2. Objectives
• At the end of this lecture, pharmacy students
should be able to:
– describe the overall neurochemistry of seizures
(AED targets).
– list the procedures to induce seizures.
– contrast by PD and AE the different 1st generation
AED.
8. Overall Incidence of Convulsive Disorders: Increased
frequency at extremes of age (Rochester, MN 1935-84)
300
Incidence Per 100,000 Patient Years
250 Alcohol
Other provoked
Epilepsy
200 Single
150 Total
100
50
0
0 20 40 60 80 100
Age
Hauser, W. A. et al. (1995). Epilepsia, 34(3), 453-458.
9. * *
* *
*
*
->
->
White (2005). American Epilepsy Proceedings.
10. GABA Biosynthesis & Breakdown
(so many drug targets)
• GAD: glutamic acid decarboxylase
converts glutamate to GABA
• VGAT: vesicular GABA transporter
• GAT-1, GAT-2: membrane GABA
transporter found on neurons &
astrocytes
• GAT-3: membrane GABA transporter
found on astrocytes
• GABA-T: GABA Aminotransferase,
begins conversion of GABA to succinic
semialdehyde (SSA)
Meyer & Quezner (2008). Psychopharmacology, Chapter 7.
11. GABAA & Adult Brain
Vm : membrane potential
cotransporter: transports ions against
concentration gradient
GABA Neuron
<- Cl- pool
White, H. S. & Rho, J. M. (2010). Mechanisms of AED, p. 67.
13. History of AEDs
• 1857: Sir Charles Locock reports on KBr for hysterical epilepsy
• 1912: Alfred Hauptmann’s sleep problems lead to phenobarbital
• 1938: Maximal electroshock seizure (epilepsy?) model used to identify phenytoin
1) Apply electrode to cornea
2) Apply current
3) Rate tonic-clonic behavior
4) Repeat 1-3 with drug
Brodie, M. J. (2010). Seizure, 19, 650-665; Castel-Branco et al. (2009). Meth Find Clin Exp Pharma, 31(2), 101-106.
14. Phenytoin (1938)
• History: less sedative than
phenobarbital
• MOA: decreased recovery of
voltage gated Na+ channels from
inactivation
• PK: 3A4 inducer
• Adverse Events: lethargy
(transient), gingival hyperplasia
Goodwin & Gillman (2011). p. 588.
Sharma & Dasroy (2000). NEJM, 342, 325.
15. Phenytoin & Category D
• ↓ growth AED Syndrome?
• Facial Abnormalities
– nasal hypoplasia
– maxilla hypoplasia
– flat philtrum
• ↓ IQ (variable)
• ↓ K+
Howe et al. (1995). American Journal of Medical Genetics, 58, 238-248.
16. Pentylenetetrazol (1938)
• MOA: GABA antagonist
EEG fMRI shows thalamus activation 4 s before PTZ seizure.
Brevard et al. (2006). Epilepsia, 47(4), 745-754.
17. Valproate (1962)
• History: Pierre Eymard is using pentylenetetrazol
to induce convulsions with valproate as
solvent/vehicle.
• Uses: different seizure types
• MOA: ?, ↑GABA, ↓ aspartate
Stahl (2008).Essential Psychopharm, p. 678.
18. Valproate: Category D
• 2% risk of spina bifida
• ↓ Cmax
• folic acid supplementation
Perukka, E. (2002). CNS Drugs, 16(10), 695-714.
19. Status Epilecticus (SE)
• continuous, unremitting seizure lasting > 5
min
• convulsive > non-convulsive
• mortality = 20%
• medical emergency
Trinka et al. (2012). Epilepsia, 53(4), 127-138.
20. Lorazepam (1977)
• MOA: GABAA α1,2,3,5
• Dose: 2 mg/ml per min x 2
• Adverse Effects: heavy sedation, especially
with alcohol
• t1/2 : 12 hours
21. Summary
MOA Concern
phenobarbital GABAA sedation
Cl- channel duration
phenytoin voltage gated Category D
Na+ channels
lorazepam GABAA α1,2,3,5 addiction (Schedule IV)
Cl- channel frequency
valproate ↑ GABA (?) Category D
22. GABAA & Neonatal Brain
Vm : membrane potential
cotransporter: transports ions against
concentration gradient
GABA Neuron
<- Cl- pool
White, H. S. & Rho, J. M. (2010). Mechanisms of AED, p. 67.
