Acid-Base Balance: Buffers and Physiology

42. Acid-Base Balance: Cheatsheet

I. pH and Proton Concentration

II. Acids and Bases

III. Buffers and pH Regulation

IV. Mechanisms of pH Regulation (Compensations)

V. Renal HCO3- Reabsorption and Excretion

VI. Urinary Buffers and Ammonium Production

VII. Parameters for Acid-Base Status

VIII. Acid-Base Disturbances and Compensations

Acid-Base Balance: Comprehensive Notes

Acid-base balance refers to the homeostatic regulation of hydrogen ion () concentration in body fluids. Maintaining a stable pH is crucial for optimal enzyme activity, protein structure, electrolyte distribution, and energy production. The body employs multiple systems, including chemical buffers, respiratory adjustments, and renal mechanisms, to protect against significant changes in concentration.

1. Defining pH and Normal Blood Values

The term pH is a measure of the hydrogen ion concentration in a solution. Mathematically, it is defined as the negative logarithm(base 10) of the concentration:

A higher concentration corresponds to a lower pH (more acidic), while a lower concentration results in a higher pH (more alkaline or basic).

• Normal arterial blood concentration is approximately .

• The normal range of blood pH values is critical for physiological function: .

• Values below indicate acidemia, and values above indicate alkalemia.

• Extreme deviations (e.g., below or above ) can be life-threatening, as they impair enzyme function, protein conformation (like hemoglobin's oxygen binding), and membrane excitability.

Importance of pH for Biological Functions:

• Enzyme Activity: Most human enzymes function optimally around . Deviations can lead to denaturation and loss of function. For example, pepsin in the stomach works best at .

• Protein Structure: pH affects hydrogen bonds and ionic interactions within proteins. For hemoglobin, pH influences oxygen binding affinity (Bohr effect):

  • Acidosis: Hemoglobin releases more readily, potentially impairing oxygen transport.

  • Alkalosis: Hemoglobin binds more tightly, reducing oxygen delivery to tissues.

• Electrolytes & Membrane Excitability:

  • Distribution: Acidosis can lead to a shift of from intracellular to extracellular fluid (hyperkalemia), causing cardiac arrhythmias and weakness.

  • Binding: Alkalosis decreases ionized , increasing neuromuscular excitability, leading to muscle cramps, tetany, and seizures.

  • Na+ Channel Function: Alterations in pH can impact the function of voltage-gated ion channels.

• Energy Production: pH affects various transporters, mitochondrial function, and overall ATP production pathways.

2. Sources of Acids and Bases in the Body

The body continuously produces acids through metabolic processes:

Acids:

• Volatile Acids: Primarily carbonic acid (), formed from the reaction of carbon dioxide () and water. is a product of complete oxidation of carbohydrates and lipids. It is called "volatile" because it can be eliminated via the lungs.

• Non-Volatile (Fixed) Acids: These cannot be eliminated by the lungs and must be buffered and excreted by the kidneys.

  • Incomplete Oxidation of Carbohydrates and Lipids:

    • Lactic acid () – produced during anaerobic metabolism.

    • Beta-hydroxybutyric acid, Acetoacetate (ketone bodies) – produced during excessive fat breakdown (e.g., in uncontrolled diabetes or starvation).

  • Breakdown of Proteins, Phospholipids, and Nucleic Acids:

    • Sulphuric acid (from sulfur-containing amino acids like methionine and cysteine).

    • Phosphoric acid (from phosphoproteins and phospholipids).

Bases:

The primary base in the blood is bicarbonate (). Other bases come from proteins, particularly plasma proteins and hemoglobin (due to histidine residues).

Under normal conditions, the amount of synthesized protons is equal to the amount of excreted protons, maintaining acid-base balance.

3. Buffer Systems in Blood

A buffer is a solution containing a weak acid and its conjugate base, or a weak base and its conjugate acid. It resists changes in pH when small amounts of acid or base are added. In the body, buffers provide the first line of defense against pH shifts.

The general principle of a buffer solution:

When is added, combines with it to form . When is added, dissociates to replenish , which then neutralizes .

The effectiveness of a buffer depends on two factors:

1. Its pK value (the negative logarithm of the dissociation constant ) being close to the physiological pH.

2. Its concentration in the body fluid.

List of important buffers in the blood:

• Bicarbonate Buffer System: This is the most important extracellular buffer. It consists of carbonic acid () and bicarbonate ions (). Its pK is , which is not ideal for blood pH , but its high concentration and ability to be regulated by both lungs () and kidneys () make it highly effective.

• Plasma Proteins: Proteins, especially albumin, contain numerous dissociable groups (e.g., histidine residues) that can accept or donate . They have a pK value closer to physiological pH than bicarbonate.

• Hemoglobin Buffer System: This is an excellent intracellular buffer, particularly within red blood cells. Deoxygenated hemoglobin is a better buffer than oxygenated hemoglobin. Its histidine residues can bind produced from entering the red blood cell.

