ANTICONVULSANTS

BY
DR. UMARUDEEN AJIBOLA M.
DEPT. OF PHARMACOLOGY, CHS, UNIABUJA
ANTICONULSANTS: DEFN.

 Chemical compds capable of:

preventing/reducing/Stopping/arr
esting seizures
What is a seizure/convulsion?

 Seizure = convulsion

 Convulsion: result of abnormal bursts of

electrical discharges of brain neurons

 Recurrent/chronic seizures = Epilepsies

Seizure/Epilepsy

 Partial – localized seizure foci/one

hemisphere
- consciousness preserved

 Generalized - Seizure foci multiple/ both

hemispheres/loss of
consciousness
Seizure mech./epileptogenesis
 Loss of balance bt. excitatory & inhibitory
brain neuronal electrical discharges

 Excessive glutamate-mediated neuronal

excitation

 Loss of GABA-A-mediated neuronal inhibition

Causes of seizures/Epilepsies
 Idiopathic
 Infections e.g. meningitis
 Hereditary factors e.g. dominant gene defects
 Head injuries
 Cerebral tumours
 Metab. Dxs e.g. hypoglycemia, hypocalcemia
 Degenerative diseases
Partial seizure classification:
 Simple partial seizures – seizure foci localized
to a brain portion; consciousness preserved
 Complex partial seizures – seizure foci more

generalized; involves limbic system and

temporal lobe; consciousness impaired
 Partial seizures secondarily generalized –

seizure foci localized initially and become

generalized subsequently –even may involve
both hemispheres; consciousness impaired
Generalized seizures

 Generalized tonic-clonic (grand mal) seizures

– tonic-clonic jerks
 Absence (petit mal) seizures – no jerks but

zoning or passing out

 Tonic seizures – sustained muscular

contraction
 Atonic seizures – atonic muscular paralysis
 Clonic and myoclonic seizures
 Infantile spasms
Therapeutic essence of seizure
classification:
 Petil mal or absence seizures respond well to
ethosuximide & valproate but exacerbated by
phenytoin and carbamazepine.

 In contrast, generalized tonic-clonic seizures

and complex partial seizures respond well to
phenytoin, carbamazepine, and lamotrigine
MECHANISMS OF ACTION OF ANTICONVULSANT
DRUGS

 ↑ of GABAergic (↓) brain ↓neuronal electrical

transmission
 ↓ of glutamate-mediated excitatory brain

neuronal electrical transmission

 Modulation of ionic conductance of the brain

neurons
 Pre-synaptic modulation of transmitter

release
Chemistry of Anti-seizure Drugs

 Anticonvulsant drugs: sev. chemical classes

 For many of these drugs: strong SAR

 Most of anticonvulsants: apolar in nature

Chemical classes of anticonvulsants
 Barbiturates e.g. Phenobarbital
 Hydantoins e.g. Phenytoin
 Bromides e.g. Potassium bromide
 Fatty acids e.g. Valproic acid, Sodium

valproate. Tiagabine
 Benzodiazepine e.g. diazepam, clobasam,

clonazepam, lorazepam
Chemical classes of anticonvulsants
 GABA analogs e.g. Gabapentin
 Fructose derivatives e.g. Topiramate
 Pryrimidinediones e.g. Primidone
 Oxazolidinediones e.g. Ethadione
 Carboxamides e.g. carbamazepine,

oxcarbazepine
 Succinimides e.g. ethosuximide
 Aromatic allylic alcohols e.g. Stiripentol
Chemical classes of anticonvulsants
 Carbamates e.g. Felbamate
 Propiionates e.g. Beclamide
 Aldehydes e.g. Paraldehyde
 Sulfonamides e.g. Acetazolamide
 Triazines e.g. lamotrigine
 Ureas e.g. Pheturide
 Pyrrolidines e.g Levetiracetam
Pharmacokinetics of Anticonvulsant
drugs
 P/kinetics according to chemistry
 Mostly apolar /limited water solubility
 Most readily absorbed across cell membranes
 High oral bio-availability
 Most of anti-seizure drugs not protein-

bound
 Except phenytoin/tiagabine/valproic acid
 Most liver-metabolized/cleared
INDIVIDUAL DRUGS: PHENYTOIN

 Phenytoin: A diphenylhydantoin
 Phenytoin: prototype of the grp.
 Other hydantoin derivatives: fosphenytoin,

mephenytoin, ethotoin & phenacemide

 Marktd. as Eptoin/Phenytek/ Dilantin
 Avail. as oral and IV formulations
Pharmacokinetics of Pheytoin

 Good GIT absorp. c ≈ 100% bio-availabilty

 Peak plasma levels from oral dose at 3-

12hours
 IM Absorption unpredictable/IM precipitation
 IM route not recommended for phenytoin
 In contrast, fosphenytoin good IM absorption
 Phenytoin: high plasma protein binding
 Plasma levels ↓ c uremia/ hypoalbuminemia
 Drug CSF levels = free plasma level
 Phenytoin accumul. in brain/liver/muscle/fat
Pharmacokinetics of Pheytoin

 Inactive metabolites excreted in the urine

 Only a very small proportion of dose excreted unchanged
 Elimin. dose-dependent
 At very low blood levels, elimin. 1st order kinetics
 High plasma levels: zero order kinetics & t1/2 ↑
 Toxicity risks
 Normal t1/2 from 12 to 36 hours
 At low blood levels, it takes 5–7 days to reach steady-
state
 At higher levels: 4–6 weeks before blood levels are
stable
Mechanism of Action of Phenytoin:

 ↓ of high-frequency firing of neurons through

action on voltage-gated (VG) Na+ channels

 ↓ of synaptic release of excitatory glutamate

neurotransmitter
Clinical Uses of Phenytoin:

 Partial seizures / generalized tonic-clonic

seizures (pry or 2ndary to another seizure
type)
 Focal seizures - Mainly used to protect against

the development of focal seizures with

complex symptomatology (psychomotor
and temporal lobe seizures)
 Also effective in controlling partial seizures

with autonomic symptoms

 Used as prevention and Rx of seizures

occurring during/after neurosurgery

Clinical Uses of Phenytoin:

 Status epilepticus - Considered after failed

treatment using a benzodiazepine due to slow onset
of action
 Abnormal heart rhythms- may be used in the Rx
of ventricular tachycardia and sudden episodes
of atrial tachycardia after other antiarrhythmic
medications or cardioversion has failed. It is a class
1b antiarrhythmic
 Digoxin toxicity - IV phenytoin is drug of choice for
arrhythmias caused by cardiac glycoside toxicity
 Trigeminal neuralgia - 2nd choice drug to
carbamazepine
Therapeutic Levels & Dosage of Phenytoin:

