Second-Generation Anticonvulsant Drugs

Anticonvulsant Anticonvulsant Anticonvulsant drugs are pharmacological agents used to achieve seizure control and/or prevent seizure episodes. Anticonvulsants encompass various drugs with different mechanisms of action including ion-channel (Na+ and Ca+2) blocking and GABA reuptake inhibition. First-Generation Anticonvulsant Drugs drugs are pharmacological agents used for seizure control and/or to prevent seizure episodes. Anticonvulsants encompass various drugs with different mechanisms of action, including ion-channel (Na+, calcium) blocking and inhibition of GABA reuptake. Second-generation anticonvulsants exert their effects via these mechanisms and are associated with good efficacy, fewer toxic effects, and better tolerability, and generally do not require blood level monitoring. Medications in this class include felbamate, gabapentin, pregabalin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, zonisamide, and lacosamide. Anticonvulsant Anticonvulsant Anticonvulsant drugs are pharmacological agents used to achieve seizure control and/or prevent seizure episodes. Anticonvulsants encompass various drugs with different mechanisms of action including ion-channel (Na+ and Ca+2) blocking and GABA reuptake inhibition. First-Generation Anticonvulsant Drugs drugs are indicated for focal seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, generalized tonic-clonic seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, myoclonic seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, and Lennox-Gastaut syndrome. Some anticonvulsants are also indicated in conditions unrelated to seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures (e.g., bipolar disorder Bipolar disorder Bipolar disorder is a highly recurrent psychiatric illness characterized by periods of manic/hypomanic features (distractibility, impulsivity, increased activity, decreased sleep, talkativeness, grandiosity, flight of ideas) with or without depressive symptoms. Bipolar Disorder). The most common adverse effects include dizziness, headache, and somnolence.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definitions

Antiseizure drugs (ASDs) are used to suppress abnormal electrical activity in the brain through various mechanisms.

  • Seizures are episodes of neurologic dysfunction caused by uncontrolled, abnormal neuronal activity in the brain and are characterized by sudden changes in senses, perception, motor activity, or behavior.
  • Epilepsy Epilepsy Epilepsy is a chronic brain disorder marked by recurrent and unprovoked seizures. These seizures can be classified as focal or generalized and idiopathic or secondary to another condition. Clinical presentation correlates to the classification of the epileptic disorder. Epilepsy is a condition with an enduring risk of recurrent unprovoked seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures (at least 2 or more episodes occurring > 24 hours apart).

Pathophysiology of seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures

The hyperexcitable state of neurons results from 3 steps:

  • Paroxysmal depolarization shifts:
    • ↑ Excitatory synaptic neurotransmission Neurotransmission The junction between 2 neurons is called a synapse. The synapse allows a neuron to pass an electrical or chemical signal to another neuron or target effector cell. The plasma membranes of the 2 neurons are placed very close together, and the space between the 2 neurons is called the synaptic cleft. The molecules that mediate the interaction are called neurotransmitters. Synapses and Neurotransmission
    • Glutamate is the most abundant excitatory neurotransmitter.
      • ↑ Na+ and calcium (Ca2+) influx through glutamate-gated channels (and in the process, K+ goes out of the cell)
      • Other receptors trigger the release of intracellular Ca2+ stores → increase in intracellular Ca2+
      • Generation of repetitive action potentials
  • Increased excitation of surrounding neurons:
    • Repeated depolarization → ↑ extracellular K+
    • Elevated K+ drives the depolarization of surrounding neurons.
  • Failure to inhibit excitatory feedback circuit:
    • Excess glutamate stimulation
    • Loss of refractory period occurs (where neurons are unable to generate action potentials).
    • Decreased activity of GABA:
      • Main inhibitory neurotransmitter in the brain
      • Defects in GABA activation or inhibition → seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures

Second-generation antiseizure drugs

  • Newer drugs with good efficacy, fewer toxic effects, better tolerability; no blood-level monitoring required
  • Can have a combination of mechanisms of action
  • Some of these drugs may also be used as monotherapy or adjunctive therapy.
  • As with 1st-generation ASDs, the use of newer medications has been associated with increased suicidal ideation.
  • Medications in this class:
    • Felbamate
    • Gabapentin
    • Pregabalin
    • Lacosamide
    • Lamotrigine
    • Levetiracetam
    • Oxcarbazepine
    • Perampanel
    • Tiagabine
    • Topiramate
    • Vigabatrin
    • Zonisamide

