anticonvulsants 2 Flashcards
what is the mechanism of action of GABA related target?
2- GABA Related Target: Potentiation of GABA effect
Increased chloride channel current of the GABAA receptor
increase Duration of Cl- channel opening: Phenobarbital
increase Frequency of Cl- channel opening: Benzodiazepines
Felbamate, Topiramate, and Valproic Acid may have similar effect (not their main mechanism of action)
Blockade of GABA degradation by GABA transaminase (GABA-T) blockade:
Vigabatrin
Valproic acid at high concentrations
Blockade of GABA transporter (GAT-1) in neurons and glial cells: Tiagabine
what is GABA effect potentiation?
where drugs increase the effect of GABA
Benzodiazepines Lorazepam Diazepam Clobazam Clonazepam Midazolam
Barbiturates
Phenobarbital
Primidone
what are benzodiazepines?
Lorazepam and Midazolam: intravenous forms are used in the emergency situations to treat ongoing seizures or status epilepticus. Lorazepam sublingual can be used by the patient at aura to avoid seizure generalization. Rectal Diazepam (Diastat) is used in children by their parents at home to stop seizures. Only Clobazam and Clonazepam are used as an adjunctive AEDs for long-term seizure treatment. Benzodiazepine withdrawal may case seizures even in non-epileptic persons.
when are barbiturates used ?
Phenobarbital is used in neonatal seizures.
In adults, they are rarely used.
Phenobarbital withdrawal may cause prolonged seizures even in non-epileptic persons.
Primidone is occasionally used to treat tremors and not used for seizures any more.
what are the specific side effects of benzodiazepines and bariturates? as well as vigabatrin and tiagabine?
Benzodiazepines and Barbiturates: respiratory suppression and respiratory arrest at higher doses.
Vigabatrin: retinitis and loss of vision-baseline and frequent visual assessment required
Tiagabine: depression and psychosis
what is the mechanism of action of calcium channel blockades?
3- Calcium channel blockade
Low threshold T-type Ca++ channels in thalamus, the pacemaker for absence seizures
Ethosuximide
Valproic Acid
Zonisamide
Also blocks Na channels
FDA approved for partial seizures
Not approved for use in children No data on effect on absence seizure
A sulfonamide derivative → beware of sulfa allergy, may cause rash
Presynaptic voltage-gated calcium channels
Gabapentin
Pregabalin
what does ethosuximide do?
Blockade of T-Type Ca channels in thalamic relay neurons (TR)
Specific for absence seizure treatment
Also may use Valproic acid for absence
what do gabapentin and pregabalin do?
Two ADEs with “GABA” used in their name
Not working via potentiating effect of GABA as their main mechanism of action
Gabapentin and Pregabalin: molecular structure similar to GABA but no direct activation of receptor.
May increase GABA release in vitro but not proven in vivo.
Bind to α2δ subunit of presynaptic voltage dependent Ca2+ channel → ↓ Ca2+ entry → ↓ excitatory neurotransmitter Glutamate release
They block Ca channel α2δ subunit →↓ presynaptic Ca entry →↓ Glutamate release
what are other mechanisms?
4- Increased K+ channel permeability Valproic acid Ezogabine 5- Glutamate antagonism Phenobarbital Felbamate: NMDA blocker Topiramate: AMPA blocker Perampanel: AMPA blocker 6- Binding to SV2A synaptic vesicle protein →↓ stimulatory neurotransmitter release Levetiracetam: depression, Suicidal ideas, aggression
levetiracetam - Binding to SV2A inhibits release of neurotransmitter from synaptic vesicles
what are the general principles of antiepileptic drugs?
The antiepileptic drugs are used for long period of time-so important to know pharmacokinetic to avoid toxicity or interactions
They are generally well absorbed with high bioavailability
Most are metabolized by hepatic enzymes except:
Gabapentin
Pregabalin
Vigabatrin
Levetiracetam
These are excreted by kidney
Resistance may develop with increased expression of drug transporters at blood brain barrier
what about drug interactions?
Drug interactions are common
By blocking antiseizure drug metabolism
By displacing the drugs from plasma proteins binding sites
Increased potency (VPA increased PHT levels)
Induction of antiseizure drug metabolism (e.g. by Rifamipin, or some antiseizure meds themselves)
decreased potency (CBZ decreases CBZ levels)
Liver P450 enzyme inducers: Phenytoin Phenobarbital Carbamazepine (even increase self metabolism) → ↓ Levels of other drugs (e.g. elderly on statin) → ↓ Active VitD → Osteroporosis → ↓ Effect of oral contraceptives Valproic Acid blocks liver metabolism → ↑ Lamotrigine levels
what are some important side effects of these medications?
Nausea/ vomiting: Lacosamide, ethosuximide, VPA Sedation and ataxia (imbalance): almost all Weight gain: VPA, Gabapentin Teratogenicity: VPA > CBZ = PHT Hyponatremia: OXC > CBZ Osteoporosis: all P450 enzyme inducers Bone marrow suppression: CBZ, Ethosuximide Renal stone: Topiramate, Zonisamide Rash: almost all but more with PHT, CBZ (Asians: HLAB*105), OXC LTG : Stevens Johnson’s syndrome
what are some side effects in reality?
Purple gloves: subcutaneous leakage of Intravenous Phenytoin
A few more side effects of phenytoin
Phenytoin is given in normal saline, precipitates with dextrose water
Is infused slowly (not > 50 mg/ min) to avoid ↓ blood pressure and heart rate
Fosphenytoin: newer compound, more water soluble → faster infusion, hypotension less common
Phenytoin rash: dominant in trunk (drug rash pattern)
- Stevens Johnson Syndrome (Lamotrigine)
- Ruptured blisters: act like 2nd degree burn
what is a useful clinical classification?
Anti seizure medications -->Narrow Spectrum--->Work well for partial (focal onset) seizures--->*Phenytoin *Carbamazepine *Oxcarbazepine Lacosamide Gabapentin Pregabalin Tiagabin
- May worsen generalized onset seizures
Anti seizure medications--->Wide Spectrum--->Help both focal & generalized onset seizures--->Valproic Acid (myoclonic) Lamotrigine Levetiracetam (myoclonic) Topiramate Zonisamide Felbamate Benzodiazepines Ethosuximide (Absence)
what’s the ideal treatment?
Effective (in all seizure types) No adverse effects No long term risks No interactions with other drugs Long lasting action Safe in pregnancy
Inexpensive
Start 1 AED, low, go slow
Taper slowly
If adding a 2nd AED, add one with a different mechanism of action
Always add folate in pregnancy (4 mg/ day)
