Anti-Epileptic Drugs Pharmacodynamics and Pharmacokinetics of Anti-Epileptic Drugs Jose Paciano B.T....

Anti-Epileptic DrugsAnti-Epileptic Drugs

Pharmacodynamics and Pharmacodynamics and Pharmacokinetics of Pharmacokinetics of Anti-Epileptic DrugsAnti-Epileptic Drugs

Jose Paciano B.T. Reyes, MD, FPNAJose Paciano B.T. Reyes, MD, FPNA


DefinitionsDefinitions

SeizureSeizure• Transient episodes of supratentorial originTransient episodes of supratentorial origin• Abrupt and temporary alteration in neuronal Abrupt and temporary alteration in neuronal

activityactivity• Abnormal movements or abnormal sensationAbnormal movements or abnormal sensation• Spontaneous excessive discharge of cortical Spontaneous excessive discharge of cortical

neuronsneurons– Increase in neuronal activityIncrease in neuronal activity

Excessive excitatory synaptic inputExcessive excitatory synaptic inputDecrease in normal inhibitory mechanismsDecrease in normal inhibitory mechanisms


DefinitionsDefinitions

EpilepsyEpilepsy• Disorder of brain function characterized by Disorder of brain function characterized by

periodic & unpredictable occurrences of periodic & unpredictable occurrences of seizuresseizures

• Recurrent seizuresRecurrent seizures


Mode of action of antiepileptic drugsMode of action of antiepileptic drugs

Enhancem ent of G ABA-m ediated inhibition

Phenobarbital, D iazepam , V igabatrin, T iagabine, Topiram ate, Valproic ac id, G abapentin

Inhibition of ionic ac tivity

Phenytoin, C arbam azepine, Valproic ac id, E thosuxim ide, Topiram ate

Inhibition of exc itatory ac tivity

Phenobarbital, Topiram ate


GABAGABA•Major inhibitory Major inhibitory neurotransmitter in neurotransmitter in mammalian CNSmammalian CNS

•Neutral amino acid Neutral amino acid derivativederivative

•Estimated that it serves as Estimated that it serves as transmitter in 30% of all transmitter in 30% of all synapses in the CNSsynapses in the CNS

•Mediates slow & fast Mediates slow & fast components of the components of the inhibitory post-synaptic inhibitory post-synaptic potentials (IPSPs) in the potentials (IPSPs) in the brainbrain

•In the spinal cord In the spinal cord synthesized by neurons in synthesized by neurons in the dorsal horn that form the dorsal horn that form axoaxonic synapses axoaxonic synapses responsible for pre-responsible for pre-synaptic inhibitionsynaptic inhibition


GABAGABA

•Formed from glutamate by the action of Formed from glutamate by the action of glutamic acid decarboxylaseglutamic acid decarboxylase

•Destroyed by a transamination reaction Destroyed by a transamination reaction catalyzed by GABA-transaminase (GABA-T), catalyzed by GABA-transaminase (GABA-T), inhibited by vigabatrineinhibited by vigabatrine

•Action terminated mainly by a GABA active Action terminated mainly by a GABA active uptake mechanism uptake mechanism


Inhibitory Postsynaptic PotentialsInhibitory Postsynaptic Potentials

Results in inhibitory postsynaptic potentialResults in inhibitory postsynaptic potential

Increased net outward hyperpolarizing currentIncreased net outward hyperpolarizing current

• Stabilization effect on excitatory synaptic responsesStabilization effect on excitatory synaptic responses

• Nullifies the inward NaNullifies the inward Na++ movement movement

Presynaptic InhibitionPresynaptic Inhibition

Involves axoaxonic synapseInvolves axoaxonic synapse

Decreases the amount of excitatory neurotransmitter Decreases the amount of excitatory neurotransmitter releasedreleased

Inhibits depolarization of the nerve terminal or inhibits Inhibits depolarization of the nerve terminal or inhibits resultant increase in Caresultant increase in Ca++

Longer duration inhibition than postsynaptic inhibitionLonger duration inhibition than postsynaptic inhibition

Involves inhibition of of spinal afferent inputInvolves inhibition of of spinal afferent input

GABA – principle presynaptic inhibitory neurotransmitter GABA – principle presynaptic inhibitory neurotransmitter


• Major type of GABA receptor in the brainMajor type of GABA receptor in the brain• Ligand-gated ion channel Ligand-gated ion channel • Increases the ClIncreases the Cl- - conductance of the neuronconductance of the neuron• Mediates fast IPSPsMediates fast IPSPs• Pentamer consisting of Pentamer consisting of subunitssubunits• Contains benzodiazepine and barbiturate Contains benzodiazepine and barbiturate

modulatory receptor sitesmodulatory receptor sites

Muscimol – powerful GABAMuscimol – powerful GABAAA-receptor agonist-receptor agonist

Bicuculline – antagonist Bicuculline – antagonist Picrotoxin – blocks the chloride channelPicrotoxin – blocks the chloride channel

GABAGABAAA Receptor Receptor


• Coupled to G-protein-coupled receptors, inhibit cAMP Coupled to G-protein-coupled receptors, inhibit cAMP formationformation

• Mediates slow IPSPs Mediates slow IPSPs • Cause pre- and postsynaptic inhibition by inhibiting Cause pre- and postsynaptic inhibition by inhibiting

calcium channels and activate potassium channelscalcium channels and activate potassium channels

