DRUGS AFFECTING THE

CENTRAL NERVOUS SYSTEM

KULIAH FK UHT 2020
DISEASE STATES OF CENTRAL NERVOUS
SYSTEM
• Typically caused by too much, or too little neurotransmission
• Too much
• Hyperexcitable neurons fire in absence of stimuli (e.g. seizure
disorders)
• Too many neurotransmitter molecules binding to post-synapse receptors
• psychoses
• Too little
• Too few neurotransmitters binding to post-synapse receptors
 MAJOR PARTS OF THE BRAIN
• Cerebrum
• Brainstem
• Cerebellum
 CEREBRUM

• Largest and uppermost part of the brain

• Divided into right and left hemispheres
• Controls all the higher intellectual and motor functions of the
body
• Cerebrum composed of an outer cortex and an inner medulla
 CEREBRAL CORTEX

• Contains neuronal cell bodies (gray matter) that control all

voluntary activities of the body
• Divided up into 4 lobes: frontal, parietal, temporal, and
occipital, each controlling specific brain functions
• Electroencephalogram (EEG) is a recording of the electrical
activity of the cortex
 CEREBRAL MEDULLA

• Referred to as the “white matter” and is composed of

myelinated nerve axons
• Functions to conduct nerve impulses to and from different
parts of the nervous system
• Basal ganglia are neuronal cell bodies (gray matter) located
within the cerebral medulla that function in the regulation of
motor activity
 BRAINSTEM AND SPINAL CORD

• Located below the cerebrum and is continuous with the spinal

cord
• Brainstem divided into the thalamus, hypothalamus, pons, and
medulla oblongata
• Spinal cord is a collection of all the sensory and motor nerves
going to and from the brain
 RETICULAR FORMATION

• A network of nerves and brain areas involved in

regulating alertness, wakefulness, and sleep
• Composed of both inhibitory and excitatory nerves
• Excitatory nerves collectively referred to as the
reticular activating system (RAS)
• Many stimulants (amphetamines) and depressants
(alcohol, barbiturates) affect the RAS
 LIMBIC SYSTEM

• Network of nerves and brain areas involved in emotional and

behavioral responses
• Associated with emotional responses to fear, anger, anxiety,
sexual behavior, and reward and punishment
• Affected by drugs of abuse and involved in the development
of drug dependency
NEUROTRANSMITTERS
• Current models of CNS diseases often attribute the
physiological cause of the disease to an imbalance of
neurotransmitters.
 NOREPINEPHRINE
• The Locus ceruleus, also spelled locus caeruleus or locus coeruleus (Latin
for 'the blue spot'), is a nucleus in the brain stem responsible for
physiological responses to stress and panic. The locus ceruleus (or "LC")
is located within the dorsal wall of the upper pons, under the cerebellum in
the caudal midbrain, surrounded by the 4th ventricle. This nucleus is one of
the main sources of Norepinephrine in the brain, and is composed of
mostly medium-sized neurons.
• Adrenergic hormone released at the effector organ by sympathetic neurons
• Monamine
• Depression thought be caused by impaired monoamine transmission
• Drugs that stimulate monoamine release are indicated for ADD or
narcolepsy
 DOPAMINE

• Another monoamine derived from the amino acid tyrosine

• Binds dopamine receptors (D1 or D2)
• Antipsychotics prevent signals activated by dopamine binding
• Parkinson’s disease also caused by altered dopamine binding
• A decreased brain dopamine concentration is a
contributing factor in Parkinson’s disease,
while an increase in dopamine concentration
has a role in the development of Schizophrenia
 SEROTONIN (5-HT)

• Monoamine hormone derived from the amino acid tryptophan

• Typically released by inhibitory neurons
• Lysergic acid diethylamide binds to serotonin receptors
• Depression, Attention Deficit Disorder and headaches
associated with serotonin imbalance
• In the central nervous system, serotonin is believed to
play an important role in the regulation of body
temperature, mood, sleep, vomiting, sexuality, and
appetite. Low levels of serotonin have been associated
with several disorders, namely clinical depression,
obsessive-compulsive disorder (OCD), migraine,
irritable bowel syndrome, tinnitus, fibromyalgia, bipolar
disorder, and anxiety disorders.
GAMMA-AMINO BUTYRIC ACID (GABA)

