Exam 3- L27 And 28 Anticonvulsants Flashcards
Epileptic Seizures
Short term alterations in behavior due to disordered, synchronous, rhythmic firing of brain neurons.
Non Epileptic Convulsions
Electroshock Therapy
Chemical convulsants
Myotonia Congenita
Neurocysticerosis
Parasitic worms causing seizures
Newer anti-epileptic drugs
Lack serious side effects
Do not induce liver enzymes, less drug interaction
Less efficacious than traditional AEDs
Less known about mechanism of action
Gabapentin (neurontin)
Used for adjunctive treatment partial with and without generalized secondary seizures
Mech: Binds to L type Ca channels, no change in Ca conductance
Pharmacokinetics: Not metabolized, excreted unchanged in urine
Side effects: fatigue, ataxia
Pregabalin also used for fibromiaglia
Felbamate (felbatol)
Taken off market then reintroduced with black box warning
Use: mono therapy and adjunctive treatment of Lennox gustaut syndrome, generalized seizures in adults
Mech: inhibitor Ca, Na channels as well as NMDA and AMPA kainate receptors
Side effects: GI upset anroexia, insomnia, aplastic anemia, hepatotoxicity
Last resort for treatment of resistant seizures/conditions
Lennox-Gastaut syndrome
Childhood onset epilepsy
Severe cognitive dysfunction
Multiple seizure types including atonic
Resistant to drug therapy
Ketogenic diet
Lamotrigine (lamictal)
Use: mono and adjunctive treatment partial, generalized tonic/clonic seizures, broad spectrum AED LGS**
Mech: prolong rate of recovery of voltage gated Na channels from inactivation, inhibit Ca to lesser extent
Kinetics: T 1/2 = 35 hours phenytoin, carbamazepine, phenobarbital, primidone reduce t1/2 to 15 hours, reduces valproate by 25%
Side effects: dizziness, ataxia, blurred vision, nausea, rash and Sjs when in addition to other AEDs
Topiramate (topomax)
Use: mono and adjunctive therapy for partial and tonic/ clonic seizures.LGS** Broad Spectrum
Mech: inhibit Na channels and AMPA kainate receptors enhance GABA receptors
Kinetics: little protein binding, mostly excreted in urine
Side effects: ataxia, fatigue, somnolence, weight loss. Reduces plasma levels of oral contraceptives
Levetiracetam (keppra)
Use: adjunctive treatment for partial and tonic/clonic seizures in adults and myoclonic seizures in children. IV preparation for status epilepticus
Mech: ?? may prevent presynaptic glutamate release
Kinetics: 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
Status epilepticus
Series of seizures where full recovery from one seizure does not occur before onset of next seizure
Treatment: benzodiazapine urgently and initially, lorazepam preferable as acts longer
Once seizures controlled, give fosphenytoin (water soluble prodrug of phenytoin)
Alternatives to fosphenytoin: levetiracetam, phenobarbital, valproic acid
AEDs and Osteoporosis
Long term use of older or traditional AEDs may cause osteoporosis
May be due to altered vitamin D metabolism in liver
AED and pregnancy
Failure rate of oral contraceptives is 3x more likely in women taking AEDs
2-3 fold increase in birth defects while taking AEDs during pregnancy
Give folate to help reduce likelihood of neural tube birth defects
Epilepsy
One of the most common neurological disorders.(40 distinct syndromes)
Usually begins in childhood
Alcohol, fatigue, lights are triggers.
Recognized more than 2400 years ago.
Seizure Types
Partial (Focal) begin at a single site in cortex.
- Simple seizures: consciousness is preserved e.g. focal motor, jacksonian, somatosensory, lasting 20-60 seconds.
- Complex Seizures: loss of consciousness. May begin with a simple seizure, hallucination, or strong emotions. Automatisms including lip smacking and hand wringing. 30 seconds to 2 minutes.
Partial vs Generalized Epilepsies
Partial epilepsies are confined to one region of the brain, while generalized epilepsies involve both hemispheres.
Shown on EEG as spikes in only 2/3 electrodes vs many electrodes respectively.
Absence Seizures
Less than 30 seconds, sudden impaired consciousness, staring, blinking, thalmic T type Ca channels are responsible for the 3Hz spikes.
Mechanism of Carbamazepine, Oxycarbazepine, Phenytoin, and Valproic Acid.
Inhibit propagation of neuronal action potentials by inhibiting voltage gated Na channels. Prolong the inactive state.
Mechanism of Ethosuximide and Valproic Acid
Inhibit T-type calcium channels on the postsynaptic neuron. Treatment of absence seizures.
