1. Anti-Epileptic Agents
AMD

2. Introduction
It is a Chronic medical condition produced by sudden changes in the electrical function of the brain.
CNS is highly stimulated due to repeated neural discharges
Violent involuntary spasmodic contraction of the skeletal musculature

3. Etiology Congenital defects, head injuries, trauma, hypoxia
Infection e.g. meningitis, brain abscess, viral encephalitis
Depressed skull, fractures.
Brain tumours
Drug withdrawal, e.g. CNS depressants
Hypoglycemia
PKU
Photo epilepsy

4. Types

5. Types

6. B) Primary generalized
Types
Focal or partial
1) Simple partial( Jacksonian )- The electrical discharge is cofined to the motor area.
2)Complex partial( psychomotor )- The electrical discharge is confined in certain parts of the temporal lobe concerned with mood as well as muscle.
B) Primary generalized
1) Tonic- clonic. Pt fall in convulsion & may bite his tongue & may lose control of his bladder or bowel.
2) Tonic. Some pts, after dropping unconscious experience only the tonic or clonic phase of seizure.
3) Atonic ( akinetic). Starts between the ages 2-5 yrs. The pt’s legs simply give under him & drops down.
4) Myoclonic . Sudden, brief shock like contraction which may involve the entire body or be confined to the face, trunk or extremities.
5) Absence . Loss of consciousness without involving motor area. Most common in children ( 4-12 yrs ).
6) Status epilepticus ( re-occuring seizure ). Continuous seizure without intervening return of consciousness.

7. Treatment
Up to 80% of pts can expect partial or complete control of seizures with appropriate treatment.
Antiepileptic drugs suppress but do not cure seizures
Antiepileptics are indicated when there is two or more seizures occurred in short interval (6m -1 y)
An initial therapeutic aim is to use only one drug (monotherapy)

8. Treatment of Seizures Drugs Seizure disorder Carbamazepine or
Valproate or
Phenytoin or
Phenobarbital
Tonic-clonic(Grand mal)
Drug of Choice
Topiramte
Lamotrigine (as adjunct or alone)
Gabapentin (as adjunct)
Alternatives:
Carbamazepine or Topiramte or
Valproate
Partial (simple or complex)
Drug of choice
Lamotringine (as adjunct or alone)
Gabapentin (as adjunct )

9. Treatment Valproate or Ethosuximide Absence ( petit mal)
Drug of choice
Clonazepam
Lamotrigine
Alternatives:
Valproate
Myoclonic, Atonic
Diazepam, i.v.
or Phenytoin, i.v. or Vaproate
Status Epilepticus
Phenobarbital, i.v
Diazepam, rectal*
Diazepam ,i.v
Febrile Seizures

10. Drugs Used (Crude Classification)
Sr.No
Class
Structure 1
Aldehydes-Paraldehyde 2
Aromatic allylic alcohols- Stiripentol 3
Barbiturates- Phenobarbital, methylphenobarbital 4
Benzodiazepines- Clobazam, Clonazepam, Clorazepate

11. Bromides- Potassium bromide KBr
Sr.No
Class
Structure 5
Bromides- Potassium bromide
KBr 6
Carbamates- Felbamate 7
Carboxamides- Carbamazepine, Oxcarbazepine, Eslicarbazepine acetate 8
Fatty acids- valproic acid, sodium valproate, and divalproex sodium 9
Fructose derivatives- Topiramate

12. GABA analogs- Gabapentin (1993). Pregabalin (2004)
Sr.No
Class
Structure 10
GABA analogs- Gabapentin (1993).
Pregabalin (2004) 11
Hydantoins- Ethotoin (1957).
Phenytoin (1938), Mephenytoin
Fosphenytoin 12
Oxazolidinediones- Paramethadione, Trimethadione (1946), Ethadione 13
Propionates- Beclamide