 The therapeutic plasma level of phenytoin for most

patients is between 10 and 20 mcg/mL. A loading
dose can be given either orally or intravenously; the
latter, using fosphenytoin, is the method of choice for
convulsive status epilepticus.
When oral therapy is started, it is common to
begin adults at a dosage of 300 mg/d, regardless of
body weight. This may be acceptable in some
patients, but it frequently yields steady-state blood
levels below 10 mcg/mL, which is the minimum
therapeutic level for most patients. If seizures
continue, higher doses are usually necessary to
achieve plasma levels in the upper therapeutic range.
 Therapeutic Levels & Dosage of Phenytoin:

 Because of its dose-dependent kinetics, some toxicity

may occur with only small increments in dosage. The
phenytoin dosage should be increased each time by only
25–30 mg in adults, and ample time should be allowed
for the new steady state to be achieved before further
increasing the dosage. A common clinical error is to
increase the dosage directly from 300 mg/d to 400
mg/d; toxicity frequently occurs at a variable time
thereafter. In children, a dosage of 5 mg/kg/d should be
followed by readjustment after steady-state plasma levels
are obtained.
 Fosphenytoin sodium is available for IV or IM use and
replaces iv phenytoin sodium, a much less soluble form
of the drug.
Drug-drug Interactions & Interference
with Laboratory Tests of Phenytoin
 Adverse drug interactions prily due to protein binding or
to metabolism
 Since phenytoin is 90% bound to plasma proteins, other
highly bound drugs, such as phenylbutazone and
sulfonamides, can displace phenytoin from its binding site
 A decrease in protein binding—eg, from hypoalbuminemia
— results in a decrease in the total plasma concentration
of drug but not the free concentration. Intoxication may
occur if efforts are made to maintain total drug levels in
the therapeutic range by increasing the dose
 Phenytoin Protein binding ↓ in renal disease
Drug-drug Interactions & Interference
with Laboratory Tests of Phenytoin
 The drug has an affinity for thyroid-binding
globulin, which confuses some tests of
thyroid function; the most reliable screening
test of thyroid function in patients taking
phenytoin appears to be measurement of
thyroid stimulating hormone (TSH)
 Phenytoin has been shown to induce

microsomal enzymes responsible for the

metabolism of a number of drugs. Auto
stimulation of its own metabolism, however,
appears to be insignificant
 Phenytoin Toxicity:

 Nystagmus occurs early, as does loss of smooth

extraocular pursuit movements, but neither is an
indication for decreasing the dose.
 Diplopia and ataxia are the most common dose-
related adverse effects requiring dosage
adjustment
 Sedation occurs only at considerably higher
levels.
 Gingival hyperplasia
 Hirsutism
Phenytoin Toxicity:

 Mild peripheral neuropathy

 Vitamin D metabolism, leading to

osteomalacia.
 Low folate levels and megaloblastic anemia
 Fever
 Lymphadenopathy
 Agranulocytosis
CARBAMAZEPINE

 Carbamazepine, oxycarbazepine &

eslicarbazine
 Tricyclic carboxamide derivatives
 Structurally similar to imipramine and

phenytoin
 Oxycarbazepine & eslicarbazine are prodrugs

with mech. of action, activity spectrums and

p/kinetic profiles similar to carbamazepine
Phenytoin pharmacokinetics:

 Absorp. varies among pts, almost complete

absorp. in all pts
 Peak levels 6–8 hours after administration
 Slowing absorp. by giving the drug after meals

helps pt tolerate larger total daily doses.

 Slow distrib. & vol. of distri. ≈ 1 L/kg
 ≈ 70% protein bound but no displacement of

other drugs from protein binding sites

 Very low systemic clearance of ≈ 1 L/kg/d at

the start of therapy

Carbamazepine pharmacokinetics:

 Sig. ability to induce microsomal enzymes

 Typically, the half-life of 36 hours observed in
subjects after an initial single dose decreases to
as little as 8–12 hours in subjects receiving
continuous therapy.
 Carbamazepine also alters the clearance of
other drugs
 Carbamazepine is completely metabolized in
humans to several derivatives
 One of these, carbamazepine-10, 11-epoxide,
has been shown to have anticonvulsant activity
Mechanism of Action of
carbamazepine:
 ↓ Na + channels at therapeutic conc.
 ↓ of high-frequency repetitive firing in brain

neurons
 pre-synaptically decreasing synaptic

transmission across brain neurons

 potentiation of a voltage-gated K + current in

brain neurons
Clinical Uses of Carbamzepine:

 Partial seizures
 Generalized tonic-clonic seizures
 Trigeminal neuralgia – carbamazepine is drug

of first choice,
 Mania in bipolar disorder – Carbamazepine

also useful
Therapeutic Levels & Dosage of
Carbamazepine:
 Carbamazepine is available only in oral form
 Effective in children: dosage of 15–25 mg/kg/d is appropriate.
 In adults, daily doses of 1 g or even 2 g are tolerated

 Higher dosage achieved by giving multiple divided doses daily.

Extended release preparations permit bid dosing for most pts

 In patients in whom the blood is drawn just before the morning

dose (trough level), the therapeutic level is usually 4–8 mcg/mL.

 Although many patients complain of diplopia at drug levels

above 7 mcg/mL, others can tolerate levels above 10 mcg/mL,
especially with monotherapy. Extended-release formulations
that overcome some of these issues are now available
Adverse drug Interactions of
Carbamazepine:
 These are majorly related to the drug’s enzyme-inducing
properties. As noted previously, the increased metabolic capacity
of the hepatic enzymes may cause a reduction in steady-state
carbamazepine concentrations and an increased rate of
metabolism of other drugs, eg, primidone, phenytoin,
ethosuximide, valproic acid, and clonazepam

 Other drugs such as valproic acid may inhibit carbamazepine

clearance and increase steady-state carbamazepine blood levels

 Other anticonvulsants, however, such as phenytoin and

phenobarbital, may decrease steady-state concentrations of
carbamazepine through enzyme induction.
No clinically significant protein-
binding interactions have been reported
Carbamazepone Toxicity:

 Diplopia /ataxia. The diplopia often occurs first and

may last less than an hour during a particular time of
day. Rearrangement of the divided daily dose can
often remedy this complaint.
 Mild GIT upset
 Unsteady gait
 Drowsiness
 Hyponatremia and water intoxication
 Idiosyncratic blood dyscrasias: erythrmatous skin
rash, leucopenia and fatal cases of aplastic anemia
and agranulocytosis
 Hepatic dysfunction
PHENOBARBITAL
(PHENOBARBITONE )
Phenobarbital, mephobarbital, metharbital, and
primidone are barbituric acid derivatives
 Phenobarbital – the prototype of the barbiturates

is one of the oldest clinical anticonvulsant drugs

still in use in modern medicine
 However, the sedative side effect of the

barbiturates has relegated its anticonvulsant

usage to the background by newer less sedative
anticonvulsant drugs
 Used as drugs of choice for seizures only in

infants
Pharmacokinetics of Phenobarbital:

