What is the goal of Anti-epileptic drugs?
GOAL: max quality of life by minimizing seizures and adverse drug effects but may not be lifelong treatment
Decrease the frequency and/or severity of seizures
Treats the symptom of seizure but no the underlying epileptic condition
[currently, no anti-epileptogenic drugs available]
Factors to consider when selecting AED regimen?
Describe the difference between Narrow Spectrum and Broad Spectrum AEDs?
Monotherapy vs polytherapy
Narrow Spectrum - 1 Mechanism of Action for PArtial Seizures
Broad Spectrum - for all and have more than 1 mechanism of action
Name the Broad Spectrum drugs we learned about....Whats the way to remember them eh?
[Valery Likes To Lick Zeus}
Name the Narrow Spectrum Agents by old and new generation
Old - Carbamazepine, Phenytoin, Phenobarbital
New - Gabapentin, Oxcarbazepine, PRegabalin, Lacosamide
What seizures are the Narrow Spectrum drugs (GLOP and CPP) used for?
Partial Onset that can be simple, complex, or tonic-clonic but with focal/partial onset
What is the Treatment for Absence seizures and briefly describe it's mechanism of action?
Targets T type Caclcium channels
What is the like most severe way to KO generalized onset seizures?
Benzodiazepines or barbituates
Like hitting with a sledge hammer
Describe the role of "weighted inhibition" or Inhibitory surround in the brain and what types of neurons are in competition for balance in the pathology of seizures.
Normally, Inhibitory (GABA/Glycine interneurons) outweigh excitatory NT/inputs - hence the term "Weighted Inhibition" and they perform surround inhibition to prevent synchronization of adjacent neurons so you dont get excitatory spread with signaling (excitatory signaling with Glutamate and Aspartate)
Seizure generation occurs when you lose GABA input and excitation is weighted more than inhibitory
- get bursts of EPSPs and Na and Ca currents and burst firing in Paroxysmal Depolarization (generation of seizure)
Describe the cellular mechanisms for Partial and Secondary Generalized seizures and highlight the areas where we use drugs to intervene
Main Mechanism: Depolarizing Shift!!!
see burst of high electrical activity by a column of neurons that's lost inhibitory inputs
Recurrent EPSP --> Ca spikes --> repetive spike
Rapid Neuronal Discharge at Seziure Foci OPENS NA CHANNEL!!
Therefore drug-targets are to either BLOCK NA CHANNELS or INCREASE GABA INHIBITIOIN
What are the Na Channel blockers used as narrow spectrum and how do they work?
Na Channel Blockers: Phenytoin, Carbamazepine, Oxcarbemazepine, ESL (Stedesa), Lacosamide
Prevent prolonged activation but dont block the initial opening of the channel so neurons retain their ability to generate APs at lower frequencies but not get rapid generation like with seizures
"Use-Dependent BLockade" = Work only AFTER channel has been opened under normal circumstances and prolons inactivation state and increased refractory period
How does Phenytoin work? What is it used for?
Phenytoin is a Na Channel blocker that is a first-line agent in treatment of partial seizures and should be considered/compared with Carbemazepine and Lamotrigine for risk/benefit
First line agent partial seizures
GIVEN IV IN STATUS EPILEPTICUS
What are the "TO KNOW" Facts about Phenytoin?
Name some specific adverse events.
Phenytoin is 95% bound to plasma albumin, inactivated by metabolism in liver, is a P450 inducer (can induce its own metabolism)
SATURATION KINETICS (linear at low doses zero order at higher doses) so small increase in dose can cause large, unpredictable increase in plasma concentration
- Cerebellar effects= Ataxia, Nystagmus, Incoordination
-Cerebral effects = Confusion
-Ugly Effects = Hirsuitism and Facial coarsening and systemic skin rash
The worst - 15-50% get GINGIVAL HYPERPLASIA!
What kind of drug is Carbemazepine? How does it work? When is it used?
Carbemazepine is actually a tricyclic antidepressant that here is a Na-Channel blocker used as a first line agent in Partial Seizures (especially good when effects of Phenytoin are too great)
Occasionally used in Tonic-Clonic
What are the TO KNOW facts about Carbemazepine metabolism and side effects?
Carbemazepine is inactivated by metabolism in liver and its active metabolite, 10-11 Epoxy Metabolite, may contribute to neurotoxicity
It induces its own metabolism and increases rate of metab during first 3-6 weeks so neets to be titrated correctly, large doses may be necessary
What is Oxcarbazepine? How does it work? What is it used for?
Oxcarbazepine is a newer drug closely related to Carbamazapine but with a lower side effect profile and less induction of P450 enzymes in liver metabolism
Used in kids >4 yo
Used as first-line monotherapy or in add-on therapy for partial seizures
Slows Na channel recover - NA channel blocker
Also may augment K+ and Ca+ channels to help hyperpolarize cells
What are the TO KNOW facts about Oxcarbazepine and its side effects?
some induction of P450 but much less
LOW side effect profile including simply sedation!