13. Pyrimidinediones- Primidone
Sr.No
Class
Structure 14
Pyrimidinediones- Primidone 15
Pyrrolidines- Brivaracetam
Levetiracetam (1999), Seletracetam 16
Succinimides- Ethosuximide (1955), Phensuximide
Mesuximide 17
Sulfonamides- Acetazolamide (1953).Sultiame
Methazolamide, Zonisamide

14. Triazines- Lamotrigine
Sr.No
Class
Structure 18
Triazines- Lamotrigine 19
Ureas- Pheneturide, Phenacemide 20
Valproylamides (amide derivatives of valproate)- Valpromide, Valnoctamide

15. Possible Mechanism of Action
1) By acting on the neuronal membrane action potential:
Membrane Stabilization: Phenytoin; Carbamazepine: Phenobarb; Lamotrigine; Topiramate, Zonisamide.
Prolong refractory period: e.g: Ethosuximide; Valproate
2) By enhancement of GABA neurotransmissions:
Inhibit GABA catabolism (inhibit GABA transaminase) e.g: Valproate; Vigabatrin
Inhibit re-uptake of GABA: benzodiazepines
Analog of GABA: e.g: Gababentin
Increase the activity of GABA: phenobarbitone; Topiramate; Gabapentin
3) By antagonizing the action of Aspartate and Glutamate e.g: Lamotrigine

16. Classification- Depending on timeline
1) Drugs which introduced before hydantoins, phenobarbital, oxazolidinediones
2) Drugs which introduced from benzodiazepins, iminostillbenes
3) Drugs which introduced after GABA-nergic agonists- progabide

17. Chemical Classification
Barbiturates
Hydantoins
Oxazolidinedienos
Succinimides
Phenacemides
Miscellaneous
Benzodiazepines

18. Chemistry

19. Antiepileptic General Structure
Overall, R1 and R2 should be hydrocarbon
Lower alkyls tend to be active against absence seizures and not active against generalized tonic-clonic or partial seizures
If one of the hydrocarbon substituent is an aryl group activity tends to be directed toward generalized tonic-clonic and partial seizures and not absence seizures

20. Barbiturates
First synthesized in 1864 by German researcher Adolf von Baeyer, the founder of Bayer pharmaceuticals company by combining urea with malonic acid
The first pharmacologically active compound discovered (1903) was barbital which was very effective in putting dogs to sleep
In the 1950s and 1960s, reports began to be published about side effects and dependence related to barbiturates
In 1970 several barbiturates were designated as controlled substances with the passage of the Controlled Substances Act of 1970

21. Barbiturate Structures
The main antiepileptic drug is Phenobarbital major metabolite of which is the p-hydroxyl and/or the p-hydroxyglucuronide; about 25% excreted unchanged
Mephobarbital is N dealkylated to phenobarbital which many think is the active drug and thus Mephobarbital is a PRODRUG
N1 and N3 are not distinguishable.
Both drugs being substituted with an aromatic ring at R2 are effective against generalized tonic-clonic and partial seizures.

22. Barbiturate Relatives
Primidone is a pyrimidinedione and not a barbiturate but is related where C2 oxidation leads to conversion into Phenobarbital in vivo which is thought to be the active constituent
Glutethimide is another non barbiturate sedative hypnotic used as safe alternative to barbiturates to treat insomnia.

23. SAR of Barbiturates 5 Both hydrogen atoms at C5 must be substituted
There is a decrease in onset time and a decrease in duration as C5 alkyl chain length increases.
Due to increasing lipid solubility increases rate of CNS penetration for shorter onset and increases susceptibility to microsomal metabolism due to penetration into hepatic cells
Common metabolic pathway is ω and ω-1 oxidation
Except for those with very high lipid solubility (Thiobarbiturates), the barbiturates have short duration
Thiobarbiturates undergo slow metabolism; most are in the adipose tissue (depot) and not available to hepatic enzymes which can be converted to corresponding oxybarbiturate by desulfuration
Bulk on C5 (i.e., aromatic ring) is a common feature for drugs with activity for generalized seizures and also for partial seizures and status epilepticus, but not good for absence seizures

