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Pharmacy I > Epilepsy Drugs > Flashcards

Epilepsy Drugs Flashcards

1
Q

Anticonvulsants - what are the 3 possible mechanisms of action?

A
  1. Prolonged inactivation of voltage-sensitive sodium channels
  2. Enhance GABA-mediated inhibition (directly or indirectly)
  3. Reduce glutaminergic excitation (glutamate is excitatory)
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2
Q

Preferred drugs for focal epilepsy (longer time to treatment failure)?

A

Lamotrigine and Oxcarbazepine

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3
Q

Preferred drugs for generalized epilepsy?

A

Valproate and Lamotrigine are better than Topiramate (they have longer time to treatment failure)
BUT
Topiramate is better than Lamotrigine for 12 month seizure remission

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4
Q

What are the drugs that affect voltage gated sodium channels for epilepsy treatment?

A

Carbamazepine, Eslicarbazepine, Oxcarbazepine, Lamotrigine, Lacosamide, Zonisamide, Rufinamide, and Phenytoin

CEOs laugh loudly at ze ruffians and pheeble (feeble)

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5
Q

Carbamazepine (Tegretol)

A

Blocks sodium channels

Indications: focal and generalized seizures, biopolar disorders, and chronic pain

Dosing: need to monitor serum concentration to be effective at 3, 6, 9 weeks followed by bimonthly

Metabolism: 70% protein bound, metabolized through autoinduction, is a strong non-specific inducer mostly through CYP3A4

ADRs: dose-related (vertigo to ataxia to diplopia etc.), CNS (HA, psychosis etc.), and non-specific (Stevens-Johnson Syndrome so screening for HLA-B*1502 rec in Asians, SIADH which means affects the kidneys etc.)

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6
Q

Oxcarbazepine (Trileptal)

A

Active metabolite blocks sodium channels

Indications: focal and secondarily generalized tonic-clonic seizures

Metabolism: This drug is an analogue of Carbamazepine and has minimal P450 interactions, there is no autoinduction, and no PK monitoring needed

ADR: Equal efficacy with fewer side effects compared to Carbamazepine and Phenytoin (but 30% cross reactivity for rash with CBZ)

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7
Q

Phenytoin (Dilantin)

A

Blocks sodium channel and affects second messenger systems

Indications: focal and generalized seizures, status epilepticus

Metabolism: metabolized by P450 system (2C9 and 2C19) and is a non-specific inducer, highly protein bound, non-linear kinetics so needs close monitoring

Route: enteral feeding has reduced oral absorption, oral suspension needs to be shaken well, if via IV then concerns with basic pH (phlebitis and extravasation) or hypotension, NO IM injection

ADR: do not stop abruptly because it is an antiarrhythmic,
Depletes folic acid,
Dose related (nystagmus to ataxia to cognitive impairment etc.),
Non-dose related (gingival hyperplasia but less severe if replenish folic acid, hirsutism, decreased bone density etc.),
Interacts with inducers (carbamazepine, OCP, doxycycline, quinidine, cyclosporin, methadone, levadopa),
Interacts with inhibitors (chloramphenicol, cimetidine, sulfonamide, isoniazid),
Teratogenic = Fetal Hydantoin Syndrome

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8
Q

Fosphenytoin (Cerebryx)

A

Prodrug of Phenytoin (it is H2O soluble and converted by plasma esterases)

Dosing: Doses expressed as Phenytoin equivalents and available as IV or IM, compatible with most IV solutions with less phlebitis… but results in more paresthesias and pruritis than Phenytoin

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9
Q

Lamotrigine (Lamictal)

A

Blocks sodium and calcium channels (to diminish glutamate activity)

Indications: ADJUNCTIVE in focal seizures for adults and children older than 2, also adjunctive for generalized seizures

Metabolism: 100% orally absorbed, 55% protein bound, metabolized through Phase II so will have increased levels if given with drugs that inhibit glucuronidation (Valproate, Phenytoin, Carbamazepine, Phenobarbitol, Primidone, Estrogen BC, Rifampin, protease inhibitor)

ADR: rash, confusion, depression, N/V, diplopia, severe indiosyncratic ones (skin, blood)

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10
Q

Zonisamide (Zonegran)

A

Blocks sodium and calcium channels, enhances GABA-receptor function (it is a sulfonamide derivative)

Indications: ADJUNCTIVE therapy for focal and generalized seizures

Metabolism: through the P450 system but isn’t an inducer or an inhibitor

ADR: dose-related (sedation to dizziness to cognitive impairment etc.), non-dose related (rash, oligohydrosis, kidney stones)

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11
Q

Lacosamide

A

Enhances slow inactivation of voltage-gated sodium channels without affecting fast inactivation (meaning typically only affects neurons that are depolarized/active for long periods of time)

Indications: Monotherapy or adjunctive therapy for focal onset seizures

ADR: (actually is quite well tolerated), dizziness, vertigo, nausea, abnormal coordination

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12
Q

What anti-epileptic drug affects calcium currents?

