(DPH, diphenylhydantoin) Phenytoin (DPH, diphenylhydantoin)

-MOA: At therapeutic dose, prolongs inactive state of Na+ channel, reduced neural firing

-Use: PS GTC (not for absence type) Absorption: Complete but variable time (3-12h), not for IM, can give IV emergency

-Metabolism: Biphasic, patient variability Therapeutic levels = 10-20 µg/ml Phenobarb and carbamaz. enhance phen. metab.

-DPH decreases effectiveness of oral contraceptives

DPH Toxicities Little sedation (major factor)

-Acute: Nystagmus, diplopia, GI, CNS -Chronic: Gingival hyperplasia, hirsutism, abnormal vit. D,K metabolism, idiosyn. rx.

-High dose toxicity: Cardiac arrhythmias, CNS depression

DPH -Assessment First good anti-conv. with minimal sedation

Multiple SEs and issues with absorption and serum levels, high variability

-Good alternatives now available so no longer a first line drug

-Phenytoin has low solubility, can precipitate out when given IM or IV Fosphenytoin is a phosphate ester prodrug of phenytoin with good solubility

-Rapidly converted to phenytoin in body

*Can be given either IM or IV (for status)

-MOA: Na+ channel to prolong inactive state, also enhance GABA activity

Use: Widely for PS+GTC (not for absence seizures), Trigeminal neuralgia + bipolar affective disorder

Absorption: Variable between patients Metabolism: Significant enzyme induction, enhances own/other drug met.

Interactions: increases met. of DPH, ethosux., valproate, oral contraceptives

High dose toxic.: stupor, coma, convuls.

Chronic tox: diplopia, ataxia, GI, fluid retention

Blood tox: Major concern, idiosyn. rx., aplastic anemia and agrunulocytosis, in elderly and first 4 mo., trigem. neur. Stevens-Johnson syndrome: skin rash with blisters over extensive areas that may be fatal. Rare but in Asian population 10X higher so test for susceptibility

MOA: inactivates Na+ channel, prolongs GABA channel opening, AMPA antagonist

Uses/Limitations: Too sedating so little used alone, usually an add-on, sometimes used in infants, not in children due to covert behavioral toxicities

Clinical use: PS+GTC (not absence or atonic- may worsen)

Toxicities: Sedation, ataxia, resp. dep. (OD), exacerbation of porphyria, tolerance and withdrawal syndrome

-Add on for refractory, also monotherapy for partial, -can worsen myoclon in children;

-use increasing

*may see idiosyncratic rash in 1-2% that can become severe--> so DQ at first sign of rash

*Low rate of birth defects compared to others if taken during pregnancy

-useful in uncontrolled or poorly controlled partial seizures (PS+GTC)

*Good but too TOXIC, aplastic anemia and hepatic toxicity

-GABA analog, main advantage is kidney excretion so liver effects of other drugs not as much interference

*Use: PS+neuropathic pain (diabetic neuropathies)+ alcoholism

*popular because no liver involvement

-block Na+channels, enhance GABA activity

*Weight loss-being used for this effect in many cases (not just as anti-convulsant)  

-SEs include somnolence, cognitive slowing, fatigue, psychiatric signs

-Newly approved GABA analog

-PS+ neuropathic pain of post herpetic neuralgia and diabetic neuropathy

-produce euphoria

*PS

-Unusual profile, effective in kindling model, binds synaptic vesicle protein SV2A, may influence glutamate and GABA release

*Absence seizures, often drug of choice for monotherapy

-MOA: Inhibits T-type Ca++ channel at low dose, reduces rhythmic thalamic activity

-Toxicities: Few, GI main one, others lethargy, rash (rare), bone marrow suppression (rare)

Benzodiazepines

-Most benzodiazepines have anti-convulsant activity, but limitations are the side effects they produce and the abuse potential

*Diazepam: For status epilepticus

-Toxicities sedation, tolerance, withdrawal syndrome

Benzodiazepines

*Clonazepam: absence, myoclonic and infantile spasms

-Toxicities sedation, tolerance, withdrawal syndrome