Felbamate

Chemistry and pharmacodynamics

  • Dicarbamate derivative
  • Mechanism of action: blocks the channel at the N-methyl-D-aspartate (NMDA) excitatory receptor (a binding site for glutamate)
Felbamate

Chemical structure of felbamate

Image: “Felbamate” by Harbin. License: Public Domain

Pharmacokinetics

  • Oral, with rapid and almost complete absorption
  • Food does not affect absorption.
  • Half-life: 20–23 hours
  • Hepatic metabolism (cytochrome P450 (CYP) system: primarily CYP3A4)
  • Excretion: urine (50% excreted unchanged)

Indications

  • Partial seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Lennox-Gastaut syndrome

Adverse effects and contraindications

  • Adverse effects:
    • Aplastic anemia Aplastic Anemia Aplastic anemia (AA) is a rare, life-threatening condition characterized by pancytopenia and hypocellularity of the bone marrow (in the absence of any abnormal cells) reflecting damage to hematopoietic stem cells. Aplastic anemia can be acquired or inherited, however, most cases of AA are acquired and caused by autoimmune damage to hematopoietic stem cells. Aplastic Anemia
    • Hepatic failure
    • Anorexia, nausea, vomiting
    • Drowsiness, headache, irritability
  • Contraindications:
    • Hypersensitivity to the drug
    • Blood dyscrasias
    • Hepatic dysfunction
  • Precautions:
    • Not the 1st-line therapy for seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
    • Indicated only for individuals showing inadequate response to alternative ASDs

Gabapentin and Pregabalin

Chemistry and pharmacodynamics

  • Gabapentin: structurally similar to GABA, bound to a lipophilic cyclohexane ring
  • Pregabalin:
    • Chemically related to GABA
    • GABA molecule bound to isobutane
  • Mechanism of action:
    • ↓ Excitatory transmission by acting on the voltage-gated Ca2+ channels (?2? subunit) presynaptically
    • No binding to GABA receptors
Chemical structure of pregabalin

Chemical structure of pregabalin

Image: “Pregabalin” by Harbin. License: Public Domain

Pharmacokinetics and indications

Table: Gabapentin and pregabalin pharmacokinetics and indications
Drug Pharmacokinetics Indications
Gabapentin
  • Oral
  • Not bound to plasma proteins
  • Half-life: approximately 6 hours
  • Not metabolized
  • Excreted unchanged in urine
  • Focal (partial) seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Postherpetic neuralgia
Pregabalin
  • Focal (partial) seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Others:
    • Fibromyalgia Fibromyalgia Fibromyalgia is a chronic pain syndrome characterized by widespread body pain, chronic fatigue, mood disturbance, and cognitive disturbance. It also presents with other comorbid symptoms such as migraine headaches, depression, sleep disturbance, and irritable bowel syndrome. Fibromyalgia
    • Neuropathic pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
    • Postherpetic neuralgia

Adverse effects and contraindications

  • Adverse effects:
    • Somnolence, dizziness, ataxia
    • Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
    • Angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema, anaphylaxis
    • Infection
    • Gabapentin may exacerbate myasthenia gravis Myasthenia Gravis Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by weakness and fatigability of skeletal muscles caused by dysfunction/destruction of acetylcholine receptors at the neuromuscular junction. MG presents with fatigue, ptosis, diplopia, dysphagia, respiratory difficulties, and progressive weakness in the limbs, leading to difficulty in movement. Myasthenia Gravis.
  • Contraindications:
    • Drug hypersensitivity
    • Both drugs are pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care category C.

Lacosamide

Chemistry and pharmacodynamics

  • Amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids (L-serine) derivative
  • Mechanism of action: enhances slow inactivation of voltage-dependent Na+ channels without affecting the fast inactivation phases
Chemical structure of lacosamide

Chemical structure of lacosamide

Image: “Lacosamide” by Fvasconcellos. License: Public Domain

Pharmacokinetics

  • Oral, with complete absorption; IV
  • Half-life: approximately 13 hours
  • Hepatic metabolism (CYP)
  • Excretion: urine

Indications

  • Focal (partial) seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Primary generalized tonic-clonic seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures

Adverse effects and contraindications

  • Adverse effects:
    • Prolonged PR interval, cardiac arrhythmias
    • Blurred vision, diplopia
    • Dizziness, drowsiness, headache
    • Nausea
  • Contraindications:
    • Hypersensitivity to the drug
    • 2nd- or 3rd-degree atrioventricular block Atrioventricular block Atrioventricular (AV) block is a bradyarrhythmia caused by delay, or interruption, in the electrical conduction between the atria and the ventricles. Atrioventricular block occurs due to either anatomic or functional impairment, and is classified into 3 types. Atrioventricular Block