Baclofen – selective agonistBaclofen – selective agonist

GABAGABABB Receptor Receptor


Model of GABAModel of GABAAA

receptor receptor chloride ion chloride ion channel channel macromolecular macromolecular complexcomplex


Mechanisms to Mechanisms to enhance GABA enhance GABA synaptic synaptic transmission and transmission and drugs that act drugs that act through themthrough them


Anti-epileptic drug-enhanced NaAnti-epileptic drug-enhanced Na+ + channel inactivationchannel inactivation


Anti-epileptic drug-induced reduction of current Anti-epileptic drug-induced reduction of current through T-type Cathrough T-type Ca2+ 2+ channelschannels


Anti-epileptic DrugsAnti-epileptic Drugs

• Used for the symptomatic treatment of Used for the symptomatic treatment of epilepsyepilepsy

• Used to lower the probability that a patient will Used to lower the probability that a patient will have additional seizureshave additional seizures

• Used to abort a seizure in progressUsed to abort a seizure in progress



• Increase seizure threshold without affecting Increase seizure threshold without affecting motor excitabilitymotor excitability

• No sedative-hypnotic effectNo sedative-hypnotic effect• Few side-effects with chronic useFew side-effects with chronic use

*dose should be as low as possible*dose should be as low as possible

*patient should be supervised closely*patient should be supervised closely*monotherapy*monotherapy


Factors influencing the decision to treatFactors influencing the decision to treat

• DiagnosisDiagnosis– Establish a firm diagnosis of epilepsyEstablish a firm diagnosis of epilepsy

• The risk of seizure recurrenceThe risk of seizure recurrence– Overall risk after 1Overall risk after 1stst seizure 50-80% seizure 50-80%– Risk is high initially and then falls over timeRisk is high initially and then falls over time– Risk is greater in those with structural brain diseaseRisk is greater in those with structural brain disease

• The type, timing and frequency of seizuresThe type, timing and frequency of seizures• Reflex seizures and acute symptomatic Reflex seizures and acute symptomatic

seizuresseizures• The risks of therapy and of epilepsyThe risks of therapy and of epilepsy



RR22 OO RR33 OO

CC CC NN CC

RR11

R1 & R2: alkyl or aryl R1 & R2: alkyl or aryl groupsgroupsR3: H or alkylR3: H or alkyl

BarbituratesBarbituratesHydantoinsHydantoinsOxazolidinedionesOxazolidinedionesSuccinimidesSuccinimides

Benzodiazepines, carbamazepine Benzodiazepines, carbamazepine and valproic acid do not belong to and valproic acid do not belong to these groupsthese groups


SEIZURE TYPE DRUGS OF CHOICE ALTERNATIVE

Partial-onset Seizures

Sim ple and com plexpartia l

Carbam azepine orphenytoin or valproate

O xcarbazepine,phenobarbita l, prim idone

Secondarilygeneralized

Carbam azepine orphenytoin or valproate

O xcarbazepine,phenobarbita l, prim idone

Generalized seizures

Tonic-clonic Valproate Carbam azepine, phenytoin,phenobarbita l, prim idone,fe lbam ate,

Absence Ethosuxim ide orvalproate

C lonazepam

M yoclonic Valproate C lonazepam , zonisam ide

Tonic Valproate Felbam ate, clonazepam

Atonic Valproate Felbam ate, clonazepam ,ethosuxim ide


Desirable Pharmacokinetic Desirable Pharmacokinetic Characteristics for AEDCharacteristics for AED

1. High oral bioavailability, unaffected by food1. High oral bioavailability, unaffected by food

2. Not significantly bound to plasma proteins2. Not significantly bound to plasma proteins

3. Linear kinetics3. Linear kinetics

4. Not vulnerable to drug interactions, does not 4. Not vulnerable to drug interactions, does not significantly alter kinetics of concomitantly significantly alter kinetics of concomitantly administered drugsadministered drugs


Philippine National Drug FormularyPhilippine National Drug Formulary

CarbamazepineCarbamazepine

ClonazepamClonazepam

DiazepamDiazepam

LorazepamLorazepam

Magnesium SulfateMagnesium Sulfate

PhenobarbitalPhenobarbital

PhenytoinPhenytoin

Valproate Disodium/ Valproate Disodium/ Valproic AcidValproic Acid

GabapentinGabapentin

Thiopental SodiumThiopental Sodium


BenzodiazepinesBenzodiazepines

Modes of action:Modes of action:• Enhance GABA-induced increases in the Enhance GABA-induced increases in the

conductance of Clconductance of Cl--

does not directly activate GABA receptorsdoes not directly activate GABA receptors• Increases the frequency of channel openingIncreases the frequency of channel opening• At higher concentrations, can reduce At higher concentrations, can reduce

sustained high frequency firing of neuronssustained high frequency firing of neurons


Benzodiazepines

Indications:• Often used clinically as sedatives and anti-

anxiety agents• Absence seizures (clonazepam)• Myoclonic seizures in children (clonazepam)• Status epilepticus (diazepam)

Flumazenil is used to reverse benzodiazepine induced CNS depression. It is a competitive antagonist that has high affinity for the benzodiazepine receptor.


