypo- and hyperkalemia • heterogeneous group of diseases characteristic by transient attacks of muscle weakness (hours to weeks depending on type) • usually a hereditary disease • often caused by channelopathies (Na, K and Ca) • secondary periodic paralysis may occur in changes of K+ levels in both directions, thyreotoxicity (enhanced sodium-potassium pump activity) • mediated either by hyperpolarization or by continuous depolarization of the muscle cell, which is followed by Na+ channel deactivation • triggering factors: K+or sugar intake, decrease of K+, cold environment, muscular effort alternating with resting periods • Ion that is necessary for muscle contraction • Intracellular^ It Is present In very low concentration (making high gradient between cytoplasm and cell) • In cardiomyocyte and skeletal muscle, it is also present in sarcoplasmic reticulum • Cardiomyocyte (and smooth muscle cell) bears specific Ca2+-channels, that are necessary for phase 2 (plateau), pacemaker function and conduction through slow cells • They can be blocked by specific agents to slow the heart rate and enhance vasodilatation by smooth muscle relaxation Calcium and the membrane potential Extracellular ion - membrane potential gets into more negative values • More than expected based on the concentration, because Ca2+ binds to phospholipid bilayers and tends to concentrate in their proximity During the action potential, Ca2+activate potassium (and chloride) channels, which shortens the phase 2 -> repolarization leads into the closing of Ca2+ L-channels • the proces is impostant for maintaining the calcium homeostasis in the cell • in extreme hypercalcemia, phase 2 may be missing • opposite effect may be present in hypocalcemia Mechanical effects • Extreme hypercalcemia: triggered activity (DAD), systolic arrest (very rare) • Extreme hypocalcemia: triggered activity (EAD), hypocalcemic cardiomyopathy, heart failure ■ The Ca2+ channels-blockers mainly induce the conduction (SAorAV) node blocks and slower pacemaker function Calcium and tetany Physiologically, neurons have lower difference between resting and threshold membrane potentia compared to myocytes When Ca2+decreases, membrane potential locally shifts to more positive values, which leads into neuronal and muscular depolarizations Skeletal muscle cell has a short refractory period and the contraction starts after its end - new activation may thus occur during the contraction This leads into the summation of muscle contractions Tetany also occurs in alkalosis, when ionized Ca2+ decreases (Ca2+ competes with H+for protein binding), or in 4/Mg2+, when Ca2+decreases in the ECF (both locally and systemically 4/PTH) In hypercalcemia, excitability decreases with hyporeflexia or even coma (similarly to acidosis and tMg2+) Action potential in a neuron Hypocalcemia f excitability ON SWITCH - Calcium Influx induces an action,"on switch"eg; a thought, muscle nirtv;ii-:Mi -;t«:r~i el-: OFF SWITCH - Magnesium is shuttled out of the cell and blocks Calcium influx blocking the "on switch". Taurine holds Magnesium in the channel to enforce the Magnesium blockade. Chlorine and ABB Electroneutrality principle: positive charge in plasma = negative charge Cationic side: Na+, K+, Ca2+, Mg2+ • Relative fixed, rather long-term regulation Anionic side: CI", HC03", proteins, fixed acids • Strong link to AB Chlorine itself is fully ionized in the water solution and does not act as either donor or acceptor of H+ • but HC03" and fixed acids (part of anion gap) do Anions - Cations and the anion gap -m-■-1 m r JEHU Na - uc { 4. _ AG = AG = [(Na + K) - {CI + HCO3)] [HA - [CI + HC03)] Hyper- a hypochloremia • Is not a problem itself, Na+ and HC03" levels are key • If the changes of CI" levels are accompanied by corresponding adequate changes of Na+ in the same direction -> osmolarity disorder • E.g. loss of net water, Dl x SIADH • HC03" and anion gap do not change • On contrary „pure" change of CI" (without Na+) is always accompanied with changes of other anions • „Pure" hypochloremia -> 1^HC03" , metabolic alkalosis • Mental bulimia, secretion diarrhea with high losses of CI", Bartter syndrome in low renal Na+/K+/2CI" cotransporter aktivity • „Pure" hyperchloremia -> \|/HC03" , metabolic acidosis • Rapid administration of hyperchloremic saline solution („physiologic saline" has 154 mmol/l of both Na+ and CI", CI" thus increases more rapidly than Na+) Snímek 32 JM1 Jan Máchal; 29.05.2024 Secondary „pure" hyper- and hypochloremia „evens up"HC03~ or anion gap changes (electroneutrality principle) Hyperchloremia • Renal tubular acidosis -HC03" losses • Hyperparathyreosis - losses of the phosphate anion Hypochloremia • Posthypercapnic alkalosis following the rapid correction of chronic respiratory acidosis (tHC03) • Diabetic ketoacidosis - increase of ketone bodies (part of anion gap) with both CI" and HC03" losses