Anticonvulsants Flashcards
Name 6 traditional anticonvulsants
Phenobarbitol
Phenytoin
Carbamazepine
Ethosuximide
Valproic Acid
Fosphenytoin
Name 5 of the newer antiepileptic drugs
Gabapentin
Oxcarbazepine
Lamotrigine
Levetiracetam
Topiramate
Name drugs that prolong the inactive state of Na+ channels
Carbamazepine
Oxycarbazepine
Phenytoin
Valproic Acid
What drugs block T-type Ca+ channels and what kinds of seizures do they specifically treat?
Ethosuximide
Valproic Acid
Absence seizures
What drugs enhances the effect of GABA on GABAa receptors, inhibiting post synaptic potential generation
Phenobarbitol and other barbiturates and benzodiazepines
Phenobarbital: Type, Use (seizure type), MOA, Pharmacokinetics, Side effects
Type: Barbituate, first anti-seizure drug
Use: monotherapy for generalized tonic-clonic and partial seizures
MOA: – acts on GABA-A receptors to allow more Cl- ions to enter cells
Pharmacokinetics: 40-60% bound to plasma proteins, 25%
eliminated unchanged in urine, rest is metabolized in liver
(CYP2C9)
Side Effects - Sedation in adults, irritability/ hyperactivity in
children (why pheno. is not first line medication). Induction of CYP3A4 resulting in increased drug metabolism (e.g. oral contraceptives).
- Minor drug allergy occurs in 1-2% of patients taking phenobarbital
Side effects of Phenytoin
Side effects – Because CYP2C9/10/19 are saturable
enzymes, concentrations of other drugs metabolized by
CYP2C9/10/19 will be affected e.g. warfarin.
- Induction of CYP3A4 resulting in increased drug metabolism (e.g. oral contraceptives).
- Gingival hyperplasia (20%). Minor rash (2 - 5%)
- occasionally Stevens-Johnson Syndrome (SJS)
Phenytoin (Dilantin, Diphenylan): Use, MOA, Pharmacokinetics (protein binding, t1/2, liver enzymes
Use - monotherapy generalized tonic-clonic and partial
seizures; IV fosphenytoin for status eplipticus
Mechanism of Action – prolong rate of recovery of voltage gated Na+ channels from inactivation
Pharmacokinetics – 90% bound to plasma proteins
(albumin) t1/2 6 – 24hrs @ 10 µg/ml but t1/2 increases at
higher concentrations (drug concentration increases disproportionately as dosage is increased), 95% metabolized in liver (CYP2C9/10/19)
What is Stevens-Johnson Syndrome, symptoms, treatment, and what anticonvulsant it is a possible side effect of?
Stevens-Johnson Syndrome (SJS) < 10% surface area, 5% mortality
Adverse, immune system-mediated, drug reaction (not just anticonvulsants) characterized by blistering of skin and mucous membranes.
Starts as a flu with persistent fever progressing to blisters then
sloughing off of skin.
Treatment, discontinuation of use of suspected drug,immunosuppressives
Toxic Epidermal Necrolysis (TEN) > 30% SA, 20 – 40% mortality
Adverse effect of Phenytoin
Carbamazepine (tegretol, carbatrol): Use, MOA, Pharmakokinetics (what drugs increase its metabolism), Side effects (acute / chronic)
- Use - monotherapy generalized tonic-clonic and partial
seizures (also used in manic-depressive patients) - Mechanism of Action – prolong rate of recovery of voltagegated Na+ channels from inactivation
- Pharmacokinetics – metabolized to 10,11 epoxide (just as effective as carbamazepine), induces own metabolism,
difficult to maintain constant plasma concentration.
-Phenobarbital, phenytoin, valproic acid increase
metabolism of carbamazepine - Side effects – Acute: stupor, coma, hyperirritability
convulsions.
