ANXIOLITYCS, SEDATIVES,

HIPNOTICS, ANTISEIZURE DRUGS

o What is “anxiety”?
 Apprehensive anticipation of future danger
 Experienced as dysphoric (unpleasant)-
hence ego-dystonic
 Often accompanied by somatic/physical
symptoms (e.g., muscle tension, elevated
heart rate, etc.)
Relationship Between Arousal
(anxiety) and Performance
What is “anxiety”?
 Apprehensive anticipation of future danger
 Experienced as dysphoric (unpleasant)- hence ego-
dystonic
 Often accompanied by somatic/physical
symptoms (e.g., muscle tension, elevated heart rate,
etc.)

Is “Anxiety” Always Pathological?

 Some anxiety is advantageous
 Helps in novel situations
 Helps mobilize individual for quick response- fight or
flight response for survival
 Anxiety can heighten one’s awareness/alertness,
prepare a defense to a threatening situation
Genesis of “anxiety”?
 Limbic region - hippocamp and amigdala receives
imput from the locus coeruleus and dorsal rafhe
 And turn the projects to the subcortical and cortical
nuclei

 Dysfunction of neurotransmission in limbic region

(hippocamp and amigdala) of brain underlies
 Exccesive excitatory neurotransmission
(serotoninergic and noradrenergic) in the limbic system
 Deficient inhibition of limbic neurotransmission by
GABA receptors
What Causes Anxiety?
-Some Fears are Innate
- Some learned fears are adaptive and
appropriate; others are not and result from
faulty learning…
- Thru Classical Conditioning: pairing of a
threatening stimulus with a non-threatening
one
- Hence, safe or innocuous stimuli (e.g.,
situations, objects) acquire a meaning of
danger

When anxiety is excessive, becomes

generalized, or is inappropriate for the
situation, it becomes pathological
Anxiety Disorders

 Panic disorder (agoraphobia)

 Posttraumatic stress disorder
 Social Phobia
 Specific phobia
 Obsessive-compulsive disorder
 Generalized anxiety disorder
Anxiety Disorders

Generalized anxiety disorder (GAD): People suffering from

GAD have general symptoms of motor tension,
autonomic hyperactivity, etc. for at least one month.
Phobic anxiety:
Simple phobias. Agoraphobia, fear of
animals, etc.
Social phobias.
Panic disorders: Characterized by acute attacks of fear as
compared to the chronic presentation of GAD.
Obsessive-compulsive behaviors: These patients show
repetitive ideas (obsessions) and behaviors
(compulsions).
Panic ATTACK
Discrete period of intense fear or discomfort accompanied
by at least four of the following physical sensations…

- Accompanying Symptoms:
 Chest pain
 Palpitations
 Sweating
 Trembling or shaking
 Paresthesias (numbness, tingling)
 Dizzy, faint
 Derealization, depersonalization
 Fear losing control or going crazy
 Fear of dying
 Shortness of breath, choking, smothering
 Nausea or GI distress
 Chills or hot flashes
Panic Attack
Episodes have a sudden onset and peak
rapidly (usually in 10 minutes or less)
 Often accompanied by a sense of
imminent danger or doom and an urge to
escape
 May present to ER with fear of catastrophic
medical event (e.g., MI or stroke)
Generalized Anxiety Disorder
 Excessive worries about real life problems
such as school and work performance (“worry
wort”)
 Typically seek help for somatic concerns in
primary care setting
 Accompanying anxiety symptoms:
 Muscle tension
 Restlessness or feeling keyed-up or on edge
 Easy Fatigability
 Irritability
 Trouble Concentrating
 Sleep disturbance
Anxiety as a symptom of…

 Anxiety Disorder due to a General Medical Condition

 Anxiety judged to be due to direct physiological effects of a
general medical condition such as:
 Tumors (ex. Pheocromocytoma)
 Hypoxia (from a Pulmonary Embolus, Chronic Obstructive
Pulmonary Disease)
 Hyperthyroidism (thyroid storm)
 Myocardial infarction, arrhythmias, mitral valve prolapse
 Hypoglycemia
 Substance Induced Anxiety Disorder
 Anxiety judged to be due to direct physiological effects of a
substance (i.e., a drug of abuse, a medication, or toxin exposure)
 Alcohol/sedative withdrawal
 Cocaine/stimulant intoxication
 Cannabis intoxication
 Caffeine intoxication
Anxiolytics

Strategy for treatment

Reduce anxiety without causing sedation.

