Biochemical mechanismsof acid base balance and acid base disorders
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Transcript of Biochemical mechanismsof acid base balance and acid base disorders
Biochemical Mechanisms of Acid-Base Balance and
Acid Base disorders Dr. Rohini C Sane
Acid-base balance
Site pH maintained under physiological conditions
Arterial blood 7.4
Venous blood 7.43
Intestinal fluid Between plasma & cells
Osteoblast 8.0
Prostrate 5.0
Mitochondria 6.6
Acids & Bases
Acid : yields H⁺ ions ( HCl H⁺ + Cl⁻ )
Base :combines with H⁺ ions ( Na⁺ + HCO₃⁻ ) combines with H⁺
HCl ( strong acid ) H⁺ + Cl⁻ ( weak base )
Conjugate acid base pair
H₂CO₃( weak acid ) H⁺ + HCO₃⁻ ( strong base )
Buffers & their types involved in Acid-base balance
Buffers : solutions resists the change in p H on addition of acid or base
Acidic buffer : weak acid + its salt with strong base
eg H₂CO₃( weak acid ) + NaHCO₃⁻ ( strong base )
Basic /Alkaline buffer : weak base + its salt with strong acid
eg NH₄OH + NH ₄Cl
Mechanism of action of Buffer system for acid base balance
HA weak acid
BA salt of weak acid
A- largely salt component of buffer
Added strong base HA ACID
(OH⁻) H⁺
A- HA (weak acid )
H⁺ OH⁻ (H⁺)Added strong acid
(H₂O)
BA B⁺ + A ⁻
Acids produced in a human body during metabolisms
• Carbonic acid - oxidation of carbon compounds ---CO₂—H ₂ CO₃
• Sulphuric acid - oxidation of sulphur containing amino acids (Cysteine ,Cystine, Methionine)
• Phosphoric acid –metabolism of Phospho proteins ,nucleoproteins, phosphatides
• Organic acids –metabolism of fat ,protein, carbohydrates (Pyruvic acid ,Lactic acid, Acetic acid)
• Latrogenic –Medicines like NH₄Cl , Mandelic acid
Regulation of pH in body *( acid base balance )
FRONT LINE DEFENSE :
Buffer systems
Respiratory mechanism –increased or decreased excretion of CO₂ depending upon need therefore concentration ofH2CO3 (Carbonic acid ) or base in extracellular fluid maintained.
SECOND LINE DEFENSE (KIDNEY ):
Renal mechanisms – excretion of acids or base (concentration of hydrogen (H⁺ ),bicarbonate ( HCO⁻³) controlled.
DILUTION FACTOR :
Acids are diluted in extra cellular fluid (adverse effects in dehydration )
BLOOD BUFFERS INVOLVED IN ACID BASE BALANCE site of acids /alkali production in tissue site of their excretion at( Lung, kidney)
PLASMA BUFFERS
a) Na HCO₃ /H₂CO ₃
b) Na ₂ HPO₄/NaH ₂PO ₄
c) Na –Protein /H-Protein
d) Na organic acids /H –organic acids
BUFFERS OF RED BLOOD CELLS
a) K HCO ₃ /H ₂ CO ₃
b) KHPO₄ / KH₂PO ₄
c) K Hb /HHb
d) KHbO ₂ /HHbO ₂
Bicarbonate Buffer System in acid base balance• Ratio -NaHCO3 :H2CO3= 20: 1 (plasma under physiological conditions )
Advantagesa) High concentration
b) produces volatile & weak acid H₂CO₃
c) physiological buffer front line defenseDisadvantages
• PKA≠ Physiological pH
Neutralization of acids by Bicarbonate Buffer salt component of buffer strong acid (non volatile) added
NaHCO ₃ H+L
_
Na+
H CO3 _
↘ ↙ H+
L_
H₂CO₃
H₂CO₃ ( Carbonic acid ) weak & volatile CO ₂(eliminated by lungs ) + H ₂ OBicarbonate buffer system linked up with respiration.
