50 to 100 m mol of H ions produced daily in to 15 to 20 liters of ECF
PHOSPHORIC ACIDS
Dietry sources , casien Phosphoprotein
From nucleoprotein and phosphtides
SULPHURIC ACIDS
Oxidation of sulpher containing amino acids
Cysteine Cystine Methionine
Citric acids
Dietry sources ( fruits & vegetables)
Pyruvic acids End product of aerobic
glycolysis
Lactic acids
End product Anaerobic glycolysis
RBC SKELTAL MUSCLES (EXERCISE) CONVERTS TO GLUCOSE IN LIVER
CARBONIC ACIDS
20 MOLES / 24 HOURS Formed from carbon dioxide and
water CO2 + H2O H2CO3 H + + HCO3
–
Abnormal production of organic acids
Acetoacetate Beta hydroxy butyric acids Acetone Called them ketone bodies
Conversion of amino nitrogen to urea
Produces hydrogen ion
I. regulation of acid-base balance
1. origin of acid and base in the body volatile acid: H2CO3 (20mol/day) sulfuric acid 1) acids phosphoric acid fixed acid: uric acid (90mmol/L) mesostate 2) base: salt of organic acid; NH3 mesostate ( product of metabolic action)
Types of Acids in the Body
• Volatile acids:• Can leave solution and enter the atmosphere.
• H2C03 (carbonic acid).
• Pco2 is most important factor in pH of body tissues.
Types of Acids in the Body
• Fixed Acids:• Acids that do not leave solution.• Sulfuric and phosphoric acid.• Catabolism of amino acids, nucleic acids,
and phospholipids.
Types of Acids in the Body
• Organic Acids:• By products of aerobic metabolism,
during anaerobic metabolism and during starvation, diabetes.
• Lactic acid, ketones.
Buffer
• Defined as a solution containing two or more chemical components that resist in change in pH, when a strong acid or base is added to it.
• It usually consists of; • a week acid and• its conjugate base.
• The normal processes of metabolism result in the net formation of ;
• 50-100 mmol of hydrogen ions per 24 h, principally from the oxidation of sulphur-containing amino acids.
• This burden of hydrogen ions is excreted by the kidneys, in the urine.
Sources of H+ in the body
• Incomplete oxidation of energy substrates generates acid e.g.
lactic acid by glycolysis, ketoacids from triacylglycerols,• While further metabolism of these intermediates
consumes it e.g. gluconeogenesis from lactate, oxidation of ketones.
Sources of H+ in the body
• Temporary imbalances between the rates of production and consumption may arise in health (e.g. the accumulation of lactic acid during anaerobic exercise),
• But overall they are in balance and so make no contribution to net hydrogen ion excretion.
Sources of H+ in the body• 1. A.A Metabolism: Conversion of A.A to
urea and sulphydryl groups of A.A to sulphate releases H+.
• 50 – 100 m mol of H+ are produced per day and released in E.C.F.
• But contribution of H+ in E.C.F is 35 – 45 n mol/l at pH 7.36 – 7.42.
• Excess is excreted by kidneys
Hydrogen Ions Homeostasis• Hydrogen ions can be incorporated into water.
H+ + HCo3– H2CO3 H2O + CO2
• This is normal mechanism during oxidative phosphorylation.
• As this reaction is reversible, H+ is inactivated by combining with HCO3
– only if the reaction is driven to the right by the removal of CO2.
• By itself this would cause bicarbonate depletion.
• Buffering of hydrogen ions is a temporary measures as the H+ has not been excreted from the body.
• The production of weak acid of the buffer pair causes only a small changes in pH.
• If hydrogen ions are not completely;• neutralized or • eliminated from the body and • if production continues, • buffering power will eventually be so depleted
that the pH will change significantly.
• Hydrogen ions can be lost from the body only through the kidneys and the intestine.
• This mechanism is coupled with the generation of bicarbonate ion (HCO3
-) .
• In the kidney this is the method by which secretion of excess H+ ensures regeneration of buffering capacity.
• Bicarbonate system is the most important buffer in the body because:
• It accounts for over 60 percent of the blood buffering capacity;
• It is necessary for efficient buffering by haemoglobin, which provides most of the rest of the blood buffering capacity;
• H+ secretion by the kidney depends on it.
The control of CO2 (Pco2) by the Respiratory Centre and Lungs• The partial pressure of CO2 in plasma is
normally about 5.3kPa (40 mmHg).
• The rate of respiration and therefore the rate of CO2 elimination, is controlled by
• chemoreceptors in the respiratory centre in the medulla of the brainstem
• cartoid and • aortic bodies.
• The receptors respond to changes in the [CO2] or [H+] of plasma or of the cerebrospinal fluid.
• If the Pco2 rises much above 5.3 pKa or, if the pH falls, the rate of respiration increases.
• Normal lungs have a very large reserve capacity for CO2 elimination.
The Control of Bicarbonate by The Kidneys and Erythrocytes
• The renal tubular cells and • erythrocytes • generate bicarbonate, the buffer base in the
bicarbonate system, from CO2.
• Under physiological conditions:
• The erythrocytes mechanism makes fine adjustments to the plasma bicarbonate concentration in response to changes in Pco2 in the lungs and tissues:
• The kidneys play the major role in maintaining the circulating and in eliminating H+ from the body.
The Carbonate Dehydratase System
• Bicarbonate is produced following the dissociation of carbonic acid formed from CO2 and H2O.
• This is catalysed by carbonate dehydratase (CD; carbonic anhydrase), present in high concentration in erythrocytes and renal tubular cells.
• CD• CO2 + H2O H2CO3 H+ + HCO3
-
• Not only do erythrocytes and renal tubular cells have a high concentration of CD,
• But they also have means of removing one of the products, H+; thus both reactions continue to the right and HCO3
- is formed.
• One of the reactants, water, is freely available and one of the products, H+, is removed.
