Monitoring therapeutic Dilantin in renal failure requires looking at the free not total Dilantin.

My fellowship director was the Great Brain, Dr Patrick Murray. Pat is quadruple boarded:

  1. internal medicine
  2. critical care
  3. nephrology 
  4. clinical pharmacology

Pretty intimidating. (If you have the time, check out his 179-slide presentation. Wow!)

One of the side effects of doing my fellowship under a professor in clinical pharmacology is that I learned more about drug monitoring in renal failure than any innocent nephrology fellow should.

One of the pearls he taught regarded the monitoring of therapeutic Dilatin (phenytoin) levels. the Renal Fellow Network discussed Dilantin pharmacokinetics twice but neither of the posts noted the change in protein binding that occurs with renal failure.

Dilantin is highly protein bound (90%) and only the free dilantin is therapeutically active. Uremia is associated with plasma molecules which displace Dilantin from albumin. This increases the active fraction of Dilantin, so sub-therapeutic total levels of Dilantin may represent appropriate free levels in the presence of renal failure.

I currently have a dialysis patient in the ICU who was seizing following a cardiac arrest. He was loaded with Dilantin and a few days later his labs showed:

Total phenytoin level of 5 mcg/mL, below the therapeutic target of 10-20. Simultaneously his free level was 1.14 mg/L. (Rant: How can the EMR express the total level as mcg/ml and the free level as mg/L. THEY ARE EQUIVALENT. Don’t hide it.)

So in this case the free dilantin is 23% of the total, rather than the normal 10%. Note that the total level appears sub-therapeutic but this patient would be poorly served by a re-loading of Dilantin as his free level is therapeutic.

Summary: in uremia always use the free dilantin level and don’t trust the total Dilantin level.

How do you go from an EGD to acute kidney injury?

We had an interesting consult a few weeks ago.

The patient was an elderly gentleman who recently underwent an EGD for gastritis-like symptoms. A few days after the procedure he received a call from his gastroenterologist telling him that he had H. Pylori and needed to start an antibiotic. He was prescribed PrevPac for 10 days. He almost immediately began to feel worse. His wife ultimately stopped giving him the PrevPack after about four days of increasing weakness, lethergy and nausea. Despite stopping the new medicine the patient continued to deteriorate. He was admitted about 2 weeks after the EGD.

His creatinine had risen from a baseline of 1.2 mg/dL to 4.5 mg/dL. Our initial thought was that he was pre-renal. We prescribed 0.9% saline but the patient didn’t respond, and his creatine continued to rise.

One clinical pearl that I repeatedly teach fellows is not to under treat pre-renal azotemia. If you think the patient is volume depleted give enough fluid that the next day if the creatinine has not improved you will be convinced that the patient is no longer volume depleted. You want to fully rule-out volume depletion after the first day.

This patient didn’t respond to fluids so we reevaluated the history. PrevPac, what’s in that?

  • Lansoprazole
  • Amoxicillin
  • Clarithromycin
Clarithromycin is a potent inhibitor of CYP3A4 so it interacts with a lot of medications. Our patient was on simvastatin. Let’s check out what does Dr. Google has to say about that:
We check his CPK and its 8,000 almost a week after he stopped taking the Clarithro.

Rhabdo induced acute kidney injury due to a drug interaction.

Rhabdomyolysis secondary to a drug interaction between simvastatin and clarithromycin. Clarithromycin is a potent inhibitor of CYP3A4, the major enzyme responsible for simvastatin metabolism.

Effects of Clarithromycin on the Pharmacokinetics of SimvastatinCompared with simvastatin alone, coadministration of clarythromycin and simvastatin significantly increased the peak concentration and the area under the curve for simvastatin by approximately 8-fold (p<0.0001). Levels of simvastatin acid were also significantly (about 14-fold) higher during clarythromycin treatment compared with simvastatin alone (p<0.0001).