• Inhibitory neurotransmitter of the brain and central nervous

system
• Synthesized from the amino acid glutamate
• Cause Ca2+ influx into the neuron resulting in
hyperpolarization
• More difficult to excite
• Benzodiazepines and barbituates enhance GABA effects
GABA
 EXCITATORY AMINO ACIDS

• Amino acid glutamate or structurally related chemicals

• Important for learning and memory
• Abnormal increased activity will result in toxicity
• Alzheimers, ALS, stroke, Huntington’s
ANTIDEPRESSANTS
 MENTAL DEPRESSION

• Exogenous or reactive depression usually occurs in response

to some external factor or adverse life event
• Endogenous depression usually originates from within the
psyche of the individual and the causes are less well
understood
• Bipolar mood disorder involves alternating cycles of
depression and mania
CAUSES OF MENTAL DEPRESSION

• Exact causes not well understood

• Mental depression appears to involve the development of low
levels of the brain monoamine neurotransmitters, serotonin
(SER) and norepinephrine (NE)
• This explanation is referred to as the “Monoamine Theory of
Mental Depression”
 TREATMENT OF DEPRESSION

• Treatment involves a combination of psychotherapy

and antidepressant drugs
• Antidepressant drugs act to increase NE and SER
levels in the brain
• Tricyclic antidepressants (TCA) and selective
serotonin reuptake inhibitors (SSRI) are the two most
important antidepressant drug classes
• Monoamine oxidase inhibitors (MAOI) are less
frequently used and require dietary restriction
 MONOAMINE OXIDASE
INHIBITORS (MAOI)
• Monoamine oxidase is the enzyme that metabolizes
the monoamines NE and SER
• Inhibition of MAO increases SER and NE levels
and functional activity in the brain
• Requires 2–4 weeks for maximum effects
• Foods containing tyramine must be avoided
• Tyramine stimulates the release of NE and may
cause a hypertensive crisis
• MAOIs are indicated for patients who cannot tolerate
TCAs and SSRIs
TRICYCLIC ANTIDEPRESSANTS (TCA)

• Mechanism of action of TCAs is to block reuptake

of NE and SER into nerve endings
• Blockage of reuptake increases NE and SER levels
and stimulation of NE and SER receptors
• Requires 2–4 weeks for maximum effect
• TCAs are divided into secondary amines which
increase NE more than SER and are less sedating than
tertiary amines which increase SER more than NE
 AUTONOMIC EFFECTS OF TCAS

• TCAs possess anticholinergic activity which can cause dry

mouth, visual disturbances, constipation, and urinary
retention
• TCAs also possess alpha blocking activity that can lower
blood pressure
• TCAs can also affect cardiac rhythm and may cause cardiac
arrhythmias
SELECTIVE SEROTONIN REUPTAKE
INHIBITORS (SSRI)
• Selectively block the reuptake of SER
• Cause little if any anticholinergic and alpha blocking effects
• Are generally not sedating, and in some cases cause CNS
stimulation
• Common adverse effects include nausea, agitation,
restlessness, and less frequently seizures
 PSYCHOMOTOR STIMULANTS

• Generally referred to as the amphetamines

• Produce CNS stimulation more than an antidepressant
effect, little used for depression
• Act by increasing NE and DA activity
• Clinical use for narcolepsy and treatment of
hyperkinetic children
• Amphetamines have a high abuse potential
• Adverse effects due to excessive CNS and autonomic
stimulation
 LITHIUM

• Lithium is an elemental ion similar to sodium

• Acts to depress nerve excitability that helps prevent
mood swings and manic behavior
• Common adverse effects include nausea, diarrhea,
tremors, increased thirst, ringing in the ears (tinnitus),
and more seriously kidney and heart damage
• Periodic blood levels to prevent over dosage
 ALCOHOL
• Classified as a CNS depressant drug
• Unlike other drugs, alcohol provides nutritional
calories
• Like other drugs of abuse, alcohol causes
development of drug tolerance, dependency, and
withdrawal reactions
• Most of the pharmacology of alcohol centers around
its chronic use, abuse, and toxicology
 DISULFIRAM

