Neurology PDF

Neurology I. EPILEPSY A. Epidemiology 1. Epilepsy is the fourth most common neurologic disorder. Ten percent of the U.S. population will have a seizure. Around 7.6 of 1000 individuals will develop epilepsy at some point in their lives (WHO 2019). 2. Around 50 million people worldwide have...

Neurology I. EPILEPSY A. Epidemiology 1. Epilepsy is the fourth most common neurologic disorder. Ten percent of the U.S. population will have a seizure. Around 7.6 of 1000 individuals will develop epilepsy at some point in their lives (WHO 2019). 2. Around 50 million people worldwide have epilepsy. 3. A round 50% of newly diagnosed patients become seizure free on their first treatment, with up to 70% becoming seizure free after treatment adjustment and 30% continuing to have seizures (Neurology 2012;78:1548-54). B. C  lassification of Seizures: Seizures are traditionally classified according to the International League Against Epilepsy (ILAE) scheme, adopted in 1981, with modifications in 2001 and 2010. In 2017 the ILAE developed and implemented a revised classification scheme for seizures.. 1. Focal-onset seizures start in an area or network of cells on one side of the brain. a. Focal seizures can further be classified as: i. Aware or impaired awareness ii. Motor or nonmotor iii.  Focal or bilateral tonic-clonic b.  The terms simple partial seizure, complex partial seizure, and secondarily generalized seizure have been eliminated from the official classification; however, they are still commonly used to describe seizures. 2. Generalized onset seizures engage or involve networks on both sides of the brain at the onset. Can be classified as nonmotor or motor type a. Nonmotor (absence) seizures: i. Typical nonmotor seizures are brief and abrupt, last 10–30 seconds, and occur in clusters. They usually result in a short loss of consciousness, or patients may stare, be motionless, or have a distant expression on their face. Electroencephalograms (EEGs) during seizure activity usually show 3-Hz spike-and-wave complexes. ii. Other nonmotor seizure classifications include typical, atypical, myoclonic, and eyelid myoclonia. b. Motor: Myoclonic seizures: Consist of brief, rapid jerking movements of the entire body or the upper body and occasionally the lower extremities. Motor myoclonic-type seizures can further be classified as myoclonic, myoclonic atonic, or myoclonic tonic. c. Tonic-clonic seizures: Typically has five phases: flexion, extension, tremor, clonic, and postictal. During the flexion phase, the patient’s mouth may be held partly open, and the patient may have upward eye movement, involvement of the extremities, and loss of consciousness. In the extension phase, patients may be noted to extend their back and neck; have contraction of the thoracic and abdominal muscles; be apneic; and have flexion, extension, and adduction of the extremities. The patient may cry out as air is forced from the lungs in this phase. The tremor phase occurs as the patient goes from tonic rigidity to tremors and then to a clonic state. During the clonic phase, the patient will have rhythmic jerks. The entire seizure usually lasts 1–3 minutes. After the seizure, the patient may be postictal. During this time, the patient can be difficult to arouse or very somnolent. Before the seizure, a patient may have a prodrome but not an aura. d. Clonic seizures: Only the clonic phase of a motor tonic-clonic seizure; rhythmic, repetitive, jerking muscle movements e. Tonic seizures: Only the flexion or extension phases of a motor tonic-clonic seizure f. Atonic seizures: Characterized by a loss of muscle tone. Motor-atonic seizures are often described as drop attacks, in which a patient loses tone and falls to the ground. ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 1-484 Neurology 3. Seizures of unknown onset: Seizure onset cannot be determined as focal or generalized. a. Motor b. Nonmotor c. Unclassified 4. Epilepsy is a disease of the brain defined by any of the following conditions: a. Two unprovoked (or reflex) seizures occurring more than 24 hours apart; b. One unprovoked (or reflex) seizure and a probability of subsequent seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; c. Diagnosis of an epilepsy syndrome (Epilepsia 2014;55:475-82) 5. Status epilepticus is caused either by the failure of the mechanisms responsible for seizure termination or by the initiation of mechanisms, which lead to abnormally prolonged seizures after 5 minutes. At this point, treatment for status epilepticus should be initiated. After 30 minutes, status epilepticus can have long-term consequences, including neuronal death, neuronal injury, and alteration of neuronal networks (depending on the type and duration of seizures). Mortality is up to 20% for status epilepticus (Epilepsia 2015;56:1515-23). 6. Nonepileptic seizures are paroxysmal nonepileptic episodes (according to EEG) resembling epileptic seizures that can be organic or psychogenic. 7. Other associated symptoms a. Prodrome: Awareness of an impending seizure before it occurs. The prodrome may consist of headache, insomnia, irritability, or a feeling of impending doom. b. Aura: A focal seizure, without loss of consciousness, consisting of sensory or autonomic symptoms that may precede evolution to a bilateral, convulsive seizure. Patients may have feelings of fear, embarrassment, or déjà vu. Automatic behavior (automatism) and psychic symptoms may occur. Automatisms may include lip smacking, chewing, swallowing, abnormal tongue movements, scratching, thrashing of the arms or legs, fumbling with clothing, and snapping the fingers. Psychic symptoms include illusions, hallucinations, emotional changes, dysphasia, and cognitive problems. C. Diagnosis 1. Physical examination should occur, with special attention given to neurologic findings. The neurologic examination may include examination of the head, vision, cranial nerves, motor function, cerebellar function, and sensory function. 2. Laboratory tests are based on the patient’s history and physical examination results; a full diagnostic panel is unnecessary in many patients. Because metabolic causes of seizures are common, serum glucose, electrolytes, calcium, CBCs, and renal function tests may be necessary. A toxicology screen may also be prudent. 3. EEGs are used to help confirm the diagnosis, classify seizures, locate the site of the seizures, and select the best seizure medication. The best time for an EEG is while the patient is having seizures. If doing an EEG is not possible during seizures, the EEG should be done as soon after the seizure as possible. Depending on the clinical situation, an EEG may be obtained under normal conditions, when the patient is sleep deprived, or when the patient is asleep. Patients whose seizures are difficult to diagnose or control may need prolonged video-EEG monitoring or ambulatory EEG. Although an interictal (when the patient is not having clinical seizures) EEG may be normal, this does not preclude the diagnosis of epilepsy. 4. MRI is the neuroimaging technique of choice for epilepsy. CT scanning can reveal brain lesions when an MRI cannot be done in a timely fashion. ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 1-485 Neurology D. Treatment 1. Medications (see Tables 1–4) a. Benzodiazepines i. Mechanism of action: Augment γ-aminobutyric acid (GABA)-mediated chloride influx ii. Tolerance may develop: Usually used as adjunctive, short-term therapy iii. Most commonly used agents: Clorazepate (Tranxene), clobazam (Onfi, Sympazan), clonazepam (Klonopin), diazepam (Valium), and lorazepam (Ativan) iv. All benzodiazepines are controlled substances, scheduled as C-IV. v. For acute repetitive seizures: Intranasal midazolam (Nayzilam), intranasal diazepam (Valtoco), rectal diazepam (Diastat) vi. Nonepileptic indications: Clorazepate (anxiety disorders, anxiety), clonazepam (panic disorder with or without agoraphobia), lorazepam (anxiety disorders, anxiety, alcohol withdrawal) b. Brivaracetam (Briviact) i. Mechanism