acid-base regulation

block 2 week 1 ctb

sources of H+ in the body

• volatile acids

  • 14000 mmol H+ generated each day from aerobic metabolism and C02 production by tissues (H2CO3)

  • can leave solution and enter atmosphere

  • excreted by lungs

• non-volatile (fixed/non-respiratory) ACIDS

  • 70-100 mmol H+ generated each day from other metabolic processes forming (e.g sulphuric acid)

  • organic acids such as lactic acid/keto acids may also be formed in certain circumstances

  • excreted by kidneys

H+ regulation

• acid-base regulation is the control of H+ concentration

• as for other ions, a balance of intake, production and excretion is needed to maintain homeostasis (kidneys have a key role)

• regulation of H+ is more complex and tighter than for other ions due to the effect of H+ on protein function

  • H+ is small and charged

• alters protein activity, especially enzymes body wide effects as many physiological processes sensitive to small changes in H+

• alters binding of other ions: e.g a low H+ increases Ca2+ binding to albumin

3 main mechanisms to minimise changes in pH:

1. buffer systems

2. lungs

3. kidneys

buffer systems

• rapid chemical reactions that minimise any sudden changes in pH

• unable to change overall body H+

lungs

can rapidly adjust excretion of C02

kidneys

• can slowly adjust the excretion of H+ in the urine (altering body bicarbonate: HC03-) levels)

buffer systems: principles

• a buffer is any substance that can reversibly bind H+

• buffer + H⁺ ⇋ HBuffer

• if H+ is added, buffer binds it to form HBuffer (removes H+)

• if H+ removed, HBuffer releases H+ (adds H+)

• rapidly adds or removes H+ so as to minimise overall changes in [H+] → as long as buffer is available

3 main buffer systems in the body

1. bicarbonate buffer system (extracellular)

H+ + HCO₃^- ↔ H2CO3 (carbonic acid)

2. phosphate buffer system (intracellular and in urine)

HPO₄^2- + H⁺ ↔ H₂PO₄^- 

3. protein buffer system (mainly intracellular)

Pr^- + H⁺ ↔ HPr

buffer systems: bicarbonate

• Connects lung control of [CO₂] to kidney control of bicarbonate [HCO₃^-] in acid-base balance – shows how the systems can compensate for each other

• H⁺ + HCO₃^- ↔ H₂CO₃ ↔ H₂O + CO₂

Henderson-Hasselbach Equation

• this equation allows us to calculate pH based on measurements of [HCO₃^-] and [CO₂]

• pK is a constant for this reaction

• [CO₂] is calculated from partial pressure of CO₂ (pCO₂)

concentration for arterial blood in Henderson-Hasselbach Equation

acid base regulation

• maintaining pH depends on:

  • functional lungs to maintain CO₂

  • functional kidneys to maintain HCO₃

• lungs

  • rapid response to alter CO₂

• kidney

  • slow response to alter HCO₃ production and H+ excretion so as to restore pH

acid base balance

renal control of acid base

• kidneys control extracellular fluid pH by adjusting the amount of H+ excreted in urine

• to maintain acid-base balance, kidneys must excrete 70-100 mmol/day of H+ from non-volatile acid production

  • therefore: urine is usually acidic

• kidneys must also reclaim the filtered HCO3- to avoid a reduction in HCO3-

• the loss of H+ is equivalent to gain of HCO3-

renal control of acid-base

2 main processes by which kidneys regulate extracellualr fluid pH

1. reabsorption of filtered HCO3-

2. excretion of H+ (production of new HCO3-)

• both processes rely on ability to secrete H+

peritubular circulation

reabsorption of filtered HCO3-

• kidneys filter 4500mmol HCO3-

• 180 litres (filtrate/day) x 25 mmol/L [HCO₃^-]

• usually must reabsorb all of this to maintain the blood HCO3- and avoid lowering the pH

• majority reabsorbed in proximal convoluted tubule (85-90%)

reabsorption of filtered HCO3- in PCT

• HCO3- can’t be directly transported from lumen: needs carbonic anhydrase and secreted H+

• no net gain or loss of H+ or HCO3- so no change in acid-base status despite H+

secretion of H+ in late distal and collecting tubules

• 5% filtered HCO₃^- reabsorbed in late distal and collecting tubules by similar mechanism – method of H⁺ secretion into lumen differs

• Uses H⁺ (and H⁺/K⁺) ATPase transporters in type A intercalating cells to pump H⁺ into tubular lumen

• Activity can be stimulated by aldosterone and hypokalaemia

secretion of H+ in late distal or collecting tubules

• H⁺ ATPase important in secreting H⁺ into tubule lumen – can generate an 800 fold H⁺ gradient, giving a minimum urinary pH of ~4.5

• However this is still not sufficient alone to secrete all the 70-100mmol of non-volatile H⁺

excretion of H+

• Urinary buffers are essential both for comfort and to allow sufficient H⁺ to be excreted in the urine

• The two main urinary buffers are phosphate and ammonia

• The process of excreting H⁺ generates new HCO₃^-

• Important to generate new HCO₃^- as some is consumed buffering the 70-100 mmol of non-volatile (fixed) acids produced each day

urinary phosphate buffer

• filtered phosphate has 2 forms (monoprotic and diprotic) that create a buffer pair in renal tubular fluid

• relative monoprotic form which is able to ‘pick up’ any excess secreted H+ in lumen and excrete it in urine