• Used to treat alcoholism and deter drinking

• Disulfiram inhibits metabolism of alcohol, allowing
acetaldehyde to accumulate
• Increased acetaldehyde produces severe nausea,
vomiting, headache, and hypotension
• Alcoholics take the drug on a daily basis, knowing
that if they drink any alcohol they will become
violently ill
 Parkinson’s Disease

• A neurological movement disorder of the brain involving the

basal ganglia
• Symptoms include tremor, muscular rigidity, and disturbances
of movement
• Major cause is a deficiency of the inhibitory neurotransmitter
dopamine (DA) and the resulting excessive activity of the
excitatory neurotransmitter acetylcholine (ACH)
 DRUG THERAPY

• Primary therapy is the administration of drugs that increase the

levels of DA in the basal ganglia
• Secondary therapy is the administration of anticholinergic
drugs that decrease ACH activity in the basal ganglia
• Goal is to restore the balance between DA and ACH activity
DRUGS THAT INCREASE DOPAMINE

• Levodopa
• Dopamine agonists
• Amantadine
• Enzyme inhibiting drugs that slow the metabolic breakdown of
dopamine
 LEVODOPA

• The precursor of DA that is taken orally and

converted into DA in the basal ganglia
• Administered in combination with carbidopa that
increases the amount of DA that enters the brain
• Levodopa and carbidopa drug combination known as
Sinemet
• Levodopa is considered the most effective drug for
the treatment of Parkinson’s disease
• Combined Drug For Parkinson:
• 2 drugs = levodopa + carbodopa
• 3 drugs = levodopa + carbidopa + …
ADVERSE EFFECTS OF LEVODOPA

• Nausea, vomiting, and loss of appetite

• Hypotension, and rapid/irregular heart rate
• Dystonias, slow or weak movements that usually
occur when levels of DA are low
• Dyskinesias, uncontrolled or involuntary movements
when DA levels are too high
• “On-off” phenomenon when drug effects suddenly
increase or decrease due to fluctuating levels of DA
in the basal ganglia
• Behavioral and mental disturbances
 DOPAMINE AGONISTS

• Drugs: bromocriptine, pergolide, pramipexole, and

ropinirole
• Stimulate DA receptors in the basal ganglia
• Used alone or in combination with levodopa
• Adverse effects similar to levodopa: nausea, hypotension,
dyskinesias, and mental disturbances
 AMANTADINE (SYMMETREL)

• An antiviral drug that additionally increases the

release of DA in the brain
• Used in early stages of treatment and in combination
with other drugs
• Effectiveness usually decreases in 6–12 months
• Adverse effects include nausea, mental disturbances,
and occasionally skin discoloration
 ENZYME INHIBITORS

• Selegiline (Eldepryl) inhibits MAO-B enzyme that slows

metabolism of DA in the brain, increases DA levels; used
alone or with levodopa
• Tolcapone (Tasmar) and entacapone (Comtan) inhibit another
enzyme, COMT, that also slows metabolism of DA; usually
used with levodopa
 ANTICHOLINERGIC DRUGS

• Used to decrease the activity of ACH and restore the

normal balance between DA and ACH
• Benztropine (Cogentin)and trihexyphenidyl (Artane)
most widely used drugs
• Antihistamine drugs, diphenhydramine (Benadryl),
with high anticholinergic activity occasionally used
• Used alone early in treatment or in combination with
other drugs
THE OPIOID SYSTEM
 CLINICAL INDICATION

• Prevent or interrupt moderate to severe pain of any

origin without a loss of consciousness
• Acute pain-during or after surgical procedures
• Chronic pain-of any etiology from back pain to
cancer pain
SOURCE OF OPIOID ANALGESICS

Opioid analgesics are derivatives of the

• naturally occurring plant substance opium

OR

• synthetic substances that produce the same pharmacologic

effects as opium
 Types of Analgesics

Opiates-opium, heroin
codeine, morphine, hydromorphone, oxycodone,
oxymorphone

Opioids-synthetic
butorphanol, fentanyl, levorphanol,
meperidine, methadone, propoxyphene