1) Benzodiazepines (BZDs).
2) Barbiturates (BARBs).
3) 5-HT1A receptor agonists.
4) 5-HT2A, 5-HT2C & 5-HT3 receptor
antagonists.

If ANS symptoms are prominent:

• ß-Adrenoreceptor antagonists.
∀ α 2-AR agonists (clonidine).
Anxiolytics
 Other Drugs with anxiolytic activity.
 TCAs (Fluvoxamine). Used for
Obsessive compulsive Disorder.
 MAOIs. Used in panic attacks.
 Antihistaminic agents. Present in over
the counter medications.
 Antipsychotics (Ziprasidone).
Sedative/Hypnotics

A hypnotic should produce, as much as possible, a

state of sleep that resembles normal sleep.
 By definition all sedative/hypnotics will induce sleep at
high doses.
 Normal sleep consists of distinct stages, based on
three physiologic measures: electroencephalogram,
electromyogram, electronystagmogram.

Two distinct phases are distinguished which occur

cyclically over 90 min:
1) Non-rapid eye movement (NREM). 70-75% of total
sleep. 4 stages. Most sleep  stage 2.
2) Rapid eye movement (REM). Recalled dreams
Properties of Sedative/Hypnotics

1) The latency of sleep onset is decreased (time to fall asleep).

2) The duration of stage 2 NREM sleep is increased.
3) The duration of REM sleep is decreased.
4) The duration of slow-wave sleep (when somnambulism and
nightmares occur) is decreased.
Tolerance occurs after 1-2 weeks.

 Some sedative/hypnotics will depress the CNS to stage

III of anesthesia.
 Due to their fast onset of action and short duration,
barbiturates such as thiopental and methohexital are
used as adjuncts in general anesthesia
Sedative/Hypnotics
1) Benzodiazepines (BZDs):
Alprazolam, diazepam, oxacepam, triazolam
2) Barbiturates:
Pentobarbital, phenobarbital
3) Alcohols:
Ethanol, chloral hydrate, paraldehyde, trichloroethanol,
4) Imidazopyridine Derivatives:
Zolpidem
5) Pyrazolopyrimidine
Zaleplon
Sedative/Hypnotics

6) Propanediol carbamates:
Meprobamate
7) Piperidinediones
Glutethimide
8) Azaspirodecanedione
Buspirone
9) β -Blockers**
Propranolol
10) α 2-AR partial agonist**
Clonidine
Sedative/Hypnotics
Others:
11) Antyipsychotics **
Ziprasidone
12) Antidepressants **
TCAs, SSRIs
13) Antihistaminic drugs **
Dephenhydramine
Sedative/Hypnotics
All of the anxiolytics/sedative/hypnotics should be used only
for symptomatic relief.
*************
All the drugs used alter the normal sleep cycle and
should be administered only for days or weeks, never for
months.
************
USE FOR
SHORT-TERM TREATMENT

ONLY!!
 SEDATIVE/HYPNOTICS
ANXYOLITICS

B E N Z O D I A Z B E A P R I BN I E T SU R

GABAergic SYSTEM
GABAergic SYNAPSE

glucose

glutamate
GAD
GABA

-
Cl
GABA-A Receptor
 Oligomeric (abdgepr)
glycoprotein.
BDZs  Major player in
Inhibitory
BARBs Synapses.
GABA AGONISTS
 It is a Cl- Channel.
 Binding of GABA
causes the channel to
γ open and Cl- to flow
into the cell with the
α
δ resultant membrane
hyperpolarization.
β ε
GABA-A Receptor
Benzodiazepines acts
at three specific
BDZs binding sites:
 ω 1 - omega 1,
BARBs
GABA AGONISTS  ω 2 - omega 2,
 ω 3 - omega 3
subtypes receptors
γ
α
δ

β ε
Benzodiazepines
- are the most important sedative hypnotics.
- developed to avoid undesirable effects of barbiturates
(abuse liability).