DiazepamDiazepamOnset of action:Onset of action:• Oral: 30 min - 1 hrOral: 30 min - 1 hr• IM: 15 - 30 minIM: 15 - 30 min• IV: IV: << 15 min 15 min

Peak plasma levels:Peak plasma levels:• Oral: 30 - 60 minOral: 30 - 60 min• IM: 30 - 90 minIM: 30 - 90 min• IV: 15 minIV: 15 min

Protein binding:Protein binding:• 98% bound98% bound

Plasma T1/2:Plasma T1/2:• 14 - 60 hrs for diazepam14 - 60 hrs for diazepam• 20 -70 hrs for active 20 -70 hrs for active metabolite nordiazepammetabolite nordiazepam• Prolonged in obese patientsProlonged in obese patients

Bioavailability:Bioavailability:• Taken rapidly to brainTaken rapidly to brain• Oral absorption 85-100% Oral absorption 85-100% • Absorption after IM dose is Absorption after IM dose is slow and erratic except when slow and erratic except when given into the deltoid given into the deltoid


DiazepamDiazepam

Metabolism:Metabolism:• Hepatic Hepatic • Active metabolites Active metabolites desmethyldiazepam (nordiazepam) desmethyldiazepam (nordiazepam) methloxazepem (temazepam) methloxazepem (temazepam) oxazepamoxazepam

Excretion: Excretion: • Diazepam and metabolites Diazepam and metabolites eliminated in the kidneyseliminated in the kidneys• Excreted in the urine as Excreted in the urine as oxidized and glucoronide-oxidized and glucoronide-conjugated metabolitesconjugated metabolites

Renal impairment:Renal impairment:• Clearance depends on Clearance depends on renal blood flowrenal blood flow

Hepatic impairment:Hepatic impairment:• Disposition altered with Disposition altered with chronic liver diseasechronic liver disease


DiazepamDiazepam

Adverse Reactions:Adverse Reactions:

Cardiovascular: Cardiovascular: bradycardia/tachycardia, bradycardia/tachycardia, hypotension cardiac arresthypotension cardiac arrest

CNS: amnesia, anxiety, CNS: amnesia, anxiety, depression, drowsiness, depression, drowsiness,

Dermatologic: rashDermatologic: rash

GIT: constipation/diarrhea, GIT: constipation/diarrhea, nausea, vomitingnausea, vomiting

Local: pain with injection, Local: pain with injection, phlebitisphlebitis

Respiratory: apnea, decrease Respiratory: apnea, decrease respiratory rate, laryngospasmrespiratory rate, laryngospasm

Drug Interaction:Drug Interaction:

CYP1A2 and 2C8 enzyme CYP1A2 and 2C8 enzyme substrate, CYP219 enzyme substrate, CYP219 enzyme substrate substrate

Stability:Stability:

Do not mix iv medication with Do not mix iv medication with other productsother products

Protect iv preparation from lightProtect iv preparation from light

Administration:Administration:

IVPIVP

Children 1-2 mg/minuteChildren 1-2 mg/minute

Adults 5 mg/minuteAdults 5 mg/minute



Onset of action:Onset of action:• RapidRapid

Peak plasma levels:Peak plasma levels:• 1- 4 hrs 1- 4 hrs

Plasma T1/2:Plasma T1/2:• 19 - 49 hrs19 - 49 hrs

Plasma protein binding:Plasma protein binding:• ~90% (mostly to albumin)~90% (mostly to albumin)

Bioavailability:Bioavailability:

• 81 - 98% 81 - 98%

• Unknown effect of food on Unknown effect of food on absorption absorption

Metabolism:Metabolism:

• Extensive hepatic Extensive hepatic microsomal metabolismmicrosomal metabolism

• Reduction of nitro group to Reduction of nitro group to inactive 7-amino derivativesinactive 7-amino derivatives



Excretion:Excretion:• < 5% excreted < 5% excreted unchanged unchanged • Metabolites renally Metabolites renally excretedexcreted

Renal impairment:Renal impairment:• Metabolism of parent Metabolism of parent compound does not appear compound does not appear changed as renal function changed as renal function decreasesdecreases

Hepatic impairment:Hepatic impairment:• Potentially decreased Potentially decreased clearance with increase T 1/2clearance with increase T 1/2• Possible increase in free Possible increase in free (non-protein bound) fraction(non-protein bound) fraction




CNS: drowsiness, CNS: drowsiness,

dermatologic: rashdermatologic: rash



CYP3A3/4 enzyme CYP3A3/4 enzyme substratesubstrate


LorazepamLorazepam

Peak plasma levels:Peak plasma levels:• Oral: 1 - 6 hrsOral: 1 - 6 hrs• IM: 1 - 1.5 hrs IM: 1 - 1.5 hrs

Plasma T 1/2:Plasma T 1/2:• 10 - 20 hrs10 - 20 hrs

Bioavailability:Bioavailability:• Oral: ~90%Oral: ~90%• Parenteral: rapid and Parenteral: rapid and complete absorptioncomplete absorption

Protein binding:Protein binding:

• 85% bound85% bound


• One-step inactivation of One-step inactivation of parent drugparent drug

• Inactive glucoronide Inactive glucoronide metabolitemetabolite


LorazepamLorazepam

Excretion:Excretion:

•Eliminated through Eliminated through

kidneyskidneys

•Excreted in urineExcreted in urine

Renal Impairment:Renal Impairment:

