Comprehensive Study Notes on Antiseizure Agents

Overview of Epilepsy

• Definition and Prevalence:

  • Epilepsy is the most prevalent of the neurological disorders.

  • It is not classified as a single disease but rather as a chronic disorder characterized by seizures.

  • Loss of control during seizures can be highly frightening to patients.

• Nature of Seizures:

  • Description: A seizure is a sudden abnormal discharge of excessive electrical energy from nerve cells in the brain.

  • Signs and Symptoms: The specific signs and symptoms depend on the area of the brain affected by the electrical discharge.

  • Form of Seizures: The physical form a seizure takes is determined by the location of the cells involved and the specific neural pathways utilized.

  • Theories on Causation:

    • Impairment of cell membranes in specific neurons.

    • Structural differences in the brain.

    • Neurotransmitter imbalances: Higher amounts of Acetylcholine or a deficiency of Gamma-aminobutyric acid ($GABA$).

    • Genetic mutations.

  • General Pathophysiology: Most epilepsy cases appear to be caused by abnormal neurons that are either overly sensitive to stimulation or respond excessively.

• Primary vs. Secondary Seizures:

  • Primary Seizures: Seizures without an underlying identifiable cause.

  • Secondary Seizures: Seizures resulting from a known event or condition (e.g., trauma, infection, metabolic disturbance).

Classification of Seizures

• Importance of Classification: Identifying the specific seizure type is critical for determining the correct medication and treatment path.

• International League Against Epilepsy ($ILAE$) 2017 System:

  • The $ILAE$ developed a multilevel classification system based on the onset of the seizure.

• Basic Classification Categories:

  1. Focal Onset:

     • Aware: Patient remains conscious and aware.

     • Impaired Awareness: Patient's consciousness or awareness is compromised.

     • Motor Onset: Involves physical movement.

     • Nonmotor Onset: Does not involve movement.

     • Focal to Bilateral Tonic-Clonic: Starts in one area and spreads to both sides of the brain.

  2. Generalized Onset:

     • Motor:

       • Tonic-Clonic (formerly "Grand Mal").

       • Other motor types.

     • Nonmotor (Absence): (formerly "Petit Mal").

  3. Unknown Onset:

     • Motor: Includes tonic-clonic and other motor types.

     • Nonmotor: Absence-type seizures.

     • Unclassified: Seizures that do not fit other categories.

• Specific Types of Seizures:

  • Tonic-Clonic: Characterized by muscle rigidity (tonic phase) and rhythmic jerking (clonic phase).

  • Absence: Brief loss of consciousness without motor involvement.

  • Myoclonic: Short, muscle-jerk movements.

  • Febrile: Seizures triggered by a high fever, usually in children.

  • Atonic: Sudden loss of muscle tone ("drop attacks").

  • Status Epilepticus: A state of constant or repetitive seizure activity without recovery of consciousness between events, requiring emergency intervention.

Antiepileptic Agents Across the Lifespan

• Children:

  • Developmental Impact: Drugs can impact learning and social development.

  • Dosing: Usually based on age and weight; requires close monitoring and frequent adjustments.

  • Newborns ($1 \text{ to } 10 \text{ days old}$): Respond best to intramuscular ($IM$) Phenobarbital if an antiepileptic is required.

  • Transition to Adult Dosing: Drugs can often transition to standard adult doses after the age of $10 \text{ to } 14 \text{ years}$.

  • Support: Parents need education and community support to manage the emotional frightening experience of tonic-clonic seizures.

• Adults:

  • Monitoring: Regular care for adverse effects is necessary.

  • Safety: Patients should wear MedicAlert identification.

  • Lifestyle: Education is needed regarding seizure stigma and drug effects.

• Pregnancy and Lactation:

  • Registry: Patients are encouraged to enroll in the Antiepileptic Drug Pregnancy Registry.

  • Risks: Documented fetal risks exist for several medications; however, stopping medication can lead to seizures causing anoxia for both patient and fetus.

  • Contraception: Antiepileptics may decrease the efficacy of oral contraceptives.

  • Breast/Chestfeeding: Discouraged due to the potential for the drugs to cause sedation and Central Nervous System ($CNS$) effects in the infant.

• Older Adults:

  • Sensitivity: Increased susceptibility to adverse effects; lower dosages may be required.

  • Safety: Close monitoring for toxic effects and $CNS$ effects; wear MedicAlert identification.

  • Organ Function: Renal and hepatic function must be baselined and monitored; serum levels should be checked frequently.

