Antiepileptic Drugs

  • Antiepileptic drugs are used for seizures
  • MOA: they either ↓start of seizures or ↓ its spread to other previously unaffected brain regions, or do both
  • Antiepileptic drugs act on GABA (BENZOS also work on GABA)
  • Selecting the drug should be based on seizure type, not the cause
  • 1st line drugs <effective but <side effects so usually start with a 1st line
  • You want to maximize the first drug. You want to minimize the side effects
  • Monotherapy is preferred so you know where the side effects are coming from
  • If the old drug is working well leave them alone
  • Compliance is the number one reason why drugs usually don’t work


  • Seizure= abnormal discharge/firing of neurons in brain
  • Convulsions=abnormal motor activity (not all seizures/epilepsies have convulsions)

Classification of Seizures

  • Generalized vs. focal
  • Convulsive vs.  nonconvulsive
  • Absent or focal seizures are treated a little different. Some of the regular drugs will make it worse
  • Absent seizures: involve a brief, abrupt and self-limiting LOC. The onset occurs from 2-5 and lasts until puberty.  The pt stares and exhibits rapid eye-blinking which lasts 3-5 seconds.

AED- The Old/New Agents

The Old Agents The New Agents
Carbamazepine (TEGRETOL) Gabapentin 
Ethosuximide (Zarontin) Lamotrigine 
Phenobarbital Levetiracetam (Keppra)
Phenytoin (Dilantin) Tiagabine (Gavitril)
Valproic acid (Depakene) Topiramate (Topamax)


AED: The Old vs. The New Agents

Older Agents Newer Agents
Efficacy Well established Probably as good
Clinical exp Considerable Still quite new
Current role Well established Evolving, mainly used as add ons to older AEDs
Pharmacokentics Complex, sometimes dose dependent influenced by other AEDs Simplier more predictable
DDIs Many Far fewer
Use in pregnancy More problematic Safer
Cost Relatively inexpensive More expensive



Phenytoin (Dilantin)


P P450 hepatic elimination, phlebitis (burns like hell), purple hand syndrome. peripheral neuropathy (interferes with B-6 and B-12)
H Hepatic toxicity have to monitor, Facial/Cosmetic: hirsutism (coarse facial structures), Hyperglycemia (interferes with the release of insulin);
E Enlarged gum, gingivitis; with mentally challenged pt
N Nystagmus
Y Yellow discoloration of skin
T Teratogenicity (birth defects)
O Osteoporosis. Interferes with vitamin d absorption more likely to fractures
I interferes with B12, vitamin K, folic acid, {weigh risk for benefits with pregnant pt bc of fetal hydantoin syndrome}
N Neurotoxicity Ataxia, sedation, lethargic, confusion 
s suicidal ideation
  • Treat patient not the lab values; a small change in dose can have an effect in neurotoxicity
  • Cerebyx can be given 150 ml/hr 3 X faster than Dilantin (50mg/hr) bc Dilantin can turn into propylene glycol in the blood
    • pt with underling cardiac or elderly must slow down Dilantin to 25mg/hr
    • Cerebyx is a PRO drug and turns to Phenytoin in the body (National shortage list)
    • Less burning of vessels
    • It will crystalize fast and MUST BE MIXED IN NORMAL SALINE and must use a 22g filter
    • Only stable for 2 hrs.
  • Fetal Hydantoin Syndrome: birth defect caused from mother who is taking Phenytoin during pregnancy
    • Characteristics are wide spread face and flat nose & interferes with a host of vitamins and nutrition
    • Supplement mother with Folic Acid and Vit B-12 to ↓chance of neural tube defect
    • Baby must be given Vit K to ↓risk of bleeding (bc vitamin k factors are inhibited)



  • Hepatic metabolism by the P450 system important to eliminate/inactivate the drug and prevent most adverse responses/toxicity
  • Its metabolic rate depends on blood levels. Zero order elimination. The body will only remove a certain amount at a time.
  • Blood levels (and so, effects) are not proportional to the dose given…
  • As blood levels ↑ towards and into the toxic range, enzymes that metabolize drugs at previous and faster rate), and so T ½ becomes longer than it was at lower blood levels
  • Phenytoin is both a cause and a target of DDIs (Drug drug interactions)
  • It induces metabolism of many other drugs, and its metabolism is affected by many other drugs, including other AEDs
  • If the dose of phenytoin rises too much, blood levels go up much faster than you would otherwise predict. That’s because the P450 system can’t metabolize the drugs as quickly as it did before; the half-life gets longer.