• Kinetic effects prolonged Kinetic effects prolonged

with mild to moderate with mild to moderate

kidney diseasekidney disease

Hepatic Impairment:Hepatic Impairment:

• Kinetic effects prolonged Kinetic effects prolonged

with mild to moderate liver with mild to moderate liver

diseasedisease


LorazepamLorazepam


Cardiovascular: chest pain, Cardiovascular: chest pain, bradycardiabradycardia

CNS: amnesia, anxiety, CNS: amnesia, anxiety, depression, drowsiness, depression, drowsiness, paradoxical excitement paradoxical excitement




Respiratory: hyperventilationRespiratory: hyperventilation


Intact vials refrigeratedIntact vials refrigerated

Protect from lightProtect from light


Dilute iv dose with equal Dilute iv dose with equal volume (Dvolume (D55W, NS)W, NS)

2 mg/min2 mg/min



One of the oldest anti-epileptic drugs (1912) in use

Modes of action:• Potentiates GABA-induced increases in Cl-

conductance• Prolongs the periods of channel opening• In high concentrations, GABA-mimetic• Reduces glutamate-induced depolarizations (AMPA

subtypes of glutamate receptors)• Inhibits the function of voltage dependent Na+ & K+

channels



Indications:Indications:• Generalized tonic-clonic seizures Generalized tonic-clonic seizures • Partial seizuresPartial seizures• Status epilepticusStatus epilepticus



Onset of action:Onset of action:• >> 1 hr after oral dose 1 hr after oral dose

Peak plasma levels:Peak plasma levels:• 2 hrs after oral dose2 hrs after oral dose

Plasma T1/2:Plasma T1/2:• ~100 hrs for adults~100 hrs for adults• ~65 hrs for children~65 hrs for children• Unknown in the elderlyUnknown in the elderly

Bioavailability:Bioavailability:• 100% after oral dose 100% after oral dose • Food affects absorption rate Food affects absorption rate but not overall bioavailability but not overall bioavailability

Protein binding:Protein binding:• 45% - 50% bound45% - 50% bound

Metabolism:Metabolism:• Hepatic microsomal P450Hepatic microsomal P450• Metabolites mostly inactiveMetabolites mostly inactive




• Up to 25% eliminated by pH Up to 25% eliminated by pH

dependent renal excretion of dependent renal excretion of

unchanged drugunchanged drug

• Remainder inactivated by Remainder inactivated by

hepatic microsomal enzymeshepatic microsomal enzymes

• % unchanged drug % unchanged drug

increased when urine increased when urine

alkaline, decreased with alkaline, decreased with

decreased urine flowdecreased urine flow

Renal impairment:Renal impairment:

• Modify dose when GFR Modify dose when GFR < 20 mL/min< 20 mL/min

Hepatic impairment:Hepatic impairment:

• T 1/2 increased with liver T 1/2 increased with liver cirrhosiscirrhosis

• Excretion prolonged with Excretion prolonged with cirrhosis and viral hepatitiscirrhosis and viral hepatitis




Cardiovascular: bradycardia, Cardiovascular: bradycardia, hypotension cardiac arresthypotension cardiac arrest

CNS: anxiety, depression / CNS: anxiety, depression / excitation, drowsiness, excitation, drowsiness, hallucinations, nightmares, hallucinations, nightmares, “hangover”“hangover”


GIT: constipation, nausea, GIT: constipation, nausea, vomitingvomiting


Respiratory: apneaRespiratory: apnea


CYP1A2, 2B6, 2C, 2C8, 3A3/4 CYP1A2, 2B6, 2C, 2C8, 3A3/4 and 3A5-7 inducerand 3A5-7 inducer


Do not mix iv medication with Do not mix iv medication with other productsother products

Protect elixir preparation from Protect elixir preparation from lightlight


IVPIVP

50 mg/minute50 mg/minute


Ce

ntr

al n

erv

ous

syst

em

effe

cts

Increasing sedative-hypnotic dose

Coma

Medullary depression

Anesthesia

Hypnosis

Sedation, disinhibition, anxiolysis

Possible selective anticonvulsant and muscle-relaxing activity

Barbiturates

Benzodiazepines



• An amino acid analogue of GABAAn amino acid analogue of GABA

Mode of action:Mode of action:• Alters GABA metabolismAlters GABA metabolism• Alters non-synaptic GABA releaseAlters non-synaptic GABA release

does not act on GABA receptorsdoes not act on GABA receptorsIndications:Indications:• Adjunct for partial seizuresAdjunct for partial seizures• Adjunct for generalized tonic-clonic seizuresAdjunct for generalized tonic-clonic seizures



Onset of action:Onset of action:• UnknownUnknown

Peak plasma levels:Peak plasma levels:• 2 - 3 hrs2 - 3 hrs


Protein binding:Protein binding:• < 3%< 3%

Bioavailability:Bioavailability:• Dose-dependentDose-dependent• ~60% at 300 mg dose ~60% at 300 mg dose • ~35% at 1600 mg dose~35% at 1600 mg dose• Food does not affect itFood does not affect it

Metabolism:Metabolism:• No hepatic metabolismNo hepatic metabolism• No other knownNo other known




