Acid-base balance importance, Defense against changes in Hydrogen ion and Threats of pH

The normal pH of arterial plasma = 7.4 ± 0.02, the pH of venous plasma and of interstitial fluids= 7.38 ± 0.02 because of the extra quantities of carbon dioxide that form carbonic acid in these fluids, Acidosis is present when arterial pH falls below 7.38 and alkalosis when the arterial pH rises above 7.42.

Hydrogen ion balance

Hydrogen ions are the most reactive cations in body fluids, and they interact with negatively charged ions of other molecules, such as those of body proteins, Interactions of hydrogen ions with negatively charged functional groups of proteins can lead to marked changes in protein structural conformations with resulting alterations in the behavior of the proteins.

Alterations in the structural conformations and charges of protein enzymes will obviously affect their activities, with resulting alterations in the functions of body tissues, The absorption, and efficacy of drugs administered by the physician may also be affected by the pH.

PH = log 1/(H⁺ conc) = – log H⁺ concentration

Extreme changes in the hydrogen ion concentration of the body can result in loss of organ system function and structural integrity; under acute conditions, arterial pH above approximately 7.80 or below 6.9 is not compatible with life, Control of pH is necessary because of the marked effects of pH changes on protein conformation, enzymatic reactions, and central nervous system function.

Threats to PH

The major threats to the pH of the body fluids are acids formed in metabolic processes, These metabolic acids can be divided into three categories.

Volatile acids: Carbon dioxide

CO₂, a major end product in the oxidation of carbohydrates, fats, and amino acids, can be regarded as an acid because of its ability to react with water to form carbonic acid (H₂ CO₃) which in turn can dissociate to form H⁺ and HCO₃:

CO₂ + H₂O ⇔ H₂CO₃ ⇔ H⁺ + HCO₃⁻

CO₂ adds approximately 10.000 mmol. of H⁺ to the body fluids per day.

Fixed acids

Sulphuric acid and phosphoric acid

Sulphuric acid is an end product of the oxidation of sulphur-containing amino acids, methionine, and cysteine. However, phosphoric acid is formed in the metabolism of phospholipids, nucleic acids, phosphoproteins, and phosphogly cerides, In contrast to CO₂, sulphuric acid and phosphoric acid are non-volatile, They result in the formation of 50-100 mmol. of H⁺ /day.

Organic acids

Lactic acid, acetoacetic acid, and B-OH-butyric acid are formed during the metabolism of carbohydrates and fats. Normally, these acids are further oxidized to CO₂ and H₂O and therefore do not directly affect the pH of the body fluids. However, in certain abnormal circumstances, these organic acids may accumulate causing acidosis.

1. In hypovolemic and other forms of circulatory shock, lactic acid levels may accumulate due to inadequate perfusion of tissues resulting in an increase of anaerobic glycolysis (lactic acidosis).
2. In uncontrolled diabetes mellitus, acetoacetic acid and B-OH-butyric acid may accumulate due to increased lipid metabolism (diabetic ketoacidosis).

Defense against changes in H⁺ concentration 

1. Acid-base buffer systems in body fluids.
2. The respiratory system.
3. The kidneys.

The buffer systems can act within a fraction of a second, The respiratory system takes 1-12 minutes to act, The kidneys though the most powerful require several hours to several days to readjust the H⁺ concentration.

Acid-base buffers

An acid-base buffer is a solution containing a combination of two or more chemical compounds that prevent marked changes in hydrogen ion concentration when either an acid or a base is added to the solution. An acid is a substance that can add hydrogen ions to a solution. A base is a substance that combines with hydrogen ions in a solution and will thereby remove them.

The bicarbonate buffer system

A typical bicarbonate buffer system consists of a mixture of carbonic acid (H₂CO₃) and sodium bicarbonate (NaHCO₃) in the same solution. Carbonic acid is a very weak acid. When a strong acid, such as hydrochloric acid, is added to a bicarbonate buffer, the following reaction takes place.