Phenytoin Metabolism, Half-Life, and Blood Levels Looked-At another Way

  • At toxic- or High Therapeutic Blood Levels: Relatively Slow Metabolism
  • At Low-Therapeutic or Subtherapeutic Blood Levels: Faster, First-Order Elimination
    • Implication: If phenytoin blood levels are too high and you stop the drug to allow them to fail, it will take much longer for them to fall than you might otherwise expect (or want)

Phenytoin Uses

  • Tonic-clonic seizures (most)-Grand mal seizures
    • Chronic tx, prophylaxis—a preferred drug for many patients
  • Acute (status epileptics)-Seizure that lasts longer than 30min
  • Also useful for some partial seizures
  • WARNING: May worsen absence seizures: avoid phenytoin if the patient has absence seizures, or be sure to add another drug that “targets” the absence seizures (but be aware of drug-drug interactions if a 2nd drug is added)


Side Effects of Phenytoin (And Most Other Anticonvulsants Too)

  • CNS
    • Drowsiness or sleepiness, Dizziness, Ataxia, Cognitive difficulties, Folic acid deficiencies, Osteomalacia, Carbohydrate intolerance, Hypothyroidism, peripheral neuropathy

Other Side Effects Rather Unique to Phenytoin

  • Gingival hyperplasia
  • Facial/Cosmetic: hirsutism, Skin, Coarsening, Acne
  • Vitamins, mineral deficiencies and clotting problems in pregnancy


Phenytoin and Several Other Anticonvulsants Can Cause Vitamin Deficiencies That are Particularly Important for Pregnant Women

  • Folate (folic acid) deficiency…can → fetal “neural tube” defects (malformation of spinal cord, face): important to supplement mom’s diet with folic acid
  • Vitamin K deficiency can →clotting/bleeding problems in newborns
  • Give oral Vitamin K supplements to mom starting at least 1 month before delivery
  • Baby gets Vitamin K injection at birth


Carbamazepine (TEGRETOL)


  • Still a mainstay for most partial and tonic-clonic seizures
  • A LOT OF DDI Hepatic metabolism by P450 is important for elimination, detoxification
  • REGULATES ITS OWN HALF-LIFE → so with each increasing dose of medication that is given the half-life will change (this is caused by the metabolism of the P450 system)
  • Like phenytoin, carbamazepine is both a target and a cause of many DDIs

Carbamazepine Uses

  • Uses, CI, Pregnancy issues: like phenytoin…for tonic-clonic seizures, partial seizures, but NOT absence seizures
  • Increasing use as mood-stabilizing drugs for in bipolar illness, as alternative to lithium (or some other anticonvulsants with mood-stabilizing properties (valproic acid)

Side Effects:

  • Neurotoxicity (most common)
  • CNS→N/V, Drowsiness, Blurred Vision, Vertigo, HA, Nystagmus
  • Hyponatremia →↑ with advancing age
  • Bone marrow suppressant
  • Idiosyncratic reactions
    • Rashes (may be severe)
    • Agranulocytosis (FEVER & SORE THROAT 1st sign)
    • aplastic anemia (both are very serious/fatal blood dyscrasias, but fortunately rare) bone marrow suppressant
C Cranial Nerve 5, Trigeminal Neuralgia  Tic Douloureux (used for neuropathic pain)
B Bipolar disorder
Z Seizure disorders


  • Tegretol will cause SIADH (syndrome of inappropriate ADH)=Hyponatremia
    • excessive release of antidiuretic hormone from the posterior pituitary gland or another source and result is Hyponatremia and sometimes fluid overload
    • LOW NA LEVEL; hypotonic urine
    • Usually seen in elderly, pt with tumor, stroke, pneumonia or lung tumor, something wrong in head or lung


Valproic Acid

(Depakene, Depakote)