• HCO3- generation is therefore accelerated if the
concentration of:
• CO2 rises;
• HCO3- falls;
• H+ falls because it is either buffered by erythrocytes or excreted from the body by renal tubular cells.
Bicarbonate Generation by the Erythrocytes
• Haemoglobin is an important blood buffer.
• However it only works effectively in cooperation with the bicarbonate system.
• pH = pK + log[Hb-] / [HHb]
• Erythrocytes produce little CO2 as they lack aerobic pathways.
• Plasma CO2 diffuses along a concentration gradient into erythrocytes, where carbonate dehydratase catalyses its reaction with water to form carbonic acid (H2CO3) which then dissociates.
• Much of the H+ is buffered by the haemoglobin and the HCO3
– diffuses out into the extracellular fluid along a concentration gradient.
• Electrochemical neutrality is maintained by diffusion of chloric in the opposite direction into cells.
• This movement of ions is known as the chloride shift.
• Extra and Intracellular buffer other than bicarbonate and haemoglobin do not contribute significantly to blood buffering.
• They include; Phosphate & Proteins buffers
• Phosphate; which has a plasma concentration of about 1 mmol/L, but a higher concentration in bone and inside cells where buffering capacity is of more importance;
• Proteins which, because of their low concentration in plasma, also have little blood buffering capacity.
THE NEPHRON
• The functional unit of the kidney is a nephron.
• Each kidney contains approximately 1 to 1.5 million nephrons.
• A nephron is in fact a long microscopic tubule, consisting of different anatomic and functional units and supplied by a rich blood supply.
The structure of the nephron and the processes of urine formation. (Source: Pearson Education/PH College)
• Tubular reabsorption• Include water and electrolytes
• Tubular secretion• Urine concentration
03/05/20
11
72
Urine formation requiers :
Urine Formation
Glomerular Filtration Due to differences in pressure water,
small molecules move from the glomerulus capillaries into the glomerular capsule
a)
b)
Tubular reabsorption many molecules are reabsorbed from the nephron into the capillary (diffusion, facilitated diffusion, osmosis, and active transport)i.e. Glucose is actively reabsorbed with transport carriers.If the carriers are overwhelmed glucose appears in the urine indicating diabetes
Urine Formation
Tubular secretionSubstances are actively removed from blood and added to tubular fluid (active transport)ie. H+, creatinine, and some drugs are moved by active transport from the blood into the distal convoluted tubule
c)
The Kidneys
• Hydrogen ions are secreted from renal tubular cells into the lumina where they are buffered by constituents of the glomerular filtrate.
• Unlike haemoglobin in erythrocytes, urinary buffers are constantly being replenished by continuing glomerular filtration.
• For the above mentioned reason, • and because most of the excess H+ can only be
eliminated from the body by the renal route. The kidneys are of major importance in compensating for chronic acidosis.
• Without them the haemoglobin buffering capacity would soon become saturated.
• Two renal mechanism control [HCO3-] in the
extracellular fluid:
• Bicarbonate reclamation (reabsorption), the predominant mechanism in maintaining the steady state.
• The CO2 driving the carbonate dehyderatase mechanism in renal tubular cells is derived from filtered bicarbonate.
• There is no loss of hydrogen ions.
• Bicarbonate generation, a very important mechanism for correcting acidosis.
• In which the level of CO2 or [HCO3-] affecting
the carbonate dehyderatase reaction in renal tubular cells reflect those in the extracellular fluid.
• There is a net loss of hydrogen ions.
Bicarbonate Reclamation• Normal urine is almost bicarbonate-free.
• An amount equivalent to that filtered by the glomeruli is returned to the body by the tubular cells.
• The luminal surfaces of renal tubular cells are impermeable to bicarbonate.
Bicarbonate Reclamation• Therefore bicarbonate can only be returned to
the body if ;
• first converted to CO2 in the tubular lumina and
• an equivalent amount of CO2 converted to bicarbonate within tubular cells.
• The mechanism depends on the actions of carbonate hydratase, both in the brush border on the luminal surfaces and within the tubular cells and on H+ secreted into the lumina in exchange for sodium.
• The sequence of events, which occurs predominantly in the proximal tubules but also in the first part of the distal tubules.
• Bicarbonate is filtered through the glomeruli at a plasma concentration about 25 mmol/L.
• Filtered bicarbonate combines with H+, secreted by tubular cells, to form H2CO3.
• The H2CO3 dissociates to form CO2 and water.
• In the proximal tubules this reaction is catalysed by carbonate dehydratase in the brush border.
• In the distal tubules, where the pH is usually lower, H2CO3 probably dissociates spontaneously.
• As the luminal PCO2 rises, CO2 diffuses into tubular cells along a concentration gradient.
• As the intracellular concentration of CO2 rises, carbonate dehydratase catalyse its combination with water to form H2CO3.
• Which dissociates into H+ and HCO3-.
• H+ is secreted in the tubular lumina in exchange for sodium ions and so the reactions start again from the second stage.
• As the intracellular concentration of HCO3-
rises, HCO3- diffuses into the extracellular
fluid accompanied by sodium.
• Which has been reabsorbed in exchange for H+.
• This self-perpetuating cycle reclaims buffering capacity that would otherwise have been lost from the body by glomerular filtration.
• The secreted H+ is derived from cellular water and is incorporated into water in lumina.
• Because there is no net change in hydrogen ion balance.
• And no net gain of bicarbonate, this mechanism cannot correct an acidosis but can maintain a steady state.
Bicarbonate Generation
• The mechanism in renal tubular cells for generating bicarbonate is identical with that of bicarbonate ‘reabsorption’,
• But there is net loss of H+ from the body as well as a net gain of HCO3
-.
• Therefore this mechanism is well suited to correct any type of acidosis.
• Within tubular cells, carbonate dehydratase may be stimulated by;
• A rise in PCO2: In this case the rise in CO2 is the indirect result of rise in the extracellular PCO2.
