Acid-base Balance and Acid-base Imbalance

In this article we will discuss about the Acid-base Balance and Acid-base Imbalance.

Acid-base Balance in Normal Health:

An acid may be defined as substance that produces H⁺ (protons) in solution, and a base is a particle that combines with hydrogen ions (H⁺).

Example:

Carbonic acid is an acid which is dissociated into H⁺ and HCO₃⁻ and its anionic com­ponent is a base. NaHCO₃ acts as a base since it produces HCO₃ which can combine with hydrogen ion (H⁺).

Other examples:

Hydrochloric acid (HCl) is a strong acid since it is extensively dissociated into H⁺ and CI⁻. Chlo­ride ion (CI⁻) is a very weak base since it has got very little capacity in combining firmly with H⁺. But HCO₃^–, HPO₄⁻⁻, and protein are comparatively strong bases since they have got strong affinity for H⁺ forming weak acids.

The stronger the acid, the weaker is the base. Such pairs are termed as conjugate acid base pairs.

Chloride ion (CI⁻) is the conjugate base of the acid HCl.

The cations such as Na⁺, K⁺, Ca⁺⁺, Mg⁺⁺, can­not donate or accept protons. So, they are neither acids nor bases. Such cations are termed as aprotes.

Buffers:

Buffers are the mixtures of weak acids and their salts of strong bases.

Example:

(CH₃COOH + CH₃COONa).

Principles of buffers:

HAC + NaAC Na⁺ + H⁺ + 2AC^–

[where HAC = Acetic acid; NaAC = Sodium ac­etate]

If alkali (NaOH) is added to this system, it will form salt and no free H⁺ or OH^– will be available.

HAC + NaAC + NaOH → 2NaAC + H₂O

If acid (HCl) is added to this system, it will also form salt and no free H⁺ or OH⁻ will be available.

HAC + NaAC + HCl → NaCl + 2HAC

In either cases, there is no change in hydrogen ion concentration. The buffer acts almost as if it were “absorbing” the added free hydrogen or hydroxyl ions.

Major sources of acids produced in the body:

i. Carbonic acid (H₂CO₃):

This acid is pro­duced in the body during oxidation in the cells. The C-compounds on oxidation pro­duces CO₂. About 300 litres of CO₂ are produced and eliminated from the body of an adult daily.

ii. Sulphuric acid (H₂SO₄):

This acid is formed by the oxidation of sulphur-containing amino acids e.g., methionine and cystine or cysteine.

iii. Phosphoric acid:

The dietary phospho-proteins, nucleoproteins, and phosphati­des are metabolized to produce this acid.

iv. Abnormal quantities of pyruvic acid, lac­tic acid, acetoacetic acid, and β-hydroxy-butyric acid are formed from the oxida­tion of carbohydrates, fats and proteins.

v. When some medicines like mandelic acid, ammonium chloride are administered in excess, they may increase hydrogen ion concentration of blood.

Mechanisms of regulation of pH:

The following factors are involved in the regula­tion of blood pH:

i. Buffer systems in the blood.

ii. Respiratory mechanisms.

iii. Renal mechanisms.

iv. Dilution factor.

Physiological buffer systems:

E.C. fluids are capable of transporting acids from the cells to the lungs and kidneys without the change in pH depending mainly on the efficient buffer systems in these fluids and in the erythro­cytes.

The most important blood buffer systems are as follows:

(a) Plasma buffers:

(b) Buffers of red blood cells:

The buffer systems in the interstitial fluids and lymph are almost the same as in the blood plasma except the proteins which are present in muscle in smaller quantities.

The followings are the most important buffers:

(a) In plasma:

The bicarbonate buffer and plasma proteins.

(b) In erythrocytes:

The bicarbonate buffer and Hb-system.

Role of different buffer systems:

a. Bicarbonate buffer system:

This consists of carbonic acid and sodium bi­carbonate. The normal ratio of it in blood is 20 : 1. These chief buffers constitute the alkali reserve. The bicarbonate buffers neutralize the strong and non-volatile acids entering the ECF.

Thus, lactic acid is buffered as follows:

A strong and non-volatile acid (lactic acid) is converted into weak and volatile acid at the ex­pense of NaHCO₃ (the salt component of the buffer). H₂CO₃ thus formed is eliminated through diffusion of CO₂ through alveoli of lungs.

Therefore, bicarbonate buffer system is directly linked up with respiration.

