Pharmacological treatment of seizures

Question 1

What is the goal of therapy and mechanisms of action for antiepileptic drugs (AEDs)

Answer 1

Antiepileptic drugs

1. goal: to suppress the formation or spread of abnormal electrical discharges in the brain
2. Mechanisms:
   
   1. inhibition of Na+ or Ca++ influx responsible for neuronal depolariztion
   2. increase inhibitory neurotransmission by GABA (opening of Cl- channels)
   3. inhibit excitatory glutamate neurotransmission

Question 2

Phenytoin

1. MOA:
2. Use:

Answer 2

Phenytoin

1. MOA:
   
   1. alters Na+: prolongs the INACTIVE state of the Na+ channel and inhibits the generation of repetitive action potentials
   2. Decreases glutamate release
   3. Increases GABA release
2. Use: All forms of focal seizures
   
   1. simple partial
   2. complex partial
   3. partial with secondarily generalized tonic-clonic

Question 3

General Pharmacokinetics of Seizure medications

1. Most are cleared through _____
2. most older AED are inducers of ______.

Answer 3

General Pharmacokinetics of Seizure medications

1. Most are cleared through hepatic mechanisms
2. most older AED are inducers of cytochrome P450.

**Lots of drug interactions*

Question 4

Phenytoin- Pharmacokinetics

1. administration route:
2. _____ bound by protein
3. metabolized by_______
4. Induces hepatic enzymes:
5. what determines the rate of elimination?

Answer 4

Phenytoin- Pharmacokinetics

1. administration route: orally, extended or rapid release.
   
   1. absorption is 100%
2. Highly bound by protein
3. metabolized by CYP2C9
4. Induces hepatic enzymes: CYP2C
5. Elimination is dose-dependent. Low blood levels follow first order kinetics, increasing the blood levels saturates the liver’s ability to metabolize the drug (zero order kinetics)

Question 5

General Pharmacokinetics of Seizure Medications

1. most are ______ active
2. most are ______ to plasma proteins
3. Predominately distributed into ________.
4. plasma clearance is ______.
   
   1. Most considered to be ________ acting.

Answer 5

General Pharmacokinetics of Seizure Medications

1. most are orally active- 80-90% of the drug makes it into circulation
2. most are not highly bound to to plasma proteins
3. Predominately distributed into total body water.
4. plasma clearance is slow.
   
   1. Most considered to be medium to long acting.

Question 6

Phenytoin- Interactions

1. Valproate:
2. warfarin
3. OCC
4. Carbamazepine
5. what affect does it have on thyroid function tests?

Answer 6

Phenytoin- Interactions

1. Valproate: competes with the binding protein leading to increased phenytoin plasma levels
2. warfarin: prevents degredation leading to bleeding disorders
3. OCC: enhanced metabolism of OCC leading to babies
4. Carbamazepine: faster metabolism of both drugs
5. what affect does it have on thyroid function tests? has an affinity for thyroid-inding globulin which may afect thyroid function tests. Measure TSH instead

Question 7

Phenytoin- Toxicity

1. 5 adverse effects
2. long-term effects:
3. black box warning

Answer 7

Phenytoin- Toxicity

1. 5 adverse effects DANG
   
   1. ​Diplopia and Ataxia (requires dose adjustment
   2. Nystagmus and loss of smooth extraocular pursuit movements (DON’T CHANGE THE DOSE)
   3. Gingival Hyperplasia
   4. Hirsutism
2. long-term effects: coarsening of facial features, mild peripheal neuropathy, osteomalacia
3. black box warning: hypotension and cardiac arrhythmias with rapid infusion

Question 9

Carbamazepine

1. MOA
2. Uses:
3. Administration:

Answer 9

Carbamazepine

1. MOA: blocks Na+ channels and inhibits high-frequency repetitive firing of neurons, reduces pre-synaptic transmission
2. Uses:
   
   1. Seizures: all partial AND tonic- clonic
   2. Bipolar disorder
   3. Trigeminal neuralgia
3. Administration: Oral only!

Question 10

Carbamazepine- Drug Interactions:

1. metabolism of carbamazepine changes:
   
   1. increased
   2. decreased:
2. What enzyme does it induce?
3. Carbamazepine ncreases the metabolism of what other drugs?

