Anticonvulsants Part II

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This PPT is part two of two lectures given to second year pharmacy students in a pharmacology & toxicology class.

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  • Stevens-Johnson syndrome
  • Carbamazapine levels, if the same dose is given over 1 week, will gradually decrease. http://www.howjsay.com/index.php?word=carbamazepine&submit=Submit
  • Carbamazepine keeps the cations on the outside.
  • Stevens Johnson syndrome (SJS) is an acute life-threatening dermatoses characterized by extensive epidermal sloughing at the dermoepidermal junction resulting from keratinocyte apoptosis. Lower-Left: Stevens-Johnson syndrome in a patient that received Carbamazepine (had a reaction but didn’t tell health care providers!) and was later treated with Carbamazepineagain!
  • Oxcarbazepine is a structural derivative of carbamazepine, with a ketone in place of the carbon-carbon double bond on the dibenzazepine ring.
  • Approved as an adjunctive therapy for epilepsy gut generally used as a monotherapy.Lamotrigine was first drug approved for BPI since lithium (30 years earlier!). Pronounced Lenox Gesto. Half-life can be reduced to 14 hours with other enzyme inducing drugs. Nice overview (6 min): http://www.youtube.com/watch?v=wiHcSj1k-yA8.9/1000 babies have cleft-lip/palate, 24 times higher risk than normal of cleft-lip/palate.
  • PDR.net suggests that the carbamazepine dose is on the low side with typical doses being 800 – 1200 with max being 1600.
  • Gabapentin blocks voltage sensitive calcium channels, increases release of GABA (but does not bind to GABAA or GABAB receptors). Short-half life requires multiple dosing times/day. As polypharmacy is very common, the lack of bioactive metabolites and drug interactions is key here.
  • Other AEDs: PRM: primidone; VGB: vigabatrin; LEV: levetiracetam; TPM: topiramate; CLB: clobazam.
  • Other AEDs: PRM: primidone; VGB: vigabatrin; LEV: levetiracetam; TPM: topiramate; CLB: clobazam.
  • Neuropsychological testing completed between 4 months and 2 years of age. As a group, monotherapy did significantly less well than NoMe. Neuropsych test included items about locomotor, social skills, hearing & language, nonverbal performance, and hand-eye coordination.
  • Only valproate (single/poly) was statistically significant although others (LTG) are concerning.
  • There are now 24 antiepileptic drugs (AEDs) approved for use in epilepsy by the U.S. Food and DrugAdministration!
  • 0.7% of the U.S. population has been diagnosed with epilepsy.
  • Suicide rates of epileptics with mood disorders are 12 times higher than the general public. Suicide rates are elevated 3-4 fold in oxcarbazepine and sodium valproate relative to other AEDs.
  • Anticonvulsants Part II

    1. 1. Anticonvulsants IIBrian J. Piper, Ph.D., M.S. piperbj@husson.edu February 8, 2013
    2. 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. 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. 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. 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 GABAStahl (2008). Essential Psychopharmacology.
    6. 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 SJSBae et al. (2013). Korean Journal of Pain, 26(1), 80 – 83.
    7. 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. 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. 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. 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 interactionsPorter & Meldrum (2011). In Katzung’s Basic & Clinical Pharmacology, p. 413.
    11. 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. 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. 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 < ControlBromley et al. (2010). Epilepsia, 51(10), 2058-2065.
    14. 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. 15. Future Pipeline 15
    16. 16. FDA Approved IndicationsAgent Epilepsy Seizure Type Otherphenobarbital partial & generalizedphenytoin partial & generalizedvalproic acid absence & partial manic episodes, migrainecarbamazepine partial & generalized bipolar I, pain (neuralgia)oxcarbazepine partiallamotrigine partial & generalized bipolar Igabapentin partial pain (neuralgia)
    17. 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. 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. 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.

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