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BB Test 4 > Antiepileptics > Flashcards

Antiepileptics Flashcards

1
Q

What the mechanism by which focal seizures occur?

A
  • Abnormal synaptic transmission causes a paroxysmal depolarization shift (PDS) that is seen on EEG as a spike and wave discharge
  • Feed-forward and feedback inhibition limit duration and spread of epileptiform activity
  • Surround inhibition prevents spikes form becoming seizures
  • Failure of inhibition can allow excessive sychronous activity to propogate and cause a seizure
  • Seizure activty is a “network property” - Requires recurrent activation , not just a “focus” where they start
  • Failure of surround and feedforward inhibition results in spread of seizure actiity to other cortical areas (or secondary generalization)
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2
Q

What causes tonic stiffening and the clonic jerking phase of seizures?

A
  • Tonic Stiffening - Prolonged PDS (paroxysmal depolarization shift)
  • Clonic Jerking Phase - Intermittent return of GABAergic inhibition of seizure activity
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3
Q

What are the two mechanism by which AEDs prevent focal seizures?

A

Reduce Excessive Excitation

  • Prevent repetitive AP propgation of seizure discharge by inactivation of voltage-gated Na+ channels
  • Reduce excessive glutamate releae by:
    • Binding to presynaptic Ca2+ channels at the α2δ subunit (gabapentin)
    • Binding to presynaptic SV2A protein (levitiracetam)
  • Block AMPA glutamate receptors (perampanel)

Increase Inhibition

  • Increase GABA-mediated neurotransmission
  • Activate inhibitory K+ channels (ezogabine)
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4
Q

Describe how Na+ channel AEDs function.

A

Bind to the open voltage-gated Na+ channels and stabilize it in the inactivated state

  • Prevents additional firing
  • Prevents propagation of epileptic discharges from focus
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5
Q

What are the common side effects for the Na+ channel AEDs?

A
  • Diplopia (AED “poisons” high frequency firing in MLF)
  • Nystagmus (AED “poisons” high frequency firing in MLF)
  • Ataxia (Coordination problems)
  • Vertigo
  • Sleepiness, lethargy, cognitive slowing

All are dose-dependent and REVERSIBLE

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6
Q

A patient that is experiencing ____________ can indicate that they are indeed taking their sodium channel AEDs, but that they cannot tolerate an increase in dosage.

A

Nystagmus

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7
Q

What are the Sodium Channel AEDs?

A
  • Phenytoin
  • Carbamazepine
  • Valproic Acid
  • Phenobarbital (also acts on GABAa)
  • Lamotrigine
  • Topiramate
  • Zonisamid
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8
Q

MOA of Phenytoin

A

Na+ channel blocker AED

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9
Q

What type of seizures is Phenytoin used to treat?

A
  • Focal
  • Generalized tonic-clonic seizures

Not absence seizures

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10
Q

PCKN of Phenytoin

A
  • Low water solubility
  • 80-90% protein bound; free levels actually cross BBB to get to brain
  • Low doses: Hepatic metabolism by P450 (95%) is first-order kinetics
  • High doses: P450 gets saturated and metablosim slows to zero-order kinetics
    • Small increases in dose can result in VERY high drug levels and side effects
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11
Q

What are the side effects of Phenytoin?

A
  • Acute: Allergic rash, cardiotoxic
  • Dose Dependent: All side effects of Na+ channel blockers
  • Idiosyncratic (long term use)
    • Fibroblast Stimulation
      • Gingival hyperplasia (gum overgrowth)
      • Hirsutism
      • Coarse facial features
    • Altered Vitamin D metabolism
      • Osteopenia (reduced bone density due to decrease Ca2+ absorption)
    • Peripheral neuropathy
  • Teratogenic - Fetal Hydantoin Syndrome
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12
Q

What drug causes Gingival Hyperplasia?

A

Phenytoin

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13
Q

What drug causes osteopenia?

A

Phenytoin

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14
Q

What drug is associated with fetal hydantoin syndrome?

A

Phenytoin

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15
Q

What is special about Fosphenytoin?