When NaOH enters the ECF, it reacts with H₂CO₃ of the buffer system:

(ii) When an alkali enters, it is buffered by the acid phosphate resulting the alkaline phos­phate which is excreted in urine showing the increased alkalinity of urine.

NaHCO₃ concentration in the blood is repre­sented as the alkali reserve since it does not com­bine with strong and non-volatile acid.

Advantage:

Bicarbonate buffer system is quite efficient as compared to other buffer systems since it is present in very high concentration and it pro­duces H₂CO₃ from which CO₂ is exhaled out.

Disadvantage:

Bicarbonate buffer is very weak as a chemical buffer and hence PKa is far away from the physiological pH.

b. Phosphate buffer system:

The normal ratio of Na₂HPO₄/NaH₂PO₄ in plasma is 4 : 1 and this ratio is kept constant by the help of the kidneys for which phosphate buffer sys­tem is directly related to the kidneys.

(i) When a strong acid enters the blood, it is fixed up by Na₂HPO₄ which is converted to acid phosphate (NaH₂PO₄). This acid phosphate is excreted by the kidneys showing that the urine becomes more acidic.

(ii) When an alkali enters, it is buffered by the acid phosphate resulting the alkaline phosphate which is excreted I urine showing the increased alkalinity of urine.

So, phosphate buffer system works in conju­gation with the kidneys.

Advantage:

It is very effective as a chemical buffer and PKa approaches physiological pH bet­ter.

Disadvantage:

Phosphate buffer is low in con­centration in blood and less efficient as a physi­ological buffer.

c. Protein buffer system:

The capacity of plasma protein buffer (Na⁺Pr⁻/ H⁺Pr⁻) is less than that of Hb which is only involved in erythrocytes.

Buffering action of proteins:

(i) In acidic medium, protein acts as a base and NH₂ group takes up H⁺ from the me­dium forming NH₃⁺. Protein becomes posi­tively charged.

(ii) In alkaline medium, protein acts as an acid and acid group (COOH) dissociates into COO⁻ and H⁺. This H⁺ combines with OH^– producing a molecule of H₂O. Proteins be­come negatively charged.

(iii) The salt component (Na⁺ proteinate) com­bines with strong acid producing weak acid (H⁺Pr⁻).

(iv) CO₂ is removed by other factor with the formation of carbamino compounds. The binding of CO₂ is performed without pass­ing through the carbonic acid stage.

PrNH₂ + CO₂ ⇌ PrNHCOOH (Carbamino compound)

d. Hemoglobin as a buffering agent:

The capacity of Hb as a buffer fully depends on the number of dissociable buffering groups, namely -COOH group, -NH₂ group, guanido group and the important imidazole group.

The physiological buffering action of Hb to maintain the pH range of blood from 7.0 to 7.8 is due to imidazole group of histidine.

Imidazole contains two groups:

(a) Fe⁺⁺ containing group which is concerned with carriage of O₂.

(b) Imidazole N₂ group which can give up H⁺ and accept H⁺ depending on the pH of the medium.

Therefore, the buffering capacity of Hb entirely depends on the presence of imidazole nitrogen group which remains dissociated in acidic medium and conjugated base forms.

(a) The imidazole N₂ group being oxygen­ated acts as an acid and donates protons in the medium. Oxygenated Hb is a stronger acid than de-oxygenated Hb.

(b) The deoxygenated Hb is less acidic and the imidazole N₂ group acts as a base and takes up protons from the medium.

(c) The delivery of O₂ is favoured by the acid­ity of the medium.

(d) The oxygenation of Hb is favoured by the alkalinity of the medium.

In the lungs:

(a) H⁺ is released during the formation of Oxy-Hb (HbO₂) from deoxygenated Hb (H.Hb). This H⁺ then reacts with HCO₃⁻ to form H₂CO₃.

(b) The low CO₂ tension in the lungs shifts the equilibrium towards the production of CO₂ which is continually eliminated in the expired air.

In the tissues:

(a) The reduced O₂ tension and the local acid­ity compel oxy-Hb (HbO₂) to deliver O₂ to the cell forming deoxygenated Hb (H.Hb).

(b) The metabolic CO₂ in the cells is hydrated to form H₂CO₃ which is dissociated to form H⁺ and HC0₃^–.

The deoxygenated Hb (H.Hb) is formed from oxygenated Hb(HbO₂) by the effect of H+ with the little change in pH.