Lamotrigine

Chemistry and pharmacodynamics

  • Phenyltriazine derivative
  • Mechanisms of action:
    • Inhibition of voltage-sensitive Na+ channels
    • Inhibition of glutamate release
Chemical structure of lamotrigine

Chemical structure of lamotrigine

Image: “Lamotrigine” by Harbin. License: Public Domain

Pharmacokinetics

  • Oral, almost completely absorbed (90%)
  • Half-life: up to 33 hours
  • 55% bound to plasma proteins
  • Hepatic metabolism
  • Excretion: urine

Indications

  • Focal (partial)-onset seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Generalized-onset seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Lennox-Gestaut syndrome
  • Bipolar disorder (as maintenance therapy)

Adverse effects and contraindications

  • Adverse effects:
    • Dizziness, headache
    • Nausea, vomiting
    • Blurred vision, diplopia
    • Rash (with potential to escalate to Stevens–Johnson syndrome)
    • Aseptic meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis
    • Blood dyscrasias
    • Arrhythmias
  • Contraindications: hypersensitivity to the drug
  • Precautions in:
    • Cardiac conduction disorders
    • Structural cardiac disease

Levetiracetam and Brivaracetam

Chemistry and pharmacodynamics

  • Chemistry:
    • Levetiracetam: pyrrolidine derivative
    • Brivaracetam: levetiracetam analog
  • Mechanism of action: binds the synaptic protein SV2A, affecting neuronal excitability (↓ SV2A → ↓ action potential-dependent neurotransmission Neurotransmission The junction between 2 neurons is called a synapse. The synapse allows a neuron to pass an electrical or chemical signal to another neuron or target effector cell. The plasma membranes of the 2 neurons are placed very close together, and the space between the 2 neurons is called the synaptic cleft. The molecules that mediate the interaction are called neurotransmitters. Synapses and Neurotransmission)
Chemical structure of levetiracetam

Chemical structure of levetiracetam

Image: “Levetiracetam” by Harbin. License: Public Domain

Pharmacokinetics and indications

Table: Pharmacokinetics and indications for levetiracetam vs brivaracetam
Drug Pharmacokinetics Indications
Levetiracetam
  • Oral, almost complete absorption
  • Half-life: 6–8 hours
  • Not bound to plasma proteins
  • Minimal metabolism by hydrolysis to an inactive metabolite
  • Excretion: approximately 66% excreted unchanged in urine
  • Focal (partial) seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Generalized-onset juvenile myoclonic epilepsy
  • Generalized tonic-clonic seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
Brivaracetam
  • Oral, almost complete absorption
  • Half-life: 9 hours
  • Metabolism by hydrolysis to an inactive metabolite
  • Excretion: urine
Focal (partial) seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures

Adverse effects and contraindications

  • Adverse effects:
    • Fatigue
    • Dizziness, somnolence
    • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
    • Upper respiratory infection
    • Vomiting
    • Brivaracetam: psychiatric symptoms (e.g., psychosis), leukopenia
  • Contraindications: hypersensitivity to the drug

Oxcarbazepine

Chemistry and pharmacodynamics

  • Chemically related to carbamazepine
  • Effects are from the drug as well as the monohydroxy metabolite.
  • Mechanisms of action:
    • Blocking of voltage-sensitive Na+ channels
    • Also known to ↑ K+ conductance and modulate high-voltage Ca+2-channel activity

Pharmacokinetics

  • Oral, with complete absorption
  • Half-life: 8–10 hours
  • Extensive hepatic metabolism (to its active metabolite)
  • Excretion: urine

Indications

Oxcarbazepine is indicated in focal (partial)-onset seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures.