*Watch out for low sodium of on concomitant Diuretics
ORAL CONTRACEPTIVE INTERACTION
What is Elsicarbazepine Acetate (ELS/Stedesa)? How does it work? what is it used for?
similar to Carbamazepine/oxcarb by blocking fast-acting GV Na channel but has greater affinity for inactive state (vs resting state) so more selective for rapidly firing neurons!!!!
ELS is a pro-drug and so metabolized into active compound at active site so relatively little side effects
Used mostly now as add=on therapy for Partial Seizures
No auto-induction of metabolism
What are the TO KNOW facts for ESL/Stedesa and Adverse effects?
Decreases ORAL CONTRACEPTIVE AVAILABILITY
Favorable drug-drug interaction profile, low protein binding and minimal effect on hepatic cytochrome P450 enzyme
Well-tolerated and most common effects are Dizziness, Somnolence, HA, N/V
Once Daily Dosing
What is LAcosamide? How does it work/what is it used for?
Add-on therapy for poorly controlled partial seizures
Mechanism is unclear but appears to change shape of Na-Channel to slow rate of synaptic transmission
Well-tolerated - dizziness main side effect
What are the Benzodiazepines? What are they used for? How do they work?
Benzodiazepines - Diazepam and Lorazepam
Enhance effectiveness of GABA-mediated inhibtion and icnrease frequency of Cl channel opening when GABA bound to receptor
LAST LINE of choice bc prominent adverse effects and can develop tolerance
Now used only to ablate seizures acutely and IV infusion for treatment of Status Epilepticus
What are the TO KNOW facts and side effects about Benzodiazepines?
NOT first line choice - last line because prominent side effects of Sedation, Dizziness, Ataxia, Drowsiness
TOLERANCE - can lose effectiveness in as short as 6 months
What are the Barbituates used in Seizures? How do they work and how are they used?
What are the side effects?
Barbituates = Phenobarbital
GABA-mimetic and GABA-potentiating - can open Cl channel and interact with GABA-A at binding site separate from benzo site
Used in Partial Seizures and Tonic clonic as an alternative drug and used less clinically bc of heavy side effects:
- HEAVILY sedating
- Cognitive Defects
Tolerance and Withdrawal
What are Gabapentin and PRegabalin? How do they work? How are they used?
Gabapentin (Neurontin) and Pregabalin (Lyrica) are GABA-like compounds that do NOT act at that receptor --> Instead, they acts on Alpha2-Delta1 subunit on VG Ca2+ channels on Excitatory neurons to reduce Ca current and decrease neuron firing and excitatory transmission
Used as add-on therapy for PArtial Seizures and Tonic Clonic seizures
What are the TO KNOW about Gabapentin/Pregabalin?
Both are excreted unchanges into the urine and so do not interfere with the metabolism of other drugs!
Approved for children - BERRY FLAVORED LIQUID!
Well-tolerated with limited side effects including Somnolence, Dizziness, Ataxia
Some behavior and learning difficulties reported in kids but less sedating than classic AEDs
What's happening in the phases of Tonic Clonic seizures?
Tonic Phase - seizure with long train of neuronal firing from acute sudden loss of GABA input
Clonic Phase - Gaba back in alternating fashion and oscilation of currents
Post-Ictal GABA re-maintains inhibitory control
What drugs are used as Broad Spectrum AEDs? just List them!
Valery Likes To Lick Zeus
What is Valproate? Mechanism of Action and uses?
Valproate (Valproic Acid aka Depakene) has 3 mechanisms:
1) Inhibits Low-Threshold T-Type Ca Channels
2) Slows Rate of Na channel Recovery
3) Increases Availability of GABA at synapse
Has many uses:
First line Therapy for Generalized Seizures but also used in Partial and Absent Seizures
What are the notable drug interactions for Valproate? aka What other AEDs would you NOT use Valproate with?
Valproate and Carbamazepine induce eachothers metabolism so dont used togheter
Valproate inhibits Phenobarbitol metabolism - so dont use together
Valproate displaces Phenytoin from binding proteins --> increases its concentration in plasma and increases toxicity
Dont use with old CPP PArtial Seizure Narrow Spectrum meds!
What are the adverse effects of Valproate?
Tremor, Hair Loss, WEight gain
Elevated liver enzymes
TERATOGENICITY - Autism, Sensory deprivation, Spina bifida
What is Lamotrigine? How does it work? What is it used for?
Lamotrigine (Lamictal) is a broad spectrum drug used as an add-on or monotherapy in partial and Secondarily Generalized Tonic-Clonic seizures (not primary)
1) Slows rate of recovery of VG Na channels
2) Inhibits Glutamate Release
3) Potential inhibition of Ca channels
What are the side effects of Lamotrigine? How is it metabolized?