Central analgesics (nonopioid)-tramadol

DRUG SCHEDULE FEDERAL COMPREHENSIVE
DRUG ABUSE PREVENTION AND CONTROL ACT

Because of their liability to produce physical

dependence, opioid analgesics are included
in the class of controlled substances as Schedule II drugs

• Restricted to prescription use

• No refill without new written prescription
• Regulated by the FDA (Food and Drug Administration) and DEA
(Drug Enforcement Agency)
 SENSATION OF PAIN

Pain is composed of at least two elements

• localized stimulation of peripheral nerves

through damage or inflammation

• recognition of pain within the CNS that

can intensify the reaction to pain
 MECHANISM OF
ACTION
O P I O I D A N A L G E S I C S R E L I E V E PA I N B Y
S E L E C T I V E LY A C T I N G O N R E C E P T O R S W I T H I N T H E
C N S ( R AT H E R T H A N O N P E R I P H E R A L N E RV E
ENDINGS) TO

• DECREASE ANXIETY
• R E D U C E T H E R E A C T I O N T O PA I N
• I N T E R R U P T PA I N S I G N A L T R A N S M I S S I O N W I T H I N
THE SPINAL CORD
 MECHANISM OF ACTION (CONTINUED)

Opioid analgesics mimic the action of endorphins

produced in the brain and spinal cord by
selectively stimulating receptors

• mu (µ) receptors mediate analgesia, euphoria, and respiratory depression

• kappa (κ) receptors mediate sedation, dysphoria
• delta (δ) receptors mediate, hallucinations, and increased respiration and
blood pressure
 Pharmacological Effects

CNS
• Change in mental alertness, sedation (μ, κ)
• Change mood, euphoria (µ) or dysphoria (κ)
• Stimulation of chemoreceptor trigger zone
initiating nausea and vomiting
• Dose dependent depression of the vomiting center
• Depression of respiratory centers (µ)
• Headache
• Cough suppressant (antitussive)
• Secretion of antidiuretic hormone
 PHARMACOLOGICAL EFFECTS
(CONTINUED)
• Tolerance
• Decreased response to euphoria, sedation, respiratory depression and
analgesia with chronic daily use
• Response returns when the dose is increased
• Physical dependence
• Chronic use establishes an internal expectation within the body of receiving
receptor activiation
• Withdrawal symptoms (abstinence syndrome) occur when the drug is
abruptly discontinued. (This can be minimized by gradual taper down)
PHARMACOLOGICAL EFFECTS (CONTINUED)
Smooth Muscle (μ receptor mediated)
• Spasmogenic
• Intestine- constipation
• Gall bladder common bile duct- increase
pressure, pain
• Bronchial constriction
• Urinary sphincters- oliguria
• Histamine release
• Bronchial constriction
• Vasodilation-orthostatic hypotension
 ANTITUSSIVE ACTIVITY
Natural opiates such as codeine, hydrocodone,
and hydromorphone suppress coughs by
inhibiting centers in the brain

At present, dextromethorphan is the only opioid

that is used in commercial over-the-counter
cough suppressant products

Usually OTC products include additional active

ingredients that treat other symptoms of cold & flu
ADVERSE EFFECTS
• Mental confusion
• Sedation
• Headache
• Nausea
• Vomiting
• Dry mouth
• Constipation
• Urinary retention
• Itching, rash, anaphylaxis
• Orthostatic hypotension
• Physical dependence
 ACUTE OPIOID POISONING
Accidental ingestion of a large dose by
children or attempted suicide may produce
• Coma
• Decreased respiration
• Cyanosis
• Hypotension
• Drop in body temperature
• Death
 OPIOID ANTAGONISTS
A pure opioid antagonist fits the opiate
receptor, cannot stimulate the receptor, and
blocks the opioid analgesic from attaching
to the receptor.
• naloxone, naltrexone

