1. Antiseizure Drugs
Kaukab Azim, MBBS, PhD

2. First Generation Drugs Second Generation Drugs
Drug Groups
First Generation Drugs
Second Generation Drugs
Others
For Partial and Generalized Tonic-Clonic Seizures
For Absence Seizures
Gabapentin
Felbamate
Levetiracetam
Lamotrigine
Tiagabine
Topiramate
Zonisamide
Acetazolamide
ACTH
Glucocorticoids
Carbamazepine
Valproic acid
Phenytoin
Clonazepam
Diazepam
Lorazepam
Ethosuximide

3. Learning Outcomes
By the end of this course the students should be able to:
List the main classes of anti-epileptic drugs
Explain the mechanism of action of each drug in each group
Describe the pharmacological effects of each drug in each group
Describe the main pharmacokinetic features or each drug in each group
Describe the main adverse effects of each drug in each group
List the main contraindications of antiseizure drugs
Outline the main therapeutic uses of antiseizure drugs

4. Classification of epilepsy
Generalized
Tonic clonic seizure
Absence seizure
Myoclonic
Tonic
Atonic
Partial
Simple
Complex
Partial with secondary generalization

5. Antiseizure Drugs
Antiseizure (also called anticonvulsant, antiepileptic) drugs are compounds fully effective in controlling seizures in % of patients.
The inhibition of seizure activity in the CNS is accomplished without major disturbances in the normal electrical activity.
Sustained, high frequency, repetitive firing are inhibited much more effectively than low- frequency, non-repetitive firing.
Antiseizure drugs do not cure epilepsy; they just suppress seizures on a temporary basis. Therefore most patients must take them for life.

6. The therapeutic index of most antiseizure drugs is low and adverse effects are common. They are usually mild, but most antiseizure drugs may cause occasionally life-threatening adverse reactions.
Most antiseizure drugs can cause malformations when given during pregnancy. Since also seizures per se can cause malformations a careful assessment of the risk/benefit ratio is mandatory in each epileptic woman who want to have a baby.
The mechanisms of action of antiseizure drugs are still not well understood but they have been found to concern mainly:
a) voltage-gated ion channels
b) inhibitory and excitatory synaptic functions

7. 1. Carbamazepine and Congeners
Drugs
Carbamazepine, oxcarbazepine.
Mechanism of action
Frequency-dependent and voltage-dependent blockade of inactivated Na+ channels (most likely the main mechanism).
Interaction with other ion channels and several neurotransmitters (at high doses. Their contribution to its antiseizure effects is uncertain)

8. Pharmacological Effects
Inhibition of post tetanic potentiation, which may prevent the spread of seizure from the epileptic focus (the discharge of the focus itself is not prevented and therefore aura and EEG alterations are not eliminated)
Analgesic actions (in some type of neuropathic pain).
Antidepressant actions (mechanism likely similar to that of tricyclic antidepressants)
Strong CYP3A4 inducing action (which leads to many pharmacokinetics interactions).

9. Carbamazepine and Congeners
Pharmacokinetics
Oral bioavailability: . 90%
Biotransformation: 99% by the CYP3A4 (biotransformation rate is low).
Adverse effects
Dizziness, drowsiness, blurred vision diplopia, ataxia (common, dose related).
Neutropenia, thrombocytopenia, agranulocytosis, aplastic anemia (the risk of these reactions is 5-8 times greater in patients treated with carbamazepine than in the general population)
Confusion, agitation, hallucinations (after high doses).
Cardiac arrhythmias.
Heart failure, after long treatments (rare).
Water retention and hyponatremia, after long treatments.
Hepatic failure, after long treatments (rare).
Allergic reactions: skin rash (. 5%), Stevens-Johnson syndrome, lupoid syndrome, aplastic anemia (rare).
The risk of malformations (mainly related to neural tube defect) is increases 2-3 fold during pregnancy
[Adverse effects of oxcarbazepine are similar but less frequent]

10. Carbamazepine – Therapeutic Uses
1. Epilepsy
It is a first choice drug for partial seizures and for generalized tonic-clonic seizures (It has been the most widely prescribed anticonvulsant drug world wide. No newer drug has been found to be superior in efficacy).
In complex partial seizures it prevents the attacks in 60-65% of patients.
The antiepileptic effect can undergo tolerance in 10-20% of patients.
(Absence, myoclonic, tonic and atonic seizures may worsen in patients treated with carbamazepine).
Diabetes insipidus
Rarely used to treat pituitary diabetes insipidus. The drug is not effective in nephrogenic diabetes insipidus, which indicates that functional V2 receptors are required for the antidiuretic effect of the drug.

