Managing epilepsy in individuals with liver disease presents a unique challenge for healthcare providers. The presence of liver disease can have a substantial impact on how medications, particularly anti-epileptic drugs (AEDs), are metabolized and eliminated from the body. As a result, there is a
potential for complications to arise and for the effectiveness of these drugs to be altered. Consequently, it is of utmost importance for healthcare providers to understand the implications and factors to consider when ensuring the safe administration of AEDs in this specific patient population.
RED : AEDs with well-recognized hepatotoxicity
YELLOW:
AEDS with low or unclear hepatotoxic potential
GREEN: AEDs with no known hepatotoxicity
|
CARBAMAZEPINE |
·
Carbamazepine is a potent inducer of hepatic enzymes and has
been associated with hepatotoxicity and serious allergic reactions in
genetically predisposed individuals. ·
May precipitate decompensation in patients with cirrhosis. |
·
In general, Carbamazepine should be avoided as there are better options for management of
seizures in patients with CLD. |
|
PHENYTOIN/ FOSPHENYTOIN |
·
Extensively metabolised in liver and potent
inducer of hepatic CYP enzymes. ·
Highly bound to serum albumin.
|
·
In general, Phenytoin should be avoided in patients with cirrhosis. ·
In the absence of other effective optive for the
control of seizure, use cautiously. ·
Avoid in patients who are actively using alcohol. |
|
VALPROATE |
·
Extensively metabolized in liver and highly bound
to serum albumin. ·
Valproate associated hyperammonimea may complicate
management of HE. |
·
Valproate should generally be avoided in advanced CLD or Cirrhosis. |
|
DIVALPROEX |
·
metabolized almost entirely by the liver |
·
should be avoided
in patients with hepatic disease or significant hepatic dysfunction |
|
PHENOBARBITAL |
·
Phenobarbital is primarily metabolized in the
liver and therefore can be potentially harmful in patients with liver
disease. ·
The drug may accumulate in the body and cause
toxic effects in patients with impaired liver function. |
·
It is generally recommended to avoid or use phenobarbital with
caution in patients with liver disease. |
|
DIAZEPAM |
·
Extensive metabolism in liver by CYP to active
metabolites. ·
Clearance decreased by 50%. ·
Half-life of drug and active metabolites prolonged
two- to fivefold (ie, up to 500 hours). · |
·
No adjustment needed for initial dose. ·
Risk of accumulation and over-sedation with
repeated doses. ·
Reduce maintenance dose and frequency by up to 50%
or consider another sedative option. ·
Prolonged effect might be useful for patients
being treated for alcohol withdrawal or seizures. ·
Avoid in
patients with HE.
|
|
LORAZEPAM |
·
Undergoes metabolism by glucuronidation, which is
relatively preserved in mild to moderate hepatic insufficiency.
|
·
Generally a good choice when benzodiazepine
treatment indicated. ·
No specific dose adjustment; titrate gradually due
to prolonged onset. ·
With prolonged use or use as a continuous infusion
risk of drug accumulation and oversedation. ·
Avoid in
patients with HE.
|
|
MIDAZOLAM |
·
Extensively metabolized in the liver by CYP3A4
and, when administered orally, undergoes first-pass hepatic extraction. ·
Half-life of drug and active metabolite are
increased in hepatic impairment.
|
·
Oral preparation should be avoided in patients
with advanced CLD or cirrhosis due to unpredictable bioavailability. ·
For IV use, no specific dose adjustment; once
adequately sedated using small incremental doses, a reduced maintenance dose
and frequency may be needed to avoid accumulation and oversedation of
patients with advanced CLD or cirrhosis. ·
Avoid in
patients with HE.
|
|
CLOBAZAM |
·
Undergoes extensive hepatic metabolism
|
·
mild to moderate hepatic impairment, the starting
dose should be 5 mg/day. maximum: 40 mg/day ·
not studied in severe impairement, hence avoid use |
|
OXCARBAZEPINE |
·
PK seems to be unaltered in mild to moderate hepatic
impairment with adequate renal function (Crcl ≥30 mL/minute).