• 100% renal 100% renal


• T 1/2 increases as renal T 1/2 increases as renal

function declinesfunction declines

• Significantly removed Significantly removed

from plasma by from plasma by

hemodialysishemodialysis


• Effect unknownEffect unknown

• Direct metabolic effect Direct metabolic effect

not expectednot expected




Cardiovascular: Cardiovascular: bradycardia/tachycardia, bradycardia/tachycardia, hypotension cardiac arresthypotension cardiac arrest

CNS: somnolence, CNS: somnolence, dizziness dizziness

Dermatologic: pruritusDermatologic: pruritus

GIT: nausea, vomitingGIT: nausea, vomiting


PhenytoinPhenytoin

• Oldest non-sedating anti-epileptic drugOldest non-sedating anti-epileptic drug• Diphenyl-substituted hydantoin (1938)Diphenyl-substituted hydantoin (1938)

Mode of action: Mode of action: • Blocks sodium channels and inhibit generation of Blocks sodium channels and inhibit generation of

repetitive action potentialsrepetitive action potentialsIndications:Indications: • Partial seizures Partial seizures • Generalized tonic-clonic seizuresGeneralized tonic-clonic seizures• Status epilepticusStatus epilepticus


PhenytoinPhenytoin

Onset of action:Onset of action:• Formulation dependentFormulation dependent• IV loading dose: 15 minIV loading dose: 15 min

Peak plasma levels:Peak plasma levels:• 1- 3 hrs to 4 - 14 hrs 1- 3 hrs to 4 - 14 hrs depending on formulationdepending on formulation

Plasma T1/2:Plasma T1/2:• 6 - 42 hrs 6 - 42 hrs • Average 20 - 30 hrsAverage 20 - 30 hrs

Bioavailability:Bioavailability:• ~90%~90%• Slow and occasionally Slow and occasionally incomplete absorption after incomplete absorption after oral dose oral dose

Plasma protein binding:Plasma protein binding:• ~90% (mostly to albumin)~90% (mostly to albumin)• more unbound fraction in more unbound fraction in neonates, patients with neonates, patients with hypoalbuminemia and renal hypoalbuminemia and renal insufficiencyinsufficiency


PhenytoinPhenytoin


• Hydroxylated by Hydroxylated by

saturable hepatic P450 saturable hepatic P450

microsomal enzyme microsomal enzyme

systemsystem

•Small dose increment Small dose increment

may increase T 1/2 & may increase T 1/2 &

cause substantial cause substantial

nonlinear increase in nonlinear increase in

serum concentrationserum concentration


• < 5% excreted < 5% excreted

unchanged in urineunchanged in urine

• Mostly metabolized in Mostly metabolized in

hepatic endoplasmic hepatic endoplasmic

reticulum to inactive formsreticulum to inactive forms

• Initially through bile but Initially through bile but

reabsorbed and excreted reabsorbed and excreted

as glucoronide conjugates as glucoronide conjugates

in urine in urine


PhenytoinPhenytoin

Renal impairment:Renal impairment:• Increase unbound Increase unbound fractionfraction• Decrease T ½Decrease T ½

Hepatic impairment:Hepatic impairment:• Slowed metabolismSlowed metabolism• Altered protein bindingAltered protein binding


PhenytoinPhenytoin


Cardiovascular: bradycardia, Cardiovascular: bradycardia, hypotension, cardiac arresthypotension, cardiac arrest

CNS: amnesia, anxiety, CNS: amnesia, anxiety, depression, drowsiness, depression, drowsiness,


GIT: gingival hyperplasia, GIT: gingival hyperplasia, nausea, vomiting, constipationnausea, vomiting, constipation

Hematologic: agranulocytosis, Hematologic: agranulocytosis, leukopenia, thrombocytopenialeukopenia, thrombocytopenia

Local: phlebitisLocal: phlebitis


CYP2C9 and 2C19 enzyme CYP2C9 and 2C19 enzyme substrate, CYP1A2, 2B6, 2C, substrate, CYP1A2, 2B6, 2C, 3A3/4, 3A5-7 enzyme inducer3A3/4, 3A5-7 enzyme inducer


IV form is incompatible with IV form is incompatible with many drugs (incl.Dmany drugs (incl.D55W, some W, some

saline solutions)saline solutions)

Dilute with NSDilute with NS


IVPIVP

50 mg/minute50 mg/minute



• Spatial conformation is similar to phenytoinSpatial conformation is similar to phenytoin• Tricyclic compound also effective in the Tricyclic compound also effective in the

treatment of bipolar depressiontreatment of bipolar depression

Mode of action:Mode of action:• blocks sodium channels and inhibit blocks sodium channels and inhibit

generation of repetitive action potentialsgeneration of repetitive action potentials



Indications:Indications:• Partial seizures (drug of choice)Partial seizures (drug of choice)• Generalized tonic-clonic seizuresGeneralized tonic-clonic seizures• Trigeminal neuralgiaTrigeminal neuralgia



Onset of action:Onset of action:• slowslow• absorption determined absorption determined


Plasma T 1/2:Plasma T 1/2:• Initially 18 - 55 hrsInitially 18 - 55 hrs• Later 5 - 26 hrs Later 5 - 26 hrs • Autoinduction plateaus in Autoinduction plateaus in 3 - 4 wks3 - 4 wks

Bioavailability:Bioavailability:• 75 - 85%75 - 85%• Not affected by foodNot affected by food

Protein binding:Protein binding:

• Carbamazepine: 74% (to Carbamazepine: 74% (to albumin and albumin and 11 acidacid-

glycoprotein)glycoprotein)