 Diazepam
 Chlordiazepoxide
 Triazolam
 Lorazepam
 Alprazolam
 Clorazepate => nordiazepam
 Halazepam
 Clonazepam
 Oxazepam
 Prazepam
Benzodiazepines -
Mechanisms of Action
Enhance GABAergic Transmission
 frequency of openings of GABAergic
channels. Benzodiazepines
 opening time of GABAergic channels.
Barbiturates
 receptor affinity for GABA. BDZs and
BARBS
2) Stimulation of 5-HT1A receptors.
3) Inhibit 5-HT2A, 5-HT2C, and 5-HT3 receptors.
Pharmacokinetics of Benzodiazepines
• Although BDZs are highly protein bound (60-95%),
few clinically significant interactions.*
• High lipid solubility  high rate of entry into CNS 
rapid onset.

*The only exception is chloral hydrate and warfarin Hepatic

metabolism. Almost all BDZs undergo microsomal oxidation (N-
dealkylation and aliphatic hydroxylation) and conjugation (to
glucoronides).

• Rapid tissue redistribution  long acting  long half

lives and elimination half lives (from 10 to > 100 hrs).
• All BDZs cross the placenta  detectable in breast
milk  may exert depressant effects on the CNS of the
lactating infant.
Pharmacokinetics of Benzodiazepines
• Many have active metabolites with half-lives greater than
the parent drug.
• Prototype drug is diazepam (Valium), which has active
metabolites (desmethyl-diazepam and oxazepam) and is long
acting (t½ = 20-80 hr).
• Differing times of onset and elimination half-lives (long
half-life => daytime sedation).
• Keep in mind that with formation of active metabolites, the
kinetics of the parent drug may not reflect the time course of
the pharmacological effect.
• Estazolam, oxazepam, and lorazepam, which are directly
metabolized to glucoronides have the least residual
(drowsiness) effects.
• All of these drugs and their metabolites are excreted in
urine.
Properties of Benzodiazepines

• BDZs have a wide margin of safety if used for short periods.

Prolonged use may cause dependence.
• BDZs have little effect on respiratory or cardiovascular
function compared to BARBS and other sedative-hypnotics.
• BDZs depress the turnover rates of norepinephrine (NE),
dopamine (DA) and serotonin (5-HT) in various brain nuclei.

Side effects
• CNS depression: drowsiness, excess sedation, impaired
coordination, nausea, vomiting, confusion and memory
loss. Tolerance develops to most of these effects.
• Dependence with these drugs may develop.
• Serious withdrawal syndrome can include convulsions
and death.
Toxicity/Overdose with Benzodiazepines
• Drug overdose is treated with flumazenil (a BDZ receptor
antagonist, short half-life), but respiratory function should be
adequately supported and carefully monitored.

• Seizures and cardiac arrhythmias may occur following

flumazenil administration when BDZ are taken with TCAs.

• Flumazenil is not effective against BARBs overdose.

Drug-Drug Interactions with BDZs

• BDZ's have additive effects with other CNS depressants
(narcotics), alcohol => have a greatly reduced margin of safety.
• BDZs reduce the effect of antiepileptic drugs.
• Combination of anxiolytic drugs should be avoided.
• Concurrent use with ODC antihistaminic and anticholinergic
drugs as well as the consumption of alcohol should be avoided.
• SSRI’s and oral contraceptives decrease metabolism of BDZs.
Barbiturates

 Phenobarbital
 Pentobarbital
 Amobarbital
 Mephobarbital
 Secobarbital
 Aprobarbital
Pharmacokinetics of Barbiturates

 Rapid absorption following oral administration.