• Renal tubular cells, unlike erythrocytes with anaerobic pathways, constantly produce CO2 aerobically.
• This diffuses out of cells into the extracellular fluid along a concentration gradient.
• An increase in extracellular PCO2, by reducing the gradient, slows this diffusion and the intracellular PCO2 rises.
• A fall of [HCO3-]: Reduction of extracellular
[HCO3-], by increasing the concentration
gradient across renal tubular cell membranes, increase the loss of HCO3
- from cells.
• Normally almost all the filtered bicarbonate is ‘reabsorbed’.
• Once the luminal fluid is bicarbonate-free, continued secretion of H+ and the intracellular generation of HCO3
- depends on the presence of other filtered buffer bases (B-).
URINARY BUFFER
• The two most important urinary buffer other than bicarbonate are:
• phosphate and • ammonia; • they are also involved in bicarbonate
generation.
Urinary Buffer• 1. Phosphate Buffer Pair:• In plasma and in glomerular filtrate at pH 7.4, most
of the phosphate is in HPo4–2 (mono-hydrogen
phosphate) form.• It can combine with H+ e.g.
• HPO4–2 + H+ H2PO4
– Excreted in urine
• with each H+ ion secreted, one HCO3– is generated
which is returned back to plasma. • In acidosis, more and more phosphate is released
from bone.•
• Phosphate is normally the most important buffer in the urine .
• Because its pKa is relatively close to the pH of the glomerular filtrate and
• because the concentration of phosphate increase 20-fold to nearly 25mmol/L as water is reabsorbed from the tubular lumen.
• Even in a mild acidosis more phosphate ions are released from bone than at normal pH;
• the need of increase urinary H+ secretion is linked with increased buffering capacity in the glomerular filtrate due to the increase of phosphate.
• The Role of Ammonia:• As the urine becomes more acidic it can be
shown to contain increasing amounts of ammonium ion (NH4
+).
• Urinary ammonia probably allows H+ secretion and therefore bicarbonate formation to continue after other buffers have been depleted.
• The Role of Ammonia:
• Ammonia produced by hepatic deamination of amino acids is rapidly incorporated
• into urea • with a net production of hydrogen ions.
• The fate of the glutamate (GluCOO-) produced at the same time as the ammonium ion.
• However, as the systemic hydrogen ion concentration increases,
• there is some shift from urea to glutamine synthesis with a slight fall in hepatic H+ production.
• Glutamine (gluCONH2) is taken up by renal tubular cells
• where it is hydrolysed by glutaminase to glutamate (gluCOO-) and ammonium ion.
• After further deamination to 2-oxoglutarate• it can be converted to glucose;
gluconeogenesis uses an equivalent amount of H+ to that of NH4
+ produced from glutamine.
• Therefore, the H+ liberated into the cell is probably incorporated into glucose.
• A shift from urea synthesis to glutamine production in the liver with a fall in systemic H+ production in the presence of an acidosis.
Increase in acid excretion; increase in reabsorption of HCO3
Respiratory Alkalosis
in plasma pCO2
in plasma HCO3
Suppression of acid excretion; decrease in reabsorption of HCO3
Non-respiratory (metabolic) acidosis
• The primary abnormality in non-respiratory acidosis is either
• increased production or
• decreased excretion of hydrogen ions other than from carbon dioxide.
Non-respiratory (metabolic) acidosis
• In some cases, both may contribute.
• Loss of bicarbonate from the body can also, indirectly, cause an acidosis.
• Excess hydrogen ions are buffered by bicarbonate and other buffers.
• The carbonic acid thus formed dissociates and the carbon dioxide is lost in the expired air.
• This buffering limits the potential rise in hydrogen ion concentration.
• But at the expense of a reduction in bicarbonate concentration.
• The latter is always a feature of non-respiratory acidosis.
• Compensation is effected by hyperventilation.
• Which increases the removal of carbon dioxide and lowers the PCO2.
• The PCO2/[HCO-3] ratio falls, thus tending to reduce the [H+].
• Hyperventilation is a direct result of the increased [H+] stimulating the respiratory center.
• Respiratory compensation can not completely normalize the [H+].
• Since it is the high concentration itself that stimulates the compensatory hyperventilation.
• Furthermore, the increased work of the respiratory muscles produces carbon dioxide,
• thereby limiting the extent to which the Pco2 can be lowered.
• If the cause of the acidosis is not corrected, a new steady state may be attained;
• with a raised [H+],
• low bicarbonate and
• low pCO2.
• The extent to which compensation can take place will be limited if respiratory function is compromised.
• Even with normal respiratory function, it is exceptional for a pCO2 of <1.5 kPa (11.3 mmHg) to be recorded, however severe the non-respiratory acidosis.
• In a healthy person, hyperventilation would produce a respiratory alkalosis.
• In general, the compensatory mechanism for any acid-base disturbance involves the generation of a second, opposing disturbance.
• In the case of a metabolic acidosis, • compensation is through the generation of a respiratory alkalosis (although this only limits the severity of the acidosis: the patient does not become alkalotic).
• In a respiratory acidosis, compensation is through the generation of a metabolic alkalosis.
• If renal function is normal in a patient with non-respiratory acidosis, excess hydrogen ions can be excreted by the kidneys.
• However, in many cases there is impairment of renal function, although this may not be the primary cause of the acidosis.
• The complete correction of a non-respiratory acidosis requires;
• reversal of the underlying cause.
• For example • rehydration and • insulin for diabetic ketoacidosis and• removal of salicylate in salicylate overdose.
• It is important to maintain adequate renal perfusion to maximize renal hydrogen ion excretion.
• The use of exogenous bicarbonate to buffer hydrogen ions.
Increased production of hydrogen ions
• This is the cause of the acidosis in ketoacidosis (diabetic, alcoholic),
• lactic acidosis and acidosis seen in poisoning, for example with salicylate and ethylene glycol.