  • Depakene is the active form. Depakote is EC. Used as an add on drug for depression
V Vomiting (why in EC now), GI distress
A Alopecia- hair loss (with long term use)  Good for absent seizures but watch SE, ↑ ammonia levels without show hepatic encephalopathy
L Liver toxicity, very bad for kids under 2 with mental disorder

Monitor liver profile→ ALT, AST, total bilirubin (indirect and direct). You can just order the  ALT it is specifically about the liver

P Pancreatitis- drug induced hyperglycemia. Acute /Chronic pancreatitis A patient will have a low Ca level with pancreatitis. Bc pancreas auto digests itself and binds up all the calcium 
O oedema- Retention of fluid and water
R  Rash. Retention of fat
A Appetite stimulation and weight gain
T tremors, thrombocytopenia (inhibit platelet count)
E enzyme Inhibits the metabolism of drugs and will ↑therapeutic effects of drugs and put you into toxicity


  • For all seizure types, increasing use overall, but there are still “concerns/cautions”
  • SLOW ONSET, ↑ dose too soon(→↑ risk of toxicity)
  • Inhibits hepatic metabolism
  • Protein-bound, easily displaced
  • Increasing use as mood-stabilizing drug for bipolar illness as an alternative to lithium

Adverse Effects

  • GI-distress (can be↓ by use of enteric-coated tablets Depakote)
  • Appetite stimulation (→ weight gain, sometimes considerable)
  • Edema 
  • ↑ ammonia levels
  • Trembling
  • Alopecia
  • Pancreatitis
  • ↓ platelet count, platelet function
  • Altered liver function tests/hepatotoxicity
    • relatively rare in adults
    • risk ↑ in kids on multiple anticonvulsants

Concerns for Women

  • No interference with oral contraceptive action (which occurs with many other AEDs)
  • May→ amenorrhea, dysmenorrhea
  • Best avoided in pregnancy, but if it must be used…
    • folic acid prophylaxis for prevention of CNS defects in baby
    • diligent prenatal care is essential


Barbiturates: Phenobarbital


  • Phenytoin is an alternative in children mainly because of no gingival hyperplasia
  • Induce P450 systems and causes DDIs with many other drugs
  • There are a few other barbiturates’ or barbiturates-like drugs, besides phenobarbital, that can be used for epilepsy
  • Long-term use of barbiturates for epilepsy, nowadays, probably the only valid long-term use for this class of drugs


  • tolerance, sedationphenytoin-like bleeding problems


  • Carbamazepine, Phenytoin, Barbs, Rifampin, Alcohol, Nicotine




  • Usually preferred for uncomplicated absence seizures… its only approved use


  • No effects on liver drug-metabolizing enzymes
  • But its metabolism is affected by other AEDs

Adverse Effects of Ethosuximide

  • Side effects( not always dependent on dose or blood levels of drugs)
    • GI distress
    • CNS side effects similar to other AED’s            
    • Rare, occasionally fatal, blood dyscrasias


Newer AEDs

Gabapentin (Neurontin) Lamotrigine (Lamictal)

Levetiracetam (Keppra) Tiagabine (Gabitril)

Topiramate (Topamax)


  • These and newer AEDs were developed mainly as add-on therapies for a relatively small numbers of epilepsy pts who are truly “ refractory” to other usually-effective drugs
  • Some are used  as “ mood stabilizing “ drugs for bipolar, instead of lithium, carbamazepine, or valproic acid


  • used for atypical pain, diabetic neuropathy, trigeminal neuralgia, somatic nerve damage
  • cleared 100% renal must adjust dose for renal patients
  • minimal DDI
  • Large amount doses (3,000mg) must increase dose slowly
    • SE: Weight gain, lethargic, edema


  • First cousin to Neurontin used for diabetic neuropathy atypical pain.
  • Same drug profile is not cleared 100 % by renal
  • Schedule 5 controlled drug


  • Used as an add on drug


  • Used for migraine may cause SI. Pay close to their lens (eyes), will cause a rash and may escalate to Stevens Johnson syndrome.
  • L-LENS
  • Used for migraines causes weight loss, kidney stones,” Dopamax” somewhat out of it, drowsy, out of it