of action: Unknown mechanism, but has high affinity for synaptic vesicle protein 2A ii. Adverse effects: Somnolence, sedation, dizziness, fatigue iii. Drug interactions: Carbamazepine, phenobarbital, phenytoin c. Cannabidiol (Epidiolex) i. The only FDA-approved cannabis product for epilepsy ii. Approved for seizures caused by Dravet syndrome, tuberous sclerosis, and Lennox-Gastaut syndrome iii. Adverse effects: Sedation, drowsiness, diarrhea, intestinal cramping, increased liver transaminase (11% of patients); cannabidiol for 3% of patients is discontinued because of increased liver function tests iv. Metabolized by CYP2C19 and CYP3A4 v. Inhibitor of UGT1A9, UGT2B7, CYP2C8, CYP2C9, CYP2C19 vi. Possible inhibitor of CYP1A2, CYP2B6 vii. Inhibits metabolism of desmethylclobazam, the active metabolite of clobazam viii. Increased hepatotoxicity with concomitant valproate ix. Maintenance dose: 10–20 mg/kg/day in two divided doses; initiate with 5 mg/kg/day in two divided doses and titrate to optimal dose d. Carbamazepine (Carbatrol, Epitol, Equetro, Tegretol, Teril) i. Mechanism of action: Fast sodium channel blocker ii. Pharmacokinetics: Enzyme inducer, autoinduction iii. Adverse effects: Rash (occurs after a delay of 2–8 weeks), syndrome of inappropriate antidiuretic hormone release, aplastic anemia, thrombocytopenia, anemia, leukopenia, hyponatremia iv. Extended-release tablets (Tegretol XR) 100, 200, and 400 mg; extended-release capsules (Carbatrol) 100, 200, and 300 mg available. Dosing is still twice daily. Do not crush or chew. Extended-release capsules (Carbatrol) can be opened and sprinkled on food. Ghost tablets can occur in the stool with the extended-release tablets (Tegretol XR). v.  Patients with the HLA-B*1502 allele have a 10-fold elevated risk of Stevens-Johnson syndrome. (a) Testing is recommended for Asian populations (including Asian Indian populations). (b) More than 15% of populations in Hong Kong, Malaysia, the Philippines, and Thailand have this allele. vi.  Patients with the HLA-A*3101 allele have a 12-fold elevated risk of hypersensitivity syndrome and a 3-fold elevated risk of maculopapular exanthema. (a) Prevalence of this allele is 2%–5% in northern European populations and 9.1% in Japanese populations. (b) No recommendations have been issued for testing for this allele. vii. Nonepileptic indication: Trigeminal neuralgia ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 1-486 Neurology e. Cenobamate (Xcopri) i. Mechanism of action: Inhibits voltage-gated sodium channels, modulates GABA receptors ii. Titrate slowly because of DRESS (drug rash with eosinophilia and systemic symptoms). iii. Contraindications: Familial short QT syndrome iv. Adjust dosing with renal function. v. CYP3A4 inducer; CYP2C19 inhibitor vi.  Schedule V drug f. Eslicarbazepine acetate (Aptiom) i. Mechanism of action: Fast sodium channel blocker ii. Prodrug for eslicarbazepine, with active metabolites; R-licarbazepine 5%, oxcarbazepine 1% iii. Adverse effects: Similar to those of carbamazepine; possibly reduced risk of rash, aplastic anemia, thrombocytopenia, and leukopenia iv. Adjust dose if CrCl is less than 50 mL/minute/1.73 m2. g. Ethosuximide (Zarontin) i. Mechanism of action: T-type calcium current blocker ii. Useful only for absence seizures iii. Adverse effects: Anorexia, gastric upset, nausea, vomiting, epigastric/abdominal pain, drowsiness, leukopenia, agranulocytosis, pancytopenia h. Felbamate (Felbatol) i. Mechanism of action: Blocks glycine site on N-methyl-d-aspartate receptor ii. Serious adverse effects: Hepatotoxicity, aplastic anemia. Patient or guardian must sign consent form. iii. Uses: Only when seizures are severe and refractory to other medications and when the benefit clearly outweighs the potential adverse effects i. Fenfluramine (Fintepla) i. Mechanism of action for seizures: Unknown ii. Indication: Seizures caused by Dravet syndrome in individuals older than 2 years iii. Warnings: Valvular heart disease, pulmonary arterial hypertension iv. Only