Antiepileptic Drugs Part 2 PDF

# Part 2-1 ## Antiepileptic Drugs **AM Fouda MD, PhD** Professor of Clinical Pharmacology Mansoura University Faculty of Medicine Egypt 35516 [email protected] # Epilepsy and Antiepileptic Drugs ## Epilepsy - **Focal** - Preserved awareness - Lost awareness - Secondary Generali...

# Part 2-1 ## Antiepileptic Drugs **AM Fouda MD, PhD** Professor of Clinical Pharmacology Mansoura University Faculty of Medicine Egypt 35516 [email protected] # Epilepsy and Antiepileptic Drugs ## Epilepsy - **Focal** - Preserved awareness - Lost awareness - Secondary Generalization - **Generalized** - Absence Seizures - Tonic-clonic Seizures - Myoclonic Seizures ## Mechanisms of Action - **Enhance GABA Inhibition** - T-type Ca2+ Channels - **Block Excitatory Transmitters** - Glutamate - Aspartate - NMDA - Na+ Channels ## Classification of Antiepileptic Drugs according to Mechanism of Action | Group | Drugs | |---|---| | Enhance GABA Inhibition | Phenobarbital, Benzodiazepines, Vigabatrin, Tiagabine | | Block Excitatory Transmitters | Felbamate, Topiramate | | Block Neuronal Na+ Channels | Phenytoin, Carbamazepine, Lamotrigine | | Block T-type Ca+ Channels | Ethosuximide | | Mixed or Unknown | Valproic Acid, Levetiracetam, Gabapentin | ## Classification of Antiepileptic Drugs according to Therapeutic Uses | Seizure Type | Drugs | |---|---| | Focal Seizures | Carbamazepine, Lamotrigine | | Absence Seizures | Ethosuximide, Valproic Acid, Clonazepam | | Tonic-clonic Seizures | Phenytoin, Valproic Acid, Lamotrigine, Phenobarbital | | Myoclonic Seizures | Valproic Acid, Lamotrigine | ## Classification of Antiepileptic Drugs according to Generation - **First Generation (Classic) Drugs** - Phenytoin - Carbamazepine - Valproic Acid - Ethosuximide - Phenobarbital - Benzodiazepines - **Second Generation (Newer) Drugs** - Vigabatrin (1989) - Lamotrigine (1991) - Topiramate (1995) & Felbamate - Levetiracetam (2000) - Gabapentin & Pregabalin (2005) - Tiagabine (1998) ## First Generation (Classic) Drugs ### 1. Phenytoin (Diphenylhydantoin) | Category | Description | |---|---| | Mechanism | Blocks Na+ Channels (brain and heart) | | Therapeutic Uses | Tonic-clonic Seizures, Class I Antiarrhythmic | | Adverse Effects | CNS: NDA (nystagmus, diplopia, ataxia), Liver: micr enz induction, Blood: megaloblastic anemia (due to folic a. metabolism), Teratogenic: Craniofacial anomalies (fetal hydantoin syndrome), Neural tube defect (spina bifida), Gingival hyperplasia, Lymphadenopathy, Hirsutism, Osteomalacia due to ↑ vit D metabolism | | Important Points | Zero-order elimination, Fosphenytoin is a water-soluble prodrug; it can be used parenterally | ### 2. Carbamazepine (Tegretol) | Category | Description | |---|---| | Mechanism | Blocks Na+ Channels (brain) | | Therapeutic Uses | 1st line in Focal Seizures, 2nd line in Tonic-clonic Seizures, Trigeminal Neuralgia | | Adverse Effects | CNS: NDA (nystagmus, diplopia, ataxia), Liver: micr enz induction, Blood: megaloblastic anemia (due to ↑ folic a. metabolism), Teratogenic: Craniofacial anomalies (cleft palate), Neural tube defect (spina bifida), Increase ADH secretion → hyponatremia & edema | | Important Points | Induces its own metabolism (autoinduction) | ### 3. Valproic Acid (Depakin) | Category | Description | |---|---| | Mechanism | Mixed mechanisms: Inhibits GABA transaminase→↑ GABA↓ neuronal firing, Blocks Na+ Channels, Blocks Ca2+ Channels | | Therapeutic Uses | ALL types of seizures (focal & generalized) | | Adverse Effects | CNS: NDA (nystagmus, diplopia, ataxia), Liver: micr enz inhibition, Blood: neutropenia., Teratogenic: Craniofacial anomalies, Neural tube defect (spina bifida), Alopecia, Pancreatitis, Fulminant hepatic toxicity (rare but fatal) | | Important Points | Has higher risk of major congenital malformation than other antiepileptics, N.B. Phenytoin → hirsutism Valproic → alopecia | ### 4. Ethosuximide | Category | Description | |---|---| | Mechanism | Blocks T-type Ca2+ channels in thalamocortical neurons | | Therapeutic Uses | First line drug for Absence seizures | | Adverse Effects| GIT upset, Headache, dizziness | | Important Points | The LEAST toxic antiepileptic drug | ### 5. Phenobarbital | Category | Description | |---|---| | Mechanism | 1. Allosteric modulation of GABA-A receptors, 2. GABA-like action (=GABA agonist) | | Therapeutic Uses | 1. Tonic-clonic seizures, 2. Status epilepticus | | Adverse Effects | 1. CNS: NDA (nystagmus, diplopia, ataxia), 2. Liver: micr enz induction, 