Session 6 Flashcards
Describe and state the normal range of plasma pH
[*] Normal cellular function depends critically on ECF pH which must be maintained within very narrow limits.
[*] This is achieved by an interaction between the respiratory and renal systems controlling different components of the buffer system that stabilise ECF pH.
[*] The normal range of plasma pH is 7.38-7.45, which is a concentration of between 37-43 nmol/L of H+
[*] If the pH is below this range, the condition is known as acidaemia.
[*] If the pH is above this range, the condition is alkalaemia and alkalaemia is more dangerous than acidaemia.
[*] The kidneys control plasma pH by filtering and variably recovering hydrogen carbonate and active secretion of hydrogen ions
Describe the clinical effects of acidaemia
[*] Acidaemia affects enzyme function in many tissues and leads to potassium movement out of cells => hyperkalaemia which can be fatal.
Affects many enzymes:
- Alters excitable tissues such as cardiac muscle – reduced cardiac and skeletal muscle contractility
- Reduced glycolysis in many tissues
- Reduced hepatic function
- Increased plasma potassium
The effects can be severe at pH’s below 7.1 and life threatening below 7.0
Describe the clinical effects of alkalaemia
[*] Alkalaemia reduces the solubility of calcium salts, which means that free Ca2+ leaves the ECF, binding to bones and proteins.
- The resulting hypocalcaemia makes nerves much more excitable, producing paraesthesia (abnormal sensations) and eventually uncontrolled muscle contractions – tetany.
- If the pH rises above 7.55, 45% of patients die.
- Above 7.65, the mortality is 80%
Describe the carbon dioxide/hydrogen carbonate buffer system
[*] As the H+ ion concentration in ECF is so low, the addition of very small amounts of acid would change the concentration and therefore pH dramatically. This does not happen because H+ ions are buffered by binding to various sites.
[*] The most important ECF buffer is the carbon dioxide / hydrogen carbonate system:
CO2 + H20 < = > H+ + HCO3-
[*] The extent to which the reversible reaction proceeds is determined by the ratio of [HCO3-] to [Dissolved CO2]. Ideally the ratio should be 20:1
- Dissolved CO2 is determined by the pCO2 of plasma, which is controlled by the lungs.
- HCO3- is largely created by reactions in the red blood cells, but concentration of HCO3- is controlled by the kidney
- Disturbed by metabolic and renal diseases
[*] The Hendelson-Hasselbalch equation describes this relationship: pH = 6.1 + log [(HCO3-) / (0.23 x pCO2)]. pCO2 is expressed in kPA and and [HCO3-] in mmol/L
[*] Normal pCO2 is between 4.2 and 6.0 kPa (maintained by breathing)
- Controlled by chemoreceptors
- Disturbed by respiratory diseases
[*] Normal [HCO3-] in plasma is 22-29 mmol/L (~25mmol/L)
[*] At the mid-range of pCO2 of 5.4kPA and HCO3- of 24 mmol/L, the pH will be 7.3
Describe respiratory alkalaemia
[*] Falls in pCO2 produce respiratory alkalaemia (respiratory alkalosis is technically incorrect) – pH>7.45
- Hyperventilation leads to hypocapnia
- Falls in pCO2 causes pH to rise (ratio gets bigger as there is more than 20x the amount of HCO3- than CO2, so relatively more H+ ions are buffered, causing the pH increase)
Describe respiratory acidaemia
[*] Rises in pCO2 produce respiratory acidaemia (respiratory acidosis is technically incorrect) – pH < 7.35
- Hypoventilation leads to hypercapnia
- Hypercapnia causes plasma pH to fall (there is less than 20x the amount of HCO3- than CO2 so relatively less H+ ions are buffered, causing the pH to decrease).
How may respiratory alkalosis and acidaemia be compensated?
[*] Central chemoreceptors normally control pCO2 within tight limits.
- Respiratory changes CORRECT respiratory disturbances of pH
- Peripheral chemoreceptors enable changes in respiration driven by changes in plasma pH
[*] As the pH depends on the ratio of [HCO3-] and pCO2, not absolute values, respiratory acidaemia or alkalaemia can be COMPENSATED for by changes in [HCO3-] produced by the kidney.