A
  • It is a water SOLUBLE phosphorylated pro-drug that gets dephosphorylated to phenytoin in serum
  • This allows phenytoin to be IV (otherwise IV phenytoin requires propylene glycol to make it soluble which can lead to tissue damage)
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16
Q

What are the important side effects to remember about Carbamazepine?

A
  • Dose Dependent Adverse Effects:
    • Normal dose dependent Na channel blocker side effects of nystagmus, diplopia, ataxia, etc
    • Neutropenia (Decreased WBC)
  • Idiosyncratic Adverse Effects (Long Term Use):
    • Aplastic anemia
    • Rash (can progress to Stevens-Johnson Syndrome)
    • Hyponatremia
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17
Q

What are the uses of Carbamazepine?

A
  • Focal seizures
  • Generalized Tonic-Clonic seizures

Also for neuropathic pain, trigeminal neuralgia

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18
Q

What is the metabolism of Carbamazepine?

A

Autoinduces cytochrome P450 (Hepatic Metabolism)

  • Increases expression of same isozymes that metabolize it
  • Must start with low dose and increase gradually over 2-3 weeks

By product of 10,11 epoxide metabolite that increases dose dependent side effects

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19
Q

What is the MOA of Carbamazepine?

A

Na+ channel blocker

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20
Q

What part of the breakdown of carbamazepine is not good?

A

Breakdown will form 10,11 epoxide metabolite which is active against seizures BUT it alsoINCREASES dose dependent adverse affects like double vision, sleepiness , etc

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21
Q

What side effect is more common with oxcarbazepine than carbamazepine?

A

Hyponatremia

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22
Q

What is the difference between oxcarbazepine and carbamazepine?

A
  • The epoxide is not formed in the metabolite of oxcarbazepine (so better tolerated at higher levels)
  • Also little induction of hepatic enzymes which is unline CBZ
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23
Q

Phenobarbital is a unique AED in that aside from acting upon Na+ channels, it also acts upon ______________ receptors.

A

GABAA receptors

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24
Q

What drug auto-induces its own metabolism and needs to be started at a lower dose to prevent side effects?

A

Carbamazepine

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25
Q

What are the uses of Oxcarbazepine?

A
  • Focal seizures
  • Generalized Tonic-Clonic seizures
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26
Q

What are the uses of Valproic Acid?

A

Broader Spectrum

  • Focal seizures
  • Generalized Tonic-Clonic (GTC)
  • Also for generalized epilepsies:
    • Absence, juvenile myoclonic, etc.
    • Good choice if you can’t tell whether patient has a focal or generalized seizure disorder
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27
Q

What is a good choice if you can’t tell if seizure is focal or generalized?

A

Valproic acid

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28
Q

What is the MOA of Valproic Acid?

A
  • Blocks Na+ channel to inhibit repetitive AP firing
  • Also blocks T-type Ca2+ currents
  • May affect GABA inhibition
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29
Q

PCKN of Valproic Acid:

A
  • >90% protein bound (displaces phenytoin)
  • Glucuronidated in liver (inhibits hepatic metabolism of other AEDs)
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30
Q

What drug will inhibit the hepatic metabolism of other AEDs?

A

Valproic Acid

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31
Q

What are some advers side effects of Valproic Acid?

A
  • GI irritation
  • Thrombocytopenia
  • “Fat, Shaky, Bald, Yellow = Homer!”
    • Weight gain
    • Tremors
    • Hair loss
    • Jaundice from possible liver toxicity
  • Pancreatitis (rare)
  • Teratogenic (cognitive deficits and neural tube defects)
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32
Q

The liver toxicity of Valproic acid is seen most in?

A

Children less than 2 yrs when they used other AEDs

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33
Q

What are the contraindications of Valproic Acid?

A

Patients that are pregnant

  • Valproic acid is teratogenic and increases the risk of cognitive deficits and neural tube defects
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34
Q

What drug can cause weight gain, tremors, hair loss, jaundice?

A

Valproic acid

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35
Q

What are the uses of Lamotrigine?

