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Pharm Block 2 > Anti-Epileptic drugs > Flashcards

Anti-Epileptic drugs Flashcards

1
Q

What is the effect of GABA binding to its receptor?

A

GABA binding to its receptor opens a chloride channel that hyperpolarizes the cell. This makes neuronal firing and seizures less likely.

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2
Q

How do benzodiazepines, barbiturates, and topiramate act?

A

They are GABA agonists

- These have a non-specific effect (overall sedating)

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3
Q

What is the effect of glutamate binding to its receptor?

A

Glutamate binding to its receptors opens Na+ and Ca++ channels that depolarize the cell, making neuronal firing and seizures more likely.

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4
Q

How does lamotrigine act?

A

Blocks the release of glutamate

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5
Q

How does topiramate act?

A

It is a glutamate receptor antagonist AND it is a GABA agonist

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6
Q

What is the consequence of blocking Na channels?

A

Na+ channels are a final common pathway for seizures.

- Blockade of channels slows repetitive firing and stops seizures.

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7
Q

Which AEDs are Na channel blockers?

A
  • Phenytoin, carbamazepine, valproate, topiramate and lamotrigine.
    • HOWEVER, these drugs act selectively at fast opening Na channels, otherwise all brain activity would cease
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8
Q

What is the action of Ethosuximide?

A

Ethosuximide blocks T-type Ca++ channels found in the thalamus.
- Absence (petit mal) seizures have a 3 Hz spike wave discharge which probably involves a cortico-thalamic loop.

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9
Q

Describe the absorption traits of most anti-epileptic drugs.

A
  • Well absorbed by mouth/GI
  • Generally slowed by foods
  • Usually takes several hours to go into effect
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10
Q

Describe the steady state/half life traits of most anti-epileptic drugs.

A
  • It takes 5 half-lives to reach steady state

- It the drug has a long half life, one needs a loading dose to reach the therapeutic range rapidly

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11
Q

Why is it important to measure the concentration of anti-epileptic drugs in serum?

A

Serum concentrations are useful when optimizing AED therapy, assessing compliance, or teasing out drug-drug interactions

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12
Q

How are most anti-epileptics excreted/metabolized?

A

1) Metabolism/biotransformation — hepatic; usually rate-limiting step.
2) Excretion — mostly renal.

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13
Q

What is the importance of the cytochrome P450 system?

A

These enzymes are most involved with drug metabolism; they are found in the liver

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14
Q

What are the principle enzymes involved in P450 anti-epileptic drug metabolism?

A

The principle enzymes involved with AED metabolism include CYP2C9, CYP2C19, CYP3A4

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15
Q

What is the importance of the UGT?

A

Important pathway for drug metabolism/inactivation, found in the liver

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16
Q

What are the principle enzymes involved in UGT anti-epileptic drug metabolism?

A

UGT1A9 (valproate), UGT2B7 (valproate, lorazepam), UGT1A4 (lamotrigine).

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17
Q

What is a cytochrome p450 inducer?

A

Inducers increase clearance and decrease steady-state concentrations of other drugs

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18
Q

What is a cytochrome p450 inhibitor?

A

Decrease clearance and increase steady-state concentrations of other drugs

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19
Q

What are examples of P450 inducers?

A 
phenobarbital	
ethosuximide	
phenytoin	
carbamazepine	
tobacco/cigarettes
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20
Q

What are examples of P450 inhibitors?

A 
Erythromycin
Ca++ channel blockers
Trimethoprim/sulfate
Fluconazole
Valproate
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21
Q

What are differences in anti-epileptic drug pharmacokinetics in the elderly?

A
  • Absorption: little change.
  • Distribution:
    • decrease in lean body mass important for highly lipid-soluble drugs.
    • fall in albumin leading to higher free fraction.
  • Metabolism:
    • slowed because of decreased hepatic enzyme content.
    • slowed because of decreased blood flow.
  • Excretion: decreased renal clearance.
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22
Q

What are differences in anti-epileptic drug pharmacokinetics in pediatric patients?

A

Neonates often need lower per kg doses.

  • Low protein binding.
  • Low metabolic rate.

Children often need higher per kg doses.
- Faster metabolism.

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23
Q

What are differences in anti-epileptic drug pharmacokinetics in pregnant patients?

A
  • Increased volume of distribution because of hemodilution.
  • Lower serum albumin leads to lower protein-bound drug levels, but free drug levels may be unchanged.
  • Faster hepatic metabolism.
  • Higher doses of AEDs are sometimes needed
  • Consider more frequent dosing.
  • Lamotrigine levels, particularly, tend to fall, and it is the favored drug in pregnancy because of few birth defects.
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24
Q

What drugs need to be adjusted with anti-epileptic drugs?