available through a Risk Evaluation and Mitigation Strategies (REMS) program v. Increased risk of serotonin syndrome when used in combination with other serotonergic agents j. Fosphenytoin (Cerebyx) i. Mechanism of action: Prodrug for phenytoin; fast sodium channel blocker ii. Uses: Parenteral formulation for loading or maintenance dosing in place of phenytoin; status epilepticus iii. Pharmacokinetics: Enzyme inducer, nonlinear kinetics iv. Dosing: Phenytoin equivalents (PE) (1.5 mg of fosphenytoin is equivalent to 1 mg of phenytoin sodium or 1 PE) are used. Loading dose: 10–20 mg of PE/kg intravenous or intramuscular dosing is appropriate. Maintenance dosage: Begin with 4–6 mg PE/kg/day in divided doses after administration of the loading dose. v. Adverse effects: Hypotension, perianal itching, other adverse effects of phenytoin vi. Advantages over phenytoin (a) Intramuscular or intravenous dosing (b) Phlebitis is minimized. (c) Infusion can be up to 150 mg PE per minute. In status epilepticus, infusion should be at 100–150 mg PE per minute. Maximum infusion rate is not to exceed 150 mg PE per minute because of the risk of severe hypotension and cardiac arrhythmias. (d) Can deliver in normal saline solution or 5% dextrose in water injection ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 1-487 Neurology k. Gabapentin (Neurontin) i. Mechanism of action: Inhibition of α2δ subunit of voltage-dependent calcium channels ii. Pharmacokinetics: Not metabolized, eliminated renally; adjustments may be necessary for renal dysfunction and hemodialysis iii. Nonepileptic indication: Postherpetic neuralgia pain iv. Doses often exceed product information maximum of 3600 mg/day. v. Extended-release tablets (Gralise) 300 and 600 mg are available. Their indication is for postherpetic neuralgia, not epilepsy. vi. Gabapentin enacarbil (Horizant) extended-release tablets 300 and 600 mg are available. This is a prodrug for gabapentin and is indicated for postherpetic neuralgia and restless legs syndrome, not epilepsy. vii. Increased risk of sedation and respiratory depression when used in combination with other sedating medications or opioids l. Ganaxolone (Ztalmy) i. Indicated for the treatment of seizures associated with cyclin-dependent kinase-like deficiency disorder in patients 2 years and older ii. Mechanism of action: Positive modulation of the GABA A receptor in the CNS iii. Dosage form: Oral suspension 50 mg/mL iv. Dosing: Orally three times daily with food, titrated slowly (a) Dosage for patients weighing 28 kg or less: (1) The starting dosage is 6 mg/kg three times daily (18 mg/kg/day) for days 1–7; then: (2) 11 mg/kg three times daily (33 mg/kg/day) for days 8–14; then (3) 16 mg/kg three times daily (48 mg/kg/day) for days 15–21; then (4) Maximum dosage is 21 mg/kg three times daily (63 mg/kg/daily) on day 22 to ongoing. (b) Dosage for patients weighing over 28 kg: (1) The starting dosage is 150 mg three times daily (450 mg daily) for days 1–7; then (2) 300 mg three times daily (900 mg daily) for days 8–14; then (3) 450 mg three times daily (1350 mg daily) for days 15–21; then (4) Maximum dosage is 600 mg three times daily (1800 mg daily) on day 22 to ongoing. v. Adverse reactions: Somnolence, pyrexia, salivary hypersecretion, and seasonal allergy vi. Controlled substance scheduled C-V because of euphoric effects vii. Drug interactions: CYP3A4 inducers will decrease ganaxolone exposure. It is recommended to avoid concomitant use with strong or moderate CYP3A4 inducers; if unavoidable, consider a dosage increase, but do not exceed the maximum recommended dosage. m. Lacosamide (Vimpat) i. Mechanism of action: Slow sodium channel blocker ii. Maximum dose is 300 mg/day with a CrCl of 30 mL/minute/1.73 m 2 or less or with mild to moderate hepatic impairment. iii. Adverse effects: PR interval prolongation or first-degree atrioventricular block; baseline and steady-state ECG recommended in patients with known cardiac conduction problems, taking medications known to induce