Bicarbonate Buffer System in acid base balance
strong base added
NaOH H₂CO₃
Na +
OH ⁻ H+
HCO₃_
↘ H₂O ↙
NaHCO ₃ weak base
Bicarbonate Buffer System in acid base balance
Phosphate buffer system in acid base balance
Ratio in plasma : Na₂HPO₄ : NaH₂PO ₄ = 4 : 1 maintained constant by kidney
• Ratio in urine: Na ₂ HPO ₄ :NaH ₂PO₄ = 1 :9
↙Na₂HPO₄↘ HCl (Strong acids added )
Na +
NaHPO4-
H +
Cl-
↘ ↙
NaCl + NaH₂PO₄(excreted in urine)urinary pH decreases
↙ NaH₂PO₄↘ NaOH (strong base added )
NaHPO4-
H +
OH-
Na+
Na₂HPO₄ + H ₂O excreted in urine –pH of urine increases
Phosphate buffer system works in conjugation with kidney.
Advantage : PKa = Physiological p H
Disadvantage: low concentration (2) Physiologically less effective
Protein buffer system in acid base balance
Na + Pr⁻ /H + Pr⁻ ← Plasma
K Hb / HHb ← Erythrocytes
I
1 gm. Hemoglobin= 0.183 mequ H+
1 gm. protein = 0.110 mequ H+
II
Hb / 1000 ml of blood = 27.5 mequ H+
Protein / 1000 ml of blood = 4.24 mequ H+
Hb has more buffering action than plasma proteins
Protein buffer system in acid base balance
• (1 )Buffering action of proteins
(2 ) Na proteinate ( salt component )
Na⁺Pr ⁻ + HL Na L + H ⁺Pr ⁻ (weak acid )
(3 ) formation of carbamino compounds
PrNH₂ + CO ₂ PrNH COOH
p H of medium Protein acts as Charge on protein
Acidic Base Positive ( NH₂ NH₃ ⁺ )
alkaline Acidic Negative ( COOH C00⁻ + H ⁺)
Hemoglobin buffer system in acid base balance
1. COOH
2. NH₂
3. Gaunido group differential ionization of groups based upon pH of ompartment
4. Imidazole group
38 Imidazole groups (from 38 Histidine present in Hb )
(a ) Fe ²⁺ containing group which concerned with O₂ carrier.
TYPE OF GLOBIN CHAIN Histidine linked with Fe ²⁺
Alpha 87 th
Beta 92 th
Alkalinity favors oxygenation
Hemoglobin buffer system in acid base balance
In alkaline medium –imidazole N₂ donates H⁺ (behaves as a acid )
In acidity medium - imidazole N₂ accepts H⁺ (behaves as a base )
TISSUE P CO ₂ Condition Reaction of Hb
Lung LOW Alkaline OxygenationRelease of H⁺Release of CO₂
Tissue HIGH Acidic De oxygenationHb accepts H⁺ to form reduced hemoglobin (HHb) CO₂(Carbamino compounds )CO₂ -Formation of H₂CO₃
Hemoglobin buffer system in acid base balance
Hemoglobin buffer system *( Imidazole group ) for acid base balance
Conditions -Alkaline ( H⁺ low ), PO₂ High , PCO ₂ LOW
Changes in Hb- oxygenation ,release of CO ₂,Release of H⁺
Conditions –Acidic ( High H⁺ ), PO₂ low , PCO ₂ high
Changes in Hb- de oxygenation ,binding of CO ₂,binding of H⁺
Acts as a acid gives proton ↓ Acts as a base & takes up proton
↓
Hemoglobin buffer system *( Imidazole group ) for acid base balance
Hemoglobin buffer system in acid base balance
Hemoglobin buffer systemin acid base balance(in tissue )
Hemoglobin buffer systemin acid base balance(in lungs )
Role of respiratory system in acid base balance :Mechanism
• Sensitivity of respiratory Centre ( RC ) to changes in p H & CO ₂
• Diffusibility of CO ₂ from Blood to alveolar air
• Hyperventilation- high speed /deep
• Hypoventilation- slow (kasumal ) / shallow