 Rapid onset of central effects.
 Extensively metabolized in liver (except phenobarbital),
however, there are no active metabolites.
 Phenobarbital is excreted unchanged. Its excretion can
be increased by alkalinization of the urine.
 In the elderly and in those with limited hepatic function,
dosages should be reduced.
 Phenobarbital and meprobamate cause autometabolism
by induction of liver enzymes.
 Properties of Barbiturates

Mechanism of Action.
• They increase the duration of GABA-gated
channel openings.
• At high concentrations may be GABA-mimetic.

Less selective than BDZs, they also:

• Depress actions of excitatory neurotransmitters.
• Exert nonsynaptic membrane effects.
 Toxicity/Overdose

 Strong physiological dependence may develop upon

long-term use.
 Depression of the medullary respiratory
centers is the usual cause of death of
sedative/hypnotic overdose. Also loss of brainstem
vasomotor control and myocardial depression.
 Withdrawal is characterized by increase anxiety,
insomnia, CNS excitability and convulsions.
 Drugs with long-half lives have mildest
withdrawal
 Drugs with quick onset of action are most abused.
 No medication against overdose with BARBs.
 Contraindicated in patients with porphyria
Miscellaneous Drugs

 Buspirone
 Chloral hydrate
 Hydroxyzine
 Meprobamate (Similar to
BARBS)
 Zolpidem (BZ1 selective)
 Zaleplon (BZ1 selective)
BUSPIRONE

Mechanism of Action:
• Acts as a partial agonist at the 5-HT1A
receptor presynaptically inhibiting
serotonin release.
• The metabolite 1-PP has α 2 -AR
blocking action.
BUSPIRONE
• Most selective anxiolytic currently available.
• The anxiolytic effect of this drug takes several
weeks to develop => used for GAD.
• Buspirone does not have sedative effects and
does not potentiate CNS depressants.
• Has a relatively high margin of safety, few side
effects and does not appear to be associated with
drug dependence.
• No rebound anxiety or signs of withdrawal when
discontinued.
• Not effective in panic disorders.
Pharmacokinetics of BUSPIRONE
• Rapidly absorbed orally.
• Undergoes extensive hepatic metabolism
(hydroxylation and dealkylation) to form
several active metabolites (e.g. 1-(2-
pyrimidyl-piperazine, 1-PP)
• Well tolerated by elderly, but may have
slow clearance.
• Analogs: Ipsapirone, Gepirone,
Tandospirone.
BUSPIRONE

Side effects:
• Tachycardia, palpitations,
nervousness, GI distress and
paresthesias may occur.
• Causes a dose-dependent pupillary
constriction.
Zolpidem
• Structurally unrelated but as effective as
BDZs.
• Minimal muscle relaxing and anticonvulsant
effect.
• Rapidly metabolized by liver enzymes into
inactive metabolites
• Dosage should be reduced in patients with hepatic
dysfunction, the elderly and patients taking
cimetidine.
Properties of Zolpidem
Mechanism of Action:
• Binds selectively to BZ1 receptors - ω 1 .
• Facilitates GABA-mediated neuronal
inhibition.
• Actions are antagonized by flumazenil
Properties of Other drugs.

Chloral hydrate
 Is used in institutionalized patients. It
displaces warfarin (anti-coagulant) from
plasma proteins.
 Extensive biotransformation.
Properties of Other Drugs

α 2-Adrenoreceptor Agonists (eg. Clonidine)

• Antihypertensive.
• Has been used for the treatment of panic
attacks.
• Has been useful in suppressing anxiety during the
management of withdrawal from nicotine
and opioid analgesics.
• Withdrawal from clonidine, after protracted
use, may lead to a life-threatening hypertensive
crisis.
Properties of Other Drugs

β -Adrenoreceptor Antagonists
(eg. Propranolol)
• Use to treat some forms of anxiety,
particularly when physical (autonomic)
symptoms (sweating, tremor, tachycardia) are
severe.
• Adverse effects of propranolol may include:
lethargy, vivid dreams, hallucinations.
ANTIEPILEPTIC DRUGS
A group of chronic CNS disorders characterized
by recurrent seizures.

