Antiepileptic Drugs Flashcards
What is a seizure?
Short term episode of abnormal firing of cerebral neurons
A paroxysmal event characterized by abnormal, excessive hypersynchronous discharge of cortical neuron activity
What is the mech of action of Gabapentin?
Modulation of Α2δ Ca2+ channels inhibit release of excitatory neurotransmitter, hence, inhibit depolarization (AP)
What is the mech of action of Phenytoin (PHT)?
Modulation of Na+ Channels
Inhibit depolarization (AP), hence, calcium influx and release of excitatory neurotransmitter
What is the mech of action of CBZ?
Modulation of Na+ Channels
Inhibit depolarization (AP), hence, calcium influx and release of excitatory neurotransmitter
What is the mech of action of OXC?
Modulation of Na+ Channels
Inhibit depolarization (AP), hence, calcium influx and release of excitatory neurotransmitter
What is the mech of action of Valproate?
Modulation of Na+ Channels
Inhibit depolarization (AP), hence, calcium influx and release of excitatory neurotransmitter
What is the mech of action of Lomotrigine?
Modulation of Na+ Channels
Inhibit depolarization (AP), hence, calcium influx and release of excitatory neurotransmitter
What is the mech of action of Topiramate?
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).
What is the mech of action of Vigabatrin?
Inhibit GABA-T, hence, decrease metabolism of GABA in presynaptic neuron and glia cells.
Increasing the inhibitory neurotransmitter
Leading to decrease in depolarization (AP).
What is the mech of action of Barbiturates (Phenobarbital)?
Activating GABA (Cl-) r., hence, increase in inhibitory NT leading to decrease in depolarization (AP)
Older-generation AEDs…
remain highly valuable in the modern treatment of epilepsy, they have considerable side effects and show undesirable PK properties.
Several new-generation AEDs…
differ greatly not only in efficacy spectrum and side-effect profile but also, they have improved PK profile.
_____ plasma protein binding is usually regarded as unfavorable
HIGH
Most AEDs exhibit little or no protein binding, but…
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.
Which drugs have 0% serum protein binding
Ethosuximide, gabapentin, levetiracetam, pregabalin and vigabatrin
should give HIGH dose (b/c excreted faster therefore give higher dose)
Compared to the first- and second-generation, third-generation ASMs show better…
bioavailability, decreased binding to plasma proteins.
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.
inversely
direct
Serum albumin levels ______ as pregnancy progresses.
DECLINE
Hence, total serum concentrations of AEDs that are highly bound to serum albumin, e.g., decline in parallel with the falling albumin levels.
Most AEDs undergo metabolic conversion to active or inactive metabolites in the liver. This is primarily through…
hydroxylation via the CYP450 enzyme system and/or conjugation with glucuronide metabolites by uridine glucuronate-glucuronyltranferase (UGT).
Hence, susceptible to drug interaction with agents with induction or inhibition
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).
What is CZB?
Na+ channel blocker
What is CZB therapeutic use?
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
What is CZB pharmacokinetics?
- 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)
What are the AE’s of CZB?
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
What is Oxcarbazepine (OXC) & Eslicarbazepine?
Na+ channel blocker
OXC is a prodrug
Eslicarbazepine (structural analog of Carbamazepine & active moiety of OXC)
-Eslicarbazepine acetate is a prodrug; active moiety = Eslicarbazepine
What is Oxcarbazepine (OXC) & Eslicarbazepine therapeutic use?
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
What is Oxcarbazepine (OXC) & Eslicarbazepine pharmacokinetics?
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
What is Oxcarbazepine (OXC) & Eslicarbazepine AE’s?
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
What is Phenytoin (PHT), Fosphenytoin?
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
What is Phenytoin (PHT), Fosphenytoin therapeutic use?
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
What is Phenytoin (PHT), Fosphenytoin pharmacokinetics?
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
What is Phenytoin (PHT), Fosphenytoin AE’s?
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
What is Phenobarbital (PHB) & Primidone?
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
What is Phenobarbital (PHB) & Primidone therapeutic use?
