First-Generation Anticonvulsant Drugs

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 Ca2+) blocking and GABA reuptake inhibition. Phenobarbital, phenytoin, carbamazepine, valproic acid, and ethosuximide are the 1st-generation antiseizure drugs. Anticonvulsant drugs generally have complicated pharmacokinetics, multiple drug interactions, and narrow therapeutic ranges compared with new-generation drugs.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definitions

Anticonvulsant drugs 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 is a disease with an enduring risk of recurrent unprovoked seizures (> 2 episodes occurring > 24 hours apart).

Pathophysiology of seizures

The hyperexcitable state of neurons results via the following 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 (K+ efflux occurs during this process.)
      • Other receptors trigger the release of intracellular Ca2+ stores → increase in intracellular Ca2+
      • Generation of repetitive action potentials
  • Increased excitation of the surrounding neurons:
    • Repeated depolarizations → ↑ extracellular K+
    • Elevated K+ drives depolarization of the surrounding neurons.
  • Failure to inhibit excitatory feedback circuit:
    • Stimulation by excess glutamate
    • Loss of refractory period (neurons unable to generate action potential)
    • Decreased activity of GABA:
      • The main inhibitory neurotransmitter in the brain
      • Defects in GABA activation or inhibition → seizures

General mechanisms of first-generation antiseizure drugs

  • Na+ channel blockers:
    • Phenytoin
    • Carbamazepine
    • Valproic acid
  • Promotion of GABA-related inhibition:
    • Benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines
    • Phenobarbital
    • Valproic acid
  • Ca2+ channel blocker:
    • Ethosuximide

Phenobarbital

Chemistry and Pharmacodynamics

  • Barbiturates, to which phenobarbital belongs, are sedative-hypnotic agents. Only a few are effective antiseizure drugs (effective below the hypnotic dose).
    • Phenobarbital:
      • 5-Ethyl-5-phenylbarbituric acid
      • Low toxicity, inexpensive
    • Primidone is a less used barbiturate:
      • Largely replaced by new-generation anticonvulsants
      • Converted into phenobarbital and phenylethylmalonamide (PEMA)
  • Mechanism of action:
    • Binds to GABA-A receptor, potentiating synaptic inhibition
    • Leads to neuronal hyperpolarization by extending the duration of chloride channel opening
Chemical structure of phenobarbital 1st generation anticonvulsant drugs

Chemical structure of phenobarbital

Image: “Phenobarbital” by Harbinary. License: Public Domain

Pharmacokinetics

  • Absorption:
    • IV, IM, or oral administration (with varying levels of absorption)
    • Peak concentrations are achieved several hours after the dose.
  • Distribution: 40%–60% is bound to plasma proteins.
  • Metabolism: hepatic metabolism via hepatic microsomal 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 or the cytochrome P450 (CYP) system (primarily CYP2C9)
  • Excretion: renal (up to 25% excreted unchanged in urine)

Indications

  • Generalized and focal tonic-clonic seizures
  • Partial seizures
  • First-line treatment in neonatal seizures
  • Off-label: treatment of symptoms of alcohol withdrawal

Drug-drug interactions

  • Induces uridine 5′-diphosphoglucuronyltransferase (UGT) and CYP:
    • When coadministered with phenobarbital, drugs metabolized by UGT and CYP are more rapidly degraded.
    • Oral contraceptives (metabolized by CYP3A4) have decreased efficacy.
  • CNS-depressant effect of alcohol is enhanced.

