Antiepileptics Flashcards
What the mechanism by which focal seizures occur?
- Abnormal synaptic transmission causes a paroxysmal depolarization shift (PDS) that is seen on EEG as a spike and wave discharge
- Feed-forward and feedback inhibition limit duration and spread of epileptiform activity
- Surround inhibition prevents spikes form becoming seizures
- Failure of inhibition can allow excessive sychronous activity to propogate and cause a seizure
- Seizure activty is a “network property” - Requires recurrent activation , not just a “focus” where they start
- Failure of surround and feedforward inhibition results in spread of seizure actiity to other cortical areas (or secondary generalization)
What causes tonic stiffening and the clonic jerking phase of seizures?
- Tonic Stiffening - Prolonged PDS (paroxysmal depolarization shift)
- Clonic Jerking Phase - Intermittent return of GABAergic inhibition of seizure activity
What are the two mechanism by which AEDs prevent focal seizures?
Reduce Excessive Excitation
- Prevent repetitive AP propgation of seizure discharge by inactivation of voltage-gated Na+ channels
- Reduce excessive glutamate releae by:
- Binding to presynaptic Ca2+ channels at the α2δ subunit (gabapentin)
- Binding to presynaptic SV2A protein (levitiracetam)
- Block AMPA glutamate receptors (perampanel)
Increase Inhibition
- Increase GABA-mediated neurotransmission
- Activate inhibitory K+ channels (ezogabine)
Describe how Na+ channel AEDs function.
Bind to the open voltage-gated Na+ channels and stabilize it in the inactivated state
- Prevents additional firing
- Prevents propagation of epileptic discharges from focus
What are the common side effects for the Na+ channel AEDs?
- Diplopia (AED “poisons” high frequency firing in MLF)
- Nystagmus (AED “poisons” high frequency firing in MLF)
- Ataxia (Coordination problems)
- Vertigo
- Sleepiness, lethargy, cognitive slowing
All are dose-dependent and REVERSIBLE
A patient that is experiencing ____________ can indicate that they are indeed taking their sodium channel AEDs, but that they cannot tolerate an increase in dosage.
Nystagmus
What are the Sodium Channel AEDs?
- Phenytoin
- Carbamazepine
- Valproic Acid
- Phenobarbital (also acts on GABAa)
- Lamotrigine
- Topiramate
- Zonisamid
MOA of Phenytoin
Na+ channel blocker AED
What type of seizures is Phenytoin used to treat?
- Focal
- Generalized tonic-clonic seizures
Not absence seizures
PCKN of Phenytoin
- Low water solubility
- 80-90% protein bound; free levels actually cross BBB to get to brain
- Low doses: Hepatic metabolism by P450 (95%) is first-order kinetics
-
High doses: P450 gets saturated and metablosim slows to zero-order kinetics
- Small increases in dose can result in VERY high drug levels and side effects
What are the side effects of Phenytoin?
- Acute: Allergic rash, cardiotoxic
- Dose Dependent: All side effects of Na+ channel blockers
- Idiosyncratic (long term use)
- Fibroblast Stimulation
- Gingival hyperplasia (gum overgrowth)
- Hirsutism
- Coarse facial features
- Altered Vitamin D metabolism
- Osteopenia (reduced bone density due to decrease Ca2+ absorption)
- Peripheral neuropathy
- Fibroblast Stimulation
- Teratogenic - Fetal Hydantoin Syndrome
What drug causes Gingival Hyperplasia?
Phenytoin
What drug causes osteopenia?
Phenytoin
What drug is associated with fetal hydantoin syndrome?
Phenytoin
What is special about Fosphenytoin?
- It is a water SOLUBLE phosphorylated pro-drug that gets dephosphorylated to phenytoin in serum
- This allows phenytoin to be IV (otherwise IV phenytoin requires propylene glycol to make it soluble which can lead to tissue damage)
What are the important side effects to remember about Carbamazepine?
-
Dose Dependent Adverse Effects:
- Normal dose dependent Na channel blocker side effects of nystagmus, diplopia, ataxia, etc
- Neutropenia (Decreased WBC)
-
Idiosyncratic Adverse Effects (Long Term Use):
- Aplastic anemia
- Rash (can progress to Stevens-Johnson Syndrome)
- Hyponatremia
What are the uses of Carbamazepine?
- Focal seizures
- Generalized Tonic-Clonic seizures
Also for neuropathic pain, trigeminal neuralgia
What is the metabolism of Carbamazepine?
Autoinduces cytochrome P450 (Hepatic Metabolism)
- Increases expression of same isozymes that metabolize it
- Must start with low dose and increase gradually over 2-3 weeks
By product of 10,11 epoxide metabolite that increases dose dependent side effects
What is the MOA of Carbamazepine?
Na+ channel blocker
What part of the breakdown of carbamazepine is not good?