A
  • Focal seizures
  • Generalized Tonic-Clonic (GTC) seizures
  • Also effective for generalized epilepsies (absence, myoclonic)
36
Q

PCKN of Lamotrigine:

A
  • Hepatic glucuronidation
  • Long half life of 24-37 hours (but SLOWED by valproic acid which decreases hepatic metabolism of other AEDs)
37
Q

What are some adverse side effect of Lamotrigine?

A
  • Dose Dependent Effets (Diplopia, ataxia, nystagmus, etc.)
  • Rash (due to rapid titration; incidence reduced by slow titration)
    • Rash may progress to Stevens-Johnson Syndrome.
38
Q

What is the MOA of Lamotrigine?

A

Na+ channel blocker

39
Q

What are the uses of Topiramate?

A
  • Focal seizures
  • Generalized Tonic-Clonic (GTC) seizures
  • Also used for generalized types of seizures
  • Also used to migrane prevention
40
Q

What is the MOA of Topiramate?

A
  • Na+ channel blocker
  • Enhances GABAA receptor currents
  • Weak carbonic anhydrase inhibitor
41
Q

What drugs are weak carbonic anhydrase inhibitors?

A

Topiramate (topamax)
Zonisamide

42
Q

What are some adverse effects of Topiramate?

A
  • Confusion/psychosis
  • Renal stones (Always avoid in patients with history of renal stones)
  • Somnolence (sleepiness)
  • Paresthesias (tingling; due to carbonic anhydrae inhibition)
43
Q

What are some contraindication of Topiramate?

A

Avoid in patients with history of renal stones

44
Q

What drugs can cause kidney stones?

A

Topiramate

45
Q

What is the drug used to treat Lennox-Gastaut Syndrome?

A
  • Rufinamide
  • Clobazam
46
Q

What drugs enhance GABAa?

A

Benzodiazepines (diazepam, lorazepam, clonazepam, etc.)

47
Q

What drug enhances GABA synthesis?

A

Gabapentin

48
Q

What drug decreases GABA metabolism?

A

Valproic acid (increases GABA concentration)

49
Q

What are the uses of Clonazepam?

A

Adjunctive against focal and GTC seizures (absence, atonic, and myoclonic)

50
Q

What are some adverse effects of Clonazepam?

A
  • Sedation, ataxia, psychosis, memory problems
  • Tolerance
  • Can wosren seizures
51
Q

What are the uses of Diazepam & Lorazepam (benzodiazepines) as seizure meds?

A

Status epilepticus

  • NOT for long term use because of rapid dependence potential
52
Q

What is the MOA of Phenobarbital?

A
  • Prolongs duration of GABAA receptor channel opening
  • Also inhibits repetitive Na+ channel activation
53
Q

What are some adverse effects of Phenobarbital?

A

Cognitive slowing
Dizziness
Mood change
Paradoxical hyperactivity in kids
Tolerance to sedation
Cognitive effects worse than for other AED

54
Q

Which AED causes noticeable cognitive slowing?

A

Phenobarbital

55
Q

What AED can cause hyperactivity in kids?

A

Phenobarbital

56
Q

What are the places that AEDs can bind to inhibit the release of excitatory amino acids in synapse?

A
  • Presynaptic Calcium channel α2δ subunit - Inhibits glutamate release (gabapentin)
  • Synaptic vesicle protein SV2A - Prevents release of glutamate (levetiractetam)
57
Q

Where does levetiractetam work?

A
  • Synaptic vesicle protein SV2A (inhibits NT release)
  • No effect on GABA or glutamate receptors or sodium channel
58
Q

Where does Gabapentin bind?

A

α2δ subunit of Ca2+ channel to inhibit release of glutamate

59
Q

What are the uses of Gabapentin?

A
  • Adjunct for focal and GTC seizures (not effective as monotherapy)
  • Diabetic neuropathy and other neuropathic pain
  • Headache
60
Q

What are some adverse effects of Gabapentin?

A
  • Peripheral edema (swelling)
  • Sedation, ataxia at high doses, weight gain

Overall well tolerated (few drug interactions; so good for elderly)

61
Q

What AED is good for elderly?

A

Gabapentin because of few drug interactions

62
Q

What is the MOA of pregabalin (Lyrica)?

