Why do NSAIDs and ACE-inhibitors cause lithium toxicity? - USMLE Forums
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Old 05-17-2013
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Default Why do NSAIDs and ACE-inhibitors cause lithium toxicity?

Hi everyone. I was going through this for my revision (plan to take the exam in 6 weeks) and couldn’t understand why NSAIDs and ACE-Is cause lithium toxicity. Thiazides I can understand because they lower fluid volume which prods the kidney to reabsorb sodium and water, Lithium mimcs sodium so is also reabsorbed more.
But NSAIDs reduce the formation of local PGE2. This prevents dilation of the afferent arterioles which should cause less filtration and hence less fluid loss, leading to there being a decrease in the amount of Sodium/water/lithium the kidneys receive signals to reabsorb.
Similarly, ACE-inhibitors reduce the amount of AT-II, which prevents contraction preferentially of the efferent arteriole, thereby decreasing GFR and hence reducing the amount of body water lost by filtration. The kidneys would hence be directed to reabsorb less sodium/water/lithium. This could perhaps be stretched to somehow rope in the contribution of AT-II to Aldosterone synthesis, but is can be really be this indirect?
PS I'm also freaking out heavily. Any general advice would be deeply appreciated.
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Old 05-17-2013
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NSAIDs affect the afferent arterioles by inhibiting prostaglandins and thus causing constriction of the afferent arterioles. This reduces the filtration fraction and thus the elimination of lithium.
Lithium has a narrow therapeutic index, and anything that reduces its excretion will result in toxicity.
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As far as I recall, afferent arteriole contraction has no effect on Filtration Fraction because it reduces GFR and Renal Plasma Flow to an identical degree.
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I think its because affrent arteriolar constriction induced by NSAID and efferent arteriolar dilation induced by ACEI cause decrease in GFR, leading to solute reabsorption, not sure though.

Last edited by Hopefulhelpful; 05-17-2013 at 09:25 AM.
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Old 05-17-2013
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Quote:
Originally Posted by ashratnam View Post
As far as I recall, afferent arteriole contraction has no effect on Filtration Fraction because it reduces GFR and Renal Plasma Flow to an identical degree.
GFR not filtration fraction, my bad.
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Old 05-17-2013
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Quote:
Originally Posted by GamX View Post
GFR not filtration fraction, my bad.
Again, what difference does it make? The clearance of lithium will not be affected by any change in GFR alone, the formula for clearance of a substance doesn't factor in GFR, it's only (UxV)/P, U being urinary Conc, V is rate of urine flow and P is plasma concentration.

Even just plain taking a step back and looking at it, if we merely send in less fluid through the afferent arteriole, it will mean less lithium is filtered out, but it also means that less solvent fluid per se is filtered out, leaving the concentration in plasma relatively stable.

Last edited by ashratnam; 05-17-2013 at 10:51 AM. Reason: More precision
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Old 05-17-2013
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Lithium is excreted almost entirely by the kidneys. Lithium is freely filtered by the glomerulus since it is not bound to serum proteins. In the proximal tubule, lithium is handled similarly to sodium. Thus, factors that decrease GFR or increase proximal tubule reabsorption, such as volume depletion, will increase serum lithium levels. Conversely, factors that decrease proximal tubule sodium reabsorption, such as carbonic anhydrase inhibitors, aminophylline, or osmotic diuretics, will increase lithium excretion and decrease serum lithium levels.

So what decreases GFR, I believe, is the right question. Don't you agree?

Here's the list below. It's useful

Drug Effect on Lithium Concentration

Diuretics

thiazide Increase

loop diuretics Decrease

osmotic diuretics Decrease

K+ sparing Decrease

methyl xanthine Decrease

acetazolamide Decrease

ACE inhibitors Increase


NSAID

indomethacin Increase

ibuprofen Increase

mefenamic acid Increase

naproxen Increase

sulindac None

aspirin None
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Thanks a lot! This makes sense now. Basically to consider Lithium clearance an entity identical to sodium clearance in all respects and take things from there.
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Old 05-18-2013
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Quote:
Originally Posted by ashratnam View Post
As far as I recall, afferent arteriole contraction has no effect on Filtration Fraction because it reduces GFR and Renal Plasma Flow to an identical degree.
I agree that is correct.
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In USMLE, “Any fool can know. The point is to understand.”
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