Breakdown will form 10,11 epoxide metabolite which is active against seizures BUT it alsoINCREASES dose dependent adverse affects like double vision, sleepiness , etc
What side effect is more common with oxcarbazepine than carbamazepine?
Hyponatremia
What is the difference between oxcarbazepine and carbamazepine?
- The epoxide is not formed in the metabolite of oxcarbazepine (so better tolerated at higher levels)
- Also little induction of hepatic enzymes which is unline CBZ
Phenobarbital is a unique AED in that aside from acting upon Na+ channels, it also acts upon ______________ receptors.
GABAA receptors
What drug auto-induces its own metabolism and needs to be started at a lower dose to prevent side effects?
Carbamazepine
What are the uses of Oxcarbazepine?
- Focal seizures
- Generalized Tonic-Clonic seizures
What are the uses of Valproic Acid?
Broader Spectrum
- Focal seizures
- Generalized Tonic-Clonic (GTC)
- Also for generalized epilepsies:
- Absence, juvenile myoclonic, etc.
- Good choice if you can’t tell whether patient has a focal or generalized seizure disorder
What is a good choice if you can’t tell if seizure is focal or generalized?
Valproic acid
What is the MOA of Valproic Acid?
- Blocks Na+ channel to inhibit repetitive AP firing
- Also blocks T-type Ca2+ currents
- May affect GABA inhibition
PCKN of Valproic Acid:
- >90% protein bound (displaces phenytoin)
- Glucuronidated in liver (inhibits hepatic metabolism of other AEDs)
What drug will inhibit the hepatic metabolism of other AEDs?
Valproic Acid
What are some advers side effects of Valproic Acid?
- GI irritation
- Thrombocytopenia
- “Fat, Shaky, Bald, Yellow = Homer!”
- Weight gain
- Tremors
- Hair loss
- Jaundice from possible liver toxicity
- Pancreatitis (rare)
- Teratogenic (cognitive deficits and neural tube defects)
The liver toxicity of Valproic acid is seen most in?
Children less than 2 yrs when they used other AEDs
What are the contraindications of Valproic Acid?
Patients that are pregnant
- Valproic acid is teratogenic and increases the risk of cognitive deficits and neural tube defects
What drug can cause weight gain, tremors, hair loss, jaundice?
Valproic acid
What are the uses of Lamotrigine?
- Focal seizures
- Generalized Tonic-Clonic (GTC) seizures
- Also effective for generalized epilepsies (absence, myoclonic)
PCKN of Lamotrigine:
- Hepatic glucuronidation
- Long half life of 24-37 hours (but SLOWED by valproic acid which decreases hepatic metabolism of other AEDs)
What are some adverse side effect of Lamotrigine?
- Dose Dependent Effets (Diplopia, ataxia, nystagmus, etc.)
-
Rash (due to rapid titration; incidence reduced by slow titration)
- Rash may progress to Stevens-Johnson Syndrome.
What is the MOA of Lamotrigine?
Na+ channel blocker
What are the uses of Topiramate?
- Focal seizures
- Generalized Tonic-Clonic (GTC) seizures
- Also used for generalized types of seizures
- Also used to migrane prevention
What is the MOA of Topiramate?
- Na+ channel blocker
- Enhances GABAA receptor currents
- Weak carbonic anhydrase inhibitor
What drugs are weak carbonic anhydrase inhibitors?
Topiramate (topamax)
Zonisamide
What are some adverse effects of Topiramate?
- Confusion/psychosis
- Renal stones (Always avoid in patients with history of renal stones)
- Somnolence (sleepiness)
- Paresthesias (tingling; due to carbonic anhydrae inhibition)
What are some contraindication of Topiramate?
Avoid in patients with history of renal stones
What drugs can cause kidney stones?
Topiramate
What is the drug used to treat Lennox-Gastaut Syndrome?
- Rufinamide
- Clobazam
What drugs enhance GABAa?
Benzodiazepines (diazepam, lorazepam, clonazepam, etc.)
What drug enhances GABA synthesis?
Gabapentin
What drug decreases GABA metabolism?
Valproic acid (increases GABA concentration)
What are the uses of Clonazepam?
Adjunctive against focal and GTC seizures (absence, atonic, and myoclonic)
What are some adverse effects of Clonazepam?
- Sedation, ataxia, psychosis, memory problems
- Tolerance
- Can wosren seizures
What are the uses of Diazepam & Lorazepam (benzodiazepines) as seizure meds?
Status epilepticus
- NOT for long term use because of rapid dependence potential
What is the MOA of Phenobarbital?
- Prolongs duration of GABAA receptor channel opening
- Also inhibits repetitive Na+ channel activation
What are some adverse effects of Phenobarbital?
