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Any abnormal neuronal discharge in the brain
Seizure
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Chronic, recurrent seizures
Epilepsy
*Epilepsy is a disease, seizure is a symptom
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Consciousness preserved; manifested variously as convulsive jerking, paresthesia, psychic symptoms and autonomic dysfunction
Partial seizure, simple
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Impaired consciousness that is preceded, accompanied, or followed by psychiatric symptoms.
Partial seizures, complex
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Involve both hemispheres of the brain
Generalized seizures
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2 Types of Generalized Seizures
- Absence (juvenile)
- Myoclonic
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Brief altered state of conscious and staring episodes
Absence (Juvenile) seizure
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Large amplitude of T-type Ca2+ currents in thalamus
Generation of thalamic oscillatory activity (3 Hz spike and wave rhythms)
Absence (Juvenile) seizure
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Drug of choice for Absence Seizures
- Ethosuxamide OR
- Valproic Acid- esp. useful in patients who have concommitant generalized tonic-clonic or myoclonic seizures
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Can be used to treat Absence seizures, but can cause sedation and toleranze
Clonazepam
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Brief contraction of muscles
Myoclonic seizure
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Drug of choice for Myoclonic Seizures
- Levetiracetam OR
- Zonisamide
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Tonic-Clonic Seizure Phases
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3 things that happen in tonic phase of tonic clonic seizure
- Loud moan, secretions, and cyanosis
- Increased sympathetic tone
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Clonic phase of seizure is characterized by
Shaking
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Postictal phase of seizures characterized by
- Unresponsiveness, muscular flaccidity
- Excessive salivation
- Bladder/bowel incontinence
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Barbituates:
Name 2
MoA?
Treats?
- Phenobarbital, Primidone
- Increases duration of GABA channel opening (Increases Cl- conductance at GABAA channel)
- Epilepsy (Status epilepticus)
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Benzodiazepines:
Name 2 long-acting
MoA?
Treats what type of seizure?
- Diazepam, Lorazepam
- Increases frequency of GABA channel opening (Increases Cl- conductance at GABAA channel)
- Tonic Clonic Seizures
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Both barbituates and benzodiazepines can have what adverse effects
Respiratory depression
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Name 2 Hydantoins
- Phenytoin- bound to plasma protein
- Fosphenytoin- water-soluble, converted to phenytoin by phosphatases in the liver
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Phenytoin: MoA
Blocks voltage-gated Na+ channels in neuronal membranes -> prolonged inactivation of Na+ channel (and thus refractory period of the neuron)
*Carbamazepine, Lamotrigine, and Zonisamide also do this
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Phenytoin: Treats
Partial & Tonic/Clonic Seizures (does NOT treat Absence Seizures)
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Drug interaction: Degrades oral contraceptives -> unwanted pregnancy
Phenytoin
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Fetal Hydantoin Syndrome (Phenytoin teratogenicity)
- Cleft lip, palate
- Congenital Heart Disease
- Skeletal malformation
- Impaired intellectual development
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Phenytoin interaction w/ Carbamazepine, sulfonamides, valproic acid
These drugs displace phenytoin from the plasma membrane proteins -> Increased free phenytoin in plasma
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Phenytoin interaction w/ Phenobarbital and Rifampin
Increases metabolism of Phenytoin in the liver (CYP inducers) -> need to increase dosage of phenytoin
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Phenytoin interaction w/ Cimetidine and Isoniazid
Decrease metabolism of Phenytoin in the liver (CYP inhibitors) -> decrease amnt of Phenytoin administered
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Phenytoin's effects on other antiepileptic drugs
Phenytoin induces hepatic drug metabolism -> decreased effects of other antiepileptic drugs including carbamazepine, clonazepam, and lamotrigine
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2 Phenytoin toxicities
- Osteomalacia w/ hypocalcemia and increased alkaline phosphatase activity
- Gingival hyperplasia
- Peripheral Neuropathy (diminished deep tendon relfexes in the lower extremities)
*Small increase can have drastic effects
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Name 4 drugs that block the voltage-gated Na+ channels and prolonged the inactivated state of the neuron
- Phenytoin
- Carbamazepine
- Lamotrigine
- Zonisamide
Please Call Loren Zo
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Carbamazepine treats
- Partial AND Tonic-Clonic Seizures
- Bipolar pts (where Li isn't effective)
- Trigeminal and Glossopharyngeal nerve neuralgias
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Drug that increases ADH (anti-diuretic hormone)
Carbamazepine
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CYP effects:
Phenytoin?