A

Binds to α2δ subunit of Ca2+ channel (inhibits glutamate release)

63
Q

What are the uses of Pregabalin?

A
  • Focal and generalized seizures
  • Also for neuropathic pain syndromes
64
Q

What are some adverse effects of Pregabalin?

A
  • Peripheral edema (swelling)
  • Sedation, ataxia at high doses, weight gain
65
Q

What are the uses of Levatiracetam?

A
  • Focal seizures
  • Generalized Tonic-Clonic seizures
  • Myoclonic and generalized seizures
66
Q

What are some adverse effects of Levatiracetam?

A
  • Somnolence
  • Ataxia
  • Irritability 10% (well tolerated in most people)
67
Q

PCKN of Levatiracetam:

A
  • Minimal protein binding
  • Minimal drug interactions
  • Mostly unchanged in urine
68
Q

What is the MOA of Ezogabine?

A
  • Activates K+ channel (leads to hyperpolarization and decreased excitability)
  • Broad spectrum of AED efficacy
69
Q

What is the “smurf” drug?

A

Ezogabine. It can turn your skin blue.

70
Q

What are some adverse side effects of Ezogabine?

A
  • Urinary retention
  • Irreversible vision and skin problems -Can turn you blue (rare)
71
Q

What drug works by activating K+ channels?

A

Ezogabine

72
Q

What AED mechanism works for absence seizures?

A
  • T-Type Ca2+ channel in thalamic relay neuron blockers
    • Stabilize the inactivated state for these channels preventing rhythmic firing
    • These are useful for absence but NOT for partial or GTC seizures
73
Q

What are the normal functions of T-type Ca 2+channels?

A

Low threshold activated Ca2+ channels in thalamic relay neurons generate rhythmic pacemaker activity (resets channels to activatable state)

74
Q

What are the T-type Ca2+ channel blockers?

A
  • Ethosuximide
  • Valproic Acid
  • Zonisamide
  • Lamotrigine

Thus these are for absence seizures

75
Q

What is the 1st line AED for absence?

A
  • Ethosuximide (if only absence) – ONLY for absence not for GTC seizures
  • Valproic Acid for absence + GTC or other types
76
Q

First line treatment for focal seizures +/- secondary generalizations?

A
  • Carbamazepine
  • Phenytoin
  • Lamotrigine

2nd line - Valproic acid, oxcarbazepine, topiramate
Adjunct - Gabapentin,topiramate, levatiracetam, zonisamide

77
Q

What is the first line treatment for Primary generalized seizure (GTC, myoclonus)?

A
  • Valproic Acid
  • Lamotrigine
  • Topiramate
  • Levetiracetam

Clonazepam sometimes for myoclonic seizures

78
Q

What are the uses of Levetiracetam?

A

Myoclonic seizures

79
Q

What drug is for infantile spasms?

A

Vigabatrin

80
Q

AEDs in pregnancy:

A
  • Double risk for teratogen but still 90% will be fine
  • Valproic acid - Neural tube defects risk and cognitive slowing
  • Carbamazepine increase risk
  • Give folic acid to reduce risk
81
Q

What is the treatment for Status epilepticus?

A
  • First - Airway, Breathing, Circulation
  • IV benzodiazepines next
  • Follow with IV fosphenytoin
82
Q

Most common surgery to treat seizures?

A
  • Anterior temporal lobectomy
    • 70% seizure free after surgery in carefully selected patients
  • Can give Vagus nerve stimulator
83
Q

What AEDs can also be used for headache prophylaxis?

A
  • Valproic Acid
  • Topiramate
84
Q

What AEDs can also be used as mood stabilizers?

A
  • Valproic Acid
  • Carbamazepine
85
Q

What are some alternative uses of benzodiazepines?

A
  • Anxiety disorders
  • Sedation / sleep
  • Adjuncts for anesthesia
  • Prevention of ETOH withdrawal symptoms
86
Q

What are some alternative uses for barbiturates?

A
  • Sedation
  • Anesthesia
  • Headache
  • Tremors
87
Q

What is status epilepticus?

A

A period of at least five minutes in which seizures are continuous or there is no recovery of consciousness between seizures

BB Test 4 (14 decks)

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