antiepileptic pharmacology notes

PART 1 - Seizures vs Epilepsy

• seizure: a transient alteration of behavior due to disordered synchronous firing of populations of brain neurons

• epilepsy: a condition in which a person has recurrent and unpredictable occurrence of seizures

• causes of seizures

  • primary: genetic predisposition may lower threshold for seizures

  • secondary: trauma, infection, tumors/neoplasms, circulatory disturbances. drug induced or drug withdrawal induced seizure

• types of seizures

  • absence, generalized tonic-clonic, simple partial, complex partial, myoclonic, and infantile spasms

• seizures can be focal or generalized

  • focal seizure: originate within networks located in one hemisphere

  • generalized seizure: arise within one hemisphere and rapidly engage networks distributed across both hemispheres

  • depending on the site of origin in the brain partial/focal seizures can manifest in different ways

• simple vs complex seizures

  • simple

    • only part of the brain/focus is involved

    • no impairment in consciousness

    • pts with simple partial seizures remain aware and awake throughout the seizure

    • some pts can even talk during the episode

  • complex

    • refer to focal seizures that start in one hemisphere of the brain

    • associated with impairment in consciousness

• most common type of generalized seizure is the tonic-clonic type of generalized seizure

  • tonic phase: muscles are contracted

  • clonic phase: muscles are rhythmically contract and relax

• absence seizure

  • generalized seizure w no motor manifestation

  • causes a short period of “blanking out” or staring into space

  • pt appears lost; can be termed as daydreaming

  • teachers will report students as doing poorly in school/daydreaming

• other generalized seizures

  • myoclonic seizures: brief involuntary twitching or jerking of a muscle or group of muscles; involves muscles in different parts of the body

  • tonic seizures: seizures in which sudden tension or stiffness or extension of the arms or legs or body

  • clonic seizures: rhythmic jerking movements of the arms or legs or both

  • atonic seizures: sudden loss of tone

• infantile spasms

  • manifestation: body stiffens suddenly, back may arch, the arms, legs, and may bend forward

  • sometimes the seizure involves only roll up of the eyes or a small tummy contraction

  • seizure may only last a second or two and seizures may occur at 5-10 second interval

  • they can be hard to notice and occur most commonly after a baby wakes up and rarely occur during sleep

  • typically begins between 2-12 months of age and peaks 4-8 months of age

PART 2- What is epileptogenesis? Why do we need to treat epilepsy?

• recurrent seizures/epilepsy needs to be treated as every seizure lays the foundation for another seizure

  • transformation of neuronal network into one that is chronically hyperexcitable

• loss of inhibitory GABA neurons

• decrease in GABA transmission

• increase in glutamate transmission

• reorganization of surviving neurons that leads to hyperexitable neuronal networks

• alteration in expression of ion channels which makes neurons more excitable

PART 3 - Antiepileptic medications

• multiple types of epilepsies with different underlying pathological causes

  • one drug is not effective in all types of epilepsies

  • drugs w multiple mechanisms more effective in some pts

• multiple drugs can help in reducing dose of effective drugs, which may have serious adverse events at high doses

• some antiepileptic drugs influence CYP450 liver enzyemes, which limit their use in patients taking drugs for other disease states

• be alert to drug interactions when treating pts w epilepsy

• pharmacoresistant epilepsy

  • in approx. 20-30% of pts suffering from epilepsy, seizure control w pharmacological meds is difficult to achieve

  • the international league against epilepsy defines pharmacoresistant epilepsy as the failure of a patients seizures to respond to at least 2 antiepileptic meds that are appropriately chosen and used for an adequate period

PART 4 General mechanisms of antiepileptic meds

• antiepileptic meds decrease neuronal activity

  • seizures/epilepsy occurs due to disordered synchronous, uncontrolled firing of neurons

  • firing of neurons is reculates by voltage-gates ion channels (sodium, potassium, and calcium)

  • firing of neurons is regulated by excitatory glutamate and inhibitory GABA neurotransmitters

  • antiepileptics meds target voltage-gated ion channels or chemical neurotransmission

• epilepsy is associated w dysfunctional voltage-gated ion channels

  • mutations/polymorphisms in genes coding for ion channels have been reported in pts suffering from epilepsy

  • mutations can result in

    • prolonged or increased frequency of opening of sodium and calcium VGIC can prolong the depolarization phase leading to uncontrolled firing

    • delayed opening or early closure of potassium and chloride VGIC leads to abnormal repolarization of neurons

    • increased frequency of opening of sodium channels and/or ealry closure of potassium channels can decrease the refactory periods between neuronal action potentials

• VGIC and antiepileptic meds

  • sodium and calcium depolarize

  • potassium and chloride ions repolarize

  • antiepileptic meds block sodium and calcium channels and activate potassium and chloride ion channels

• antiepileptics manipulate chemical neurotransmission

  • decrease glutamate through blocking synaptic vesicle proteins and postsynaptic glutamate receptors