Adverse effects and contraindications

  • Adverse effects:
    • Sedation (can lead to coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma, respiratory depression)
    • Bradycardia, hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
    • Ataxia, nystagmus (with high dosage)
    • 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, nausea, vomiting
    • Stevens-Johnson syndrome Stevens-Johnson syndrome Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome ( SJS SJS Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome) (rare)
  • Warnings:
    • Risk of respiratory depression and death with high doses or when coadministered with other depressants (e.g., narcotics, benzodiazepines)
    • ↑ Risk of psychological and physical dependence
    • 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 occur with abrupt cessation.
  • Contraindications:
    • Hypersensitivity to barbiturates
    • Hepatic impairment
    • Dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea or airway obstruction Airway obstruction Airway obstruction is a partial or complete blockage of the airways that impedes airflow. An airway obstruction can be classified as upper, central, or lower depending on location. Lower airway obstruction (LAO) is usually a manifestation of chronic disease, such as asthma or chronic obstructive pulmonary disease (COPD). Airway Obstruction
    • Porphyria
  • 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 considerations:
    • Associated with fetal abnormalities
    • When used in the 3rd trimester → ↑ risk of neonatal withdrawal symptoms (seizures, hyperirritability)

Phenytoin

Chemistry and pharmacodynamics

  • Phenytoin:
    • 5,5-Diphenylhydantoin
    • Antiseizure activity, generally without CNS depression
  • Fosphenytoin is a related antiseizure drug:
    • Phenytoin prodrug (water soluble)
    • Administered IV or IM
  • Mechanism of action:
    • Protects against seizures by blocking voltage-gated Na+ channels
    • Blocks sustained, high-frequency, repetitive firing of action potentials
Chemical structure of phenytoin 1st generation anticonvulsant drugs

Chemical structure of phenytoin

Image: “Phenytoin structure” by Harbin. License: Public Domain

Pharmacokinetics

  • Absorption:
    • 2 oral formulations: rapid-release and extended-release forms. Once-daily dosing is possible with extended-release phenytoin.
    • Generic and brand-name phenytoin may differ in phenytoin content:
      • Affects phenytoin levels
      • Checking levels is important when changing routes and preparations.
  • Distribution:
    • Extensively bound to plasma proteins (90%)
    • Unbound (free) phenytoin exerts biological effects.
    • Populations such as neonates, the elderly, and individuals with hypoalbuminemia may exhibit toxicity even if drug levels in serum are normal.
  • Metabolism:
    • Hepatic metabolism with > 90% metabolized by microsomal 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 (particularly CYP2C9)
    • The inactive metabolite is excreted in the bile.
  • Excretion:
    • Metabolite is reabsorbed in the GI tract and excreted in urine.
    • <5% of phenytoin is excreted unchanged by the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys.

Indications

  • Treatment of generalized and focal seizures
  • Mixed seizures (myoclonic and tonic clonic)
  • Status epilepticus
  • Seizure prophylaxis (for craniotomy)

Drug-drug interactions

  • Induces CYP and UGT:
    • Phenytoin can affect warfarin in different ways, thus monitoring is needed:
      • ↑ INR: When phenytoin is initiated, it displaces warfarin from the protein-binding sites.
      • ↓ INR: observed in long-term phenytoin use, as phenytoin is a CYP inducer
    • Phenytoin can decrease the effects of:
      • Oral contraceptives
      • Carbamazepine
  • Notable interactions that increase phenytoin effects:
    • Alcohol
    • Amiodarone
    • Cimetidine
    • Chlordiazepoxide
    • Diazepam
    • Ethosuximide
    • Sulfamethoxazole
    • Valproic acid
  • Notable interactions that may decrease phenytoin effects:
    • Carbamazepine
    • Sucralfate

