Anticonvulsants

Question 1

Note that fosphenytoin is a pro-drug for phenytoin

Question 2

What are the types of partial seizures?

Answer 2

simple partial

complex partial

partial seizures secondarily generalized

Question 3

What are the types of generalized seizures?

Answer 3

generalzed tonic-clonic (grand mal)

absence (petit mal)

tonic

atonic

clonic and myoclonic

Question 4

How do seizures arise?

Answer 4

they begin discretely with depolarization of neurons via influx of Ca2+ and activation of voltage dependent Na+ channels, resulting in high-frequency bursts of action potentials

These APs are then carried forward through GABA and K+-mediated actions, where activation of NMDA excitatory neurons, cell swelling, and changes in tissue osmolarity prevent inactivation

Question 5

How do AEDs work?

Answer 5

• limit the sustained firing of neurons by promoting/prolonging the inactivated state of voltage-gated Na+ channels (partial and 2ndarily generalized tonic-clonic seizures)
• pre- or post-synaptic enhancement of GABA-mediated synaptic inhbition, an effect mediated by either a presynaptic or postsynaptic action (partial and 2ndarily generalized tonic-clonic seizures)
• Inhibition of voltage-gated Ca2+ channels responsible for T-type Ca2+ currents (absence seizures)

Question 6

What AEDs work by limiting the sustained firing of neurons by promoting/prolonging the inactivated state of voltage-gated Na+ channels?

Answer 6

Carbamazepine

Phenytoin

Topiramate

Lamotrigine

Valproate

Zonisamide

Question 7

Note that GABA works primarily via chloride gated channels, to inhibit transmission. How do benzodiapines and barbiturates promote this?

Answer 7

They bind seperately at sites on the multimeric ion channel complex to enhance the inhibitory effect of GABA

Question 8

Note that GABA works primarily via chloride gated channels, to inhibit transmission. How does gabapentin promote this?

Answer 8

It acts presynaptically to promote GABA release

Question 9

Question 10

What drugs work via the blockade the T-type calcium channels, which reduce the activity of pacemaker currents (thus, both sodium and calcium blockers diminish the effects of glutamate)?

Answer 10

Valproate and Ethosuximide

Question 11

Answer 11

Question 12

Question 13

What are the main Na+ channel inhibitor AEDs?

Answer 13

Carbamazepine

Lacosamide

Lamotrigine

Oxcarbazepine (+ possible increased K+ and decreased Ca2+ effects)

Phenyotin

Zonisamide (and decreased T-type Ca2+ actions)

Question 14

What are the main Ca2+ channel inhibitor AEDs?

Answer 14

Ethosuximide (t-type)

Pregabalin and Gabapentin (a2 delta-1 subunit of Ca channel)

Question 15

What is the MOA of Felbamate?

Answer 15

decreased NMDA and increased GABA

Question 16

What is the MOA of Clonazepam?

Answer 16

GABA allosteric agonist

Question 17

What is the MOA of Topiramate?

Answer 17

decreased Na channels and glutamate activity

increased K+ current and GABA activity

Question 18

Describe the ADME of AEDs

Answer 18

• Most administered PO
• limited plasma protein binding except phenyotin and valproate
• long half lives
• predominantly hepatic metabolism with urine output

slow release (facilitates adherence- fewer doses/day)

CYP interactions

Question 19

Answer 19

Question 20

Routine monitoring of serum drug levels is required with what AEDs?

Answer 20

carbamazepine

Ethosuzimide

Gabpentin

Phenytoin

Valproate

Question 21

What is ano important thing to note about topiramate and zonisamide?

Answer 21

they are both weak carbonic anhydrase inhibitors, which cause of loss renal HCO₃- and promote renal stones by reduing urinary citrate excretion and by icnreasing urinary pH

monitor serum HCO_3^-

Question 22

What can occur with abrupt termination of AED therapy?

Answer 22

It can precipitae the onset of status epilepticus, increase the frequency of seizures, and cause anxiety

Taper down termination over time

Question 23

Important points about Phenytoin

Answer 23

• shows 0-order pharmacokinetic behavior (thus, the half-life varies with drug dose)
• metabolism highly variable
• CYP DDIs (confounding effects- age, cigs, and hepatic smoking all affect)
• fosphenytoin pro-drug (dose adjustment needed when switching)

Question 24

What are the AEs of Phenytoin?