Answer 10

Carbamazepine- Drug Interactions:

1. metabolism of carbamazepine changes:
   
   1. increased: valproic acid
   2. decreased:phenytoin and phenobarbital
2. What enzyme does it induce? CYP450s
   
   1. the active metabolite has anticonvulsant activity
3. Carbamazepine ncreases the metabolism of what other drugs?

Question 11

Carbamazepine- Toxicity

1. Black Box Warnings
2. Other adverse effects

Answer 11

Carbamazepine- Toxicity

1. Black Box Warnings:
   
   1. Blood dyscrasias: mild leukopenia that requires careful monitoring and can cause fatal cases of aplastic aneia and agranulocytosis
   2. Asian ancestry leads to an increases risk of Stevens-Johnson syndrom and/or toxic epidermal necrolysis
2. Other adverse effects: diplopia, ataxia, and CNS depression

Question 12

Phenobarbital

1. MOA:
2. Clinical Indications?

Answer 12

Phenobarbital

1. MOA: ENHANCEMENT OF INHIBITORY NEUROTRANSMISSION
2. Clinical Indications?
   
   1. uncontrollable seizures of all types
   2. partial with secondarily generalized tonic-clonic
   3. tonic-clonic

Question 13

Primidone

1. what are the active metabolites of primidone?
2. MOA:
3. Uses:

Answer 13

Primidone

1. The 2 active metabolites of primidone are phenobarbital (oxidation) and phenylethylmalonamide (PEMA) (scission)
2. MOA:
   
   1. blocks Na+ channel
   2. Potentiates GABA
3. Uses: Seizures in infants and elderly
   
   1. simple partial
   2. partial with secondarily generalized tonic-clonic
   3. tonic-clonic

Question 14

Vigabatrin

1. MOA
2. Clinical Uses:
3. Toxicity:
   
   1. black box warning

Answer 14

Vigabatrin

1. MOA:
   
   1. GABA- irreversile inhiitor of GABA aminotransferase (GABA doesn’t breakdown)
   2. inhibition of the GABA transporter
   3. Decreased brain glutamine synthetase activity
2. Clinical Uses: infantile Spasms, Refractory Complex Partial
3. Toxicity:
   
   1. black box warning: Vision loss (permanent!!)
   2. other Adverse effects: anemia, somnolence, suicidal ideations

Question 15

What drug has a restricted distribution?

Answer 15

Vigabatrin has a restricted distribution- only specific physicians andd pharmacists can prescribe and distribute this drug

Question 16

Lamotrigine:

1. MOA:
2. Clinical Use:
   3.

Answer 16

Lamotrigine:

1. MOA: suppress the rapid firing of neurons, produces a voltage- andd use- dependent inactivation of Na+ channels, inhibits voltage gated Ca+ channel, may also decrease the release of glutamate
2. Clinical Use:
   
   1. can be adjunctive or monotherapy for partial seizures
   2. absence and myoclonic seizures in Children
3. 1. Black box:

Question 17

Lamotrigine

1. Adverse effects:
2. Black Box:

Answer 17

Lamotrigine

1. Adverse effects: dizziness, headache, diplopia, nausea, somnolence and skin rash
2. Black Box:
   
   1. life threatening dermatitis in 1-2% of pediatric patients
   2. possiblity for Steens-Johnson Syndrom or Toxic Epidermal Necrosis

Question 18

Gabapentin and Pregabalin

1. MOA:
2. Clinical Use:
3. Adverse Effects

Answer 18

Gabapentin and Pregabalin

1. MOA: both block Ca++ channels, modify the release of GABA, decrease release of glutamate at synapse (DO NOT DIRECTLY ACTIVATE THE GABA RECEPTOR)
2. Clinical Use: typically give as adjunct therapy
   
   1. gabapentin: partial and generalized tonic-clonic
   2. pregabalin- partial
   3. both can be used to treat post-herpetic neuralgia
3. Adverse Effects:
   
   1. Gabapentin: somnolene, dizziness, ataxia, headache and tremor
   2. pregabalin: schedule V for euphoria