Adverse effects and contraindications

  • Adverse effects:
    • Nausea, 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
    • Anorexia
    • Incoordination
    • Nystagmus
    • ↑ Risk of suicidal risk/behavior
    • Hepatic injury
    • Hypertrichosis
    • Gingival hypertrophy
    • Folic acid depletion
    • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones density
    • SJS SJS Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome and toxic epidermal necrolysis (TEN)
  • Warnings:
    • Narrow therapeutic index
    • Abrupt withdrawal of phenytoin may result in seizures.
    • Rapid IV infusion can lead to cardiac arrhythmias and hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension.
    • Hepatotoxicity: Obtain baseline and periodic hepatic function tests.
  • Contraindications:
    • Hypersensitivity to the drug or its components
    • Sinus bradycardia
    • 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
    • Adams-Stokes syndrome
  • 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 considerations: associated with teratogenesis (e.g., neural tube defects Neural tube defects Neural tube defects (NTDs) are the 2nd-most common type of congenital birth defects. Neural tube defects can range from asymptomatic (closed NTD) to very severe malformations of the spine or brain (open NTD). Neural tube defects are caused by the failure of the neural tube to close properly during the 3rd and 4th week of embryological development. Neural Tube Defects, cleft palate cleft palate The embryological development of craniofacial structures is an intricate sequential process involving tissue growth and directed cell apoptosis. Disruption of any step in this process may result in the formation of a cleft lip alone or in combination with a cleft palate. As the most common craniofacial malformation of the newborn, the diagnosis of a cleft is clinical and usually apparent at birth. Cleft Lip and Cleft Palate, microcephaly, and mental defects)

Carbamazepine

Chemistry and pharmacodynamics

  • Carbamazepine:
    • Iminostilbene derivative (with a carbamyl group at position 5)
    • Chemically related to tricyclic antidepressants Tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications used in the management of mood disorders, primarily depression. These agents, named after their 3-ring chemical structure, act via reuptake inhibition of neurotransmitters (particularly norepinephrine and serotonin) in the brain. Tricyclic Antidepressants
  • Oxcarbazepine is a related antiseizure drug:
    • Carbamazepine analog
    • Similar mechanism as that of carbamazepine but a less potent enzyme inducer (minimal effect on the CYP system)
  • Mechanism of action:
    • Na+ channel blocker
    • Binds to voltage-gated Na+ channels in its inactive conformation, limiting the repetitive and sustained firing of action potentials
Chemical structure of carbamazepine

Chemical structure of carbamazepine

Image: “Carbamazepine structural formulae” by Jü. License: Public Domain

Pharmacokinetics

  • Absorption:
    • Slow absorption after an oral dose
    • Peak concentrations are achieved after up to 8 hours of ingestion.
  • Distribution:
    • 70% protein bound
    • Distribution in all tissues, drug concentration in CSF is similar to that of the free drug in plasma
  • Metabolism:
    • Metabolized in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver via hepatic CYP3A4
    • Potent and broad-spectrum CYP inducer
  • Excretion: renal

Indications

  • Seizure disorder (focal and generalized)
  • 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 (e.g., trigeminal neuralgia Trigeminal neuralgia Trigeminal neuralgia (TN) is an often chronic and recurring pain syndrome involving the sensory distribution of the trigeminal nerve (cranial nerve (CN) V). The pain is typically unilateral and described as an acute, sharp, electric-shock-like pain involving the maxillary or mandibular areas and often associated with spasm of facial muscles. Trigeminal Neuralgia)
  • 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

Drug-drug interactions

  • Carbamazepine is a potent inducer of CYP and UGT (may reduce plasma concentrations of concurrently administered medications by inducing their metabolism):
    • Clonazepam
    • Topiramate
    • Valproic acid
    • Zonisamide
    • Nonnucleoside reverse-transcriptase inhibitors
  • Drugs/foods that increase carbamazepine effects:
    • Brivaracetam
    • Felbamate
    • Levetiracetam
    • Lamotrigine
    • Grapefruit
  • Drugs that decrease carbamazepine effects:
    • Clonazepam
    • Phenytoin