24. Hydantoins Close structural relatives of barbiturates
Only lacking the 6-oxo group and are cyclic monoacylureas rather than diacylureas
As a consequence of losing a carbonyl group weaker organic acids than barbiturates and thus their sodium salt (e.g., phenytoin sodium) generates stronger alkaline solution
SAR of Hydantoins- Most of the clinically used drugs in this class possess bulky aromatic ring in position C5 that confers usefulness in generalized seizures, partial seizures and status epilepticus but not well for absence seizures

25. Hydantoins
Phenytoin is metabolized by p-hydroxylation followed by conjugation similar to Phenobarbital. Mephenytoin is the hydantoin analogue of mephobarbital which is also a prodrug, converted into the dealkylated derivative. Metabolism is also by p-hydroxylation and then glucuronidation
Ethotoin is dealkylated to the active drug. In this case there is free hydrogen at C5, which explains its very low potency. Metabolism is also by p-hydroxylation and then glucuronidation

26. Hydantoins
Fosphenytoin is Phosphate ester of phenytoin, rapidly hydrolyzed to phenytoin in vivo. Phenytoin sodium must be buffered to an alkaline pH to maintain solubility, thus is very irritating when injected. Fosphenytoin is neutral (pH~7) so is less irritating

27. Oxazolidinediones
Replacement of the N-H group at position 1 of the hydantoin with an oxygen atom yields the oxazolidine-2,4-dione system
Trimethadione is useful for absence seizures. Note the absence of bulky substituents at the C5 position which are useful in absence seizures.
It is metabolized to 5,5 dimethyl oxazolidine 2,4 dione (dimethadione) which is also active. Both trimethadione and dimethadione are excreted in the urine and are very toxic
Paramethadione is also N dealkylated, half life is hours. Some excreted by kidney.

28. Succinimides
less toxic version of the oxazolidinediones by replacing the “O” with CH2
Ethosuximide is lacking bulky groups attached at C3 which corresponds to C5 in the other related structures and thus is good for absence seizures.
Major metabolite is from oxidation of the ethyl group, hydroxyethyl and conjugated hydroxyethyl, both are inactive
Methsuximide has a bulky group at C3 which is good for absence but also picks up some partial seizures activity.
It is N-dealkylated to an active metabolite, followed by p-hydroxylation and conjugation

29. Succinimides
Phensuximide possesses the bulky group at C3 which is good for absence but also picks up some generalized tonic-clonic activity. Because of the free hydrogen at C3, it is much weaker than the disubstituted compounds.
N-dealkylated to an active metabolite, Followed by p-hydroxylation and conjugation

30. Miscellaneous Dibenzazepines structurally related to the TCAs.
Oxcarbazepine does not undergo such epoxidation so is expected to be less toxic

31. Valproic Acids Discovered accidentally, n-dipropylacetic acid
Valproic acid is a liquid and so is used as a liquid filled capsule
Being an organic solvent not soluble in water for intravenous use. Valproate sodium was developed as a water soluble salt, but too hygroscopic for solid oral dosage forms. Also causes GI irritation and cannot formulate a liquid into sustained release forms
Divalproex sodium is a stable salt for oral tablets and less irritating to the stomach
anticonvulsant activity increases with increase in chain length
introduction of unsaturation decreases activity
blocks succinic semialdehyde dehydrogease, enzyme involved in GABA metabolism pathway

32. GABA-nergic Drugs

33. GABA-nergic Drugs

34. New Molecular Entity in 2009: Vigabatrin
(±)-4-amino-5-hexenoic acid
A GABA analog and is dosed as a racemic compound, with the S-enantiomer being the pharmacologically active form.
The alkene group forms an irreversible, covalent bond with the gamma-aminobutyric acid transaminase (GABA-T) and irreversibly inhibits it.
The enzyme (GABA-T) is responsible for the metabolism of the inhibitory neurotransmitter GABA; its blockade leads to increased levels of GABA in the central nervous system.