• NaHCO₃ : H₂CO₃ = 20: 1 ( maintained constant by respiratory system under physiological conditions )
PCO ₂ H⁺ RESPIRATORY CENTRE VENTILATION STATUS OF CO₂
HIGH HIGH STIMULATED HYPERVENTILATION EXCESS OF CO₂ REMOVED
LOW LOW REPRESSED HYPOVENTILATION CO₂ RETENTION
Role of respiratory system in acid base balance :Mechanismduring acidosis
Role of respiratory system in acid base balance :Mechanism during acidosis
Role of respiratory system in acid base balance :Mechanism during alkalosis
Renal Mechanism for Acid –Base balance1. Elimination of non volatile acids ,Lactic acids, H₂SO₄ buffered with cations (Na⁺ ) are removed by glomerular filtration
2. (Na⁺ ) ↔ H⁺ across tubular membrane to prevent loss of Na⁺
• H⁺ secretion ,NaHCO₃ recovery
• Loss of Na ⁺ is prevented by :
a) Bicarbonate mechanism
b) Phosphate mechanism
c) Ammonia mechanism
3. HCO³⁻ reabsorption
4. NH ₃ production
Bicarbonate mechanism of proximal renal tubular cells for acid base balance
BLOOD Proximal tubular cells Tubular filtrate
CO2 CO2↘
Carbonic unhydrase * H₂ CO₃
H₂O H₂O↗ ↙ * ↘
↙HCO₃⁻ HCO₃⁻ H⁺ H⁺ H₂ CO₃
NaHCO₃⁻
↖Na ⁺ Na ⁺ Na ⁺+ HCO₃⁻
NaHCO₃⁻
Bicarbonate mechanism of proximal renal tubular cells for acid base balance
Bicarbonate mechanism of proximal renal tubular cells for acid base balance
The exchange of H⁺ ions proceed first against Sodium Bicarbonate
1. Complete reabsorption of NaHCO₃
2. Reduction of H⁺ ions load of plasma with little change in pH of urine
Bicarbonate mechanism of proximal renal tubular cells for acid base balance
Bicarbonate mechanism of proximal renal tubular cells for acid base balance
Factors affecting bicarbonate reabsorption in proximal renal tubular cells
1. pCO₂
2. Concentration of K⁺ in ICF ( intracellular fluid )
3. Plasma Concentration of Cl⁻
4. Concentration of adreno-corticoids Hormones
Bicarbonate mechanism of proximal renal tubular cells for acid base balance
Factors affecting bicarbonate reabsorption
1. pCO₂
pCO₂ ↑ H₂CO₃↑ H⁺ secretion↑ HCO₃⁻reabsorption ↑ HCO₃⁻ excretion in urine ↓
pCO₂↓ H₂CO₃↓ H⁺ secretion ↓ HCO₃⁻reabsorption↓ HCO₃⁻ excretion in urine ↓
Urine alkaline
urine acidic
Bicarbonate mechanism of proximal renal tubular cells for acid base balance
Factors affecting bicarbonate reabsorption
2a. Concentration of K⁺ in ICF ( intracellular fluid )
K⁺( ICF )concentration ↑
HCO₃⁻ excretion ↑, HCO₃⁻ absorption↓
HCO₃⁻ secretion↓
Urine alkaline
Bicarbonate mechanism of proximal renal tubular cells for acid base balance
Factors affecting bicarbonate reabsorption
2 b. Concentration of K⁺ in ICF ( intracellular fluid )
K⁺( ICF )concentration ↓
HCO₃⁻ excretion ↓, HCO₃⁻ absorption↑
HCO₃⁻ secretion↑
Urine acidic
Bicarbonate mechanism of proximal renal tubular cells for acid base balance
Factors affecting bicarbonate reabsorption
2 C.Intra cellular concentration of K⁺ isn’t plasma factor that controls the HCO₃⁻
(K⁺ administration )
K⁺ enters the cell(tubular )
H⁺ ions leave cell
H⁺ ions buffered by HCO₃⁻ H₂CO₃
Conc of HCO₃⁻↓
↓secretion H⁺ across tubular epithelial cells
