Segars: Antiepileptic Agents Flashcards
List the 9 antiepileptic drugs which work as pre-synaptic voltage-gated Na+ channels blockers via enhanced fast inactivation.
1) Carbamazepine
2) Oxcarbazepine
3) Lamotrigine
4) Phenytoin
5) Rufinamide
6) Topiramate
7) Valproic acid
8) Zonisamide
9) Lacosamide
Which AED is unique in its ability to prolong fast inactivation of Nav ion channels and also enhance slow inactivation of Nav channels?
Lacosamide
Which 2 antiepileptic drugs are AMPA-receptor antagonists?
MOA?
- Topiramate
- Perampanel
MOA = bind AMPA receptor and block glutamate binding; channel doesn’t open –> AP does not propogate downstream
Which antiepileptic drug is an NMDA-receptor antagonist?
Felbamate
The pharmacological activity of AED Nav channel blockers is _______ and ________-dependent
State and Use-dependent
Which gate must be open for AED’s to access the pore of Nav channels?
Which states can this occur?
- Activation gate
- Open state and Fast-inactivated state
The probability of Nav blockade is proportional to what?
FREQUENCY of Nav channel opening and dose
Why do the AED’s that are Nav blockers act preferentially on the neurons involved in epileptic seizures?
The neurons involved will be firing at higher freqeuncy than normal, allowing more chances for these drugs to slip right in and bind
What is the water-soluble pro-drug of phenytoin which is given via IV and is an Nav channel blocker used as an antiepileptic?
Fosphenytoin
Which AED acts as a Nav channel blocker (fast inactivation), AMPA-receptor antagonist, and GABAA agonist?
Topiramate
What occurs when the post-synaptic GABAA receptor becomes occupied by GABA?
- Cl- channel opens
- Hyperpolarization occurs blunting AP propogation
What is the MOA of the AED, Tiagabine?
- Blocks pre-synaptic reuptake of GABA by blocking the GABA transporter, GAT-1
- Causes GABA to go post-synaptically, bind GABAA receptor leading to hyperpolarization and decreased AP propogation
What are the 3 MOA’s of Valproic acid used as a AED at the pre-synaptic GABA terminal?
1) Increase activity of glutamic acid decarboxylase, leading to increased GABA presynaptically
2) Inhibit GABA-T, which typically metabolizes GABA
3) Inhibit Succinic Semialdehyde Decarboxylase (SSD), which typically metabolized GABA
Which 2 AED’s inhibit the metabolism of GABA through the inhibition of GABA-T?
- Vigabatrin
- Valproic acid
Which drug in the barbiturate family gets metabolized to phenobarbital in the body?
Primidone
Where do Benzodiazepines bind the GABAA receptor and what effects does this have?
- Bind to a distinct site –> Allosteric change potentiate GABA binding
- Cl- channel opens with greater frequency
Where do Barbiturates bind the GABAA receptor and what is their effect?
- Bind a distinct site
- Increases the duration of Cl- channel opening
Of the GABAA receptor agonists used as AED’s which is more lethal at higher doses and why?
- Barbituates are more lethal due to being GABA INdependent
- Benzodiazepines are GABA-dependent
What are the 7 AED’s which act post-synaptically to potentiate GABAA-receptor Cl- currents?
1) Phenobarbital
2) Primidone
3) Clonazepam
4) Lorazepam
5) Diazepam
6) Clobazam
7) Topiramate
Which type of ion channel mediates the 3-Hz spike and wave activity in the thalamus which is the hallmark of absence (petit mal) seizures?
T-type Ca2+ channels
Which narrow spectrum drug is only used for absence seizures and only limits excitation (Ca2+ channels)?
Ethosuximide
Which 3 AED’s are antagonists of T-type Ca2+ channels?
- Ethosuximide (narrow spectrum)
- Valproic acid (also GABA-T inhibitor and prolongs fast inactivation of Nav channels)
- Zonisamide (also prolongs fast inactivation of Nav channels)
Which 2 AED’s act as both antagonists of T-type Ca2+ channels and prolong fast inactivation of Nav channels?
- Valproic acid (also GABA-T inhibition)
- Zonisamide
Which AED blocks synaptic vesicle 2A protein on the presynaptic terminal of glutamate neuron?