[*] If the pCO2 rises, a proportionate rise in [HCO3-] will restore pH. If the pCO2 falls, a proportionate fall in [HCO3-] will restore pH (by restoring the ratio) These compensatory changes are produced by variable renal excretion or production of HCO3-. The original problem still occurs.
- Respiratory acidaemia (acidosis) is compensated by the kidneys increasing [HCO3-]
- Respiratory alkalaemia (alkalosis) is compensated by the kidneys decreasing [HCO3-]
Describe metabolic acidosis
[*] If H+ ions are produced metabolically in the tissues (e.g. from metabolism of amino acids or production of ketones), they react with HCO3- to produce CO2 in venous blood, which is then breathed out through the lungs, leaving a directly proportional deficit of [HCO3-] in arterial blood (one mmol acid added to blood will remove one mmol HCO3-). This alters the [HCo3-]: pCO2 ratio meaning that there is less than 20x the amount of HCO3- than CO2. Relatively less H+ ions are buffered, causing a pH decrease.
Reductions in [HCO3-] are known as metabolic acidosis (pH <7.35)
Describe metabolic alkalosis
[*] Increases in [HCO3-] are known as metabolic alkalosis (pH > 7.45) e.g. after persistent vomiting
There is more than 20x the amount of HCO3- than CO2 will be present so relatively more H+ ions are buffered, causing a pH increase.
How can metabolic acidosis and metabolic alkalosis be compensated?
- These changes may be compensated by altering pCO2 by changing ventilating
- pCO2 is normally kept within tight limits by the Central Chemoreceptors
- Changes in plasma pH drive chains in pCO2 via the Peripheral Chemoreceptors
- In metabolic acidosis, pCO2 is lowered proportionately by increasing ventilation.
- In alkalosis, pCO2 can be slightly raised by decreasing ventilation but compensation is limited (partial compensation) by hypoxia resulting from hypoventilation
- Correction depends upon the kidney variably excreting or creating HCO3-. The handling of hydrogen carbonate by the kidney is therefore critical for maintaining acid base balance.
Describe and be able to identify from values, respiratory acidaemia (acidosis) and alkalaemia (alkalosis) and metabolic acidosis and alkalosis
[*] Respiratory Acidaemia (acidosis): hypoventilation has raised pCO2. Hypercapnia leads to low pH. [HCO3-] is unchanged.
[*] Compensated (partially or fully) Respiratory Acidaemia: Kidneys have increased [HCO3-]. This increases the buffering of H+ ions caused by increased pCO2.
[*] Respiratory alkalaemia (alkalosis): Hyperventilation has lowed pCO2. Hypocapnia leads to high pH. [HCO3-] unchanged.
[*] Compensated (partially or fully) Respiratory Alkalaemia: kidneys have decreased [HCo3-]. Decreased buffering of H+ ions.
[*] Metabolic Acidosis: Decreased [HCO3-] leads to less buffering of H+ ions. Increase in unmeasured anions (anion associated with the increase in H+ has taken [HCO3]’s place.
[*] Compensated (partially or fully) Metabolic Acidosis: increased respiratory rate => hypocapnia => raised pH. Anion gap still increased.
[*] Metabolic Alkalosis: increased [HCO3-] leads to buffering of H+
[*] Compensated (partially or fully) Metabolic Alkalosis: decreased respiratory rate => hypercapnia => decreased pH. Can only partially compensate
See Groupwork and actual notes + lusuma notes
Describe the renal control of HCO3-
[*] Hydrogen carbonate is filtered in considerable quantities at the glomerulus – at 180mmol/hour or 4500mmol/day.
[*] This needs to be recovered to maintain acid base status unless the patient is alkalotic.
[*] If the acid is produced metabolically, recovery of all filtered [HCO3-] will be insufficient to restore plasma [HCO3-] so HCO3- will have to be created within the kidney
[*] This will create H+ ions which are then excreted directly or indirectly into the urine, and to avoid a damaging urinary acidity, it must be buffered by either other filtered substances or buffers created by the kidney.