Iso-hydric transport of CO₂:

The newly formed H⁺ in the tissues from H₂CO₃ does not bring about a change in pH. This circumstance in the role of Hb buffers is sometimes referred to as iso-hydric trans­port of CO₂.

Role of Respiration in Acid-base Regulation:

The respiratory mechanism depends on:

(a) The response of the respiratory centre (RC) in medulla oblongata to a very slight change in pH and pCO₂.

(b) The diffusibility of CO₂ from the blood into the alveolar air across the pulmonary alveolar membrane.

Therefore, the lungs become healthy for which diffusion of CO₂ occurs properly.

(i) 0.2 per cent increase in CO₂ results in 100 per cent increase in pulmonary ventila­tion which causes slight increase in H⁺ con­centration of the blood (acidosis). The excess CO₂ is promptly removed from the ECF in the expired air.

(ii) A decrease in H⁺ concentration (alkalo­sis) causes depression of respiratory cen­tre with slow and shallow respiration (hypoventilation) resulting in the reten­tion of CO₂ in the blood until the normal pCO₂ and pH are restored.

Hence, the respiratory mechanism tends to maintain the normal BHCO₃/H₂CO₃ ratio in the EC fluids.

Renal Mechanisms for Regulation of Acid- base Balance:

Kidneys are also involved in acid-base equilibrium.

(a) By eliminating the non-volatile acids, e.g., lactic acid, sulphuric acid, acetoacetic acid, β-hydroxy butyric acid, etc. after be­ing buffered with Na⁺ through the glomerular filtration.

(b) Na⁺ exists as NaHCO₃ (alkali reserve) in the renal tubules by reabsorption by the renal tubules in exchange of H⁺ which are secreted.

Three mechanisms are involved in the above mechanism:

i. Bicarbonate mechanism.

ii. Phosphate mechanism.

iii. Ammonia mechanism.

i. Bi-carbonate mechanism:

(a) Carbonic acid (H₂CO₃) is ionized as H⁺ and HCO₃⁻ and this H⁺ is mobilized for tubular secretion. The formation of H₂CO₃ from CO₂ and H₂O is catalysed by the zinc- containing enzyme carbonic anhydrase, present in real tubular epithelial cells. Car­bonic anhydrase is also present in RB cells, parietal cells of stomach, most of tissues, and small quantities in muscle tissue, pan­creas, spermatozoa as per recent informa­tion.

(b) All of the bicarbonate ions (HCO₃⁻) are normally reabsorbed by the proximal tu­bular epithelial cells but a slight excess of hydrogen ions (H⁺) remains in the tubules to react with other substances to be ex­creted in urine.

(c) In the tubular filtrate, hydrogen ions are exchanged against sodium ions.

(d) Increase in pCO₂ accelerates formation of H₂CO₃ and thus increases H⁺ secretion by the renal tubular epithelial cells which help in the reabsorption of HCO₃⁻.

(e) In the excess administration of K⁺, K⁺ quickly enters into the cell in exchange of H⁺ and hydrogen ions are buffered by bicarbonate of ECF for which plasma bi­carbonate content is diminished. As a re­sult, the renal tubular epithelial cells se­crete less hydrogen ions (H⁺), and less bi­carbonate ions (HCO₃⁻) are absorbed. The excretion of bicarbonate in urine becomes more and the urine becomes alkaline al­though ECF is acidic.

(f) The clinical importance shows that potas­sium ions (K⁺) leave the cell in K⁺ defi­ciency and hydrogen ions (H⁺) enter the cells producing intracellular acidosis. ECF becomes alkaline. Increased excretion of H⁺, NaH₂PO₄, and NH₄Cl increase the titratable acidity. ECF is though alkaline, highly acidic urine is excreted. This con­dition is referred to as paradoxic aciduria. This occurs in patients treated for long with cortisone, Cushing’s syndrome, and in patients with potassium free fluids.

(g) Increase in Cr causes decrease in HCO₃⁻_.

(h) The enzyme carbonic anhydrase is inhib­ited by Diamox. The urine becomes alka­line when the drug is administered and increased amount of NaHCO₃ appears in urine. There is reduction in titratable acid­ity and ammonia excretion in the urine. Drug is used clinically as a diuretic to in­duce a loss of Na⁺ and water in congestive cardiac failure and in hypertensive heart diseases.

ii. Phosphate mechanism:

(a) The ratio of plasma Na₂HPO₄ and NaH₂PO₄ determines the pH of the urine. The ratio of these two in plasma is main­tained to 4 : 1 if the concentration of Na₂HPO₄ exceeds that of NaH₂PO₄. But the ratio becomes 9: 1 if the concentra­tion of NaHPO₄ in urine exceeds that of Na₂HPO₄.