• 10,11-epoxide 10,11-epoxide metabolite: 55 - 65% metabolite: 55 - 65%



Metabolism:Metabolism:• Autoinduces its metabolismAutoinduces its metabolism• Extensive in liverExtensive in liver• Active metabolite: Active metabolite:

10, 11-epoxide 10, 11-epoxide • 10,11-epoxide10,11-epoxide

– T 1/2 5 - 8 hrsT 1/2 5 - 8 hrs– Metabolized to inactive Metabolized to inactive compoundscompounds


• 2% excreted unchanged2% excreted unchanged

• Metabolites excreted in Metabolites excreted in

urine (72%) and feces urine (72%) and feces

(28%)(28%)

• Urinary products made up Urinary products made up

of hydroxylated and of hydroxylated and

conjugated metabolitesconjugated metabolites



Renal impairment:• Protein binding altered with uremia• Metabolism prolonged• Excretion prolonged

Hepatic impairment:• protein binding altered with cirrhosis• metabolism altered




Cardiovascular: bradycardia, Cardiovascular: bradycardia, syncope, syncope, hypotension/hypertensionhypotension/hypertension

CNS: sedation, dizziness, CNS: sedation, dizziness, fatiguefatigue



Otic: tinnitusOtic: tinnitus


CYP2C8 and 3A3/4 enzyme CYP2C8 and 3A3/4 enzyme substrate, CYP1A2, 2C, and substrate, CYP1A2, 2C, and 3A3/4 inducer3A3/4 inducer


LamotrigineLamotrigine

• A phenyltriazineA phenyltriazine

Mode of action:Mode of action:• Acts on the sodium channel byActs on the sodium channel by

1. Suppressing sustained rapid firing of neuron 1. Suppressing sustained rapid firing of neuron

2. Producing a voltage- & use-dependent inactivation 2. Producing a voltage- & use-dependent inactivation of sodium channelsof sodium channels


Indications:• Initially evaluated as add-on therapy• May be effective as monotherapy for partial

seizures

Lamotrigine



Onset of action:Onset of action:• UnknownUnknown

Peak plasma levels:Peak plasma levels:• 2 - 4 hrs 2 - 4 hrs

Plasma T 1/2:Plasma T 1/2:• Monotherapy: 25 hrsMonotherapy: 25 hrs• + CBZ, PB & PHT: 12 hrs+ CBZ, PB & PHT: 12 hrs• + Valproic acid: 70 hrs+ Valproic acid: 70 hrs

Bioavailability:Bioavailability:• 98%98%• Food slows absorption of Food slows absorption of acid but no overall effect acid but no overall effect on extent of absorptionon extent of absorption




Metabolism:Metabolism:• Extensive hepatic Extensive hepatic metabolism via primary metabolism via primary glucoronidationglucoronidation• Primary metabolites Primary metabolites inactiveinactive• Influenced by concomitant Influenced by concomitant antiepilectic medicationsantiepilectic medications• Some autoinduction after Some autoinduction after prolonged treatment prolonged treatment (clearance increased 37% (clearance increased 37% and T 1/2 declines by 25%)and T 1/2 declines by 25%)

Excretion:Excretion:• 10% lamotrigine excreted 10% lamotrigine excreted unchanged in urineunchanged in urine• Remainder excreted in Remainder excreted in urine as glucoronide urine as glucoronide conjugateconjugate

Renal Impairment:Renal Impairment:• T 1/2 increasesT 1/2 increases

Hepatic Impairment:Hepatic Impairment:• Unknown but may be Unknown but may be significantsignificant




Cardiovascular: hot flashes, Cardiovascular: hot flashes, palpitationspalpitations

CNS: anxiety, confusion, CNS: anxiety, confusion, depression, insomniadepression, insomnia



respiratory: coughrespiratory: cough


• Carboxylic acidCarboxylic acid

• Broad spectrum of anti-epileptic activityBroad spectrum of anti-epileptic activity

Modes of action:Modes of action:• Blocks sustained high-frequency firing of Blocks sustained high-frequency firing of

neurons by blocking sodium channelsneurons by blocking sodium channels• Increases the levels of GABA in the brainIncreases the levels of GABA in the brain• Inhibits low threshold (T-type) CaInhibits low threshold (T-type) Ca+2 +2 channelschannels

Sodium valproateSodium valproate


Sodium valproateSodium valproate

Indications:Indications:• Absence Absence • Partial seizuresPartial seizures• Generalized tonic-clonic seizures Generalized tonic-clonic seizures • Myoclonic seizuresMyoclonic seizures


Valproic acid and Valproate sodiumValproic acid and Valproate sodium

Onset of action:Onset of action:• RapidRapid

Peak plasma levels:Peak plasma levels:• Acid: 1 - 3 hrs Acid: 1 - 3 hrs • Compound: 3 - 8 hrsCompound: 3 - 8 hrs• Valproate injection: 1 hrValproate injection: 1 hr


Bioavailability:Bioavailability:• 100%100%• food slows absorption of food slows absorption of acid but no overall effectacid but no overall effect• does not affect valproic does not affect valproic acid compoundacid compound



