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Even when the lungs are working how many mmol of acid per day must be dealt with to avoid acidosis?
How much “potential” acid do humans produce? In what form is it in?
- humans produce 15,000 mmols a day of CO2 (from oxidation of CHOs, FAs, & some AAs)
- functioning lungs secrete most of this CO2 before it can be converted into acid
What type of acids acids & bases can’t be expelled by the lungs?
- nonvolatile kinds (not related to CO2) that are products of metabolism
- normal metabolism generates a net acid load of 40 mmols per day
- also strong acids & bases in the diet contribute an additional 30 mmol/day
What are some nonvolatile acids that the body needs to deal w/ not using the lungs?
1. H2SO4: comes from the oxidation (metabolism) of sulfur-containing AAs
2. H3PO4: from the metabolism of phosphorous-containing compounds
3. Uric & Oxalic Acid: non-metabolizable organic acids produced during metabolism
4. Lactic & Keto Acids: from incomplete oxidation of CHO & fats
5. Sulfuric & Phosphoric Acids: are just strong acids in the diet
What are some nonvolatile bases that the body needs to deal w/ not using the lungs?
1. glutamate & aspartic acids: derived from partial oxidation of anionic AAs
2. lactate & acetate: from the production of organic anions
3. hydroxide ion: a strong base in the diet
Acid v. Base
- acids are proton donors
- bases are proton acceptors
- weak acids & bases do not dissociate fully in aqueous solutions, instead, an equilibrium (dictated by an equilibrium constant) is formed between the acid & its conjugate base
Weak Acid Equilibrium
- HA ⇌ A- + H+
- eg. acetic acid will partially dissociate into acetate (conjugate base) + a proton
Ka (the equilibrium constant)
- Ka =([H+] * [A-]) / [HA]
- determines the extent an acid dissociates
- pH = pKa + log([A-] / [HA])
- tells us how pH changes as the concentration of dissociated & undissociated components change
- pH = pKa when there are equal concentrations of acid (HA) & its conjugate base (A-)
How do humans normalize the excess daily acid load (70 mMols)?
• we buffer it; however buffering is NOT a major component in the control of acid base balance
• add base or remove acid; this is what the kidneys do & they are the main controllers of blood bicarbonate concentration
Why is buffering not the main way we normalize our excess daily acid load?
• the most abundant buffer in our body is bicarbonate (HCO3-) / carbonic acid (H2CO3)
• it’s the most likely chemical pair that would be involved in buffering
• take a vessel of pure carbonic acid, add increasing amounts of NaOH (sodium hydroxide), & measure the pH at different points of the addition process
• when you plot NaOH (base) added against solution pH → a sigmoidal curve results
• it takes ~15 NaOH units to raise the solution’s pH from 4 to 5 but it takes ~20 NaOH units to raise the solution’s pH from 5 to 6
• where there are = amounts of HCO3- & H2CO3, pH = 6.1 = pKa; this is the maximal buffering capacity
• however the normal pH of blood is 7.4 → at this pH buffering capacity is NOT ideal (again, is ideal around the pKa value of pH)
• therefore a HCO3- & H2CO3 system is a POOR buffering system for the human body
In a scenario where the concentration of carbonic acid in the body is doubled (so 2.6 b/c normal concentration is ~1.3 mM), how would normal pH be restored?
- a situation that doubles the body’s carbonic acid content would lower the ratio of [HCO3-]/[H2CO3] to 10 (there’s normally 20-fold more bicarbonate than carbonic acid in a normal human body)
- the pH would fall to 7.1
- to restore normal pH, the ratio must increase back up, which can be done by either lowering the amount of acid OR increasing the amount of bicarbonate - this isn’t ‘buffering’, it’s altering concentrations
- another way to normalize the excess daily acid load
What do the kidneys do to act as the main controllers of blood bicarbonate concentration?
- they divide 70 mMols of carbonic acid into its respective “acid” & “base” components
- it excretes 70 mMols of the “acid” (proton) component into the urine & transports the 70 mMols of the “base” (bicarbonate) back into the blood to neutralize the daily acid load
What is the molecular mechanism by which the kidneys control of blood bicarbonate concentration?