Decreased excretion of hydrogen ions • Acidosis occurs in renal glomerular failure
when the decreased glomerular filtration causes a reduction in the amount of sodium that is filtered and,
• therefore, available for exchange with hydrogen ions.
• The amount of phosphate filtered and available for buffering also decreases.
Loss of bicarbonate
• Loss of bicarbonate and retention of hydrogen ions can result in acidosis in patients losing alkaline secretions from the small intestine (e.g. through fistulae).
• In the stomach, bicarbonate generated from carbon dioxide and water diffuses into the blood and hydrogen ions are secreted into the lumen.
• In the pancreas and small intestine;
• the movements of bicarbonate and
• hydrogen ions occur in the opposite directions thus hydrogen ions that are secreted into the stomach lumen are neutralized by bicarbonate in the small intestine.
• Under normal circumstances, since most of the fluid and ions secreted into the gut are reabsorbed, the gut is effectively a closed system with regard to acid-base balance.
• If, however, alkaline secretions are lost, the patient is at risk of becoming acidotic.
• Increased renal hydrogen ion excretion (with generation and retention of bicarbonate) may prevent this,
• But excessive fluid loss from the gut may deplete the ECF to such an extent that the glomerular filtration rate falls and the kidneys are no longer able to compensate.
Use of Anion Gap to Diagnose Acid-Base Disorders• The concentrations of anions and cations in
plasma must be equal to maintain electrical neutrality
• Therefore, there is no real “anion gap” in the plasma
• However, only certain cations and anions are routinely measured in the clinical laboratory
• The cation normally measured is Na+, and the anions are usually Cl– and HCO3
–
• The “anion gap” (which is only a diagnostic concept) is the difference between unmeasured anions and measured cations, and is estimated as
• Plasma anion gap
= [Na+] – [HCO3–] – [Cl–]
= 140 – 25 – 100 = 15 mEq/L
• The anion gap will increase if unmeasured anions rise or if unmeasured cations fall
• The most important unmeasured cations include
• calcium, • magnesium,• potassium
• The major unmeasured anions are;• albumin, • phosphate, • sulfate, and other organic anions• Usually the unmeasured anions exceed the
unmeasured cations, and• the anion gap ranges between 8 and 16
mEq/L
•With potassium
• The anion gap is calculated by subtracting the serum concentrations of chloride and bicarbonate (anions)
• from the concentrations of • sodium and potassium (cations):
• Omission of potassium has become widely accepted, as potassium concentrations, being very low, usually have little effect on the calculated gap. This leaves the following equation:
• = [Na+] − ([Cl-] + [HCO3−])
• 140 − (100 + 25) = 15
• The plasma anion gap is used mainly in diagnosing different causes of metabolic acidosis
• In metabolic acidosis, the plasma HCO3– is
reduced
• If the plasma sodium concentration is unchanged, the concentration of anions (either Cl– or an unmeasured anion) must increase to maintain electro neutrality
• If plasma Cl– increases in proportion to the fall in plasma HCO3
–, the anion gap will remain normal, and this is often referred to as
• hyperchloremic metabolic acidosis or • normal anion gap metabolic acidosis
• If the decrease in plasma HCO3– is not
accompanied by increased Cl–, there must be increased levels of unmeasured anions .
• Therefore an increase in the calculated anion gap
• Metabolic acidosis caused by excess nonvolatile acids (besides HCl),
• such as lactic acid or• ketoacids, is associated with an increased
plasma anion gap because the fall in HCO3– is
not matched by an equal increase in Cl–
• By calculating the anion gap, one can narrate some of the potential causes of metabolic acidosis
The Anion Gap• The Anion Gap:• Na+ & K+ provide 90% of plasma cation
con.• remaining is from Ca+, Mg+ etc.
• While 80% of Anion — Cl– & HCO3–,
• 20% is unmeasured which are protein, urate, phosphate, sulphate, lactate & organic acids etc.
• which are about 15 – 20 mg/l
Anion GapSodium - (chloride + bicarbonate)
• Normal Anion Gap– Hyperchloremic acidosis– GI or renal Loss of
• Ketoacidosis• Advanced Renal Failure• Drug and Toxin Induced
The Anion Gap• The anion gap is represented as A– in the
following equations, is the difference between the total concentration of measured cations (sodium and potassium) and measured anions (chloride and bicarbonate); it is normally about 15 to 20 mEq/L.
• [Na+] + [K+] = [HCO3–] + [Cl–] + [A–]
• 140 + 4 = 25 + 100 + 19• In the following examples, in which the
abnormal figures are in Bold type, fallen by 10mmol (mEq)/L
Increase in Anion Gap Acidosis• In renal glomerular dysfunction even if
tubular function is normal.• Bicarbonate generation is impaired because
the amount of sodium available for exchange with H+
• And the amount of filtered buffer anion B- available to accept H+ are both reduced.
• These buffer anions contribute to the unmeasured anion (A–).
• For each mEq of buffer anion retained, one mEq fewer H+ can be secreted and therefore one mEq fewer HCO3
– is generated.
• The retained A- therefore replace HCO3-.• There is no change in chloride in
uncomplicated cases.
• [Na+] + [K+] = [HCO3–] + [Cl–] + [A–]
• 140 + 4 = 15 + 100 + 29 mEq/L
• The [HCO3–] has fallen from 25 to 15 mEq/L
• And the anion gap, entirely due to [A–] has risen by the same amount from 19 to 29 mEq/L.
• If renal bicarbonate generation is so impaired that it cannot keep pace with its peripheral utilization the pH will fall.
Increase in Anion Gap• In renal glomerular and tubular dysfunction,
• HCO3– generation is ↓,
• Na+ excretion is also ↓ and• B– buffer excretion is also ↓. • Plasma conc. of B– is increased• So less amount of H+ are excreted or replaced by
HCO3–.
• So accumulation of anions results due to renal failure.
• [Na+] + [K+] = [HCO3–] + [Cl–] + [A–]
• 140 + 4 = 15 + 100 + 29
• Acidosis occurs which is compensated by respiration.