HCI + NaHCO₃ ===> H₂CO₃ + NaCl

From this equation, it can be seen that the strong hydrochloric acid is converted into very weak carbonic acid, Therefore, the HCI lowers the pH of the solution only slightly. On the other hand, if a strong base, such as sodium hydroxide, is added to the same bicarbonate buffer solution, the following reaction takes place:

NaOH + H₂CO₃ ===> NaHCO₃ + H₂O

The net result is the change of the strong base NaOH for the very weak base NaHCO₃, Fortunately, this buffer is present in all the body fluids, both extracellular and intracellular, and it plays an important role in maintaining normal acid-base balance.

The phosphate buffer system

The phosphate buffer system is composed of a mixture of acidic phosphate H₂PO₄⁻ (Na di-hydrogen phosphate: NaH₂ PO₄) and alkaline HPO₄⁻-(Na mono-hydrogen phosphate: Na₂H PO₄). The phosphate buffer system is more effective in ICF than in ECF, since:

1. The total concentration of phosphate is much greater in ICF than ECF.
2. The intracellular pH is somewhat lower than the extracellular pH and therefore is closer to the pka of the phosphate buffer, (pka = 6.8).

The phosphate buffer system is also effective in buffering the tubular fluid in the kidneys because:

1. Phosphate becomes greatly concentrated in the tubular fluid due to there absorption of water in excess of phosphate.
2. The pH of the tubular fluid is more acidic than the pH of ECF and therefore is closer to the pH of the phosphate buffer.

Protein buffer system

• The plasma and the intracellular proteins.
• Hemoglobin: Hemoglobin is a major buffer in the blood. Once hemoglobin becomes deoxygenated in the capillaries, it is more able to bind the H⁺ ions formed when CO₂ enters capillary blood from tissues. Thus, hemoglobin helps to minimize the fall in pH caused by the loading of CO₂ into capillary blood.

Respiratory regulation of acid-base balance

The lungs regulate the pH by regulating the partial pressure of CO₂ in arterial blood. When the blood carbon dioxide concentration increases, the PCO₂ in both the interstitial fluid of the medulla and the cerebrospinal fluid also increases, The CO₂ immediately reacts with water to form carbonic acid, and carbonic acid dissociates into H⁺ ions and HCO₃⁻.

Thus H⁺ concentration increases in the chemoreceptors of the medulla oblongata and stimulates alveolar ventilation by direct action, Moreover, the increase in arterial PCO₂ stimulates alveolar ventilation indirectly through the chemoreceptors in aortic and carotid bodies.

When the blood CO₂ concentration increases in the medulla oblongata, more H⁺ appear in the chemoreceptors reaction than when the blood hydrogen ion concentration increases, as H⁺ ions do not easily cross either the blood-barrier or the blood cerebro-spinal fluid barrier.

The decrease in arterial pH that occurs independently of an increase of arterial PCO₂ stimulates the chemoreceptors in the carotid bodies. However, a decrease in PCO₂ and H⁺ concentration will decrease ventilation, Respiratory regulation of the pH is effective but almost never complete. Respiratory control returns the hydrogen ion concentration 50-70% to normal.

Renal regulation of blood pH

The kidneys regulate the blood pH by secretion of hydrogen ions and by regulating the concentration of HCO₃⁻ in plasma.

1. Tubular secretion of hydrogen ions

The epithelial cells of the proximal, distal tubules and collecting ducts all secrete hydrogen ions into the tubular fluid.

2. Regulation of plasma HCO₃

The kidneys regulate the plasma HCO₃⁻ by two mechanisms:

• Reabsorption of the filtered bicarbonate.
• Generation of new bicarbonate.