- cells of the kidney contain carbonic anhydrase, which catalyzes the hydration of CO2
- CO2 + H2O → H2CO3 (+ H+)
- in the presence of proton however, carbonic anhydrase dehydrates bicarbonate
- HCO3- + H+ → CO2 + H2O
Renal Carbonic Anhydrases Drive Bicarbonate (-) Reabsorption
- • in the kidney lumen, secreted protons combine w/ filtered bicarbonate to form carbonic acid
- - passive reaction: HCO3- + H+ —> H2CO3
- • extracellular carbonic anhydrase converts lumenal carbonic acid into CO2 & water
- - enzymatic conversion: H2CO3 → CO2 + H2O
• lumenal CO2
freely diffuses INTO tubular cells
- • there intracellular carbonic anhydrase catalyzes the resynthesis of carbonic acid
- - enzymatic: CO2 + H2O → H2CO3
- • tubular carbonic acid dissociates into proton & bicarbonate
- - passive: H2CO3 —> HCO3- + H+
• that bicarbonate exits (via a Na+
dependent transporter) the cell & goes into the blood
• the proton is secreted into the lumen to initiate another cycle of bicarbonate reabsorption
What is the net effect of renal carbonic anhydrases?
- reabsorb bicarbonate, secrete water, & recycle protons
- protons essentially act as a catalytic agent to move bicarb from the lumen into the interstitium
What happens when there are no protons or bicarbonate in the renal interstitium from which to make carbonic acid (acid base profile alterations)?
• if H2CO3 can’t be passively formed in the interstitium, then extracellular carbonic anhydrase can’t use H2CO3 as a substrate to produce H2O & CO2
• if no CO2 diffuses into tubular cells, then intracellular carbonic anhydrase can take CO2 that’s made from normal tubular cell metabolism & break IT down into H+ & HCO3-
• that bicarbonate will move across the basolateral membrane into the circulation while the proton produced is transported across the apical membrane into the kidney interstitium
Metabolism of what other compound can help control acid base balance?
- metabolism of ammonia occurs in 2 organs, the liver & kidney
Hepatic Urea Synthesis
- enzymes in the liver combine 2 bicarbonates with 2 ammoniums to make urea, CO2, & water
- 2HCO3- + 2NH4+ → Urea + CO2 + 3H2O
- this reaction in the liver CONSUMES bicarbonate: this can help normalize alkalosis (however it can exacerbate acidosis)
What compound is generated in kidney glutamine metabolism?
- Glutamine → 2NH3 + α-ketoglutarate → 2HCO3-
- if this reaction is somehow inhibited (eg. due to enzyme dysfunction), the production of bicarb would DECREASE
• acid (proton) levels in kidney lumen increase (filtered bicarb is completely reabsorbed)
• hepatic urea synthesis decreases (bicarb is spared)
• there is increased renal metabolism of glutamine → ammonia (increasing bicarb levels)
• there is increased secretion of ammonia (this buffers lumenal protons leading to H+ excretion)
• lumenal acidity decreases (so bicarb reabsorption decreases)
• hepatic urea synthesis increases (serum bicarb is used up)
• kidney synthesizes glutamine instead of converting it to ammonia & bicarb (less bicarbonate is made)
In the kidney functional unit, where does bicarbonate reabsorption occur?
- bicarbonate is reabsorbed in the proximal (& distal) tubule
- new bicarb can be made if needed in those same places - b/c that’s where carbonic anhydrases are highly abundant in the tubular system
What are four conditions that may be encountered when hydrogen ion homeostasis is disrupted?
- 1. Respiratory Acidosis
- 2. Respiratory Alkalosis
- 3. Metabolic Acidosis
- 4. Metabolic Alkalosis
- arise as a result of kidney (metabolic) or lung (respiratory) malfunction
- when a person’s lungs fail to remove CO2
- their plasma pH falls BELOW 7.35 & their PCO2 is greater than 45 mmHg
- the acidosis is caused by this greater than normal PCO2 (which leads to ↑ H2CO3 & ↓ plasma pH) that can be caused by hypoventilation from pulmonary disease or drug/disease-induced respiratory center depression
How does the body compensate for Respiratory Acidosis?
- the ↑ acidity inside tubular cells causes:
- ↑ H+ secretion
- ↑ HCO3- reabsorption
- ↑ synthesis of new bicarbonate
- net excretion of titratable acid
- overall the kidney synthesizes more bicarbonate while recovering/resorbing fewer protons
- when a person’s plasma pH falls ABOVE 7.45 & their PCO2 is less than 35 mmHg due to excessive loss of CO2
- this is caused by decreased carbonic acid possibly b/c of hyperventilation, CNS lesions, or drug-induced stimulation of the respiratory center
How does the body compensate for Respiratory Alkalosis?