-Chronic: drowsiness, vertigo, ataxia, blurred
vision. Induces CYP3A4 resulting in increased drug
metabolism (e.g. oral contraceptives).
Oxcarbazepine (Trileptal): USe, MOA, Pharmacokinetics, Side effects
Structurally similar to carbamazepine
Use – monotherapy/adjunctive treatment partial seizures, in
2003 approved for monotherapy partial seizures 4 - 16 yr
olds
Mechanism of Action – prolong rate of recovery of voltagegated Na+ channels from inactivation
Pharmacokinetics – Acts as prodrug that is converted to
active metabolite in liver; inactivated by glucuronide
conjugation and eliminated by renal excretion, does not
autoinduce like carbamazepine
Side effects – Dizziness, nausea, somnolence, ataxia.
Less of a drug metabolizing enzyme inducer as
carbamazepine. However, it still induces CYP3A4 resulting
in increased drug metabolism (e.g. oral contraceptives).
Ethosuximide: Use, MOA, Pharmacokinetics, Side-effects
Use – monotherapy absence seizures
Mechanism of Action – inhibit T-type Ca channels
Pharmacokinetics – Not bound to plasma proteins, few
drug-drug interactions. 25% excreted in urine
Side effects – Nausea, vomiting, anorexia. CNS
drowsiness, lethargy, euphoria. SJS, aplastic anemia.
Valproic Acid (depakote, depakene): Use, MOA, Pharmacokinetics (protein binding, t1/2)
Use – monotherapy absence, myoclonic, partial and
tonic/clonic seizures, IV dosing, “broad spectrum” AED
Mechanism of Action – inhibit T-type Ca channels, prolong inactivation of Na channels, increase GABA synthesis (in vitro)
Pharmacokinetics – 90% bound to plasma proteins, t1/2 = 15 hrs but is reduced with other anticonvulsants
Side effects of Valproic Acid
(Hepatic toxicity)
Side effects – GI nausea, anorexia. CNS sedation, ataxia, tremor. Increase in hepatic blood enzymes (40%). Hepatic toxicity in patients < 2 yrs old on multiple AEDs including valproic acid.
-Inhibits CYP2C9 resulting in increased concentrations of phenytoin, phenobarbital, also displaces phenytoin from plasma binding proteins.
Provide some general background regarding the newer anti-epilpetic drugs
side effects, drug-interactions, effectiveness, MOA
– Lack serious side effects
– Do not induce liver enzymes, less drug-drug interaction
– Less efficacious than the traditional AEDs, approved for adjunctive treatment mostly
– Less is known about mechanism of action
Gabapentin (Neurontin): Use, MOA, Pharmacokinetics, Side effects
Use – Adjunctive treatment partial with and without genalized secondary seizures; neuropathic pain (2002) fibromyalgia.
Mechanism of Action – ?? Binds to L-type Ca channel, no
change in Ca conductance
Pharmacokinetics –Not metabolized, excreted unchanged in urine. Renal function must be determined.
- Side effects – Fatigue, ataxia
What is Lennox-Gustaut Syndrome
onset, cognition, seizures, response to therapy, mortality rate, diet?
Childhood-onset epilepsy
Severe cognitive dysfunction
Multiple seizure types including atonic
Resistant to drug therapy
Mortality rates 3 – 7%
Ketogenic Diet is a treatment for LGS
Lamotrigine (Lamictal): Use, MOA, Pharmacokinetics and side effects
Use – Monotherapy and adjunctive treatment partial- and
generalized tonic/clonic seizures; LGS. “Broad spectrum” AED
Mechanism of Action – prolong rate of recovery of voltagegated Na+ channels from inactivation, inhibit Ca to lesser extent
Pharmacokinetics –T1/2 = 24 – 35 hrs phenytoin,
carbamazepine, phenobarbital, primidone reduce t1/2 to
15hrs. Reduces valproate by 25%.