  • increase GABA transmission by increasing the synthesis of GABA, activating GABA receptors, inhibiting uptake of GABA, and inhibiting enzymes that breakdown GABA

PART 5 - antiepileptics that target VGIC

• voltage-gated sodium ion channels

  • youngest among the voltage-gated ion channels being very closely related calcium channels

  • highly conserved across species

  • 9 types of sodium channels are found

  • transmembrane complexes

    • consists of alpha and beta subunits

    • alpha subunit are large proteins of approx. 2000 AA

    • alpha subunit has 4 homologous domains

      • linked by intracellular loops

      • linked to one or more auxiliary beta subunits

    • beta subunits play an important role in kinetics and voltage dependent of channel gating and their presence is necessary for full channel functioning

    • each domain of the alpha subunit contains 6 alpha-helical transmembrane segments

  • older sodium channel blockers

    • lamotrigine

    • valproic acid

    • carbamazepine

    • phenytoin

      • all require monitoring of levels minus lamictal

      • more CYP450 drug interactions

      • cheaper

      • broad spectrum

  • newer sodium channel blockers

    • lacosamide

    • zonisamide

    • rufinamide

      • no monitoring of blood levels

      • less drug interactions

      • relatively expensive

      • used as adjuncts to older AEDs

• calcium channel blockers

  • blockade of calcium channels hastens repolarization and decreases neurotransmitter release, which ultimately decreases neuronal excitability

    • l-type: activated by large depolarization and can remain open for 500 ms

    • T-type (!): activated by small depolarization and valproate and ethosuximide can block this channel

    • N-type: not sensitive to l-type Ca channel blockers and are involved in regulation of NT release

  • made up of several subunits

    • alpha 1 is the primary subunit

      • determines the type of calcium channel

    • beta, alpha-2-delta, and gamma subunits present in only some types of calcium channels are auxiliary subunits that play secondary role

  • T-type

    • low voltage activated channels

    • important for repetitive firing of action potentials in neurons

    • are composed of only an alpha-1 subunit

    • lack beta, alpha-2-delta, and gamma subunits

    • involved in absence seizures

  • ethosuximide is used to treat absense seizures

    • reduces voltage-gated low-threshold calcium channels by blocking t-type channels

• potassium ion channels

  • simpler in structure

  • neuronal activity can also be decreased by activating potassium

    channels

    • ezogabine activated potassium channels and results in faster repolarization of neurons

PART 6 - antiepileptics that manipulate chemical neurotransmission

• levetiracetam decreases release of excitatory neurotransmitters

  • binds to specific synpatic proteins to decrease NT release, blocks calcium entry into the presynaptic neurons

  • decreases glutamate release

• felbamate

  • blocks NMDA receptor

  • blocks voltage-gated Na channels

  • enhances GABAa receptors

• topiramate

  • blocks AMPA receptors

  • blocks voltage-gated Na channels

  • enhances GABAa currents

  • activates a hyperpolarizing K+ current

• perampanel

  • seletive non-competitive AMPA receptor antagonsit

  • blocks AMPA receptor by binding to a site different from glutamate

• GABAa receptors have several modulatory binding sites for barbituates, benzos, neurosteroids, and ethanol

  • binding of GABA to these receptors allows for entry of chloride resulting in neuronal hyperpolarization and ultimately results in decreased firing of neurons

  • barbituates- enhances GABA mediated synaptic transmission by increasing the duration of GABAa channel opening

  • benzos- enhances GABA mediated synaptic transmission by increasing the frequency of GABAa channel opening

  • tiagabine- inhibitor of GABA uptake resulting in increased GABA levels

  • gabapentin- increased GABA synthesis; inhibits alpha-2-delta subunit of voltage-dependent calcium channels

  • vigabatrin- irreversible inhibitor of GABA transamininase

  • stiripentol- activates GABAa receptors

  • pregabalin- inhibits alpha-2-delta subunit of voltage dependent calcium channels

  • primidone- metabolized to active metabolites phenobarb and phenyethylmalonmide

  • cannabidol

    • activates GABAa receptors

    • blocks sodium channles

    • blocks t-type calcium channels

    • blocks GPR55

    • inhibits CYP450 isoenzymes like CYP3A4 and CYP2C19

      • necessary for degradation of benzos leading to an increase in their Tmax values and plasma half life

PART 7 - Adverse effects associated w antiepileptics

• acute effects

  • dose dependent

  • controlled/minimized by careful dose tiration

  • sedation, tremors, dizziness, ataxia, nausea, and vomiting

• idiosyncratic effetcs

  • rare but can be fatal

  • blood dyscrasiais, skin-rashed, steven-johnson syndrome, liver failure

• chronic adverse effects

  • associated with long-term admin

  • osteoporosis, behavioral changes in children, gum hyperplasia

PART 8 - Drug interactions

• often involved in drug interactions due to their action on CYP450 enzymes

  • antiepileptic medications can decrease efficacy of oral contraceptives

  • macrolide antibiotics can have decreased efficacy due to AEDs