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 Ca2+

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.

End of presentation

Next topic – Uses of anticonvulsant drugs.

Copyright 2002, The University of Toledo