- Metabolic activity of kidney produces large quantities of CO2 which can react with water to produce:
- HCO3- to enter plasma
- H+ to enter urine (but if urine becomes too acidic, this could damagae urinary tract)
[*] Can also make hCO3- from amino acids, producing NH4- to enter urine
Describe cellular mechanisms of reabsorption of HCO3- in the proximal tubule
[*] A large fraction of HCO3- is reabsorbed in the proximal tubule. H+ ions are pumped out of the apical membrane of the proximal tubule cells in exchange for the inward movement of Na+ ions down its concentration gradient.
- H+ exported from cell into lumen (up concentration gradient)
- Up concentration gradient
- Energy from movement of Na+ down concentration gradient (produced by sodium pumps on basolateral membrane)
- H+ reacts with HCO3- - making CO2 which enters cells
- To react with H20 and recreate H+ which is exported again
- Leaving HCo3- to leave by basolateral membrane to ECF.
[*] 80-90% of the filtered HCO3- is reabsorbed in the proximal tubule.
[*] Up to 15% of HCO3- is also absorbed in the thick ascending limb of the loop of Henle by a similar mechanism. (Remember ascending limb is known as the diluting segment – of urine – as it is impermeable to water)
Describe creation of HCO3- inside the proximal tubule
Glutamine is broken down to produce
- Alpha-ketoglutarate which makes HCO3- and ammonium (NH4+)
- HCO3- into ECF
- NH4+ into lumen => urine
Describe cellular mechanisms of H+ absorption andexcretion in the distal tubule
[*] HCO3- absorption and H+ excretion occur through intercalated cells in the distal nephron.
[*] H+ is pumped across the apical membrane by a H+-ATP’ase pump as the Na+ ion gradient is insufficient to drive H+ out of the cell. These proton pumps are similar to those found in the stomach.
[*] By this stage there is very little HCO3- remaining, so little CO2 enters the cell to react with water and create H+ for excretion. This is produced from CO2 produced by the cells’ own metabolism, so generating new HCO3- to enter the plasma.
[*] When the cells export H+, K+ is absorbed into the blood. So if you export a lot of H+, you will also absorb a lot (perhaps too much) K+. This relationship means that blood pH is linked to [K+].
Describe the creation of HCO3- inside the distal tubule
- By the distal tubule, all filtered HCO3- is normally recovered.
- Na gradient is insufficient to drive H+ secretion
- So active secretion of H+ into lumen is needed.
- In the lumen H+ is buffered by filtered phosphate and excreted ammonia
- H+ is generated is from metabolic CO2 which also produces HCO3- which enters ECF
Describe why the internal balance of potassium is so important
[*] Potassium ions are the most abundant intracellular cation. Some 98% of the total body potassium content (150-160 mmol/L is intraceullar or ~50mmol/kg body weight)
[*] The body tightly maintains the plasma [K+} to a range of 3.5-5.3 mmol/L
[*] The high [K+]i inside the cell and the low [K+]e outside creates a gradient for K+ to move out of the cell => creates resting membrane potential. The inside of the cell is negatively charged compared to the outside.
[*] The potentially life threatening disturbances of cardiac rhythmicity that result from a rise of plasma [K+] are particularly important (CVS unit)
[*] Extremely low ECF [K+] )chronic K+ ion depletion) leads to several metabolic disturbances which include: the inability of the kidney to form concentrated urine, a tendency to develop metabolic alkalosis, and an enhancement of renal ammonium excretion.
[*] 2 homeostatic mechanisms keep the ECF [K+] tightly controlled - external and internal balance.
- Small increases in the serum potassium concentration can be very quickly life threatening
- The kidneys cannot excrete potassium quickly enough to contain surges in oral potassium loads hence intracellular buffering plays an important role in potassium homeostates.
- As the kidneys excrete the excess and serum concentration falls, K+ is released again from the cells.
Describe how potassium handling occurs in the various segments of the nephron
[*] Potassium is freely filtered at glomerulus
[*] K+ is reabsorbed in the proximal tubule, thick ascending limb of Loop of Henle, intercalated cells of distal tubule/cortical collecting duct and intercalated cells of medullary collecting duct
[*] K+ is secreted by principal cells in the distal tubule and cortical collecting duct
How do principal cells secrete K+?