(b) The pH 7.4 of glomerular filtrate is changed to pH 6.0 or even as low as 4.8 in urine.

(c) Na⁺ is exchanged for secreted H⁺ which changes Na₂HPO₄ to NaH₂PO₄ resulting the increase in acidity of urine.

(d) This mechanism takes place in the distal tubule of kidney.

iii. Ammonia mechanism:

Na⁺ is conserved by the elimination of H⁺ for the production of NH₃ by the renal distal tubular epithelial cells.

Sources of NH₃:

(a) Glutamine is hydrolysed to produce NH₃ by the enzyme glutaminase present in these cells.

(b) It can be formed from other amino acid by oxidative deamination.

(c) It is also formed from glycine by glycine oxidase

Formation of NH₄:

NH₃ is diffused to the tubular filtrate where it combines with H⁺ to form NH₄⁺.

The renal glutaminase activity is enhanced by acidosis. NH₃ production is highly increased in metabolic acidosis and negligible in alkalosis.

Acid-base Imbalance in Normal Health:

Acidosis:

A. Metabolic acidosis;

B. Respiratory acidosis.

A. Metabolic acidosis:

(a) Metabolic acidosis occurs when a reduc­tion in plasma HCO₃⁻ (BHCO₃) takes place. In case, there is the deficit HCO₃, the ratio of [HCO3₃⁻]/[H₂CO₃] = 20/1 is decreased, i.e., pH is decreased causing metabolic aci­dosis.

(b) Acidosis stimulates the respiratory centre causing deep and rapid breathing. This in­creased ventilation results in CO₂ loss and reduction in [H₂CO₃]. Increased ventila­tion causes reduction in PCO₂ which in turn depresses the respiratory centre.

(c) Renal mechanisms can correct the distur­bances by conserving cations and by in­creasing NH₃ formation, H⁺ excretion in distal tubules, and reabsorption.

Causes:

(i) Abnormal increase in “anions” other than HCO₃⁻ caused from:

(a) Endogenous excessive production of acid ions occur in diabetic acidosis, lactic acidosis, starvation, high fever, violent exercise, hemorrhage, shock, and anoxia.

(b) Ingestion of excessive quantities of acids like phosphoric acid, hydro­chloric acid, salicylic acid, and mandelic acid, etc.

(c) Renal insufficiency causing retention of acids commonly observed in the terminal stages of nephritis, and de­structive renal lesions such as pyelonephritis, pyonephrosis, renal T.B., etc.

The main toots of these causes are:

(a) Decreased H⁺ – Na exchange.

(b) Decreased NH₃ formation.

(c) Decreased glomerular filtration with retention of acid radicals.

(d) Nephritic acidosis due to accumula­tion of certain organic acids.

(ii) Abnormal loss of HCO₃⁻ due to loss of base occurring in the loss of excessive intestinal secretions as in severe diarrheas, small bowel fistulas, and se­vere biliary fistulas.

B. Respiratory acidosis:

This is caused due to the increase in H₂CO₃ in the blood following elimination of CO₂(PCO₂) in the pulmonary alveoli. This results from breathing air containing abnormally high percentage of CO₂, and conditions in which elimination of CO₂ through lungs is retarded.

Mechanism:

(a) In the depression of respiratory centre, the excretion of CO₂ through lungs is im­paired causing more accumulation of CO₂ in blood for which there is excess forma­tion of H₂CO₃. So the ratio of [HCO₃₋]/ [H₂CO₃] is lowered resulting the decrease in pH.

(b) The increased CO₂ tension (PCO₂) causes the elevated stimulation to respiratory centre resulting increased ventilation. This mechanism is less effective.

(c) In renal mechanism, more HCO₃⁻ are reabsorbed from tubules responding to raised PCO₂ in blood and the ratio of [HCO₃⁻]/[H₂CO₃] is restored towards 20 : 1. This mechanism is an important one.

Causes:

A. Conditions Causing depression of respira­tion:

(a) Damage to CNS:

(i) Brain damage—trauma, inflamma­tion, and convulsive disorders.

(ii) Drug Poisoning—Morphine and bar­biturates.

(iii) Excessive anesthesia.

(iv) Bulbar Polio.