11. 2. Trigeminal and related neuralgias.
Carbamazepine is the first choice drug for trigeminal neuralgia (result are good in 70% of patients).
In refractory cases the addition of phenytoin can be useful.
3. Bipolar affective disorder
As an alternative to lithium for the therapy of acute mania and the prophylactic treatment of bipolar disorder.

12. 2. Phenytion and Congeners
Drugs
Phenytoin, fosphenytoin (a prodrug rapidly converted to phenytoin in plasma)
Mechanism of action
Frequency-dependent and voltage-dependent blockade of inactivated Na+ channels (most likely the main mechanism).
Induction of hepatic microsomal enzymes.

13. Pharmacological effects
Inhibition of post tetanic potentiation, which may explain the prevention of the spread of seizure from the epileptic focus (the excessive discharge of the focus itself is not prevented and therefore aura and EEG alterations are not eliminated)
Cerebellar-vestibular stimulation (with high doses).
Analgesic actions (in some type of neuropathic pain).

14. Phenytoin - Pharmacokinetics
Oral bioavailability: . 90% (absorption speed depends on pharmaceutical preparation)
Administration: oral (fosphenytoin is more soluble and available for parenteral use)
Biotransformation: 98% by the liver P450 system (biotransformation rate is low).
Elimination: is dose dependent, i.e. first order at low doses, but zero order at high doses.
Elimination: is dose dependent, i.e. first order at low doses, but zero order at high doses. (This means that when the maximum capacity of the liver to metabolize the drug is approached, even a small further increase in dosage may cause a very large increase in blood levels of the drug).

15. Phenytoin – Adverse Effects
Central nervous system
Nystagmus (frequent), diplopia, ataxia, dyskinesia, vertigo, tremor, hyperreflexia, dystonic reactions, blurring of vision.
Hyperactivity, nervousness.
Sedation, drowsiness (with high drug plasma levels).
Peripheral neuropathy (7-30% of patients treated for long time).
Phenytoin encephalopathy (with high drug plasma levels).
Gastrointestinal system
Gingival hyperplasia (30-40% of patients)
Hepatitis, hepatic necrosis (rare)
Inhibition of folate absorption (after long treatments)

16. Gastrointestinal system
Gingival hyperplasia (30-40% of patients)
Inhibition of folate absorption (after long treatments)
Endocrine system
Hyperglycemia (due to decreased insulin secretion)
Osteomalacia (due to increased metabolism of vit D and reduced intestinal Ca++ absorption)
Hematopoietic system
Blood dyscrasias (megaloblastic anemia, aplastic anemia) (rare)
Lymphoadenopathy, pseudolymphoma (after long treatments)
Malignant lymphoma (?), Hodgkin's disease (?)

17. Phenytoin – Adverse Effects
Other systems
Skin hyperpigmentation, hirsutism (mainly in women)
Coarsening of facial features (mainly in children)
Pregnancy
Risk of malformations increases 2-3 fold
A "fetal hydantoin syndrome" (cleft lip, cleft palate, congenital heart disease, slowed growth and mental deficiency)
Allergic skin reactions
Skin rashes, erythema multiforme
Exfoliative dermatitis, Stevens-Johnson syndrome, lupoid syndrome (very rare)

18. Phenytoin – Therapuetic Uses
Epilepsy
First or second choice drug for partial and generalized tonic-clonic seizures.
Fosphenytoin is drug of choice for the emergency treatment of status epilepticus.
(Absence, myoclonic and akinetic seizures may worsen in patients treated with phenytoin).
Trigeminal and related neuralgias
Carbamazepine remain the preferred agent for these conditions but phenytoin is a second choice drug and can achieve good results.
Cardiac arrhythmias
Used mainly when arrhythmias are due to digitalis toxicity.

