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P2 IDT > Epilepsy > Flashcards

Epilepsy Flashcards

1
Q

Epilepsy definition

A

a chronic disorder characterized by recurrent, unpredictable seizures. A heterogenous symptom complex - arises from abnormal electrical discharges in the brain - 40+ forms (not a single disease)

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2
Q

Acute symptomatic seizures

A

provoked by infections, tumors, trauma, toxins, metabolic disorders, drug/alcohol withdrawal, chemical convulsants, or electroshock therapy

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3
Q

Epileptogenesis

A

we may never know the factors leading to the development of epilepsy or changes in gene expression/protein function

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4
Q

What factors do you consider when a patient has a history of seizures?

A

frequency, duration, and severity

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5
Q

Seizure

A

a transient change in behavior caused by an abnormal synchronous electrical discharge in the brain - it’s thought to arise in the cortex. It’s when too much excitation or too little inhibition leads to an excessive and random discharge of a group of neurons in the brain. Note that seizures can be non-epileptic

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6
Q

What percentage of people with epilepsy are refractory to treatment?

A

30%

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7
Q

Does epilepsy have an effect on mortality?

A

Yes, mortality is higher than in the general population - the diagnosis is sudden unexplained death in epilepsy (1:1000)

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8
Q

Seizure classification

A

Partial, generalized, and status epilepticus

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9
Q

Types of partial seizures

A

simple, complex, and partial seizures that evolve into secondarily generalized tonic-clonic seizures

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10
Q

partial seizures

A

these seizures remain confined to a local area and are easier to live with and more common

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11
Q

progression of partial seizures

A
  1. Initiation: increased electrical activity in a single cell (also known as paroxysmal depolarizing shift or PDS)
  2. Synchronization of surrounding neurons (adequate inhibition should prevent this in a normal brain)
  3. Spread to adjacent areas (aura)
  4. Seizure begins when a group of neurons depolarize suddenly
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12
Q

simple partial seizures

A

consciousness is not impaired and has diverse manifestations depending on cortical region. Can be with motor symptoms (changes in movement), somatosensory or special sensory symptoms (ie tingling or flashing lights), autonomic symptoms (ie increased heart rate), or psychic symptoms (alterations of consciousness such as hallucinations)

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13
Q

complex partial seizures

A

involve impaired consciousness for 30 seconds - 2 minutes. They begin as partial seizures and progress to an impairment of consciousness, are preceded by an aura, and there is impaired memory of the ictal phase. These seizures can be pharmacoresistant and require surgical options.

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14
Q

partial seizures evolving into secondarily generalized tonic-clonic seizures

A

alternating tonic (contractions) and clonic (relaxation) lasting 1-2 minutes. There is a loss of consciousness and these seizures are preceded by an aura

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15
Q

generalized seizures

A

these seizures are bilaterally symmetrical and without local onset. These affect daily life and cause more injuries

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16
Q

absence seizures (petit mal seizures)

A

sudden (abrupt onset) interruption of consciousness, blank stare (<30 seconds), no aura

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17
Q

myoclonic seizures

A

result from random discharges in the motor cortex, brief 1-2 seconds and sudden contraction of muscles (can be one extremity or general)

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18
Q

Tonic-clonic seizures (grand mal seizures)

A

abrupt onset (usually no aura). Has no symptoms of a partial or complex seizure. Post ictal patients are flaccid and unconscious - let people wake up on their own or it could trigger another seizure

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19
Q

status epilepticus

A

seizures occurring acutely in greater intensity, number, or length than usual or a prolonged seizure lasting longer than ten minutes or repeated seizures over the course of 30 minutes. These are life threatening and emergency care should begin immediately; these are treated with benzodiazepines such as diazepam or lorazepam

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20
Q

Why are toxicities often seen with AEDs

A

since they’re dosed up to several grams per day, minor metabolism pathways can become more significant and toxicities are often associated with these minor routes

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21
Q

what severe side effect is seen with some AEDs?

A

stevens-johnson syndrome/toxic epidermal necrolysis

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22
Q

What gene puts patients more at risk for developing stevens-johnson syndrome/toxic epidermal necrolysis?

A

HLA-B*15:02 allele

23
Q

What patient population is more likely to have the HLA-B*15:02 allele?

A

Asian populations with the exception of the Japanese

24
Q

Barbiturates we covered

A

Phenobarbital and primidone

25
Q

Phenobarbital

A

Acts at the GABAA receptor.
Has a long half-life (2-6 days).
Is metabolized by p-hydroxylation via 2C9 and 2C19.
Is a potent inducer of P450s and some UDP glucuronsyltransferases (UGTs)

26
Q

Primidone

A

Primidone is converted to phenobarbital via oxidation and phenylethylmalonamide (PEMA) via an unstated mechanism. The overall action of primidone is a composite of primidone itself, phenobarbital, and PEMA. It is less sedating then phenobarbital

27
Q

Hydantoins we covered

A

phenytoin and fosphenytoin

28
Q

Phenytoin

A

Phenytoin blocks sodium channels and has less sedation than phenobarbital.
It induces P450s and UGTs.
Metabolism is by CYP2C9 (major) and 2C19 (minor).

