Anticonvulsants
BACKGROUND
Seizures may occur (a) as a manifestation of
acute porphyria, where they may be secondary
to the hyponatraemia which develops in up 35%
of acute attacks or (b) due to a cause unrelated
to porphyria. Treatment firstly involves terminating
the seizure and then assessing the likely cause
and planning the most appropriate therapy. In
the case of hyponatraemia this involves slow
correction of the electrolyte imbalance by fluid
restriction and isotonic or hypertonic saline
where necessary.
A major problem in the management of seizures
is that many of the commonly used anticonvulsants
can precipitate or worsen acute attacks. Therefore
where a primary seizure disorder is suspected
this should be fully investigated by an epilepsy
expert to ensure that treatment is absolutely
necessary.
SPECIFIC
I. Acute seizure
or status epilepticus during an acute attack
Termination of an acute convulsion should be
with an intravenous benzodiazepine such as lorazepam,
diazepam or clonazepam. The choice of diazepam
may be controversial but it is almost certainly
safe as a single intravenous dose.
Under no circumstances should phenytoin or phenobarbitone
be used.
Where benzodiazepine treatment fails, paraldehyde
or magnesium sulphate should be considered.
Where general anaesthesia is required propofol
is the drug of choice.
II. Epilepsy
a) New diagnosis
of epilepsy in patient known to have an acute
porphyria
Wherever possible an anticonvulsant should
be chosen from the list of safe alternatives
below. When control of epilepsy is particularly
difficult or no safe alternative is effective,
discussion with a recognised porphyria expert
may help in the selection of an appropriate
drug regime that minimises risk to the patient
(see
porphyria specialist centres). Close biochemical
monitoring by regular measurent of urine porphobilinogen
is advisable under these circumstances (click
to monitoring).
b) New diagnosis
of acute porphyria in an epilepsy patient on
anticonvulsants
Where the patient is on an anticonvulsant that
carries a particularly high risk (e.g. carbamazepine,
phenytoin, phenobarbitone, primidone, ethosuximide)
changing to a safer alternative is advisable.
However change of therapy may occasionally provoke
either acute porphyria or epilepsy and patient
should always be informed of the risk and carefully
monitored (click to monitoring).
In some cases the risk of changing anticonvulsant
therapy, eg in a patient whose seizures are
difficult to control, may outweigh that of inducing
an acute attack. In these circumstances, the
patient should be informed of the risk and advised
to seek medical help should symptoms of acute
porphyria develop.
ANTI-EPILEPTIC DRUGS AVAILABLE
(P; denotes porphyrogenic in cell culture/animal
model, C; denotes drug known to cause acute
attacks in patients)
|
Use |
Use with
Caution |
Avoid
(Evidence) |
No data |
Clobazam |
|
Carbamazepine5,6
(P,C) |
|
Clonazapam7 |
|
Phenytoin7
(P,C) |
|
Lorazepam8 |
|
Phenobarbitone (P,C) |
|
Gabapentin1,2 |
|
Primidone (P,C) |
|
Acetazolamide |
|
Ethosuximide (P,C) |
|
(Vigabatrin1)# |
|
Tiagabine1,3
(P) |
|
Paraldehyde |
|
(Felbamate1^)(P) |
|
Gemfibrozil |
|
Topiramate1,2
(P) |
|
|
|
Oxcarbazine (P) |
|
|
|
|
|
| #
Vigabatrin is associated with the
development of irreversible visual
field defects and is very rarely
prescribed in adults. Use should
be supervised by a neurologist experienced
in epilepsy management.
^ Felbamate is associated with bone
marrow suppression and would only
be used with great caution.
* Levetiracetam is not dependant
on hepatic cytochrome P450 system
elimination and does not induce
hepatic enzymes. The main route
of excretion of parent drug and
metabolites is renal.
In view of this it would be expected
to be safe. |
|
REFERENCES
1. Hahn M, Gildemeister OS, Krauss
GL, Pepe JA, Lambrecht RW, Donohue S, Bonkovsky
HL.
Effects of new anticonvulsant medications on
porphyrin synthesis in cultured liver cells:
potential implications for patients with acute
porphyria. Neurology 1997;49:97-106.
2. Zadra M, Grandi R, Erli LC, Mirabile
D, Brambilla A.
Treatment of seizures in acute intermittent
porphyria: safety and efficacy of gabapentin.
Seizure 1998;7:415-6.
3. Krijt J, Krijtova H, Sanitrak J.
Effect of tiagabine and topiramate on porphyrin
metabolism in an in vivo model of porphyria.
Pharmacol Toxicol 2001;89:15-22.
4. McGuire GM, Macphee GJ, Thompson
GG, Moore MR, Brodie MJ.
Effects of sodium valproate on haem biosynthesis
in man: implications for seizure management
in the porphyric patient. Eur J Clin Invest
1988;18:29-32.
5. McGuire GM, Macphee GJ, Thompson
GG, Park BK, Moore MR, Brodie MJ.
The effects of chronic carbamazepine treatment
of haem biosynthesis in man and rat. Eur J Clin
Pharmacol 1988;35:241-7.
6. Reynolds NC Jr, Miska RM.
Safety of anticonvulsants in hepatic porphyrias.
Neurology 1981;31:480-4.
7. Larson AW, Wasserstrom WR, Felsher
BF, Chih JC.
Posttraumatic epilepsy and acute intermittent
porphyria: effects of phenytoin, carbamazepine,
and clonazepam. Neurology 1978;28:824-8.
8. Lambrecht RW, Gildemeister OS, Pepe
JA, Tortorelli KD, Williams A, Bonkovsky HL.
Effects of antidepressants and benzodiazepine-type
anxiolytic agents on hepatic porphyrin accumulation
in primary cultures of chick embryo liver cells.
J.Pharmacol Exp Ther 1999;291:1150-5.
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