↓HCO₃⁻ reabsorption
HCO₃⁻ excretion ↑ →→Urine alkaline
Bicarbonate mechanism of proximal renal tubular cells for acid base balance
Factors affecting bicarbonate reabsorption
2d. Intracellular Concentration of K⁺is not a plasma factor that controls the HCO₃⁻
(K⁺ deficiency )
K⁺ leaves the cell(tubular )
H⁺ ions renter tubular cell
H⁺ ions secretion↑
Excretion of NaH₂PO₄,NH₄Cl↑
↑secretion H⁺ across tubular epithelial cells
HCO₃⁻ reabsorption↑
HCO₃⁻ excretion ↓ →→Urine acidic- paradoxic aciduria
Bicarbonate mechanism of proximal renal tubular cells for acid base balance
Factors affecting bicarbonate reabsorption
2. Intracellular Concentration of K⁺ isn’t a plasma factor that controls the HCO₃⁻
K⁺Conc↑ ECF acidic Urine alkaline
K⁺Conc↓ ECF alkaline Urine acidic
↑HCO ₃⁻ absorption
↓HCO ₃⁻ absorption, ↑HCO ₃⁻excretion
Bicarbonate mechanism of proximal renal tubular cells for acid base balance
Factors affecting bicarbonate reabsorption
3a. Plasma Concentration of Cl⁻
Plasma Cl⁻↑
HCO₃⁻ reabsorption↓
HCO₃⁻ excretion ↑
Bicarbonate mechanism of proximal renal tubular cells for acid base balance
Factors affecting bicarbonate reabsorption
3b. Plasma Concentration of Cl⁻
Plasma Cl⁻↓
HCO₃⁻ reabsorption↑
HCO₃⁻ excretion ↓
Bicarbonate mechanism of proximal renal tubular cells for acid base balance
Factors affecting bicarbonate reabsorption
4. Concentration of adrenal corticoid Hormones
Cushing syndrome K⁺ deficiency HCO₃⁻reabsorption
Reabsorption of bicarbonate ions in renal tubular cells : Summary
Bicarbonate mechanismof proximal renal tubularcells for acid base
balance : summary
Phosphate buffer mechanism ( Distal tubular cells )for acid base balance
Ratio :Na₂ HPO₄ : NaH₂PO₄ 4:1 ( Plasma )
Ratio :Na₂ HPO₄ : NaH₂PO₄1:9 ( urine )
H⁺ ↔ NaHCO₃⁻ ( reabsorbed completely )
H⁺ ↔ Na₂HPO₄
H⁺ Na⁺
Na₂ HPO₄ NaH₂PO₄ (urine acidic )
Phosphate buffer mechanism ( Distal tubular cells )for acid base balance
Blood Distal tubular cells Tubular filtrate 7.4
Na ₂HPO₄
Carbonic Anhydrase*
CO₂ ------------------------- CO₂ -------------------- H₂ CO₃ 2Na⁺ + HPO₄⁻
H₂O--------------------------------------H₂O ↗
↙ HCO₃ ⁻←------------ -------- HCO₃ ⁻ H ⁺--------------------- H⁺
NaHCO ₃
↖Na ⁺←-------←← ---------------------------Na ⁺←---------------------Na ⁺
Na ⁺ pump ( passive transport )
( active transport ) Na ⁺+ H⁺+ HPO₄⁻
NaH₂PO₄
Phosphate buffer mechanism( Distal tubular cells )for acid base balance
Phosphate buffer mechanism ( Distal tubular cells )for acid base balance
Phosphate buffer mechanism ( Distal tubular cells )for acid base balance
Anion Gap= AG
Anion Gap =Unmeasured Anion(A)- unmeasured cation ( C ) = - (C )=AG
( Cl⁻ + HCO³⁻) –( Na⁺ + K ⁺) =0
( Cl⁻ + HCO³⁻ + PO₄⁻²+ SO₄⁻²) -( Na⁺ + K ⁺+ Li + Mg²⁺)
24 mmol/lt 7 mmol/lt
Unmeasured anion
Anion Gap= AG = 17 mmol/lt
Anion Gap increases when Unmeasured Anion (A) ↑
HA H⁺ + A⁻ (H⁺ buffered ) therefore A⁻ ↑
Anion Gap= AG
Negative Anion Gap
Anion Gap
Anion Gap in Metabolic acidosis
Anion Gap in Metabolic acidosis ( acid accumulation and bicarbonate ion loss )
