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PHCL-3720 Pharmacology II Dr. William Messer Department of Pharmacology The University of Toledo March 25, 2002
Anticonvulsants Lamotrigine (Lamictal ® ). Decreases Na + channel activity. Prolongs Na + channel inactivation. Inhibits N- and P-type Ca 2+ channel.
Anticonvulsants Tiagabine (Gabatril ® ). Inhibits neuronal and glial uptake of GABA. Potentiates GABA activity. Topiramate (Topamax ® ). Blocks voltage-sensitive Na + channels. Augments GABA activity. Inhibits NMDA-glutamate receptors.
Phenobarbital disposition Absorption. ~ 90 %. Distribution. Protein binding ~50 %. V 1 l/kg. Rapid CNS distribution.
Phenobarbital disposition Elimination. 65 % hepatic oxidation, 35 % excreted in urine. Half-life 24-140 hrs. in adults, 40-70 in children. Therapeutic range. 15-40 mg/L.
Primidone disposition Absorption. ~ 90 %. Distribution. Protein binding ~ 20 %. Elimination. Hepatic oxidation to phenobarbital. Ring opening to phenethylmalonamide. Half-life ~ 30 hrs. Therapeutic range. 5-15 mg/L.
Carbamazepine disposition Absorption. ~ 75 %. Distribution. Protein binding ~ 75 %. Elimination. Hepatic oxidation 74 %; excretion in feces 25 %, urine < 1 %. Half-life 30-60 hr. initially, 12-15 hrs. after autoinduction. Therapeutic range. 5-10 mg/L.
Ethosuximide disposition Absorption. ~100 %. Distribution. No plasma binding. V ~ 0.65 – 0.7 l/kg. Elimination. Hepatic oxidation 80 %. Half-life 60 hrs. in adults, 30 in children. Therapeutic range. 40-100 mg/L.
Clonazepam disposition Absorption. 100 %. Distribution. Protein binding 82 %. V ~2-6 l/kg. Elimination. Extensive hepatic metabolism. Half-life 20-95 hrs. Therapeutic range. 0.02-0.07 mg/L.
Valproic acid disposition Absorption. 90-95 %. Distribution. Protein binding 80-95 %. V ~0.1-0.5 l/kg. Elimination. Hepatic metabolism; oxidation, glucuronidation. Half-life 8-20 hrs. Therapeutic range. 50-100 mg/L.
Phenytoin disposition Absorption. 98 %. Distribution. Protein binding 90 %. V ~0.6-0.8 l/kg. Elimination. Hepatic metabolism; oxidation, glucuronidation. Unusual kinetics. Therapeutic range. 10-20 mg/L.
Felbamate disposition Absorption. 90 %. Distribution. Protein binding 90 %. V ~0.6-0.8 l/kg. Elimination. 60 % excreted unchanged; 40 % metabolized. Half-life 24 hrs., decreases with co- administration of other anticonvulsants.
Gabapentin disposition Absorption. 24-60 %. Distribution. Protein binding low. V ~ 0.8 l/kg. Elimination. Not metabolized. 100 % excreted intact in urine. Half-life ~ 6 hrs. Therapeutic level. ~2 mg/L.
Lamotrigine disposition Absorption. 100 %. Elimination. Glucuronidation (70 %). Induces own metabolism. Half-life 24-30 hrs. Accelerated by phenobarbital, carbamazepine.
Topiramate disposition Absorption. Rapid. Elimination. Largely (70 %) excreted in urine. Half-life 21 hrs.
Tiagabine disposition Absorption. 90 - 95 %. Distribution. Binding to plasma proteins 95 %. Elimination. Metabolized by CYP3A4. Glucuronidation. Half-life 8 hrs. with monotherapy; 4- 7 hrs. with other antiepileptic drugs; even lower in children.
Adverse effects Barbiturates. Sedation, ataxia. Allergic reactions.
Adverse effects Phenytoin. Allergic reactions. Symptoms (pruritis, fever, rash) appear within a few weeks. Hepatotoxicity. Reactive epoxide intermediate in patients deficient in epoxide hydrolase. Dose-related toxicities. Nystagmus, blurred vision; ataxia; dysarthria; confusion.
Adverse effects Phenytoin (continued). Chronic toxicities. Gingival hyperplasia. Hirsutism. Folate deficiency. Hypocacemia and osteomalacia. Fetal anomalies.
Adverse effects Carbamazepine. Neurological. Disequilibrium, drowsiness, headache, confusion, blurred vision. Hematological. Transient leukopenia (decrease in white cell count). Metabolic. Hyponatremia (low blood Na + ). Osteomalacia (bone softening).
Adverse effects Benzodiazepines. Sedation. Ataxia.
Adverse effects Valproic acid. Low sedation or ataxia. Nausea, GI irritation. Pancreatitis. Acute hepatic necrosis. Occurs after 1-6 months of treatment. Oxidation of valproic acid to alkene intermediate. Allopecia. Hair thinning in children. Blood clotting impaired. Avoid in patients with bleeding disorders.
Adverse effects Succinimides. Transient leukopenia. Occasional pancytopenia (decrease in blood cellular elements). GI distress. Sedation, dizziness, anxiety, inability to concentrate, headache. Allergic reactions. Urticaria (localized swelling of skin).
Adverse effects Felbamate. Aplastic anemia. Liver failure. Insomnia, headache, somnolence, fatigue. Dyspepsia, vomiting, nausea, anorexia. Recommended as second line therapy only by FDA.
Adverse effects Lamotrigine. Rash. May be life threatening. Not recommended for children. Binding in melanin rich tissues (e.g., eye), visual disturbances. Neurological effects. Dizziness, drowsiness, confusion, depression, emotional lability, tremor.
Adverse effects Gabapentin. Fatigue. Weight gain (average 16 lbs.). Drowsiness, tremor, nervousness, irritability. Dyspepsia, constipation.
Adverse effects Topiramate. Neurological. Dizziness, drowsiness, ataxia, nystagmus, parasthesias. GI. Dyspepsia, constipation, nausea, vomiting, abdominal pain. Miscellaneous. Nephrolithiasis (2-4x higher risk). Patients with kidney stone history should increase fluid intake.
Adverse effects Tiagabine. Neurological (high incidence). Dizziness, light-headedness, drowsiness, tremor, anxiety, impaired cognition, ataxia. GI. Abdominal pain, nausea, vomiting,. Cutaneous. Serious rash (Steven’s Johnson). Teratogenic in animals. Avoid use during pregnancy.
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