• Cause of the low(HCO3) becomes obvious if urea and S. creatinine are measured and treatment is only dialysis.
↑ in single anion X – other than Cl– AND A –
• In ketoacidosis• and lactic acidosis — (X–) is ↑
with equimolar amount of (H+)• Acetoacetate and 3-hydroxybutyrate in
ketoacidosis; • Lactate in lactic acidosis.
Some weak acids and their conjugate bases, present in biological fluids Acid Conjugate base
Carbonic Acid H2Co3 ↔H+ + HCO3
– Bicarbonate ion
Dihydrogen Phosphate H2Po4
– ↔H+ + HPo42– Monohydrogen
phosphate ion
Ammonium Ion NH4
+ ↔H+ + NH3 Ammonia
Lactic Acid CH3CHOHCOOH ↔H+ + CH3CHOHCOO– Lactate ion
• In both these syndromes the rise in [X–] is • due to overproduction rather than• reduced excretion, • with the simultaneous production of
equimolar amounts of H+.
• The reduction of [HCO3-] results from its use in buffering the H+ which accompanies the X-.
• [Na+] + [K+] = [HCO3–] + [Cl–] + [A–] + [X–]
• 140 + 4 = 15 + 100 + 19 + 10
• In this example the [HCO3–] has fallen from
25 to 15 mEq/L and has been replaced by 10mEq/L of X–.
• The anion gap of 29 mEq/L is the sum of [A–] and [X–].
• In the uncomplicated cases there is no change in chloride concentration.
• The diagnosis of the underlying disorder is usually obvious and includes:
• Diabetic ketoacidosis, the commonest cause.
• Occasionally starvation ketosis can be severe enough to cause mild acidosis.
• Lactic acidosis due to:• Impaired aerobic metabolism• because of reduced tissue blood flow in the • shocked, • hypotensive patient, the commonest cause.
• This may aggravate acidosis due to ketoacidosis; such as phenformin or an over dosage of salicylates by interfering with lactate metabolism.
• Therefore a drug history should be taken;
• if low plasma [HCO3–] is found for no
immediately obvious reason.
• Loss of mixture of Anions and cations.• In this group electrochemical neutrality is
maintained by;• loss of cation (sodium) • and anion (bicarbonate) in equivalent amounts • and the anion gap is unaffected.
• The losses are variable and the affects depends on fluid intake.
• [Na+] + [K+] = [HCO3–] + [Cl–] + [A–]
• 130 + 4 = 15 + 100 + 19 mEq/L
• Loss of intestinal secretion.
• Duodenal fluid with a bicarbonate concentration about twice that of plasma, is alkaline.
• If the rate of loss, for example through small intestinal fistulae, exceeds that of the renal ability to regenerate HCO3
– , the plasma [HCO3
–] may fall enough to cause acidosis.
Loss of intestinal secretion.
• Colorectal cancer is one of the most highly diagnosed cancers in Canada.
• Surgical removal of the malignant tumor is the most common treatment for this cancer.
• • The diseased portion of the colon and/or
rectum is removed, and in most cases, the healthy portions are reattached (often referred to as anastomosis).
Loss of intestinal secretion.• Sometimes, that is not possible because of the
extent of the disease or its location.
• In this case, a surgical opening is made through the abdomen to provide a new pathway for waste elimination.
• This is what is commonly referred to as an ostomy.
Normal Anion Gap Acidosis or ↑ in [Cl–]• In the cases discussed so far [Cl–] is relatively
unchanged.
• The combination of low plasma [HCO3–] and
a high [Cl–] known as hyperchloraemic acidosis, is rare.
• The anion gap in such cases is normal.
• [Na+] + [K+] = [HCO3] + [Cl–] + [A–]
• 140 + 4 = 15 + 110 + 19
• The causes which can usually be predicted on clinical grounds include:
• HCO3– loss in a one-to-one exchange for Cl–.
• This occurs if the ureters are transplanted into the ileum or colon, usually after cystectomy for carcinoma of the bladder.
• If chloride containing fluid such as urine enters the ileum, ileal loops or colon, the cells exchange some of the chloride for HCO3
–.
• Bicarbonate depletion may occur, large does of oral bicarbonate are needed to prevent hyperchloraemic acidosis.
• Impaired hydrogen ion secretion and therefore bicarbonate production due to renal tubular disease
• If the tubular ability to handle H+ is an isolated abnormality and other functions are relatively unimpaired hyperchloraemic acidosis results.
• In normal tubules most filtered sodium is reabsorbed with chloride; the rest is exchanged for secreted H+ or K+.
• If H+ secretion is impaired and yet the same amount of sodium is reabsorbed, Na+ must be accompanied by Cl– or exchanged for K+.
• This type of hyperchloraemic acidosis is therefore often accompanied by hypokalaemia – an unusual finding in acidosis, which is usually associated with hyperkalaemia.
Because Cl– rich urine enters the intestine and due to con. gradient Cl– is absorbed and HCo3
– is excreted.
• Two causes of hyperkalaemia hyperchloraemic acidosis are:
• Renal tubular acidosis
• Administration of carbonate dehydratase inhibitors as in the treatment of glaucoma.
. simple acid-base disturbance 1. metabolic acidosis concept: the primary disturbance is a decrease
of [HCO-3] in the arterial plasma
1) cause and pathogenesis lactic acidosis: hypoxia, diabetes liver disease ketoacidosis: diabetes, starvation ① metabolic acidosis in severe renal failure: fixed acids increased AG salicylic acid acid poisoning: intake food
diarrhea; GI: intestinal suction (loss of intestinal fistula
HCO-3) biliary fistula
② metabolic acidosis in early renal failure: normal AG NH3 secretion H+ secretion Renal tubular
acidosis: H+ secretion kidney: depressant of C.A. (loss of acetazolamide
HCO-3) intake of Cl-
NaCl, NH4Cl Hyperkalemia
• The characteristic biochemical changes seen in the blood in non-respiratory acidosis can be summarized as follows:
• Non-respiratory acidosis[H+] ↑
pH ↓
pCO2 ↓
[HCO3-] ↓↓
• The decrease in pCO2 is a compensatory change; the decrement in pCO2 is approximately 0.17 kPa (1.3 mmHg) per mmol/l decrease in the concentration of bicarbonate.