Adverse effects and contraindications

  • Adverse effects:
    • Dizziness
    • Ataxia
    • Blurred vision
    • Nausea, vomiting
    • Hepatic injury
    • 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
    • Hematological toxicity ( 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, agranulocytosis)
    • Hypersensitivity reactions
    • SIADH SIADH Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of impaired water excretion due to the inability to suppress the secretion of antidiuretic hormone (ADH). SIADH is characterized by impaired water excretion leading to dilutional hyponatremia, which is mainly asymptomatic but may cause neurologic symptoms. S Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)
  • Warnings:
    • ↑ Risk of SJS SJS Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome and TEN in individuals with the HLA-B*1502 allele (often seen in individuals of Asian ancestry)
    • Obtain hematologic studies because of the risk of hematologic toxicity:
      • Monitor if a reduction in platelet and WBC counts is noted.
      • Discontinue if bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow suppression occurs.
    • Hepatotoxicity: Obtain baseline and periodic hepatic function tests.
    • As SIADH SIADH Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of impaired water excretion due to the inability to suppress the secretion of antidiuretic hormone (ADH). SIADH is characterized by impaired water excretion leading to dilutional hyponatremia, which is mainly asymptomatic but may cause neurologic symptoms. S Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) can occur, monitor electrolytes Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes especially in individuals at risk of hyponatremia (e.g., individuals on diuretic therapy).
  • Contraindications:
    • Hypersensitivity to carbamazepine or its components
    • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones marrow suppression
    • Concomitant use of delavirdine, nefazodone, or other nonnucleoside reverse-transcriptase inhibitors that are CYP3A4 substrates
    • Hepatic disease
    • Porphyria
  • 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 considerations: associated with teratogenic effects (e.g., spina bifida, craniofacial and cardiovascular malformations)

Valproic acid

Chemistry and pharmacodynamics

  • Valproic acid:
    • N-dipropylacetic acid
    • Inhibits several types of seizures
  • Divalproex is a related antiseizure drug:
    • Valproic acid derivative
    • Contains the sodium salt of valproic acid and valproic acid
  • Mechanism of action:
    • Blocks voltage-dependent Na+ channels → suppresses repetitive neuronal firing
    • Inhibits GABA transaminase → ↑ GABA levels
    • Decreases T-type Ca2+ currents
Chemical structure of valproic acid

Chemical structure of valproic acid

Image: “Valproic acid” by Harbin. License: Public Domain

Pharmacokinetics

  • Absorption:
    • Generally absorbed rapidly after oral ingestion
    • Delay in absorption noted in enteric-coated formulations or if ingested with meals
  • Distribution: 90% bound to plasma proteins
  • Metabolism:
    • Hepatic metabolism
    • Moderately inhibits CYP and UGT glucuronidation
  • Excretion: renal (<5% unchanged in the urine)

Indications

  • Generalized and focal seizures
  • Absence seizures
  • Prophylaxis of migraine Migraine Migraine headache is a primary headache disorder and is among the most prevalent disorders in the world. Migraine is characterized by episodic, moderate to severe headaches that may be associated with increased sensitivity to light and sound, as well as nausea and/or vomiting. Migraine Headache headaches
  • 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

Drug-drug interactions

  • Valproic acid inhibits CYP and UGT and can increase the effects of the following drugs:
    • Carbamazepine
    • Ethosuximide
    • Phenytoin
    • Phenobarbital
    • Lamotrigine
  • Valproic acid can decrease the effects of:
    • Felbamate (unknown mechanism)
    • Oxcarbazepine (↑ metabolism)
  • The following drugs can decrease the efficacy of valproic acid:
    • Carbamazepine
    • Ethosuximide