 Seizures are sudden, transitory, and

uncontrolled episodes of brain dysfunction
resulting from abnormal discharge of
neuronal cells with associated motor, sensory
or behavioral changes.
Epilepsy - pathophysiology
Local imbalance amongs excitatory and
inhibitory influence on the electrical activity
across the cell membrane of neurones
The brain of epileptics patients has been
found:

 A reduction in the activity of membrane – bound ATP

aze linked to neuronal transmembrane ion pumps
 A reduction in the activity of the inhibitory GABA –
ergic neurons
Causes for Acute Seizures

 High fever
 Trauma
 Hypoglycemia
 Encephalitis
 Extreme
 Drugs
acidosis
 Birth trauma
 Extreme
 Withdrawal from alkalosis
depressants Hyponatremia
 Tumor  Hypocalcemia
 Idiopathic
Classification of Seizures

Partial (focal) Seizures

I. Simple Partial Seizures
II. Complex Partial Seizures

Generalized Seizures
I. Absence Seizures
II. Tonic-Clonic seizures
III. Tonic Seizures
IV. Atonic Seizures
V. Clonic and Myoclonic Seizures
VI. Infantile Spasms
 Treatment of Epilepsies
Goals:
 Block repetitive neuronal firing.
 Block synchronization of neuronal
discharges.
 Block propagation of seizure.

Minimize side effects with the simplest

drug regimen.
MONOTHERAPY IS RECOMMENDED IN MOST CASES
 Treatment of Epilepsies

Strategies:
 Modification of ion conductances.

 Increase inhibitory (GABAergic)

transmission.

 Decrease excitatory (glutamatergic)

activity.
 Actions of Phenytoin on Na+ Channels

Na+
A. Resting State

B. Arrival of Action
Potential causes
depolarization and
channel opens Na+
allowing sodium to
flow in.

C. Refractory State,
Inactivation Na+
Sustain channel in
this conformation
GABAergic SYNAPSE

Drugs that Act at

the GABAergic
Synapse

 GABA agonists
 GABA antagonists
 Barbiturates
 Benzodiazepines
 GABA uptake
inhibitors
GLUTAMATERGIC SYNAPSE
 Excitatory Synapse.
 Permeable to Na+, Ca2+
Na+ and K+.
Ca2+ AGONISTS  Magnesium ions block
GLU channel in resting state.
GLY
 Glycine (GLY) binding
enhances the ability of
GLU or NMDA to open
the channel.
 Agonists: NMDA, AMPA,
Mg++ Kainate.

K+
Treatment of Epilepsies

1) Hydantoins: phenytoin
2) Barbiturates: phenobarbital
3) Oxazolidinediones: trimethadione
4) Succinimides: ethosuximide
5) Acetylureas: phenacemide
 Treatment of Epilepsies
1) Structurally dissimilar:
1) carbamazepine
2) valproic acid
3) BDZs.
2) As are the new compounds:
1) Felbamate (Japan)
2) Gabapentin
3) Lamotrigine
4) Tiagabine
5) Topiramate
6) Vigabatrin
Pharmacokinetic Parameters
 PHENYTOIN (Dilantin)
Toxicity:
•Ataxia and nystagmus.
•Cognitive impairment.
•Hirsutism
•Gingival hyperplasia.
•Coarsening of facial features.
•Dose-dependent zero order
kinetics.
•Exacerbates absence seizures. Alters NTs (NE, ACh, GABA)
 Oldest nonsedative
antiepileptic drug.
 Useful for partial all types of
epilepsia, except absences
 Fosphenytoin, a more
soluble prodrug is used for
parenteral use.
 “Fetal hydantoin syndrome”
 It alters Na+, Ca2+ and K+
conductances.
 Inhibits high frequency
repetitive firing.
 Alters membrane potentials.
 Alters a.a. concentration.
 CARBAMAZEPINE (Tegretol)
 Tricyclic, antidepressant (bipolar)
Toxicity:
•Autoinduction of  3-D conformation similar to
phenytoin.
metabolism.
 Useful for partial all types of epilepsia,
•Nausea and visual except mioclonic epilepsy
disturbances.  Mechanism of action, similar to
•Granulocyte phenytoin. Inhibits high frequency
supression. repetitive firing.
•Aplastic anemia.  Decreases synaptic activity
•Exacerbates presynaptically.
absence seizures.  Binds to adenosine receptors (?).
 Inh. uptake and release of NE, but not
GABA.
 Potentiates postsynaptic effects of
GABA.
 Metabolite is active.
 OXCARBAZEPINE (Trileptal)
 Closely related to
carbamazepine.
 With improved toxicity profile.
 Less potent than
carbamazepine.
 Active metabolite.
 Mechanism of action, similar to
Toxicity: carbamazepine It alters Na+
•Hyponatremia conductance and inhibits high
•Less hypersensitivity frequency repetitive firing.
and induction of hepatic
enzymes than with carb.
 PHENOBARBITAL (Luminal)

