nbme20/Block 3/Question#23

A 50-year-old woman is brought to the emergency ...

pKa: 6.0; Protein binding in plasma: 20%; Volume of distribution at steady state: 1 L/kg

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submitted by hayayah(217),

In order for a drug to be cleared by the kidney, it must first be filtered in the glomeruli. Drugs with a high VD have more of the drug in the tissue that are not available to filtered by the kidney. Drugs with high protein binding won't be filtered either. So you want a drug with low Vd and low binding if you want it cleared via the kidneys and urine.

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submitted by monoloco(27),

If you want to clear a drug, it is probably best that it not be bound to proteins (so that it gets filtered) and it has a low volume of distribution (so it isn't in the deep, hard to reach tissues).

kingtime9119  But that doesn't make sense. Page 233 of First Aid 2019 edition clearly states that being plasma protein bound creates the lowest volume of distribution, because not being bound to proteins increases the chance it will reach deep into the tissues before it reaches the kidneys. Discrepancy with First Aid? +  
haliburton  my reasoning was comparing two drugs, both with Vd of 1, the drug with the lower albumin binding would be cleared faster @kingtime. I don't think you're considering that A and B have equal Vd. +  

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submitted by lispectedwumbologist(9),

Can somebody please explain why the pKa has to be 6 instead of 10?

masonkingcobra  Since an ionized form is charged (by definition), it will not easily cross a nonpolar lipid membrane. Thus, it is important to recognize the potential of the drug to ionize in order to predict its solubility and the degree to which it can be reabsorbed. The degree of ionization is determined by the drug’s pKa and the pH of its environment. Weak acids and bases are 50% ionized and 50% unionized when the surrounding pH equals the drug’s pKa. At 2 pH units above or below the pKa of the drug, nearly 100% of the drug is ionized or unionized. +1  
masonkingcobra  Basically weak acids are best excreted in alkaline urine, but weak bases are excreted more readily in acid urine. +  
masonkingcobra  In summary, because this is a weak acid at pKa 6, making the urine alkaline will result it its ionization and excretion. Ionized cant move through lipid membranes so can't get reabsorbed and is pissed out. +1  

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submitted by kingtime9119(0),

[comment moved to subcomment]

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submitted by strugglebus(43),

I was wondering if it was to allow for partial CNS penetration since the drug is supposedly supposed to have CNS effect

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submitted by haliburton(25),

[comment moved to subcomment]