If the figures on pharmacokinetics from that last article are to be believed then 500 mg of clarithromycin magnifies 80 mg of daily simvastatin to an equivalent daily dose of 640 to 1,120 mg.

Rhabdomyolysis induces acute kidney injury from myoglobin. Myoglobin can precipitate in the presence of acidic urine. The heme component of myoglobin can generate free-radicals which can damage lipid membranes. Patients develop vasoconstriction in response to rhabdomyolysis, both from the direct effect of the myoglobin on the renal vasculature and due to the movement of intravascular fluid into the damaged muscles. This gives a pre-renal picture on the fractional excretion of sodium.

Evaluating volume status can be tricky because patients will often have peripheral edema from the inflammation associated with the rhabdomyolysis. Additionally the BUN:Cr will often be low as the creatinine tends to rise quicker in rhabdomyolysis than in other forms of renal failure. This is usually explained by the release of intramuscular creatinine rather than just a failure to clear creatinine. The younger age and increased frequency of men suffering from rhabdomyolysis may also play a role in this observation.

The electrolyte abnormalities of rhabdomyolysis:

  • Hyperkalemia
  • Hyperphosphatemia
  • Hypocalcemia (early)
  • Hypercalcemia (late)
  • Hyperuricemia
  • Anion gap metabolic acidosis

 The NEJM recently did a nice review of rhabdomyolysis which presents the recent inconclusive data on alkalinization (not proven to be helpful but the animal/disease models make it look like the right thing to do), mannitol and diuretics and use of high flux dialyzers.

The Annals of Internal Medicine recently published a review of Statin-Related Myopathy. Here is what they had to say about drug interactions:

Because simvastatin, lovastatin, and atorvastatin are primarily metabolized through the cytochrome P450 3A4 (CYP3A4) isoenzyme (43), inhibitors of CYP3A4 could theoretically increase serum statin levels and exposure to susceptible tissues. Drugs known to interact with statins include protease inhibitors, cyclosporine, amiodarone, and fibrates (44, 45). Protease inhibitors are potent CYP3A4 inhibitors and thus can increase up to 30 times the plasma concentrations of certain statins (45, 46). Consequently, both simvastatin and lovastatin should be avoided in pa- tients receiving protease inhibitors (42, 45, 47). Cyclosporine is a potent inhibitor of not only CYP3A4 but also several membrane transporters, and it increases the phar- macokinetic area under the curve of statins by 2- to 25- fold, with many reported cases of rhabdomyolysis (44). Statin dosages in patients receiving cyclosporine have therefore been limited to 5 mg/d for rosuvastatin, 10 mg/d for simvastatin and atorvastatin, and 20 mg/d for lovastatin (42, 47–49).

Pravastatin is not metabolized by the P450 system but is excreted renaly. Fluvastatin and rosuvastatin are metabolized by an alternative enzyme, CYP2C9.

The things patients bring in

My favorite patient encounters almost always involve the patient bringing in something they found in a newspaper or magazine. The best ones are fully annotated with the patients thoughts and comments. Typical subjects are: alternative medicine, vitamins, noni juice (don’t get me started), new tests or scare mongering articles about drugs I have prescribed.

The other day one of my patients brought in a list of the 50 most prescribed medications according to the AARP. Jackpot.
I have transcribed the data into excel so I could abstract some of the data. The raw excel file is here.
I have three charts from the excel file that are interesting, the first is just a graph of the number of prescriptions with the retail cost overlaid. Can you spot the brand name drugs:
I then simplified the data by removing the noise from the individual drugs and used the indications for each drug. Here is that data by number of prescriptions and then by cost:
You can see the disruption caused by the brand name drugs which catapult PPI (ulcer/heart burn medications) from 5% of the prescriptions to 17% of the cost and take statins (cholesterol) from 9% of the prescriptions to 18% of the cost. Can you imagine how the chart looked before Zocor (simvastatin) went generic?
There are no insulins on the list, so I wonder if there other absences.
What does it say about the U.S. that 3 of the top 6 indications for therapy are pain, depression and anxiety?