 Oral bioavailability of about 90%

 Peak plasma conc. 8 to 12 hours after oral

dose
 One of the longest-acting barbiturates

available
 T1/2 2-7 DAYS
 Very low protein binding(20 to 45%)
 Hepatic metab.
 Induces Cytochrome P450 2B6
 Excreted primarily by the kidneys
Mechanism of Action of
Phenobarbital:
 The exact mechanism of action of
phenobarbital is unknown

 But enhancement of phasic GABAA receptor

responses

 Inhibition of glutamate-mediated excitatory

synaptic responses of the brain neurons
Clinical Uses of Phenobarbital:

 Partial seizures

 Generalized tonic-clonic seizures

 Resistant seizures of any type

Therapeutic Levels, & Dosage:
 Therap. levels in most pts range from 10
mcg/mL to 40 mcg/mL effective for febrile
seizures
 Levels below 15 mcg/mL appear ineffective

for prevention of febrile seizure recurrence

 Upper end of therap. range difficult to define

because many pts tolerate chronic levels

above 40 mcg/mL
Adverse effects of Phenobarbital:

 Sedation and hypnosis -principal side effects

 CNS effects e.g.

izziness, nystagmusand ataxia
Adverse drug-drug interactions:
 Phenobarbital is a Cytochrome P450 hepatic
enzyme inducer
 Drugs that are metabolized by the CYP450

enzyme system will decrease effectiveness

because of faster clearance from the syste.
 Caution is to be used with children on

anticonvulsant drugs: behavioural

disturbances occur most frequently
with clonazepam and phenobarbital
Contra-indications to Phenobabital use:

 Acute intermittent porphyria

 Hypersensitivity to any barbiturate
 Prior dependence on barbiturates
 Severe respiratory insufficiency
 Hyperkinesia in children
PRIMIDONE:

 Another barbiturate anticonulsant

 A pro-drug metab. to phenobarbital &

phenylethylmalonamide (PEMA)

 Both of which are anticonulsants

Pharmacokinetics of Primidone:
 Primidone is completely absorbed, usually reaching peak
concentrations about 3 hours after oral administration, although
considerable variation has been reported

 Primidone is generally distributed in total body water, with a

volume of distribution of 0.6 L/kg. It is not highly bound to
plasma proteins; approximately 70% circulates as unbound drug.

 Primidone is metabolized by oxidation to phenobarbital, which

accumulates very slowly, and by scission of the heterocyclic ring
to form PEMA

 Both primidone and Phenobarbital also undergo subsequent

conjugation and excretion.
Pharmacokinetics of Primidone:
 Primidone has a larger clearance than most other antiseizure
drugs (2 L/kg/d), corresponding to a half-life of 6–8 hours

 PEMA clearance is approximately half that of primidone, but

phenobarbital has a very low clearance. The appearance of
phenobarbital corresponds to the disappearance of
primidone. Phenobarbital therefore accumulates very slowly
but eventually reaches therapeutic concentrations in most
patients when therapeutic doses of primidone are
administered.

 During chronic therapy, phenobarbital levels derived from

primidone are usually two to three times higher than
primidone levels
Mechanism of Action:

 Although primidone is converted to

phenobarbital, it exhibits phenytoin-like
mechanism of anticovuksant effect.
Clinical Uses of Primidone and
metabolites:
 Partial seizures

 Generalized tonic-clonic seizures and may be

more effective than phenobarbital

 Complex partial seizures – primidone may be

used after carbamazepine and phenytoin
Therapeutic Levels & Dosage
 Most effic. when plasma levels - 8–12 mcg/mL
 Concomitant levels of its metabolite, phenobarbital, at
steady state usually vary from 15 to 30 mcg/mL
 Dosages of 10–20 mg/kg/d neces. to obtain these
levels
 Very important to start primidone at low doses and
gradually increase over days to a few weeks to avoid
prominent sedation and gastrointestinal complaints
 When adjusting doses of the drug, it is important to
remember that the parent drug reaches steady state
rapidly (30–40 hours), but the active metabolites
phenobarbital (20 days) and PEMA (3–4 days) reach
steady state much more slowly
Primidone Toxicity

 Dose-related primidone toxicities similar to

those of its metabolite, phenobarbital, except
that drowsiness occurs early in treatment and
may be prominent if the initial dose is too
large
 Gradual increments are indicated when

starting the drug in either children or adults

GABAPENTIN AND PREGABALIN

 GABA analogs effective

against partial seizures
Pharmacokinetics of Gabapentin and Pregabalin:

 Gabapentin not metab./not induce hepatic

enzymes
 Absorp. non-linear/dose-dependent at very

high doses
 But linear elimin. Kinetics
 Not bound to plasma protein
 Drug-drug interactions negligible
 Elimin. Renal & excreted unchanged
 Half-life is 5 to 8 hours; the drug is

administered two or three times per day

Pharmacokinetics of Pregabalin
 Pregabalin, like gabapentin, not metabolized &
almost entirely excreted unchanged in the
urine
 Not protein bound & virtually no drug-drug

interactions, again resembling the

characteristics of gabapentin
 Likewise, other drugs do not affect the

pharmacokinetics of pregabalin
 Half-life of pregabalin is 4.5 hours to 7.0

hours, thus requiring more than once-daily

dosing in most patients
Mechanism of Action of Gabapentin
and Pregabalin:
 In spite of their close structural resemblance to GABA,
gabapentin and pregabalin do not act directly on GABA
receptors
 May, however, modify the synaptic or nonsynaptic release
of GABA. An increase in brain GABA concentration is
observed in patients receiving gabapentin. Gabapentin is
transported into the brain by the L -amino acid transporter
 Gabapentin and pregabalin bind avidly to the α2 subunit of
voltage-gated Ca2+ channels. This appears to underlie the
main mechanism of action, which is decreasing Ca2+
entry, with a predominant effect on presynaptic N-type
channels. A decrease in the synaptic release of glutamate
provides the antiepileptic effect.
Clinical Uses of Gabapentin and Pregabalin:

 Gabapentin is effective as:

 An adjunct against partial seizures and

generalized tonic-clonic seizures

 Gabapentin is now indicated for postherpetic

neuralgia in adults at doses of 1800mg


Pregabalin is used as:

 Adjunctive treatment of partialseizures,

 Painful diabetic peripheral neuropathy and

postherpetic neuralgia
 Fibromyalgia
 Generalized anxiety disorder.
Adverse effects of gabapentin and
Pregabalin:
 Somnolence
 Dizziness
 Ataxia
 Headache
 Tremor
LAMOTRIGINE
 Marketed as Lamictal

 A phenyltriazine derivative unrelated

chemically with any other class of
anticonvulsants

 Exhibits weak anti-folate property..