Carbamazepine?
Valproic Acid?
- P= inducer
- C= inducer
- V= inhibitor
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Carbamazepine toxicities
- CYP inducer
- Hematological abnormalities
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Inhibits low-threshold (T-type) Ca2+ currents (in thalamic neurons)
Ethosuxamide
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Ethosuxamide: MoA
Inhibits low-threshold (T-type) Ca2+ currents (in thalamic neurons)
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Ethosuxamide treats
Generalized absence seizures
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Valproic Acid treats
Partial and primary generalized epilepsies
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Irreversibly inactivates GABA-T (enzyme that terminates GABA action) -> prolonged inhibitory action of GABA
Vigabatrin
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Vigabatrin: MoA
Irreversibly inactivates GABA-T (enzyme that terminates GABA action) -> prolonged inhibitory action of GABA
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Vigabatrin treats
- Partial seizures
- Infantile spasms
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Long-term use of Vigabatrin can result in
Irreversible visual field defects
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Metabolized by UGT
Lamotrigine
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Lamotrigine is metabolized by ___ and therefore interacts with
UGT
Valproate
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Drug that can cause Stevens-Johnson Syndrome, TEN
Lamotrigine
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Drug that inhibits GAT-1 (The drug is a GABA reuptake inhibitor)
Tiagabine
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Tiagabine: MoA
Inhibits GAT-1 (a GABA reuptake transporter)
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Structural analogue of GABA that stimulates GABA release indirectly
GABApentin
*It also binds the alpha2delta subunit of neuronal voltage-gated Ca2+ channels -> decreased Ca2+ entry
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Gabapentin interaction w/ other anticonvulsants
Does NOT interact w/ other anticonvulsants, excreted unmetabolized in the urine
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GABApentin treats
Adjunct therapy for partial seizures
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Inhibits voltage gated Na+ and Ca2+ channels -> increased GABA release
Topiramate (GABA to the top!)
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Topiramate complication
Renal stone formation
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Renal stone formation
Topiramate
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Zonisamide complicatoins
- Renal stone formation (like Topiramate)
- Oligohydrosis
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Zonisamide metabolism
Metabolized by CYPs
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Drugs of Choice: Generalized Tonic-Clonic Seizure
- Valproic Acid
- Carbamazepine
- Phenytoin
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Drugs of Choice: Partial Seizures
- Carbamazepine (or oxcarbazepine)
- Lamotrigine
- Phenytoin
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Drugs of Choice: Absence Seizures
- Ethosuxamide
- Valproic acid (esp. w/ concommitant tonic-clonic or myoclonic seizures)
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Drugs of Choice: Myoclonic & Atypical Absence Syndromes
Valproic Acid (Lamotrigine can be used as adjunctive therapy; or you can just use V as monotherapy)
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Drugs of Choice: Status Epilepticus
- IV Diazepam or Lorazepam (terminate attacks, short-term control)
- IV Phenytoin or Fosphenytoin (long-term control)
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Tx cross-over: Valproic Acid
- Generalized tonic-clonic seizures
- Absence seizures + tonic-clonic/myoclonic
- Myoclonic and Atypical Absence Syndromes
- Mania (first line tx)
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Tx cross-over: Carbamazepine
- Generalized tonic-clonic seizures
- Partial seizures
- Bipolar disorder
- Trigeminal neuralgia
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Tx cross-over: Lamotrigine
- Partial Seizures
- Bipolar Disorder
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Tx cross-over: Gabapentin, Topiramate
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Teratogenicity: Valproic Acid
Neural tube defects (spina bifida)
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Teratogenicity: Carbamazepine
- Craniofacial anomalies
- Spina bifida
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Teratogenicity: Phenytoin
Fetal Hydantoin Syndrome (cleft lip/palate, congenital heart disease, impaired intellectual development)
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Anticonvulsant OD causes
CNS depression (respiratory depression)
*Manage w/ supportive care
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Benzodiazepine OD can be treated w/
Flumazenil
Benzos= F (Frequency, flumazenil)
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Ethosuximide can NOT treat
- Partial seizures
- Generalized tonic-clonic seizure states
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Weight gain is common with
Valproic acid
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Withdrawal of drugs from what kind of seizures is the easiest?
What drugs produce the most severe withdrawals?
Absence seizures is easiest
Benzos and barbituates= severe withdrawal
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