Antiepileptic Drugs Flashcards by Chrissa Constantinides | Brainscape

Q

What is a seizure?

A

Short term episode of abnormal firing of cerebral neurons

A paroxysmal event characterized by abnormal, excessive hypersynchronous discharge of cortical neuron activity

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Q

What is the mech of action of Gabapentin?

A

Modulation of Α2δ Ca2+ channels inhibit release of excitatory neurotransmitter, hence, inhibit depolarization (AP)

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Q

What is the mech of action of Phenytoin (PHT)?

A

Modulation of Na+ Channels
Inhibit depolarization (AP), hence, calcium influx and release of excitatory neurotransmitter

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Q

What is the mech of action of CBZ?

A

Modulation of Na+ Channels
Inhibit depolarization (AP), hence, calcium influx and release of excitatory neurotransmitter

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Q

What is the mech of action of OXC?

A

Modulation of Na+ Channels
Inhibit depolarization (AP), hence, calcium influx and release of excitatory neurotransmitter

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Q

What is the mech of action of Valproate?

A

Modulation of Na+ Channels
Inhibit depolarization (AP), hence, calcium influx and release of excitatory neurotransmitter

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Q

What is the mech of action of Lomotrigine?

A

Modulation of Na+ Channels
Inhibit depolarization (AP), hence, calcium influx and release of excitatory neurotransmitter

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Q

What is the mech of action of Topiramate?

A

Modulation of AMPA/Kainate receptor inhibit binding of excitatory neurotransmitter, hence, inhibit depolarization (AP)

Activating GABA(Cl-) receptor, hence, increase in inhibitory neurotransmitter
Leading to decrease in depolarization (AP).

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Q

What is the mech of action of Vigabatrin?

A

Inhibit GABA-T, hence, decrease metabolism of GABA in presynaptic neuron and glia cells.
Increasing the inhibitory neurotransmitter
Leading to decrease in depolarization (AP).

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Q

What is the mech of action of Barbiturates (Phenobarbital)?

A

Activating GABA (Cl-) r., hence, increase in inhibitory NT leading to decrease in depolarization (AP)

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Q

Older-generation AEDs…

A

remain highly valuable in the modern treatment of epilepsy, they have considerable side effects and show undesirable PK properties.

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Q

Several new-generation AEDs…

A

differ greatly not only in efficacy spectrum and side-effect profile but also, they have improved PK profile.

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Q

_____ plasma protein binding is usually regarded as unfavorable

A

HIGH

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Q

Most AEDs exhibit little or no protein binding, but…

A

phenytoin, valproic acid, benzodiazepines, and tiagabine (>90% serum protein binding).

should give LOW dose (b/c excreted slowly therefore a lot more in body)

Drugs that are highly bound to plasma proteins (> 90% bound) compete for the same site of the same plasma protein.

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Q

Which drugs have 0% serum protein binding

A

Ethosuximide, gabapentin, levetiracetam, pregabalin and vigabatrin

should give HIGH dose (b/c excreted faster therefore give higher dose)

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Q

Compared to the first- and second-generation, third-generation ASMs show better…

A

bioavailability, decreased binding to plasma proteins.

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Q

Conjugation occurs with blood proteins, mainly albumin, and is reversible.

Degree of drug conjugation (DC) is Drug (free drug+blood proteins) is _______ proportional to the free drug in the blood, volume of distribution (distribution of drug to tissue), therapeutic effect, side effects from high dose, half life of drug, drug metabolism and excretion.

But ______ proportional to the half life of drug.

A

inversely

direct

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Q

Serum albumin levels ______ as pregnancy progresses.

A

DECLINE

Hence, total serum concentrations of AEDs that are highly bound to serum albumin, e.g., decline in parallel with the falling albumin levels.

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Q

Most AEDs undergo metabolic conversion to active or inactive metabolites in the liver. This is primarily through…

A

hydroxylation via the CYP450 enzyme system and/or conjugation with glucuronide metabolites by uridine glucuronate-glucuronyltranferase (UGT).

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Q

Hence, susceptible to drug interaction with agents with induction or inhibition

A

induction
(eg, rifampin, phenytoin, carbamazepine, phenobarbital, primidone, and St John’s wort)

inhibition
(eg, cimetidine, azole antifungals, macrolide antibiotics, non dihydropyridine calcium channel blockers, and grapefruit juice).

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Q

What is CZB?

A

Na+ channel blocker

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Q

What is CZB therapeutic use?

A

One of the most widely used AEDs in world!

1st choice for ALL PARTIAL seizures

1st choice for TONIC-CLONIC seizures

Recom. for Trigeminal neuralgia

SAFE during BREASTFEEDING

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Q

What is CZB pharmacokinetics?

A

Unstable substance (protect from hot/humid)
Absorbed slowly following oral admin; absorption may be erratic! (smaller, freq. doses are preferred)
High lipid solubility – enters brain rapidly

Induces CYP 1A2, 2C9, 3A4

Metabolized in liver by CYP3A4

Induces its own hepatic metabolism (autoinduction)

Enzyme Inducer:
- Shortens t1/2 of AEDs & other drugs
- Hepatic metabolism is enhanced/induced by CYP3A4 inducers: decrease CBZ level/effect
- Hepatic metabolism is inhibited CYP3A4 inhibitors: increase CBZ level/effect

The Phase I metabolite of CBZ is toxic (forms epoxide)

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Q

What are the AE’s of CZB?

A

Dose related: double vision & ataxia

Idiosyncratic: skin rash, leukopenia

Potential for serious liver toxicity – ALL pt’s should have liver function tests monthly for 3-4 months

Teratogenicity – is a human teratogen (developmental abnormal IQ & growth retardation in foetus)

NOT SAFE DURING PREGNANCY

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Q

What is Oxcarbazepine (OXC) & Eslicarbazepine?

A

Na+ channel blocker

OXC is a prodrug

Eslicarbazepine (structural analog of Carbamazepine & active moiety of OXC)
-Eslicarbazepine acetate is a prodrug; active moiety = Eslicarbazepine

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Q

What is Oxcarbazepine (OXC) & Eslicarbazepine therapeutic use?

A

OXC: AED used as monotherapy & adjunctive therapy for tx of partial seizures in adults/children
-developed through structural variation of CBZ w/ the intent to avoid metabolites causing SE’s
-works via its active metabolite, Eslicarbazepine

Eslicarbazepine alone or together w/ other medicines to control partial seizures (convulsions) in the tx of epilepsy

Eslicarbazepine acetate has minimal interaction w/ P450 liver enzymes, thereby decreasing the risk for drug-drug interactions compared to CZB & OXC

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Q

What is Oxcarbazepine (OXC) & Eslicarbazepine pharmacokinetics?

A

CYP 3A4 inducers (but less than CBZ)

NOT metabolized by CYP450 enzymes

BOTH OXC & Eslicarbazepine acetate are prodrugs & has better safety profile & modest CYP-interactions

Q

What is Oxcarbazepine (OXC) & Eslicarbazepine AE’s?

A

Dose related: double vision & ataxia

Idiosyncratic: skin rash, leukopenia

Potential for serious liver toxicity – ALL pt’s should have liver function tests monthly for 3-4 months

Q

What is Phenytoin (PHT), Fosphenytoin?

A

Blocks voltage-gated Na+ channels

Class IB antiarrhythmic drug – increased the conduction in myocardial junctions

Prodrug for parental admin; its active admin is PHT
- Safer & better tolerated than PHT & can be infused 3x faster than IV

Better IV prep than PHT, b/c of tolerability & safety
- It also may allow faster achievement of therapeutic serum PHT levels

Q

What is Phenytoin (PHT), Fosphenytoin therapeutic use?

A

1st choice for ALL partial seizures

1st choice of seizure prophylaxis in head injury

One of the most used 1st line/adjunctive tx’s for partial & generalized seizures, Lennox-Gastaut syndrome, status epilepticus, & childhood epileptics syndromes
*may even worsen absence & myoclonic seizures! Contraind – bradyarrhythmias

(decrease HR b/c it’s a big antiarrhythmia)

PHT IS SAFE during BREASTFEEDING

Q

What is Phenytoin (PHT), Fosphenytoin pharmacokinetics?

A

NONlinear kinetics (i.e. dose UP = UP UP UP level)
- As dosage increases, hydroxylation system becomes saturated

1st order  0 order
- Relatively SMALL increases in each dose can product LARGE exponential increases in plasma level
- One of the main causes of acute phenytoin toxicity!

Metabolized by hepatic microsomal system

Poorly soluble at LOW pH (i.e. stomach)
- Will be toxic even w/ a little dose b/c it’s nonlinear; 1st  0 order)
Absorption increases when drug passes into duodenum & continues at a slower rate in the jejunum & ileum (absorption from colon is poor)

Avoid IM (crystallization)

INcompatible (precipitates) w/ glucose-containing solutions!
- NaCl & lactated Ringer’s injections are suitable diluents for the IV admin. of phenytoin

One of the most PROBLEMATIC DRUG INTERACTION profiles among all AEDs (refer to slide 35 for names of drugs)

Metabolism is inhibited by some drugs b/c *displaces PHT from protein-binding site
Metabolism is enhanced by some drugs
PHT is strong inducer – enhances metabolism of other AEDs, anticoagulants, steroids, oral contraceptives
PHT is extensively metabolized & its reactive intermediate is responsible for AE’s such as hepatoxicity, Steven’s-Johnson syndrome

Q

What is Phenytoin (PHT), Fosphenytoin AE’s?

A

Hirsutism, coarsening of facial features, hyperpigmentation, acne in girls

Megaloblastic anemia (dysfunctional RBCs) can occur due to altered folate metabolism

Osteomalacia can occur, due to altered vitamin D metabolism

“Purple Glove Syndrome” – progressive edema, discolouration, & pain in limb after IV phenytoin extravasation; rarely can lead to limb amputation

Teratogenic effects

“Fetal Hydrantoin Syndrome”

Gingival hyperplasmia

NOT SAFE DURING PREGNANCY

Q

What is Phenobarbital (PHB) & Primidone?

A

PHB – directly interact w/ GABA-A r’s or Cl channels

Primidone – alters transmembrane Na+ & Ca2+ channel transport
- Metabolized in liver to active metabolites: phenobarbital & PEMA

Q

What is Phenobarbital (PHB) & Primidone therapeutic use?

A

PHB – tonic-clonic & simple partial seizures
- Induces liver microsomal enzymes & thus DI’s are common

PEMA – complex partial seizures

Q

What is Phenobarbital (PHB) & Primidone AE’s?

A

Dose-related: respiratory depression, impaired judgement

Idiosyncratic (unpredictable drug immune mediated toxicity): skin rash due to hypersensitivity

NOT SAFE DURING PREGNANCY

Q

What is Gabapentin?

A

Inhibit a2delta-1 subunit of VG Ca2+ channels

Q

What is Gabapentins therapeutic use?

A

Tx: partial seizures, nerve pain from shingles & restless leg syndrome

Adjunctive therapy (used together w/ the primary tx)

Q

What is Gabapentins pharmacokinetics?

A

NOT metabolized & does NOT induce/inhibit hepatic enzymes

Readily crosses BBB & achieves plasma-to-CSF ratio 1:10

NO plasma protein binding

Excreted in urine entirely unchanged; not metabolized, does NOT induce hepatic enzymes

NO DI’s!

Q

What is Gabapentins AE’s?

A

NO CYP-related interactions

Antacids DECREASE Gabapentin absorption

Not known to be teratogenic

*Exposure during early pregnancy does NOT appear to be associated w/ teratogenic effects = safe in pregnancy

Q

What is Valproate?

A

One of the most used AEDs around world!

Increasing the amount of GABA in brain (inhibiting its metabolism) &, blocking Na+ channels

Q

What is Valproate therapeutic use?

A

Very potent AED, effective against ALL types (generalized & partial) of seizures!

Useful in pt’s w/ concomitant migraine headaches (prophylaxis)

SAFE during BREASTFEEDING

Q

What is Valproate’s AE’s?

A

For all women of childbearing age:
(1) Avoid due to risk of congenital & cognitive defects

Thrombocytopenia & inhibition of platelet aggregation

Risk of spina bifida (in babies born to mother taking VPA)

Alopecia

Hepatotoxicity

Q

What is LamoTRIgine?

A

Inhibits release of glutamate; inhibits Na+ channels

Q

What is LamoTRIgine therapeutic use?

A

BROAD SPECTRUM AGENT: focal seizures, Lennox-Gastaut syndrome, absence seizures

Q

What is LamoTRIgine pharmacokinetics?

A

NO effect on CYP enzymes
- INCREASE levels by VPA
- DECREASE levels by: CZB, phenytoin, phenobarbital, primidone, rifampin, ritonavir

Q

What is LamoTRIgine AE’s?

A

Potentially life threatening ex: Stevens Johnson syndrome (serious rash that’s drug induced)

*NOT associated w/ an increased risk of major congenital malformations

Q

What is Vigabatrin (VGB)?

A

Close structural analogue of GABA

Inhibits the enzyme GABA-transaminase (GABA-T)

Q

What is Vigabatrin (VGB) therapeutic effect?

A

LESS effective against primarily generalized tonic-clonic seizures & may worsen myoclonic seizures or generalized absence seizures

Q

What is Vigabatrin (VGB) AE’s?

A

Vision loss >30%, may be permanent, onset unpredictable, weight gain

CYP2C9 inducer ex: DECREASE levels of: diazepam, fluoxetine, phenobarb, phenytoin, warfarin

Q

What is Topiramate?

A

Derived from D-fructose & initially was developed as an antidiabetic drug (repurposed drug)

Multiple mech’s of action:
- It exerts an inhibitory effect on Na conductance
- Enhances GABA
- Inhibits the AMPA subtype glutamate r.
- Weak inhibitor of carbonic anhydrase

Q

What is Topiramate pharmacokinetics?

A

Absorbed rapidly after oral admin & has a bioavailability close to 100% (WIDE SPECTRUM OF ACTIVITY)

Q

What is Topiramate AE’s?

A

Glaucoma visual field detects; renal stones 1.5% (INCREASE fluid intake)

CBZ, phenytoin, valproate DECREASE Topiramate level

Acetazolamide, ketogenic diet INCREASE renal stone risk w/ topiramate

Q

Pregnancy req’s tx considerations - need to switch drugs or to increase dose?

A

always a challenge since AEDs can harm fetus but so can uncontrolled seizures
risk to fetus from uncontrolled seizures appears to be a greater risk
lowest effect dose should be used
only one drug at a time

Q

Why is an INCREASE in dose necessary during pregnancy?

A

due to increase in renal excretion & changes in metabolism (that occur in pregnancy) - but need to monitor blood levels at least once a month

Q

What drug is NOT associated with an increased risk of major congenital malformations?

A

Lamotrigine

Q

What drug is this?

Exposure during early pregnancy does NOT appear to be associated with teratogenic effects?

A

Gabapentin

Q

What drugs are safe during lactation?

A

CZB

Phenytoin

Valproate

Q

What drugs have possible SE’s for infants during lactation?

A

BZDs

Phenobarbital

Primidone

Q

What are some factors about pregnancy?

A

many factors lead to DECREASED DRUG ABSORPTION DURING PREGNANCY - the rise in progesterone leads to a delay in gastric emptying (therefore, absorption will be decreased)

Q

Common medications used to treat the sx’s associated with ___________, such as ______, may interact w/ co-administered medications, further decreasing their absorption

A

decreased gastric emptying during pregnancy

antacids

Q

__________ DECLINE as pregnancy progresses, hence, there is increase in elimination of __________

A

Serum albumin & a1-acid glycoprotein levels decline

highly protein bound drug

Q

____________ can be induced during pregnancy. Hence, declining serum concentrations of AEDs during pregnancy

A

Phase I CYP enzymes as well as phase II enzymes

Q

The mech by which AEDs could cause bleeding in new borns involves ______

A

alterations in vitamin K metabolism

Q

Enzyme-induced AEDs, such as __________, cross the placenta & induce hepatic microsomal enzymes in the fetal liver

A

Phenobarbital, Phenytoin, & CZB

these enzymes might induce degradation of vitamin K

Q

Interfere with Vitamin K metabolism as indicated by…

A

a raised serum osteocalcin level (has to do this test 1st & if needed they can take vitamin K supplements)