29
Q

Phenytoin metabolism

A

Metabolism is by CYP2C9 (major) and 2C19 (minor). Para hydroxylation leads to a p-hydroxylated metabolite which is inactive. The CYPs can also form an arene oxide intermediate, which usually goes to the p-hydroxylated metabolite. The arene oxide intermediate can also react with glutathione to form glutathione and mercapturic acid metabolites. Arene oxide could also reach with cellular proteins and explain the toxicities.

30
Q

Fosphenytoin

A

Fosphenytoin is a water soluble prodrug of phenytoin for IV/IM injections. It is converted to the active phenytoin molecule via phosphatases. The conversion half-life is 15 minutes

31
Q

Succinimides we covered

A

Ethosuximide

32
Q

Ethosuximide

A

Ethosuximide contains small alkyl groups instead of aromatics, which correlates with effectiveness against absence seizures. It blocks calcium channels and is metabolized via CYP3A4 and 2E1 which hydroxylates the ethyl. The toxicities limit its use – rare anemias, hepatotoxicity, and reduced kidney function. Blood and liver tests are required.

33
Q

Valproic acid

A

It has multiple mechanisms, so we can’t pinpoint exactly why it works. It is metabolized by direct glucuronidation (inactive) and double bond formation (β-oxidation) leads to an active 2-ene metabolite. The half-life is often reduced when taking other epilepsy drugs (ie phenytoin and phenobarbital). Valproate can inhibit CYP2C9, some UGTs, and epoxide hydrolase. There is a minor metabolite that is reactive and alkylates liver proteins if it occurs in the liver. The alkylation leads to hepatotoxicity, so liver function monitoring is required. Also, rare pancreatitis can occur and cause fetal malformations.

34
Q

Carbamazepine

A

The structure contains an azepine and a urea, which is carbamate like. It blocks sodium channels and is a strong P450 and UGT inducer. Carbamazepine is an autoinducer because it induces CYP3A4, which is what metabolizes it. Carbamazepine has black box warnings for aplastic anemia (agranulocytosis) and serious skin reactions (Stevens-Johnson syndrome). There are also reports of rare liver toxicity. Clinical monitoring is required.

35
Q

Carbamazepine metabolism

A

Carbamazepine can be metabolized to carbamazepine iminoquinone, which is toxic. Carbamazepine can also be metabolized by CYP3A4 to carbamazepine epoxide, which is an active anticonvulsant. Carbamazepine epoxide is also a reactive species which may alkylate biomolecules and lead to toxicities. Carbamazepine epoxide can be further metabolized by epoxide hydroxylase to carbamazepine diol, which is inactive and excreted. Carbamazepine epoxide can also be metabolized to toxic alkylated proteins.

36
Q

Oxcarbazepine

A

Oxcarbazepine is a carbamazepine analog that can’t form the “toxic” epoxide. Oxcarbazepine has a half-life of two hours and is reduced into the monohydroxy metabolite, which has a half-life of 9-11 hours. Oxcarbazepine lacks the major blood toxicity (and minor liver toxicity) of carbamazepine, but can still cause some skin reactions – although much less common than with carbamazepine

37
Q

Eslicarbazepine acetate

A

Eslicarbazepine acetate is a prodrug (only the S enantiomer) that undergoes rapid ester hydrolysis into eslicarbazepine, which is the active drug. Eslicarbazepine is the same monohydroxy metabolite of oxcarbazepine. Oxcarbazepine and licarbazepine (mono hydroxyl) still induce CYP3A4 (but less than carbamazepine); both also inhibit CYP2C19. Eslicarbazepine lacks the major blood toxicity (and minor liver toxicity) of carbamazepine, but can still cause some skin reactions – although much less common than with carbamazepine.

38
Q

GABA metabolism overview

A

L-glutamate is catalyzed by glutamic acid decarboxylase to GABA. GABA is catalyzed by GABA aminotransferase or GABA transaminase to succinate semialdehyde. Succinate semialdehyde is catalyzed by SSA dehydrogenase into succinate.

39
Q

Gabapentin

A

Gabapentin contains GABA and 5 additional carbons (pentin). It was originally designed to be a more lipophilic version of GABA. It doesn’t act at GABA receptors, it acts at a specific type of calcium channel (α2δ).
Gabapentin isn’t appreciably metabolized, doesn’t induce/inhibit hepatic enzymes, doesn’t alter the pharmacokinetics of AEDs, its pharmacokinetics are not altered much by other AEDs, and it lacks blood/liver toxicities

40
Q

Gabapentin enacarbil

A

Gabapentin enacarbil is a lipophilic prodrug of gabapentin. It is used to treat pain associated with shingles, not epilepsy.