Therapeutic dosage &
Pharmacokinetics of lamotrigine:
 Almost completely absorbed
 Vol. of distr. of 1–1.4 L/kg
 ≈ 55% Protein binding
 Linear kinetics & met.d prily by glucuronidation to the 2- N
-glucuronide, which is excreted in the urine
 Half-life of ≈ 24 hours: this decreases to 13–15 hours in
patients taking enzyme-inducing drugs
 Effective against partial seizures in adults at 100 and 300
mg/d and with a therapeutic blood level near 3 mcg/mL
 Valproate causes a twofold increase in the drug’s half-life;
in patients receiving valproate, the initial dosage of
lamotrigine must be reduced to 25 mg every other day
Mechanism of Action of lamotrigine:
 Inhibition of sustained rapid firing of neurons
via a voltage- and use-dependent blockade
of Na+ channels
 Inhibition of voltage-gated Ca 2+ channels,

particularly the N- and P/Q-type channels,

 Inhibition of the synaptic release of glutamate
Clinical Uses of lamotrigine:

 Lamotrigine is effective in:

 Partial seizures
 Absence and myoclonic seizures in children
 Seizure controlin the Lennox-Gastaut

syndrome
 Bipolar disorder


Adverse effects of lamotrigine:

 Dizziness, headache
 Diplopia
 Nausea
 Somnolence
 Skin rash
LEVETIRACETAM

 Levetiracetam is a piracetam analog

 Ineffective against seizures induced by
maximum electroshock or pentylenetetrazol but
has prominent activity in the kindling model
 First major drug with this unusual preclinical
profile that is effective against partial seizures
 Oral formulations include extended release
tablets
 An IV preparation also available
Pharmacokinetics of Levetiracetam

 Oral absorption of levetiracetam is nearly

complete
 Absorp. Rapid/ unaffected by food
 Peak plasma concentrations in 1.3 hours
 Kinetics are linear
 Protein binding is less than 10%
 Half-life is 6–8 hours, but may be longer in the
elderly
 Two thirds of the drug excreted unchanged in
urine
 Drug has no known active metabolites
Mechanism of Action of Levetiracetam

 Binds selectively to the synaptic vesicular

protein SV2A. The function of this protein is
not understood but it is likely that
levetiracetam modifies the synaptic release of
glutamate and GABA through an action on
vesicular function
Clinical Uses of levetiracetam:

 Adjunctive treatment of partial seizures in

adults
 Primary generalized tonic-clonic in children

seizures
 Myoclonic seizures of juvenile myoclonic

epilepsy

Therapeutic dosage of levetiracetam:
 Adult dosing can begin with 500 or 1000
mg/d

 The dosage can be increased every 2–4

weeks by 1000 mg to a maximum dosage of
3000 mg/d

 The drug is dosed twice daily

Adverse effects of levetiracetam:

 Somnolence
 Asthenia
 Ataxia
 Dizziness
 Psychotic reactions
TOPIRAMATE

 A substituted monosaccharide

 Structurally different from all other anti-

seizure drugs
Pharmacokinetics of Topiramate:
 Rapidly absorbed within 2 hours and i80%
bioavailable.
 No food effect on absorption/15% plasma
protein binding
 20–50% metabolism
 No active metabolites formed
 Drug is pryly excreted unchanged in urine
 Half-life is 20–30 hours
 Birth control pills may be less effective in the
presence of topiramate, and higher estrogen
doses may be required
Mechanism of Action of Topiramate
 blockade of voltage-gated Na+ channels
 ↓ of high-voltage activated (L-type) Ca2+
channels
 Potentiation of the inhibitory effect of GABA, at a
site different from benzodiazepine or barbiturate
sites
 Depression of the excitatory action of kainate on
glutamate receptors
 Multiple effects of topiramate may arise through a
pry action on kinases altering the phosphorylation
of voltage-gated and ligand-gated ion channels
Clinical Uses of Topiramate:

 Partial and generalized tonic-clonic seizures

 Lennox-Gastaut syndrome

 Infantile spasms and even absence seizures

 Migraine headaches.
Therapeutic dosages of Topiramate
 Dosages typically range from 200 to 600
mg/d, with a few patients tolerating dosages
higher than 1000 mg/d
 Most clinicians begin at a low dose (50 mg/d)

and increase slowly to prevent adverse effects

 Several studies have used topiramate in

monotherapy with encouraging results.

Adverse effects of Topiramate:
 Somnolence
 Fatigue
 Dizziness
 Cognitive slowing
 Paresthesias
 Nervousness
 Confusion
 Acute myopia and glaucoma
 Urolithiasis
 Teratogenic potential
VIGABATRIN
 Vigabatrin is a novel anticonvulsant drug
novel molecular targets for therapeutic
efficacy:
 GABA agonists and prodrugs
 GABA transaminase inhibitors
 GABA uptake inhibitors
Mechanism of Action of Vigabatrin:

 Vigabatrin is an irreversible inhibitor of GABA

aminotransferase (GABA-T), the enzyme responsible
for the degradation of GABA
 It may also inhibit the vesicular GABA transporter
 Vigabatrin produces a sustained increase in the
extracellular concentration of GABA in the brain.
This leads to some desensitization of synaptic
GABAA receptors but prolonged activation of
nonsynaptic GABAA receptors that provide tonic
inhibition. A decrease in brain glutamine synthetase
activity is probably secondary to the increased GABA
concentrations
Clinical Uses of Vigabatrin:

 Rx of partial seizures

 Infantile Spasms (resistant form only)

Therapeutic dosages and
Pharmacokinetics of Vigabatrin:
 The half-life is approximately 6–8 hours, but
considerable evidence suggests that the
pharmacodynamic activity of the drug is more
prolonged and not well correlated with the
plasma half-life.
 In infants, the dosage is 50–150 mg/d. In
adults, vigabatrin should be started at an oral
dosage of 500 mg twice daily; a total of 2–3 g
(rarely more) daily may be required for full
effectiveness.