Valproic acid and Valproate sodiumValproic acid and Valproate sodiumMetabolism:Metabolism:• 20 - 40% converted to 20 - 40% converted to conjugate ester of conjugate ester of glucoronic acid in hepatic glucoronic acid in hepatic microsomesmicrosomes• Rest undergo Rest undergo mitochondrial or mitochondrial or peroxisomal peroxisomal -oxidative -oxidative metabolismmetabolism• Major metabolites: Major metabolites:

2-propyl-3-keto-pentanoic 2-propyl-3-keto-pentanoic acidacid2-propylhydroxypentanoic 2-propylhydroxypentanoic acidacid

Excretion:Excretion:• 2% valproate excreted 2% valproate excreted unchanged in urine & fecesunchanged in urine & feces• Primarily excreted in urine Primarily excreted in urine as biotransformed productsas biotransformed products

Renal Impairment:Renal Impairment:• No effectNo effect

Hepatic Impairment:Hepatic Impairment:• Protein binding, clearance, Protein binding, clearance, distribution, half-life altereddistribution, half-life altered


Valproic acid and Valproate sodiumValproic acid and Valproate sodium


Cardiovascular: tachycardia, Cardiovascular: tachycardia, hypertension, palpitationshypertension, palpitations

CNS: somnolence, insomnia, CNS: somnolence, insomnia, dizziness dizziness


GIT: diarrhea, nausea, GIT: diarrhea, nausea, vomitingvomiting

Hematologic: thrombocytopeniaHematologic: thrombocytopenia


CYP2C19 enzyme substrate, CYP2C19 enzyme substrate, CYP2C9 and 2D6 enzyme CYP2C9 and 2D6 enzyme inhibitorinhibitor


EthosuximideEthosuximide

• Derived from cyclic ureide structureDerived from cyclic ureide structure

Mode of action:Mode of action:• Inhibits low threshold calcium (T-type) Inhibits low threshold calcium (T-type)

currents in thalamic neuronscurrents in thalamic neurons

Indication:Indication:• Simple absence seizures (drug of choice)Simple absence seizures (drug of choice)



Onset of action:Onset of action:• IntermediateIntermediate


Plasma T 1/2:Plasma T 1/2:• Adults: 60 hrsAdults: 60 hrs• Children: 36 - 39 Children: 36 - 39 hrshrs

Protein binding:Protein binding:• 0%0%

Bioavailability:Bioavailability:• > 90%> 90%• Rapid GI absorptionRapid GI absorption• Food does not affect itFood does not affect it

Metabolism:Metabolism:• Extensive hepatic microsomalExtensive hepatic microsomal• Major metabolite: hydroxyl Major metabolite: hydroxyl derivativederivative• Others: hydroxylated compounds Others: hydroxylated compounds & products of secondary & products of secondary glucoronidationglucoronidation




• ~20% of parent ~20% of parent

compound excreted compound excreted

unchanged in urineunchanged in urine

• ~20% of hydroxylethyl- ~20% of hydroxylethyl-

derived metabolite derived metabolite

excreted in urine as excreted in urine as

inactive metabolite and inactive metabolite and

glucoronideglucoronide


• Clearance prolonged Clearance prolonged

with severe insufficiencywith severe insufficiency


• Severe hepatic disease Severe hepatic disease

may affect clearancemay affect clearance




CNS: somnolence, insomnia, CNS: somnolence, insomnia, dizziness dizziness


GIT: diarrhea, nausea, GIT: diarrhea, nausea, vomitingvomiting

Hematologic: thrombocytopeniaHematologic: thrombocytopenia


CYP3A3/4 enzyme substrate, CYP3A3/4 enzyme substrate, CYP3A3/4 enzyme inducerCYP3A3/4 enzyme inducer


Newer AEDsNewer AEDs

VigabatrinVigabatrinTiagabineTiagabineTopiramateTopiramateLevetiracetamLevetiracetamOxcarbazepineOxcarbazepine


VigabatrinVigabatrin

• A A -vinyl substituted analogue of GABA-vinyl substituted analogue of GABA• Adjunctive therapy for adults with complex partial Adjunctive therapy for adults with complex partial

seizuresseizures• Monotherapy, adjunctive therapy for infantile spasmsMonotherapy, adjunctive therapy for infantile spasms• Designed as an irreversible inhibitor of GABA-Designed as an irreversible inhibitor of GABA-

transaminasetransaminase• Minimal hepatic metabolismMinimal hepatic metabolism• > 70% renally excreted unchanged> 70% renally excreted unchanged


• An analogue of GABAAn analogue of GABA• Adjunctive therapy for partial onset seizuresAdjunctive therapy for partial onset seizures• Inhibits GABA uptakeInhibits GABA uptake• Binds selectively to one of four known molecular Binds selectively to one of four known molecular

subtypes of the GABA transportersubtypes of the GABA transporter• Enhances extracellular GABA concentrationEnhances extracellular GABA concentration• Hepatic metabolismHepatic metabolism

TiagabineTiagabine


TopiramateTopiramate

• Sulfamate-substituted monosaccharideSulfamate-substituted monosaccharide• Adjunctive therapy for adults and children with partial-Adjunctive therapy for adults and children with partial-

onset seizures or primary generalized tonic-clonic onset seizures or primary generalized tonic-clonic seizuresseizures

