Why is Loading Doseunchanged in liver disease?

[hotchik]

According to the pharmacology section in FA 2012 p 259:

Loading dose = C(p) x V(d)/F
V(d) = amount of drug in body/plasma drug concentration

According to FA, V(d) would increase in liver failure due to decreased albumin --> decreased protein binding --> thus allowing drug to distribute out into the tissue. (Am I getting this logic correct???)

If that's true, liver failure --> increased V(d) --> increased loading dose (plug into loading dose formula, assuming F remains constant)

Could someone explain to me why this logic is false and why FA says loading dose doesn't change with liver disease?

Thanks in advanced!

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[Phloston]

Loading dose = Cp/F x Vd
Maintenance dose = Cp/F x CL

In liver disease, clearance (CL) increases, so maintenance dose has to increase.

For loading dose, volume of distribution doesn't change just because the liver has problems, so loading dose is constant. In other words, in order to get to the initial desired plasma concentration, the liver's capacity to metabolize is irrelevant.

 

[kaleerkalut]

Loading dose = Cp/F x Vd
Maintenance dose = Cp/F x CL

In liver disease, clearance (CL) increases, so maintenance dose has to increase.

For loading dose, volume of distribution doesn't change just because the liver has problems, so loading dose is constant. In other words, in order to get to the initial desired plasma concentration, the liver's capacity to metabolize is irrelevant.

Wait why does CL increase in liver disease? I know its late but I'm not making sense of that. Thanks.

 

[Phloston]

Good catch, Kaleerkalut. It should be maintenance dose decreases, not increases.

I could edit my post, but I'll leave it for the sake of your attentiveness.

And it may be late for you, but it's not over here in Australia, so no excuses for my typo there.

 

[kaleerkalut]

Good catch, Kaleerkalut. It should be maintenance dose decreases, not increases.

I could edit my post, but I'll leave it for the sake of your attentiveness.

And it may be late for you, but it's not over here in Australia, so no excuses for my typo there.

No worries. I actually thought you were right and I kept trying to come up with reasons haha.

Edit: to clarify, clearance DEcreases leading to a DEcrease in maintenance dose right?

 

[Phloston]

to clarify, clearance DEcreases leading to a DEcrease in maintenance dose right?

yeah. if the drug can't be cleared as quickly, then a lesser dose is needed to maintain the steady state concentration.

 

[hotchik]

thanks for the reply!

I understand the changes in maintenance dose...

you said volume of distribution doesn't change in liver disease, but on the top of page 259 in FA 2012 it says that Volume of distribution would increase when protein decreases (I thought this was referring to decrease in albumin during liver disease?)...could you clarify for me?

Thanks!

 

[hotchik]

Loading dose = Cp/F x Vd
Maintenance dose = Cp/F x CL

In liver disease, clearance (CL) increases, so maintenance dose has to increase.

For loading dose, volume of distribution doesn't change just because the liver has problems, so loading dose is constant. In other words, in order to get to the initial desired plasma concentration, the liver's capacity to metabolize is irrelevant.

thanks for the reply!

I understand the changes in maintenance dose...

you said volume of distribution doesn't change in liver disease, but on the top of page 259 in FA 2012 it says that Volume of distribution would increase when protein decreases (I thought this was referring to decrease in albumin during liver disease?)...could you clarify for me?

Thanks!

 

[Phloston]

In terms of an increased Vd with hypoalbuminaemia secondary to liver or renal disease, it would require the assumption that the patient is hypoalbuminaemic to begin with, then Cp could theoretically drop and Vd could increase to keep loading dose constant, but that's dependent on whether the liver insult is chronic or if the renal disease is nephrotic vs nephritic. My interpretation of the dosage calculations from FA (which any pharmacologist would likely say that they're over-simplified) is that they are predominantly highlighting the mere impaired rate of metabolism by the liver or clearance by the kidney, because Vd wouldn't increase with every hepatic or renal pathology. Warfarin would likely be more sensitive to a possible Vd-change because it's substantially protein-bound, but that would also require specifically a nephrotic syndrome or chronic liver disease, which of course neither have to be the case.

 

[hotchik]

In terms of an increased Vd with hypoalbuminaemia secondary to liver or renal disease, it would require the assumption that the patient is hypoalbuminaemic to begin with, then Cp could theoretically drop and Vd could increase to keep loading dose constant, but that's dependent on whether the liver insult is chronic or if the renal disease is nephrotic vs nephritic. My interpretation of the dosage calculations from FA (which any pharmacologist would likely say that they're over-simplified) is that they are predominantly highlighting the mere impaired rate of metabolism by the liver or clearance by the kidney, because Vd wouldn't increase with every hepatic or renal pathology. Warfarin would likely be more sensitive to a possible Vd-change because it's substantially protein-bound, but that would also require specifically a nephrotic syndrome or chronic liver disease, which of course neither have to be the case.

K thanks! that does make more sense!