Adverse effects of Vigabatrin:
 Drowsiness
 Dizziness
 Weight gain
 Agitation
 Confusion
 Psychosis; preexisting mental illness is a relative
contraindication. The drug was delayed in its worldwide
introduction by the appearance in rats and dogs of a
reversible intramyelinic edema. This phenomenon has
now been detected in infants taking the drug; the clinical
significance is unknown
 Peripheral visual field defects in 30–50% of long term
patients
ETHOSUXIMIDE

 Ethosuximide, phensuximide, and

methsuximide: succinimides derivatives

 Basic cyclic ureide structure

 Ethosuximide is 2-ethyl-2-
methylsuccinimide.
Pharmacokinetics of Ethosuximide:
 Absorp.complete ff. oral dosage forms
 Peak levels 3–7 hours after oral capsules
 Ethosuximide not protein-bound
 Drug hydroxylated to inactive metabolites

Ethosuximide has a very low total body

clearance (0.25 L/kg/d)
 Half-life of approximately 40 hour
Mechanism of Action of
Ethosuximide:
 The anti-absence attack effect of
ethosuximide is achieved by:
 Inhibition of the T-type Ca2+ currents are

thought to provide a pacemaker current in

thalamic neurons responsible for generating
the rhythmic cortical discharge of an absence
attack
 Inhibition of inwardly rectifying K+ channels
Clinical Uses of Ethosuximide:

Particularly
effective
against absence
seizures
Therapeutic Levels & Dosage of
Ethosuximide:
 Therapeutic levels of 60–100 mcg/mL can be
achieved in adults with dosages of 750–1500
mg/d, although lower or higher dosages and
blood levels (up to 125 mcg/mL) may be
necessary and tolerated in some patients
 Ethosuximide has a linear relationship

between dose and steady-state plasma levels.

The drug might be administered as a single
daily dose were it not for its adverse
gastrointestinal effects; twice-a-day dosage
is common
 Drug Interactions & Toxicity of
Ethosuximide:
 Administration of ethosuximide with valproic
acid results in a decrease in ethosuximide
clearance and higher steady-state
concentrations owing to inhibition of
metabolism

 No other important drug interactions have

been reported for the succinimides.
Adverse effects of Ethosuximide:
 Gastric distress - pain, nausea, and vomiting
 Transient lethargy or fatigue
 Headache
 Dizziness
 Hiccup
 Euphoria
VALPROIC ACID & SODIUM
VALPROATE:
 The anti-seizure property of sodium valproate and valproic acid
was discovered serendipitously when they were used as solvents
for other drugs in the search for therapeutic agents effective
against seizures.

 Valproic acid is fully ionized at body pH, and for that reason the
active form of the drug may be assumed to be the valproate ion
regardless of whether valproic acid or a salt of the acid is
administered.
 Valproic acid is one of a series of fatty carboxylic acids that have
antiseizure activity; this activity appears to be greatest for
carbon chain lengths of five to eight atoms. The amides and
esters of valproic acid are also active antiseizure agents.

 It is available as oral syrups and capsules and IV formulation

Pharmacokinetics of Valproic acid:
 Valproate is well absorbed after an oral dose, with bioavailability
greater than 80%. Peak blood levels are observed within 2 hours.
 Food may delay absorption, and decreased toxicity may result if the
drug is given after meals.
 Valproic acid is 90% bound to plasma proteins, although the fraction
bound is somewhat reduced at blood levels greater than 150
mcg/mL. Since valproate is both
highly ionized and highly proteinbound, its distribution is essentially
confined to extracellular water with a volume of distribution of
approximately 0.15 L/kg. At higher doses, there is an increased free
fraction of valproate, resulting in
 lower total drug levels than expected. It may be clinically useful,
therefore, to measure both total and free drug levels.
Clearance for valproate is low and dose
dependent; its half-life varies from 9 to 18 hours. Approximately 20%
of the drug is excreted as a direct conjugate of valproate.
Mechanism of Action of Valproic
acid:

 Inhibition of Na + currents
 Blockade of NMDA receptor-mediated

excitation
 Inhibition of the GABA transporter GAT-1
 Inhibition of GABA transaminase and thus

blockade of degradation of GABAin the brain

 Clinical Uses of Valproic acid:

 Very effective against absence seizures

 Absence seizures with concomitant generalized
tonic-clonic attacks: preferred to ethosuximide
 Certain types of myoclonic seizures
 Effective in tonic-clonic seizures, especially those
that are primarily generalized
 Atonic attacks may also respond
 Partial seizures
 Status epilepticus: IV formulation
 Bipolar disorder
 Migraine prophylaxis
Therapeutic dosages of valproic
acid:

 Dosages of 25–30 mg/kg/d may be adequate

in some patients, but others may require 60
mg/kg/d or even more
 Therapeutic levels of valproate range from 50

to 100 mcg/mL.
Drug Interactions of Vaproic acid:
 Valproate displaces phenytoin from plasma
proteins In
addition to binding interactions, valproate inhibits
the metabolism of several drugs, including
phenobarbital, phenytoin, and carbamazepine,
leading to higher steady-state concentrations of
these agents
 Inhibition of phenobarbital metabolism, for
example, may cause levels of the barbiturate to
rise steeply, causing stupor or coma
 Valproate can dramatically decrease the clearance
of lamotrigine.
Toxicity of Vaproic acid:
 GIT effects: nausea, vomiting, abdominal pain
and heartburn
 Sedation is uncommon with valproate alone but
may be striking when valproate is added to
Phenobarbital
 A fine tremor is frequently seen at higher levels
 Weight gain, increased appetite, and hair loss
 Hepatoxicity
 Thrombocytopenia
 Teratogenic risk to fetuses of mothers on the
dru
BENZODIAZEPINES
 Benzodiazepines are primarily anxiolytic
sedatives whose anticonvulsant usage has
gained currency in the therapy of epilepsy
 They are chemically 1,4-benzodiazepines,

