Theme 4: Disorders of Metabolism - Part 1 Flashcards
In a titration apparatus, what is put in the burette and what is put in the flask?
- burette contains the base
- the flask contains the acid with a suitable indicator
Why is the maintenance of [H+] so important?
- changes in [H+] can affect the surface charge and physical conformation of proteins, changing their function
- the gradient of [H+] between the inner and outer mitochondrial membrane drives oxidative phosphorylation so the body won’t be able to produce ATP
Where do we remove H+ ions?
- Lungs - excretion of CO2 in expired air
2. Kidney - excretion of H+ in urine
What is the concentration of H+ in the plasma?
40 mol/L
-H+ ions are produced in mmol quantities, yet must be kept at nmol concentrations
Where do our H+ ions come from?
- Glucose (incomplete metabolism)
Glucose —> 2 lactate + 2H+ - Triglycerides (incomplete metabolism - ketogenesis)
- Amino acid metabolism (urea genesis)
-metabolism of neutral amino acids results in the generation of H+
What are acid and bases also known as?
Acids - H+ donors
Bases - H+ acceptors
What is pH and how do you calculate it?
Negative logarithm of the hydrogen ion concentration (mol/L)
pH = -log10[H+]
Why is the pH scale used rather than [H+]?
logs make the wide range of H+ concentrations more manageable
If a patient is acidotic, what does this mean?
[H+] > 45nmol/L
pH < 7.35
If a patient is alkalaemic, what does this mean?
[H+] < 35 nmol/L
pH > 7.45
What is Ka and how do you calculate pKa?
Ka - acid dissociation constant
pKa = -log10Ka
What does it mean if there is a high Ka?
high Ka = greater the dissociation = stronger acid
What is the Henderson-hasselbalch equation?
pH = pKa + log10 [[base]/[acid]]
How does CO2 act as an acid?
when dissolved in plasma, CO2 becomes an acid (carbonic acid; H2CO3) which readily dissociates to release H+
how does HCO3- act as a base?
HCO3- accepts a proton to form carbonic acid, which is converted to CO2 for excretion in the lungs
How can you convert partial pressure of CO2 into a concentration?
x by a
alpHa is the solubility constant
What is a buffer?
A buffer is a solution which resists change in pH when an acid or base is added
Buffering ensures H+ ions are transported and excreted safely without affecting physiological processes
Name 5 buffers in the body
- bicarbonate
- haemoglobin
- phosphate
- ammonia
- proteins
Why does equilibrium of CO2 require a non-bicarbonate buffer?
because buffering CO2 by bicarbonate would only result in the production of more CO2
Describe haemoglobin as a buffer
- principle non-bicarbonate buffer - important for buffering CO2
- reduction of CO2
- production of HCO3
Describe phosphate as a buffer
-Monohydrogen phosphate and dihydrogen phosphate from a buffer pair:
HPO42- + H+ —> H2PO4-
-important buffer in urine, where phosphate is present at a much higher concentration
Describe ammonia as a buffer
-Ammonia and ammonium ions form a buffer pair:
NH3+H+ —> NH4+
-Vast majority of ammonia in the body is already in ammonium form, limiting its buffering capacity
-Most important role in urinary ammonium excretion is providing a route for ammonium disposal that does not result in the generation of H+
Describe proteins as a buffer
- Proteins contain weakly acidic and basic groups due to their amino acid composition, and can therefore accept and donate H+ ions to some extent
- Albumin is the predominant plasma protein, and is the main protein buffer in this compartment (it has a net negative charge, so can “mop up” H+ ions)
- bone proteins also play a role in buffering
Describe the relationship between Hb saturation and pO2
- sigmoid relationship
- pO2 can decrease significantly before saturation is affected
When would the curve shift to the right?
- If body temp increases
- If patient is hypoxic or anaemic (increase in 2,3-DPG)
- [H+] increases - Bohr effect
Hb then has a reduced affinity for O2 and O2 is more available to the tissues
Why does an increase in 2,3-DPG shift the curve to the right?
