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What is epilepsy?
A group of chronic CNS disorders that are characterized by recurrent seizures
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What are the causes for acute seizures?
- trauma
- stroke
- encephalitis
- drugs
- withdrawl from antidepressants
- tumor
- high fever
- hypoglycemia
- extreme acidosis/alkadosis
- Hypoatremia
- Hypocalcemia
- Idiopathic
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Are more seizures partial or generalized epilepsy?
Partial (about 60%)
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Where is the common problem for partial seizures and what does it result in?
- temporal lobe epilepsy
- limbic, complex partial or psychomotor epilepsy)
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Inherited idiopathic epilepsies account for less than 1% of epilepsies in America. However, of the genetic links found in these inherited epilepsies, what do the mutations always affect?
subunits of voltage or ligand-gated ion channels (Na+, K+, GluR, GABAR, and nAchR)
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What is the basic mechanism underlying epilepsy?
 dysregulation of either excitation or feed-back/forward inhibition
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What is an example of a gain of function mutation in epilepsy?
- SCN1B mutation (generalized epilepsy w/ ferbile seizures)
- increases sodium influx into the neuron, therefore too much depolarization, too often
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What is an example of a loss of function mutation in epilepsy?
KCNQ2, KCNQ3 mutations where K+ cannot get out of the cell; therefore cannot hyperpolarize
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What kind of mutation is most severe/fatal in Na+ channels?
Loss of function
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What are the 2 types of partial seizures?
- Simple (did not lose consciousness)
- Complex(did lose consciousness)
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What are the three strategies in treatment of epilepsy?
- stabalize membrane potential and prevent depolarization by action on voltage-gated ion channels
- increase GABAergic transmission
- decrease excitatory amino acid transmission
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What are 5 different types of drugs that act on GABAergic synapses?
What do they do?
- GABA agonists: hyperpolarize the neuron
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The Glutamergic Synapse
ligand
co-agonist
natural blocker
ions that are transported
- ligand: glutamate
- co-agonist: glycine
- natural blocker: magnessium
- ions that are transported: Na+/Ca++ out and K+ in
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What are the ultimate goals of anti-epileptic drugs that target glutamergic synapses?
decrease glutamate
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What are the ultimate goals of anti-epileptic drugs that target GABAergic synapses?
increase GABA
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What is epileptogenesis?
How is it caused?
- the generating of more seizures
- cause is not clear b/c pathways are unknown; we do know that influx of Ca++ inhibits:-inhibitory transcription factors
- -upregulates AMPAR
- -down regulates GABA receptors
- -increases Mossy Fiber growth (not sure about this one)
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The Ca++ channel is often targeted by drugs, what ligand-binding site on this channel is the target?
- alpha 2 delta
- Calcium is the regulator of pre-synaptic vessel release in pre-synaptic neurons. so it makes sense that if you can block this channel, there will be little intracellular Ca++ to let the NTs be released
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How does phenytoin work on Na+ channels?
sustains sodium channel in the refractory state conformation so that it cannot return to resting state and subsequently cannot return to open state
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What are six drugs that will keep Na+ channels in the inactive conformation?
- carbamazepine
- phenytoin
- topiramate
- lamotrigine
- valproate
- zonisamide
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What is a major drawback, besides side effects, for anti-epileptic drugs (AED)?
that there operating range is minimal or non-exisitent; effective levels and toxic levels overlap
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Phenytoin
MOA
Side Effects
Special Interests
- MOA: targets Na+ channels primarily, K+/Ca++ channels secondarily decreasing frequency of APs
- Side Effects: ataxia, nystagmus, cognitive impairment, hirsutism (female hair in places where it shouldnot be), gingival hyperplasia, coarsining of facial features, exacerbates absence features, tetarogen
- Special Interests: do not give to pregnant women or absence epileptics, 0th order kinetics, oldest non-sedative epileptic, has a parenteral sister drug: Fosphenytoin
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Carbamezepine
MOA
Side Effects
Special Interests
- MOA: blocks Na+ channels, therefore decreasing the frequency of APs
- Side Effects: Aplastic Anemia, Nausea and visual disturbances, autoinduction of metabolism
- Special Interests: Do not give to Absence epileptics, most effective against partial seizures and has less side effects than phenytoin, Active metabolite
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Oxcarbazepine
MOA
Side Effects
Special Interests
- MOA: alters Na+ conductance and decreases the frequency of APs
- Side Effects: Hyponatremia
- Special Interests: very similar to carbamazepine but better side effects and less effectivity, Active metabolite
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Phenobarbital
MOA
Side Effects
Special Interests
- MOA: prolongs opening of GABA-gated Cl- channels
- Side Effects: sedation, cognitive impairment, induction of liver enzymes, may worsen absence seizures/atonic seizures
- Special Interests: drug of choice for febrile seizures in infants, useful for partial and generalized tonic-clonic seizures, considered a very safe drug, one of the oldest AEDs
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Primidone
MOA
Side Effects
Special Interests
- MOA: not really known, but probably like phenytoin
- Side Effects: sedation, cognitive impairment, induction of liver enzymes, may worsen absence/atonic seizures, also GI complaints