3. Blood: megaloblastic anemia (due to ↑ folic a. metabolism), 4. Teratogenic: Craniofacial anomalies, Neural tube defect, 5. Tolerance & physical dependence, 6. Respiratory depression in toxic doses | | Important Points | Its use is limited by its many adverse effects | ### 6. Benzodiazepines | Category | Description | |---|---| | Mechanism | Allosteric modulation of GABA-A receptors | | Therapeutic Uses | 1. First line in Status epilepticus, 2. First line in Febrile convulsions in children, 3. Absence seizures | | Adverse Effects | 1. Tolerance & physical dependence, 2. Memory disturbance | | Important Points | Its use in absence seizures is limited by its many adverse effects | ## Second Generation (Newer) Drugs ### 1. Vigabatrin | Category | Description | |---|---| | Mechanism | Inhibits GABA transaminase irreversibly →↑ GABA | | Therapeutic Uses | 1. Focal seizures only, 2. Infantile spasms (West syndrome) | | Adverse Effects | Irreversible visual loss (40% of patients) Vi = Vision | | Important Points | It is usually reserved for patients with seizures refractory to other drugs. Visual fields should be checked every 6 months | ### 2. Lamotrigine | Category | Description | |---|---| | Mechanism | 1. Block Na+ channels, 2. ↓ glutamate release | | Therapeutic Uses | ALL types of seizures (focal & generalized) | | Adverse Effects | 1. Skin rash and Stevens-Johnson syndrome (the risk of SJS is high if combined with valproic acid), 2. Insomnia | | Important Points | - It is now one of the most widely prescribed drugs for focal seizures, - Preferred in pregnancy due to low teratogenic potential | ### 3. Topiramate | Category | Description | |---|---| | Mechanism | 1. Block Na+ channels, 2. ↑ GABA, 3. Blocks AMPA/kinate receptors | | Therapeutic Uses | ALL types (Focal and generalized) seizures, 2. Migrain prophylaxis | | Adverse Effects | 1. ↑ IOP (glaucoma), 2. Renal stones, 3. Teratogenic → Cleft palate, 4. Weight loss →↓ body fat mass | | Important Points | | ### 4. Levetiracetam | Category | Description | |---|---| | Mechanism | Binds to SV2A, a synaptic vesicle protein, →↓ glutamate release | | Therapeutic Uses | ALL types (Focal and generalized) seizures | | Adverse Effects | Very low | | Important Points | - Broad spectrum, - Low toxicity, - Favorable pharmacokinetic profile, - No drug interactions | ## Adjuvant Drugs ### 5. Gabapentin and Pregabalin | Category | Description | |---|---| | Mechanism | Inhibition of presynaptic P/Q-type Ca2+ channels via action on the a2δ subunit →↓ Ca2+ influx ↓ glutamate release | | Therapeutic Uses | 1. As adjuvant drugs in focal seizures, 2. Neuropathic pain | | Adverse Effects | 1. Sedation, 2. Physical dependence | | Important Points | | ### 6. Tiagabine | Category | Description | |---|---| | Mechanism | Inhibits GABA reuptake --> ↓ GABA conc | | Therapeutic Uses | As adjuvant drugs in focal seizures | | Adverse Effects | GIT upset, Dizziness | | Important Points | | ## Choice of AEDs | Seizure Type | 1st Line | 2nd Line | 3rd Line | |---|---|---|---| | Focal (partial) seizures | Carbamazepine | Lamotrigine, Valproic Acid | Levetiracetam | | Generalized tonic-clonic seizures | Valproic Acid | Lamotrigine, Carbamazepine | Childhood absence seizures | Ethosuximide | Valproic Acid, Lamotrigine | Clonazepam | | Myoclonic Seizures | Valproic Acid | Lamotrigine | Levetiracetam | | Seizures in Pregnancy | Lamotrigine OR Levetiracetam | | | | Status epilepticus | Diazepam IV (adult) - Rectal (children) | Fosphenytoin, Levetiracetam | | ## Guidelines - Start antiepileptic drugs (AEDs) following a second epileptic seizure. - Therapy should be started with ONE drug (monotherapy): - if failed, SUBSTITUTE with another drug. - if failed, use combination of 2 drugs. - Combination of valproic acid + lamotrigine --> Stevens-Johnson's syndrome - Stopping of AEDs can be considered if seizure free for > 2 years, with AEDs being stopped over 2-3 months. ## AEDs in Pregnancy and Breast Feeding - Around 1-2% of newborns born to non-epileptic mothers have congenital defects. This rises to 3-4% if the mother takes antiepileptic medication. - The risks of uncontrolled epilepsy during pregnancy generally outweigh the risks of medication to the fetus, so her drug should be continued. - Pregnant should be advised to take folic acid 5 mg/day well before pregnancy to minimize the risk of neural tube defects. - Best drugs in pregnancy: lamotrigine - levetiracetam - Breast feeding is acceptable with nearly ALL anti-epileptic drugs.