Mechanisms and Sites of Action

• General Action: Stabilization of nerve membranes by blocking channels (Sodium/Calcium) or altering neurotransmitter receptor sites.

• Side Effects: Because they work broadly on the $CNS$, sedation is a primary effect.

• Subtype Specifics:

  • Barbiturates: Depress conduction in the brainstem, cortex, and cerebellum.

  • Benzodiazepines/Valproic Acid: Potentiate $GABA$ effects to inhibit neuron firing.

  • Hydantoins: Stabilize nerve membranes to inhibit cell firing.

  • Acetazolamide/Zonisamide: Alter $\text{Na}^{+}$ and $\text{Ca}^{2+}$ channels.

  • Serotonin/Melatonin (Zaleplon, Zolpidem, Ramelteon): Affect the Reticular Activating System ($RAS$).

Hydantoins

• Drugs: Phenytoin (Dilantin), Fosphenytoin (Cerebyx, Sesquient).

• Characteristics: Phenytoin is older and cost-effective; generally less sedating/dependency-forming than barbiturates or benzodiazepines.

• Therapeutic Actions:

  • Directly influence ionic channels to decrease neuronal excitability and hyperexcitability throughout the $CNS$.

  • Reduce tonic-clonic, muscular, and emotional responses to stimulation.

• Pharmacokinetics:

  • Phenytoin: Well absorbed from GI tract, metabolized in the liver, excreted in urine.

  • Phenytoin Therapeutic Serum Levels: $10–20 \text{ mcg/mL}$.

  • Fosphenytoin: Administered $IM$ or intravenously ($IV$). Peak serum level reached $10–20 \text{ min}$ after infusion.

• Contraindications and Cautions: Allergy, pregnancy/lactation, older/debilitated patients, impaired renal/liver function, coma, depression, or psychoses.

• Adverse Effects:

  • $CNS$ depression (most common).

  • Cellular toxicity: Severe liver toxicity, bone marrow suppression.

  • Gingival hyperplasia (overgrowth of gum tissue).

  • Dermatological reactions (potentially serious).

  • Frank malignant lymphoma.

• Drug-Drug Interactions: Alcohol and other $CNS$ depressants.

• Prototype Summary: Phenytoin

  • Indications: Control of tonic-clonic and psychomotor seizures; prevention of neurosurgery seizures; control of status epilepticus.

  • Actions: Neuronal membrane stabilization, prevents hyperexcitability, limits spread of activity. Has lidocaine-like cardiac antiarrhythmic effects.

  • Kinetics (Oral): Onset: Slow; Peak: $2–12 \text{ h}$; Duration: $6–12 \text{ h}$.

  • Kinetics (IV): Onset: $1–2 \text{ h}$; Peak: Rapid; Duration: $12–24 \text{ h}$.

  • Half-life ($T_{1/2}$): $6 \text{ to } 24 \text{ hours}$.

  • Specific Toxicities: Ataxia, dysarthria, slurred speech, mental confusion, Stevens-Johnson syndrome, nystagmus (at high doses).

Barbiturates and Barbituratelike Drugs

• Drugs: Phenobarbital (Solfoton, Luminal), Primidone (Mysoline).

• Therapeutic Actions:

  • Inhibit impulse conduction in ascending $RAS$.

  • Depress cerebral cortex, alter cerebellar function, and depress motor nerve output.

  • Stabilize nerve membranes by influencing ionic channels to decrease excitability.

• Pharmacokinetics:

  • Phenobarbital: Well absorbed from GI tract, liver metabolism, urine excretion. Features slow onset but very long duration.

  • Primidone: Similar to phenobarbital but with a longer half-life.

• Adverse Effects:

  • Significant $CNS$ depression (somnolence, vertigo, lethargy).

  • Physical dependence and withdrawal syndrome.

  • Drug tolerance.

  • Severe dermatological reactions.

  • Bradycardia, hypotension, and respiratory depression.

• Drug-Drug Interactions: Alcohol, other $CNS$ depressants, Warfarin, Vitamins $K$ and $D$.

• Prototype Summary: Phenobarbital

  • Indications: Long-term tonic-clonic and focal seizures; emergency control for status epilepticus, tetanus, eclampsia, or meningitis.

  • Kinetics: Oral onset: $30–60 \text{ min}$. $IV$ onset: $5 \text{ min}$.

  • Half-life ($T_{1/2}$): $79 \text{ hours}$.

