This document discusses various anticonvulsants, focusing on their mechanisms of action, indications, side effects, and pharmacokinetics. It highlights the differences in adverse events associated with different antiepileptic drugs (AEDs), particularly noting the occurrence of rashes and the implications of prenatal exposure. Additionally, it mentions the higher suicide rates among epileptics and emphasizes that while newer AEDs may be better tolerated, efficacy improvements are limited, leading to common use of polytherapy.

1. Anticonvulsants II
Brian J. Piper, Ph.D., M.S.
piperbj@husson.edu
February 8, 2013

2. Objectives
• Pharmacy students will be able to:
– describe the MOA of recently developed AEDs.
– identify and contrast the relative frequency of
adverse events for AEDs.

3. Voltage Sensitive Ion Channels
• Composed of multiple subunits (α,β,δ)
• α subunit, transmembrane 4 = voltometer
• can exist in open, closed, or inactive states
Pore inactivator
Stahl (2008). Essential Psychopharmacology, p. 149, 152.

4. Carbamazepine
• Structure: similar to TCAs
• Indications: generalized & partial seizures
• PK: CYP3A4 inducer (↓ Carb t1/2 from 36 to 10!, ↓ birth
control)
• Adverse Events: diplopia, ataxia (not sedation)
• Pregnancy Category: D
• MOA: stabilizes the inactivated state of voltage-gated sodium
channels

5. MOAs of Carbamazepine (& others)
• Prolong inactive state of voltage sensitive ion
channel for Na+, Ca2+, K+
• Bind to α subunit of Na+ channel
• Increase inhibitory effects of GABA
Stahl (2008). Essential Psychopharmacology.

6. Stevens-Johnson Syndrome
• Potentially lethal drug induced hypersensitivity
• Carbamazepine (1/5,000), phenobarbital,
phenytoin, lamotrigine
• Symptoms: fever, sore throat, skin sloughing
(mouth/lips, genitals, anus)
• Adults (Han Chinese) > children
Conjunctivitis in SJS
Bae et al. (2013). Korean Journal of Pain, 26(1), 80 – 83.

7. Oxcarbazepine (& Eslicarbazepine)
• Structure: similar to carbamazepine
• Indications: generalized & partial seizures
• Adverse Events: diplopia, ataxia, hyponatremia
• PK:
– CYP3A4 inducer
– t1/2 = 2 / 10
• AE: SJS (rare)
(Europe only)

8. Lamotrigine
• Indications:
– partial & generalized seizures
– Lennox-Gastaut syndrome
– Bipolar I
• MOA: voltage gated ion channels, ↓ glutamate
release
• Adverse Effects: dizziness, headache, somnolence
• PK: t1/2 = 24 h
• Pregnancy Category: C

9. Comparative Efficacy & Tolerability
• AED naïve epileptics (age 13-80) randomized to
lamotrigine (150 mg/day) or carbamazepine (600
mg/day)
->
->
Brodie et al. (1995). Lancet, 345, 476-479.

10. Gabapentin
• MOA:
– voltage sensitive Ca2+ channels
– ↑ GABA
– ↓ glutamate
• Indications: partial seizures, pain, not bipolar
• Adverse Events: somnolence, ataxia, headache
• PK:
– t1/2 = 6 hours
– not CYP inducer, negligible drug interactions
Porter & Meldrum (2011). In Katzung’s Basic & Clinical Pharmacology, p. 413.

11. AED Rash
• Rashes, commonly minor, are commonly experienced by epileptics (16%).
• Comparison of rash rates in practices of 13 epileptologists (N = 1,890 adults)
• Average rate of rash = 2.8%
• Significantly above average: phenytoin (PHT), lamotrigine (LTG)
• Average: oxcarbazepine (OXC), carbamazepine (CBZ)
• Significantly below average: gabapentin (GBP), valproate (VPA)
Arif et al. (2007). Neurology, 68, 1701-1709.

12. AED Rash
• Rashes, commonly minor, are commonly experienced by epileptics (16%).
• Comparison of rash rates in practices of 13 epileptologists (N = 1,890 adults)
• AED discontinuation due to rash = 1.3%
• Significantly above average: phenytoin (PHT), lamotrigine (LTG)
• Average: oxcarbazepine (OXC), carbamazepine (CBZ)
• Significantly below average: gabapentin (GBP), valproate (VPA)
Arif et al. (2007). Neurology, 68, 1701-1709.

13. No malformations = safe?
• Prospective study of offspring of
epileptics that received:
– sodium valproate
(VPA, N=42)
– carbamazepine (CBZ, N=48)
– lamotrigine (LTG, N=34) --------------------------------------------------
– polytherapy (Poly, N=30), *
– no medications
(NoMe, N=27).
• Offspring of non-epileptics
(control, N=230) were also
examined
• Neuropsychological test ≈ 1 year
• Monotherapy < Control
Bromley et al. (2010). Epilepsia, 51(10), 2058-2065.

14. Prenatal AEDs & Autism
• Neurodevelopmental disorders (Autism
Spectrum Disorders, ADHD & dyspraxia) at age
6 in a prospective study.
Bromley et al. (2013). Journal of Neurology, Neurosurgery, & Psychiatry, in press.

15. Future Pipeline
15

16. FDA Approved Indications
Agent Epilepsy Seizure Type Other
phenobarbital partial & generalized
phenytoin partial & generalized
valproic acid absence & partial manic episodes, migraine
carbamazepine partial & generalized bipolar I, pain (neuralgia)
oxcarbazepine partial
lamotrigine partial & generalized bipolar I
gabapentin partial pain (neuralgia)

17. AED & Suicide
• Suicide rates are 3-fold higher among epileptics relative
to the general population.
• The FDA issued an alert that all AEDs “may increase risk
of suicidal thoughts/behavior; monitor for worsening of
depression and any unusual changes in mood or
behavior.”
• Evidence is currently inconclusive whether increased
suicide following AEDs (oxcarbazepine, valproate) occurs
only in high risk populations (bipolar, chronic pain) or in
epileptics without comorbid conditions.
Patorno et al. (2010), JAMA, 303(14), 1401-1409; Hecimovic et al. (2011). Epilepsy & Behavior, 22, 77-84.

18. General AED Principles
• At least 50% of epileptics have a substantial
reduction in seizure frequency with AEDs.
• If one AED doesn’t work, the likelihood that a
second won’t work is greater.
• Seizures are intractable in 30% of epileptics.
Brodie, M. J. (2010). Seizure, 19, 650-655,

19. Summary
• AEDs target voltage gated channels & GABA.
• 2nd generation AED are better tolerated than
older agents but offer limited improvements
in efficacy.
• Polytherapy is very common for seizure
control which presents opportunities to
manage drug interactions.