A

Doses of birth control pills, coumadin, anti-depressants, and cholesterol-lowering drugs need to be adjusted, and cancer chemotherapy may be less effective

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25
Q

What is the effect of Ca channel blocking and macrolide antibiotics of AEDs?

A

Ca++ channel blockers and macrolide antibiotics raise levels of carbamazepine

Valproate raises levels of lamotrigine.

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26
Q

What are common side effects in AEDs?

A
  • Allergic reactions:
    • rash is common (1-5%).
    • mucositis, hepatitis, bone marrow suppression are fortunately rare (<1%).

-Gastrointestinal problems:
- nausea, diarrhea, constipation, dry mouth
(1-10%).

  • Fatigue is common.
  • Headaches, blurred vision, double vision and imbalance are also common.
  • Mild confusion is common, psychosis is rare
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27
Q

Which AEDs cause weight gain?

A

carbamazepine, gabapentin, valproate.

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28
Q

Which AEDs cause weight loss?

A

topiramate

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29
Q

What endocrine effect may AEDs have on women?

A

May be linked to polycystic ovaries

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30
Q

What is the effect of phenobarbital, phenytoin, and carbamazepine on bone?

A

Phenobarbital, phenytoin and carbamazepine have been implicated in osteoporosis.
- The mechanisms include malabsorption of vitamin D, stimulation of PTH action, and stimulation of osteoclast activity.

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31
Q

Which AED has the worst birth defect outcome?

A

Valproate produces neural tube defects and learning disabilities

32
Q

What is the use of phenobarbitol and how is it given?

A

Effective for all seizure types except absence.

  • Can be given PO or IV.
  • IV form very useful in status epilepticus.
33
Q

What is the mechanism of phenobarbitol?

A

GABA agonist.

  • Opens chloride channel.
  • Produces hyperpolarization.
34
Q

Describe the metabolism of phenobarbitol.

A
  • Long half life (100 hours).
  • Needs to be loaded.
  • Hepatic metabolism.
  • Hepatic enzyme inducer.
35
Q

What toxicity is associated with phenobarbitol?

A
  • Hyperactivity in children.
  • Sedation in adults.
  • Joint and connective tissue problems.
36
Q

What is the use of phenytoin?

A

Effective against all seizure types except absence.

Better for focal and secondarily generalized seizures than for primary generalized ones.

37
Q

What is the mechanism of phenytoin?

A

Blocks voltage-gated Na+ channels.

38
Q

Describe the metabolism of phenytoin.

A
  • Can be given PO or IV.
    • Poorly absorbed PO in children.
  • Has zero-order kinetics at high doses because of enzyme saturation.
  • Hepatic metabolism.
  • Hepatic enzyme inducer
  • Variable half- life (6-24 hours).
39
Q

What toxicity is associated with phenytoin?

A

Gingival hyperplasia, osteomalacia, ataxia.

- Need to supplement calcium, vitamin D, vitamin K, and folate.

40
Q

What are the uses/indications for benzodiazepines (diazepam, lorazepam)?

A
  • Effective against all seizure types.
  • Tolerance develops rapidly (months).
  • Drugs of choice for status epilepticus, alcohol withdrawal symptoms and alcohol withdrawal seizures.
  • Good sedatives and anxiolytics.
41
Q

What is the mechanism of benzodiazepines?

A

Agonists at the GABA receptor.

42
Q

Describe the metabolism of benzodiazepines.

A

PO or IV administration. Hepatic metabolism, but not major enzyme inducers.

43
Q

Why are benzodiazepines not used chronically?

A

High prevalence of tachyphylaxis

44
Q

What toxicity is associated with benzodiazepines?

A

Sedation, depression, withdrawal seizures.

45
Q

What are the uses for carbamazepine?

A
  • Excellent for focal and secondarily generalized seizures.
  • Less effective for primary generalized seizures.
  • Also a mood stabilizer for bipolar disorder.
  • Works for neuropathic pain and trigeminal neuralgia.
46
Q

What is the mechanism of carbamazepine?

A

Na+ channel blockade.

47
Q

Describe the metabolism of carbamazepine.

A
  • Only has oral preparation.
  • ½ life 12 hours.
  • Hepatic metabolism.
  • Hepatic enzyme inducer.
  • Levels increased by Calcium channel blockers, and macrolide antibiotics.
48
Q

What toxicity is associated with carbamazepine?