35. Gabapentin
Gabapentin is GABA plus 5 carbons. The idea was to make GABA more lipid soluble for better CNS penetration, Widely used for neuropathic pain where it is thought to involve voltage-gated N-type calcium ion channels.
The more potent successor drug that is also used to treat neuropathic pain (fibromyalgia) is pregabalin approved in Its S-isomer is the active form.

36. Baclofen
Baclofen modulates mammalian (but not fruit fly) GABAB receptor.
It is used for the treatment of spastic movement, especially in instances of spinal cord injury,
It appears to have reduced abuse and dependence potential. The drug is rapidly absorbed after oral administration and is widely distributed throughout the body.
Biotransformation is low and the drug is predominantly excreted in the unchanged form by the kidneys.

37. Today
Your original ideas need to be protected right now -- they are in danger of being stolen! Not everyone is as creative as you are, and some unscrupulous people have no problem taking your ideas and promoting them as their own. You have a good idea of who a likely thief could be, so be tight lipped when you are around them, today. There's no need to elaborate why you are being so elusive -- it will only get them angry. Let them find out what you're cooking up when everyone else does.
Tomorrow  |  2016
Right now your brain is wide open to new ideas and new ways of doing things. Stepping out of your comfort zone has never felt so good, so take a walk on the wild side and remind yourself what it's like to feel a little out of your element! There has never been a better time in your life to explore a new hobby or interest. How about checking out a career opportunity that you have been thinking about pursuing for a while? You are about to enter a very sweet and worry-free time in your life.
Today
Your original ideas need to be protected right now -- they are in danger of being stolen! Not everyone is as creative as you are, and some unscrupulous people have no problem taking your ideas and promoting them as their own. You have a good idea of who a likely thief could be, so be tight lipped when you are around them, today. There's no need to elaborate why you are being so elusive -- it will only get them angry. Let them find out what you're cooking up when everyone else does.
Tomorrow  |  2016
Right now your brain is wide open to new ideas and new ways of doing things. Stepping out of your comfort zone has never felt so good, so take a walk on the wild side and remind yourself what it's like to feel a little out of your element! There has never been a better time in your life to explore a new hobby or interest. How about checking out a career opportunity that you have been thinking about pursuing for a while? You are about to enter a very sweet and worry-free time in your life.

38. Equality Act 2010
The Equality Act (opens new window) aims to protect people against discrimination. Epilepsy is a condition that is covered by the Equality Act, even if a person’s seizures are controlled with medication.
This means it is against the law for education and training providers to discriminate against people with epilepsy. This includes nurseries and playgroups, primary and secondary schools, and further and higher education.
The Equality Act covers extra curricular activities. It also covers how the curriculum is delivered and so methods of teaching need to treat all pupils fairly and not put any pupils with epilepsy at a disadvantage. However, the Equality Act does not cover the content of the curriculum.

39. Dynamic target of seizure control in management of epilepsy is achieving balance between factors that influence excitatory postsynaptic potential (EPSP) and those that influence inhibitory postsynaptic potential (IPSP).

43. Alpha waves have a frequency of 8 to 12 cycles per second
Alpha waves have a frequency of 8 to 12 cycles per second. Alpha waves are present only in the waking state when your eyes are closed but you are mentally alert. Alpha waves go away when your eyes are open or you are concentrating.
Beta waves have a frequency of 13 to 30 cycles per second. These waves are normally found when you are alert or have taken high doses of certain medicines, such as benzodiazepines.
Delta waves have a frequency of less than 3 cycles per second. These waves are normally found only when you are asleep or in young children.
Theta waves have a frequency of 4 to 7 cycles per second. These waves are normally found only when you are asleep or in young children.