Mechanism of Barbituates(Phenobarbital and Primidone) and Benzodiazepines(Diazapam)
Enhance activity of GABAa receptor which hyperpolarizes the postsynaptic neuron through influx of Chloride ions.
Mechanism of Tiagabine.
Inhibits GABA reuptake.
Mechanism of Vigabatrin
Inhibits GABA breakdown.
Diagnosis criteria for Epilepsy
2 unprovoked seizures.
First monotherapy 70% are seizure free.
If not move on to second monotherapy or combination therapy.
Surgical Assessment possible later.
What needs to be diagnosed before starting therapy with an older AED?
Type of seizure. Only ethosuximide and Valproic acid are efficacious monotherapies for absence seizures. Phenytoin, carbamazepine, gabapentin, tiagabine, oxycarbazepine, pregabalin, and viagabatrin are associated with exacerbation of absence and myoclonic seizures.
Treatment prior to 1912
Gram quantities of Na or K bromide as sedatives. Side effects included profound sedation and skin rashes and lesions.
Phenobarbital
Barbiturate 1912, first anti seizure drug, still used today, cheap and accessible.
-Used for tonic-clonic and partial seizures.
-Enhances activity of GABAa receptor
-40-60% bound to plasma proteins, 25% excreted in urine unchanged, rest is metabolized in liver by CYP2C9.
-Side Effects: Sedation in adults, irritability/hyperactivity in children. Induction of CYP3A4, increased drug metabolism.
-Rash in 1 to 2% of patients
Primidone
-Barbiturate 1954, metabolized to phenobarbital and PEMA.
-Monotherapy for generalized tonic clonic, partial, and adolescent myoclonic seizures. Not as effective as phenobarbital.
-Enhances GABAa receptor
-Rapidly absorbed, but half life is variable 5-15 hours. Variation between dose and plasma concentration.
-Side Effects: Same as Phenobarbital plus nausea, dizziness, ataxia, and nystagmus.
Phenytoin
-Monotherapy for tonic-clonic and partial seizures.
-Prolong inactivation in voltage gated Na channels.
-Half life increases at higher concentrations. Drug concentration increases disproportionately as dosage is increased.
-Metabolized by CYP2C9, so other drugs metabolized by it will have increased concentrations. Induces CYP3A4(increased drug metabolism). Gingival hyperplasia and SJS.
Stevens-Johnson Syndrome
<10% surface area 5% mortality.
-Adverse immune mediated drug reaction categorized by blistering of skin and mucous membranes.
-Flu with persistent fever progressing to blisters then sloughing off of skin.
-Discontinue the drug and use immunosuppressives.
-Toxic epidermal necrolysis is more extreme.
Carbamazepine
Monotherapy for tonic-clonic and partial seizures.
-Prolong inactivation of voltage gated Na channels
-metabolized to 10.11 epoxide which is just as effective and induces its own metabolism. Hard to maintain plasma concentration. Phenobarbital, phenytoin, and Valproic acid increase metabolism of carbamazepine.
-Acute Side Effects: stupor, coma, hyper-irritability, convulsions.
-Chronic Side Effects: Drowsiness, vertigo, ataxia, blurred vision, CYP3A4 induction.
Oxycarbazepine
-Monotherapy/adjunctive treatment for partial seizures in adults and children.
-Mechanism is the same as carbamazepine.
-Acts as a prodrug that’s converted to an active metabolite in the liver. Inactivated by glucuronide conjugation. Does not autoinduce.
-Side Effects: Dizziness, Nausea, Somnolence, Ataxia. Induces CYP3A4, but less than carbamazepine.
Ethosuximide
-Absence seizures
-Inhibits T-type calcium channels on the postsynaptic neuron.
-Not bound to plasma proteins, few drug-drug interactions.
Side Effects: Nausea, vomiting, anorexia.
CNS Side Effects: Drowsiness, lethargy, euphoria, SJS, aplastic anemia.
Valproic Acid
-Monotherapy for absence, myoclonic, partial and tonic-clonic seizures. IV dosed.
-Inhibits T-type Ca channels on the postsynaptic neuron, prolongs inactivation of Na channels, increases GABA synthesis.
-90% bound to plasma proteins. Half life is reduced by other anticonvulsants.
-Side Effects: Nausea, anorexia, sedation, ataxia, tremor, increase in hepatic blood enzymes, hepatotoxicity in patients less than 2 years old on multiple AEDs.
Inhibits CYP2C9, so increases concentration of phenytoin and phenobarbital.
