1. ANTICONVULSANT ANTIEPILEPTIC DRUGS

2. Cellular and Synaptic Mechanisms of Epileptic Seizures
(From Brody et al., 1997)

3. Treatment of Seizures Goals: Block repetitive neuronal firing.
Block synchronization of neuronal discharges.
Block propagation of seizure.
Minimize side effects with the simplest drug regimen.
MONOTHERAPY IS RECOMMENDED IN MOST CASES

4. Treatment of Seizures Strategies: Modification of ion conductances.
Increase inhibitory (GABAergic) transmission.
Decrease excitatory (glutamatergic) activity.

5. Classification of CONVULSION
Generalized seizures: which essentially involve the entire brain and do not have an apparent local onset.
Unilateral seizures: which involve one entire side of the body.
Partial seizures: that have a focus.
Erratic seizures: of the newborn.
Unclassified seizures: (severe seizures associated with high mortality such that time does not permit a precise categorization).

6. Drugs that Act at the GABAergic Synapse
GABA agonists
GABA antagonists
Barbiturates
Benzodiazepines
GABA uptake inhibitors
Goal :  GABA Activity

7. GLUTAMATERGIC SYNAPSE
Excitatory Synapse.
Permeable to Na+, Ca2+ and K+.
Magnesium ions block channel in resting state.
Glycine (GLY) binding enhances the ability of GLU or NMDA to open the channel.
Agonists: NMDA, AMPA, Kianate.
Goal:  GLU Activity
Na+
Ca2+
AGONISTS
GLU
GLY
Mg++ K+

8. GLUTAMATERGIC SYNAPSE
                                                                                 

9. Treatment of Seizures
Most classical antiepileptic drugs exhibit similar pharmacokinetic properties.
Good absorption (although most are sparingly soluble).
Low plasma protein binding (except for phenytoin, BDZs, valproate, and tiagabine).
Conversion to active metabolites (carbamazepine, primidone, fosphenytoin).
Cleared by the liver but with low extraction ratios.
Distributed in total body water.
Plasma clearance is slow.

10. Treatment of Seizures Hydantoins: phenytoin
Barbiturates: phenobarbital
Oxazolidinediones: trimethadione
Succinimides: ethosuximide
Acetylureas: phenacemide
Other: carbamazepine, lamotrigine, vigabatrin,
Surgery, Vagus Nerve Stimulation (VNS).

11. Chemical Structure of Classical Antiseizure Agents
X may vary as follows:
Barbiturates O= C – N
Hydantoins N –
Oxazolidinediones – O –
Succinimides – C –
Acetylureas NH2 –
*(N connected to C2) *

12. Treatment of Seizures Structurally dissimilar drugs: New compounds:
Carbamazepine
Valproic acid
BDZs.
New compounds:
Felbamate
Gabapentin
Lamotrigine
Tiagabine
Topiramate
Vigabatrin

13. SARs among Anticonvulsants
R and R' should both be hydrocarbon side chain.
If both R and R' are lower alkyls, the tendency is to be active against absence seizures (petit mal) and not active against generalized tonic-clonic (grand mal) or partial seizures.
If one of the hydrocarbon substituents is an aryl group, activity tends to be directed toward generalized tonic-clonic and partial seizures and not antiabsence activity.
A conformational analysis of the aryl-containing antigeneralized tonic-clonic agents indicates that the conformational arrangement of the hydrophobic groups is important.

14. SARs among Anticonvulsants
A conformational analysis of the aryl-containing antigeneralized tonic-clonic agents indicates that the conformational arrangement of the hydrophobic groups is important.
R and R’
absence (petit mal)
generalized tonic-clonic (grand mal) or partial
Alkyl Groups
active
inactive
Aryl Groups

15. Barbiturates
Phenobarbital and mephobarbital display enough anticonvulsant selectivity for use as antiepileptics.
The metabolism of phenobarbital involves p-hydroxylation, followed by conjugation.
Mephobarbital is extensively N-demethylated in vivo and is thought to owe most of its activity to the metabolite phenobarbital.
In keeping with their structures, both agents are effective against generalized tonic-clonic and partial seizures.

16. Hydantoins
The hydantoins are close structural relatives of the barbiturates, differing in lacking the 6-oxo group. They are cyclic monoacylureas rather than cyclic diacylureas. As a consequence of losing a carbonyl group, they are weaker organic acids than the barbiturates, thus, aqueous solutions of sodium salts, such as of phenytoin sodium, generate strongly alkaline solutions.

17. The compounds have antigeneralized tonic-clonic activity
The compounds have antigeneralized tonic-clonic activity. Hydantoins with lower alkyl substituents reportedly have antiabsence activity.

18. Phenytoin and Phenytoin Sodium
Is the first anticonvulsant in which it was clearly demonstrated that anticonvulsant activity could definitely be separated from sedative-hypnotic activity.
Acting as a sodium channel blocker.
The drug is useful against all seizure types except absence.
Is incompletely or erratically absorbed from sites of administration due to its very low water solubility.
Metabolism proceeds by p-hydroxylation of an aromatic ring, followed by conjugation.