• Changes due to the underlying condition will also be present.
• Hyperkalaemia is common in acidotic patients, except in bicarbonate-wasting conditions.
Respiratory acidosis
• There are many conditions associated with the development of respiratory acidosis.
• They are all characterized by an increase in pCO2.
• For every hydrogen ion that is produced, a bicarbonate ion is also generated.
• With an acute rise in pCO2, every 1 kPa (7.5 mmHg) increase is associated with a concomitant increase in bicarbonate concentration of less than 1 mmol/l
• But in [H+] of only 5.5 nmol/l:
• This apparent discrepancy occurs because the majority of the hydrogen ions are buffered by intracellular buffers, particularly haemoglobin.
• In chronic carbon dioxide retention, when renal compensation is maximal;
• the [H+] is increased by only 2.5 nmol/L for
each 1 kPa (7.5 mmHg) rise in pCO2
• Whereas bicarbonate concentration increases by 2-3 mmol/L.
• A respiratory acidosis can only be corrected by means that restore the pCO2to normal
• But, if a high pCO2 persists, compensation occurs through increased renal hydrogen ion excretion.
• In acute respiratory acidosis, unless very severe,
• the bicarbonate concentration, although increased, is usually within the reference range.
• If the bicarbonate concentration is clearly elevated in a respiratory acidosis,
• either a more chronic course with renal compensation
• or a coexisting non-respiratory alkalosis is suggested.
• A low bicarbonate would suggest
• a coexisting non-respiratory acidosis.
Acute Chronic
[H+] ↑ Slight ↑ or high-normal
pH ↓ Slight ↓ or low-normal
PCO2 ↑ ↑
[HCO3-] Slight ↑ ↑
Respiratory acidosis
. respiratory acidosis concept: The primary disturbance is an
elevation in plasma [H2CO3]
1) cause and pathogenesis
Barbital
depression of CNS head injury
① CO2 breathe paralysis of respiratory muscles
out disease of airway or lung
chest injury
② inhalation of CO2
Metabolic Alkalosis
• May result from• a) the excessive loss of hydrogen ions,
• b) the excessive reabsorption of bicarbonate
• c) the ingestion of alkalis.
Metabolic Alkalosis• a) Excess H+ loss: gastric secretions contain
large quantities of hydrogen ions.
• Loss of gastric secretions, therefore, results in a metabolic alkalosis.
• This occurs in prolonged vomiting for example, pyloric stenosis or anorexia nervosa.
Metabolic Alkalosis• b) Excessive Reabsorption of Bicarbonate: as
discussed earlier ;• bicarbonate and chloride concentrations are
linked.
• If chloride concentration falls or chloride losses are excessive
• Then bicarbonate will be reabsorbed to maintain electrical neutrality.
Metabolic Alkalosis• b) Excessive Reabsorption of Bicarbonate: • Chloride may be lost from the gastro-intestinal
tract
• Therefore, in prolonged vomiting it is not only the loss of hydrogen ions that results in the alkalosis
• But also chloride losses resulting bicarbonate reabsorption.
Metabolic Alkalosis• Chloride losses may also occur in the kidney
usually as a result of diuretic drugs.
• The thiazide and loop diuretics a common cause of a metabolic alkalosis.
• These drugs cause increased loss of chloride in the urine resulting in excessive bicarbonate reabsorption.
Metabolic Alkalosis
• c) Ingestion of Alkalis: alkaline antacids when taken in excess may result in mild metabolic alkalosis.
• This is an uncommon cause of metabolic alkalosis.
Metabolic alkalosis
concept: the primary disturbance is
an increase of [HCO-3] in the
arterial plasma
1) causes and pathogenesis
digestive tract
vomiting; gastric suction(loss of HCl)
①loss diuretics distal flow rate
of H+ (furosemide) blood volume
kidney hyperaldosteronism H+-Na+exchange
H+-K+exchange between
Hypokalemia intra- and extra-cell
renal secretion of H+
hypochloremia
renal secretion of H+
NaHCO3
②intake transfusion of banked blood of base (citrate) 2) compensation of the body ① respiration compensation are limited (hypoxia) ② cells compensation hypokalemia ③ kidney pH inhibition of carbonic anhydrase (C.A.)
secretion of H+
Three moles of H+ is consumed with each mole of citrate metabolized
Non-respiratory (metabolic) alkalosis
• Non-respiratory alkalosis is characterized by
• a primary increase in the ECF bicarbonate concentration,
• with a consequent reduction in [H+].
Non-respiratory (metabolic) alkalosis• In normal subjects, increases in plasma
bicarbonate concentration lead• to incomplete renal tubular bicarbonate
reabsorption and • excretion of bicarbonate in the urine.
• Massive quantities of bicarbonate must be ingested to produce a sustained alkalosis.
• Since the body is a net producer of acid, it might be supposed;
• that non-respiratory alkalosis should be corrected by normal acid production.
• In practice, and in contrast to non-respiratory acidosis and to respiratory disorders of acid-base balance,
• a non-respiratory alkalosis may persist even after the primary cause has been corrected.
• It is thus necessary to consider both the mechanisms that can cause non-respiratory alkalosis and those that can perpetuate it.
• Causes of non-respiratory alkalosis.
• They can be divided into • those associated with chloride or• ECF volume depletion (sometimes termed
'saline-responsive') • And those in which there is potassium
depletion; in some instances, both are present.
• Alkali loading causes only a transient alkalosis unless there are additional factors operating to sustain it.
• The maintenance of a non-respiratory alkalosis requires
• inappropriately high renal bicarbonate reabsorption
• and hydrogen ion excretion.
