Anti-epileptic drugs

- used as prophylactics
-most are analysed by Immunoassay or Chromatographic methods
- Measurement of the free or bound drug in a serum or plasma sample
-Total Drug concentration is usually measured for those with normal physiological state
- Free Drug Measurement may only be necessary when there is cause for alteration in patient plasma protein
*Pregnancy
*Liver or Kidney Dss
*Malnutrition
*Drug-drug interaction
-TDM indicated in initially establishing individual baseline concentrations at which the patient is responding well
-consistent sampling time
-preferred specimen: Trough serum concentration collected at the end of the dosing interval
Prevelant Neurological disorders: Epilepsy, convulsions, and seizures

FIRST GENERATION ANTI-EPILEPTIC DRUGS (AED)

Phenobarbital Phenytoin Valproic acid Carbamazepine Ethosuximide Felbamate

Importance slow acting barbiturate “ Dilantin” monotherapy to treat “Tegretol” “Zarotin” Indicated in severe
petit mal and absence epilepsies such as
Effective in treating Commonly used for seizures Effective treatment for Controlling petit mal Lennox-Gastaut
seizures seizures and as short seizures seizures Syndrome and
term prophylactic refractory epilepsy
agent Highly toxic, less used

Route of Oral adm.,., slow but Oral adm.,., Oral adm.,., rapid and Oral adm., Oral adm., Oral adm.,,
administration complete absorption incomplete absorption complete absorption complete
absorption

therapeutic 1-2 ug/ml (free) 50-120 ug/ml 4-12 ug/ml 40-100 ug/ml 30-60 ug/ml
range
10-20 g/ml (total)

major toxicities depression, fatigue, initiation of seizures hepatic dysfxn (in leukopenia, febrile rxn, aplastic anemia
reduced mental therapeutic conc.) rashes and hepatic failure
capacity Vitamin D def.,
hirsutism, hyperplasia Pancreatitis, Mild transient liver
hyperammonemia (high dysfxn
serum level)
hematologic dyscrasia
Nausea, lethargy, weight and aplastic anemia
gain (common ) ( conc . >15)

half life 70-100 hrs 14-22 hrs

(In renal failure =
27-34 hr)

peak/trough peak serum is reached dose dependent

serum in 10hrs
concentration

% serum 50% 87-97% 93% 70-80% 30%

protein binding

Tests Total potential amount Peak levels are Determination of free

of phenobarbital; evaluated after the fraction
trough levels are conversion of
usually evaluated Fosphenytoin

route of hepatic mixed hepatic metabolism hepatic metabolism hepatic metabolism renal and hepatic
elimination function oxidase (zero order kinetics) metabolism
system

OTHERS primidone- inactive fosphenytoin- inactive inhibited by Felbamate enhanced by:

form form (75 minutes to primidone,
Induction period- 10- convert into active phenytoin,
15 days form) carbamazepine

Kaori Sembrano ‘17||1

 Gabapentin Lamotrigine Levetiracetam Oxcarbazepine Tiagabine Zonisamide Topiramate

Importance monotherapy for indicated with indicated in partial A Prodrug treating partial therapy for partial for partial and
complex partial partial and and generalized seizures and generalized generalized
seizures with/or generalized seizures Metabolized, active seizures seizures
generalized seizures form =
seizures Licarbazepine Accumulates in the
erythrocytes
most likely Monotherapy of
treatment partial seizures and
consideration in 2* tonic-clonic
patients with seizures
Liver dss and
partial-onset
seuizures with
acute
intermittent
porphyria

route of Oral adm., Oral adm.,., rapid Oral adm.,., entirely Oral adm.,., Oral adm.,., Oral adm.,., Oral adm.,.,
administratio and complete bioavailable rapid and
n absorption complete
absorption

therapeutic 12-20 ug/ml 2.5-15 ug/ml 8-26 ug/ml licabazepine= 12-35 20-100 ug/ml 10-38 ug/ml
range ug/ml

major Kidney CNS: CNS, parasthesia

toxicities impairment paraesthesia,
mild sedation,
confusion

half life 5-9 hrs (linear 15-30 hrs 6-8 hrs 8-10 hrs 4-13 hrs 50-70 hrs 20-30 hrs
increase) (30% decrease in the (prolonged in (in monotherapy)
(With valproic elderly) Hepatic
(Children needs acid= 60 hrs) dysfunction) (Reduced to 25-35
30% more dose hrs if added with
to attain the half- other AEDs)
life)

peak/trough -low level trough peak conc.: 8 hrs peak conc.: peak conc. at 4-7 peak conc at 1-4
serum conc. concentrations 0.5-2 hrs hrs hrs
lead to
breakthrough
seizures

% serum Does not bind 55% Does not bind with 40% 96% 60% 15%
protein with serum serum CHON
binding CHON

route of renal clearance hepatic metabolism glomerular filtration Hepatic metabolism.: hepatic mixed hepatic met: renal filtration
elimination (unchanged (dependent on Age, rate/ renal clearance Keto reduction and function Glucuronide (remainder is
drug) Physiologic Glucuronide oxidase Conjugation, eliminated in
Condition, conjugation system/pathwa Acetylation, hepatic
Pregnancy At 32 y (MFO) Oxidation and metabolism)
Weeks And Renal excretion
Recognized
Enzyme-Inducing
AEDs)

OTHERS bioavailability of enzyme-inducing Rate of clearance licarbazepine is ratio of free to Absorbed by GIT/ use of Dose
60% (reduced if AEDs: correlates well with sensitive to Phenytoin bound drug is bioavailable 65% titration to
administered phenobarbital, glomerular filtration and. Phenobarbital affected by: or higher balance
with Antacids) phenytoin, Rate= use in valproic acid, therapeutic effect
carbamazepine monitoring patients TDM is indicated: naproxen, TDM is indicated
multiple daily with -steady state is salicylates and to establish a TDM is indicated
doses- preferred Inhibited by: renal impairment established pregnancy baseline level, to if:
regimen: Valproic acid -therapeutic failure detect drug-drug -steady state is
- Excessively Lacks -drug – drug Dose Titration interactions and established
high blood TDM is needed Pharmacokinetic interactions is used in therapeutic failure -there is
concentrations because of the variability, hence -pregnancy balancing therapeutic
lead to toxic drug-drug cannot est. TDM therapeutic failure
effects interactions effects with -drug – drug
adverse CNS interactions
side-effects

Kaori Sembrano ‘17||2