Adverse effects and contraindications

  • Adverse effects:
    • Nausea, vomiting
    • Hair loss
    • Tremors
    • Weight gain, obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity, and metabolic syndrome Metabolic syndrome Metabolic syndrome is a cluster of conditions that significantly increases the risk for several secondary diseases, notably cardiovascular disease, type 2 diabetes, and nonalcoholic fatty liver. In general, it is agreed that hypertension, insulin resistance/hyperglycemia, and hyperlipidemia, along with central obesity, are components of the metabolic syndrome. Metabolic Syndrome
    • Hepatic injury
    • Thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia and other coagulation disturbances
  • Warnings:
    • Hepatotoxicity:
      • ↑ Risk of acute liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver failure (especially in neurometabolic syndromes from mitochondrial DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure polymerase gamma (POLG) gene mutations)
      • Baseline and periodic hepatic function tests
    • Acute pancreatitis Acute pancreatitis Acute pancreatitis is an inflammatory disease of the pancreas due to autodigestion. Common etiologies include gallstones and excessive alcohol use. Patients typically present with epigastric pain radiating to the back. Acute Pancreatitis (medical evaluation required if individuals present with 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 and symptoms indicative of pancreatitis)
  • Contraindications:
    • Known hypersensitivity to valproic acid
    • Liver disease
    • Mitochondrial disorders (Alpers-Huttenlocher syndrome)
    • Urea cycle disorders Urea cycle disorders Urea cycle disorders (UCDs) are caused by genetic defects and result in deficiencies of enzymes and transporters of the urea cycle. As a result of the defects, individuals are unable to rid the body of nitrogen waste. Common symptoms include vomiting, lethargy, seizures, and respiratory alkalosis. Urea Cycle Disorders (valproic acid inhibits urea synthesis → ↑ ammonia levels)
  • 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 considerations:
    • Teratogenic
    • Fetal abnormalities (valproate syndrome) include:
      • Neural tube defects such as spina bifida
      • Developmental delay
      • Cleft lip/ palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Oral Cavity: Palate
      • Congenital heart defects
      • Limb abnormalities

Ethosuximide

Chemistry and pharmacodynamics

  • Ethosuximide:
    • α-Ethyl-α-methylsuccinimide
    • Effective in absence seizures (when not accompanied by other types of seizures)
  • Mechanism of action: reduces T-type Ca2+ channels of the thalamic neurons
Chemical structure of ethosuximide

Chemical structure of ethosuximide

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

Pharmacokinetics

  • Absorption:
    • Bioavailability is 93% after an oral dose.
    • Peak drug concentration in the blood is attained between 3 and 4 hours.
  • Distribution:
    • Little or no protein binding
    • Drug distribution in CSF is similar to that in plasma.
  • Metabolism: hepatic microsomal 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 (particularly CYP3A)
  • Excretion: renal (25% unchanged)

Indications

Treatment of absence seizures

Drug-drug interactions

  • CNS-depressant effects can be exacerbated by other drugs and lead to drowsiness.
  • Orlistat may decrease ethosuximide levels.

Adverse effects and contraindications

  • Adverse effects:
    • Nausea, vomiting, anorexia
    • Drowsiness, lethargy, euphoria, dizziness, headache
    • Parkinson’s disease-like symptoms
    • Photophobia
    • Hypersensitivity reactions
  • Warnings:
    • Exercise caution when performing tasks (can cause drowsiness).
    • Monitor CBC as ethosuximide can cause blood dyscrasias.
    • Exercise caution in individuals with renal and hepatic impairment.
  • Contraindications: hypersensitivity to ethosuximide or its ingredients
  • 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 considerations: associated with birth defects