19. 3. Phenobarbital Mechanism of action
Enhancement of GABA-mediated inhibition (the opening of Cl- channels is prolonged by facilitating GABA action)
Blockade of AMPA receptors
Direct opening of Cl- channels (after high doses)
Blockade of Na+ and Ca++ channels (at high doses)

20. Pharmacological effects
Suppression of the excessive discharge of the seizure focus
Prevention of the spread of excitation from seizure focus.
All other effects of the barbiturate class.
Pharmacokinetics
Oral bioavailability: 100%
Biotransformation: 75% by the liver (biotransformation rate is low)
Excretion by the kidney: 25% (in acid urine) up to 75% (in alkaline urine)

21. Adverse effects, contraindications
All the adverse effects and contraindications of barbiturate class (dependence occurs with barbiturates, but not with phenobarbital)
Therapeutic uses
Second choice drug for:
Partial seizures,
Generalized tonic-clonic seizures
Status epilepticus.

22. 4. Valproic Acid Mechanism of action
The drug likely acts with multiple mechanisms, including:
State-dependent blockade of inactivated Na+ channels.
Blockade of NMDA receptor mediated excitation.
Blockade of T type Ca++ channels in thalamic neurons.
Chemistry
Valproic acid is the dipropylacetic acid. Salts, ester and amides of this acid (i.e. sodium valproate) are also active antiseizure agents.
Mechanism of action
The drug likely acts with multiple mechanisms, including:
a) State-dependent blockade of inactivated Na+ channels.
b) Blockade of NMDA receptor mediated excitation.
c) Blockade of T type Ca++ channels in thalamic neurons.
d) Increased GABA content in the brain (mechanism is uncertain)
e) Opening K+ channels (at high doses)

23. Pharmacological effects
A broad spectrum antiepileptic drug
The drug can inhibit CYP2C9 and glucuronosyltransferase, so inhibiting the biotransformation of many drugs.
Pharmacokinetics
Oral bioavailability: 100%
Biotransformation: > 95% by the liver (some metabolites are active)

24. Valproic Acid – Adverse Effects
CNS
Sedation, drowsiness (when given with other CNS depressants)
Dizziness, tremor, ataxia, nystagmus , diplopia, dysarthria
Nervousness, agitation (mainly in children).
Gastrointestinal system
Nausea, vomiting, anorexia, weight gain (up to 20%).
Hyper-ammon-emia (50%), fulminant hepatitis

25. Hematopoietic system
Thrombocytopenia, mainly-dose related (up to 30% of patients).
Allergic reactions
Skin rashes, photosensitivity, erythema multiforme
Reproductive system.
Menstrual disturbances (up to 20% of patients).
Increased risk of neural tube defect (up to 20 fold) when given during pregnancy. Spina bifida can ensue.

26. Therapeutic Uses 1. Epilepsy
Valproic acid can be considered a first or second line therapy in all forms of epilepsy in all age groups.
It is the best drug available to control myoclonic seizures (results are good and sometimes excellent) and atonic seizures (results are sometimes rather good)
It is a first line agent (together with carbamazepine and phenytoin) for tonic-clonic seizures.

27. It is a first line agent (together with ethosuximide) in absence seizures (for uncomplicated absence seizures ethosuximide is preferred because of valproate hepatotoxicity)
It is the preferred drug in patients with absence seizures and concomitant grand mal seizures.
It is considered equally effective as carbamazepine in simple and complex partial seizures.
It is an alternative drug in infantile spasms and Lennox Gastaut syndrome.
Lennox–Gastaut syndrome (LGS), also known as Lennox syndrome, is a difficult-to-treat form of childhood-onset epilepsy that most often appears between the second and sixth year of life, and is characterized by frequent seizures and different seizure types; it is often accompanied by developmental delay and psychological and behavioral problems.
West syndrome or infantile spasms is a severe epilepsy syndrome composed of the triad of infantile spasms, an interictal electroencephalogram (EEG) pattern termed hypsarrhythmia, and mental retardation,

28. 2. Bipolar affective disorder
It is considered a drug of choice (together with lithium) for the therapy of acute mania and the prophylactic treatment of bipolar disorder, especially in rapid cycling patients.
3. Migraine prophylaxis
It has been approved by FDA for the prevention of migraine attack (mechanism is still uncertain).
There is no evidence that it might be useful in treatment of acute migraine attack.

29. 5. Ethosuximide Mechanism of action
Blockade of voltage-sensitive T type Ca++ channels in thalamic neurons
The T type Ca++ current is thought to provide a pacemaker current in thalamic neurons responsible for generating the rhythmic cortical discharge of an absence attack.