- Special Interests: absorbed completely, should be administered slowly, metabolized into 2 metabolites: phenobarbital and phenylethylmalonamide (PEMA)
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Valproate
MOA
Side Effects
Special Interests
- MOA: inhibits succinate semialdehyde dehydrogenase and GABA transanimase, therefore increasing levels of GABA in the brain. Also increases potassium conductance
- Side Effects: elevated liver enzymes, nausea, vomiting, abdominal pain, heartburn, tremor, alopecia, weight gain, teratogen (spina bifida)
- Special Interests: used to treat absence and myoclonic seizures, good for controlling generalized seizures
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Ethosuximide
MOA
Side Effects
Special Interests
- MOA: reducing low-level threshold Ca++ channel current (T-type) in the thalamus
- Side Effects: gastric distress (nausea, pain, vomiting), lethargy, fatigue, hiccups, headaches, skin rashes
- Special Interests: drug of choice for absence seizures, very safe, little/no binding to plasma proteins
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Clonazepam
MOA
Side Effects
Special Interests
- MOA: increases the frequency of GABA-gated Cl- channels being open
- Side Effects: sedation, ataxia
- Special Interests: a Benzodiazepine, long-lasting drug for absence seizures and sometimes for myoclonic seizures
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Vigabatrin
MOA
Side Effects
Special Interests
- MOA: irreversible inhibitor of GABA-transaminase, therefore increases inhibitory effects of GABA in synaptic cleft
- Side Effects: drowsiness, dizziness, weight gain, agitation, confusion, psychosis
- Special Interests: contraindicated for mentally ill patients, good for partial seizures
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Lamotrigine
MOA
Side Effects
Special Interests
- MOA: inactivates sodium channels and suppresses rapid firing of neurons
- Side Effects: dizziness, headache, diploia, nausea, somnolence, rash
- Special Interests: BS-drug, can be used with valproate, especially good for depressed patients (with bi-polar disorder), must be titrated slowly to avoid rash
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Felbamate
MOA
Side Effects
Special Interests
- MOA: Antagonist for Na+ channels and NMDA receptors at glycine site
- Side Effects: severe! aplastic anemia, severe hepatitis, lethargy, anorexia, nausea, vomiting, headache, dizziness, insomnia
- Special Interests: not first line medication! BS-drug, has black box warning for side effects
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Topiramate
MOA
Side Effects
Special Interests
- MOA: block voltage gated sodium channels, antagonist for glutamate receptors
- Side Effects: somnolence, fatigue, dizziness, cognitive slowing, altered verbal fluency, decreased appetite
- Special Interests: BS-drug, may help with migranes, teratogenic in animals
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Tiagabine
MOA
Side Effects
Special Interests
- MOA: GABA uptake inhibitor
- Side Effects: dizziness, tremor, difficulty concentrating, depression, asthenia, emotional liability, skin rash
- Special Interests: BS-Drug
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Zonisamide
MOA
Side Effects
Special Interests
- MOA: voltage gated Na+ channels and T-Type Ca++ channels
- Side Effects: drowsiness, rash, cognitive impairment, weight loss, renal stones
- Special Interests: BS-Drug, sulfonamide deravitive
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Gabapentin
MOA
Side Effects
Special Interests
- MOA: GABA-like molecule that does not act on GABA receptors, but rather acts on alpha2-delta subunits of Ca++ channels preventing GABA release
- Side Effects: Somnolence, dizziness, ataxia, weight-gain, behavioral changes
- Special Interests: used for adjunctive therapy to treat partial seizures w or w/o secondary generation
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Levetiracetam
MOA
Side Effects
Special Interests
- MOA: unknown
- Side Effects: very safe: somnolence, asthenia, behavioral disturbances, headaches
- Special Interests: used as an adjunctive for partial seizures
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Pregabalin
MOA
Side Effects
Special Interests
- MOA: very similar to Gabepentin, binds alpha2-delta subunit of calcium channel, thereby inactivating it and reducing NT release
- Side Effects: none
- Special Interests: also used for fibromyalgia and spinal cord injuries
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Diazepam (Valium)
MOA
Side Effects
Special Interests
- MOA: potentiates GABA function
- Side Effects: sedation, paradoxical hyperactivity in children, tolerance
- Special Interests: a benzodiazepine, primary for status epilepticus
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Lorazepam (Ativan)
MOA
Side Effects
Special Interests
- MOA: potentiates GABA function
- Side Effects: sedation, paradoxical hyperactivity in children, tolerance
- Special Interests: a benzodiazepine, primary for status epilepticus
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What is status epilepticus?
a condition where seizures recur within a short period of time for at least 30 minutes and such that baseline consciousness is never regained
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What is both the initial treatment of Status Epilepticus and what is the follow up treatment?
- Initial: Diazepam/Lorazepam
- Follow Up: Phenytoin, Phenobarbitol
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What are 5 BS AEDs we learned about?
- valproate
- lamotrigine
- topiramate
- levetiracetam
- zonisamide
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What are 6 NS AEDs we learned about?
- carbazepine
- phenytoin
- gabapentin
- tiagabine
- oxcarbazepine
- pregabalin
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What two drugs can be administered with carbamazepine to increase the effect?
- phenytoin: increased metabolism of carbamazepine pharmakokinetic
- Phenylbarbital: increased production of epoxide pharmakodynamic
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What drug can administered with phenytoin?
primidone: it increases the conversion to phenobarbital
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What two drugs should valproic acid not be administered with?
- phenobarbitol: decreased metabolism, increased toxicity
- phenytoin: displacement from binding, increased toxicity
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