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BlondeCookie

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Why is it that in patients with impaired renal or hepatic function, the loading dose remains unchanged, although the maintenance dose in decreased?
 

indo

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think of the loading dose as an instantaneous application of the desired concentration of the drug. Since it is instantaneous, excretion and metabolism don't really matter. The therapeutic concentrationof the drug won't change and so the same "instant" loading dose must be used. However, when it comes to maintaining the plasma concentration of the drug at the therapeutic level you must remember that in=out for steady state. In people with renal or hepatic disease, out is lower and thus in must be lower too to prevent that huge list of side effects you are memorizing from happening.
 

Blesbok

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Why is it that in patients with impaired renal or hepatic function, the loading dose remains unchanged, although the maintenence dose in decreased?
Depends how you are loading it.

You have a given volume of distribution and a given plasma concentration that you are aiming for. Since you are loading, you are trying to hit the goal at once, which negates metabolism whether hepatic, renal, or otherwise as long as it is not an oral drug.

HOWEVER, this does not apply to oral loading. Since oral loading both takes time (which means metabolism does apply) and also because a big part of oral bioavailability depends on first pass metabolism through the liver, a decreased liver metabolism will change the loading dose.
 

ASDIC

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the purpose of the loading dose is to achieve plasma concentrations extremely quickly, without regards to steady state. In most cases the importance of acheiving such plasma levels is more important than the metabolism of the drug, such as in emergencies.

The purpose of the maintenance dose is used to obtain steady state plasma concentrations (which is heavily dependent on drug excretion). Thus the maintenance dose is adjusted proportionally to creatinine clearance of the patient.

maintenance dose = dose in a patient with no renal problems x [(creatinine clearance of the patient with renal problems)/(normal creatinine clearance)]
 
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BlondeCookie

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In people with renal or hepatic disease, out is lower and thus in must be lower too to prevent that huge list of side effects you are memorizing from happening.

OK, thanks guys, I appreciate the help. I get most of the logic behind why maintenance dose is decreased in renal failure, but I'm stumped on why maintenance dose is also decreased in hepatic failure... :confused: What is wrong with my reasoning?

In renal failure, clearance (out) is lower, so maintenance dose must be decreased to keep steady state at its non-toxic normal level. I get that. However, in hepatic failure, I reason that the liver is not producing adequate albumin levels. Low albumin doesn't bind to the drug as well and thus more unbound free drug is renally filtered and excreted. Therefore, clearance (out) is higher in hepatic failure per my logic. So, if this is so, why would you not increase maintenance dose in hepatic failure due to lower albumin levels?
 

ASDIC

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ok...albumin is mainly to transport the drug around and not for metabolism.

Maintenance dose will be decreased in hepatic failure due to decreased metabolism via Phase 1 and Phase 2 reactions. Remember cytochrome P450?

I think its beyond the scope of Step 1 on how you wud adjust this dose.
 

BlondeCookie

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ok...albumin is mainly to transport the drug around and not for metabolism.

Maintenance dose will be decreased in hepatic failure due to decreased metabolism via Phase 1 and Phase 2 reactions. Remember cytochrome P450?

I think its beyond the scope of Step 1 on how you wud adjust this dose.


Oh OK. So, since the cytochrome P450 enzyme levels are either decreased or not functioning as well in a patient with hepatic failure, then they don't metabolize drugs as well as the normal patient. Thus, their renal clearance is less and the drug stays in the body more. So, to compensate we lower maintenance dose so that toxic levels do not build up in the body. I guess this explanation trumps my albumin theory above.

Can we just say that decreased drug metabolism (leading to decreased renal clearance) has more of an effect on steady state drug concentration than does decreased albumin protein binding (leading to increased renal clearance)?
 
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