Henderson-Hasselbalch equation:

For carbonic acid/bicarbonate buffer system pK = 6.1.

The normal ratio of bicarbonate to dissolved carbon dioxide in plasma is (25 mmol/L)/(1.25 mmol/L) = 20/1. This equation shows any change in bicarbonate or dissolved CO₂ is accompanied by change in pH.  The numerator characterizes primary metabolic disturbance and is the renal component and denominator characterizes primary respiratory disturbance and is the respiratory component. 

The application of Henderson-Hasselbalch equation to human acid-base physiology can be illustrated by lever-fulcrum (teeter-totter) diagram:

 

BUFFER SYSTEMS AND THEIR ROLES IN REGULATING THE pH OF BODY FLUIDS

A buffer is a mixture of a weak acid and salt of its conjugate base that resists the change in pH upon the addition of acid or base. If acid and base components of buffer are equal, the pH is equal of pK. Generally buffer works best at pH ±1 unit of its pK. Buffer work best when the ratio of acid : base is within the range of 10 : 1 to 1 : 10. Buffers are also effective at higher concentration.

Alkaline pH of Blood: Benefits

Blood pH Level - The Benefits Of Alkaline pH Blood

We are all born with a very high alkaline blood pH of 7.4. Over the years as we age this pH level gets more acidic. An acidic environment is like a magnet for all diseases. It also speeds up the aging process. So if the aging process is to be slowed down and lost years regained then one must work towards an increased pH.

METABOLIC ALKALOSIS (PRIMARY BICARBONATE EXCESS):

Alkalosis occurs when excess base is added, elimination of base is impaired or loss of acid. Any of these can lead to primary bicarbonate excess, such that the ratio of bicarbonate/carbonic acid becomes >20:1. If severe alkalosis occurs there is tetany even calcium is normal. The cause of tetany is due to loss of ionized calcium due to increased binding of calcium ion by proteins (mainly albumin) and other anions. Measurement of Cl^- status is helpful, as cause of metabolic alkalosis fall into Cl^- responsive, Cl^- resistant, and exogenous base categories.

Chloride responsive metabolic alkalosis:

The cause of this condition is due to hypovolemia. When ECF is severely depleted, the resulting acid-base disorder is referred to as contraction alkalosis. Renal bicarbonate retention will occur in response to hypovolemia under the action of increased aldosterone. This will also result in increased reabsorption of sodium together with bicarbonate and excretion of K and H. The resulting hypokalemia contributes to alkalosis. Urine Cl^- will be <10 mmol/L as both available Cl and HCO₃ are reabsorbed with Na. Common cause of contraction alkalosis include prolonged vomiting, duodenal obstruction, villous adenoma (unregulated secretion of HCl) and use of diuretics.

Gastrointestinal loss of HCl: 

There is excessive loss of HCl from stomach and hypovolemia. In this hypochloremic, hypovolemic setting the kidney reabsorb Na to store volume and excess bicarbonate is reabsorbed in the absence of sufficient Cl^- to maintain electrical neutrality. In addition H⁺ and K⁺ are secreted in exchange for Na⁺. Urine Cl^- will be <10 mmol/L.

Diuretic therapy: 

Use of diuretics like Lasix, bumex blocks sodium, potassium and chloride reabsorption. These acts of ascending limb of loop of henle. The resulting increase in sodium concentration reaching the DCT, when combined with activation of renin-angiotensin-aldosterone axis, leads to increased urinary excretion of K⁺ and H⁺. This is commonly seen among patients abusing diuretics for the purpose of weight loss.

Chloride resistant metabolic alkalosis:

This is almost always associated with either an underlying disease (primary hyperaldosteronism, Cushing’s syndrome or Bartter’s syndrome) or with excess addition of exogenous base. In these conditions urine Cl will be >20 mmol/L.

During excess adrenocortical excess K and H are wasted by kidney due to increased Na reabsorption stimulated by elevated aldosterone or cortisol. The hypokalemia often contributes to alkalosis. The resulting decreased tubular K concentration stimulates ammonia production and thus renal H excretion and ammonium. This is accompanied by enhanced bicarbonate reabsorption. During primary and secondary hypoeraldosteronism, ACTH producing adenoma (Cushing’s disease), and primary adrenal adenomas producing glucocorticoid (Cushing’s syndrome) or aldosterone in these conditions there is increased mineralocorticoid, glucocorticoid, or both. The excess cortisol exerts a mineralocorticoid effect on the distal tubule aldosterone receptors.