Answer 24

CNS effects (nystagmus, HA, atacia; drowsiness not common)

• Gingival hyperplasia
• Derm effects are rare (rash to SJS, TEN, and DRESS; hypertrichosis or hirsutism)
• Heme changes

Question 25

What are the AEs of Carbamazepine?

Answer 25

-CNS effects during initial tx phase (Dizziness, drowsiness, ataxia) Heme changes- **agranulocytosis** or aplastic anemia Derm effects are rare (rash to SJS, TEN, etc.) -Constipation or dry mouth, N/V

Question 26

Who is at a higher risk of developing SJS and TEN when using AEDs?

Answer 26

Asians with a SNP mutation in their human leukocyte antigen-B 1502 allele (most common with carbamazepine, phenytoin, and fosphenytoin). Whole blood EDTA testing is available

Question 27

What are the AEs of Valproic Acid?

Answer 27

-CNS effects related to infusion rate (somnolence, dizziness, asthenia, HA) Heme changes- thrombocytopenia, prlonged bleeding time Derm effects are rare (rash to SJS, TEN) Nausea, diarrhea Hepatotoxicity in children rarely

Question 28

What are the main AEs of Felbamate?

Answer 28

asplastic anemia, bone marrow suppression, hepatic disease

Question 29

What are the main AEs of Lamotrigine?

Answer 29

serious rash (TEN/SJS) dizziness, diplopia, ataxia

Question 30

Question 31

What AEDs are contraindicated in pregnancy (teratogenic)?

Answer 31

**Valproate (worst)- Cat X** Lamotrigine- C Carbamazepine- D Phenytoin- D Phenobarbital- D

Question 32

How does fetal hydrantoin syndrome present (similar effects seen with phenobarbital and carbamazepine)?

Answer 32

upper facial features including upturned nose, mild midface hypoplasia, and long upper lip with thin vermillion vorder lower distal digital hypoplasia

Question 33

What drugs should be used to tx partial, including 2ndarily generalized seizures?

Answer 33

lamotrigine carbamazepine levetiracetam oxcarbazapine

Question 34

What drugs should be used to tx primary, generalized tonic-clonic seizures?

Answer 34

Valproate Lamotrigine Levetriacetam

Question 35

What drugs should be used to tx absence seizures?

Answer 35

ethosuximide valproate These are equally effective (50-75% of pts experience complete control)

Question 36

What drugs should be used to tx atypical absence, myoclonic, and atonic seizures?

Answer 36

valproate lamotrigine levatiracetam

Question 37

What is status epilepticus?

Answer 37

A prolonged seizure, or cluster, without a return to baseline, lasting 30+ minutes These seizures can be generalzied tonic-clonic, complex or simplex partial, absence, or subclinical

Question 38

Up to 50% of cases of SE occur in pts with epilepsy due to what?

Answer 38

recent changes in AEDs or non-adherence The remainder of cases in adults are most often due to strokes

Question 39

T or F. SE is a medical emergency

Answer 39

T. With a 7-40% mortality rate. predictors of mortality include generalized seizure, increased pt age, anoxic brain injury, stroke, CNS infection or tumor, and long duration of SE. Successful outcomes require early and aggressive tx

Question 40

How should SE be handled?

Answer 40

Benzodiazepines are the DOA Backups: IV lorazapam, IM midazolam, or rectal diazepam, followed by: IV valproate, phenytoin, midazolam, levetiracetam, or phenobarbital

Question 41

Compare and contrast Phenobarbital and Benzodiazepine

Answer 41

Both work on GABA receptors, but at different site Barburates prolong the opening time of Cl- channels Benzodiazepines shift the dose-response curve of GABA BOTH have issues of dependence and withdrawal, develop tolerance, will produce dose-related sedation, and can be given rapid IV, unlike phenyotin or valproate Only phenobarbital will induce CYP2B6 and 3A4 levels

Question 42

Why are benzodiazepines first line for tx of SE?

Answer 42

They can be given rapidly IV, where the admin of other drugs is limited. Thus, the benzodiazepine can rapidly terminate the SE\< but short BNZ half-lives mean that additional drugs must be given to provide more drug control

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Question 46

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