• Phosphate Buffer System: Consists of dihydrogen phosphate () and monohydrogen phosphate (). Its pK is , which is very close to physiological pH, making it an ideal buffer. However, its concentration in extracellular fluid is relatively low compared to bicarbonate. It is more important as an intracellular buffer and a urinary buffer.

The Henderson-Hasselbalch Equation:

This equation quantitatively describes the relationship between pH, pK, and the concentrations of the weak acid and its conjugate base in a buffer system. For the bicarbonate buffer system:

Since concentration is directly proportional to partial pressure of carbon dioxide () dissolved in plasma (, where is the solubility coefficient), the equation can be rewritten as:

This equation highlights that pH is determined by the ratio of bicarbonate (, regulated by kidneys) to (regulated by lungs). If any two of , , or are known, the third can be calculated.

• Normal values: , . Plugging these into the equation gives .

4. Parameters for Determining Acid-Base Status

Several parameters are used to assess the body's acid-base status, distinguishing between respiratory and metabolic components:

• pH: The primary indicator of acidemia or alkalemia. Normal arterial blood pH: .

• Partial Pressure of Carbon Dioxide (): Reflects the respiratory component of acid-base balance. Normal range is .

  • High (hypercapnia) indicates respiratory acidosis.

  • Low (hypocapnia) indicates respiratory alkalosis.

• Bicarbonate (): Reflects the metabolic component of acid-base balance. There are two important measures:

  • Actual Bicarbonate: The bicarbonate concentration measured in blood at the current of the sample. Its value is influenced by both metabolic and respiratory factors.

  • Standard Bicarbonate (): The bicarbonate concentration of a blood sample if it were equilibrated to a normal of . This value removes the respiratory influence, providing a clearer picture of the metabolic contribution to acid-base changes.

    • Normal standard bicarbonate: .

    • If actual and standard bicarbonate are the same, it implies the of the patient is .

• Buffer Base (BB): Represents the total concentration of all buffer anions in the blood, including bicarbonate, plasma proteins, and hemoglobin.

  • Normal buffer base range: .

  • Changes in BB primarily reflect metabolic (non-respiratory) acid-base disorders.

• Base Excess/Deficit (BE): This is the amount of acid or base required to return 1 liter of blood to a normal pH of at a standard of and .

  • Normal range: .

  • A positive BE indicates a metabolic alkalosis, while a negative BE (base deficit) indicates a metabolic acidosis.

• Anion Gap: The difference between the concentrations of measured cations () and measured anions () in serum. It helps determine the cause of metabolic acidosis.

  A high anion gap suggests acidosis due to an accumulation of unmeasured acids (e.g., lactic acid, ketone bodies). A low anion gap is rare and often associated with low albumin levels.

5. Role of Lungs in Acid-Base Balance (Respiratory Adjustments)

The respiratory system provides a rapid but temporary control over pH by regulating the excretion of , the volatile acid.

• The enzyme carbonic anhydrase facilitates the reaction:

• Respiratory Acidosis: Caused by hypoventilation (decreased excretion), leading to increased and a drop in pH.

  • To compensate, the body would hyperventilate (if possible) to expel more .

  • Renal compensation, which is slower, would increase secretion and reabsorption.

• Respiratory Alkalosis: Caused by hyperventilation (increased excretion), leading to decreased and an increase in pH.

  • To compensate, the body would hypoventilate (reduce breathing rate/depth).

  • Renal compensation would decrease secretion and reabsorption.

Chemoreceptors in the carotid and aortic bodies monitor arterial concentration (and indirectly ), providing feedback to the respiratory center to adjust ventilation.

6. Role of Kidneys in Acid-Base Balance (Renal Adjustments)

The kidneys are the most powerful acid-base regulators, providing long-term control. They achieve this through three main mechanisms:

1. Reabsorption of filtered .

2. Secretion of .

3. Generation of new and excretion of acid in the form of urinary buffers (e.g., ammonium and phosphate).

The kidneys must excrete of non-volatile acids while simultaneously reabsorbing the approximately of that is filtered at the glomerulus.

6.1. Reabsorption along the Nephron

The vast majority of filtered is reabsorbed, primarily in the proximal tubule. This process is critically linked to secretion.

• Proximal Tubule (PT): About of filtered is reabsorbed here.

  • Mechanism:

    1. is secreted into the tubular lumen by the exchanger (NHE3) on the apical membrane and by -ATPase.

    2. In the lumen, secreted combines with filtered to form .

    3. Lumenal carbonic anhydrase (CA IV) rapidly converts to and .

    4. diffuses readily into the tubular cell.

    5. Inside the cell, cytoplasmic carbonic anhydrase (CA II) converts and back into , which then dissociates into and .

    6. The newly generated is transported across the basolateral membrane into the peritubular capillary blood, primarily via a cotransporter (NBCe1).

    7. The is re-secreted into the lumen, perpetuating the cycle.

  • This process effectively reclaims filtered ; it does not result in net acid excretion or new synthesis.

• Thick Ascending Limb (TAL): Reabsorbs a small amount of .

• Distal Tubule and Collecting Duct: Reabsorb the remaining .

  • Intercalated A cells in the collecting duct are responsible for secretion and reabsorption. This is crucial for acidifying the urine and generating new .

