Antiepileptic Drugs Part 2 PDF
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Uploaded by TranquilLarimar
Mansoura University Faculty of Medicine
AM Fouda MD, PhD
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Summary
This document discusses antiepileptic drugs, covering their mechanisms of action, classifications, and therapeutic uses. It details the different types of seizures and how various antiepileptic drugs are used for treating them. The document also explores the different generations of these drugs.
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# 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.