and most contain a carboxamide group in the

7-membered heterocyclic ring structure. Six
benzodiazepines are known to be used in the
management of seizures
Pharmacokietics of Benzodiazepines:
 The rates of oral absorption of sedative-hypnotics differ depending
on a number of factors, including lipophilicity. For example, the
absorption of triazolam is extremely rapid, and
 that of diazepam and the active metabolite of clorazepate is more
rapid than other commonly used benzodiazepines.
 Clorazepate, a prodrug, is converted to its active form,
desmethyldiazepam (nordiazepam), by acid hydrolysis in the stomach.
 High lipid solubility is responsible for the rapid onset of central
nervous system effects of triazolam, All benzodiazepines cross the
placental barrier during pregnancy. If enzodiazepines are given during
the predelivery period, they may contribute to the depression of
neonatal vital functions. Benzodiazepines are also detectable in breast
milk and may exert depressant effects in the nursing infant.
 Metabolic transformation to more water-soluble metabolites is
necessary for clearance of benzodiazepines from the body. The
microsomal drug-metabolizing enzyme systems of the liver are
Pharmacokietics of Benzodiazepines:
 Hepatic metabolism accounts for the clearance of all
benzodiazepines. The patterns and rates of metabolism depend on
the individual drugs. Most benzodiazepines undergo microsomal
oxidation (phase I reactions), including N- dealkylation and aliphatic
hydroxylation catalyzed by cytochrome P450 isozymes, especially
CYP3A4. The metabolites are subsequently conjugated (phase II
reactions) to form glucuronides that are excreted in the urine.
However, many phase I metabolites of benzodiazepines are
pharmacologically active, some with long half-lives. For example,
desmethyldiazepam, which has an elimination half-life of more than
40 hours, is an active metabolite of chlordiazepoxide, diazepam,
prazepam, and clorazepate. Alprazolam and triazolam undergo α-
hydroxylation, and the resulting metabolites appear to exert short-
lived pharmacologic effects because they are rapidly conjugated to
form inactiveglucuronides. The short elimination half-life of
triazolam (2–3 hours) favors its use as a hypnotic rather than as a
sedative drug.
Pharmacokietics of Benzodiazepines:
 The formation of active metabolites has complicated studies on
the pharmacokinetics of the benzodiazepines in humans because
the elimination half-life of the parent drug may have little relation
to the time course of pharmacologic effects. Benzodiazepines for
which the parent drug or active metabolites have long half-lives
are predictably more likely to cause cumulative effects with
multiple doses. Cumulative and residual effects such as excessive

 drowsiness appear to be less of a problem with such drugs as

estazolam, oxazepam, and lorazepam, which have relatively short
half-lives and are metabolized directly to inactive glucuronides.

 The metabolism of several commonly used benzodiazepines

including diazepam, midazolam, and triazolam isaffected by
inhibitors and inducers of hepatic P450 isozymes
Mechanisms of action of the
benzodiazepines:
 Although the benzodiazepines are similar
chemically, subtle structural alterations result
in differences in activity
 The main mechanism of anti-seizure action,

which is shown to different degrees by the six

compounds is as follows:
Mechanisms of action of the
benzodiazepines:

 Bind to specific GABAA receptor subunits at

central nervous system (CNS) neuronal
synapses facilitating frequency of GABA-
mediated chloride ion channel opening—
enhance membrane hyperpolarization
Diazepam:
 Highly effective for stopping continuous
seizure activity, especially generalized tonic-
clonic status epilepticus. It is given IV or PR

 Very effective refractory patients who need

acute control of bouts of seizure activity.
Given PR.
Lorazepam:

More effective and longer

acting than diazepam in the
treatment of status
epilepticus and is preferred
by some experts
Clonazepam:
 Long-acting drug with efficacy against absence seizures

 One of the most potent antiseizure agents known

 Effective in some cases of myoclonic seizures

 Helpful ininfantile spasms

 Sedation is prominent, especially on initiation of therapy

 Starting doses should be small. Maximal tolerated doses

are usually in the range of 0.1–0.2 mg/kg, but many weeks
of gradually increasing daily doses may be needed to
achieve these dosages in some patients within a few
months. The remarkable antiseizure potency
Nitrazepam:

 Less potent than clonazepam for infantile

spasms and myoclonic seizures
Clorazepate dipotassium:

 Adjunct in treatment of complex partial

seizures in adults
 Drowsiness and lethargy are common adverse

effects
Clobazam:
 It is a 1,5- benzodiazepine (other marketed
benzodiazepines are 1,4-benzodiazepines)
 Less sedative potential than others
 Half-life of 18 hours
 Effective at dosages of 0.5–1 mg/kg/d
 Does interact with some other anti-seizure

drugs
Limitations of benzodiazepines in
Seizure treatment
 Pronounced sedative effect, which is
unfortunate both in the treatment of status
epilepticus and in chronic therapy. Children
may manifest a paradoxical hyperactivity, as
with barbiturates
 Tolerance, in which seizures may respond

initially but recur

ACETAZOLAMIDE

 Acetazolamide is a sulfonamide derivative

whose diuretic whose main action is the
inhibition of carbonic anhydrase
Acetazolamide anti-seizure
mechanisms:
 Via carbonic anhydrase inhibition/Mild
acidosis in the brain

 GABA receptor ion channel-mediated hyper-

polarizing action
Therapeutic indications of Acetazolamide:

 Special role in epileptic women who experience

seizure exacerbations at the time of menses
 Seizure control may be improved and tolerance
may not develop because the drug is not
administered continuously
 The usual dosage is approximately 10 mg/kg/d
to a maximum of 1000 mg/d
 Its uses for long-term anti-seizure control
limited largely by tolerance development to the
drugs
FELBAMATE

 Felbamate use as anti-seizure agent stopped on the

ground of severe adverse effects such as aplastic
anemia and severe hepatitis at unexpectedly high
rates and has been relegated to the status of a third-
line drug for refractory cases
 In spite of the seriousness of the adverse effects,
thousands of patients worldwide utilize this
medication. Usual dosages are 2000–4000 mg/d in
adults, and effective plasma levels range from 30
mcg/mL to 100 mcg/mL. In addition to its usefulness
in partial seizures, felbamate has proved effective
against the seizures that occur in Lennox-Gastaut
syndrome
THERAPEUTIC STRATEGY

 It is often clinically cost-effective when

initiating anti-seizure therapy to start with
the use of a single drug, especially in patients
who are not severely affected and who can
benefit from the advantage of fewer adverse
effects using monotherapy

 For patients with hard-to-control seizures,

multiple drugs are usually utilized
simultaneously.
THERAPEUTIC STRATEGY

 For most of the older anti-seizure drugs, relationships

between blood levels and therapeutic effects have
been characterized to a high degree
The same is true for the
pharmacokinetics of these drugs. These relationships
provide significant advantages in the development of
therapeutic strategies for the treatment of epilepsy
 The therapeutic index for most anti-seizure drugs is
low, and toxicity is not uncommon. Thus, effective
treatment of seizures often requires an awareness of
the therapeutic levels and pharmacokinetic profiles of
the drugs in question
MANAGEMENT OF EPILEPSY: PARTIAL SEIZURES
& GENERALIZED TONIC-CLONIC SEIZURES
 It is clinically trending to use newer drugs such as
gabapentin, Primidone, sodium valproate, and
topiramate in place of phenytoin, carbamazepine
and barbiturates for most partial and general
seizures, This is because these newer anti-seizure
agents not only have broader activity spectrum but
also safer toxicity profiles than the older group
 Whichever anti-seizure drug used, it must be
gradually withdrawn whenever a drug’s use is to be
terminated. When there is no seizure attack for 3-4
years, therapy termination can be iniated albeit
gradually
GENERALIZED SEIZURES
 The drugs used for generalized tonic-clonic
seizures are the same as for partial seizures;
in addition, valproate is clearly useful.
 At least three drugs are effective against
absence seizures. Two are non-sedating and
therefore preferred: ethosuximide and
valproate.
 Clonazepam is also highly effective but has
disadvantages of dose-related adverse effects
and development of tolerance. Lamotrigine
and topiramate may also be useful.
 GENERALIZED SEIZURES