  • Intercalated B cells, less common, can secrete and reabsorb during alkalosis.

6.2. Secretory Mechanisms

The secretion of is fundamental for both reabsorption and net acid excretion.

• Proximal Nephron (-ATPase and Exchanger): As described above for reabsorption, is secreted into the lumen.

• Distal Nephron (Collecting Duct, primarily Type A Intercalated Cells):

  • -ATPase: Actively pumps into the tubular lumen against a steep electrochemical gradient. This is responsible for generating highly acidic urine (down to ).

  • -ATPase: Secretes into the lumen while reabsorbing . This exchanger is important when levels are low, as it helps conserve at the expense of exacerbating alkalosis.

  • These mechanisms are crucial for the net excretion of acid and the generation of new , which is then reabsorbed into the blood.

6.3. Cellular Mechanisms for Net Transepithelial Movement of

The net movement of bicarbonate involves coordinated transporter and enzyme activity:

1. Entry and Carbonic Anhydrase: , either from metabolism or reabsorbed from the lumen, diffuses into the renal tubular cell. Inside the cell, carbonic anhydrase (CA) catalyzes .

2. Secretion: The generated is actively transported into the tubular lumen via apical exchangers (e.g., NHE3) and -ATPases. This drives the reabsorption of filtered and allows for acid excretion.

3. Transport into Blood: The generated in the cell is then transported across the basolateral membrane into the peritubular capillaries.

   • In the proximal tubule, this is mainly via a cotransporter (NBCe1).

   • In the collecting duct (Type A intercalated cells), is exchanged for via an anion exchanger (AE1 or band 3 protein).

6.4. Importance of Urinary Buffers and Ammonium Production/Excretion

The body produces of non-volatile acids daily. These must be excreted, but the minimum urine pH only reaches about . To excrete significant amounts of acid without lowering urine pH excessively (which would stop secretion), urinary buffers are essential.

• Phosphate Buffer System: and (pK ). When is secreted into the tubular lumen, it combines with to form , which is then excreted. This is known as titratable acid.

• Ammonia () / Ammonium () System: This is the most important urinary buffer, especially during chronic acidosis.

  • Production: Ammonia () is primarily produced from the metabolism of glutamine in the proximal tubular cells. Glutamine is deaminated to form and . The is then metabolized to glucose or , generating two new ions per glutamine molecule.

  • Secretion and Buffering: diffuses into the tubular lumen, especially in the collecting duct. There, it readily combines with secreted to form ammonium ion ().

    Because is charged, it is trapped in the lumen and excreted in the urine, effectively carrying out without significantly lowering urinary pH. This process also contributes to the net generation of new .

  • Regulation: In acidosis, glutamine metabolism and excretion increase significantly over several days, becoming the primary mechanism for excreting excess acid. This is known as non-titratable acid excretion.

Total acid excretion by the kidneys = excretion + titratable acid excretion - excretion.

7. Acid-Base Disturbances and Compensations

Acid-base disturbances are classified as either metabolic or respiratory, and as acidosis or alkalosis. The body employs compensatory mechanisms to minimize the change in pH. Compensations are responses to a primary disturbance, aiming to return pH towards normal but usually not fully normalizing it. If a disturbance is successfully compensated, the pH will be near normal, but and will both be abnormal in the same direction.

Types and Reasons of Acid-Base Disturbances:

Magnitude of Compensations:

Given a sudden increase or decrease in pH, the body activates its defense mechanisms in a sequential and complementary manner to minimize the change:

1. Buffers (Immediate Response - Seconds to Minutes):

   • Chemical buffers in the blood (bicarbonate, proteins, phosphate) immediately bind to or release to maintain pH. This is the fastest response but has finite capacity.

   • Example: In metabolic acidosis, buffers the excess , being consumed in the process, hence drops.

2. Respiratory Adjustments (Rapid Response - Minutes to Hours):

   • The respiratory system alters ventilation to adjust .

     • In acidosis (metabolic or respiratory), peripheral chemoreceptors detect (or direct for respiratory acidosis) and stimulate increased ventilation, leading to .

     • In alkalosis (metabolic or respiratory), (or direct for respiratory alkalosis) leads to decreased ventilation, causing .

   • Magnitude: A decrease in in metabolic acidosis typically results in a decrease in (Winters' formula for metabolic acidosis: ).

3. Renal Adjustments (Slow but Powerful Response - Hours to Days):

   • The kidneys adjust reabsorption and excretion (via titratable acid and ammonium). This is the most effective long-term compensation.

     • In acidosis, the kidneys increase secretion, increase reabsorption, and markedly increase ammonium production/excretion (generating new ).

       Example: In chronic renal failure, the kidney's ability to excrete acid is impaired, leading to metabolic acidosis.

     • In alkalosis, the kidneys decrease secretion, decrease reabsorption, and increase excretion.

   • Renal compensation for chronic respiratory acidosis can take 3-5 days to reach full effect.

The Acid-Base Nomogram is a diagnostic tool used to visualize and interpret multiple acid-base parameters simultaneously, helping to identify primary disturbances and compensatory responses.