Finally a rare etiology of Cl resistant alkalosis is a genetic (autosomal recessive) defect in Cl^- reabsorption within the thick ascending limb of loop of Henle, a condition known as Bartter’s syndrome.

Exogenous base:

It includes citrate toxicity following massive blood transfusion, iv therapy of bicarbonate solutions, ingestion of large quantity of milk and antacids in treatment of gastritis and peptic ulcers (milk-alkali syndrome).

Compensatory mechanism:

Respiratory mechanism:

The increase in pH depress respiratory center, causing hypercapnia, which in turn cause increase in cH₂CO₃ and cdCO₂. Thus the ratio of cHCO₃/cdCO₂ approaches normal value.

Renal compensatory mechanism:

The kidney respond to alkalosis by decrease in Na-H exchange, decreased formation of ammonia, and decrease reclamation of bicarbonate.

Laboratory findings:

Blood plasma value for cHCO₃^-, cdCO₂ and plasma total CO₂ concentration are increased and the ratio is high. A higher than expected pCO₂ indicates superimposed respiratory acidosis. In prolonged vomiting Cl^- (sometimes K⁺) are low due to loss in vomitus. Proteins may be falsely increased due to dehydration, and if food intake is inadequate ketone bodies are formed increasing the organic acid fraction.  

Laboratory findings in metabolic acidosis:

Bicarbonate concentration have been used to estimate pH and pCO₂.

E.g. if HCO₃^- = 10 mmol/L

Then for pH determination,

10 + 15 = 25, Thus pH = 7.25

For estimating pCO₂ (mm Hg), following formula is used:

pCO₂ ± 2 = 1.5 (cHCO₃^-) + 8

1.5 (10) + 8 or 23 ± 2 is pCO₂.

Electrolytes are also altered depending upon the cause of metabolic acidosis. Eg. in diabetic ketoacidosis (DKA), the increase in organic acids caused by increased ketone bodies is reflected by decrease in plasma bicarbonate and sometimes chloride. Plasma sodium and potassium are also decreased due to polyuria and coexcretion with acetoacetate and beta hydroxy butyrate. Fruthermore, because of high glucose, there is dilutional effect as a result of osmotically induced increase in vascular volume. When glucose concentration decreases following insulin treatment, water leaves the vascular compartment and sodium concentration increases.

Chronic metabolic acidosis enhances mobilization of calcium from bones; the decrease in plasma pH increases dissociation of plasma proteins bound calcium so that more calcium is filtered through the glomerulus and less is reabsorbed. 

Compensatory mechanism in metabolic acidosis:

The buffer system mainly bicarbonate/carbonic acid minimizes the changes in pH. In acidosis the bicarbonate concentration decreases to give a ratio of <20:1. The respiratory compensatory mechanism is by hyperventilation.

Respiratory compensation mechanism:

The decrease in pH stimulates respiratory compensatory mechanism and produces hyperventilation (Kussmaul respiration), which results in elimination of carbonic acid as carbondioxide, a decrease in pCO₂ and decrease in cdCO₂. As cdCO₂ diminishes, the ratio of cHCO₃/cdCO₃ returns to normal 20:1.

Renal compensatory mechanism:

There is increase excretion of acid and preservation of base (increased rate of Na-H exchange, increased ammonia formation, and increased reabsorption of bicarbonate). This results in increase in ratio. 22:1.1 for pH of 7.40 (fully compensated metabolic acidosis as pH is normal).

Normal anion gap acidosis (Inorganic acidosis):

Fig. Table showing metabolic acidosis with high and normal anion gaps

Normal anion gap acidosis (Inorganic acidosis):

Here the cause of acidosis in the presence of normal anion gap is the loss of bicarbonate-rich fluid from either kidney or GIT. As bicarbonate is lost, more Cl^- ions are reabsorbed with Na⁺ or K⁺ to maintain electrical neutrality so that hyperchloremia ensues. Normal anion gap acidosis can be divided into hypokalemic and normokalemic acidosis.

Diarrhea: It causes acidosis due to loss of Na⁺, K⁺, and HCO₃^-. As bicarbonate is produced by exocrine pancreas. There is hyperchloremia occurs as response to replacement of lost bicarbonate to maintain electrical balance. This is associated with hypokalaemia.

