Antiepileptic drugs Flashcards
What causes a seizure? What is a seizure?
1) Abnormal, excessive, hyper-synchronous discharge of population of cortical neurons.
2) Massive disruption of electrical communication between neurons in the brain.
This is promoted by:
A) Increased excitatory synaptic neurotransmission
B) Decreased inhibitory synaptic neurotransmission
C) Alterations in voltage-gated ion channels to favor depolarization.
What are the goals of antiepileptic drugs?
A) Decreased excitatory synaptic neurotransmission (decreased glutamate)
B) Increased inhibitory synaptic neurotransmission (increased GABA)
C) Alterations in voltage-gated ion channels to favor polarization (alterations in sodium and calcium channels).
Voltage-gated sodium channel binders
Carbamazepine, phenytoin, lamotrigine
Neuronal voltage-gated calcium channel binders
Ethosuximide
GABA agonists
Phenobarbital
Drugs with multiple mechanisms
Valproate (sodium and calcium channels, GABA); topiarmate (sodium channels, glutamate, GABA)
Drugs with unknown mechanisms
Gabapentin, pregabalin, levetiracetam
Side effects of ALL antiepileptic drugs
Dose-related sedation Cognitive impairment Dizziness Potential for long-term bone demineralization Teratogenicity Stevens-Johnson syndrome
What is Stevens-Johnson syndrome?
Stevens-Johnson syndrome begins with flu-like symptoms, followed by a painful red or purplish rash that spreads and blisters. Then the top layer of the affected skin dies and sheds.
Stevens-Johnson syndrome is a medical emergency that usually requires hospitalization. Treatment focuses on eliminating the underlying cause, controlling symptoms and minimizing complications.
Side effects of many antiepileptic drugs (but not all)?
Bone marrow suppression and hepatotoxicity
Carbamazepine: MOA
Binds to VG Na channels extending the inactivated phase.
Phenytoin: MOA
Binds VG Na channels, prolongs inactivated phase, but also affects resting membrane potential, synaptic transmission, second messenger systems.
Lamotrigine: MOA
Not understood. Binds to and inactivates neuronal VG Na channels. May selectively influence neurons that synthesize excitatory nts such as glutamate.
Carbamazepine: Indications
Epilepsy, trigeminal neuralgia, mood stabilization in Type I bipolar disorder
Carbamazepine: Side effects
Decreased consciousness, N/V, double vision, ataxia.
Leukopenia (anemia and pancytopenia).
Hyponatremia.
Neuronal voltage-gated sodium channel binders.
Metabolized
in the liver
Which drugs are p450 inducers?
Carbamazepine and phenytoin
Which drug does not affect p450 BUT is influenced by p450 inducers/inhibitors?
Lamotrigine
Note: Most important interactions are with estrogens (OCPs and ERT) and with other AEDS because of their affects on p450 system.
Phenytoin: Indication
Epilepsy
Phenytoin: Side Effects
At toxic levels – decreased consciousness, N/V, double vision, ataxia. PHT infamous for LT bone demineralization. Specific to PHT – gingival hyperplasia. IV PHT associated with significant hypotension, cardiac arrhythmias, venous irritation and tissue necrosis (fosphenytoin used instead when IV indicated to reduce these problems).
Lamotrigine: Indications
Epilepsy, mood
stabilization in
bipolar disorder.
Lamotrigine: Side effects
At toxic levels – dizziness, somnolence. LTG is especially famous for terrible problems with life-threatening rash, initially occurring in up to 10%. This risk has been attenuated by very slow dosage titration. This slow titration is especially important when LTG is administered with VPA, which is a liver enzyme inhibitor. VPA increases the plasma concentration of LTG and thus increases the risk of life-threatening rash. Unlike many AEDs, bone marrow suppression and hepatotoxicity are uncommon. Specific to LTG – antidepressant effect.
Ethosuximide: MOA
It affects the alpha subunit of neuronal voltage-gated calcium channels heavily expressed in some thalamic neuron populations (T-type calcium channels).
Ethosuximide: Indications
It is the first-line
agent in
absence
epilepsy.
Phenobarbital: MOA
Phenobarbital binds to the GABA receptor, augmenting the effect of GABA by extending the duration of GABA-mediated chloride channel openings. The net effect is neuronal hyperpolarization.
Phenobarbital: Indications
Epilepsy, tremor (a closely related compound called primidone is still used for treatment of essential tremor)
Phenobarbital: Side Effects
At toxic levels – decreased consciousness, nausea/vomiting, double vision, ataxia. Dose-related sedation and cognitive impairment are especially severe with phenobarbital and greatly limits its use except in status epilepticus, neonatal seizures, and refractory epilepsies. Specific to PBT – hyperactivity, addiction.
