phcl-3720 pharmacology ii dr. william messer department of pharmacology the university of toledo ...
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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 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
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
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.