AEDs in Renal Failure / Hemodialysis

Capture.JPG

How does renal disease affect AED levels?

  • Renal insufficiency alters the pharmacokinetics of seizure medications that are metabolized by the kidneyes, leading to increased half-lives and accumulation of the drug.
  • Albuminuria and acidosis that frequently occur in renal failure also decreases drug binding, increasing the free levels of AEDs and volume of distribution.
  • Gastroparesis delays maximum serum levels of AEDs, intestinal edema diminishes absorption of AEDs.

Take home message:  It is difficult to predict drug levels based on the creatinine clearance.

AEDs that are extensively eliminated by kidneys:

  • hydrosoluble
  • low molecular weight
  • low Vd
  • little protein-bound
  • Examples:  gapabentin, topiramate, ethosuxamide, vigabatrin, levetiracetam
  • accumulate in renal disease
  • easily removed by hemodialysis and requires post-HD administration

AEDs that are not extensively eliminated by kidneys:

  • lipophylic
  • high protein-bound
  • Examples:  carbamazepine, phenytoin, lamotrigine, benzodiazepines, valproate
  • little affected by renal disease
  • HD has little impact on carbamazepine, phenytoin and valproate levels
  • HD has unpredictable effects on benzodiazepines or oxcarbazepine monohidroxi derivative
  • 4-hour HD decreases lamotrigine levels by ~20%

Peritoneal dialysis has variable effects on AED serum levels, check free levels for drug adjustment

LEVETIRACETAM:

  • CrCl >80 mL/minute/1.73 m2: 500 to 1,500 mg every 12 hours
  • CrCl 50 to 80 mL/minute/1.73 m2: 500 to 1,000 mg every 12 hours
  • CrCl 30 to 50 mL/minute/1.73 m2: 250 to 750 mg every 12 hours
  • CrCl <30 mL/minute/1.73 m2: 250 to 500 mg every 12 hours
  • End-stage renal disease (ESRD) requiring hemodialysis: Dialyzable (50%); 500 to 1,000 mg every 24 hours; supplemental dose of 250 to 500 mg is recommended posthemodialysis
  • Peritoneal dialysis (PD): 500 to 1,000 mg every 24 hours (Aronoff 2007)
  • Continuous renal replacement therapy (CRRT): 250 to 750 mg every 12 hours (Aronoff 2007)

PHENYTOIN:

  • There are no dosage adjustments provided in the manufacturer’s labeling; <5% excreted as unchanged drug. Serum concentration may be difficult to interpret in renal failure. Monitoring of free (unbound) concentrations or adjustment to allow interpretation is recommended.
  • Fosphenytoin:  There are no dosage adjustments provided in the manufacturer’s labeling. Free (unbound) phenytoin levels should be monitored closely in patients with renal disease or in those with hypoalbuminemia; furthermore, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance in these patients leading to increase frequency and severity of adverse events.

CARBAMAZEPINE:

  • Dosage adjustments are not required or recommended in the manufacturer’s labeling; however, the following guidelines have been used by some clinicians:
  • Children and Adults:
    • GFR <10 mL/minute: Administer 75% of dose
    • Hemodialysis, peritoneal dialysis: Administer 75% of dose (postdialysis)
  • Continuous renal replacement therapy (CRRT):
    • Adults: No dosage adjustment recommended
    • Children: Administer 75% of dose

PHENOBARBITAL

  • There are no specific dosage adjustments provided in the manufacturer’s labeling; reduced doses are recommended.
  • The following guidelines have been used by some clinicians:
    • CrCl ≥10 mL/minute: No dosage adjustment necessary.
    • CrCl <10 mL/minute: Administer every 12 to 16 hours.
    • HD (moderately dialyzable [20% to 50%]): Administer dose before dialysis and 50% of dose after dialysis.
    • PD:  Administer 50% of normal dose.
    • CRRT: Administer normal dose and monitor levels.

VALPROIC ACID:

  • Mild to severe impairment: No dosage adjustment necessary (including patients on hemodialysis); however, due to decreased protein binding in renal impairment, monitoring only total valproate concentrations may be misleading.

 

LORAZEPAM:

  • Dosing: Renal Impairment
  • Oral: No dosage adjustment necessary
  • IM, IV: Risk of propylene glycol toxicity. Monitor closely if using for prolonged periods of time or at high doses.
    • Mild-to-moderate disease: Use with caution.
    • Severe disease or failure: Use is not recommended.

MIDAZOLAM:

  • Dosing: Renal Impairment
    • There are no dosage adjustments provided in manufacturer’s labeling; however, patients with renal failure receiving a continuous infusion cannot adequately eliminate the active hydroxylated metabolites (eg, 1-hydroxymidazolam) contributing to prolonged sedation sometimes for days after discontinuation
  • Intermittent HD:  Supplemental dose not necessary
  • CVVH: Unconjugated 1-hydroxymidazolam not effectively removed; 1-hydroxymidazolamglucuronide effectively removed; sieving coefficient = 0.45
  • PD: Significant drug removal unlikely

LAMOTRIGINE:

  • There are no dosage adjustments provided in the manufacturer’s labeling. Decreased maintenance dosage may be effective in patients with significant renal impairment; has not been adequately studied; use with caution.

PROPOFOL:

  • No dosage adjustment necessary.

 

Reference:

Lacerda, Glenda Corrêa Borges de. “Treating Seizures In Renal And Hepatic Failure”. J. epilepsy clin. neurophysiol. 14 (2008): 46-50.

Uptodate.  Accessed 07/12/2016.

 

Advertisements

Tagged: , , , , , , , , ,

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

%d bloggers like this: