[10.06] Anti-Epileptic Drugs V2.2.pdf

Pathologically excitable neurons

What are the three requirements for a seizure?

Increase in glutamate

What happens to excitatory activity during a seizure?

Decrease in GABA

What happens to inhibitory activity during a seizure?

Decreasing excitatory and increasing inhibitory effects

On what two principles is the treatment with anti-seizure drugs centered?

Bromide in 1850

What is the oldest anti-seizure medication and its year of introduction?

Phenobarbital in 1910

Which anti-seizure medication was introduced in 1910?

Spectrum of efficacy, pharmacokinetic properties, safety, and tolerability

What are the four medication-related factors considered when choosing an ASD?

Teratogenicity

What specific adverse effect must be considered for patients of child-bearing age?

Ease of use in adjusting dose and frequency of administration

What two factors contribute to the "simplicity" goal of medication for a patient?

Age, gender, comorbidities, and co-medications

What are four patient-related factors considered in choosing an ASD?

HLA-B1502 allele

What genotype is a risk factor for adverse drug reactions in patients of Asian descent?

Broad spectrum, high efficacy, good tolerability, and low cost

What are four ideal properties for an easy-to-use ASD?

Linear kinetics

What type of pharmacokinetic profile is preferred for an ideal ASD?

Lennox-Gastaut Syndrome

Which syndrome has a very small selection of effective medications?

Generalized Genetic (Idiopathic) Epilepsy

In which type of epilepsy should traditional sodium channel blockers be avoided to prevent exacerbation?

Phenobarbital, Phenytoin, Carbamazepine, and Oxcarbazepine

Which four drugs can exacerbate generalized absence or myoclonic seizures?

Gabapentin and Pregabalin

Which alpha-2-delta subunit calcium channel blockers should be avoided in myoclonic seizures?

Vigabatrin and Tiagabine

Which GABA inhibitors should be avoided in generalized absence or myoclonic seizures?

Ethosuximide

Which drug has a Class 1 recommendation for generalized absence seizures?

Voltage-gated ion channels, GABA system, synaptic release machinery, and ionotropic glutamate receptors

What are the four main molecular targets of ASDs?

Phenytoin, Carbamazepine, Lamotrigine, and Lacosamide

Name four drugs that target voltage-gated sodium channels.

Ethosuximide and Valproic acid

Name two drugs that target T-type calcium channels.

Gabapentin and Pregabalin

Which two drugs target the alpha-2-delta subunit of calcium channels?

Ezogabine (Retigabine)

Which drug targets potassium channels?

Phenobarbital, Benzodiazepines, and Topiramate

Name three drugs that target the GABAA receptor.

Tiagabine

Which drug is a GAT-1 GABA transporter inhibitor?

Vigabatrin

Which drug is a GABA transaminase inhibitor?

Levetiracetam and Brivaracetam

Which two drugs target the synaptic vesicle protein SV2A?

Perampanel

Which drug is a selective non-competitive AMPA receptor antagonist?

1938

In what year was Phenytoin introduced?

5,5 diphenylhydantoin

What was Phenytoin previously known as?

First-line or adjunctive for focal and generalized seizures, and status epilepticus

What are the primary clinical indications for Phenytoin?

Myoclonic and absence seizures

In which two seizure types is Phenytoin avoided?

Prolongation of the fast inactivated state of sodium channels

What is the mechanism of action of Phenytoin?

95 percent

What is the GI absorption percentage of Phenytoin?

тенденция to precipitate and high alkalinity

Why is the intramuscular use of Phenytoin avoided and the IV use cautioned?

Polyethylene glycol

What does the IV form of Phenytoin contain that increases the risk of cardiac arrhythmias?

Slow IV infusion

What is the recommended method for IV administration of Phenytoin to avoid arrhythmias?

Fosphenytoin

What is the soluble prodrug of Phenytoin preferred for parenteral use?

90 percent

What percentage of Phenytoin is protein-bound?

Valproic acid and Warfarin

Name two highly protein-bound medications that can displace Phenytoin and cause toxicity.

Lower total levels but higher free unbound levels

How does hypoalbuminemia affect Phenytoin plasma levels?

10 to 20 mg/L

What is the ideal therapeutic total serum level for Phenytoin?

1 to 2 mg/L

What is the therapeutic level for free Phenytoin?

4 to 8 days

How long after a dosage change does Phenytoin reach a steady-state?

CYP2C9 and CYP2C19

Which two liver enzymes metabolize Phenytoin?

Phenobarbital, Primidone, and Carbamazepine

Name three enzyme inducers that decrease Phenytoin serum levels.

Isoniazid and Valproic acid

Name two enzyme inhibitors that increase Phenytoin serum levels.

Non-linear (zero-order) kinetics

What type of kinetics does Phenytoin exhibit at therapeutic levels?

Small increments in dosage can cause toxicity

What is the clinical consequence of Phenytoin non-linear kinetics?

25 to 30 mg

By how much should the daily dose of Phenytoin be increased in adults to avoid toxicity?

Nystagmus, diplopia, and ataxia

What are the three most common dose-related adverse effects of Phenytoin?

Gingival hyperplasia, hirsutism, and coarsening of facial features

What are three adverse effects observed with chronic Phenytoin use?

Osteomalacia

What condition results from Phenytoin altering Vitamin D metabolism?

Low folate and megaloblastic anemia

What hematologic adverse effects are associated with Phenytoin?

HLA-B1502

The presence of which allele is predictive of Carbamazepine-induced severe rash?

Autoinduction

What unique feature of Carbamazepine causes it to reduce its own half-life after 20 to 30 days?

36 hours initially, reduced to 8 to 12 hours

How does the half-life of Carbamazepine change due to autoinduction?

10,11 epoxide

What is the active metabolite of Carbamazepine?

CYP3A4

Which cytochrome pathway metabolizes Carbamazepine?

Erythromycin and Grapefruit juice

Name two substances that inhibit CYP3A4 and increase Carbamazepine levels.

4 to 12 mg/L

What is the therapeutic level for Carbamazepine?

Hyponatremia and water intoxication

What electrolyte imbalance is associated with Carbamazepine?

Aplastic anemia and agranulocytosis

What fatal blood dyscrasias are rare but serious adverse effects of Carbamazepine?

300 to 1600 mg/day

What is the maintenance dose range for Carbamazepine in adults?

Oxcarbazepine

Which drug is a less potent version of Carbamazepine with an improved toxicity profile?

50 percent

By how much must the dose be increased when switching from Carbamazepine to Oxcarbazepine?

Licarbazepine (10-hydroxy metabolite)

What is the active metabolite of Oxcarbazepine?

Hyponatremia

Which adverse effect occurs more commonly with Oxcarbazepine than with Carbamazepine?

Eslicarbazepine

Which 3rd generation ASM is not susceptible to metabolic autoinduction?

13 to 20 hours

What is the half-life of Eslicarbazepine?

Steroid oral contraceptives

Eslicarbazepine decreases the plasma levels of which medication?

Blocks Na channels, Blocks Ca channels, and decreases glutamate release

What are the three mechanisms of action for Lamotrigine?

Glucuronidase

By which enzyme is Lamotrigine eliminated?

Slowly

How should Lamotrigine be titrated to avoid the risk of a severe rash?

25 mg every other day

What is the starting dose for Lamotrigine when given as polytherapy with Valproic acid?

Estrogen therapy and pregnancy

What two conditions decrease the half-life of Lamotrigine?

Monotherapy Lamotrigine

Which drug has the lowest rate of teratogenicity among traditional ASDs?

Lacosamide

Which novel ASD enhances the slow inactivation phase of sodium channels?

CRMP-2

Lacosamide modulates which protein to decrease neuronal loss in status epilepticus?

100 percent

What is the bioavailability of Lacosamide?

Increase in PR interval

What cardiac change requires a baseline ECG before starting Lacosamide?

250 to 300 mg/day

What is the maximum daily dose for Lacosamide in patients with end-stage renal disease?

Na channel blocker, GABAA potentiator, AMPA/kainate depressant, Ca channel inhibitor, and Carbonic anhydrase inhibitor

What are the five mechanisms of action for Topiramate?

Cognitive slowing

What is the main tolerability issue for Topiramate?

Paresthesias and urolithiasis

What two adverse effects of Topiramate are related to carbonic anhydrase inhibition?

Chronic metabolic acidosis and osteomalacia

What skeletal-related adverse effects are associated with Topiramate?

Acute myopia and glaucoma

Topiramate is contraindicated in patients with which two eye conditions?

Weight loss

What "beneficial" side effect of Topiramate is noted for overweight patients?

Hypospadias

What teratogenic effect is associated with in utero exposure to Topiramate?

Zonisamide

Which sulfonamide derivative has a long half-life of 60 hours?

Binds to the alpha-2-delta subunit of calcium channels

What is the mechanism of action for Gabapentin and Pregabalin?

Neuropathic pain, anxiety, and depression

Besides seizures, what are three other uses for Gabapentin and Pregabalin?

Renal metabolism

How are Gabapentin and Pregabalin primarily metabolized?

Painful gynecomastia and erectile dysfunction

What are two specific adverse effects noted for Gabapentin and Pregabalin?

Increase the frequency of Cl- channel opening

What is the mechanism of action for Benzodiazepines at the GABAA receptor?

Clonazepam and Clobazam

Name two oral benzodiazepines.

Diazepam and Midazolam

Name two IV benzodiazepines.

Halogen or nitro group at the 7th position

What structural feature of Benzodiazepines is responsible for sedative-hypnotic activity?

Desmethyldiazepam

What is the active metabolite of Diazepam with a 40-hour half-life?