• process of excreting H+ leads to production of HCO3- which passes into the blood

excretion of H+ by urinary phosphate buffer

• Note that the H⁺ is excreted in combination with NaHPO₄^-

• Note that as H⁺ is excreted in the urine, HCO₃^- passes into the interstitial fluid

urinary ammonia buffer

• ammonium (NH4+) is synthesised from glutamine mainly in PCT cells (they contain glutaminase) as it is broken down to glutamate and then to alpha-ketoglutarate

• ammonia and ammonium form a buffer pair

• NH₃⁺ + H⁺ ↔ NH₄⁺

• ammonia is eventually secreted mainly in collecting duct: ‘picks up’ excess secreted H+ and excretes it in urine as ammonium

• process leads to production of HCO₃^-

excretion of H+ by urinary ammonia buffer

• H+ is excreted in combination with NH₃ as NH₄⁺

• as H+ is excreted in urine, HCO3- is being added to the blood

urinary ammonia buffer

• can respond to body’s acid-base status

• a decrease in pH stimulates renal glutamine metabolism leading eventually to increased H+ excretion (and vice versa)

• renal responses are slower than lungs (requires protein synthesis/breakdown)

excretion of H+ by urinary phosphate buffer

• H+ is excreted in combination with NaHPO₄^-

• as H+ is excreted in the urine, HCO₃^- passes into the interstitial fluid

urinary ammonia buffer

• ammonium (NH4+) is synthesised from glutamine mainly in PCT cells (they contain glutaminase) as it is broken down to glutamate and then α-ketoglutarate

• ammonia and ammonium form a buffer pair NH₃ + H⁺ ↔ NH₄⁺

• ammonia is eventually secreted mainly in collecting duct: ‘pics up’ excess secreted H+ and excreted it in urine as ammonium

• process leads to the production of HCO3-

excretion of H+ by urinary ammonia buffer

• H+ is excreted in combination with NH3 as NH4+

• as H+ is excreted in urine, HCO3- is being added to the blood

urinary ammonia buffer

• the urinary buffer can respond to the body’s acid-base status

• a decrease in pH stimulates renal glutamine metabolism leading eventually to increased H+ excretion

• renal responses are slower than lungs: requires protein synthesis/breakdown

control of H+ secretion-

• levels of H+ secretion control the amount of filtered HCO3- reabsorbed as well as new HCO3- produced

• principally stimulated by:

  • an increase in pCO2 of the extracellular fluid

  • a decreased pH of the extracellular fluid

• these mechanisms allow the kidneys to alter their H+ secretion (and in turn HCO3- reabsorption) appropriately

• increased aldosterone levels and hypokalaemia can also stimulate H+ secretion

acid-base terminology

• if a disease process alters the ratio of [HCO3-] to [CO2] then there will be a resulting change in pH

acidosis

any process that results in the blood becoming more acidic than normal

• addition of acid and/or loss of alkali (base)

alkalosis

• any process that results in the blood becoming more basic (alkaine) than normal

  • addition of alkali (base) and/or loss of acid

metabolic vs. respiratory problems

metabolic: the primary problem is affecting [HCO3-]

• metabolic acidosis

• metabolic alkalosis

respiratory: the primary problem is affecting CO2 excretion

• respiratory acidosis

• respiratory alkalosis

• both acidosis and alkalosis signify underlying disease

compensation

• because it is the ratio of [HCO3-] and [CO2] that gives us the pH, an abnormality affecting one parameter can be compensated to a certain degree by changes in the other

• pH isn’t necessarily restored to normal but minimises the changes in pH: tries to restore back towards normal

• in compensated disorders, both [HCO3-] and [CO2] values lie outside their normal ranges (in same direction- both raised and lowered)

respiratory acidosis

• low pH due to increased CO2

• causes: any disorder affecting the lungs, chest wall, nerves and muscles or CNS that leads to an inappropriate reduction in ventilation

• compensation: slowly (days) by kidney to increase the production of bicarb

respiratory alkalosis

• raised pH due to decreased CO₂

• causes: any disorder that leads to an inappropriate increase in ventilation: e.g anxiety and hyperventilation, high altitude

• compensation: slowly by kidneys to decrease the production of bicarb

metabolic acidosis

• low pH due to decreased [HCO3-]

• causes: either addition of acid- exogenous (methanol) or endogenous (lactic acid or keto acids): failure of H+ excretion or loss of HCO3- (e.g severe prolonged diarrhoea)

  • anion gap can be used to narrow the differential diagnosis

• compensation: rapidly by lungs to increase ventilation and therefore decrease CO2

metabolic alkalosis

• raised pH due to increased [HCO3-]

• causes: either addition of alkali or excess loss of H+ (e.g severe prolonged vomiting), excess aldosterone, e.g due to dehydration (stimulates H+ secretion in distal tubule)

• compensation: rapidly by lungs to decrease ventilation and thus increase [CO2]

approach to treatment of metabolic acid-base

• treat and correct the underlying problem whenever possible: most important

• use substances to neutralise acid or base: controversial and senior decision

  • sodium bicarb to treat acidosis

  • ammonium chloride for alkalosis (uncommon)

interpreting acid-base

• look at pH first

• look at [HCO3-] and pCO2

  • if due to pCO2, it is a primary respiratory disorder

  • if due to [HCO3-] then it is a primary metabolic disorder

• look for evidence of compensation

  • has the other value moved out of its normal range

acid base disorders summary