Pharm - Seizures

What are the 4 mechanisms of anti-seizure medications?

Na-channel blockade: stabilizes inactivated channels; limits sustained high-frequency firing

Ca-channel modulation: reduces neurotransmitter release; T type channels drive absence rhytms

Glutamate antagonism: dampens excitation at NMDA and AMPA receptors.

GABA potentiation: enhances inhibitory Cl influx, raising the seizure threshold.

Which drugs belong to the Na-channel blockers MOA group?

Phenytoin

Carbamazepine

Oxcarbazepine

Lamotrigine

Lacosamide

Topiramate

Zonisamide

Valproate

Which drugs belong to the high voltage N-, P/Q- and L type Ca channel modulators/blockers MOA group?

Gabapentin and pregabalin

Lamotrigine

Topiramate

Felbamate

Which drugs belong to the low voltage T-type Ca channel modulators/blockers in the thalamus MOA group?

Ethosuximide

Valproate

Zonisamide

Which drugs belong to the AMPA glutamate antagonism MOA group?

Perampanel

Topiramate

Which drugs belong to the NMDA glutamate antagonism MOA group?

Felbamate.

Which drugs belong to the GABA potentiation MOA group?

Benzo and barbiturates enhance GABA

Valproate

Tiagabine inhibits GABA reuptake

Vigabatrin inhibits GABA degradation (reserved for 2nd line)

How do Gabapentin and Pregabalin work?

They bind to the a2 delta subunit of voltage-gated Ca channels and this reduces the Ca influx into the terminal. With this lower entry of Ca, there is reduced neurotransmitter release and it leads to decreased neuronal excitability and relief of seizures and neuropathic pain.

How does Ethosuximide work?

It selectively and reversibly blocks T-type voltage-gated Ca channels in the thalamic neurons. This reduces Ca influx, decreases neurotransmitter release and stabilizes thalamic neuronal circuits. Reduced neuronal excitability and prevention of absence seizures!

How does Topiramate work?

Glutamate antagonism, which reduces excitatory neurotransmission and neuronal overactivity. It blocks glutamate, enhances GABA inhibition and reduces neuronal excitability.

How does Lorazepam work?

It enhances GABA-A receptor activity, and this hyperpolarized neurons which make them less likely to fire.

Lorazem is the FIRST-LINE treatment for status epilepticus.

What is the strategy for choosing a therapeutic regimen for newly diagnosed epilepsy?

1. First-choice drug, one that is appropriate for the seizure type and gradually titrate to maximally tolerated dose and/or optimal seizure control.

2. If seizures persist, go to second-choice drug, titrate to therapeutic levels that control seizures.

3. If they still persist, use 2 drugs with complementary mechanisms or try a different monotherapy.

4. If they STILL persist, consider neural stimulation devices.

What are the first choice drugs for simple partial focal epilepsy, and complex partial focal epilepsy with or without secondary generalization?

Lamotrigine

Levetiracetam

Topiramate

What are the second choice drugs for simple partial focal epilepsy, and complex partial focal epilepsy with or without secondary generalization?

Carbamazepine

Lacosamide

Pregabalin

Zonisamide

What are the third choice drugs for simple partial focal epilepsy, and complex partial focal epilepsy with or without secondary generalization?

Valproate

Gabapentin

Oxcarbazepine

Phenytoin

Tiagabine

What is the first choice drug for elderly patients with focal epilepsy?

Lamotrigine

What is the second choice drug for elderly patients with focal epilepsy?

Gabapentin

What is the third choice drug for elderly patients with focal epilepsy?

Carbmazepine

What is the first line choice drug for absence epilepsy?

Ethosuximide

What are the second line choice drugs for absence epilepsy?

Valproate

Lamotrigine

What are the third line choice drugs for absence epilepsy?

Levetiracetam

Topiramate

Zonisamide

What are the first line drug choices for myoclonic epilepsy?

Valproate

Levetiracetam

What are the second line drug choices for myoclonic epilepsy?

Lamotrigine

Topiramate

What are the third line drug choices for myoclonic epilepsy?

Benzos

Zonisamide

What are the first line drug choices for tonic-clonic epilepsy?

Lamotrigine

Levetiracetam

Topiramate

What are the second line drug choices for tonic-clonic epilepsy?

Valproate

Zonisamide

What are the third line drug choices for tonic-clonic epilepsy?

None! Go straight to neural stimulator.

What are the first line drug choices for status epilepticus?

Benzos

Fosphenytoin

Levetiracetam

Valproate

What are the second line drug choices for status epilepticus?

Barbiturates

What is the primary driver in drug selection for anti-seizure meds?

Seizure type/epilepsy syndrome. Match drug to type of seizure!

What should be taken into account when prescribing ASM for children?

Cognition, behavior, formulation and syndrome-specific choices.

What should be taken into account when prescribing ASM for older adults?

Lower doses, fall and polypharmacy risk. Favor lamotrigine and levetiracetam.