Side effects – dizziness, ataxia, blurred vision, nausea. Rash and SJS when in addition to other AEDs
Topiramate (Topomax): USe, MOA, Pharmacokinetics and side effects
Use – Mono and Adjunctive therapy for partial and
tonic/clonic seizures, LGS. “Broad spectrum” AED.
Mechanism of Action – Inhibit Na channels and AMPA-kainate receptors enhance GABA receptors
Pharmacokinetics – little protein binding; mostly (~ 85%)
excreted unchanged in urine
Side effects – Ataxia, fatigue, somnolence, weight loss.
Reduces plasma levels of oral contraceptives
Levetiracetam (Keppra): Use, MOA, Pharmacokinetics and side effects
Use – Adjunctive treatment for partial and tonic/clonic
seizures in adults and myoclonic seizures in children; IV
preparation for status epilepticus
Mechanism of Action – ?? May prevent presynaptic glutamate release.
Pharmacokinetics –65% excreted unchanged in urine, no
liver enzyme induction, highest safety margin in animal
studies, rapid dose titration, 3-D “printing” FDA approval.
Side effects – somnolence, dizziness, asthenia , no drug-drug interactions
What is the definition of Status Epilepticus: mortality rate and how to treat
Series of seizures (any type) where full recovery from
one seizure does not occur before onset of next seizure
– Medical Emergency ~ 20% mortality rate
Initial treatment (IV only)
* Benzodiazepine urgently
– Diazepam IV 5-10 mg initially, repeat up to 20-30 mg in no response (pt will typically need respiratory support)
– Lorazepam (ativan) IV preferable to diazepam, acts longer
What are some additional steps in the treatment of status epilepticus following intial response?
What to avoid, what drug to give once seizures are controlled. What are some alternatives to this drug?
Monitor/avoid hypoventilation and hypotension with initial treatment (caused by high dose of diazepam / lorazepam
-many patients will need ventilation with this much benzodiazepine
- Once seizures controlled give fosphenytoin (Cerebyx®) water soluble prodrug of phenytoin
– IV phenytoin not preferable due to alcohol/alkaline – irritating to veins - Alternatives to fosphenytoin are now available; levetiracetam (may be better than benzo.), phenobarbital, valproic acid.
What are some special considerations in providing anticonvulsants regarding osteoporosis?
Long term use of older or traditional AEDs
may cause osteoporosis.
* Mechanism may be due to altered vitamin D
metabolism in liver.
* Elderly patients on AEDs should have bone
mineral density measured.
What are some special considerations for antiepileptic drugs (AEDs) and pregnancy?
Failure rate of oral contraceptives is 3X more
in women taking AEDs
2 – 3 fold increase in birth defects while
taking AEDs during pregnancy.
– E.g., neural tube defects, fetal hydantoin
syndrome – facial and cranial deformities
associated with phenytoin, but all AEDs can
cause fetal hydantoin syndrome
What do you do when prescribing AEDs to pregnant women?
which drugs are class D teratogenic?
– If combination therapy, reduce to monotherapy then carefully monitor drug plasma levels/seizure activity
– Give folate (0.4 mg/day) to help reduce likelihood of neural tube birth defects
– Give vitamin K (10 mg/day) during last month of gestation to help reduce newborn blood coagulation problems/vitamin K deficiencies
– Valproic acid is teratogenic (cognitive
impairment); class D same as phenytoin
What is the ketogenic diet? What seizure disorder can it be used to treat?
Widely used prior to 1938 before phenytoin
* 10 to 15 grams of carbs a day
* Used to treat LGS and others for pediatric patients
* May involve increased GABA-A receptor
expression
Special considerations in epilepsy regarding suicide and suicidal ideation?
Manufacturers of all AEDs are required by FDA to update product labels indicating increased risk for suicidal thoughts or actions. One study shows that people taking AEDs had a 3.5 fold increase in suicide by medication overdose (e.g.
opioids).
Affects all AEDs except those indicated for
short term use
