Anti-Epileptic drugs Flashcards
What is the effect of GABA binding to its receptor?
GABA binding to its receptor opens a chloride channel that hyperpolarizes the cell. This makes neuronal firing and seizures less likely.
How do benzodiazepines, barbiturates, and topiramate act?
They are GABA agonists
- These have a non-specific effect (overall sedating)
What is the effect of glutamate binding to its receptor?
Glutamate binding to its receptors opens Na+ and Ca++ channels that depolarize the cell, making neuronal firing and seizures more likely.
How does lamotrigine act?
Blocks the release of glutamate
How does topiramate act?
It is a glutamate receptor antagonist AND it is a GABA agonist
What is the consequence of blocking Na channels?
Na+ channels are a final common pathway for seizures.
- Blockade of channels slows repetitive firing and stops seizures.
Which AEDs are Na channel blockers?
- Phenytoin, carbamazepine, valproate, topiramate and lamotrigine.
- HOWEVER, these drugs act selectively at fast opening Na channels, otherwise all brain activity would cease
What is the action of Ethosuximide?
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.
Describe the absorption traits of most anti-epileptic drugs.
- Well absorbed by mouth/GI
- Generally slowed by foods
- Usually takes several hours to go into effect
Describe the steady state/half life traits of most anti-epileptic drugs.
- 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
Why is it important to measure the concentration of anti-epileptic drugs in serum?
Serum concentrations are useful when optimizing AED therapy, assessing compliance, or teasing out drug-drug interactions
How are most anti-epileptics excreted/metabolized?
1) Metabolism/biotransformation — hepatic; usually rate-limiting step.
2) Excretion — mostly renal.
What is the importance of the cytochrome P450 system?
These enzymes are most involved with drug metabolism; they are found in the liver
What are the principle enzymes involved in P450 anti-epileptic drug metabolism?
The principle enzymes involved with AED metabolism include CYP2C9, CYP2C19, CYP3A4
What is the importance of the UGT?
Important pathway for drug metabolism/inactivation, found in the liver
What are the principle enzymes involved in UGT anti-epileptic drug metabolism?
UGT1A9 (valproate), UGT2B7 (valproate, lorazepam), UGT1A4 (lamotrigine).
What is a cytochrome p450 inducer?
Inducers increase clearance and decrease steady-state concentrations of other drugs
What is a cytochrome p450 inhibitor?
Decrease clearance and increase steady-state concentrations of other drugs
What are examples of P450 inducers?
phenobarbital ethosuximide phenytoin carbamazepine tobacco/cigarettes
What are examples of P450 inhibitors?
Erythromycin Ca++ channel blockers Trimethoprim/sulfate Fluconazole Valproate
What are differences in anti-epileptic drug pharmacokinetics in the elderly?
- 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.
What are differences in anti-epileptic drug pharmacokinetics in pediatric patients?
Neonates often need lower per kg doses.
- Low protein binding.
- Low metabolic rate.
Children often need higher per kg doses.
- Faster metabolism.
What are differences in anti-epileptic drug pharmacokinetics in pregnant patients?
- 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.
What drugs need to be adjusted with anti-epileptic drugs?
Doses of birth control pills, coumadin, anti-depressants, and cholesterol-lowering drugs need to be adjusted, and cancer chemotherapy may be less effective
What is the effect of Ca channel blocking and macrolide antibiotics of AEDs?
Ca++ channel blockers and macrolide antibiotics raise levels of carbamazepine
Valproate raises levels of lamotrigine.
What are common side effects in AEDs?
- 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
Which AEDs cause weight gain?
carbamazepine, gabapentin, valproate.
Which AEDs cause weight loss?
topiramate
What endocrine effect may AEDs have on women?
May be linked to polycystic ovaries
What is the effect of phenobarbital, phenytoin, and carbamazepine on bone?
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.
Which AED has the worst birth defect outcome?
Valproate produces neural tube defects and learning disabilities
What is the use of phenobarbitol and how is it given?
Effective for all seizure types except absence.
- Can be given PO or IV.
- IV form very useful in status epilepticus.
What is the mechanism of phenobarbitol?
GABA agonist.
- Opens chloride channel.
- Produces hyperpolarization.
Describe the metabolism of phenobarbitol.
- Long half life (100 hours).
- Needs to be loaded.
- Hepatic metabolism.
- Hepatic enzyme inducer.
What toxicity is associated with phenobarbitol?
- Hyperactivity in children.
- Sedation in adults.
- Joint and connective tissue problems.
What is the use of phenytoin?
Effective against all seizure types except absence.
Better for focal and secondarily generalized seizures than for primary generalized ones.
What is the mechanism of phenytoin?