- lower acidity in tubular cells causes ↓ H+ secretion & less excretion
- ↓ bicarbonate reabsorption leads to ↑ excretion of HCO3-, meaning less is returned to the plasma
- this is caused either by an ↑ in non-volatile acids or the loss of base (low levels of bicarbonate)
- as a result plasma pH falls below 7.35 & HCO3- < 22 meq
How does the body compensate for Metabolic Acidosis?
- increased CO2 stimulates the respiratory center to hyperventilate
- also if the kidneys are functioning there’s increased reabsorption of HCO3- & increased excretion of titratable acid
- this is caused by excessive loss of H+ or accumulation of base
- as a result high levels of bicarbonate accumulate & are characterized by a plasma pH above 7.45 & HCO3- > 26 meq
- vomiting or dehydration can cause metabolic alkalosis
- to compensate respiration patterns will change
How does the body compensate for Metabolic Alkalosis?
- pulmonary respiration will decrease, which causes retention of CO2 & therefore increased carbonic acid
- there is increased net renal excretion of HCO3-, which means less is reabsorbed into the plasma, lowering its pH
How does the body deal w/ such acid/base imbalances?
- by Compensation, an attempt by the kidneys or lungs to rebalance an acid-base disorder
- it’s a slow process that usually takes place in the organ that isn’t impaired (eg. processes in the kidney will compensate for respiratory acid or alkalosis)
- kidneys compensate for a respiratory disorder & the lungs respond to a metabolic disorder
occurs when the kidneys or lung partially restore balance to a respiratory or metabolic disorder, however pH is not fully restored to within normal range
- occurs when pH is restored to within the normal range (~7.4)
- this doesn’t necessarily normalize PCO2 or bicarbonate levels however, but can be achieved as long as there is a 20-fold difference between those components (more base than acid)
What does hypokalemia (low K+) usually lead to?
1. ↑ apical Na+/H+ exchange activity which in turn ↑ basolateral Na+/HCO3- cotransport; this results in ↑ H+ secretion & ↑ HCO3- transport into the blood from the proximal tubule
2. ↑ apical K+/H+ exchange enhances H+ secretion leading to ↑ HCO3- reabsorption in the collecting ducts
3. elevates ammonia synthesis & ammonium excretion leading to ↑ excretion of titratable acid & “new” bicarbonate synthesis
What does hyperkalemia (high K+) usually lead to?
- 1. inhibition of NH3 synthesis, leading to ↓ titratable acid excretion & therefore retention of H+
- 2. blockage of ammonium reabsorption in the ascending limb of the loop of Henle; as a result, less titratable ammonia diffuses into the collecting ducts & there is ↓ proton excretion
the overall result of that is renal tubular acidosis
What can adrenal insufficiency result in?
glucocorticoids & mineralocorticoids STIMULATE acid secretion
Glucocorticoids (eg. Cortisol)
• enhance Na+/ H+ exchange in the apical membrane, thus stimulating acid secretion
• inhibit phosphate reabsorption leading to increased lumenal buffering anions for titrating secreted protons
Mineralocorticoids (eg. Aldosterone)
• directly stimulate the electrogenic, apical proton pump → more acid secretion
• enhance Na+ reabsorption, causing ↑ negative charge in collecting ducts which indirectly elevates electrogenic, proton pumping
• prolonged elevation of mineralocorticoids causes K+ depletion, which stimulates acid secretion → alkalosis
What are some diuretics that cause acidosis?
these decrease acid secretion by antagonizing aldosterone
- inhibits intracellular carbonic anhydrase
- this blocks acid secretion & bicarbonate reabsorption → acidosis
- a potassium-sparing diuretic that inhibits apical Na+ channels
- this hyperpolarizes the apical membrane, decreasing electrogenic proton pumping, thus REDUCING proton secretion
Furosemide & Thiazide
- these diuretics can cause alkalosis by depleting plasma volume, which stimulates ANG II & aldosterone production, leading to enhanced acid secretion
- enhanced Na+ uptake into collecting tubules & ducts increases negative charge in lumen, thus stimulating electrogenic proton secretion
- they cause hypokalemia = enhanced acid secretion & bicarbonate reabsorption