41
Q

Pregabalin

A

Pregabalin contains GABA and isobutyl (stereocenter is an S enantiomer). It acts at the same type of calcium channel as gabapentin with a half-life of six hours. Less than 2% is metabolized and it has similar qualities to gabapentin as adjunctive therapy. It is classified as schedule V because some patients reported euphoria.

42
Q

Vigabatrin

A

Vigabatrin contains GABA and vinyl. It is an irreversible inhibitor of GABA aminotransferase. Only the S enantiomer is active. It is not significantly metabolized and has a half-life of 7 ½ hours. It can induce CYP2C9. It is adjunctive therapy for refractive complex partial seizures not controlled by other drugs and has a black box warning that it can cause permanent vision loss

43
Q

Felbamate

A

Felbamate contains two (bis)carmamates. It is only used in patients resistant to other treatments. It has a black box warning for aplastic anemia and hepatic failure. It requires clinical monitoring. Felbamate undergoes carbamate hydrolysis then oxidation then elimination of carbamic acid into atropaldehyde. Atropaldehyde is a good Micheal-acceptor that can alkylate biomolecules, which leads to toxicity or it can react with GSH and leads to detoxification

44
Q

Lamotrigine

A

The main route of metabolism is glucuronidation. The half-life is 24-35 hours, but it is reduced to ~15 hours with phenobarbital, phenytoin, or carbamazepine. The minor route of metabolism is through P450 into a reactive arene oxide metabolite, which becomes conjugated with glutathione (the reactive metabolite could lead to skin rashes – that there is a black box warning for).

45
Q

Topiramate

A

Topiramate contains a sulfamate and a sugar. 70% are excreted unchanged, while the other 30% is metabolized through many pathways. The half-life is 20-30 hours, but phenytoin and carbamazepine can decrease the half-life. It is a weak 3A4 inducer and a 2C19 inhibitor. 1.5% of patients who develop kidney stones due to carbonic anhydrase inhibition due to the sulfamate.

46
Q

Zonisamide

A

Zonisamide contains a sulfonamide and also has possible carbonic anhydrase inhibition. Similar to topiramate, 4% of patients taking zonisamide develop kidney stones due to the carbonic anhydrase inhibition due to the sulfonamide. There is potential for “sulfa” allergies due to the sulfonamide. The half-life is ~63 hours, but that is altered with CYP3A4 induction/inhibition. It is reduced by CYP3A4 or N-acetylation of the sulfonamide.

47
Q

Tiagabine

A

There is a component of tiagabine that is “GABA like”, the remainder is a large steric blockade (that contains thiophenes) of the GAT1 GABA transporter. The half-life is 8 hours, and it is metabolized by CYP3A4 to 5-oxometabolite.

48
Q

Lacosamide

A

Lacosamide contains D-serine. Its half-life is 12-13 hours, and 40% is excreted unchanged. The major route of metabolism is via CYP2C19, which O-demethylates it. It is not very affected by P450 inducers.

49
Q

Levetiracetem

A

Levetiracetam contains an acetamide and has levorotation at the enantiomer (S). It is involved in SV2a protein modulation and is a good choice for adjunctive therapy. The half-life is 6-8 hours and it isn’t P450 metabolized. 66% is excreted unchanged and most of the remaining is hydrolyzed to an inactive acid. There are no blood/liver/skin toxicities and no P450 or UGT induction or inhibition.

50
Q

Brivaracetam

A

Brivaracetam, a more lipophilic analog of levetiracetam (more potent SV2a ligand), was approved in February 2016. The half-life is 9 hours and 40% is excreted unchanged. CYP2C19 hydroxylates the propyl side chain although amide hydrolysis also occurs

51
Q

Rufinamide

A

Rufinamide modulates sodium channels and still has some drug interactions despite no major P450 routes of metabolism. There is extensive metabolism via hydrolysis that produces an inactive acid metabolite, which then undergoes glucuronidation. The half-life is 8-12 hours and it is a weak 3A4 inducer and a weak 2E1 inhibitor.

52
Q

Ezogabine

A

Ezogabine is a potassium channel activator with a half-life of 6-10 hours. There is no major P450 metabolism, instead metabolism is via glucuronidation and N-acetylation

53
Q

Perampanel

A

Perampanel is an AMPA receptor antagonist with a half-life of 105 hours. The major metabolism is via CYP3A4 hydroxylation.

54
Q

Cannabidiol

A

A phase III trial just finished, but it first had evidence of anti-epileptic properties in 1973

P2 IDT (7 decks)

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