A

Ethosuximide

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13
Q

Ethosuximide (Zarontin)

A

Inhibits calcium channels

Indications: For absence seizures

Metabolism: orally absorbed and not protein bound, metabolized by P450 but not an inducer

ADR: Dose-related (nausea to lethargy, headache to dizziness etc.)

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14
Q

Which drugs affect GABA?

A 
Phenobarbital
Benzodiazapenes
Clobazam
Tiagabine
Vigabatrin
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15
Q

Phenobarbital (Luminal)

A

Improves the effect of GABA (also a calcium current blocker)

Indications: focal and generalized seizures

Metabolism: mostly by P450 system, 25% just unchanged and renally excreted, induces P450 and UGT-glucoronidation

ADR: SEDATION, irritability, slowed thinking, ataxia, hyperactivity, rash

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16
Q

Tiagabine (Gabitril)

A

Competitive inhibitor of GABA transporter (inhibits re-uptake)

Indications: Adjunctive treatment for focal seizures

Metabolism: Quick and complete absorption, faster clearance in kids and with enzyme inducers, serum concentrations unecessary

ADR: dose-related (dizziness to fatigue to nervousness etc.)

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17
Q

Vigabatrin

A

Irreversible inhibitor of GABA transaminase (meaning it increases GABA concentration)

Indications: infantile seizures, refractory focal seizures (but has BLACK BOX warning, so use is limited)

Metabolism: no P450 metabolism but induces CYP2C9, it is excreted renally

ADR: PERMANENT vision loss, also drowsiness, fatigue etc.)

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18
Q

Which drugs affect glutamate receptors?

A

Perampanel (AMPA antagonist)

Felbamate and Topiramate (NMDA antagonism)

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19
Q

Perapanel

A

Non-competitive AMPA receptor antagonist

Indications: Adjunctive treatment for focal onset seizures on people at least 12 years old (Schedule III)

Metabolism: extensively metabolized by liver (CYP3A4, glucoronidation), variable half life with a mean of 105 hours

ADR: dizziness, somnolence etc. boxed WARNING of serious alteration of mood and aggression

20
Q

Which drugs have multiple mechanisms of action?

A

Topiramate
Felbamate
Valproate

21
Q

Topiramate (Topamax)

A

Blocks sodium channels, enhances GABA activity, antagonist of NMDA receptor

Indication: Adjunct therapy for focal seizures

Metabolism: Hepatic metabolism through P450 system

ADR: Teratogenic; dose-related weight loss; impaired cognition, paresthesia, decreased sweating, possible metabolic acidosis (most concerning) etc.

22
Q

Felbamate (Felbtol)

A

Augments GABA, competes for NMDA receptor

Indications: only for refractory Lennox-Gastaut syndrome (form of hard-to-treat child epilepsy)

Metabolism: its active metabolite covalently binds proteins and DNA in liver and bone marrow

ADR: Can lead to aplastic anemia and liver failure (non-dose related ADR, also need informed consent before usage); dose-related (anorexia to N/V to insomnia etc.)

*BLACK BOX, not first-line treatment

23
Q 
Valproic Acid (Depakene) and
Sodium Valproate (Depakote)
A

Sodium blockade, enhancement of GABAergic transmission, blocks calcium currents

Indication: generalized seizures, focal seizures, status epilepticus

Metabolism: Completely absorbed, 90% protein bound, hepatic metabolism (inhibitor of CYP P450 and glucuronidation)

ADR for Valproic Acid: dose-related (N/V to hair loss to abd pain… weight gain, insulin resistance etc.), non-dose related (acute hepatic failure, acute pancreatitis, thrombocytopenia, subclinical hypothyroidism)

24
Q

Which 3 drugs have different mechanisms of action? (meaning not really just enhancing sodium channel inactivation, enhancing GABA function or inhibiting glutamate function)

A

Gabapentin
Levetiracetam
Pregabalin

25
Q

Gabapentin (Neurontin)

A

Binds calcium channel

Indication: Adjunct for refractory seizures or as monotherapy for newly diagnosed focal seizures, and treatment for peripheral neuropathy

Metabolism: dose-dependent oral absorption, not protein bound, unexchanged excretion through kidneyes and does not need serum monitoring

ADR: No big drug interactions but should be given separately from antacids, some side effects (sedation, somnolence, dizziness, ataxia, nystagmus)

26
Q

Levetiracetam (Keppra)

A

MOA unknown

Indication: treatment for focal and generalized seizures

Metabolism: almost completely absorbed, metabolism not dependent on P450 system, minimal protein binding or drug interactions

ADR: sedation, behavioral abnormalities

27
Q

Pregabalin (Lyrica)

A

Chemically related to Gabapentin so similar mechanism of action (binds calcium channel)
Also modulates glutamate, noradrenaline, and substance P

Indication: Adjunctive treatment for partial onset seizure, peripheral neuropathy, postherpetic neuralgia, fibromyalgia syndrome

Metabolism: unchanged renal excretion

ADR: dizziness, somnolence, dry mouth, peripheral edema etc.

28
Q

What are the most important factors in choosing an anti-epileptic drug?