24. Summary
• MES and PTZ have been used to identify many
AED.
• Pharmacotherapy for epilepsy is complex and
polypharmacy is common.
25. Self-Test
• Match the AED on the left
with the potential adverse
effect.
– valproic acid
– phenytoin
– phenobarbital
Hinweis der Redaktion
Prequel: 0:10 to 2:00 (Skip Ad) Funny but technically accurate: http://www.youtube.com/watch?v=xPoAQaVy-7s
By 20 years of age, one percent of the population can be expected to have developed epilepsy, 3% by age 75. High-Income countries: 45/100K versus Low/Middle income 82/100K!
Complex partial may also involve hallucinations, chewing movements, and urination. Onset of petit mal seizures is typically between ages 3-5. The staring and rapid eye blinking are common. http://www.howjsay.com/index.php?word=petit+mal&submit=Submit
N-methyl-D-aspartate; Kay ah nay t or http://www.howjsay.com/index.php?word=kainate&submit=Submit
AED: Anti-Epileptic Drug, Phenytoin (fen i toe en) or http://www.howjsay.com/index.php?word=phenytoin&submit=Submit
A cotransporter is an integral membrane protein that is involved in secondary active transport. It works by binding to two molecules or ions at a time and using the gradient of one solute's concentration to force the other molecule or ion against its gradient.Membrane potential is the difference in electrical potential between the interior and the exterior of a cell (typically –70 mV for neurons).During adult life, the activity of the KCC2 cotransporter is high resulting in a low volume of intracellular Cl. Application of GABA results in the Cl channel opening which decreases the membrane potential.
Charles Locock was an obstetrician to Queen Victoria. He comments that potassium bromide produced satisfactory results in a series of 52 woman whose seizures corresponded with their menstrual cycles. KBr is still a 3rd AED for children in Europe (removed from market in US in 1975). At the time of writing, the speculated causes of epilepsy were the uterus, kidney, teeth, and, especially, masterbation (KBr calmed sexual excitement).Hauptmann is a psychiatry resident living over a psychiatric ward. Phenobarbital is still the #1 AED in developing countries.
“A 17-year-old boy had generalized tonic–clonic seizures for four years…Treatment with 300 mg of phenytoin per day was subsequently begun and continued unsupervised for a period of two years. Examination revealed … severe gingival hyperplasia (Panel A) … withdrawal of phenytoin was followed by marked regression of the gingival hyperplasia within three months” (Panel B).
Phenytoin leads to increased potassium degradation which results in a K deficiency.
Pentylenetetrazol is also known as PTZCardiazol. This was used to induce seizures in people prior to the development of Electroconvulsive Therapy. Systemic PTZ causes significant decreases in blood pressure and increases in heart rate so the ICV route was used instead. Authors note “subcutaneous electrodes were placed over the anterior and posterior cortex”.
Reported to be most widely used AED in the world as of 2002. Valproate MOA may involve increasing GABA release, inhibiting GABA reuptake, or inhibiting GABA transaminase, decreasing the opening of Ca/Na channels, as a NMDA antagonist, and modulates 5-HT and dopamine (whew)!
Spina bifida (Latin: "split spine") is a developmental congenital disorder caused by the incomplete closing of the embryonic neural tube. Some vertebrae overlying the spinal cord are not fully formed and remain unfused and open. If the opening is large enough, this allows a portion of the spinal cord to protrude through the opening in the bones. There may or may not be a fluid-filled sac surrounding the spinal cord.
Prevents seizures for 2-8 hours. This is much longer than diazepam (30 minutes). Since its introduction, Lorazepam has been marketed under 70 (!) brand names!
A cotransporter is an integral membrane protein that is involved in secondary active transport. It works by binding to two molecules or ions at a time and using the gradient of one solute's concentration to force the other molecule or ion against its gradient.Membrane potential is the difference in electrical potential between the interior and the exterior of a cell (typically –70 mV for neurons).During adult life, the activity of the KCC2 cotransporter is high resulting in a low volume of intracellular Cl. Application of GABA results in the Cl channel opening which decreases the membrane potential.
Philtrum:the vertical groove on the surface of the upper lip, below the septum of the nose.Phenytoin is associated with both gingival hypertrophy and facial dysmorphology. Valproic acid causes hair loss (uncommon) and weight gain (common).