Interaksi Obat

Antiepilepsi

Mochamad Herdi Nurzaman, S.Farm. Apt

Antiepileptic drugs (AEDs) are not only licensed for the treatment of
epilepsy and seizure disorders but also for other indications including
for neuropathic pain, generalized anxiety disorders, the management
of fibromyalgia and for migraine prophylaxis.

Additionally, AEDs are (non-licensed) used for binge-eating disorder,

bipolar disorder, depression, psychotropic drug-induced weight gain,
post-traumatic stress disorder, cluster headaches, panic disorder,
phantom limb pain, trigeminal neuralgia, mania, peripheral
neuropathy, psychosis and schizophrenia (Philip N. Patsalos, 2013).
Antiepileptic Drugs (AEDs)
Older Drugs Newer Drugs

 Carbamazepine  Felbamate  Levetiracetam

 Phenobarbital  Topiramate  Tiagabine

 Gabapentin  Vigabtrine
 Phenytoin
 Lamotrigine  Zionisamide
 Valproate

(Stockley’s Drug Interactions, 2008)

Interaksi Obat Antiepilepsi
 Antimikroba

• Phenytoin dan carbamazepine ↑ M dari Praziquantel KP (↓ 74% & 90%)

• Phenytoin, carbamazepine, dan phenobarbital ↑ M dari Albendazole KP (↓ 50-66%)

M = Metabolisme
KP = Konsentrasi Plasma

THERAPEUTIC FAILURE
 Antibacterial drugs

Antituberculosis drugs Carbapenem antibiotics Chloramphenicol Makrolida

• Isoniazid dapat mengahambat • ↓ KP asam valproate • Phenobarbital ↑ M • Erythromycin dan
M dari carbamazepine, (efektivtas menurun) cholarmphenicol (efektivtas troleandomycin mengahmbat
ethosuximide, phenytoin, dan menurun) enzim CYP3A4 dan ↑ KP
asam valproate sehingga ↑ KP Carbamazepine (Toksisitas)
(Tokisistas).
• Rifampicin ↓ KP phenytoin,
carbamazepine, valproic acid,
ethosuximide, dan lamotrigine
(Efektivitas berkurang).
(Patsalos & Perucca, 2003)
 Antifungal drugs

• The CYP3A4 inhibitors ketoconazole and fluconazole when given to patients taking
carbamazepine, cause appreciable increases in plasma concentrations of the AED,
which might result in carbamazepine toxicity.

• the CYP2C9 inhibitors miconazole and fluconazole can substantially increase

plasma concentrations of phenytoin.
 Antiprotozoal drugs

• Failure of metronidazole caused by increased metabolism has been reported in

women with vaginal trichomoniasis and giardiasis who are taking enzyme inducing
AEDs. In contrast, metronidazole can increase plasma carbamazepine
concentration
 Antiviral drugs

• antiviral agents, including nevirapine, efavirenz, delavirdine, indinavir, ritonavir, and

saquinavir are metabolised by CYP3A4.

• CYP3A4 inducing AEDs, such as carbamazepine, phenytoin, and barbiturates,

could lead to insufficient plasma concentrations of these antiviral drugs, the dose
of which may need to be increased.
 Antineoplastic drugs

• There is evidence that enzyme inducing AEDs stimulate the metabolism of many
antineoplastic drugs, including cyclophosphamide, ifosfamide, busulfan, teniposide
and etoposide, paclitaxel, methotrexate and some vinka alkaloids.

• cause toxicity or loss of efficacy from Antineoplastic drugs.

 Cardiovascular drugs (I)
• Antiarrhythmic drugs

Enzyme inducing AEDs can stimulate the metabolism of disopyramide, mexiletine, quinidine, and
amiodarone and the doses of these drugs may have to be increased

• Antihypertensive drugs

Enzyme inducing AEDs increase the metabolic clearance of extensively metabolised -adrenoceptor
blocking agents (eg, propranolol, metoprolol, and alprenolol), dihydropyridine calcium antagonists (eg,
nifedipine, felodipine, nimodipine and nisoldipine), and other hypotensive agents (eg, orally
administered verapamil)

• Antiplatelet drugs

Ticlopidine has been associated with increased plasma phenytoin and carbamazepine concentrations
and, consequently, CNS toxicity
 Cardiovascular drugs (II)
• Digoxin

Concurrent administration of phenytoin may result in reduced plasma concentrations of

digoxin.

• Lipid-lowering drugs

Enzyme inducing AEDs are expected to increase the metabolic clearance of lipid-
lowering drugs, which are substrates of CYP3A4 (eg, atorvastatin, lovastatin, simvastatin)
and CYP2C9 (eg, fluvastatin)

• Oral anticoagulants

Carbamazepine and other enzyme-inducing AEDs reduce the anticoagulant effects of

dicoumarol and warfarin by increasing their metabolism, possibly by induction of CYP2C9.
 Gastrointestinal drugs
• Antacids and surface-acting drugs

Some antacids reduce the absorption of phenobarbital, phenytoin, carbamazepine,

and gabapentin.