A partial antagonist fits the opiate receptor and

weakly stimulates the receptor while it blocks the
opioid analgesic from attaching to the receptor
• butorphanol, nalbufene
 CAUTIONS AND CONTRAINDICATIONS

Opioid analgesics should not be used in patients

with
• Bronchial asthma
• Heavy pulmonary secretions
• Convulsive disorders
• Biliary obstruction
• Head injuries
• A history of allergy or sensitivity to this class

Used with caution in

• Elderly patients
• Pregnant women
 DRUG INTERACTIONS

Potentiate CNS depression of all Opioids

• sedatives, hypnotics, general anesthetics,
alcohol

Meperidine or dextromethorphan
• MAO inhibitors- sweating, hypotension, hypertension

Methadone
• Reduced plasma levels of methadone-
rifampin, phenytoin
ANTIEPILEPTIC DRUGS
Prajogo
 TREATMENT

• Try to find a cause. (e.g. fever, head trauma, drug

abuse)
• Recurrent seizures that cannot be attributed to any
cause are seen in patients with epilepsy.
• Therapy is aimed at control

• drugs do not cure.

• The type of seizure determines the choice of drug!

• More than 80% of patients with epilepsy can have their

seizures controlled with medications.
 TREATMENT

• Monotherapy with anticonvulsant

• Increase dose gradually until seizures are controlled
or adverse effects become unacceptable.
• Multiple-drug therapy may be required.
• Achieve steady-state kinetics
• Monitor plasma drug levels
• Avoid sudden withdrawal
 Pharmacokinetics

• Most classical antiepileptic drugs exhibit similar

pharmacokinetic properties.
• Good absorption.
• Low plasma protein binding (except for phenytoin, BDZs,
valproate, and tiagabine).
• Conversion to active metabolites (carbamazepine, primidone,
fosphenytoin).
• Cleared by the liver but with low extraction ratios.
• Distributed in total body water.
• Plasma clearance is slow.
• At high concentrations phenytoin exhibits zero order kinetics.
Therapeutic Range
Notable adverse effects of antiseizure medications.
 Treatment of Seizures

Strategies:

• Modification of ion conductances.

• Increase inhibitory (GABAergic) transmission.

• Decrease excitatory (glutamatergic) activity.

 Drug treatment of seizures

• Life-long treatment may be necessary.

• It may take weeks to establish adequate drug plasma

levels and to determine the adequacy of therapeutic
improvement.

• Lack of compliance is responsible for many treatment

failures.
Classification of epilepsies and drug selection.

1. Partial seizures
1. Carbamazepine, phenytoin
2. Valproic acid, lamotrigine, gabapentin, benzodiazepines,
barbiturates
3. Adjunct: Tiagabine, topiramate, levetiracetam, zonisamide
2. Generalized seizures:

A. Tonic-clonic (grand mal):

1. Carbamazepine, phenytoin
2. Valproic acid, lamotrigine, gabapentin,
benzodiazepines, barbiturates
3. Adjunct: Topiramate, zonisamide
B. Absence (petit mal):

1. Ethosuximide
2. Valproic acid (when absence seizures coexist with
tonic-clonic seizures)
3. Clonazepam
4. Adjunct: Lamotrigine, benzodiazepines
C. Myoclonic syndromes:

1. Valproic acid
2. Clonazepam and other benzodiazepines
3. Adjunct: levetiracetam
3. Status epilepticus:

• Treatment is intravenous diazepam or lorazepam

followed by intravenous fosphenytoin (or phenytoin)
or phenobarbital.
 MECHANISMS OF ACTION
• 3 main categories of therapeutics:

1.Inhibition of voltage-gated Na+ channels to slow neuron

firing.

2.Enhancement of the inhibitory effects of the

neurotransmitter GABA.

3.Inhibition of calcium channels.