Phenobarbital: Metabolism
Metabolized in liver
Phenobarbital: Drug Interactions
p450 inducer
Valproate: MOA
VPA blocks VG sodium channels (but at a site different from that of phenytoin and carbamazepine), increases brain GABA concentrations by an unknown mechanism, and acts against T-type calcium channels.
Valproate: Indications
Epilepsy, mood stabilization in bipolar disorder, migraine prophylaxis
Valproate: Side Effects
At toxic levels – decreased consciousness, nausea/vomiting, ataxia. Nausea/vomiting especially awful in the uncoated form [brand Depakene], thus usually given in a coated form [brand Depakote]. Teratogenicity (while all AEDs pose some increased risk of fetal malformation, the risk is highest for VPA; specifically associated with neural tube defects, the incidence of which can be reduced by folate supplementation). Bone marrow suppression (thrombocytopenia is most common, anemia and pancytopenia also occur); hepatotoxicity (VPA rarely used in children under 10). Specific to VPA – low-amplitude, highfrequency tremor, weight gain, hair thinning (all common); pancreatitis (infrequent). Rarely can cause hyperammonemia with nml LFTs, leading to lethargy, increased seizures, or death.
Valproate: Metabolism
Metabolized in liver
Valproate: Drug Interactions
p450 inhibitor
Topiramate: MOA
TPM blocks VG sodium channels, enhances the action of GABA at a nonbenzodiazepine site on GABA-alpha, and antagonizes the NMDA glutamate receptor.
Topiramate: Indications
Epilepsy,
migraine
prophylaxis
Topiramate: Side Effects
Cognitive impairment is a common complaint
with TPM when compared to the other second-generation
AEDs. Unlike many AEDs, bone
marrow suppression and hepatotoxicity are
very uncommon. Specific to TPM – weight
loss, increased risk of kidney stones,
decreased sweating, paresthesias, mood
disturbances, metabolic acidosis (rare).
Topiramate: Metabolism
70% excreted unchanged by the kidney, 30% metabolized in the liver
Gabapentin: MOA
Binds to auxiliary alpha-2-delta subunit of a neuronal VG calcium channel, which may inhibit inward Ca currents and stop NT release.
Gabapentin: Indications
Epilepsy, chronic pain, neuropathic pain (not FDA approved for this but is frequently used off-label).
Gabapentin: Side Effects
At toxic levels – decreased consciousness,
ataxia. Unlike many AEDs, not associated with
hepatotoxicity or bone marrow suppression.
Specific to GBP – peripheral edema and
weight gain.
Gabapentin: Metabolism
100% excreted unchanged in the urine (requires dose adjustment for kidney dz).
Gabapentin: Drug Interactions
Must be taken at least two hours after use of antacids (which impair bioavailability)
Pregabalin: MOA
Binds to auxiliary alpha-2-delta subunit of a neuronal voltagedependent calcium channel.
Pregabalin: Indications
Epilepsy,
neuropathic
pain,
fibromyalgia.
Pregabalin: Side Effects
At toxic levels – decreased consciousness,
ataxia. Unlike many AEDs, not associated with
hepatotoxicity or bone marrow suppression.
Specific to PGB – peripheral edema and
weight gain.
Which drugs are secreted 100% unchanged in urine?
Gabapentin, pregabalin, levetiracetam (drugs with unknown mechanisms).
Pregabalin: Side Effects
Must be taken at least two hours after the use of antacids (which impair its bioavailability)
Levetiracetam: MOA
Not well-understood; available data show that it binds to SV2A, a protein in pre-synaptic neurotransmitter vesicles, and likely modulates neuronal calcium channels
Levetiracetam: Indications
Epilepsy
Levetiracetam: Side Effects
Unlike many AEDs, not associated with
hepatotoxicity or bone marrow suppression
LEV has very few serious side effects.
Irritability/other significant psychiatric problems
can occur in 10-15% of patients
Levetiracetam: Drug Interactions
No significant drug interactions!
Levetiracetam is an attractive AED because?
Very few pharmacokinetic interactions with other drugs (like other AEDs or OCPs).
Can be used in patients with hepatic failure because it’s excreted 100% renally.
LEV does not require a titration period, and it appears to have a very rapid onset of action.
- The drug is relatively well tolerated and effective (74% of people are still taking it at one year).
- An intravenous formulation of LEV has been approved for use in clinical situations when patients are temporarily unable to take oral medication.
- An extended-release formulation of LEV is available (once-a-day dosing of AEDs is associated with increased compliance).