PR interval prolongation, or with severe cardiac disease iv. Controlled substance scheduled C-V because of euphoric effects v. Parenteral formulation: Has an FDA indication only for replacement of oral formulation; however, may be used for status epilepticus n. Lamotrigine (Lamictal) i. Mechanism of action: Decreases glutamate and aspartate release, delays repetitive firing of neurons, blocks fast sodium channels ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 1-488 Neurology ii. Adverse effects: Rash is a primary concern because of concern for progression to StevensJohnson syndrome or toxic epidermal necrolysis; lamotrigine must be titrated slowly to avoid a rash. iii. Valproic acid decreases lamotrigine metabolism (increases the serum concentration of lamotrigine); this interaction requires lower starting and final doses. iv. Estrogen-containing oral contraceptives increase lamotrigine clearance, so twice the amount of lamotrigine may be necessary. Lamotrigine toxicity has been reported during the end of placebo week of oral contraceptive use. v. Extended-release tablets (Lamictal XR) are available (25 mg, 50 mg, 100 mg, 200 mg, 250 mg, 300 mg). vi. Nonepileptic indications: Maintenance treatment of type I bipolar disorder o. Levetiracetam (Keppra) i. Mechanism of action: May prevent hypersynchronization of epileptiform burst firing and propagation of seizure activity through binding at SV2A receptor ii. Pharmacokinetics: Not metabolized extensively; adjust dose in renal dysfunction; no drug interactions with other seizure medications iii. Adverse effects: Drowsiness, behavioral changes, depression, agitation, and coordination difficulties iv. Parenteral use: Currently FDA indicated only for replacement of oral dosing; however, may be used for status epilepticus v. Extended-release tablets (500 mg, 750 mg) are available for once-daily dosing. p. Oxcarbazepine (Trileptal) i. Mechanism of action: Fast sodium channel blocker ii. Pharmacokinetics: Active metabolite 10-monohydroxy oxcarbazepine; enzyme inducer, no autoinduction iii. Drug interactions: Enzyme inducer, decreases effectiveness of hormonal contraceptives iv. Adverse effects: Hyponatremia more common than with carbamazepine (increased dose and advanced age increase risk of hyponatremia); blood dyscrasias less common than with carbamazepine; 25%–30% of patients with hypersensitivity to carbamazepine will have hypersensitivity to oxcarbazepine; rash v. Extended-release tablets (Oxtellar XR) are available (150 mg, 300 mg, 600 mg). q. Perampanel (Fycompa) i. Mechanism of action: Noncompetitive antagonist of the inotropic α-amino-3-hydroxy5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptor ii. Pharmacokinetics: 95%–96% protein bound to albumin and α1-acid glycoprotein; metabolized by CYP3A4 and CYP3A5; 105-hour half-life iii. Adverse effects: Neuropsychiatric effects (irritability, aggression, anger, anxiety), dizziness, gait disturbance, weight gain iv. Perampanel is a schedule III controlled substance. r. Phenobarbital (Luminal) i. Mechanism of action: Increases GABA-mediated chloride influx ii. Pharmacokinetics: Enzyme inducer iii. Adverse effects: Hyperactivity, cognitive impairment iv. Phenobarbital is a schedule IV controlled substance. v. Nonepileptic use: Anxiety, severe alcohol withdrawal s. Phenytoin (Dilantin, Phenytek) i. Mechanism of action: Fast sodium channel blocker ii. Pharmacokinetics: Enzyme inducer, nonlinear kinetics ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 1-489 Neurology iii. Administration considerations (a) Intravenous formulation: Very basic product. Phlebitis and extravasation are concerns; hypotension; maximal infusion rate of 50 mg/minute because of risk of cardiac arrhythmias and hypotension. Can prepare only in normal saline solution (b) Oral suspension: Must be shaken well; adheres to feeding tubes and is bound by enteral nutrition products iv. Dose-related adverse effects: Nystagmus, ataxia, drowsiness, cognitive impairment v. Non–dose-related adverse