Adverse effects and contraindications

  • Adverse effects:
    • Blood dyscrasias
    • ↓ Bone mineral density (osteopenia, osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis)
    • Cognitive symptoms, somnolence, dizziness
    • Hepatic dysfunction
    • Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia
    • Hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto's disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism
    • Hypersensitivity reactions
    • Vomiting
  • Contraindication: hypersensitivity to the drug

Perampanel

Chemistry and pharmacodynamics

  • Pyridone derivative
  • Mechanism of action: noncompetitive antagonist of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor
Chemical structure of perampanel

Chemical structure of perampanel

Image: “Perampanel” by Meodipt. License: Public Domain

Pharmacokinetics

  • Oral, with complete absorption
  • Half-life: approximately 105 hours
  • Hepatic metabolism via CYP3A
  • Excretion: feces > urine

Indications

  • Focal (partial) seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Primary generalized tonic-clonic seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures

Adverse effects and contraindications

  • Adverse effects:
    • Severe psychiatric or behavioral changes (e.g., homicidal ideation, aggression, irritability, hostility)
    • Dizziness, fatigue
    • Rash
    • Weight gain, edema
    • Nausea, vomiting
  • Contraindications: hypersensitivity to the drug

Rufinamide

Chemistry and pharmacodynamics

  • Triazole derivative
  • Not related to other ASDs
  • Mechanism of action:
    • Modulating Na+-channel activity (prolonging or enhancing slow inactivation), reducing repetitive firing
    • Increasing the inactive state of channels
Chemical structure of rufinamide

Chemical structure of rufinamide

Image: “Rufinamide” by Vaccinationist. License: Public Domain

Pharmacokinetics

  • Oral, with slow absorption
  • Half-life: 6–10 hours
  • Metabolized by hydrolysis to an inactive metabolite (independent of CYPs)
  • Excretion: urine

Indications

Rufinamide is indicated in the adjunctive treatment of Lennox-Gestaut syndrome.

Adverse effects and contraindications

  • Adverse effects:
    • Shortened QT interval
    • Headache
    • Cognitive symptoms, coordination abnormalities
    • Rash
    • Vomiting
  • Contraindications:
    • Familial short QT syndrome or history of short QT
    • Hypersensitivity to the drug

Stiripentol

Chemistry and pharmacodynamics

  • Aromatic alcohol
  • Unrelated to other ASDs
  • Mechanism of action:
    • Modulates GABA-A receptor, enhancing inhibitory neurotransmission Neurotransmission The junction between 2 neurons is called a synapse. The synapse allows a neuron to pass an electrical or chemical signal to another neuron or target effector cell. The plasma membranes of the 2 neurons are placed very close together, and the space between the 2 neurons is called the synaptic cleft. The molecules that mediate the interaction are called neurotransmitters. Synapses and Neurotransmission
    • Inhibitory effect on CYP enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes, reducing the metabolism of other ASDs

Pharmacokinetics

  • Oral, well absorbed
  • Half-life: 13 hours
  • Hepatic metabolism
  • Excretion: urine

Indications

Stiripentol is indicated in the management of Dravet syndrome (previously known as severe myoclonic epilepsy in infancy).

Adverse effects and contraindications

  • Adverse effects:
    • Drowsiness
    • Behavioral changes, suicidal ideation
    • Anorexia, weight loss
  • Contraindication: hypersensitivity to the drug

Tiagabine

Chemistry and pharmacodynamics

  • Lipophilic analog of nipecotic acid
  • Mechanism of action: enhances GABA activity by inhibiting GABA reuptake
Chemical structure of tiagabine

Chemical structure of tiagabine

Image: “Tiagabine” by Fvasconcellos. License: Public Domain

Pharmacokinetics

  • Oral, rapid absorption
  • Half-life: 7–9 hours
  • Hepatic metabolism (CYP system)
  • Excretion: mostly feces

Indications

Tiagabine is indicated for the adjunctive treatment of focal (partial) seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures.

Adverse effects and contraindications

  • Adverse effects:
    • Dizziness, somnolence
    • Fatigue
    • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
    • Dermatologic reactions
  • Contraindication: hypersensitivity to the drug

Topiramate

Chemistry and pharmacodynamics

  • Topiramate: a monosaccharide structure containing sulfamate
  • Mechanism of action:
    • Blocks the voltage-dependent Na+ channels in neurons
    • Amplifies GABA-A activity
    • Antagonizes NMDA-glutamate receptors
    • Inhibits carbonic anhydrase (↑ hydrogen ions in the cell + ↓ pH leading to the extracellular shift of K+ → hyperpolarization and ↑ seizure threshold)
Chemical structure of topiramate

Chemical structure of topiramate

Image: “Topiramate” by UnicornFightCluba. License: Public Domain

Pharmacokinetics

  • Oral, rapid absorption
  • Half-life: up to 23 hours
  • Minimal hepatic metabolism
  • Excretion: urine