 Specific myoclonic syndromes are usually treated with

valproate; an intravenous formulation can be used
acutely if needed
 It is non-sedating and can be dramatically effective.
Other patients respond to clonazepam, nitrazepam, or
other benzodiazepines, although high doses may be
necessary, with accompanying
 drowsiness. levetiracetam may be useful.
Another specific myoclonic
syndrome, juvenile myoclonic epilepsy, can be
aggravated by phenytoin or carbamazepine; valproate
is the drug of choice followed by lamotrigine and
topiramate
GENERALIZED SEIZURES

 Atonic seizures are often refractory to all available medications,

although some reports suggest that valproate may be beneficial,
as may lamotrigine
 Benzodiazepines have been reported to improve seizure control
in some of these patients but may worsen the attacks in others
 Felbamate has been demonstrated to be effective in some
patients, although the drug’s idiosyncratic toxicity limits its use.
If the loss of tone
appears to be part of another seizure type (e.g. absence or
complex partial seizures), every effort should be made to treat
the other seizure type vigorously
 This is done hoping for simultaneous alleviation of the atonic
component of the seizure
 The ketogenic diet may also be useful
GENERALIZED SEIZURES
DRUGS USED IN INFANTILE SPASMS
 Repository corticotrophin
 Oral or parenteral prednisone
 Benzodiazepines e.g. clonazepam or

nitrazepam; their efficacy in this

heterogeneous syndrome may be nearly as
good as that of corticosteroids
 Vigabatrin is effective and is considered the

drug of choice by many pediatric neurologists

 STATUS EPILEPTICUS
 Some physicians prefer lorazepam, which is
equivalent to diazepam in effect and perhaps
somewhat longer acting
 For patients who are not actually in the throes

of a seizure, diazepam therapy can be

omitted and the patient treated at once with a
long-acting drug such as phenytoin
 STATUS EPILEPTICUS
 There are many forms of status epilepticus
 The most common, generalized tonic-clonic
status epilepticus, is a life-threatening
emergency, requiring immediate
cardiovascular, respiratory, and metabolic
management as well as pharmacologic therapy
 IV Diazepam is the most effective drug in most
patients for stopping the attacks and is given
directly by IV push to a maximum total dose of
20–30 mg in adults
 STATUS EPILEPTICUS
 Until the introduction of fosphenytoin, the mainstay of
continuing therapy for status epilepticus was
intravenous phenytoin, which is effective and
nonsedating. It can be given as a loading dose of 13–
18 mg/kg in adults; the usual error is to give too little.
Administration should be at a maximum rate of 50
mg/min. It is safest to give the drug directly by
intravenous push, but it can also be diluted in saline; it
precipitates rapidly in the presence of glucose. Careful
monitoring of cardiac rhythm and blood pressure is
necessary, especially in elderly people. At least part of
the cardiotoxicity is from the propylene glycol in which
the phenytoin is dissolved
 STATUS EPILEPTICUS
 Fosphenytoin, which is freely soluble in intravenous
solutions without the need for propylene glycol or
other solubilizing agents, is a safer parenteral
agent. Because of its greater molecular weight, this
prodrug is two thirds to three quarters as potent as
phenytoin on a milligram basis
 In previously treated epileptic patients, the
administration of a large loading dose of phenytoin
may cause some dose-related toxicity such as
ataxia. This is usually a relatively minor problem
during the acute status episode and is easily
alleviated by later adjustment of plasma levels
 STATUS EPILEPTICUS
 Although other drugs such as lidocaine have
been recommended for the treatment of
generalized tonic-clonic status epilepticus,
general anesthesia is usually necessary in
highly resistant cases
 For patients in absence status,

benzodiazepines are still drugs of first choice

 Rarely, intravenous valproate may be required
 STATUS EPILEPTICUS
 IV diazepam may depress respiration (less
frequently, cardiovascular function), and
facilities for resuscitation must be
immediately at hand during its
administration. The effect of diazepam is not
lasting, but the 30- to 40-minute seizure-
free interval allows more definitive therapy to
be initiated
 STATUS EPILEPTICUS
 For patients who do not respond to
phenytoin, Phenobarbital can be given in
large doses: 100–200 mg intravenously to a
total of 400–800 mg. Respiratory depression
is a common complication, especially if
benzodiazepines have already been given,
and there should be no hesitation in
instituting intubation and ventilation
Non-seizure therapeutic uses of
Anticonvulsant drugs:
 Although seizure control or epilepsy has
become the major clinical indication for
anticonvulsant therapy, there are other non-
seizure/non-epileptic clinical indications for
which anticonvulsant drugs are deployed

 These include: trigeminal neuralgia, migraine,

chronic neuropathic pain syndromes,
essential tremors, bipolar disorders and
post-herpetic neuralgia
Non-seizure therapeutic uses of
Anticonvulsant drugs:
 Trigeminal neuralgia – Carbamazepine, Primidone
 Migraine prophylaxis - Valproic acid (sodium valproate)
 Essential tremor - Valproic acid (sodium valproate) is
commonly prescribed as first-line therapy for patients
with trigeminal neuralgia. has been recently marketed
for the management of
 Diabetic neuropathic pain syndromes - Gabapentin
particularly diabetic neuropathy and
 Post-herpetic neuralgia – Gabapentin
 Bipolar disorders - Carbamazepine, Lamotrigine,
oxcarbazepine, gabapentin and topiramate valproic
acid
Non-drug anticonvulsant therapies:

 Vagal nerve stimulation

 Ketogenic diets e.g. high dose omega-3 fatty

acids
Epilepsy and Special situations

 Pregnancy

 Contraception

 Anesthesia

 Surgery
Epilepsy and Contraception

 Potential adverse drug-drug interactions between epilepsy

drugs that induce liver enzymes and can lead to increased
hepatic metabolism of oral contraceptives and hence their
lower plasma levels and risks of failure of contraception.
These drugs include:
 Carbamazepine Clobazam Eslicarbazepine
 Felbamate Lamotrigine at doses of 300 mg daily or more
 Oxcarbazepine Phenobarbital Phenytoin
 Primidone Rufinamide
 Topiramate at doses of 200 mg daily or more.