Blocks voltage-gated Na+ channels.
Describe the metabolism of phenytoin.
- 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).
What toxicity is associated with phenytoin?
Gingival hyperplasia, osteomalacia, ataxia.
- Need to supplement calcium, vitamin D, vitamin K, and folate.
What are the uses/indications for benzodiazepines (diazepam, lorazepam)?
- 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.
What is the mechanism of benzodiazepines?
Agonists at the GABA receptor.
Describe the metabolism of benzodiazepines.
PO or IV administration. Hepatic metabolism, but not major enzyme inducers.
Why are benzodiazepines not used chronically?
High prevalence of tachyphylaxis
What toxicity is associated with benzodiazepines?
Sedation, depression, withdrawal seizures.
What are the uses for carbamazepine?
- 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.
What is the mechanism of carbamazepine?
Na+ channel blockade.
Describe the metabolism of carbamazepine.
- Only has oral preparation.
- ½ life 12 hours.
- Hepatic metabolism.
- Hepatic enzyme inducer.
- Levels increased by Calcium channel blockers, and macrolide antibiotics.
What toxicity is associated with carbamazepine?
Blurred vision, sedation, neutropenia, hyponatremia, weight gain.
What is the use of ethoxusimide?
only for absence seizures
What is the mechanism of ethoxusimide?
Blocks T-type Calcium Channels
Describe the metabolism of ethoxusimide.
- Only oral preparation.
- Has good GI absorption.
- ½ life 24-48 hours.
- Mild hepatic enzyme inducer.
- Hepatic metabolism
What toxicity is associated with ethoxusimide?
Sedation, GI distress, occasional behavioral changes.
What is the use for Valproate?
Works for all seizure types.
Also used for migraine and bipolar disorder.
What is the mechanism of Valproate?
May block Na+ channels.
Probably also affects GABA levels, Ca++, and K+ conductances.
Describe the metabolism of valproate.
- Oral and IV preparation.
- Half Life ~15 hours.
- Hepatic metabolism.
What toxicities are associated with valproate?
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.
What is the use for Gabapentin?
- 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.
What is the mechanism of Gabapentin?
- Increases GABA levels in the brain.
- May have other mechanisms of action including blockade of Ca++ channels.
Describe the metabolism of Gabapentin.
- PO preparation only.
- Short ½ life (6 hours).
- Well absorbed, except at very high doses.
- Not metabolized and excreted in the urine.
What toxicity is associated with Gabapentin?
- Sedation, particularly in the elderly.
- Occasional GI distress, and pedal edema.
What is the use of lamotrigine?
- Broad spectrum efficacy against all seizure types.
- Also works for bi-polar disorder, and neuropathic pain.
What is the mechanism of lamotrigine?
Probably blocks release of glutamate pre-synaptically and blocks Na+ channels post-synaptically.
Describe the metabolism of lamotrigine.
- Only an oral preparation
- Renally excreted after hepatic glucoronidation.
- Not a major enzyme inducer.
- ½ life of 24 hours.
What toxicity is associated with lamotrigine?
- Allergic rash 5-10%.
- May cause insomnia.
What is topiramate used for?
- Broad spectrum of efficacy, but not particularly good for absence.
- Good for migraine prevention.
- Some use in neuropathic pain.
- Causes weight loss.
What is the mechanism for topiramate?
- Na+ channel blockade
- GABA agonist
- Glutamate antagonist.
Describe how topiramate is metabolized.
- Some hepatic metabolism, but mainly renal clearance
- ½ life of 24 hours.
- Only an oral preparation.
What toxicity is associated with topiramate?
Sedation
Aphasia
Parasthesias
Kidney stones.
What is levetiracetam used for?
- Broad spectrum => focal and generalized seizures.
- Favorite anti-epileptic drug in hospitals.
Describe the mechanism of levetiracetam action.
- Blocks Ca++ channels
- Interferes with action of SV2 protein which is necessary for exocytosis of neuro-transmitter vesicles.
Describe the metabolism of levetiracetam.
- 2/3 excreted renally unchanged.
- Some enzymatic hydrolysis by liver and RBCs to inactive metabolites.
- NOT protein bound
What toxicity is associated with levetiracetam?
Cognitive and behavioral problems.
Which is easier to treat, generalized or focal epilepsy/seizures?
Generalized epilepsy is easier to control
What is the most effective anti-epileptic for general epilepsy?
Valproate
Which drugs are best for women of child bearing age?
Lamotrigine and levetiracetam
Which is more common, focal or generalized epilepsy?
Focal epilepsy is more common
What are good drugs for treating focal epilepsy?
Carbamazepine (best choice)
Lamotrigine and levetiracetam (good choices)