- The Na-K-ATPase activity in the basolateral membrane creates a high intracellular [K+] and a low intracellular [Na+]
- The high intracellular [K+] creates a chemical gradient for secretion
- Na+ moves from lumen into cell downs its concentration gradient via ENaC on the apical membrane, creating an electrical gradient (Na+ absorb creates lumen negative potential which promotes K+ secretion into lumen)
- A favourable electrochemical gradient for K+ secretion is created via apical K+ cells.
Describe K+ reabsorption by the intercalated cells in the distal tubule and cortical collecting duct
- Active process
- Mediated by H+ K+ ATPase in apical membrane
What happens after you eat?
- Intestine and colon absorb dietary K+
- Substantial amount of K+ can enter the ECF e.g. 28mmol absorbed K+ => distributed in 14 L of ECF increases ECF K+ by 2mmol/L (28/14)
- 4/5ths of ingested K+ moves into cells within minutes
- After slight delay kidneys begin to excrete K+. Excretion complete in 6-12 hours
Describe External and Internal Balance
[*] External balance adjusts renal K+ excretion to match intake.
- Average K+ intake in diet is 100 mmol/day
- 5-10% loss via GI tract, rest absorbed
- The kidneys adjust K+ excretion to match intake by controlling K+ secretion (renal excretion)
- Slower to act – takes 6-12 hours to excrete a load of K+
- Responsible for control of total body potassium content over the longer term
[*] Internal balance maintains ECF [K+]
- Effect is immediate – within minutes
- Responsible for moment to moment control of ECF K+ - acts as a buffer
- Acts by shifting K+ between ECF and ICF.
- If ECF (plasma) [K+] increases, K+ moves into cells
- If ECF [plasma) [K+] decreases, K+ comes out of cells
Internal balance is the net result of 2 processes:
- Movement of K+ from ECF into cells (mediated via Na-K-ATPase)
- Movement of K+ out of cells into ECF via K+ channels (ROMK channels which determine the K+ permeability of the cell membrane
Regarding internal balance, what are the Factors promoting the uptake of K+ into cells?
- Hormones (act via Na-K-ATPase)
Insulin
- K+ in splanchnic blood stimulates insulin secretion by pancreas
- Insulin stimulates K+ uptake by muscle cells and livers via an increase in Na-K-ATPase as it provides the drive for the Na-Glucose transporter
- The increase in Na-K-ATPase results in uptake of K+
- This is why intravenous insulin is used as an emergency treatment to use bring down dangerously high K+ levels (short term, buying time)
Aldosterone
- K+ in blood stimulates Aldosterone secretion from adrenal glands => Stimulates uptake of K+ via Na-K-ATPase
- Aldosterone also increases the transcription of ENaC/K+ channels in the apical membrane which leads to increased K+ secretion
Catecholamines
- Acts via β2 adrenoceptors which in turn stimulate Na-K-ATPase
- Stimulate the cell uptake of K+
- Another emergency treatment is nebulised catecholamines
- Increased [K+] in ECF (=> increased K+ movement into cell).
- Alkalosis – low ECF [H+]: H+ moves out of cells to correct Alkalosis. There is a reciprocal K+ shift => into cells (to maintain electroneutrality which could eventually lead to hypokalaemia). This is because changes in ECF pH cause reciprocal shifts in K+ and H+ between the ECF and ICF. Hypokalaemia causes Hyperpolarization because it increases gradient)
What are the factors promoting the K+ shift out of cells?