PHB – tonic-clonic & simple partial seizures
- Induces liver microsomal enzymes & thus DI’s are common
PEMA – complex partial seizures
What is Phenobarbital (PHB) & Primidone AE’s?
Dose-related: respiratory depression, impaired judgement
Idiosyncratic (unpredictable drug immune mediated toxicity): skin rash due to hypersensitivity
NOT SAFE DURING PREGNANCY
What is Gabapentin?
Inhibit a2delta-1 subunit of VG Ca2+ channels
What is Gabapentins therapeutic use?
Tx: partial seizures, nerve pain from shingles & restless leg syndrome
Adjunctive therapy (used together w/ the primary tx)
What is Gabapentins pharmacokinetics?
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!
What is Gabapentins AE’s?
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
What is Valproate?
One of the most used AEDs around world!
Increasing the amount of GABA in brain (inhibiting its metabolism) &, blocking Na+ channels
What is Valproate therapeutic use?
Very potent AED, effective against ALL types (generalized & partial) of seizures!
Useful in pt’s w/ concomitant migraine headaches (prophylaxis)
SAFE during BREASTFEEDING
What is Valproate’s AE’s?
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
What is LamoTRIgine?
Inhibits release of glutamate; inhibits Na+ channels
What is LamoTRIgine therapeutic use?
BROAD SPECTRUM AGENT: focal seizures, Lennox-Gastaut syndrome, absence seizures
What is LamoTRIgine pharmacokinetics?
NO effect on CYP enzymes
- INCREASE levels by VPA
- DECREASE levels by: CZB, phenytoin, phenobarbital, primidone, rifampin, ritonavir
What is LamoTRIgine AE’s?
Potentially life threatening ex: Stevens Johnson syndrome (serious rash that’s drug induced)
*NOT associated w/ an increased risk of major congenital malformations
What is Vigabatrin (VGB)?
Close structural analogue of GABA
Inhibits the enzyme GABA-transaminase (GABA-T)
What is Vigabatrin (VGB) therapeutic effect?
LESS effective against primarily generalized tonic-clonic seizures & may worsen myoclonic seizures or generalized absence seizures
What is Vigabatrin (VGB) AE’s?
Vision loss >30%, may be permanent, onset unpredictable, weight gain
CYP2C9 inducer ex: DECREASE levels of: diazepam, fluoxetine, phenobarb, phenytoin, warfarin
What is Topiramate?
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
What is Topiramate pharmacokinetics?
Absorbed rapidly after oral admin & has a bioavailability close to 100% (WIDE SPECTRUM OF ACTIVITY)
What is Topiramate AE’s?
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
Pregnancy req’s tx considerations - need to switch drugs or to increase dose?
- 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
Why is an INCREASE in dose necessary during pregnancy?
due to increase in renal excretion & changes in metabolism (that occur in pregnancy) - but need to monitor blood levels at least once a month
What drug is NOT associated with an increased risk of major congenital malformations?
Lamotrigine
What drug is this?
Exposure during early pregnancy does NOT appear to be associated with teratogenic effects?
Gabapentin
What drugs are safe during lactation?
CZB
Phenytoin
Valproate
What drugs have possible SE’s for infants during lactation?
BZDs
Phenobarbital
Primidone
What are some factors about pregnancy?
- 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)
Common medications used to treat the sx’s associated with ___________, such as ______, may interact w/ co-administered medications, further decreasing their absorption
decreased gastric emptying during pregnancy
antacids
__________ DECLINE as pregnancy progresses, hence, there is increase in elimination of __________
Serum albumin & a1-acid glycoprotein levels decline
highly protein bound drug
____________ can be induced during pregnancy. Hence, declining serum concentrations of AEDs during pregnancy
Phase I CYP enzymes as well as phase II enzymes
The mech by which AEDs could cause bleeding in new borns involves ______
alterations in vitamin K metabolism
Enzyme-induced AEDs, such as __________, cross the placenta & induce hepatic microsomal enzymes in the fetal liver
Phenobarbital, Phenytoin, & CZB
these enzymes might induce degradation of vitamin K
Interfere with Vitamin K metabolism as indicated by…
a raised serum osteocalcin level (has to do this test 1st & if needed they can take vitamin K supplements)