Lamotrigine is well tolerated and less sedating than other AEDs but can cause severe dermatitis in 1-2% pediatric patients (esp if given too quickly so start slow)
Metabolized by Glucuronidation in the liver
What is Zonisamide? How does it work and how is it used?
Zonisamide is a broad spectrum anti-convulsant efficacious as adjunctive therapy for all seizure types (including absence) but only FDA approved for Partial onset
1) Blockade of Na channels
2) Reduction in VG T-type Ca Channels (like Ethosuximide)
3) REduction of glutamate induced synaptic transmission
What is interesting about Zonisamide dosing and what are the side effects of zonisamide?
Very Long Half Life (1-3 days) so 1x/day dosing
Has Sulphonamide Groups - NOT USED IN PPL WITH ALLERGY TO SULFA DRUGS
Side Effects: Causes Kidney stones and Anhydrosis
What are the newer agents that act to inhibit Glutamate Transmission?
Act on AMPA/NMDA receptors
- Topiramate - highly pleiotropic
Reduce Glutamate Synaptic Transmission
What is Topiramate? Mechanism of Action? Uses?
Topiramate is a broad spectrum agent used to treat Partial, Generalized Tonic-Clonic, Some Myoclonic seizures - NOT for Absence
1) Glutamate receptor antagonism - AMPA rec (maybe Kainate)
2) GABA potentiation
3) Na and Ca Channel Blockade
4) Carbonic Anhydrase Inhibitor
What are advantages of Topiramate? What else is it good for?
topiramate has minimal interactions with other drugs (excpet Oral Contraceptives)
Approved as a Monotherapy AND approved for kids 2yo and up
Can cause weight loss (although bad for kdis)
USED AND APPROVED FOR MIGRAINE PREVENTION
What are the Side Effects and Bad things about Topiramate?
decrease OC therapy
What is Felbamate? How does it work and what is it used for?
Extremely potent antiepileptic with inhibition of NMDA and AMPA subtypes of Glutamate receptors
*restricted for use ONLY in patients with Refractory Epilepsy
What's So bad about Felbamate that it's only used for refractory epilepsy?
While it lacks sedative effects.....it does cause:
Adverse Behavioral Effects
Fatal Aplastic Anemia and LIver Failure!!!!!
What is Levetiracetam? How does it work? What is it used for?
Levetiracetam (Keppra) is a broad spectrum AED with Novel mechanism of action where it enhances Synaptic Vesicles (SV2A) release of GABA
MAY PREVENT EPILPTOGENESIS (all others only treat symptoms)
Used for Partial and Generalized Seizures
What are the Advantages of Levetiracetam that make it so ideal?
What are the side effects?
Levetiracetam (Keppra) is *EFFECTIVE AT INITIAL DOSE so no need to titrate (great for pts with frequent seizures)
Dose-Escalation can be fairly rapid
NO KNOWN INTERACTIONS WITH AEDs
Side Effects: well-tolerated
some Mood irritability/psychosis seen
What are the different types of Generalized seizures and what do you see with them?
Absence - Petit Mal with staring, blinking, lip-smacking/hand movements
Tonic-Clonic - Gran Mal
Myoclonic - brief Jerks
Atonic - Drop attack
What are the T-Type Ca channels involved in absence seizures? What's happening where in the brain during an Absent Seizure?
T-Type channel is primary target in Absent Seizure Treatment bc:
Normally, Thalamus relay setup activated during sleep and T-Type burst firing occurs to maintain sleep state and slow sleep waves
BUT when it is active in awake state then awake but EEG looks like characteristic of sleep state
T-Type Channels fire while awake and causes you to be absent!
What are the drugs that act on T-Type Calcium Channels?
Drugs reduce activation of T-Type channels in thalamus = Anti-Absence
What is Ethosuximide? How does it work? when is it used?
First-line therapy for Absent Seizures - very effective for that!
acts specifically on T-Type Channels in thalamus
How does Ethosuximide travel in body? Side Effects?
zero to low plasma protein binding
LEss sedating than other drugs and low incidence of adverse effects!
What are the enzyme inducing AEDs for hepatic enzyme induction?
Drugs used for Epilepsy AND for Neuropathic Pain? easy way to rememebr
[Valery Got Pain Like Lenny Cravitz Ought-to}
AEDs used for Bipolar Disorder?
AED Drugs used for Migraine?
2 DRUGS GIVEN FOR STATUS EPILEPTICUS:
Drugs with ORal Contraceptive Interactions?
What is the ONLY AED with eleptogenic potential? What is it's unique mechanism of action?
Helps with veiscle docking of SV2A on GABA neurons to increase releaes of GABA
What are the drugs that act on T-Type Ca Channels?