Urinary anion gap: indicator of effective renal acid secretion during acidosis
I Clinical Conditions associated with increase in Anion Gap
• Anion Gap increases ( Lactate ,Acetoacetate ↑ )
I Condition associated with increase in Anion Gap
a) Diabetes Mellitus
b) Starvation
c) Lactic acidosis
d) ↑Plasma protein –dehydration
e) Toxin in gestation (Methanol, Salicylates )
• Acidosis HCO₃ absorption ,Anion gap ↑
• Excretion of K ⁺ ↑ ,Cation ↓
• Therefore ( A ) – ( C ) = AG ↑
II Clinical Conditions associated with increase in Anion Gap
II Condition associated with increase in Anion Gap
a) Metabolic alkalosis ( occasional )
b) Filtration of plasma proteins ( loss of H ⁺ )
c) Loss of H ⁺ negativity charge proteins ↑
Comparison of Anion Gap ibetween Metabolic acidosisAnd Metabolic alkalosis
Conditions associated with decrease in Anion Gap ( Anions ↓,Cations↑ )
Conditions associated with decrease in Anion Gap ( Anion ↓,Cation↑ )
↓UNMEASURED ANIONS(unmeasured)
(A)Hypo albuminemia
(B) Hypo natraemia
↑UNMEASURED ANIONS(unmeasured)
(A) Lithium intoxication
(B) Hypomagnesaemia
( C) Multiple myeloma
γ-Immunoglobins carry positive charge
Ammonia mechanism in kidney-Distal tubular cells for acid base balance
Ammonia mechanism in kidney-(Distal tubular cells) for acid base balance –Glutaminase
Ammonia mechanism in kidney-(Distal tubular cells )for acid base balance
Functions of Distal tubular cells
1. Elimination of H⁺ ions
2. Conservation of sodium
Sources of AMMONIA in Distal tubular cells
A. Hydrolysis of Glutamine
H₂O
Glutamine ---------------------------- Glutamic acid + NH₃
Glutaminase
B. Oxidative deamination of L amino acids
Ammonia mechanism in kidney-Distal tubular cells for acid base balance-
B. Oxidative deamination of L- amino acids by L- amino acid oxidase
Ammonia mechanism in kidney-(Distal tubular cells ) for acid base balance-L-amino acid oxidase
Ammonia mechanism in kidney(Distal tubular cells )for acid base balance- Glycine oxidase
C : Glycine oxidase
Metabolic acidosis
• 1. Primary HCO₃⁻ deficit ↓
• 2.Ratio BHCO₃:H₂CO₃ < 20:1↓ (as BHCO₃deficit↓)
• 3. p H ↓
Respiratory acidosis
• Primary H₂CO₃ excess↑
• 2.Ratio BHCO₃:H₂CO₃ < 20:1↓ (as H₂CO₃ excess↑)
• 3. p H ↓
Metabolic alkalosis
• 1.Primary HCO₃⁻ excess ↑
• 2.Ratio BHCO₃:H₂CO₃ > 20:1 ↑(as BHCO₃ excess↑)
• 3. p H↑
Respiratory alkalosis
• Primary H₂CO₃ deficit↓
• 2.Ratio BHCO₃:H₂CO₃ > 20:1↑ (as H₂CO₃ deficit↓)
• 3. p H ↑
Comparison between different types of acidosis & alkalosis
Comparison between different types of acidosis & alkalosis
Metabolic acidosis
• 1. Primary HCO₃⁻ deficit ↓
• 2.H₂CO₃ ↓
• 3.Ratio↓
• 4. p H ↓
• 5.P CO₂ ↓
• 6. TotalCO₂ ↓
Respiratory acidosis
• 1.Primary H₂CO₃ excess↑
• 2.HCO₃⁻↑
• 3. Ratio ↓
• 4. p H ↓
• 5. P CO₂↑
• 6. Total CO₂↑
Metabolic alkalosis
• 1.Primary HCO₃⁻ excess ↑
• 2. H₂CO₃↑
• 3.Ratio↑
• 4. p H↑
• 5. P CO₂↑
• 6. TotalCO₂↑
Respiratory alkalosis
• Primary H₂CO₃deficit↓
• 2. H₂CO₃ ↓
• 3.Ratio↑
• 4. p H ↑
• 5.P CO₂ ↓
• 6. TotalCO₂ ↓
Uncompensated phase of acid base imbalance