Indications

  • Focal (partial) seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Primary generalized tonic-clonic seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Adjunctive therapy for Lennox-Gastaut syndrome
  • Migraine prophylaxis

Adverse effects and contraindications

  • Adverse effects:
    • Kidney stones
    • Hepatic impairment
    • Cognitive impairment, sedation, dizziness
    • Depression and mood-related effects
    • Weight loss
  • Contraindications:
    • Hypersensitivity to the drug
    • Pregnancy

Vigabatrin

Chemistry and pharmacodynamics

  • Structural analog of GABA (but does not bind to GABA receptors)
  • Mechanism of action: inhibits GABA transaminase irreversibly (GABA uptake inhibitor)

Pharmacokinetics

  • Oral, completely absorbed
  • Half-life: approximately 11 hours
  • Minimal metabolism
  • Excretion: urine

Indications

  • Infantile spasms
  • Refractory complex partial seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures

Adverse effects and contraindications

  • Adverse effects:
    • Permanent vision loss
    • Dizziness, drowsiness
    • Peripheral neuropathy
    • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview
    • Rash
    • Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation, vomiting
  • Contraindication:
    • Hypersensitivity to the drug
    • Pregnancy

Zonisamide

Chemistry and pharmacodynamics

  • Sulfonamide Sulfonamide The sulfonamides are a class of antimicrobial drugs inhibiting folic acid synthesize in pathogens. The prototypical drug in the class is sulfamethoxazole. Although not technically sulfonamides, trimethoprim, dapsone, and pyrimethamine are also important antimicrobial agents inhibiting folic acid synthesis. The agents are often combined with sulfonamides, resulting in a synergistic effect. Sulfonamides and Trimethoprim derivative
  • Mechanism of action: decreases high-frequency firing by blocking the voltage-gated Na+ channels and T-type Ca+2 channels
Chemical structure of zonisamide

Chemical structure of zonisamide

Image: “Zonisamide” by Fvasconcellos. License: Public Domain

Pharmacokinetics

  • Oral, complete absorption
  • Half-life: 1–3 days
  • Hepatic metabolism
  • Excretion: mostly urine

Indications

Zonisamide is indicated for the adjunctive therapy of focal (partial) seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures.

Adverse effects and contraindications

  • Adverse effects:
    • Cognitive and behavioral changes
    • ↑ Ammonia, encephalopathy
    • Metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis
  • Contraindication: hypersensitivity to the drug

Comparison of 2nd-Generation Antiseizure Drugs

Antiseizure drugs and mechanisms

Table: Antiseizure drugs and mechanisms
Site/factor affected Main mechanism of action Drugs
Na+ channels Inhibition of voltage-sensitive Na+ channels
  • Lamotrigine*
  • Oxcarbazepine
  • Topiramate*
  • Zonisamide*
Enhancement of slow inactivation
  • Lacosamide
  • Rufinamide
Calcium channels Blocking of T-type calcium channels Zonisamide*
Modulation of calcium channels (α2δ subunit)
  • Gabapentin
  • Pregabalin
GABA GABA reuptake inhibitors
  • Tiagabine
  • Vigabatrin
Stimulation of GABA receptors
  • Stiripentol
  • Topiramate*
Glutamate Glutamate receptor antagonists
  • Felbamate
  • Perampanel
  • Topiramate*
↓ Glutamate release Lamotrigine*
Neurotransmitter release Synaptic vesicle 2A modulators
  • Levetiracetam
  • Brivaracetam
*Mixed mechanisms

Second-generation antiseizure drugs and indications

Table: Second-generation antiseizure drugs and indications
Indications Specific conditions Drugs
Seizure related Focal (partial) seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Brivaracetam
  • Felbamate
  • Gabapentin
  • Lacosamide
  • Lamotrigine
  • Levetiracetam
  • Oxcarbazepine
  • Perampanel
  • Pregabalin
  • Tiagabine
  • Topiramate
  • Zonisamide
Primary generalized tonic-clonic seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Lacosamide
  • Lamotrigine
  • Levetiracetam
  • Perampanel
  • Topiramate
Lennox-Gastaut syndrome
  • Felbamate
  • Lamotrigine
  • Rufinamide
  • Topiramate
Juvenile myoclonic epilepsy Levetiracetam
Infantile spasms and refractory complex partial seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures Vigabatrin
Dravet syndrome Stiripentol
Seizure unrelated
  • Fibromyalgia Fibromyalgia Fibromyalgia is a chronic pain syndrome characterized by widespread body pain, chronic fatigue, mood disturbance, and cognitive disturbance. It also presents with other comorbid symptoms such as migraine headaches, depression, sleep disturbance, and irritable bowel syndrome. Fibromyalgia
  • Neuropathic pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
Pregabalin
Postherpetic neuralgia
  • Gabapentin
  • Pregabalin
Bipolar disorder Lamotrigine
Migraine prophylaxis Topiramate