Comparison of Medications

Table: Pharmacokinetics of drugs used to treat essential tremors
Medications Mechanism of action Major adverse effects Interactions Indications
Barbiturates (phenobarbital) Binds to GABA receptor subunits → ↑ GABA inhibitory activity
  • Sedation
  • Cardiorespiratory depression
Induces CYP and UGT Generalized and focal seizures
Phenytoin Blocks voltage-gated Na+ channels
  • Gingival hypertrophy
  • ↑ Body hair
  • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones density
  • Rash
  • Ataxia
  • Nystagmus
  • Hepatotoxicity
Induces CYP and UGT
  • Generalized and focal seizures
  • Mixed seizures
  • Prevention of seizures during neurosurgery Neurosurgery Neurosurgery is a specialized field focused on the surgical management of pathologies of the brain, spine, spinal cord, and peripheral nerves. General neurosurgery includes cases of trauma and emergencies. There are a number of specialized neurosurgical practices, including oncologic neurosurgery, spinal neurosurgery, and pediatric neurosurgery. Neurosurgery
Carbamazepine Blocks Na+ channels
  • GI symptoms
  • Rash
  • 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
  • SJS SJS Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome, TEN
  • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones marrow suppression
Induces CYP and UGT
  • Generalized and focal seizures
  • 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
Valproic acid
  • Blocks Na+ channels
  • ↑ GABA transaminase → ↑ GABA
  • Nausea, vomiting
  • Metabolic syndrome
  • Hepatotoxicity
  • ↓ Platelet count
  • Coagulation problems
Inhibits CYP and UGT
  • Generalized and focal seizures
  • Absence seizures
  • Migraine prophylaxis
  • 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
Ethosuximide ↓ T-type Ca2+ channel currents Drowsiness (CNS depression) ↑ Phenytoin effects Absence seizures
Abbreviations:
UGT: uridine 5′-diphosphoglucuronyltransferase
CYP: cytochrome P450
SJS SJS Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome: Stevens-Johnson syndrome Stevens-Johnson syndrome Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome
TEN: toxic epidermal necrolysis

References

  1. Al Khalili, Y., Sekhon, S., Jain, S. (2021). Carbamazepine toxicity. StatPearls. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK507852/
  2. Bialer, M. (2012). How did phenobarbital’s chemical structure affect the development of subsequent antiepileptic drugs (AEDs)? Epilepsia, 53, 3-11. https://doi.org/10.1111/epi.12024
  3. Crader, M., Johns, T. (2021). Warfarin drug interactions. StatPearls. Retrieved Aug 29, 2021, from https://www.statpearls.com/ArticleLibrary/viewarticle/31296
  4. Lowenstein, D.H. (2018). Seizures and epilepsy. Jameson, J., Fauci, A.S., Kasper, D.L., Hauser, S.L., Longo, D.L., Loscalzo, J. (Eds.), Harrison’s Principles of Internal Medicine, 20e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=192531797
  5. Miller, C. (2020). Phenytoin toxicity. Medscape. Retrieved Aug 29, 2021, from https://emedicine.medscape.com/article/816447-overview
  6. Ropper, A.H., Samuels, M.A., Klein, J.P., Prasad, S. (Eds.) (2019). Epilepsy and other seizure disorders. Adams and Victor’s Principles of Neurology, 11e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=1477&sectionid=138318583
  7. Schachter, S. (2021). Anti-seizure medications. UpToDate. Retrieved Aug 28, 2021, from https://www.uptodate.com/contents/antiseizure-medications-mechanism-of-action-pharmacology-and-adverse-effects
  8. Shakkottai, V.G., Lomen-Hoerth, C. (2019). Nervous system disorders. Hammer, G.D., McPhee, S.J. (Eds.), Pathophysiology of Disease: An Introduction to Clinical Medicine, 8e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2468&sectionid=198220873
  9. Smith, M.D., Metcalf, C.S., Wilcox, K.S. (2017). Pharmacotherapy of the epilepsies. 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
  10. UpToDate. (2021). Carbamazepine: Drug information. UpToDate. Retrieved Aug 29, 2021, from https://www.uptodate.com/contents/carbamazepine-drug-information
  11. UpToDate. (2021) Ethosuximide: Drug information. UpToDate. Retrieved Aug 29, 2021, from https://www.uptodate.com/contents/ethosuximide-drug-information
  12. UpToDate. (2021). Phenobarbital: Drug information. UpToDate. Retrieved Aug 29, 2021, from https://www.uptodate.com/contents/phenobarbital-drug-information
  13. UpToDate. (2021). Phenytoin: Drug information. UpToDate. Retrieved Aug 29, 2021, from https://www.uptodate.com/contents/phenytoin-drug-information
  14. UpToDate. (2021). Valproate: Drug information. UpToDate. Retrieved Aug 29, 2021, from https://www.uptodate.com/contents/valproate-drug-information

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