Comparison between different types of acidosis & alkalosis
Metabolic acidosis
• 1. Primary mechanism-Respiratory
• 2.p H ↓
• 3.Respiratory centreStimulated ↑
• 4.CO₂ released
• 5.PlasmaH₂CO₃↓till physiological ratio value achieved
Respiratory acidosis
• 1.Primary mechanism- Renal
• 2.H⁺↔Na⁺↑, NH₃ Synthesis ↑
• 3. Reabsorption of HCO₃⁻↑ (renal tubular cells )
• 4. Plasma HCO₃⁻↑till physiological ratio value achieved
Metabolic alkalosis
• 1. Primary mechanism-Respiratory
• 2. p H↑
• 3. Respiratory centreinhibited
• 4. CO₂ retention↑
• 5. Plasma H₂CO₃↑ till physiological ratio value achieved
Respiratory alkalosis
• 1.Primary mechanism-Renal
• 2. H⁺↔Na⁺↓,NH₃ Synthesis ↓
• 3. Reabsorption of HCO₃⁻↓ (renal tubular cells )
• 4. Plasma HCO₃⁻↓till physiological ratio value achieved
Compensatory phase of acid base imbalance
Comparison between different types of acidosis & alkalosis
Metabolic acidosis
• 1. Secondary mechanism-Renal
• 2.H⁺↔Na⁺↑, NH₃ Synthesis ↑
• 3. Reabsorption of HCO₃⁻↑(renal tubular cells )
Respiratory acidosis
• 1.Secondary mechanism-
• 2.Lung diseases-Respiratory mechanism –fails
Metabolic alkalosis
• 1. Secondary mechanism-Renal
• 2. H⁺↔Na⁺, ↓NH₃ Synthesis ↓
• 3. Reabsorption of HCO₃⁻ ↓(renal tubular cells )
Respiratory alkalosis
• 1Secondary mechanism-Respiratory
• 2.Lung diseases-Respiratory mechanism –fails
Compensatory phase of acid base imbalance
Metabolic acidosis
• 1. pH acidic
• 2.Excretion OF NH₄Cl ↑
• 3. Excretion OF NaH₂PO₄↑(renal tubular cells )
• 4.Titrable acidity ↑
Respiratory acidosis
• 1. pH acidic
• 2.Excretion OF NH₄Cl ↑
• 3. Excretion OF NaH₂PO₄↑(renal tubular cells )
• 4.Titrable acidity↑
Metabolic alkalosis
• 1. pH alkaline
• 2.Excretion OF NH₄Cl ↓
• 3. Excretion OF NaH₂PO₄↓ (renal tubular cells )
• 4.Titrable acidity ↓
Respiratory alkalosis
• 1. pH alkaline
• 2.Excretion OF NH₄Cl ↓
• 3. Excretion of NaH₂PO₄↓(renal tubular cells )
• 4.Titrable acidity ↓
Compensatory phase of acid base imbalance-Urinary findings `
Comparison between different types of acidosis & alkalosis-Clinical conditions
Metabolic acidosis
•1. Diabetes Mellitus
•2. Starvation
•3. Lactic acidosis
•4. Violent /Heavy exercises
•5. Ingestion of acidifying salts
•6. Renal insufficiency retention of acids
•7. Loss of HC0₃⁻ ( as diarrhea , fistula )
Respiratory acidosis
•1. Damage of CNS
•2.Brain damage
•3. Drug poisoning 4.anesthesia excess
•5. Obstruction to escape of CO₂
•6. IMPAIRED DIFFUSION-
•a.Pneumonia
•b.Pulmonary edema
•c.Fibrosis
•d.Emphysema
•e.Reduction of respiratory surface
•7. Blood flow ↓congenital heart diseases
•8.Loss of ventilation function( as thorasic pressure ↑-cyst ,pulmnory cancer )
Metabolic alkalosis
•1.Excess loss of HCL
•2.Pyrolic obstruction
•3..intestinal obstruction
•4 pylori spasm
•5.Alkali ingestion
•X-ray irradiation
•K⁺ loss K ⁺deficiency
Respiratory alkalosis
•1. Stimulation of respiratory center
•2.CNS diseases –Meningitis ,Salicylates
•3.. Hysteria
•4.High altitude
•5.Unjudious use of respirator
•6.Hepatic coma
`