Benzodiazepines

• Drugs: Clobazam (Onfi, Sympazan), Clonazepam (Klonopin), Diazepam (Valium).

• Therapeutic Actions: Potentiate $GABA$ effects, cause muscle relaxation, and relieve anxiety.

• Pharmacokinetics (Diazepam): Oral, rectal, $IM$, and $IV$ forms exist. Long half-life.

• Adverse Effects: $CNS$ depression, apathy, fatigue, urinary retention, incontinence, drug dependence/withdrawal syndrome.

• Drug-Drug Interactions: Alcohol, $CNS$ depressants, and Opioids.

• Prototype Summary: Diazepam

  • Kinetics ($IV$): Onset: $1–5 \text{ mins}$. Peak: $15–60 \text{ min}$.

  • Half-life ($T_{1/2}$): $20 \text{ to } 80 \text{ hours}$.

Succinimides

• Usage: Frequently used for absence seizures.

• Drugs: Ethosuximide (Zarontin) - usually tried first; Methsuximide (Celontin).

• Therapeutic Actions: Suppress abnormal electrical activity via inhibitory neural pathways.

• Adverse Effects: $CNS$ depression, Bone marrow suppression, nausea/vomiting, Stevens-Johnson syndrome, and pancytopenia.

• Interactions: Decreases serum levels of Primidone.

• Prototype Summary: Ethosuximide

  • Indications: Control of absence seizures.

  • Peak: $3–7 \text{ h}$.

  • Half-life ($T_{1/2}$): $30 \text{ hours}$ in children; $60 \text{ hours}$ in adults.

GABA Modulators

• Drugs: Valproic acid, Divalproex (Depakote), Acetazolamide (Diamox), Zonisamide (Zonegran).

• Specific Actions:

  • Valproic acid/Divalproex: Increase $GABA$ activity.

  • Acetazolamide: Alters electrolyte movement.

  • Zonisamide: Inhibits voltage-sensitive sodium and calcium channels.

• Adverse Effects:

  • Valproic acid/Divalproex: Liver toxicity, pancreatitis, thrombocytopenia, hyperammonemia, birth defects, and DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms).

  • Zonisamide: Renal calculi (stones), bone marrow suppression.

• Prototype Summary: Valproic Acid

  • Indications: Drug of choice for myoclonic seizures; absence seizures; mania, migraine, complex focal seizures.

  • Half-life ($T_{1/2}$): $9 \text{ to } 16 \text{ hours}$.

Other Medications for Generalized Seizures

• Carbamazepine:

  • Indications: Generalized/focal seizures, trigeminal neuralgia.

  • Warnings: Boxed warning for serious dermatological reactions and aplastic anemia.

  • Interactions: CYP3A4 inhibitors/inducers, Topiramate.

• Lamotrigine:

  • Warnings: Boxed warning for life-threatening rashes; risk of aseptic meningitis.

• Levetiracetam:

  • Metabolism: Very little metabolism; most is excreted unchanged in urine.

  • Caution: Pregnancy may decrease serum levels.

• Topiramate:

  • Mechanism: Possibly blocks sodium channels, increases $GABA$, and inhibits glutamate.

  • Adverse Effects: Metabolic acidosis, angle closure glaucoma.

Drugs for Focal Seizures

• General Action: Stabilize nerve membranes via sodium/calcium channel alteration or $GABA$ activity increase.

• Fertility Caution: In animal studies, males receiving Pregabalin showed decreased fertility and associated birth defects.

• Prototype Summary: Gabapentin (Neurontin)

  • Indications: Focal onset seizures, postherpetic neuralgia.

  • Action: May bind to voltage-activated calcium channels; related to $GABA$ but does not affect $GABA$ levels.

  • Half-life ($T_{1/2}$): $5 \text{ to } 7 \text{ hours}$.

  • Bioavailability: Percentage decreases as dose increases.

Questions & Discussion

• Question 1: What drug is a hydantoin and may be the drug of choice for patients who are unable to tolerate the side effects of drowsiness and sedation?

  • Response: B. Phenytoin. Rationale: Hydantoins like phenytoin are generally less sedating compared to other classes used for generalized seizures.

• Question 2: The use of succinimides with a specific drug may cause decreased serum levels. Which of the following would require careful monitoring for this?

  • Options: Zarontin, Clonazepam, Valium, Primidone.

  • Response: D. Primidone. Rationale: Using succinimides with primidone may cause a decrease in primidone serum levels, requiring dose adjustments.