• Factors that may be responsible for this include
• a decrease in ECF volume,• mineralocorticoid excess and• potassium depletion.
• Loss of gastric acid is an important cause:
• As discussed above, the generation of gastric acid (effectively hydrochloric acid) results in the formation of bicarbonate ions, which are retained.
• Loss of chloride can also occur from lower in the gut.
• In both cases, there is also• loss of sodium • and water, tending to reduce extracellular
fluid volume • Thus stimulating renal sodium retention via
renin and aldosterone,
• And the simultaneous excretion of potassium and hydrogen ions (the latter always being accompanied by retention of bicarbonate).
• Non-potassium-sparing diuretics also cause loss of
• chloride, • sodium and water, and increase delivery of
sodium to the distal parts of the nephron.
• So increasing the amount that is available for reabsorption in exchange for potassium and hydrogen ions.
• Note that, paradoxically, as a result of the increased renal hydrogen ion excretion,
• the urine may be acidic in patients with a non-respiratory alkalosis –
• exactly the opposite of what is required to correct the disturbance.
• In potassium depletion ('saline-unresponsive alkalosis'),
• loss of intracellular potassium • leads to an intracellular shift of hydrogen ions,
tending to cause an extracellular alkalosis.
• In addition, potassium depletion results in there being less potassium available to exchange for hydrogen ion when sodium reabsorption occurs in the distal nephron.
• This effect will be exacerbated if there is
increased aldosterone secretion (which may be the cause of potassium depletion or result from a decrease in effective arterial blood volume).
• The correction of a non-respiratory alkalosis requires reversal both of the
• primary cause • and of the mechanism responsible for its
perpetuation.
• The expected compensatory change would be an increase in pCO2, which would increase the ratio pCO2/ and thus [H+].
• A low arterial [H+] inhibits the respiratory centre, causing hypoventilation, and thus an increase in pCO2.
• However, since an increase in pCO2 is itself a powerful stimulus to respiration, this compensation, particularly in acute non-respiratory alkalosis, may be self-limiting.
• In more chronic disorders, significant compensation may occur, presumably because the respiratory center becomes less sensitive to carbon dioxide.
• Should hypoventilation lead to significant hypoxaemia,
• however, this will provide a powerful stimulus to respiration and prevent further compensation.
Non Respiratory alkalosis
[H+] ↓
pH↑
PCO2 ↑
[HCO3-] ↑↑
4. respiratory alkalosis
concept: the primary disturbance is decrease
of [H2CO3] in plasma
1) cause and pathogenesis
hypotonic hypoxia
pneumonia
hyperventilation hysteria; fever; [NH3]
hyperthyroidism
misoperation of ventilator
respiration (slight inhibition)
2) compensation cells (exchange of H+-K+)
kidney secretion of H+
(
hypotonic hypoxia
• a ) Cause and mechanism• 1. inhaled air PO ₂ too low• 2 outside respiratory dysfunction• 3 venous inflow of arterial blood
• The common feature and cause of the alkalosis is a fall in pCO2,
• which reduces the ratio of pCO2 to bicarbonate concentration.
• In acute respiratory alkalosis, the [H+] falls by approximately 5.5 nmol/L for each 1.0 kPa (7.5 mmHg) fall in PCO2.
• The fall in pCO2 causes a small decrease in bicarbonate concentration.
• Compensation occurs through a reduction in renal hydrogen ion excretion,
• which further decreases plasma bicarbonate concentration.
• Renal compensation in a respiratory alkalosis develops slowly, as it does in a respiratory acidosis.
• If a steady pCO2 is maintained, maximal compensation with a new steady state develops within 36-72 h.
Respiratory alkalosis Acute Chronic
[H+] ↓ Slight ↓ or high-normal
pH ↑Slight ↑ or low-
normal
PCO2 ↓ ↓
[HCO3-] Slight ↓ ↓
Summary of Acidosis
Condition Definition Common Cause Compensatory Mechanism
Metabolic Acidosis
Decreased HCO3-
(below 22mEq/liter) and decreased pH (below 7.35) if there is no compensation.
Loss of bicarbonate ions due to diarrhea, accumulation of acid (ketosis), renal dysfunction.
Respiratory hyperventilation, which increase loss of CO2. If Compensation is complete, pH will be within normal range but pCO2 will be high.
Respiratory Acidosis
Increased pCO2 (above 45 mmHg) and decreased pH (below 7.35) if there is no compensation.
Hypoventilation due to emphysema, pulmonary edema, trauma to respiratory center, airway obstructions, or dysfunction of muscles of respiration.
Renal: Increased excretion of H+; increased reabsorption of HCO3
-. If Compensation is complete, pH will be within normal range but HCO3
- will be low.
Summary of AlkalosisCondition Definition Common Cause Compensatory
Mechanism
Metabolic Alkalosis
increased HCO3-
(above 26mEq/liter) and increased pH (above 7.45) if there is no compensation.
Loss of acid due to vomiting, gastric suctioning or use of certain diuretics; excessive intake of alkaline drugs.
Respiratory: hypoventilation, which slows loss of CO2. If Compensation is complete, pH will be within normal range but HCO3
- will be high.
Respiratory Alkalosis
decreased pCO2 (below 35 mmHg) and increased pH (below 7.45) if there is no compensation.
Hyperventilation due to oxygen deficiency, pulmonary disease, cerebrovascular accident (CVA), or severe anxiety.
Renal: decreased excretion of H+; decreased reabsorption of HCO3
-. If Compensation is complete, pH will be within normal range but pCO2 will be low.
pH Pco2 [HCO3-] Plasma [K+]
Acidosis Metabolic
Initial state ↓ N ↓Usually ↑ (↓ in renal tubular acidosis and acetazolamide) Compensated state N ↓* ↓
Respiratory
Acute Change ↓ ↑ N or ↑↑
Compensation N ↑ ↑↑*
Alkalosis Metabolic Acute State ↑ N ↑
↓ Chronic State ↑ N ↑↑ Respiratory Acute Change ↑ ↓ N or ↓
↓ Compensation N ↓ ↓↓*
Copyright 2009, John Wiley & Sons, Inc.