19. Actions of Phenytoin on Na+ Channels
Resting State
Arrival of Action Potential causes depolarization and channel opens allowing sodium to flow in.
Refractory State, Inactivation
Na+
Na+
Na+
Sustain channel in this conformation

20. Oxazolidinediones
Replacement of the N-H group at position 1 of the hydantoin system with an oxygen atom yields the oxazolidine-2,4­dione system.
The oxazolidinedione system has antiabsence activity, although these compounds is substituted with lower alkyls.
Aryl substituted oxazolidine-2,4-diones have shown activity against generalized tonic-clonic seizures.
Dermatological and hematological toxicities associated with the group may be the problem.

21. Trimethadione
Was the first drug introduced specifically for treating absence seizures.
It is important as a prototype structure for antiabsence compounds.
Dermatological and hematological toxicities limit its clinical use.
The drug is metabolized by N-demethylation to the active metabolite dimethadione.
Dimethadione is a calcium T channel blocker.
Dimethadione is a water soluble and less lipophilic and thus is excreted unchanged.

22. Succinimides
Succinimides (CH2 replaces O) have activity against generalized tonic-clonic, partial seizures absence, and complex partial seizures . Three are now in clinical use.

23. Ureas and Monoacylureas
Ureas and monoacylureas, have a long history of producing compounds with anticonvulsant activity.
The numerical yield of clinically useful compounds has not been great, however, most of the simpler compounds have gone by the way.
For convenience of grouping, carbamazepine and oxcarbazepine can be considered N,N-diacylureas.

24. Carbamazepine
SAR can be viewed either as an ethylene-bridged 1,1­diphenylurea or an amido substituted tricyclic system.
The two phenyls substituted on the urea nitrogen fit the pattern of antigeneralized tonic activity.
Mode of action: sodium channel block.
Carbamazepine is useful in generalized tonic-clonic and partial seizures.

25. The drug has the potential for serious hematological toxicity, and it is used with caution.
Metabolism proceeds largely through the epoxide formed at the (Z) cis-stilbene double bond. In humans, the epoxide reportedly is converted largely to the 10,11-trans-diol. The epoxide is a suspect in the idiosyncratic reactions carbamazepine may produce (aplastic anemia).
With this in mind, compounds designed to avoid the epoxide such as oxcarbazepine were developed.

26. Oxcarbazepine
Oxcarbazepine is reduced to the monohydroxy compound.
The monohydroxy compound is considered the major active metabolite.
The drug is used against partial seizures.
The major mechanism of action is sodium channel block.

27. Miscellaneous Agents
Many carboxylic acids have anticonvulsant activity, although often of low potency, possibly in part because extensive dissociation at physiological pH produces poor partitioning across the blood brain barrier.

28. Valproic acid
2-propylpentanoic acid (Depakene) has good potency and is used against typical and atypical absence seizures and absence seizure with generalized tonic-clonic seizure.
Mechanistically, the drug is a sodium channel blocker.
Metabolism is by conjugation of the carboxylic acid group and oxidation of one of the hydrocarbon chains.
Many of the side effects are mild. Rare, but potentially fatal, fulminant hepatitis has caused concern.

30. Gabapentin
Despite the fact that gabapentin is a relative of GABA with increased hydrophobic character; a binding site on calcium channels has been identified.
The drug is said to have a good pharmacokinetic profile and to cross the blood-brain barrier well.
It was introduced for adjunctive therapy of refractory partial seizures and, secondarily, generalized tonic-clonic seizures.

31. Tiagabine (Gabitril) It blocks GABA reuptake.
Its use is against partial seizures.

32. Lamotrigine (Lamictal)
Lamotrigine has been found effective against refractory partial seizures.
It is act by blocking sodium channels and preventing glutamate release.

33. Felbamate It is a sodium channel blocker.
Felbamate has been used successfully in refractory patients with generalized tonic-clonic seizures and complex partial seizures.
The drug is associated with a serious risk aplastic anemia.
It is used with extreme caution after other anticonvulsants have been tried and a careful risk-to-benefit has been made.

35. Zonisamide (Zonegran)Topiramate (Topamax)
Zonisamide and Topiramate have, respectively, the sulfonamide and sulfate amido (sulfamate) as the small polar group and an extensive hydrophobic group as the large end.
Both are sodium channel blockers. Zonisamide also blocks calcium-T channels and Topiramate increases the effect of GABA and antagonizes glutamate receptor. Each of the drugs is employed adjunctively against partial seizures.

36. Ca2+ Channels B Ion Channels Voltage-gated
Multiple Ca2+ mediated events
Drugs Used:
Calcium Channel Blockers B
: sites of N-linked glycosylation.
P: cAMP-dependent protein kinase phosphorylation sites

37. QUESTIONS