2,3-DPG binds to haemoglobin and rearranges it to the T state, which decreases its affinity for O2
Explain the 3 acid-base processes in the kidney?
Why are they important?
- Excretion of H+ (distal tubule)
- Reabsorption of bicarbonate (proximal tubule)
- Regeneration of bicarbonate (distal tubule)
These functions create acidic urine containing almost no bicarbonate
How do we reabsorb bicarbonate?
-bicarbonate cannot be directly reabsorbed, as luminal membranes are impermeable to it
- so we rely on CO2 to diffuse
see process acid base lecture part 1
What is the function of carbonic anhydrase in renal bicarbonate reabsorption?
H2CO3 generated from CO2 and H2O under action of carbonic anhydrase –> H2CO3 formed dissociates into H+ and HCO3-
How do we maintain buffering capacity in renal tubular cells?
Continued formation of H+ in the renal tubular cells is accompanied by stoichiometric generation of bicarbonate —> excretion of H+ results in bicarbonate generation
What does aldosterone do in the kidney?
-increase aldosterone leads to increase sodium reabsorption and potassium /hydrogen ion excretion in the distal tubule
In what ways do we consume or produce H+ in the kidneys?
- CO2 production from complete oxidation of carbohydrates and fats
- metabolism of lactate, ketones and amino acids (consumption of H+)
- metabolism of NH4+ to urea via the urea cycle (producer of H+
- production of plasma proteins e.g albumin (buffering)
What is hyperammoniaemia in liver failure?
- in liver failure, liver is unable to perform urea cycle, which normally converts toxic ammonia to urea for excretion in urine
- ammonia stimulates the respiratory centre, causing the patient to hyperventilate and blow off CO2 —> leads to increase in blood pH —> respiratory alkalosis
- metabolic alkalosis can also arise as a result of reduced production of H+
How do we determine the acid-base status of a patient
Blood gas machine:
- pH
- gases
- pCO2, pO2 - metabolites
- glucose
- lactate - electrolytes
- sodium, potassium, chloride, calcium - co-oximetry
- total Hb, O2 saturation, OxyHb, COHb, MetHb
How can you ensure samples for blood gas analysis are going to be accurate?
Samples must be:
- well-mixed, heparinised whole blood with no air bubbles (air bubbles can affect pO2, can increase pH and can decrease pCO2)
- analysed immediately (in-vitro glycolysis can cause a time dependent decrease in pO2 and increase in pCO2)
- Not sent via pneumatic tube system (rapid deceleration of sample can affect pO2 and pCO2 if air bubbles present)
What are the two main types of samples you can obtain?
- arterial blood (much more painful to obtain)
2. venous blood
What is the principle feature of respiratory acidosis?
increase in pCO2
lungs can’t get rid of enough CO2 to maintain acid-base homeostasis
What is the principle feature of respiratory alkalosis?
decrease in pCO2
lungs get rid of too much CO2
What is the principle feature of metabolic acidosis?
decrease in HCO3-
low bicarb because it is being used up buffering excess hydrogen ions
What is the principle feature of metabolic alkalosis?
increase in HCO3-
What is the pH range for acidosis?
pH < 7.35
What is the pH range for alkalosis?
pH > 7.45
How do you work out if the alkalosis/ acidosis is respiratory or metabolic?
look at the pCO2
Acidosis:
-increase pCO2 = respiratory
-normal pCO2 (or decrease CO2 if there is compensation) = metabolic
Alkalosis:
-decrease pCO2 = respiratory
-normal pCO2 (or increase pCO2 if there is compensation) = metabolic
What is compensation?
- secondary changes in bicarbonate and pCO2 to correct for the primary disorder
- changes in bicarb concentration (brought about by renal regeneration) can compensate for respiratory disorders - slow
- changes in pCO2 (respiratory rate) can occur to compensate for metabolic disorders - fast
- compensatory mechanisms aim to restore a neutral pH
- but full compensation rarely occurs, and overcompensation never occurs
How would we compensate for respiratory alkalosis?
decrease HCO3-
How would we compensate for metabolic acidosis?
decrease pCO2
What are the two ways of measuring bicarb?
