Tuesday, 8-23-Seizures And Epilepsy Pharmacology (Fitzpatrick) Flashcards
Benzodiazepines and Clonazepam are used for the treatment of these seizure disorders
Generalized onset-Myotonic, atonic, clonic
Phenytoin and phenobarbital are used for the tx of these types of seizure disorders
Generalized onset-Tonic/clonic
Can be used to tx partial onset seizure disorders as well
List some anti-epilepsy drugs used to tx partial onset simple and complex seizures
Carbamezapine Gabapentin Pregabalin Oxcarbazepine Lacosamide Tiagabine Vigabatrin Ezogabin
These drugs can be used to treat partial onset seizures of the tonic/clonic variety:
Carbamezepine
Phenytoin
Phenobarbital
These broad spectrum anti-epilepsy drugs can be used alone or in combo with adjuvant agents to treat generalized onset and partial onset seizures
Valproate Lamotrigine Topirimate Levetiracetam Zonisamide
AEDs antagonize excitation by targeting:
1) voltage gated Na ion channels (Nav)
2) Low threshold (T Type) Ca channels
These drugs prolong fast inactivation state of Nav ion channels:
Traditional AED: Phenytoin, carbamazepine
New AEDs: Lamotrigine, Oxcarbazepine
This drug enhances slows inactivation of Nav channels
Lacosamide
In regards to AED’s, the binding site is on the interior site of the Nav channels pore. When can the AED access the pore?
If the activation gate OPENS, AEDs can access pore. If activation gate is CLOSED, cannot access pore
The pharmacological activity of AED Nav blockers is state or use-dependent
Nav blockers act preferentially on the ___
Neurons involved in the disease
The probability of a Nav blockade is proportional to the frequency of Nav channel opening and dose
___ are STATE-DEPENDENT agents that slow the recovery of Nav ion channels from inactivation
Phenytoin and Carbamazepine
___ is a state-dependent agent that is most effective at depolarized membrane potentials and high-frequency action potential firing. The state dependence of this drug causes minimal effects on cognitive functions (low-frequency firing)
Phenytoin
__ is a state-dependent agent that binds Nav less effectively, but with a much faster rate than Phenytoin, making this drug more effective in blocking high-frequency firing. These differences may correlate with different clinical responses
Carbamazepine
The MOA of this drug on Nav ion channels is similar to that of Phenytoin and Carbamazepine (voltage use and dependence). However, this drug also acts on other molecular targets, such as N- and P-type voltage-gated Ca channels in cortical neurons and neocortical K currents.
Lamotrigine
Its anti-epileptic action is not identical to carbamazepin and phenytoin
What drugs and standard protocol is used to manage status epilepticus?
Diazepam or lorazepam with fosphenytoin if needed
___ is a novel AED that effectively treats partial seizures and stabilizes the slow-inactivated state
Lacosamide
How does Lacosamide differ in its MOA on Na channels compared to other AEDs?
It acts on/stabilizes the SLOW-INACTIVATED state whereas other AEDs act primarily on the fast-inactivation state
In a prolonged train of depolarizing stimuli, ___ is more effective at reducing the amplitudes and frequency of sustained repetitive firing spikes when the stimulus was prolonged to tends of seconds as opposed to less than 1 sec
Lacosamide
T-type Ca channels mediate 3 Hz spike and wave activity in the thalamus-the hallmark of ___ seizures
Absence (petit mal) seizures
AEDs that inhibit these T-type Ca channels are particularly useful for controlling absence seizures
This narrow spectrum AED is ONLY used for absence seizures and ONLY limits excitation (Ca channel). It is a non-sedating drug
Ethosuximide
If ethosuximide doesn’t work for an absence seizure, what else can you do?
Some broad spectrum drugs can be used. The most common one used as an alternative is Valproate and then Lamotrigine
Broad spectrum will also affect T-type Ca channels
This drug was the only broad-spectrum agent available and is still considered first line therapy by many for generalized-onset seizures. It does have ‘intolerable’ adverse effects such as weight gain, tremor, hair loss, and lethargy.
Valproate
___ has been associated with neural tube defects in the offspring of women who take it during pregnancy
Valproate
The MOA of ___ on Nav ion channels is similar to that of Phenytoin and Carbamazepine. However, it also acts on other molecular targets such as N- and P-type voltage gated Ca channels in cortical neurons and neocortical K currents. Therefore, its anti-epileptic action is not identical to carbamazepine and phenytoin
Lamotrigine
__ is a sulfonamid derivative that is chemically and structurally unrelated to other anticonvulsants. Its primary MOA appears to be 1) blocking voltage-dependent Na channels and 2) blocking T-type Ca channels
Zonisamide
AEDs can augment inhibition by:
- Blocking GABA re-uptake or metabolism
- Potentiate GABAa receptor Cl currents
What cells are involved in pre-synaptic GABAergic transmission?