Metabolic Acidosis
Results from changes in HCO3- concentration
Metabolic acidosis – abnormally low HCO3- in
systemic arterial blood Loss of HCO3
- from severe diarrhea or renal dysfunction Accumulation of an acid other than carbonic acid –
ketosis Failure of kidneys to excrete H+ from metabolism of
dietary proteins Hyperventilation can help Administer IV sodium bicarbonate and correct cause of
acidosis
Copyright 2009, John Wiley & Sons, Inc.
Metabolic alkalosis
Abnormally high HCO3- in systemic arterial blood
Non-respiratory loss of acid: vomiting of acidic stomach contents, gastric suctioning
Excessive intake of alkaline drugs (antacids) Use of certain diuretics Severe dehydration Hypoventilation can help Give fluid solutions to correct Cl-, K+ and other electrolyte
deficiencies and correct cause of alkalosis
Copyright 2009, John Wiley & Sons, Inc.
Respiratory acidosis
Abnormally high PCO2 in systemic arterial blood Inadequate exhalation of CO2
Any condition that decreases movement of CO2 out – emphysema, pulmonary edema, airway obstruction
Kidneys can help raise blood pH Goal to increase exhalation of CO2 – ventilation
therapy
Copyright 2009, John Wiley & Sons, Inc.
Respiratory alkalosis
Abnormally low PCO2 in systemic arterial blood Cause is hyperventilation due to oxygen
deficiency from high altitude or pulmonary disease, stroke or severe anxiety
Renal compensation can help One simple treatment to breather into paper bag
for short time
Copyright 2009, John Wiley & Sons, Inc.
27_table_04
27_table_04
27_table_04
• About 50 to 100 millimoles of hydrogen ions are released from cells into extracellular fluid each day.
• Despite fluctuations in the rate of release throughout the day, due to varying loads, the extracellular hydrogen ion concentration ([H+]) is maintained between 35 and 45 nano mol/L (40 nmol/L = pH 7.40).
• .
• Control of hydrogen ion balance depends ultimately on the secretion of H+ from the body, mainly into the urine.
• Renal impairment causes acidosis.
• Aerobic metabolism of the carbon skeletons of organic compounds converts hydrogen, carbon and oxygen to water and carbon dioxide (CO2).
• Although CO2 does not directly affect the hydrogen ion balance, it is an essential component of the extracellular buffering system.
• Control of CO2 depends on normal lung function.
• The principal sources of hydrogen ions are:• The metabolism of amino acids.• Conversion of amino nitrogen to urea in the
liver, or of the sulphydryl groups of some amino acids to sulphate, released equimolar amounts of hydrogen ions.
• Although a high protein diet may increase the H+ load and aggravate a pre-existing acidosis, it is rarely of clinical importance.
• The incomplete metabolism of carbon skeletons of organic compounds.
• Anaerobic carbohydrate metabolism produces lactate and anaerobic metabolism of fatty acids and ketogenic amino acids produces acetoacetate; these processes release equimolar amounts of H+, either directly or indirectly.
• In pathological lactic acidosis or ketoacidosis the rate of these reactions is so rapid that the capacity of the compensatory mechanisms is exceeded and the H+ concentration in blood rises significantly (pH falls).
• Many anabolic processes, including gluconeogenesis, use hydrogen ions.
• Acidosis is commoner than alkalosis because metabolism produces hydrogen and not hydroxyl ions.
• It would appear that the mechanisms that protect extracellular fluid volume take precedence over those that regulate acid-base status.
• A mild alkalosis may develop during the treatment of oedema with diuretics ('contraction alkalosis'); the loss of chloride-rich fluid causes a decrease in the volume of the extracellular fluid in which bicarbonate is distributed, thus increasing its concentration.
• A non-respiratory alkalosis due to loss of gastric acid may occur in patients
• undergoing nasogastric aspiration,
• Vomiting with pyloric stenosis is an unusual cause of non-respiratory alkalosis but the disturbance can be severe; other causes rarely result in such a severe disturbance.
• A third factor relating potassium depletion and alkalosis is that;
• potassium depletion stimulates the formation of ammonia,
• Thus increasing the capacity of the kidneys to excrete acid.
• In metabolic alkalosis caused by potassium depletion, urine chloride concentration is typically >20 mmol/L; in saline responsive alkalosis, it is usually <20 mmol/L.
The anion gap • When bicarbonate concentration falls in a
non-respiratory acidosis, electrochemical neutrality must be maintained by other anions.
• In many cases, anions are produced simultaneously and equally with hydrogen ions, for example acetoacetate and β-hydroxybutyrate in diabetic ketoacidosis and lactate in lactic acidosis.
• When this does not occur, the deficit is met by chloride ions.
• The difference between the sums of the concentrations of the principal cations (sodium and potassium) and of the principal anions (chloride and bicarbonate) is known as the 'anion gap'.
• Anion Gap = ([Na+] + [K+]) – ([Cl-] + [HCO3-])
• In health, the anion gap has a value of 14-18 mmol/l and mainly represents the unmeasured net negative charge on plasma proteins.
• In an acidosis in which anions other than chloride are increased, the anion gap is increased.
• In contrast, in an acidosis due to loss of bicarbonate, for example renal tubular acidosis, plasma chloride concentration is increased and the anion gap is normal.
• It has therefore been suggested that calculation of the anion gap is of value in the diagnosis of acidosis.
• In the majority of cases of acidosis, however, the cause is obvious clinically and can be confirmed by the results of simple tests.
• The anion gap may be useful in the analysis of complex acid-base disorders, but some laboratories do not routinely measure chloride as part of an 'electrolyte profile' and the anion gap cannot then be calculated.
