The oxidation of dietary carbohydrates, fats, and amino acids yields CO₂. About 15,000 mmol of CO₂ are produced by cellular metabolism daily. This CO₂ combines with water in the blood to form carbonic acid (H₂CO₃):

This reaction is catalyzed by carbonic anhydrase (CA), an enzyme present in tissues and red blood cells but absent in plasma. When H₂CO₃ dissociates into CO₂ and H₂O (a process called dehydration), the CO₂ is eliminated by the lungs. For this reason, H₂CO₃ is called a volatile acid .

In addition to volatile acid, the body also generates nonvolatile (fixed) acids from cellular metabolism. These nonvolatile acids are produced from sulfur-containing amino acids (i.e., cysteine and methionine) and phosphoproteins. The acids produced are sulfuric acid and phosphoric acid, respectively. Other sources of endogenous nonvolatile acids include glucose, which yields lactic and pyruvic acids; triglycerides, which yield acetoacetic and β-hydroxybutyric acids; and nucleoproteins, which yield uric acid. Hydrochloric acid is also formed from the metabolism of cationic amino acids (i.e., lysine, arginine, and histidine). Sulfuric acid accounts for 50 % of all acids produced. A typical North American diet produces 1 mmol/kg/day of endogenous nonvolatile acid.

Under certain conditions, acids are produced from sources other than the diet. For example, starvation produces ketoacids, which can accumulate in the blood. Similarly, strenuous exercise generates lactic acid. Drugs such as corticosteroids cause endogenous acid production by enhancing catabolism of muscle proteins .

Endogenous base (HCO₃ ⁻) is generated from anionic amino acids (glutamate and aspartate) in the diet. Also, citrate or lactate generated during metabolism of carbohydrate yields HCO₃ ⁻. Vegetarian diets contain high amounts of anionic amino acids and small amounts of sulfur and phosphate-containing proteins. Therefore, these diets generate more base than acid. In general, the production of acid exceeds that of base in a person ingesting a typical North American diet .

All acids that are produced must be removed from the body in order to maintain normal blood pH. Although the kidneys eliminate most of these acids, it takes hours to days to complete the process. Buffers (both cellular and extracellular) are the first line of defense against wide fluctuations in pH.

The most important buffer in blood is bicarbonate/carbon dioxide (HCO₃ ⁻/CO₂). Other buffer systems are disodium phosphate/monosodium phosphate (Na₂HPO₄ ²⁻/NaH₂PO₄ ⁻), and plasma proteins. In addition, erythrocytes contain the important hemoglobin (Hb) system, reduced Hb (HHb⁻) and oxyhemoglobin (HbO₂ ²⁻). Bones also participate in buffering.

The HCO₃ ⁻/CO₂ system provides the first line of defense in protecting pH. Its role as a buffer can be described by incorporating this system into the Henderson–Hasselbalch equation as follows:

Although H₂CO₃ cannot be measured directly, its concentration can be estimated from the partial pressure of CO₂ (pCO₂) and the solubility coefficient (α) of CO₂ at known temperature and pH. At normal temperature of 37 °C and pH of 7.4, the pCO₂ is 40 mmHg, α is 0.03, and pK_a is 6.1. The Henderson–Hasselbalch equation can be appropriately written as:

Normal plasma [HCO₃ ⁻] is 24 mEq/L. Therefore,

It should be noted from the Henderson–Hasselbalch equation that the pH of a solution is determined by the pK_a and the ratio of [HCO₃ ⁻] to pCO₂, and not by their absolute values. Thus, because the kidneys regulate the [HCO₃ ⁻] and the lungs pCO₂, the kidneys and lungs determine the pH of extracellular fluids.

Phosphate buffers are effective in regulating intracellular pH more efficiently than extracellular pH. Their increased effectiveness intracellularly is due to their higher concentrations inside the cell. Also, the pK_a of this system is 6.8, which is close to the intracellular pH .

Plasma proteins contain several ionizable groups in their amino acids that buffer either acids or bases. For example, the imidazole groups of histidine and the N-terminal amino groups have pK_a that are close to extracellular pH and thus function as effective buffers. In blood, Hb is an important protein buffer because of its abundance in red blood cells.

Extracellular buffering to an acid load is complete within 30 min. Subsequent buffering occurs intracellularly and takes several hours to complete. Most of this intracellular buffering occurs in bone.

It is apparent from the Henderson–Hasselbalch Eq. 26.3 that any change either in [HCO₃ ⁻] or pCO₂ can cause a change in blood pH. The acid–base disturbance that results from a change in plasma [HCO₃ ⁻] is termed a metabolic acid–base disorder , whereas that due to a change in pCO₂ is called a respiratory acid–base disorder .

After buffers, the lungs are the second line of defense against pH disturbance. In a normal individual, pCO₂ is maintained around 40 mmHg. This pCO₂ is achieved by expelling the CO₂ that is produced by cellular metabolism through the lungs. Any disturbance in the elimination of CO₂ may cause a change in blood pH. Thus, alveolar ventilation maintains normal pCO₂ to prevent an acute change in pH. Alveolar ventilation is controlled by chemoreceptors located centrally in the medulla and peripherally in the carotid body and aortic arch. Blood [H⁺] and pCO₂ are important regulators of alveolar ventilation. The chemoreceptors sense the changes in [H⁺] or pCO₂ and alter alveolar ventilatory rate. For example, an increase in [H⁺], i.e., a decrease in pH, stimulates ventilatory rate and decreases pCO₂. These responses, in turn, raise pH (see Eq. 26.4). Conversely, a decrease in [H⁺] or an increase in pH depresses alveolar ventilation and causes retention of pCO₂ so that the pH is returned to near normal. An increase in pCO₂ stimulates ventilatory rate, whereas a decrease depresses the ventilatory rate. The respiratory response to changes in [H⁺] takes several hours to complete .

As stated earlier, 1 mmol/kg/day of fixed acid is produced from the diet. If not removed, this acid is retained and plasma [HCO₃ ⁻] decreases. The result is metabolic acidosis. In a healthy individual, metabolic acidosis does not occur because the kidneys excrete the acid load and maintain plasma [HCO₃ ⁻] around 24 mEq/L. The maintenance of [HCO₃ ⁻] is achieved by three renal mechanisms :