• Histamine H2-receptor antagonists

Cimetidine can reduce the metabolic clearance of phenytoin and carbamazepine

• Proton-pump inhibitors

By inhibition of CYP2C19, omeprazole increases plasma concentrations of phenytoin

by about 25%.
 Immunosuppressant drugs
• Ciclosporin

• The plasma concentration of ciclosporin, a substrate of CYP3A4, is decreased by

enzyme inducing AEDs (ie, carbamazepine, phenobarbital, phenytoin.

• Tacrolimus

Tacrolimus is primarily metabolised by CYP3A, and phenytoin increases its metabolism and
therefore reduces plasma concentrations of tacrolimus at steady-state.

• Sirolimus

Sirolimus is metabolised by CYP3A4 and CYP3A5 and might therefore be associated with
similar interactions described for tacrolimus. Indeed there is evidence that phenytoin can
increase the metabolism of sirolimus by up to four times
 Antidepressant drugs
• Enzyme inducing AEDs increase the metabolism and decrease the plasma
concentration of tricyclic antidepressants such as amitriptyline, nortriptyline,
imipramine, desipramine, clomipramine, desmethylclomipramine, protriptyline, and
doxepin
 Antipsychotic drugs
• carbamazepine and other enzyme inducing AEDs have been shown to decrease the
plasma concentration of many antipsychotics, including haloperidol,
chlorpromazine, mesoridazine (the active metabolite of thioridazine), clozapine,
olanzapine, risperidone, quetiapine, and ziprasidone.
 Steroids
• Corticosteroids

The metabolism of corticosteroids is highly sensitive to enzyme induction.

Carbamazepine, phenytoin, and barbiturates may increase the metabolism of various
steroids, including cortisol, hydrocortisone, dexamethasone, prednisone,
prednisolone, and methylprednisolone.
 Sex hormones
Danazol, a synthetic oestrogen used in the management of endometriosis, is a potent
inhibitor of carbamazepine metabolism and causes 50–100% increases in plasma
concentration of carbamazepine
Newer Drugs
 Eslicarbazepine Acetate
• decreased mean plasma digoxin maximum concentration (Cmax) values by 19 % and
mean plasma digoxin AUC values by 8 %.

• decreased mean plasma metformin Cmax values by 13 % and mean plasma metformin
AUC values by 6 %

• can enhance the metabolism of simvastatin, probably via an action on cytochrome

P450 (CYP) 3A4, and decreases mean plasma simvastatin AUC values by 50 %;

• decreased mean plasma S-warfarin Cmax and AUC values by 20 and 21 %,

respectively
 Felbamate
• Oral contraceptions

decrease in plasma gestodene (progestin) AUC values of 42 % whilst mean plasma

ethinyl estradiol AUC values decreased by13 %,suggesting that their metabolismis
enhanced probably via an action on CYP3A4 .

• Warfarin A single case report describes that felbamate inhibits the metabolism of
warfarin which necessitated a warfarin dose reduction so as to maintain
anticoagulant control.
 Gabapentin
• Aluminum Hydroxide and Magnesium Hydroxide

Gabapentin bioavailability was observed to decrease by ~ 20 % when administered

simultaneously or 2 hours after antacid ingestion, whilst antacids ingested 2 hours
before gabapentin resulted in a ~ 10 % decrease in bioavailability.

• cimetidine increased mean plasma gabapentin Cmax and AUC values by 5 and 24 %,
respectively; mean gabapentin clearance values decreased by 20 %

• Hydrocodone a narcotic analgesic and antitussive, can increase gabapentin

absorption and increase plasma gabapentin concentrations.
 Gabapentin (II)
• Morphine Morphine, a potent opiate analgesic drug that is used to relieve
moderate to severe pain, can increase gabapentin absorption and increase plasma
gabapentin concentrations; no other information is provided

• Naproxen

• During co-medication with naproxen, mean plasma gabapentin Cmax and AUC
values were increased by 7 and 13 %, respectively
 Lacosamide
• To date, no clinically significant pharmacodynamic interactions involving lacosamide
and other non-AEDs have been reported.
 Levetiracetam
• To date, no clinically significant pharmacodynamic interactions involving
levetiracetam and other non-AEDs have been reported.
 Pregabalin
• Oxycodone

Pregabalin has been shown to exert additive effects on the alterations in cognitive
and motor functions caused by oxycodone.
 Daftar Pustaka
• Patsalos, P. N. (2013). Drug interactions with the newer antiepileptic drugs (AEDs) - Part 2: Pharmacokinetic
and pharmacodynamic interactions between AEDs and drugs used to treat non-epilepsy disorders. Clinical
Pharmacokinetics, 52(12), 1045–1061. https://doi.org/10.1007/s40262-013-0088-z.
• Patsalos, P. N., & Perucca, E. (2003). Clinically important drug interactions in epilepsy: Interactions between
antiepileptic drugs and other drugs. Lancet Neurology, 2(8), 473–481. https://doi.org/10.1016/S1474-
4422(03)00483-6.
• Baxter, Karen. 2008. Stockley’s Drug Interactions. 1 Lambeth High Street, London SE1 7JN, UK : the
Pharmaceutical Press.