(b) Loss of ventilatory functions:

(i) Tension.

(ii) Pulmonary and mediastinal tumors.

(iii) Emphysema.

(c) Effect of pain, e.g., pleurisy.

B. Conditions causing impairment of diffu­sion of CO₂ across alveolar membrane:

(a) Emphysema.

(b) Pulmonary edema and congenital alveo­lar dysplasia.

C. Conditions in which there is an obstacle to the escape of CO₂ from:

The alveoli:

(a) Obstruction to respiratory tract-Laryngeal obstruction and asthma.

(b) Rebreathing from a closed space.

D. Conditions in which pulmonary blood flow is insufficient:

(a) Certain congenital heart diseases.

(b) Ayerza’s disease.

Alkalosis:

A. Metabolic Alkalosis:

(a) The accumulation of excess of HCO₃^– causes an increase in the ratio of [HCO₃^–]/ [H₂CO₃], i.e., pH is elevated.

(b) Alkalosis inhibits the respiratory centre (RC) developing irregular breathing. This reduced ventilation causes CO₂ retention and carbonic acid level [H₂CO₃] eleva­tion.

(c) Since the levels of both in blood are in­creased the ratio of [HCO₃^–]/[H₂CO₃] are restored towards 20:1.

(d) Decreased ventilation raises PCO₂ which stimulates the respiratory centre.

(e) In renal mechanisms, there is the increased excretion of cations, bicarbonates, K⁺ but reduced excretion of NH₃.

(f) There is the decreased urinary acidity and titratable acidity.

Causes:

(a) The excessive loss of HCl from stomach is associated with high intestinal obstruc­tion, pyloric obstruction, pylorospasm in infants.

(b) Na⁺ and K⁺ are mainly retained in the body in the form of bicarbonate due to the loss of Cl^– from the blood. Thus, a neutral salt (NaCl) is replaced by an alkaline salt (NaHCO₃).

(c) Excessive intake of bases like NaHCO₃, and acetates, lactates, citrates of sodium and potassium. Lactates and citrates are converted into HCO₃^–_.

(d) Potassium deficiency.

(e) Deep X-ray therapy, radium therapy, and prolonged exposure to ultra violet rays cause a decrease in the H⁺ concentration in the blood plasma.

(f) Excessive vomiting.

Clinical manifestations:

Alkalosis is observed in:

(a) Decreased ionic calcium in blood produc­ing tetany.

(b) Hypokalemia due to the increased excre­tion of K⁺ from the distal tubules.

(c) Kidney damage caused by the degenera­tive changes in the tubules (nephrosis) oc­curring with oliguria and nitrogen reten­tion.

(d) Ketosis and ketonuria due to excessive vomiting for the insufficient carbohydrate intake.

B. Respiratory Alkalosis:

Respiratory alkalosis occurs when there is a de­crease in [H₂CO₃] with no change in HCO₃ in plasma. As a result, pH is increased.

Mechanism:

(a) [H₂CO₃] is reduced as a result of increased loss of CO₂ and the ratio of [HCO₃^–]/ [H₂CO₃] is elevated for which pH is in­creased.

(b) Owing to increased loss of CO₂ less bicar­bonate is reabsorbed by the renal tubules for which the ratio of [HCO₃^–]/[H₂CO₃] re­turns towards normal (20: 1).

(c) The respiratory centre is depressed by al­kalosis and PCO₂ and CO₂ excretion is reduced.

(d) In renal mechanism, there are excretion of alkali in the form of bicarbonate, de­creased excretion of acid, decreased ex­cretion of ammonia, and retention of chlo­ride ion (Cr) in the blood.

(e) Other features are the same as that of meta­bolic alkalosis.

Causes:

(a) The respiratory centre (RC) is stimulated by CNS diseases like meningitis, encepha­litis due to hyperventilation in some cases of these diseases manifesting hyperpnea over long periods.

(b) Large doses of salicylate cause stimula­tion of respiratory centre (RC) with hy­perventilation showing alkalosis.

(c) Hyperventilation is caused by the in­creased respiratory rate associated with increased body temperature.

(d) Hysterical attacks cause hyperventilation and hyperventilation tetany with alkalo­sis is also observed in hyper-excitable do­nors.

(e) Hyperpnoea occurring in untrained indi­viduals ascending to high altitudes results in H₂CO₃ deficit and alkalosis.

(f) Hepatic coma is also another cause of res­piratory alkalosis.

(g) Injudicious use of respirator.