A

Tolerance and long-term safety

29
Q

How is dosing determined/guided?

A

Ultimate guide is the patient’s clinical status

If the 1st anti-epileptic drug (AED) is POORLY tolerated or fails to control the seizure, then an alternative is tried

If the 1st AED is WELL tolerated but does not completely control the seizure, then a combo should be tried

30
Q

When can an effective AED be discontinued? (aka when is the patient considered in remission)

A

Seizure-free for 2-5 years on an AED (patient should have a single type of partial or primarily generalized tonic-clonic seizure)

Patient should have a normal neuro-exam and normal IQ

Patient EEG should be normalized on AED treatment

31
Q

HOW should the medication be discontinued?

A

Titrate off for several months

i.e. reduce dose by 1/3 for a month, then another 1/3 for the next month, then completely discontinue

32
Q

Define status epilepticus. What comprises the majority of SE?

A

SE is continuous/intermittent seizures lasting more than 5 minutes without full recovery in between episodes (life-threatening)

75% are generalized convulsive, 25% are nonconvulsive

33
Q

What is the main cause of SE?

A

Low blood concentration of AED

followed by remote symptomatic causes, CVA, anoxia/hypoxia, and alcohol or drug withdrawal

34
Q

What is the predictor for poor outcomes after SE?

A

Prolonged SE and refractoriness to treatment

35
Q

What are the 3 phases of treatment for SE?

A

Initial assessment and supportive care (neurologic exam, CAB eval and support i.e. O2, IV insertion, blood work, fingerstick glucose, consider giving glucose or thiamine)

Initial therapy with benzodiazepine (all meds should be given parenterally and should treat reversible causes of the SE)

Urgent therapy for long-term control with a non-benzodiazepine AED

36
Q

What are the 1st and 2nd line drugs for treating SE?

A 
1st line (initial, to terminate seizure) = benzodiazepines
-Lorazepam is the first line because it has a longer duration (other options are Diazepam and Midazolam)... concern is for respiratory depression and to a lesser extent CV depression
2nd line (loading dose of a longer acting anticonvulsant while continuing work-up = nonbenzo AED
-Fosphenytoin preferred
37
Q

Benzodiazepines general MOA and role in seizure therapy? ADR?

A

Enhances channel gating in the presence of GABA (positive allosteric modulator)

Benzos are the 1st line to terminate seizures (giving 1-3 doses/min before moving to 2nd line)

*NOT indicated for maintenance therapy or if the seizure has already stopped

ADR: infusion rate-related arrhythmia and hypotension, respiratory depression, impaired consciousness

38
Q

Lorazepam (Ativan)

A

1st choice for patient with IV access (onset of action is 3-5 minutes)

Since can cause vein irritation should dilute dose with equal volume D5W, NS, SWI

39
Q

Why is Lorazepam (Ativan) preferred over Diazepam (Valium)?

A

Lorazepam has a longer duration of action (12-24 hours) versus Diazepam (15min-2 hours).

Diazepam is also very lipophillic so it quickly redistributes out of the brain and into other fat stores

40
Q

If IV route is not available or Lorazepam, what other Benzos are options for treatment?

A

Diazepam (Valium) which has rapid onset yet short duration and can be given parenterally

Midazolam (Versed) which can given buccal, intranasal, and IM routes…also by continous infusion for refractory SE

41
Q

What are Hydantoins used for?

A

2nd line therapy if seizure continues after 2-3 doses of Benzos (they have less CNS and respiratory depression than Benzos and barbituates) i.e. Fosphenytoin

Consider a loading AND maintenance dose of seizure recurs or if is expected to recur
(maintenance dose starts 12-24 hours after loading dose)

ADR: arrhythmia, nystagmus etc.

42
Q

As another option, what are Levetiracetam or Lacosamide possibly useful for?

A

Focal or nonconvulsive status epilepticus

43
Q

What place do Phenobarbitals have in therapy? (1st, 2nd, 3rd)

A

It is debated

As a 3rd line = if seizure PERSISTS despite 2-3 doses of Benzos and loading dose of hydantoin

As a 2nd line = if seizures PERSIST despite 2-3 doses of Benzos and hydantoins are CONTRAINDICATED.. or in pediatrics

44
Q

What are ADRs of Phenobarbitals?

A

Onset of action is rapid (within minutes of loading dose)

Has more CNS and respiratory depression than hydantoins,
Also contains propylene glycol (related to ethylene glycol/antifreeze ingredient)

45
Q

When is maintenance dosing indicated for SE? What does maintenance therapy consist of?

A

Do it if the cause is not determined or treatable (i.e. if SE is due to hyponatremia, hypocalcemia, hypoglycemia etc.)

Hydantoins and Phenobarbitals used alone or in combination for maintenance

46
Q

When should maintenance dosing for SE be started?

A

Timing of first dose should be guided by the maintenance dosing interval
i.e. if the drug is to be loaded q12h then start maintenance dosing 12 hours after the loading dose

Children may need q8h interval for hydantoin (aka start 8 hours after loading dose)

Pharmacy I (13 decks)

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