|
·
No specific adjustment recommended for compensated
cirrhosis with mild to moderate hepatic impairment. ·
Use in severe hepatic impairment or decompensated
disease is not recommended as data are
lacking.
|
|
PRIMIDONE |
·
Predominantly metabolized in liver |
·
In mild to moderate liver disease, may be used but
with close monitoring for any signs of toxicity. ·
In severe
liver disease, primidone should be avoided
. |
|
PERAMPANEL |
·
Primarily metabolized in liver ·
The t1/2 was prolonged in subjects with mild
impairment and moderate impairment. ·
Perampanel has not been studied in subjects with
severe hepatic impairment. |
·
In patients with mild and moderate hepatic
impairment, the starting dose is 2 mg once daily. Increase dosage by
increments of 2 mg once daily no more frequently than every 2 weeks. The maximum recommended daily dose is 6 mg
for patients with mild hepatic impairment and 4 mg for patients with moderate
hepatic impairment. ·
Not recommended for use in patients with
severe hepatic impairment. |
|
LACOSAMIDE |
·
The pharmacokinetics of lacosamide have not been
evaluated in severe hepatic impairment |
·
A maximum dose of 300 mg/day is recommended for
patients with mild or moderate hepatic impairment . ·
not
recommended in patients with severe hepatic impairment. |
|
TOPIRAMATE |
·
Topiramate clearance can be reduced in patients
with advanced CLD or cirrhosis who are also receiving enzyme-inducing
antiseizure medications and/or with renal insufficiency (Crcl <70
mL/minute). ·
Metabolic acidosis is a frequent adverse effect of
topiramate treatment. |
·
Topiramate dose adjustment may be needed in
patients with advanced CLD or cirrhosis receiving enzyme-inducing antiseizure
medications and/or renal impairment. ·
Drug interactions between topiramate and
enzyme-inducing antiseizure medications may be intensified in hepatic
impairment. ·
Topiramate can produce hyperammonemia when
combined with valproic acid,
|
|
LAMOTRIGINE |
·
Half-life is increased up to threefold in moderate
to severe hepatic impairment.
|
·
No adjustment required for mild impairment. ·
Reduce dose by 25% for moderate to severe hepatic
impairment without ascites. ·
Reduce dose by 50% for moderate to severe
impairment with ascites.
|
|
LEVETIRACETAM |
·
PK unaltered in liver disease in patients with
adequate renal function (Crcl ≥60 mL/minute). ·
Drug accumulation may occur in patients with renal
insufficiency and advanced cirrhosis.
|
·
No adjustment required for compensated cirrhosis. ·
Reduce dose by approximately 50% in patients with
advanced CLD and renal insufficiency (Crcl <60 mL/minute).
|
|
BRIVARECETAM |
·
Partly metabolized by liver. |
·
Dosage adjustment is recommended for all stages of
hepatic impairment ·
Recommended initial dose : 50 mg/day. Maximum
dose:150mg/day. |
|
VIGABATRIN |
·
Extrahepatic metabolism.
|
·
Considered to be safe in liver disease. |
|
PREGABALIN |
·
Pregabalin is primarily excreted unchanged in the
urine and does not undergo significant hepatic metabolism |
·
Considered to be safe in liver disease. |
|
GABAPANTIN |
·
Gabapantin is primarily excreted unchanged in the
urine and does not undergo significant hepatic metabolism |
·
Considered to be safe in liver disease. |
REFERENCE:
1. Uptodate
2. Fda product label
3. Vidaurre J, Gedela S, Yarosz S. Antiepileptic
Drugs and Liver Disease. Pediatr Neurol. 2017;77:23-36.
doi:10.1016/j.pediatrneurol.2017.09.013
4. Ahmed SN, Siddiqi ZA. Antiepileptic drugs and liver
disease. Seizure. 2006;15(3):156-164. doi:10.1016/j.seizure.2005.12.009
Comments
Post a Comment