- Bicarb (main lab) (22-29 mmol/L)
- approximation of bicarb, calculated in part from CO2 - Bicarb (standard) (22-26 mmol/L)
- Removes respiratory contribution so an abnormal standard bicarb tells us there is a metabolic component to the disorder
- uses Henderson-hesselbalch equation to calculate bicarb from pH and “corrected” pCO2
What is:
- Base Excess
- Anion Gap
- Base excess (-2.3 to +2.3 mmol/L)
- amount of acid or alkali to titrate blood pH to 7.4
- normal base excess = purely respiratory disorder
- tells us if there is a metabolic component to the disorder - Anion gap (8-16 mmol/L)
- difference between the sum of measured anions and cations
- anion gap = ([Na+] + [K+]) - ([Cl-] + [HCO3-])
- increased anion gap indicates that there are significant amounts for “unmeasured” anions e.g ketones, lactate, salicylate, proteins etc
- can be useful in determining the cause of a metabolic acidosis
What are the biological features of metabolic acidosis?
- decrease pH
- increase [H+]
- decrease CO2
- decrease HCO3-
- increase pO2
What are the signs and symptoms of metabolic acidosis?
- nausea, vomiting and anorexia frequently present
- subjective sense of dyspnoea caused by stimulation of the respiratory centre
- deep laboured breathing pattern, known as Kussmaul breathing, seen in severe acidosis
- other symptoms caused by underlying disorder
What are the causes of metabolic acidosis?
- Increased acid formation (caused by increased anion gap metabolic acidosis)
- ketoacidosis (diabetic, alcoholic or starvation)
- lactic acidosis
- poisoning (salicylate, toxic alcohols) - Acid ingestion
- Decreased acid excretion
- uraemia, RTA type 1 (distal) - Loss of bicarb
- GI: diarrhoea/fistula- intestinal fluid v rich in bicarb
- RTA type 2 (proximal)
- carbonic anhydrase inhibitors e.g acetazolamide
What is the physiological response to metabolic acidosis?
Buffering:
-acute increase [H+] resisted by bicarb buffering, causing decrease HCO3
-protein buffering important in chronic acidosis
Compensation:
-respiratory: respiratory centre stimulated —> hyperventilation (blows off CO2, but self-limiting as generates additional co2)
-renal (urine H+ excretion maximised, increased rate of regeneration of bicarb)
How do we treat metabolic acidosis?
IV sodium bicarb
- usually only given if pH < 7.00
- caution: rapid correction impairs O2 delivery, rebound alkalosis possible
What are the chemical features of metabolic alkalosis?
- increase pH
- decrease [H+]
- increase/N pCO2
- increase HCO3-
- decrease O2
What are the signs and symptoms of metabolic alkalosis?
- usually related to underlying disorder
- more severe alkalosis increases protein binding of Ca2+, leading to hypocalcaemia —> causes headache, lethargy, and neuromuscular excitability, sometimes with delirium, tetany and seizures
- lowers threshold for arrhythmias
What are the causes of metabolic alkalosis?
- Loss of H+
- vomiting (gastric secretions full of HCl) - Administration of bicarbonate
- Potassium depletion
Why can hypokalaemia cause a metabolic alkalosis?
- kidneys: excretion of H+ favoured in order to spare K+ at aldosterone controlled renal transporter
- cells: K+ ions are transported out of the RBCs to increase plasma concentration –> H+ ions move into cells to maintain electroneutrality. This leads to a decrease in plasma [H+]
What is the physiological response of metabolic alkalosis?
- buffering: release of H+ from buffers
- compensation: respiratory - reduced respiratory rate to retain CO2
- renal:
- decrease GRF leads to inappropriately high bicarb reabsorption
- potassium deficiency contributes to persistence of alkalosis
How do we treat metabolic alkalosis?
- treat underlying cause
- treat factors that sustain alkalosis e.g replace potassium
How do we treat respiratory acidosis?
- decrease pH
- increase [H+]
- increase pCO2
- increase/N HCO3-
- decrease pO2
What are the signs and symptoms of respiratory acidosis?
- usually related to underlying disorder
- some patients may complain of dyspnoea
What are the two causes of respiratory acidosis?
- Defective control of respiration
- CNS depression - anaesthetics, sedatives, narcotics
- CNS disease - trauma, haemorrhage, infarction, tumour
- neurological disease - spinal cord lesions, Guillain-barre - Defective respiratory function
- mechanical - myopathies, pneumothorax, pleural effusion
- pulmonary disease - COPD, severe asthma, impaired perfusion
What is the physiological response of respiratory acidosis?
- Buffering - limited buffering by haemoglobin
- Compensation
- metabolic compensation tends to be slow
- respiratory: increase pCO2 stimulate respiratory centre
- renal: max bicarb reabsorption, increase in urinary NH4+, almost all phosphate excreted as H2PO4-
How do we treat respiratory acidosis?
- treat underlying cause
- maintain adequate arterial pO2, but avoid loss of hypoxic stimulus to respiration
- avoid rapid correction of pCO2 (risk of alkalosis due to persistence of compensation)
What are the signs of respiratory alkalosis?
- increase pH
- decrease [H+]
- decrease pCO2
- decrease/N HCO3-
- increase pO2
What are the symptoms of respiratory alkalosis?
- Usually related to underlying disorder
- principle feature is decreased pCO2
- More severe alkalosis increases protein binding of Ca2+, leading to hypocalcaemia –> causes headache, lethargy and neuromuscular excitability, delirium, tetany and seizures
What are the causes of respiratory alkalosis?
increase in respiratory rate or volume or both
- Central:
- head injury
- stroke
- hyperventilation
- drugs
- sepsis
- chronic liver disease - Pulmonary
- pulmonary embolism
- pneumonia
- asthma
- pulmonary oedema - iatrogenic
- excessive mechanical ventilation
What is the physiological response of respiratory alkalosis?
- buffering: release of H+ from non-bicarbonate buffers
- compensation:
- respiratory: inhibitory effect of decreased pCO2 overwhelmed by primary cause
- renal: decreased renal regeneration of bicarb (CO2 is substrate, therefore CO2 is preserved)
What are mixed disorders?
- two or more primary acid base disorders presenting in the same patient
- can be either additive or counterbalancing
How would respiratory failure come about from two additive disorders?
Respiratory acidosis (increase pCO2) and metabolic acidosis (increase lactic acid)
How would vomiting and CCF failure come about from two additive disorders?
metabolic alkalosis (loss of H+) and respiratory alkalosis (increase respiratory rate)
What would salicylate poisoning cause?
- counterbalancing
- metabolic acidosis and respiratory alkalosis (increase respiratory rate)
What would vomiting and renal failure cause?
- counterbalancing
- metabolic alkalosis (loss of H+) and metabolic acidosis (decrease renal H+ excretion)
How can vomiting cause hypokalaemia?
- gastric fluid is not very rich in potassium, but it is very rich in H+ ions
- loss of H+ ions from vomiting causes potassium depletion by:
1. kidneys: excretion of K+ favoured in order to spare H+ ions at aldosterone-controlled renal transporter
2. cells: H+ ions are transported out of the RBCs to increase plasma concentration - K+ moves into cells to maintain electroneutrality - this leads to a decrease in plasma [K+]
What happens to calcium levels in acidosis?
as H+ binds to albumin to reduce plasma [H+], Ca2+ must be released, resulting in hypercalcaemia
What happens to calcium level in alkalosis?
as H+ is released from albumin to increase plasma [H+], Ca2+ must bind to albumin
How do you know if compensation is full or partial?
if the pH has not returned to normal, compensation is partial
