The major buffering systems in the body are proteins, particularly those with the amino acids histidine and cysteine exposed to the outside environment, phosphate, and bicarbonate. All three of these are weak acids with pK_a values lower than physiological pH. As a consequence, buffering capacity increases as the pH is lowered from the physiological range. This meets the needs of most organisms because physiological pH excursions generally occur in the acid direction. Hence, the low pK_a of these buffering systems is poised to respond to metabolic acidosis.

Of these three, only the bicarbonate system, which is critical for buffering extracellular fluids such as blood, is in steady-state between production and removal. Thus, pH changes via this dynamic bicarbonate system are taking place on a background provided by the more static protein and phosphate systems.

Production of Bicarbonate
Cells generate and excrete large quantities of carbon dioxide (CO₂) during aerobic metabolism of glucose and fats. CO₂ is subsequently converted to carbonic acid (H₂CO₃), which serves as the basis for the bicarbonate buffering system. Hence, the body is not dependent on ingestion of exogenous compounds or complex syntheses to maintain this buffering system.

Removal of Bicarbonate
The bicarbonate buffering system is in volatile equilibrium (via breathing) with the external environment (lungs and air). Thus it is able to respond rapidly to endogenous alterations. It can also be affected, either positively or negatively, by environmental manipulation.

Movement into and out of cells

The acid components of the bicarbonate system (i.e. H⁺ and CO₂) cross biological membranes rapidly, thus do not depend on complex transport kinetics. The base component (HCO₃^-), on the other hand, is transported rapidly in all cells via anion exchange. Consequently, the bicarbonate buffering system helps to maintain both intracellular and extracellular pH.

Role of other blood components

The acid components of the bicarbonate system are transported from the tissues to the lungs by hemoglobin. Thus, this important protein participates in both the production and removal of metabolic acid.

Condition	Possible causes
respiratory acidosis	apnea or impaired lung capacity, with a build-up of CO2 in the lungs
metabolic acidosis	ingestion of acid, production of ketoacids in uncontrolled diabetes, or kidney failure Note: These conditions all result in build-up of H+ from sources other than excess CO2.

Condition	Possible causes
respiratory alkalosis	hyperventilation, with a net loss of CO2 from the blood.
metabolic alkalosis	ingestion of alkali, prolonged vomiting leading to a loss of HCl, or extreme dehydration leading to kidney retention of bicarbonate. Note: The common thread here is the loss of H+ for reasons other than depletion of CO2.

For respiratory problems caused by alterations in CO₂, the best treatment involves ventilation. If bicarbonate is used to raise the pH in cases of respiratory acidosis, the result can be fatal, since compensation is also working to increase the blood bicarbonate concentration.

For metabolic problems that involve HCO₃^-, the best treatment is either bicarbonate infusion (for acidosis) or NH₄Cl infusion (for alkalosis). NH₄Cl dissociates into NH₄⁺ and Cl^-. The NH₄⁺ (ammonium ion) is in equilibrium with NH₃ (ammonia) and H⁺. Because ammonia is volatile, it is respired through the lungs, leaving behind H⁺ and Cl^- or hydrochloric acid, which lowers the pH. Often, metabolic acidosis is found in combination with respiratory alkalosis (e.g. compensated). This is a fragile situation because the buffering power is significantly reduced.