effects: Gingival hyperplasia, hirsutism, acne, rash, hepatotoxicity, coarsening of facial features t. Pregabalin (Lyrica) i. Mechanism of action: Inhibition of α2δ subunit of voltage-dependent calcium channels ii. Pharmacokinetics: Not metabolized, renally excreted; reduce dose in renal dysfunction iii. Adverse effects: Drowsiness, blurred vision, weight gain, edema, angioedema, CK elevations (three reports of rhabdomyolysis), rash iv. Schedule V controlled substance: Insomnia, nausea, headache, diarrhea reported after abrupt discontinuation; gradually discontinue over at least 1 week v. Nonepileptic indications: Neuropathic pain associated with diabetic neuropathy, postherpetic neuralgia, spinal cord injury, generalized anxiety disorder, and fibromyalgia vi. Increased risk of sedation and respiratory depression when used in combination with other sedating medications or opioids Table 1. Medication Selection for Various Seizure Typesa Medication Brivaracetam Cannabidiol Carbamazepine Cenobamate Clobazam Clonazepam Diazepam Eslicarbazepine Ethosuximide Felbamate Fenfluramine Gabapentin Lacosamide Lamotrigine Levetiracetam Lorazepam Oxcarbazepine Perampanel Phenobarbital Phenytoin Pregabalin Primidone Rufinamide Focal 3 — 1 4 4 3 — 4 — 5 — 1 1 1 1 3 1 4 2 2 4 2 4 Generalized Motor — — 1 — 4 3 — — — 5 — 2 — 1 1 3 1 — 2 2 — 2 3 Absence — — — — 3 2 — — 1 5 — — — 2 4 3 — — 2 — — 2 3 Atonic — — 4 — — 1 — — — — — — — 3 — — 3 — — — — — 3 Myoclonic — — 4 — 3 2 4 — 4 5 — — — 3 3 3 3 — 3 3 — — — Infantile Spasms — — — — — 2 4 — — — — — — — — — — — — — — — — Dravet Syndrome — 3 — — 2 — — — — — 5 — — — 1 — — — — — — — — LennoxGastaut Syndrome — 3 — — 1 1 2 — — 5 — — — 1 — — — — — — — — 1 ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 1-490 Neurology Table 1. Medication Selection for Various Seizure Typesa (Cont’d) Medication Stiripentol Tiagabine Topiramate Valproic acid Vigabatrin Zonisamide Focal — 4 1 2 5 1 Generalized Motor — — 1 1 5 3 Absence — — 3 1 — 3 Atonic — 4 3 1 — — Myoclonic — 4 1 1 — 4 Infantile Spasms — — — 1 5 — Dravet Syndrome 6 — — 2 — — LennoxGastaut Syndrome — — 4 — — — Not all uses are FDA-approved indications. 1 = first-line agent; 2 = second-line agent; 3 = some therapeutic effect; 4 = adjunctive therapy; 5 = used only when benefits outweigh risks; 6 = in combination with clobazam. a Table 2. Selected Interactions of Non–Antiseizure Medications on Seizure Medications Seizure Medication Carbamazepine Clobazam Other Medication Effect on the Seizure Medication Mechanism Cimetidine Increased serum concentration Inhibition of carbamazepine metabolism Diltiazem Increased serum concentration Inhibition of carbamazepine metabolism Erythromycin Increased serum concentration Inhibition of carbamazepine metabolism Isoniazid Increased serum concentration Inhibition of carbamazepine metabolism Nefazodone Increased serum concentration Inhibition of carbamazepine metabolism Theophylline Decreased serum concentration Increased carbamazepine metabolism Verapamil Increased serum concentration Inhibition of carbamazepine metabolism Fluconazole Increased serum concentration Inhibitor of CYP2C19 Fluvoxamine Increased serum concentration Inhibitor of CYP2C19 Omeprazole Increased serum concentration Inhibitor of CYP2C19 Gabapentin Antacids Decreased serum concentration Decreased bioavailability Lamotrigine Estrogen-containing contraceptives Decreased serum concentration Possibly induction of glucuronidation of lamotrigine Rifampin Decreased serum concentration Possibly induction of glucuronidation of lamotrigine Ethanol and other CNS depressants CNS additive or supra-additive effects Additive CNS depression Rifampin Decreased serum concentration Increased metabolism St. John’s wort Decreased serum concentration Increased metabolism Ethanol Acute ethanol ingestion may cause CNS additive effects and respiratory depression; chronic ethanol ingestion may result in variable effects Additive CNS depression and decreased barbiturate metabolism with acute ethanol ingestion