 Except for the bromides, it is the

oldest antiepileptic drug.
 Although considered one of the
safest drugs, it has sedative
effects.
 Many consider them the drugs of
Toxicity: choice for seizures only in infants.
 Sedation.  Acid-base balance important.
 Cognitive  Useful for partial, generalized
impairment. tonic-clonic seizures, and febrile
 Behavioral seizures
changes.  Prolongs opening of Cl- channels.
 Induction of liver  Blocks excitatory GLU (AMPA)
enzymes. responses. Blocks Ca2+ currents (L,N).
 May worsen  Inhibits high frequency, repetitive
absence and atonic firing of neurons only at high
seizures. concentrations.
 PRIMIDONE (Mysolin)
Toxicity:
•Same as phenobarbital
•Sedation occurs early.
•Gastrointestinal complaints.  Its mechanism of action may be
 Metabolized to phenobarbital and
phenylethylmalonamide (PEMA),
both active metabolites.
 Effective against partial and
generalized tonic-clonic
seizures.
 Absorbed completely, low binding
to plasma proteins.
 Should be started slowly to avoid
sedation and GI problems.
closer to phenytoin than the
barbiturates.
 VALPROATE (VALPROIC ACID)
Toxicity:
•Elevated liver enzymes
including own.
•Nausea and vomiting.
•Abdominal pain and
heartburn.
•Tremor, hair loss,
•Weight gain.
•Idiosyncratic
hepatotoxicity.
•Negative interactions with
other antiepileptics.
•Teratogen: spina bifida
 Fully ionized at body pH, thus active
form is valproate ion.
 One of a series of carboxylic acids
with antiepileptic activity. Its amides
and esters are also active.
 Mechanism of action, similar to
phenytoin.
 ⇑ levels of GABA in brain.
 May facilitate Glutamic acid
decarboxylase (GAD).
 Inhibits GAT-1. ⇓ [aspartate]Brain ?
 May increase membrane potassium
conductance.
 Useful for partial all types of
epilepsia
 ETHOSUXIMIDE (Zarontin)

 Drug of choice for absence

seizures.
 High efficacy and safety.
 Not plasma protein or fat binding
 Mechanism of action involves
Toxicity: reducing low-threshold Ca2+ channel
current (T-type channel) in thalamus.
•Gastric distress,
At high concentrations:
including, pain, nausea  Inhibits Na+/K+ ATPase.
and vomiting  Depresses cerebral metabolic rate.
•Lethargy and fatigue  Inhibits GABA aminotransferase.
•Headache  Phensuximide = less
•Hiccups effective
•Euphoria  Methsuximide = more toxic
•Skin rashes
•Lupus erythematosus (?)
 CLONAZEPAM (Klonopin)

 A benzodiazepine.
 Long acting drug with efficacy
for absence seizures.
 One of the most potent
antiepileptic agents known.
 Also effective in some cases of
myoclonic seizures.
 Has been tried in infantile
Toxicity: spasms.
 Doses should start small.
•Sedation is prominent.  Increases the frequency of Cl-
channel opening.
 VIGABATRIN (γ -vinyl-GABA)