References

  1. Kim, K.S., et al. (2015). Antiepileptic drugs: Second-generation/Newer agents. In Cohen, H. (Ed.), Casebook in Clinical Pharmacokinetics and Drug dosing, 1st ed., Vol. 1. pp 43-53. McGraw-Hill Education.
  2. Ochoa, J.G. (2020). Antiseizure drugs. In Benbadis, S.R., et al. (Ed.), Medscape. Retrieved September 22, 2021, from https://emedicine.medscape.com/article/1187334
  3. Porter, R.J., Rogawski, M.A. (2018). Antiseizure drugs. In Katzung, B.G. et al. (Ed.), Basic and Clinical Pharmacology, 14th ed., Vol. 1. pp. 409-437. McGraw Hill.
  4. Schachter, S.C. (2021). Antiseizure medications: Mechanism of action, pharmacology, and adverse effects. In Garcia, P. et al. (Ed.), UpToDate. Retrieved October 11, 2021, from https://www.uptodate.com/contents/antiseizure-medications-mechanism-of-action-pharmacology-and-adverse-effects
  5. Smith, M.D., Metcalf, C.S., Wilcox, K.S. (2017). Pharmacotherapy of the epilepsies. In Brunton, L.L., & Hilal-Dandan, R., & Knollmann, B.C.(Eds.), Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2189&sectionid=170106435
  6. UpToDate, Inc. (2021) Felbamate: Drug information. UpToDate. Retrieved Oct 10, 2021, from https://www.uptodate.com/contents/felbamate-drug-information
  7. UpToDate, Inc. (2021). Gabapentin: Drug information. UpToDate. Retrieved Oct 10, 2021, from https://www.uptodate.com/contents/gabapentin-drug-information
  8. UpToDate, Inc. (2021). Pregabalin: Drug information. UpToDate. Retrieved Oct 10, 2021, from https://www.uptodate.com/contents/pregabalin-drug-information
  9. UpToDate, Inc. (2021). Lacosamide: Drug information. UpToDate. Retrieved Oct 10, 2021, from https://www.uptodate.com/contents/lacosamide-drug-information
  10. UpToDate, Inc. (2021). Lamotrigine: Drug information. UpToDate. Retrieved Oct 10, 2021, from https://www.uptodate.com/contents/lamotrigine-drug-information
  11. UpToDate, Inc. (2021). Levetiracetam: Drug information. UpToDate. Retrieved Oct 10, 2021, from https://www.uptodate.com/contents/levetiracetam-drug-information
  12. UpToDate, Inc. (2021). Brivaracetam: Drug information. UpToDate. Retrieved Oct 10, 2021, from https://www.uptodate.com/contents/brivaracetam-drug-information
  13. UpToDate, Inc. (2021). Oxcarbazepine: Drug information. UpToDate. Retrieved Oct 11, 2021, from https://www.uptodate.com/contents/oxcarbazepine-drug-information
  14. UpToDate, Inc. (2021). Perampanel: Drug information. UpToDate. Retrieved Oct 11, 2021, from https://www.uptodate.com/contents/perampanel-drug-information
  15. UpToDate, Inc. (2021). Stiripentol: Drug information. UpToDate. Retrieved Oct 11, 2021, from https://www.uptodate.com/contents/stiripentol-drug-information
  16. UpToDate, Inc. (2021). Tiagabine: Drug information. UpToDate. Retrieved Oct 11, 2021, from https://www.uptodate.com/contents/tiagabine-drug-information
  17. UpToDate, Inc. (2021). Topiramate: Drug information. UpToDate. Retrieved Oct 11, 2021, from https://www.uptodate.com/contents/topiramate-drug-information
  18.  UpToDate, Inc. (2021). Vigabatrin: Drug information. UpToDate. Retrieved Oct 11, 2021, from https://www.uptodate.com/contents/vigabatrin-drug-information
  19. UpToDate, Inc. (2021). Zonisamide: Drug information. UpToDate. Retrieved Oct 11, 2021, from https://www.uptodate.com/contents/zonisamide-drug-information

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