2021A14 Discuss how the body handles a metabolic acidosis.

List:

· Intro

· Dilution

· Buffering

· Compensation

· Correction

Intro:

Definition	· Excess production or addition of metabolic acid or excess loss of base
Diagnosis	· HH approach: pH <7.4, PaCO₂ <40mmHg, HCO₃^- <24mmol/L · Stewart approach: SID <42 (where SID = [Na + K + Ca + Mg] – [Cl + Lac] )
Classification	· NAGMA: loss of HCO₃^- or base (e.g. diarrhoea, renal tubular acidosis) · HAGMA: addition of fixed acid (e.g. lactic acidosis, ketoacidosis)
Summary of response	1. Dilution 2. Buffering: ICF and ECF 3. Compensation: respiratory and renal 4. Correction of the underlying cause

Dilution (immediate)

Purpose	· Minimise fall in local or plasma pH
Mechanism	· Distribution of acid across body fluid compartments

Buffering – minutes:

Purpose

· Resists the fall in pH when acid is added or base removed

Mechanism

· System comprises a weak acid and its conjugate base

· H⁺ readily exchanged

· AH <-> A^- + H⁺

· Hence ↓[H⁺]

Ideal properties

· Abundant

· Rapid

· pKa = prevailing pH +/- 1

· Open-ended

Intracellular buffering (60%)

Proteins

· Imidazole groups of histidine residues

· Abundant

· pKa = pH ICF = 6.8

Phosphate

· H₂PO₄- <-> H⁺ + HPO₄^2-

· High concentration (30-60mmol/L)

· pKa = pH of ICF = 6.8

Extracellular buffering (40%)

Bicarbonate

· Most important ECF buffer

· CO₂ + H₂O <-> H⁺ + HCO₃^-

· ↑[H⁺] -> L shift -> ↑CO₂ formation -> exhaled

· pKa 6.1 is distant to pH 7.4, however…

· High concentration - 24mM

· Rapid enzyme - carbonic acid

· Open ended - can exhale CO₂, can urinate H⁺

Haemoglobin

· Second most important ECF buffer

· Compared with plasma proteins:

o ~2x concentration (140g/L cf. 70g/L)

o ~3x imidazole groups per molecule (38 cf. 13)

· Imidazole groups on histidine residues

o HHb + K⁺ <-> KHb + H⁺

o pKa = pH of ICF in RBCs = 6.8

· Carbamino compounds

o CO₂ + Hb-NH₂ <-> Hb-NHCOO^- + H⁺

o CO₂ binds terminal amino groups, and amino groups on side chains

o Released H⁺ is buffered by imidazole groups as above

Plasma proteins

· Imidazole groups of histidine residues

o AH <-> A^- + H⁺

· pKa 6.8 is moderately close to pH 7.4

Respiratory compensation: (minutes)

Mechanism

· Acidosis -> stimulate peripheral chemoreceptors -> ↑ MV -> ↓ PaCO₂ -> ↓[H⁺]

· From HH equation: pH = 6.1 + [HCO₃] / 0.03 x PaCO₂

Extent

· Winter’s formula: PaCO₂ = 8 + 1.5 x HCO₃^-

· ECF pH approaches but does not reach or exceed 7.4

· *Note respiratory compensation is ineffective for fixed acid, because both H⁺ and HCO₃^- are being removed as CO₂*

Renal compensation: (hours-days)

Anion exchange

· ↑HCO₃^-/Cl^- exchange in proximal > distal tubule

o HH approach: hence ↑HCO₃^- reabsorption

o Stewart approach: hence ↑Cl^- excretion -> ↑SID

o KN: Stewart correct, but kidneys respond to pH and HCO₃^-, not SID
(N.B. the vast majority of HCO^3- is absorbed regardless)

· Multiple structures involved:

o Carbonic anhydrase – cellular & tubular

o Basolateral Na⁺K⁺ATPase

o Apical H⁺ATPases

o Na⁺3HCO₃^- symporter

↑Excretion of titratable acid

· Buffered: as phosphoric and sulfuric acid

· ↑Activity of H⁺ATPase and H⁺K⁺ATPase in type A intercalated cell

· Minimal HCO₃^- in distal tubule; hence H⁺ combines with PO₄^3- and SO₄^2-

· Usual 30mmol/day, max 60mmol/day

↑Excretion of ammonium

· ↓pH -> ↑uptake and oxidation of glutamine in proximal tubule

· Glutamine + H⁺ -> α-ketoglutarate + NH₄⁺

o Occurs when titratable acid exhausted

· 50% NH₄⁺ reabsorbed and recycled, other 50% excreted

o HH approach: hence net ↑HCO₃^- reabsorption

o Stewart approach: hence ↑NH₄⁺ excretion (strong ion) -> ↓SID

· Up to 300mmol/day, i.e. high capacity system

Ion exchange:

Cells (minutes)

· H⁺/K⁺ exchange

o ↓pH 0.1 -> ↑K⁺ 0.6mM

o Can conceal K⁺ depletion e.g. DKA

Bone
(days-weeks)

· H⁺/Ca²⁺ exchange

Correction:

NAGMA

· Treatment of the underlying disease

o N.B. in hyperchloraemic acidosis, renal compensation = correction

HAGMA

· Treatment of underlying disease

o E.g. Lactic acidosis: tissue oxygenation

o E.g. ketoacidosis: insulin

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