30. Pharmacological effects
Suppression of the oscillating discharge of the thalamic seizure focus.
Prevention of the spread of excitation through thalamocortical and corticothalamic circuits.
Other brain circuits are unaffected at therapeutic concentrations.
Pharmacokinetics
Biotransformation: 75% by the liver
Half-life: 45 hours

31. Therapeutic uses
It is the preferred drug in absence seizures (it prevents the attacks in more than 60% of patients and diminishes their frequency in 20-30% of patients).
The earlier is the treatment, the greater the efficacy of the therapy (best results are obtained if therapy is started within 1-3 months since the beginning of attacks).
It is considered a second choice drug in myoclonic and atonic seizures.

32. 6. Benzodiazepines
All benzodiazepines have antiseizure properties but some selectivity seems to exist since certain compounds, like clonazepam, appear more effective than others in specific seizure types.
Diazepam and clonazepam are the drugs most frequently used as anticonvulsants

33. Mechanism of action
Enhancement of GABA-induced increased frequency of bursts of openings of chloride channels.
Pharmacological effects
Prevention of the spread of excitation from seizure focus
All other effects of benzodiazepine class.

34. 7. Carbonic Anhydrase Inhibitors
Drugs
Acetazolamide is the drug most frequently used
Mechanism of action
Inhibition of carbonic anhydrase increases the CO2 content in the brain.
Decrease in tissue pH seems to inhibit Na+ entrance into the cells.
Anticonvulsant effects (which are similar to those of carbon dioxide) rapidly undergo tolerance.

35. Toxicity
Paresthesias, drowsiness (10%)
Nephrolithiasis
Hyperchloremic metabolic acidosis (with high doses)
Sulfonamide-type allergic reactions
Therapeutic uses
As an alternative drug in all type of seizures (efficacy is low and tolerance limit the use).
The drug may have special role in epileptic women with seizure exacerbation at the time of menses.

36. Second Generation Antiseizure Drugs

37. All second generation drugs are effective when taken in addition to another anti-seizure drug (adjuvant therapy).
All drugs can be used as second choice in tonic-clonic seizures
Most drugs can be used as first-choice in simple partial seizures
Some drugs can be used as first choice in generalized seizures:
Tonic clonic seizures (lamotigrine, topiramate, levetiracetam)
Absence seizure (lamotigrine)

38. 1. Lamotrigine Mechanism of action
The drug likely acts with multiple mechanisms, including:
Voltage- and frequency-dependent blockade of Na+ channels (most likely the main mechanism).
Blockade of voltage-gated Ca++ channels
Adverse effects
Generalized skin rash (8%, incidence, higher in children)
Severe rash and Sevens-Johnson syndrome (up to 0.8%).

39. 2. Topiramate Mechanism of action Likely multiple, including:
Blockade of voltage-gated Na+ and Ca++ channels
Potentiation of inhibitory effects of GABA at GABA-A receptors.

40. Adverse effects
Most common (10%) and dose-related: drowsiness, dizziness, fatigue, ataxia, aphasia, nystagmus, paresthesias.
Occasional: ocular hypertension, angle-closure glaucoma, metabolic acidosis.
Contraindications and precaution
Glaucoma, COPD, nephrolithiasis, porphyria.
Other uses
Migraine prophylaxis.

41. 3. Gabapentin Mechanism of action Still uncertain. It may involve:
Decreased release of glutamate from presynaptic terminals (most likely due to blockade of presynaptic voltage-gated Ca++ channels)
Adverse effects
Most common (10%) and dose-related: fatigue, drowsiness, dizziness, ataxia.
Abrupt discontinuation can cause a withdrawal reaction (anxiety, insomnia, sweating).
Other uses
Essential tremor.
Neuropathic pain (post-herpetic neuralgia).

42. 5. Levetiracetam Mechanism of action
Still uncertain. The drug binds selectively to a synaptic vesicular protein.
This can likely modify the synaptic release of glutamate and GABA.

43. 6. Tiagabine Mechanism of action
Inhibition of GABA reuptake in both neurons and glia, so enhancing GABAergic transmission.
Adverse effects
Most common (10%) and dose-related: nervousness, dizziness, fatigue, tremor.
Increased incidence of status epilepticus in patients with refractory partial epilepsy.

44. FDA Pregnancy Risk for Antiseizure Drugs
FDA Category
Carbamazepine D
Lamotrigine C
Phenytoin
Topiramate
Valproic acid
Levetiracetam
Phenobarbital
Felbamate
Clonazepam
Gabapentin
Ethosuximide
Tiagabine
Acetazolamide
Zonisamide