Cognitive slowing
Dizziness
Mood change
Paradoxical hyperactivity in kids
Tolerance to sedation
Cognitive effects worse than for other AED
Which AED causes noticeable cognitive slowing?
Phenobarbital
What AED can cause hyperactivity in kids?
Phenobarbital
What are the places that AEDs can bind to inhibit the release of excitatory amino acids in synapse?
- Presynaptic Calcium channel α2δ subunit - Inhibits glutamate release (gabapentin)
- Synaptic vesicle protein SV2A - Prevents release of glutamate (levetiractetam)
Where does levetiractetam work?
- Synaptic vesicle protein SV2A (inhibits NT release)
- No effect on GABA or glutamate receptors or sodium channel
Where does Gabapentin bind?
α2δ subunit of Ca2+ channel to inhibit release of glutamate
What are the uses of Gabapentin?
- Adjunct for focal and GTC seizures (not effective as monotherapy)
- Diabetic neuropathy and other neuropathic pain
- Headache
What are some adverse effects of Gabapentin?
- Peripheral edema (swelling)
- Sedation, ataxia at high doses, weight gain
Overall well tolerated (few drug interactions; so good for elderly)
What AED is good for elderly?
Gabapentin because of few drug interactions
What is the MOA of pregabalin (Lyrica)?
Binds to α2δ subunit of Ca2+ channel (inhibits glutamate release)
What are the uses of Pregabalin?
- Focal and generalized seizures
- Also for neuropathic pain syndromes
What are some adverse effects of Pregabalin?
- Peripheral edema (swelling)
- Sedation, ataxia at high doses, weight gain
What are the uses of Levatiracetam?
- Focal seizures
- Generalized Tonic-Clonic seizures
- Myoclonic and generalized seizures
What are some adverse effects of Levatiracetam?
- Somnolence
- Ataxia
- Irritability 10% (well tolerated in most people)
PCKN of Levatiracetam:
- Minimal protein binding
- Minimal drug interactions
- Mostly unchanged in urine
What is the MOA of Ezogabine?
- Activates K+ channel (leads to hyperpolarization and decreased excitability)
- Broad spectrum of AED efficacy
What is the “smurf” drug?
Ezogabine. It can turn your skin blue.
What are some adverse side effects of Ezogabine?
- Urinary retention
- Irreversible vision and skin problems -Can turn you blue (rare)
What drug works by activating K+ channels?
Ezogabine
What AED mechanism works for absence seizures?
-
T-Type Ca2+ channel in thalamic relay neuron blockers
- Stabilize the inactivated state for these channels preventing rhythmic firing
- These are useful for absence but NOT for partial or GTC seizures
What are the normal functions of T-type Ca 2+channels?
Low threshold activated Ca2+ channels in thalamic relay neurons generate rhythmic pacemaker activity (resets channels to activatable state)
What are the T-type Ca2+ channel blockers?
- Ethosuximide
- Valproic Acid
- Zonisamide
- Lamotrigine
Thus these are for absence seizures
What is the 1st line AED for absence?
- Ethosuximide (if only absence) – ONLY for absence not for GTC seizures
- Valproic Acid for absence + GTC or other types
First line treatment for focal seizures +/- secondary generalizations?
- Carbamazepine
- Phenytoin
- Lamotrigine
2nd line - Valproic acid, oxcarbazepine, topiramate
Adjunct - Gabapentin,topiramate, levatiracetam, zonisamide
What is the first line treatment for Primary generalized seizure (GTC, myoclonus)?
- Valproic Acid
- Lamotrigine
- Topiramate
- Levetiracetam
Clonazepam sometimes for myoclonic seizures
What are the uses of Levetiracetam?
Myoclonic seizures
What drug is for infantile spasms?
Vigabatrin
AEDs in pregnancy:
- Double risk for teratogen but still 90% will be fine
- Valproic acid - Neural tube defects risk and cognitive slowing
- Carbamazepine increase risk
- Give folic acid to reduce risk
What is the treatment for Status epilepticus?
- First - Airway, Breathing, Circulation
- IV benzodiazepines next
- Follow with IV fosphenytoin
Most common surgery to treat seizures?
- Anterior temporal lobectomy
- 70% seizure free after surgery in carefully selected patients
- Can give Vagus nerve stimulator
What AEDs can also be used for headache prophylaxis?
- Valproic Acid
- Topiramate
What AEDs can also be used as mood stabilizers?
- Valproic Acid
- Carbamazepine
What are some alternative uses of benzodiazepines?
- Anxiety disorders
- Sedation / sleep
- Adjuncts for anesthesia
- Prevention of ETOH withdrawal symptoms
What are some alternative uses for barbiturates?
- Sedation
- Anesthesia
- Headache
- Tremors
What is status epilepticus?
A period of at least five minutes in which seizures are continuous or there is no recovery of consciousness between seizures