- Low ECF [K+]
- Exercise
- Skeletal muscle contraction => net release of K+ during recovery phase of action potential (K+ exits cell)
- Also skeletal muscle damage during exercise releases K+
- The increase in plasma [K+] is proportional to the intensity of exercise
- Uptake of K+ by non-contracting tissues e.g. liver prevents dangerously high hyperkalaemia
- Exercise and trauma also increase catecholamines which offset ECF [K+] rise by increasing K+ uptake by other cells
- Cessation of exercise results in a rapid decrease in plasma [K+], often to <3mmol/L (thought to be one of the contributing factors in sudden death in athletes)
- Cell lysis (when the membrane ruptures, K+ leaks out)
- E.g. trauma to skeletal muscle causing muscle cell necrosis (rhabdomyolysis) – can cause hyperkalaemia
- Intravascular haemolysis – (breakdown of RBC within vascular tree) e.g. incompatible blood transfusion, G-6-P-D deficient patients treated with certain drugs
- Cancer chemotherapy – tumour cell lysis could lead to intravascular haemolysis which could lead to hyperkalaemia
- Increase in ECF osmolality (plasma hyposmolarity)
- Increased plasma tonicity e.g. in diabetic ketoacidosis could lead to an increase in plasma osmolarity and ECF tonicity
- Water moves from cells into ECF
- This increases [K+] in ICF
- K+ leaves down concentration gradient
- Acidosis – increased ECF [H+] leads to shift of H+ into cells. There is a reciprocal K+ shift => out of cells to maintain electroneutrality. This could lead to hyperkalaemia. Changes in ECF pH causes reciprocal shifts in K+ and H+ between the ECF and ICF.
Describe hyperkalaemia
[*] Hyperkalaemia = [K+] > 5.0mmol/L
Hyperkalaemia depolarises cardiac tissue => initially heart becomes more excitable => more fast Na channels remaining in inactive form – heart less excitable => cardiac arrest
Clinical features
- Heart: altered excitability => arrhythmias, heart block
- Gastrointestinal: neuromuscular dysfunction => paralytic ileus (paralysed gut), abdominal distension
- Acidosis
Describe ECG changes seen in hyperkalaemia
- High T waves
- Depressed ST segment
- Prolonged PR interval (as heart rate slows)
- Eventually Atrial standstill (p wave absent) – intraventricular block
- Ventricular fibrillation would eventually lead to cardiac arrest
Describe treatment for hyperkalaemia
Emergency treatment
- Reduce K+ effect on heart (give intravenous calcium gluconate which stabilizes cardiac RMP and reduces initial cardiac excitability – prevents heart slowing down)
- Shift K+ into ICF by glucose + insulin IV, nebulised Beta2-agonists (salbutamol)
- Remove excess K+ (dialysis)
Longer term treatment:
- Treat cause
- Reduce intake
- Measures to remove K+ e.g. via dialysis or oral K+ binding resins to bind K+ in gut
Describe hypokalaemia
[*] Hypokalaemia = [K+] < 3.5mmol/L
- Hypokalaemia hyperpolarises cardiac cells => more fast Na channels available in active form => heart more excitable
Clinical features
- Heart: altered excitability => arrhythmias
- Gastrointestinal: neuromuscular dysfunction => paralytic ileus
- Skeletal muscle: neuromuscular dysfunction => muscle weakness
- Renal: dysfunction of collecting duct cells => unresponsive to ADH => nephrogenic diabetes insipidus
Describe ECG changes and treatment for hypokalaemia
ECG changes
- Low T waves (low and flat)
- High U waves (small deflection following the T wave, best seen in leads V2 and V3 – U-wave size is inversely proportional to heart rate: the U wave grows bigger as the heart rate slows down)
- Low ST segment
Treatment
- Treat cause
- Potassium replacement – IV/oral
- If due to increased mineralocorticoid activity, potassium sparing diuretics which block action of aldosterone on principal cells e.g. spironolactone.
What might cause hyperkalaemia?
Problems of external balance
- Increased intake of K+ only causes hyperkalaemia if there is renal dysfunction unless inappropriate doses given IV
- OR inadequate renal excretion
Inadequate urinary excretion of K+ could be due to:
- Acute kidney injury
- Chronic kidney injury
- Reduced aldosterone (with normal functioning kidneys) due to adrenal insufficiency, drugs which reduce/block aldosterone action, K-sparing diuretics and ACE inhibitors (reduce amount of aldosterone)
Internal shifts
- Diabetic ketoacidosis: no insulin (insulin helps to shift K+ into cells), also hyper osmolarity and metabolic acidosis
- Other causes of metabolic acidosis
- Cell lysis (muscle-crush injuries)
- Exercise