 Absorption is rapid, bioavailability is

~ 60%, T 1/2 6-8 hrs, eliminated by
the kidneys.
 Use for partial seizures and
West’s syndrome.
 Contraindicated if preexisting mental
Toxicity: illness is present.
•Drowsiness  Irreversible inhibitor of GABA-
aminotransferase (enzyme
•Dizziness responsible for metabolism of GABA)
•Weight gain => Increases inhibitory effects of
GABA.
•Agitation  S(+) enantiomer is active.
•Confusion
•Psychosis
 LAMOTRIGINE (Lamictal)

 Presently use as add-on therapy

with valproic acid (v.a. conc. are
be reduced).
 Almost completely absorbed
 T1/2 = 24 hrs
 Low plasma protein binding
Toxicity:  Suppresses sustained rapid firing
•Dizziness of neurons and produces a voltage
•Headache and use-dependent inactivation
of sodium channels, thus its
•Diplopia efficacy in partial seizures.
•Nausea  Also effective in myoclonic and
•Somnolence generalized seizures in
•Rash childhood and absence attacks.
 FELBAMATE (Felbatrol)

 Effective against partial

seizures but has severe side
effects.
 Because of its severe side
effects, it has been relegated
Toxicity: to a third-line drug used only
•Aplastic anemia for refractory cases.
•Severe hepatitis
 TOPIRAMATE
 Rapidly absorbed, bioav. is > 80%,
has no active metabolites, excreted
in urine.T1/2 = 20-30 hrs
 Blocks repetitive firing of cultured
neurons, thus its mechanism may
involve blocking of voltage-
dependent sodium channels
 Potentiates inhibitory effects of
GABA (acting at a site different from
Toxicity: BDZs and BARBs).
 Somnolence  Depresses excitatory action of
 Fatigue kainate on AMPA receptors.
 Dizziness  Teratogenic in animal models.
 Cognitive slowing  It is used as an ad-on treatment for
 Paresthesias drug-resistant partial or
 Nervousness generalised seizures
 Confusion
 Urolithiasis
 TIAGABINE (Gabatril)

 Derivative of nipecotic acid.

 100% bioavailable, highly protein
Toxicity: bound.
•Dizziness  T1/2 = 5 -8 hrs
•Nervousness  Effective against partial and
•Tremor generalized tonic-clonic
•Difficulty seizures.
 GABA uptake inhibitor GAT-1.
concentrating
 Potentiates inhibitory effects of
•Depression GABA (acting at a site different
•Asthenia from BDZs and BARBs).
•Emotional lability  Depresses excitatory action of
•Psychosis kainate on AMPA receptors.
 Teratogenic in animal models.
•Skin rash
 GABAPENTIN (Neurontin)
 Used as an adjunct in partial and
generalized tonic-clonic seizures.
 Does not induce liver enzymes.
 not bound to plasma proteins.
 drug-drug interactions are negligible.
 Low potency.
 An a.a.. Analog of GABA that does not
Toxicity: act on GABA receptors, it may
•Somnolence. however alter its metabolism, non-
•Dizziness. synaptic release and transport.
•Ataxia.
•Headache.
•Tremor.
 ZONISAMIDE

 Sulfonamide derivative.
 Marketed in Japan.
 Good bioavailability, low pb.
 T1/2 = 1 - 3 days
 Effective against partial and
generalized tonic-clonic
seizures.
 Mechanism of action involves
Toxicity: voltage and use-dependent
•Drowsiness inactivation of sodium channels
(?).
•Cognitive impairment  May also involve Ca2+ channels.
•High incidence of renal
stones (?).
 ANTIEPILEPTIC DRUG INTERACTIONS

With other drugs:

antibiotics  phenytoin, phenobarb, carb.
anticoagulants phenytoin and phenobarb
met.
cimetidine displaces pheny, v.a. and BDZs
isoniazid  toxicity of phenytoin
oral contraceptives antiepileptics  metabolism.
salicylates displaces phenytoin and v.a.
theophyline carb and phenytoin may
effect.