Exam 3- L27 And 28 Anticonvulsants

Question 1

Epileptic Seizures

Answer 1

Short term alterations in behavior due to disordered, synchronous, rhythmic firing of brain neurons.

Question 2

Non Epileptic Convulsions

Answer 2

Electroshock Therapy
Chemical convulsants
Myotonia Congenita

Question 3

Neurocysticerosis

Answer 3

Parasitic worms causing seizures

Question 4

Newer anti-epileptic drugs

Answer 4

Lack serious side effects

Do not induce liver enzymes, less drug interaction

Less efficacious than traditional AEDs

Less known about mechanism of action

Question 5

Gabapentin (neurontin)

Answer 5

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

Question 6

Felbamate (felbatol)

Answer 6

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

Question 7

Lennox-Gastaut syndrome

Answer 7

Childhood onset epilepsy

Severe cognitive dysfunction

Multiple seizure types including atonic

Resistant to drug therapy

Ketogenic diet

Question 8

Lamotrigine (lamictal)

Answer 8

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

Question 9

Topiramate (topomax)

Answer 9

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

Question 10

Levetiracetam (keppra)

Answer 10

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

Question 11

Status epilepticus

Answer 11

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

Question 12

AEDs and Osteoporosis

Answer 12

Long term use of older or traditional AEDs may cause osteoporosis

May be due to altered vitamin D metabolism in liver

Question 13

AED and pregnancy

Answer 13

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

Question 14

Epilepsy

Answer 14

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.

Question 15

Seizure Types

Answer 15

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.

Question 16

Partial vs Generalized Epilepsies

Answer 16

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.

Question 17

Absence Seizures

Answer 17

Less than 30 seconds, sudden impaired consciousness, staring, blinking, thalmic T type Ca channels are responsible for the 3Hz spikes.

Question 18

Mechanism of Carbamazepine, Oxycarbazepine, Phenytoin, and Valproic Acid.

Answer 18

Inhibit propagation of neuronal action potentials by inhibiting voltage gated Na channels. Prolong the inactive state.

Question 19

Mechanism of Ethosuximide and Valproic Acid

Answer 19

Inhibit T-type calcium channels on the postsynaptic neuron. Treatment of absence seizures.

Question 20

Mechanism of Barbituates(Phenobarbital and Primidone) and Benzodiazepines(Diazapam)

Answer 20

Enhance activity of GABAa receptor which hyperpolarizes the postsynaptic neuron through influx of Chloride ions.

Question 21

Mechanism of Tiagabine.

Answer 21

Inhibits GABA reuptake.

Question 22

Mechanism of Vigabatrin

Answer 22

Inhibits GABA breakdown.

Question 23

Diagnosis criteria for Epilepsy

Answer 23

2 unprovoked seizures.
First monotherapy 70% are seizure free.
If not move on to second monotherapy or combination therapy.
Surgical Assessment possible later.

Question 24

What needs to be diagnosed before starting therapy with an older AED?

Answer 24

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.

Question 25

Treatment prior to 1912

Answer 25

Gram quantities of Na or K bromide as sedatives. Side effects included profound sedation and skin rashes and lesions.

Question 26

Phenobarbital

Answer 26

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

Question 27

Primidone

Answer 27

-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.

Question 28

Phenytoin

Answer 28

-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.

Question 29

Stevens-Johnson Syndrome

Answer 29

<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.

Question 30

Carbamazepine

Answer 30

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.

Question 31

Oxycarbazepine

Answer 31

-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.

Question 32

Ethosuximide

Answer 32

-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.

Question 33

Valproic Acid

Answer 33

-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.