What drugs should be dose-adjusted for renal disease?

Levetiracetam, gabapentin, pregabalin and topiramate

What drugs should be used with caution in hepatic disease?

Valproate, carbamazepine, phenytoin

What drugs should be watched for psychiatric changes?

Perampanel: serious psych reactions

Levetiracetam: may worsen mood/irritability

Which drugs can cause cardiac conduction issues?

Lacosamide: avoid due to conduction abnormalities

Carbamazepine: can increase tachycardia and heart failure

Phenytoin: conduction abnormalities

Which drugs have side effects that can be leveraged?

Topiramate for comorbid migraine or obesity

Lamotrigine for mood stabilizing

Describe Phenytoin (first gen)

Seizure type: Focal and GTC; MAY WORSEN MYOCLONIC

MOA: Na-channel blocker

ADRs: gingival hyperplasia (60%) , osteoporosis, hirsutism

P450: significant drug inducer

Monitoring: monitor for osteopenia/porosis, lipid profile, LFTs, levels between 10-20

Describe Ethosuximide (first gen)

Seizure type: Absence

MOA: T-type Ca blocker

ADRs: Depression, psychotic symptoms, SJS

P450: N/A

Monitoring: N/A

Describe Carbamazepine (first gen)

Seizure type: Focal and GTC; MAY WORSEN MYOCLONIC

MOA: Na-channel blocker

ADRs: Hyponatremia, neutropenia, osteoporosis

P450: Significant drug inducer

Monitoring: Monitor for osteopenia/porosis, lipid profile, serum Na, LFTs

Describe Valproate (first gen)

Seizure type: Focal, GTC, absence, myoclonic

MOA: Na-channel blocker

ADRs: Thrombocytopenia/neutropenia, weight gain (50%), osteoporosis

P450: Significant drug inhibitor

Monitoring: Monitor for osteopenia/porosis, CBC, LFTs

Describe Gabapentin (second gen)

Seizure type: Focal and GTC; MAY WORSEN MYOCLONIC

MOA: P/Q type Ca blocker

ADRs: Weight gain (2-3%), peripheral edema (2-8%)

P450: N/A

Monitoring: N/A

Describe Lamotrigine (2nd gen)

Seizure type: Focal and GTC; MAY WORSEN MYOCLONIC (unpredictable)

MOA: Na channel blocker, some GABA potentiation

ADRs: Headaches, insomnia, tremor, rash (5-17%), SJS

P450: Mild inducer/inhibitor

Monitoring: N/A

Describe Topiramate (second gen)

Seizure type: Focal and GTC

MOA: Na channel blocker, some GABA potentiation

ADRs: Weight loss (4-17%), memory and word recall difficulty, nephrolithiasis

P450: Mild inducer (dose > 200mg)

Monitoring: Metabolic acidosis

Describe Levetiracetam (second gen)

Seizure type: Focal and GTC

MOA: Binding to SV2a protein ?

ADRs: Psych sx

P450: N/A

Monitoring: N/A

Describe Oxcarbazepine (second gen)

Seizure type: Focal and GTC; MAY WORSEN MYOCLONIC

MOA: Na channel blocker

ADRs: Hyponatremia, osteoporosis, SJS

P450: Mild inducer at > 900mg

Monitoring: Monitor for osteopenia/porosis, serum Na

Describe Zonisamide (2nd gen)

Seizure type: Focal, GTC, and myoclonic

MOA: Na and Ca channel blocker

ADRs: Psych sx, memory and word recall difficulties, nephrolithiasis

P450: N/A

Monitoring: Metabolic acidosis

Describe Lacosamide (3rd gen)

Seizure type: Focal and GTC

MOA: Slows Na channel activation

ADRs: Dizziness, drowsiness, cardiac arrhythmias

P450: N/A

Monitoring: ECG (PR interval)

Describe Eslicarbazepine (3rd gen)

Seizure type: Focal; MAY WORSEN MYOCLONIC

MOA: Na channel blocker

ADRs: Hyponatremia

P450: Mild inducer

Monitoring: Monitor serum Na

What are the key CI of Valproate?

Pregnancy, hepatic disease, POLG/mitochondrial and urea cycle disordera

What are the key CI of Carbamezapine/oxcarbazepine?

HLA-B*1502

What are the key CI of Lamotrigine?

Rapid titration can lead to rash; valproate raises its level.

What are the key CI of Lacosamide?

2nd/3rd degree AV block

What are the key CI of Perampanel?

Serious psych/behavioral reactions (boxed warning)

What are the key CI of Topiramite?

Nephrolithiasis, acute glaucoma, metabolic acidosis.

Which drugs are enzyme inducers?

Carbamazepine, phenytoin, phenobarbital (all potent)

Oxcarbazepine, topiramate (weaker, dose-dependent)

Decrease efficacy of contraceptives, warfarin/DOACs, statins, antiretrovirals.

Anticipate breakthrough seizures and contraceptive failure.