Levetiracetam
Which 2 AED’s block the α2δ1 Ca2+ channel on the presynaptic terminal of the glutamate neuron?
1) Gabapentin
2) Pregabalin
The abrupt withdrawl of any antiepileptic medication may precipitate?
May lead to what type of behavior?
- Precipitate status epilepticus
- Suicidal behavior and ideation
Which AED follows zero-order (saturable) pharmacokinetics?
Phenytoin
***if you give more than the body can handle, it just builds up. thus, it is easy to give too much
Phenytoin is a well-known inducer of?
CYP-450 enzymes
*Frequent drug-drug interactions
What are 2 toxicities associated with the AED, Phenytoin?
- Gingival hyperplasia
- Hypocalcemia/Vit. D deficit/Osteoporosis
Osteopenia/Osteoporosis is a side effect associated with chronic administration of which 4 AED’s?
What do these drugs induce?
- Carbamazepine
- Phenytoin
- Phenobarbital
- Valproic acid
*These drugs induce CYP450-dependent vitamin D catabolism
What are some of the issues associated with the AED, Carbamazepine (i.e., serum drug level, inducer of, toxicities)?
- Serum drug level monitoring (4-12 mcg/mL) = narrow window
- Inducer of CYP-450 enzymes
- Induces auto-induction (self-metabolism)
- Hematological toxicities: leukopenia/neutropenia/thrombocytopenia
Which AED induces its own metabolism?
Also occurs to a lesser extent with what other AED drug?
What may occur because of this?
- Carbamazepine induces own metabolism
- Also, to lesser extent (25%), with lamotrigine
*This may lead to a potential loss of efficacy and recurrence of seizures
Before administering which AED is a CBC required as this drug has potential side effects including leukopenia, neutropenia, and thrombocytopenia?
Carbamazepine
What analogue of carbamazepine was formulated which has fewer CNS/hematological SE’s and is a less-potent CYP450 inducer?
Oxcarbazepine
What are some of the issues associated with the AED, Phenobarbital?
- Need serum drug level monitoring (10-40 mcg/mL)
- Well known inducer of CYP-450 enzymes (frequent drug-drug interactions)
- Toxicities: hypocalcemia/Vit. D deficit/Osteoporosis
Which AED is only prescribe-able via REMS program; why?
- Vigabatrin
- May cause progressive, permanent, bilateral, concentric vision loss
Which 4 AED’s are associated with hepatic CYP450 induction?
- Carbamazepine
- Phenytoin
- Phenobarbital
- Valproate
What are 3 major AED-drug interactions associated with the CYP450 inducers?
- Increased clearance of oral contraceptives –> 2-4 fold rise in OHC failure rate; risk for unplanned pregnancy
- Increase clearance of warfarin –> less anticoagulation; elevated risk for arterial/venous thrombosis
- Increase clearance of HIV meds –> elevated risk for HIV replication
Which 2 AED’s inhibit conjugation of drugs by UGT causing accumulation of parent drug (esp. each other when used together)?
Valproic acid and Lamotrigine
Which 3 AED’s induce conjugation of drugs by UGT causing a reduction of parent drug (i.e., when given with valproic acid will decrease levels of valproic acid)?
1) Phenytoin
2) Carbamazepine
3) Phenobarbital
What are some of the example causes of Status Epilepticus?
- Abrupt withdrawl of AED’s, BZD’s, Opioid’s, Alcohol
- Brain mass/trauma
- Infection
- Fever
What is the initial therapy for convulsive status epilepticus (i.e., the first IV, alternative drug, and if no IV access)?
- In first IV:
- Lorazepam
- Alternative
- Diazepam
*Wait 1 minute for response then additional lorazepam PRN
Which AED opens pre/post-synaptic K channels to prevent seizures?
Ezogabine
What are the 3 MOAs of Valproic acid?
Topiramate?
Valproic acid = Na channel blocker, GABA-T inh, Ca t-type blocker
Topiramate = Na channel blocker, AMPA blocker, post-syn GABA promotor
What drug may be beneficial for the treatment of Dravet and Lennox-Gastaut syndrome?
Cannabidiol
What are 3 options for 2nd therapy for status epilepticus?
- Fosphenytoin
- Intubation
- Continuous BP and CV monitor
- Continuous midazolam OR propofol infusion