Renal tubular Acidosis, Type I and II: These is characterized by loss of bicarbonate due to decreased tubular secretion of hydrogen ion (distal or type I RTA) or decreased reabsorption of bicarbonate (Proximal or type II RTA). Since, the major urine-acidifying power of kidney rests in distal tubules, the proximal and distal RTA may be differentiated by measuring urine pH. In proximal RTA, urine pH becomes <5.5, whereas in distal RTA the distal tubules are compromised and urine pH is >5.5. These acidosis are associated with hypokalaemia.

Carbonic anhydrase inhibitors: Acetazolamide is the most commonly used. It is used as diuretic and for Alkalinization of urine in patients with open-angle glaucoma or acute mountain sickness. Inhibition of CA cause wasting of Na, K and HCO₃ in proximal tubule.

Hyperkalaemic Normal AG acidosis (Renal tubular acidosis Type IV): Failure of kidney to synthesize renin, failure of adrenal cortex to secrete aldosterone, and renal tubular resistance to aldosterone are the most common cause of this type of acidosis (Type IV RTA). This inhibits Na reabsorption, and both K and H are thus abnormally retained. The result is decreased renal ammonia formation and therefore decreased elimination of H. 

High anion gap acidosis (organic acidosis)

High AG metabolic acidosis is explained by eight mechanisms MUDPILES as shown in the table.  High anion gap in these conditions is due to consumption of bicarbonate in buffering excess acid.

Determination of osmolal gap in the presence of high anion gap acidosis, will help in determining the source of unmeasured anion.Methanol: It is metabolized by liver to formaldehyde and formic acid. Accumulation of this acid leads to metabolic acidosis with high anion gap and clinical symptoms of blindness. Methanol as well as other alcohol will also increase the plasma osmolality.

Urea of renal failure: Due the loss of renal tubular mass there is decreased ammonia formation, decreased hydrogen ion excretion and bicarbonate reabsorption.

Diabetes or ketoacidosis: These ketoacids accumulate and represent unmeasured anions. Accumulation of these ketone bodies cause decreased in bicarbonate, a normal or low Cl^- and high AG.

Isoniazid, Iron, or Ischemia (three I’s): These all lead to lactic acidosis. Isoniazid and Iron are hepatotoxic and lead to impaired lactate clearance. Ischemia lead to anaerobic glycolysis producing lactate.

Lactic acidosis: Physiologically it exists as lactate and is mainly produced by muscle cells (mainly during exercise) and erythrocytes during anaerobic glycolysis or any other conditions that lead to hypoxia. It is normally metabolized by the liver. Increase in lactate >2 mmol/L with associated increase in H⁺ is considered lactic acidosis. Alcoholism can also cause lactic acidosis as it prevents gluconeogenesis from lactate in liver, because oxidation of ethanol to acetaldehyde competes for the NAD⁺ that is necessary for conversion of lactate to pyruvate.  

ACID-BASE BALANCE AND ACID-BASE STATUS:

Acids and bases are the product of metabolism. They are transported and handled in the lungs and kidney. They are responsible for maintaining the arterial pH of 7.35-7.45 and venous pH of 7.32-7.38 which is accomplished by buffering capacity of blood and respiratory and renal regulatory mechanism.

Our body is the net producer of acids. E.g.

ACID BASE DISORDERS:

Acid base disturbances are traditionally classified as,

1.      Metabolic acidosis/alkalosis

2.      Respiratory acidosis/alkalosis.

Last 2 digit of pH = pCO₂ (e.g., if pCO₂ = 28, pH = 7.28)

cHCO₃^- + 15 = last 2 digit of pH (cHCO₃^- = 15, pH = 7.30)

RENAL MECHANISM IN THE REGULATION OF ACID BASE BALANCE:

Since the pH of urine varies from 4.5-8.0, this indicates kidney has ability to excrete various amounts of acids and bases to maintain the normal pH of blood. This ability makes the kidney the final defense mechanism against change in body pH.

Various acids produced during metabolic process are buffered in ECF at the expense of HCO₃^-. Renal excretion of acid and conservation of bicarbonate occur through various ways.

1.      The Na⁺-H⁺ exchange
2.      Production of ammonia and excretion of NH₄⁺ and
3.      Reclamation of HCO₃^-.

RESPIRATORY MECHANISM IN THE REGULATION OF ACID-BASE BALANCE:

Respiration:

Exchange of oxygen and carbon dioxide in lungs between alveolar air and blood is called external respiration, in contrast to internal respiration occurring at tissue level. Blood (RBC) will take oxygen from lungs to tissue and carbon dioxide from tissue to the lungs for exhalation.