D fini n tion: p = = -log [H+] ph=7 me m an s 10-7 Mol M H+ + (100 nmol m /l); ) p ; H=8 me m an s 10-8 Mol M H+ + (10 (10 n nmol m /l) Nor

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1 Definition: ph regulation ph = -log [H + ] ph=7 means 10-7 Mol H + (100 nmol/l); ph=8 means 10 Normal plasma value: ; 7.45; (H Acidosis: ph<7.35; Alkalosis: ph>7.45 Intracellular ph = Mol H Mol H + (10 nmol/l) (H + : nmol/l) 6.8 =160 nmol 7.8 =16 nmol 7 =100 nmol 7.38 =41.6 nmol Venous blood 7.4 =40 nmol Arterial blood 7.5 = 31.6 nmol Significance of ph: It influences the activity and functions of enzymes, transporters and binding proteins => ph is a strictly regulated parameter. Page 1

2 Acidosis Alkalosis Glycolysis Gluconeogenesis DNA synthesis/cell proliferation Hb oxigen binding Plasma protein dissociation (Ca 2+ binding) K + channel permeability (depol) (hyperpol) Ca 2+ channel permeability Enzyme activity (except: pepsin) Gap junction (heart) Heart muscle contractility Vascular smooth muscle (local syst. Circ) vasodilation Cerebral vessels vasodilation vasoconstriction Chemoreceptor activation (syst. Circ) vasoconstriction Pulmonary vessels vasoconstriction vasodilation Page 2

3 The factors influencing ph Production of H + Volatile acid: CO 2 /H 2 CO 3-, (H + : 20 mol/day) Nonvolatile acids ( mol H + /day) Buffers Excretion of H+ through the lung and kidney Reabsorption, synthesis and/or secretion of HCO - 3 through the kidney The factors influencing ph Production of H + Volatile acid: CO 2 /H 2 CO 3-, (H + : 20 mol/day) Carbonic anhydrase CO 2 + H 2 O => H 2 CO 3- + H + (in tissues) HCO H+ => H 2 CO 3- => CO 2 + H 2 O (lung, kidney) Carbonic anhydrase H 2 CO 3- is equilibrated with CO 2 Page 3

4 The factors influencing ph Nonvolatile acids ( mmol H + /day) Fix acids phosphoric acid (phosphoprotein, phospholipid, nucleic acid) sulfuric acid (methionin, cystein metabolite) Organic acids Lactic acid (glycolysis) Acetoacetic acid, beta-hydroxybutyric acid Amino acids The factors influencing ph Buffers Definition: Weak acids or weak bases that limit the change of [H + ] by binding or detaching it. Buffer solution is able to retain almost constant ph when small amount of acid/base is added AH = H + + A - Acid = Hydrogen ion +conjugate base Page 4

5 Dissociation depends on the concentration of the buffer agent: J = k*[ah] Inverse: J-1 = (k-1)*[h]*[a] Constants: k and k-1 determining the speed of the reactions. They depend on the temperature and the types of the ions. They are independent from the concentrations. Page 5

6 In equilibrium J=J-1 k*[ah] = (k-1)*[h]*[a] /:(k-1) k*[ah]/(k-1) = [H]*[A] /:[AH] k/k-1 = ([H]*[A])/[AH] K = ([H]*[A])/[AH] /logarithm lgk = lg[h]+lg([a]/[ah]) /negative logarithm Henderson-HasselbachHasselbach equation: ph = pk + lg([a]/[ah]) If the ph = pka, the log of the ratio of dissociate acid and associated acid will be zero, => the concentrations of the two species will be the same. Thus, when the ph equals the pka, the acid will be half dissociated. Page 6

7 Buffer capacity Buffer capacity is a quantitative measure of the resistance of a buffer solution to ph change on addition of hydroxide ions. It is expressed as the concentration of acid (mmol/l) required to change ph by one unit. K p = [H]/ [H]/ ph It depends the concentration and the pk value of the buffer. Ideal buffer: pk is close to the normal ph High concentration Page 7

8 Buffers in the blood Total buffer amount: 45 mmol/l 1. H 2 CO 3 /HCO - 3 Low pk value (6.1), but the large volume => high buffer capacity cc: mmol/l Equilibrium: [CO 2 ]= [H 2 CO 3 ] (630) Both [HCO 3- ] and [CO 2 ] are changeable (kidney, lung) ph= lg [HCO 3- ] [H 2 CO 3 ] ph= =6.1 + lg20 ph= lg [HCO 3- ] 0.03*pCO 2 Buffers in the blood 2. Hemoglobin (histidine; N-terminals; pk 7.4) deoxigenated hemoglobin has a higher affinity for H + (higher pk) 3. Plasma proteins (histidine; N-terminal; pk 7.4) (protein matrix of bone) 4. H 2 PO 4- /HPO 2-4 (pk= 6.89) Page 8

9 1. H 2 CO 3 /HCO 3- pk= Proteins (pk 7.4) 3. H 2 PO 4- /HPO 2-4 (pk= 6.89) Intracellular buffers Page 9