 It is important to note that a woman already on any of these
drugs is placed on oral contraceptives she should be started
on a higher dose in order to avoid unwanted pregnancy.
Adverse effects of oral
contraceptives on lamotrigine
 Conversely, Lamotrigine plasma kevels can be
lowered by oral contraceptives since they too
are liver enzymes inducers. This scenario can
lead to breakthrough seizures when
lamotrigine dosage is not adjusted upwards
in an epilepsy patient whose seizure is well
controlled and subsequently placed on an
oral contraceptive
Anticonvulsant drugs with no adverse drug-
drug interactions with contraceptives

 Acetazolamide/ Clonazepam/ Diazepam

 Clorazepate/ valproic acid/sodium valproate
 Ethosuximide/ Gabapentin / Zonisamide
 Lamotrigine at doses less than 300 mg daily
 Lacosamide / Levetiracetam / Lorazepam
 Pregabalin / Tiagabine / Vigabatrin
 Effect of antiepileptic Drugs (AEDs) on anaesthesia

 There are important pharmacokinetic and

pharmacodynamic interactions between AEDs
and drugs commonly used in anaesthesia
These affect both drug efficacy and the risk
of seizure activity intraoperatively
 Induction and inhibition of the cytochrome

P450 isoenzymes in hepatic metabolism

constitutes the most significant mech. of
drug interactions involving AEDs
AEDs with potent enzyme-inducing properties

 Carbamazepine, phenytoin, phenobarbital,

Primidone, Topiramate , Oxcarbazepine and
eslicarbazepine
 They cause decreased plasma warfarrin,-p

antibacterials, immunosuppressants, and cvs

drugs, e.g. amiodarone, propranolol,
metoprolol, nifedipine, felodipine,
nimodipine, and verapamil concentrations
 Important to monitor plasma levels of

warfarrin and other drugs if co-administered

with any of these AEDs in peri-operative
period
AEDs with hepatic microsomal
enzyme systems inhibition

 Valproate

 May reduce the clearance of many

concurrently administered medications and
even AEDs
AEDs with no effects on hepatic
microsomal enzyme systems
 Gabapentin

 Lamotrigine

 Levetiracetam

 Tiagabine

 Vigabatrin
Antibiotics with potent inhibition or induction
of hepatic enzymatic metabolism of AEDs

 Macrolide antibiotics, particularly

erythromycin, are potent inhibitors of
carbamazepine metabolism and can lead to
carbamazepine toxicity

 Concomitant use of carbapenem antibiotics

can lead to a significant decrease in serum
valproate
Effect of anaesthetic agents on epilepsy

 Many of the agents used possess

both pro-convulsant and
anticonvulsant properties, which
could impact on the choice of
anaesthetic
Inhalational anaesthetics

 Nitrous oxide (N2O) inhalation, Isoflurane,

isoflurane and desflurane suppress seizures

 But N2O withdrawal, sevoflurane, enflurane

promote seizures

 Hyperbaric N2O in combination with

isoflurane or halothane causes myoclonus
Effects of opioids on anaesthesia

 Meperidine, remifentanil, fentanyl,

alfentanil, sufentanil, and morphine
have been associated with increased
seizure activity during anaesthesia
I.V. anaesthetic agents
 The barbiturates (thiopental, methohexital, and
pentobarbital) and propofol are well established as agents
for Rx of refractory status epilepticus
 All agents have been reported to produce excitatory activity,
such as myoclonus, opisthotonus, and rarely generalized
seizures on induction of anaesthesia
 The highest incidence of seizure induction appears to be
with etomidate, followed by thiopental, methohexital, and
propofol
 However, at higher doses, all agents act as anticonvulsants
 Ketamine is a non-competitive glutamate antagonist acting
at NMDA receptors, a property which could be beneficial in
Rx of status epilepticus refractory to other agents
 As with the other i.v. agents, low doses may facilitate
seizures, but at doses that produce sedative or anaesthetic
effects, ketamine shows anticonvulsant properties
Effects of the Benzodiazepines on epilepsy

 All benzodiazepines in clinical practice

possess potent anticonvulsant properties

 Diazepam, midazolam, and lorazepam are

widely used to terminate episodes of status
epilepticus
 Local anaesthetics
 LA agents readily cross the blood–brain
barrier, causing sedation and analgesia ff by
generalized convulsions at higher doses

 High blood levels result from an accidental

i.v. administration or rapid systemic
absorption from a highly vascular area

 I.V. lidocaine has been used to Rx status

epilepticus mainly in children
Neuromuscular blocking agents on anesthesia

 None of the neuromuscular blocking agents

e.g. atracurium, Laudanosine or
Succinylcholine appear to have any pro-
convulsant or anticonvulsant effects
Effects of Anticholinergics and anticholinesterases on
anaesthesia

 The increase in acetylcholine via

administration of atropine or scopolamine
can produce central cholinergic blockade (or
central anticholinergic syndrome)
 This manifests as agitation with seizures,

hallucinations, and restlessness or stupor,

coma, and apnoea
 Most effective Rx for this is physostigmine
 Glycopyrrolate does not cross the blood–brain

barrier, so does not produce these effects

Perioperative management of AEDs
 In pts with well-controlled epilepsy, it is vital that efforts
are made to avoid disruption of antiepileptic medication
perioperatively
 Patients should be advised to take their regular
medications on the morning of surgery and regular dosing
should be re-established as early as practicable after
surgery. If a single dose is missed (such as that might
occur with day-case surgery), it should be taken as soon
as possible after surgery
 Where multiple doses are likely to be missed, AEDs should
be administered parenterally where possible. I.V. forms of
phenytoin, sodium valproate, and levetiracetam are
available (where i.v. doses are equivalent to oral doses)
and carbamazepine is available as a suppository
 If the patient's regular AED is not available in parenteral
formulation, advice should be sought from a neurologist
regarding alternatives that may be used to cover the
perioperative period
Perioperative management of AEDs
 In general, routine drug level monitoring is not
required perioperatively as anaesthetic agents
do not significantly alter the pharmacokinetics
of AEDs
 However, prolonged intensive care unit (ICU)
stay, with attendant changes in serum pH and
albumin levels and also the use of drugs that
interact with AEDs, can affect their serum
concentrations
 Of the commonly used AEDs, phenytoin
presents the greatest challenge because of its
unique pharmacokinetic properties
 In patients admitted to ICU, it is necessary to
check serum concentrations of phenytoin daily