Reabsorption of the filtered bicarbonate

1. Step 1: Blood CO₂ is in equilibrium with CO₂ in the tubular cells. In the cell, CO₂ reacts with H₂O in the presence of carbonic anhydrase to form carbonic acid, Carbonic acid dissociates into hydrogen ions and bicarbonate ions.
2. Step 2: The hydrogen ion is secreted from the brush border of the tubular cell into the tubular fluid by sodium-hydrogen counter-transport (to maintain electroneutrality inside the tubular cells).
3. Step 3: In the tubular fluid, hydrogen ions are buffered with the filtered bicarbonate forming carbonic acid, This carbonic acid is dissociated to form CO₂ and water, The CO₂ molecule moves across the tubular epithelium.
4. Step 4: The bicarbonate ion generated in step 1 passes passively across the tubular cell membrane to the peritubular fluid accompanied by the reabsorbed sodium ion, In this way, filtered sodium bicarbonate is returned to the blood.

Generation of new bicarbonate

The kidneys generate HCO₃⁻ to replace the HCO₃⁻ lost in buffering the various strong acids formed in the body. About 100 mmol of H⁺ is added to the body fluids each day from the fixed acids produced during metabolism. The body’s buffer systems, particularly the bicarbonate buffer, provide the most immediate defense against this H⁺. For example, sulphuric acid produced during the metabolism of sulphur-containing amino acids is buffered by HCO₃⁻.

H₂SO₄ + 2NaHCO₃ → Na₂SO₄ + 2H₂CO₃ → Na₂SO₄ + 2 CO₂ + 2H₂O

CO₂ formed in this reaction is eliminated by the lungs. The net result of the reaction is the loss of two HCO₃ ions from the body, which must be replaced by the kidneys.

The main buffer in the tubular fluid is the bicarbonate buffer (HCO₃⁻). However, since the reaction between H⁺ and HCO₃⁻. results in the reabsorption of filtered HCO₃⁻, excess H⁺ must be excreted by combining with non-bicarbonate buffers in the tubular fluid, the most important of which are ammonia and phosphate.

Ammonia

Ammonia (NH₃) is a highly effective buffer for secreted H⁺, NH₃ is synthesized and its concentration in the epithelial cells increases, it diffuses out of the cells, Although it can diffuse into either the tubular lumen or the peritubular capillaries, its diffusion into the lumen (I.e. NH⁺ secretion) is favored because the secreted NH₃ immediately reacts with previously secreted H⁺ to form NH₄⁻.

Ammonium ion, due to its electrical charge, combines with a chloride ion forming ammonium chloride which is very weakly acidic, Sodium-ion is exchanged with hydrogen and is absorbed into the blood as a new sodium bicarbonate, From this reaction 2 NH₃ molecules are formed and 2 new HCO₃⁻ are generated and enter the blood.

Sufficient NH₃ is therefore secreted to react with virtually all the secreted H⁺ that cannot be buffered by the low-capacity phosphate buffer system, allowing the 50-100 mmol of excess H⁺ that must be excreted per day to be excreted with a minimum fall in the tubular fluid pH. The formation of NH₃ in the epithelial cells increases in acidosis and decreases in alkalosis.

Phosphate

In the distal nephron, the phosphate concentration in the tubular fluid is significantly increased due to the reabsorption of water in excess of phosphate. Sodium mono-hydrogen phosphate (Na₂HPO₄) changes to the more acidic sodium di-hydrogen phosphate (Na₂HPO4). One sodium ion is replaced by one hydrogen ion secreted by the tubular cells.

Sodium ion is reabsorbed with the generated bicarbonate into the blood. Thus, for each hydrogen ion combined with phosphate, one molecule of new sodium bicarbonate is added to the blood. In a normal man, the amount of phosphate delivered to the distal nephron allows only 12-40 mmol of H⁺ to be excreted as Na₂HPO₄ each day. However, the amount of available phosphate remains relatively constant even in acidotic conditions.

Variations in urinary pH

Urinary pH ranged from 4.5-8; pH 4.5 is the limiting pH, which is the minimal pH of urine below which no H⁺ secretion can occur.

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