Perampanel Phenobarbital; primidone ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 1-491 Neurology Table 2. Selected Interactions of Non–Antiseizure Medications on Seizure Medications (Cont’d) Seizure Medication Phenytoin Other Medication Effect on the Seizure Medication Mechanism Anticoagulants, oral May increase phenytoin serum concentration; decreased or increased anticoagulant effects Complex mechanism Antineoplastics (bleomycin, cisplatin, vinblastine, methotrexate, carmustine) Decreased pharmacologic effect Unknown, possible decreased absorption caused by antineoplastic mucosal damage Chloramphenicol Increased phenytoin serum concentration; decreased or increased chloramphenicol serum concentration Inhibition of phenytoin metabolism; effect on chloramphenicol unknown Cimetidine Increased serum concentration Inhibition of phenytoin metabolism Diazoxide Decreased pharmacologic effect; decreased serum concentration Increased phenytoin metabolism Diltiazem Increased serum concentration Inhibition of phenytoin metabolism Disulfiram Increased serum concentration Inhibition of phenytoin metabolism Folic acid Decreased serum concentration Complex mechanism Isoniazid Increased serum concentration Inhibition of phenytoin metabolism Phenylbutazone Increased serum concentration Inhibition of phenytoin metabolism; plasma protein displacement Rifampin Decreased serum concentration Increased phenytoin metabolism Sulfonamides Increased serum concentration Inhibition of phenytoin metabolism Trimethoprim Increased serum concentration Inhibition of phenytoin metabolism Topiramate Hydrochlorothiazide Increased serum concentration Unknown Valproic acid Estrogen-containing oral contraceptives Decreased serum concentration Possibly induction of glucuronidation of lamotrigine Meropenem Decreased serum concentration Increased valproic acid metabolism Rifampin Decreased serum concentration Increased valproic acid metabolism Salicylates Increased pharmacologic effect Plasma protein displacement; increased free valproic concentration ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 1-492 Neurology Table 3. Pharmacokinetic Parameters of Seizure Medications When Used as Monotherapy Medication Therapeutic Serum Concentration (mcg/mL) Bioavailability (%) Plasma Protein Binding (%) Volume of Distribution (L/kg) Eliminated Unchanged (%) Clinically Active Metabolites Half-Life (hr) Brivaracetam Cannabidiol 0.5–0.9 Not established < 20 > 94 0.5 232–535 < 10 Little, if any None 7-hydroxy-cannabidiol 9 56–61 Carbamazepine 4–12 mcg/mL > 90 < 20, significantly increased with fatty meal > 70 40–90 10,11-epoxide 12–17 8–14 (children) 1 Cenobamate Clobazam Not established 30–300 ng/mL 85–90 100 60 80–90 Little, if any 0.8–1.9 1.5 (neonates) 1.9 (children) 0.5–0.7 < 10 100 3 None N-desmethylclobazam – 3 Clonazepam 20–80 ng/mL 100 47–80 3.2 7-amino, low activity Eslicarbazepine 10–35 90 < 40 0.87 Low percentage 90 Ethosuximide 40–100 100 21.8 0.6–0.7 10–20 R-licarbazepine, oxcarbazepine None 50–60 36–2 71–82 (N-desmethylclobazam) 19–50 22–33 (children) 13–20 3 Felbamate 30–60b > 90 22–36 0.74–0.85 40–50 None Fenfluramine Gabapentin Ganaxolone Lacosamide Lamotrigine 1–10 2–20b Not established 1–10 1–13 68–74 Dose-dependent > 90 100 98 50 <3 99 < 15 55 12 0.65–1.04 0.8 0.6 0.9–1.2 < 25 75–80 2 40 10 Norfenfluramine None None None None Levetiracetam 12–46b 100 < 10 0.5–0.7 66 None 52–60 24–36 (children) 11–20 13–23 (children) 20 5–7 34 13 12–55 24–30 (children) 7 5 (children)c Oxcarbazepine 3–35b 100c 67 0.7 <1 10-monohydroxy Perampanel Phenobarbital 180–980 15–40 100 80–100 95–96 40–60 — 0.7–1 20–36 25 None None Phenytoin 10–20 85–95 > 90 > 90 <5 None Pregabalin Primidone 2–5 Primidone ≥ 90 90–100 0 80 0.5 0.6 90 20–40 None Phenobarbital PEMA Rufinamide Stiripentol 5–30 1–10 85 Not determined 34 99 50f 3.2 2 < 10 None None Tiagabine Topiramate Valproic acid 0.02–0.2b Topiramate 40–100 (150)e 90–95 80 100 96 13–17 > 90g 1.2 0.6–0.8 0.2 — 70 <5 None None Unknown Vigabatrin 2–10 100 0 1.1 80 None