“Refractory” Seizures

  • Most common cause of seizures is NONCOMPLIANCE not because lack of drug efficacy
  • Explore options for monotherapy before switching to add on drugs
  • Switching from one AED to another, or adding another AED, must be done carefully to avoid
    • Too much overlap will have an ↑ risk of excessive CNS depression
    • Not enough overlap (not enough of either drug during the  switch, which may allow seizures to reappear )


Status Epileptics: multiple seizures in a row

A Current Initial Approach

Thank Goodness All Cerebral Burst Dissipate

T Thiamine: for alcohol withdrawal induced seizures  (Wernicke Encephalopathy)
G Glucose: low glucose can cause a seizure. Brain doesn’t need insulin to get glucose into cells
A Ativan, versed, and valium.  Ativan gets in there quick and hangs around and causes a better suppression of seizure. Versed and valium are excreted quickly
C Cerebyx Fosphenytoin or Dilantin Drip
B Barbiturate phenobarbital- put the pt in a coma when having multiple seizures
D Diprivan – put pt in a diprivan coma when no other option
  • Try to rule out the precipitating cause of the seizure due to alcohol and put Thiamine and glucose (the glucose level in the brain is 2/3 that of the periphery=so if BG 100 than glucose in brain is 60)


Status Epileptics

  • Give IV Phenytoin Right After the Benzodiazepine
  • IV Ativan (lorazepam) first then IV phenytoin
  • immediately thereafter, “ automatically, “even if lorazepam stops seizures initially
  • Lorazepam stops seizures quickly, but effects are relatively brief
    • Slower, longer action of phenytoin provides coverage as effects of lorazepam subside
  • fos-Phenytoin


  • Prodrug (metabolized to phenytoin in the body)
  • More soluble, more physically compatible with common IV solutions, than regular phenytoin
  • Less irritating to veins, permits faster injection


“Problems’’ With IV Phenytoin

  • Slow getting into CNS(slow control of seizures)
  • Very alkaline, irritating to veins… must be diluted before use and can’t be pushed into vein quickly
  • Physically incompatible with D5W- you can’t dilute it with any of the common dextrose-containing IV fluids(must use saline)



Plasma Level Monitoring of AEDs

  • Therapeutic blood level ranges are known for just about every anticonvulsant and are easy to measure
  • “Target ranges’’ from lab tests are approximations of “ what’s good”
  • Pts aren’t all alike: response to a given blood level-treat the pt, not the blood level


Monitoring useful when:

  • Starting Tx. And adjusting dose
  • Adding or deleting AEDS(to help detect, correct, DDIs)
  • Assessing for, or reasons for, apparent failure to control seizures
  • Monitoring for, doing something  about, excessive effects/toxicity
  • Helping patients be compliant
  • Overall: Treat the patient, not the level



Anticonvulsants & Pregnancy:

  • Proper Tx. Can prevent seizures & complications for mom and baby
  • Pregnant women metabolize, respond to AEDs differently than non-pregnant women, so close monitoring is very essential
  • Serious fetal malformations
  • 2% in general population(no epilepsy, no drugs)
  • (only 3% overall ± epilepsy Tx(one drug)
  • Risk of adverse fetal effects rises dramatically as AEDs are added


Partial seizures

  • Carbamazepine (Tegretol), phenytoin(Dilantin)
  • Valproic acid (Depekote/Depakene), lamotrigine (lamicital) , gabapentin (Neurontin), benzodiazepines, barbiturates
  • Adjunct: Tiagabine(Gabitril), topiramate (Topamax) , levetiracetam (Keppra),  zonisamide


Generalized seizures: Tonic-clonic (grand mal):

  • Carbamazepine (Tegretol) , phenytoin (Dilantin)
  • Valproic acid (DDs), lamotrigine(lamicital), gabapentin, benzodiazepines, barbiturates
  • Adjunct: Topiramate (Topamax), zonisamide


Absence (petit mal):

  • Ethosuximide (Zarontin)
  • Valproic acid (when absence seizures coexist with tonic-clonic seizures)
  • Clonazepam
  • Adjunct: Lamotrigine, benzodiazepines