Which drugs are enzyme inhibitors?

Valproate, broad inhibitor increases lamotrigine and phenobarbital.

Displaces protein bound phenytoin.

Which drugs are enzyme neutral or minimal inhibitors?

Levetiracetam, brivaracetam, lacosamide, gabapentin.

Which drugs offer the best balance of efficacy and tolerability for focal epilepsy?

Carbamazepine

Lamotrigine

Levetiracetam

Topiramate

Which drugs are best for generalized tonic-clonic seizures?

Valproic acid is the most effective, but not necessarily the best choice especially for women of childbearing age

Lamotrigine

Levetiracetam

Topiramate

Which drug has a high risk of teratogenicity? Moderate risk? Low risk?

High: Valproate acid, causing neural tube defects, reduced IQ, autism-spectrum risk

Moderate: Topiramate (causing cleft, low birth weight), phenobarbital, phenytoin, carbamazepine

Lown (Preferred!!): Lamotrigine, Levetiracetam.

Which meds decrease contraceptive efficacy?

Enzyme inducing ASM, especially carbamazepine, phenytoin, topiramate (> 200mg), oxcarbazepine.

How do estrogen containing contraceptives effect Lamotrigine?

They decrease Lamotrigine levels by 50% leading to breakthrough seizures.

Which ASM have no significant interaction with estrogen containing contraceptives?

Levetiracetam

Lacosamide

Valproate

Can you breastfeed while taking ASM?

Yes

Which ASM decrease bone density?

Enzyme-inducing ASMs and valproate. Check Vitamin D, supplement Ca and vitamin D; consider DEXA with long term use

What else is Valproate linked to (hormonal effect)?

PCOS-like features: weight gain, hyperandrogenism, menstrual irregularity.

Which ASMs benefit from TDM (therapeutic drug monitoring)?

Well-validated ranges, narrow index drugs like phenytoin, carbamazepine, valproate, and phenobarbital.

Why is Phenytoin especially TDM dependent?

Therapeutic levels between 10 and 20 ug. Less than 10 is too low to control seizures, greater than 20 increases toxicity. One of the only drugs that transitions from first-order kinetics to zero-order (saturation) kinetics at therapeutic doses.

Metabolized primarily by CYP2C9.

What is first-order kinetics?

Elimination is proportional to drug concentration: doubling the dose, doubles the steady state level.

When do you draw a level on phenytoin?

1. Wait at least 7-10 days after starting or changing dose

2. Draw just before next scheduled dose

3. After dose adjustment, wait 5-7 half lives for new steady state

4. When toxicity is suspected

5. Breakthrough seizures

6. Check free level when albumin is low, renal/hepatic disease, or patient is on another highly protein-bound drug.

Why is carbamazepine unique?

It induces its own metabolism via CYP3A4.

When do you draw a level on Carbamazepine?

1. After autoinduction is complete (3-5 weeks on a stable dose)

2. After any dose change (wait another 3-5 weeks)

3. When adding or substracting a drug

4. Suspected toxicity

5. Breakthrough seizures or suspected nonadherence

6. Generally not routinely monitored if patient is on monotherapy.

What percentage of Valproate is protein bound at low concentrations?

90%

When do you check a level on Valproate?

1. Hypoalbuminemia

2. Renal disease

3. Elderly patients

4. Hyperlipidemia

5. Polypharmacy

What diet is recommended for refractory seizures?

Ketogenic diet. Strongest evidence in children.

What is vagus nerve stimulation?

Refractory seizure treatment when an implanted device delivers intermittent stimulation to the left vagus nerve. About half of patients achieve ≥50% seizure reduction over time.

What is responsive neurostimulation?

Closed loop electrodes placed at the seizure focus. Detects and aborts seizures in real time.

What is deep brain stimulation?

Open loop stimulation of the anterior thalamic nucleus. For focal epilepsy not suited to resection.

What surgery can be curative for well-localized focal seizures?

Resective surgery. Best outcomes when MRI, EEG and semiology are concordant.

What are factors the favor discontinuation of ASM?

1. Seizure free for ≥2 years on med

2. Normal neurologic exam and normal or normalized EEG

3. Single seizure type; few seizures before control was achieved

4. Self-limited, age related syndromes

5. Normal imaging with no known structural lesion.

What is the overall relapse rate and when is risk the highest?

30-40% after withdrawal; risk highest in first 1-2 years.

Taper slowly over months, never stop abruptly.

In polypharmacy, withdraw one drug at a time.

What is the step-wise management for status epilepticus treatment?

1. Stabilize (0-5 minutes): ABC, O2, IV access, check BG and electrolytes

2. First line (5-10 minutes): Benzos like IV Lorazepam 0.1 mg/kg, IM midazolam 10mg or rectal diazepam

3. Second line (10-20 minutes): IV ASM like Fosphenytoin/phenytoin, valproate or levetiracetam

4. Refractory (> 20- 40 min): Anesthesia + cEEG. Go to sleep!!