Zonisamide 10–40 50 40 1.45 35 None 9 105 80–100 45–173 (neonates) 37–73 (children) ~20d 10–140 (neonates)d 5–18 (children)d 6 10–15; 17 (PEMA) 4.5–18 (children) 10–36 (PEMA; children) 6–10 4.5–13; increases with increasing dose 3.2–5.7 12–21 8–17 4–14 (children) 7.5 5.7 (infants) 63 Level of Recommendation to Use Therapeutic Serum Concentrationa 3 – 3 3 3 – 3 – 3 2 4 2 3 1 1 3 2 2 2 2 3 1 4 2 1 = strongly recommended; 2 = recommended; 3 = useful; 4 = potentially useful. b Therapeutic serum concentrations not well established. c Bioavailability decreased in children < 8 yr and in older adults; clearance is 80% higher in children 2–4 yr and 40% higher in children 4–12 yr than in adults. d Michaelis-Menten pharmacokinetics; half-life varies with serum concentration; therefore, it might be better to express phenytoin elimination in the length of time it takes to clear 50% of the drug from the body, for example. e Upper end of the serum concentration range is not definitely established. f Depends on dose. g May vary with serum concentration. NAMR = N-acetyl metabolite of ezogabine; PEMA = phenylethylmalonamide. a ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 1-493 Neurology u. Primidone (Mysoline) i. Mechanism of action: Increases GABA-mediated chloride influx ii. Metabolized to phenobarbital and phenylethylmalonamide iii. Adverse effects: Sedation, drowsiness, ataxia, rash iv. Primidone, phenobarbital, and phenylethylmalonamide all have antiepileptic action. v. Pharmacokinetics: Enzyme inducer vi. Also used for essential tremor v. Rufinamide (Banzel) i. Mechanism of action: Fast sodium channel blocker ii. Pharmacokinetics: Absorption increased by food (should be administered with food); metabolized by hydrolysis rather than through CYP enzymes iii. Adverse effects: Headache, dizziness, fatigue, somnolence, nausea iv. Decreases concentrations of ethinyl estradiol and norethindrone v. Has an FDA indication only for Lennox-Gastaut syndrome vi. Slightly shortens the QT interval and therefore should not be used in patients with familial short QT syndrome vii. Available as an oral solution w. Stiripentol (Diacomit) i. Indicated for Dravet syndrome in combination with clobazam ii. Dose: 50 mg/kg/day in two or three divided doses iii. Adverse effects: Somnolence, decreased appetite, agitation, ataxia, weight loss, hypotonia, nausea, tremor, dysarthria, insomnia iv. Pharmacokinetics: Inhibits CYP 1A2, 2C19, 2D6, and 3A4 x. Tiagabine (Gabitril) i. Mechanism of action: Blocks GABA reuptake in the presynaptic neuron ii. Associated with new-onset seizures and status epilepticus in patients without epilepsy iii. Adverse effects: Dizziness, asthenia, somnolence, nervousness, tremor, diarrhea y. Topiramate (Topamax) i. Mechanism of action: Fast sodium channel blocker, enhances GABA activity and antagonizes AMPA/kainate activity, weak carbonic anhydrase inhibitor ii. Pharmacokinetics: Not extensively metabolized, eliminated in urine iii. Adverse effects: Drowsiness, paresthesias, psychomotor slowing (titrate slowly), weight loss, nephrolithiasis, acute angle-closure glaucoma, metabolic acidosis, hyperthermia (associated with decreased perspiration, or oligohidrosis), and decreased cognition, including word-finding difficulties iv. Extended-release formulations (Trokendi XR, Qudexy XR) v. Nonepileptic indication: Prophylaxis of migraine headaches, weight loss secondary to antipsychotic use z. Valproic acid, divalproex sodium, valproate (Depacon, Depakene, Depakote, Stavzor) i. Mechanism of action: Blocks T-type calcium currents, blocks sodium channels, increases GABA production ii.  Pharmacokinetics: Enzyme inhibitor ii. Parenteral use: Has FDA indication only for replacement of oral dosing; however, sometimes used for status epilepticus, especially if absence status epilepticus iv. Adverse effects: Hepatotoxicity, nausea and vomiting, weight gain, interference with platelet aggregation, pancreatitis, alopecia, tremor ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 1-494