A

Blurred vision, sedation, neutropenia, hyponatremia, weight gain.

49
Q

What is the use of ethoxusimide?

A

only for absence seizures

50
Q

What is the mechanism of ethoxusimide?

A

Blocks T-type Calcium Channels

51
Q

Describe the metabolism of ethoxusimide.

A
  • Only oral preparation.
  • Has good GI absorption.
  • ½ life 24-48 hours.
  • Mild hepatic enzyme inducer.
  • Hepatic metabolism
52
Q

What toxicity is associated with ethoxusimide?

A

Sedation, GI distress, occasional behavioral changes.

53
Q

What is the use for Valproate?

A

Works for all seizure types.

Also used for migraine and bipolar disorder.

54
Q

What is the mechanism of Valproate?

A

May block Na+ channels.

Probably also affects GABA levels, Ca++, and K+ conductances.

55
Q

Describe the metabolism of valproate.

A
  • Oral and IV preparation.
  • Half Life ~15 hours.
  • Hepatic metabolism.
56
Q

What toxicities are associated with valproate?

A

GI upset, weight gain, menstrual problems, hair loss, low platelet count, hepatic encephalopathy sometimes but not always associated with elevated ammonia levels and carnitine deficiency.

57
Q

What is the use for Gabapentin?

A
  • Effective against partial and secondarily generalized seizures.
  • Not good for primary generalized seizures.
  • Also a good anxiolytic, sedative, and anti-spasmodic. - Works well for peripheral neuropathy and other painful states.
58
Q

What is the mechanism of Gabapentin?

A
  • Increases GABA levels in the brain.

- May have other mechanisms of action including blockade of Ca++ channels.

59
Q

Describe the metabolism of Gabapentin.

A
  • PO preparation only.
  • Short ½ life (6 hours).
  • Well absorbed, except at very high doses.
  • Not metabolized and excreted in the urine.
60
Q

What toxicity is associated with Gabapentin?

A
  • Sedation, particularly in the elderly.

- Occasional GI distress, and pedal edema.

61
Q

What is the use of lamotrigine?

A
  • Broad spectrum efficacy against all seizure types.

- Also works for bi-polar disorder, and neuropathic pain.

62
Q

What is the mechanism of lamotrigine?

A

Probably blocks release of glutamate pre-synaptically and blocks Na+ channels post-synaptically.

63
Q

Describe the metabolism of lamotrigine.

A
  • Only an oral preparation
  • Renally excreted after hepatic glucoronidation.
  • Not a major enzyme inducer.
  • ½ life of 24 hours.
64
Q

What toxicity is associated with lamotrigine?

A
  • Allergic rash 5-10%.

- May cause insomnia.

65
Q

What is topiramate used for?

A
  • Broad spectrum of efficacy, but not particularly good for absence.
  • Good for migraine prevention.
  • Some use in neuropathic pain.
  • Causes weight loss.
66
Q

What is the mechanism for topiramate?

A
  • Na+ channel blockade
  • GABA agonist
  • Glutamate antagonist.
67
Q

Describe how topiramate is metabolized.

A
  • Some hepatic metabolism, but mainly renal clearance
  • ½ life of 24 hours.
  • Only an oral preparation.
68
Q

What toxicity is associated with topiramate?

A

Sedation
Aphasia
Parasthesias
Kidney stones.

69
Q

What is levetiracetam used for?

A
  • Broad spectrum => focal and generalized seizures.

- Favorite anti-epileptic drug in hospitals.

70
Q

Describe the mechanism of levetiracetam action.

A
  • Blocks Ca++ channels

- Interferes with action of SV2 protein which is necessary for exocytosis of neuro-transmitter vesicles.

71
Q

Describe the metabolism of levetiracetam.

A
  • 2/3 excreted renally unchanged.
  • Some enzymatic hydrolysis by liver and RBCs to inactive metabolites.
  • NOT protein bound
72
Q

What toxicity is associated with levetiracetam?

A

Cognitive and behavioral problems.

73
Q

Which is easier to treat, generalized or focal epilepsy/seizures?

A

Generalized epilepsy is easier to control

74
Q

What is the most effective anti-epileptic for general epilepsy?

A

Valproate

75
Q

Which drugs are best for women of child bearing age?

A

Lamotrigine and levetiracetam

76
Q

Which is more common, focal or generalized epilepsy?

A

Focal epilepsy is more common

77
Q

What are good drugs for treating focal epilepsy?

A

Carbamazepine (best choice)

Lamotrigine and levetiracetam (good choices)

Pharm Block 2 (15 decks)

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