Neurons and glial cells
This AED drug inhibits GABA re-uptake (transporters)
Tiagabine
This AED inhibits GABA metabolism (GABA-T)
Vigabatrin
These drugs enhance post-synaptic GABAergic neuronal transmission
Phenobarbital (& related barbiturates)
Primidone (active metabolite=phenobarbital)
Benzodiazapines (Diazapam/Lorazepam)
This AED is very powerful and non-specific CNS depressor. It can cause significant sedation, can cause lethal respiratory depression, and has abuse and addiction potential
Phenobarbital
__ binds to a distinct site on GABA channels and creates an allosteric change to potentiate GABA binding –> Cl channels open with greater frequency
Benzodiazepines
___ binds to a distinct site of GABA-binding site and increases the duration of Cl channel opening
Phenobarbital
High doses of barbiturates are GABA independent (Lethality PB >BZD)
__ is GABA independent
__ is GABA dependent
Barbiturate (phenobarbital)
Benzodiazepine (diazepam)
___ are indicated or tx of status epilepticus
Benzodiazepines (Diazepam or Lorazepam)
The goal of status epilepticus tx is to stop seizure/EEG bursts. What is the initial treatment?
IV lorazepam/diazepam ~5 min: GABA-ergic agent that increases inhibition
What do you administer if you gave IV lorazepam/diazepam for status epilepticus and the seizure did not stop?
Fosphenytoin IV –a Na channel antagonist
__ is a drug benzodiazepine drug of choice for myoclonic seizures and subcortical myoclonus. Its sedative effect and tolerance are similar to those of other benzo’s. It is very effective in the emergency tx of status epilepticus, like diazepam, and can be given IV or rectally
Clonazepam
__ binds to voltage-dependent Ca channels and has no significant drug interactions
Gabapentin
__ binds to synaptic vesicle protein SV2A and blunts glutamate release. It is generally well-tolerated and no CYP interaction
Leviteracetam
___ has multiple MOA and 100% renal clearance
Pregabalin
___ opens voltage-gated K channels and can cause urinary retention
Ezogabine
What order of pharmacokinetics does Phenytoin follow?
Zero-order –> Doubling the dose does NOT necessarily double serum level so dose adjustment is difficult
Phenytoin is an inducer of __ enzymes
Hepatic CYP450
What are some major side effects of phenytoin?
Gingival hyperplasia
Hirsutism
Hypocalcemia
Osteoporosis
Carbamazepine is an inducer of __ enzymes and can lead to these side effects:
Hepatic CYP450
Aplastic anemia (rare, but often fatal) - idiosyncratic
Leukopenia, neutropenia, thrombocytopenia (infections, bruising)
Hypocalcemia, osteoporosis
Osteopenia/osteoporosis is a serious side effect associated with chronic administration of these drugs which induce CYP450-dependent vitamin D catabolism
Carbamazepine
Phenytoin
Phenobarbital
Valproic acid
Starting ___ can increase clearance of oral contraceptives (estrogen) metabolize by CYP isoenzymes –> 4-fold rise in OCP failure rate, risk for unplanned pregnancy
Carbamazepine
Starting __ can increase clearance of warfarin (oral anti-coagulant) metabolized by CYP isoenzymes –> too rapid coagulation, elevated risk for arterial/venous thrombosis
Carbamazepine
__ is an analogue of carbamazepine but with the advantage of fewer adverse effects due to its lack of formation of an active metabolite
Oxcarbazepine
Metabolism of __ occurs in the liver, but with minimal effects on the CYP450 enzymes. This is advantageous in pts who require multiple drugs
Oxcarbazepine
What are some serious adverse affects associated with carbamazepine?
- Life threatening
- Allergic rxn (stevens-johnson syndrome)
- Aplastic anemia
What are some serious adverse affects associated with Lamotrigine?
- life threatening
- Allergic rxn (Stevens-johnson syndrome)
___ inhibit conjugation of drugs by UGT enzymes (phase 2)-causing accumulation of parent drug (e.g. each other when they are used together..which they often are)
Valproate and lamotrigine
What are serious adverse events associated with oxcarbazepine?
Hyponatremia (more common in elderly), rash
What are adverse events associated with Tiagabine?
Stupor
What are adverse events associated with Topiramate?
Nephrolithiasis, open angle glaucoma, hypohidrosis (mainly children)
What are serious adverse events associated with Zonisamide>
Rash, renal calculi, hypohidrosis (mainly children)
Several old (traditional) AEDs are Class D teratogens such as these drugs:
Valproic acid
Carbamazepine
Phenytoin
Ethosuximide and valproic acid are these major types of anti-epilepsy drugs
Generalized onset-Absence seizures