10 Buffers in the urine Daily nettó H + excretion: mmol (Free H nmol/l at ph=4.6) Urine ph: H 2 CO 3 /HCO NH 3 /NH + 4 (pk=9.25; 1:60 at ph=7.4) NH 3 /NH + 4 : production from glutamine in the proximal tubule NH 3 lipophylic NH 4 hydrophylic The synthesis of NH 3 is regulated by ph (glutaminase glutaminase) 3. H 2 PO 4- /HPO 2-4 (pk: 6.89) 4. Organic acids and bases Without buffers 2667 l urine should be excreted. Page 10

11 H + turnover Production of CO 2 : 20 mol/day Production of acids: mmol/day Excretion: 1. CO 2 : through the lung 2. H + : through the kidney: Free H nmol/l at ph=4.6; binding to NH 3 and NaHPO 4 Change in extracellular fluid ph caused by increased or decreased rate of alveolar ventilation, expressed as times normal. Page 11

12 The factors influencing ph The role of the lung in the acid-base balance Effect of blood ph on the rate of alveolar ventilation. Page 12

13 The role of the kidney in the acid-base balance Free filtration of HCO 3- (28 mmol/l; 4320 mmol/day day) 1. HCO 3- reabsorption (99.9%: 4300 mmol/day) together with H + secretion 2. HCO 3- synthesis together with H + secretion 3. HCO 3- excretion in alkalosis (ONLY) - distal tubule H + secretion Na + /H + exchanger (90%) H + -ATP-ase (10%) The factors influencing ph Reabsorption of bicarbonate in different segments of the renal tubule. Page 13

14 Hydrogen ion secretion in the proximal tubule, the thick ascending segment of the loop of Henle, and the early distal tubule. Primary active secretion of hydrogen ions through the luminal membrane of the intercalated epithelial cells of the late distal and collecting tubules. Page 14

15 Buffering of secreted hydrogen ions by filtered phosphate (NaHPO 4- ). Production, transport, and excretion of NH 4+ by the nephron. The secreted NH 4+ is reabsorbed by the thick ascending limb => accumulation in the medullary interstitium, where it exists as both NH 4+ and NH 3. NH 3 diffuses into the tubular fluid of the collecting duct, and binding to H + leads to accumulation of NH 4+ in the lumen. Page 15

16 Acid-base abnormalities Base excess: The amount of acid (in mmol) required to restore 1 litre of blood to its normal ph, at a PCO 2 of 40 mmhg. Normal value: 0 Standard bicarbonate: HCO 3- value at normal pco 2 (40 mmhg). Metabolic/respiratoric acidosis/alkalosis Causes: Excess H+ production: Metabolic acidosis skeletal muscle work, hypoxia => e.g. lactic acid overproduction diabetes mellitus => ketone bodies overproduction of acids: poisoning excretion of H+: renal diseases diarrhoea; side effects of carbonic anhydrase inhibitors Ingestion of Inadequate excretion Loss of HCO 3- : diarrhoea ph= lg [HCO 3- ] 0.03*pCO 2 Characteristics: 1. ph (<7.35) 2. Standard bicarbonate 3. pco 2 : normal 4. Base excess: negative Page 16

17 A. Compensation Lung => Hyperventilation Characteristics: 1. ph 2. Standard bicarbonate 3. pco 2 4. Base excess: negative B. Recovery Kidney H + secretion HCO 3- reabsorption + therapy of the original disease Metabolic acidosis Metabolic alkalosis Causes Loss of acids (vomitus) Infusion or ingestion of alkalis ph= lg [HCO 3- ] 0.03*pCO 2 Characteristics: 1. ph (>7.45) 2. Standard bicarbonate 3. pco 2 : normal 4. Base excess: pozitive Page 17

18 A. Compensation Lung => hypoventilation Characteristics 1. ph 2. Standard bicarbonate 3. pco 2 4. Base excess: pozitive B. Recovery Kidney: H + secretion HCO 3- reabsorption HCO 3- secretion + therapy of the original disease Metabolic alkalosis Respiratory acidosis Causes: Respiratory abnormalities (e.g. lung diseases) excessive production of CO 2 by aerobic metabolism. Page 18

19 Respiratory acidosis ph= lg [HCO 3- ] 0.03*pCO 2 Characteristics: 1. ph (< 7.35) 2. Standard bicarbonate: normal 3. pco 2 (>45 mmhg) 4. Base excess: 0 Respiratory acidosis A. Compensation: Kidney H+ secretion HCO 3- reabsorption Characteristics: 1. ph 2. Standard bicarbonate 3. pco 2 4. Base excess: pozitive B. Recovery: Lung: hyperventilation + therapy of the original disease Page 19

20 Causes: Respiratory alkalosis hyperventilation (anxiety, hysteria, CNS disturbances, asthma) ph= lg [HCO 3- ] 0.03*pCO 2 Characteristics: 1. ph (>7.45) 2. Standard bicarbonate: normal 3. pco 2 (<34 mmhg) 4. Base excess: 0 A. Compensation: Kidney H + secretion HCO 3- reabsorption HCO 3- secretion Characteristics: 1. ph 2. Standard bicarbonate: 3. pco 2 4. Base excess: negative B. Recovery: Respiratory alkalosis Lung: hypoventilation + therapy of the original disease Page 20

21 E.G. ph = 7.1 PCO 2 = 22 mmhg BE = -21 mmol ph = 7.5 PCO 2 = 48 mmhg BE = +11 mmol Page 21