• Blockade of voltage gated sodium channelsBlockade of voltage gated sodium channels• Enhancement of effects of GABA at GABA-A Enhancement of effects of GABA at GABA-A

receptorreceptor• Antagonism of glutamate at AMPA-type glutamate Antagonism of glutamate at AMPA-type glutamate

receptor complexreceptor complex• 30% metabolized in the liver30% metabolized in the liver• 70% excreted unchanged in the urine70% excreted unchanged in the urine


LevetiracetamLevetiracetam

• Chemically unrelated to other antiepileptic drugsChemically unrelated to other antiepileptic drugs• Adjunctive treatment of adults with partial onset Adjunctive treatment of adults with partial onset

seizuresseizures• Mechanism of action is unknown*Mechanism of action is unknown*• Not extensively metabolizedNot extensively metabolized• Eliminated by renal excretion as unchanged drugEliminated by renal excretion as unchanged drug

*UCB Pharma CNS scientists have identified the binding site for *UCB Pharma CNS scientists have identified the binding site for Keppra (levetiracetam) in the brain as a synaptic vesicle protein Keppra (levetiracetam) in the brain as a synaptic vesicle protein called SV2A. This protein appears to play a substantial role in the called SV2A. This protein appears to play a substantial role in the release of neurotransmitters that are essential for normal neuronal release of neurotransmitters that are essential for normal neuronal activity in the brain and spinal cord. activity in the brain and spinal cord.


OxcarbazepineOxcarbazepine

• Structurally related to carbamazepineStructurally related to carbamazepine• Monotherapy or adjunctive therapy for partial Monotherapy or adjunctive therapy for partial

seizures in adults and childrenseizures in adults and children• Rapidly reduced to 10-monohydroxy metaboliteRapidly reduced to 10-monohydroxy metabolite• Blockade of voltage-gated sensitive sodium channelsBlockade of voltage-gated sensitive sodium channels• Hepatic metabolismHepatic metabolism• Metabolites excreted by the kidneysMetabolites excreted by the kidneys


Pharmacokinetics of antiepileptic drugsPharmacokinetics of antiepileptic drugsIn general:In general:• Usually administered orallyUsually administered orally• Absorption is reasonably rapid (Absorption is reasonably rapid (ie, several hours)ie, several hours)• >90% is absorbed>90% is absorbed• Variable degrees of protein bindingVariable degrees of protein binding• Distribute widely throughout the bodyDistribute widely throughout the body• Undergo primary metabolic degradation in the liver by Undergo primary metabolic degradation in the liver by

mixed function oxidases (hepatic P450)mixed function oxidases (hepatic P450)• Some have pharmacologically active metabolitesSome have pharmacologically active metabolites• Elimination can be modeled by first-order kineticsElimination can be modeled by first-order kinetics• Metabolic products are largely excreted in the urine, Metabolic products are largely excreted in the urine,

some unchangedsome unchanged


Mechanism of ActionMechanism of Action

+++Topiramate

++Tiagabine

++Vigabatrin

+++Diazepam

+++Phenobarbitone

++Ethosuximide

+++++Valproate

+++Lamotrigine

++Carbamazepine

++Phenytoin

GlutamateGABACa2+ Channel

T N, P/Q

Na+ Channel

DRUG


Common Adverse Effects of Antiepileptic Common Adverse Effects of Antiepileptic DrugsDrugs

•Neurologic toxicityNeurologic toxicity•Drowsiness, sedationDrowsiness, sedation•Cognitive impairment (memory, Cognitive impairment (memory, cognition)cognition)•Depression, mood changesDepression, mood changes•Irritability, hyperactivityIrritability, hyperactivity•Dizziness, vertigoDizziness, vertigo•DiplopiaDiplopia•InsomniaInsomnia•NystagmusNystagmus•AtaxiaAtaxia•TremorTremor•DysarthriaDysarthria•HeadacheHeadache•Dyskinesias, dystonia, Dyskinesias, dystonia, myoclonusmyoclonus

•Systemic ToxicitySystemic Toxicity•Gastrointestinal (dyspepsia, Gastrointestinal (dyspepsia, nausea, diarrhea)nausea, diarrhea)•Serum enzyme elevation, Serum enzyme elevation, benignbenign•Weight gainWeight gain•Leukopenia, benignLeukopenia, benign•Gingival hypertrophyGingival hypertrophy•AnorexiaAnorexia•Hair loss, alteration in textureHair loss, alteration in texture•HirsutismHirsutism•HyponatremiaHyponatremia•Coarsening of facial featuresCoarsening of facial features•ImpotenceImpotence•OsteopeniaOsteopenia•Renal stonesRenal stones


Idiosyncratic ReactionsIdiosyncratic Reactions

• RashRash• Stevens-Johnson SyndromeStevens-Johnson Syndrome• Aplastic AnemiaAplastic Anemia• Hepatic FailureHepatic Failure• Lupus-like SyndromeLupus-like Syndrome• PancreatitisPancreatitis


Anti-epileptic drug interactionsAnti-epileptic drug interactions

Change in steady-state plasma concentration of first(baseline) drug following of second drug

Added drugBase-linedrug

CBZ GBP LTG PB PHT VPA TPM

CBZ epoxide

GBP ? ?LTG ? ?PB to

PHT total free

VPATPM ? ? ? Inc dec no substantial effect variable inc/dec ?unk

Anti-Epileptic Drugs Pharmacodynamics and Pharmacokinetics of Anti-Epileptic Drugs Jose Paciano B.T....

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