I. NA+ CHANNEL INHIBITORS

blocks voltage-gated sodium channels by

selectively binding to the channel in the inactive
state and slowing its rate of recovery
 Na+ Channel Inhibitors

• Phenytoin (Dilantin)
• Fosphenytoin (Cerebyx)
• Carbamzepine (Tegretol, Carbatrol)
• Oxcarbazepine (Trileptal)
• Valproic Acid (Valproate; Depakene, Depakote)
• Lamotrigine (Lamictal)
• Topiramate (Topamax)
• Zonisamide (Zonegran)
 NA+ CHANNEL INHIBITORS

1. Phenytoin (Dilantin):
• Oldest nonsedative antiepileptic drug.
• Indications:
• First choice for partial and generalized tonic-clonic seizures
• Some efficacy in clonic, myoclonic, atonic,
• No effect on infantile spasms or absence seizures
• Drug Interactions:
• Decreases blood levels of many medications
• Increases blood levels of phenobarbital & warfarin
 NA+ CHANNEL INHIBITORS

Phenytoin (Dilantin):
• Adverse Effects:
• Hirsutism & coarsening of facial features
• Acne
• Gingival hyperplasia (20-40%)
• Decreased serum concentrations of folic acid, thyroxine, and
vitamin K with long-term use.
• “Fetal hydantoin syndrome”:
• includes growth retardation, microencephaly, and craniofacial
abnormalities (e.g., cleft palate) and is possibly due to an epoxide
metabolite of phenytoin.
PHENYTOIN INDUCED GINGIVAL HYPERPLASIA

17 year old boy treated with

300mg/day phenytoin for 2
years (unsupervised)

Partial recovery at 3 months

after discontinuation
• Fosphenytoin is a prodrug
• rapidly converted to phenytoin in the blood, providing high levels of
phenytoin within minutes.
• Fosphenytoin may also be administered intramuscularly (IM).
• Phenytoin sodium should never be given IM because it can cause
tissue damage and necrosis.
• Fosphenytoin is the drug of choice and standard of care for IV and
IM administration.
• Due to sound-alike and look-alike names, there is a risk for
medication error to occur.
• The trade name of fosphenytoin is Cerebyx®
• Celebrex®, the cyclooxygenase-2 inhibitor
• Celexa®, the antidepressant.
 NA+ CHANNEL INHIBITORS

2. Carbamzepine (Tegretol):
• Tricyclic, antidepressant (bipolar)
• Indications:
• First choice for complex partial and generalized tonic-clonic
seizures.

• Contraindications:
• May exacerbate absence or myoclonic seizures.
• Blood disorders
• Liver disorders
 NA+ CHANNEL INHIBITORS
Carbamazepine (Tegretol, Carbatrol):
• Drug Interactions:
• CBZ metabolism is affected by many drugs, and CBZ affects the
metabolism of many drugs.
• Determination of plasma levels and clearance may be necessary for
optimum therapy.

• Adverse Effects:
• Common: Diplopia and ataxia (most common), gastrointestinal
disturbances; sedation at high doses
• Occasional: Retention of water and hyponatremia; rash, agitation in
children
• Rare: Idiosyncratic blood dyscrasias and severe rashes
 NA+ CHANNEL INHIBITORS

3. Oxcarbazepine (Trileptal):
• FDA approved in 2000 for partial seizures
• Complex partial seizures
• Primary & secondarily generalized tonic-clonic seizures
• Is a prodrug whose actions are similar to those of
carbamazepine; it has a short half-life of 1—2 hour.
• Its activity is due to a 10-hydroxy metabolite with a
half-life of 10 hours.
• Fewer adverse effects than CBZ, phenytoin
 NA+ CHANNEL INHIBITORS

4. Valproic Acid (Valproate; Depakene, Depakote):

• Other Mechanisms of Action:
1) Some inhibition of T-type Ca2+ channels.
2) Increases GABA production and decreases GABA
metabolism. (Inhibition of GABA transaminase )
• Indications:
• Simple or complex partial, & primary generalized tonic-clonic
• Also used for absence, myoclonic, and atonic seizures.
• Highly effective for photosensitive epilepsy and juvenile
myoclonic epilepsy.
• Contraindications:
• Liver disease
 NA+ CHANNEL INHIBITORS

4. Valproic Acid (Valproate; Depakene, Depakote):

• Drug Interactions:
• Affects metabolism of many drugs through liver enzyme inhibition
 NA+ CHANNEL INHIBITORS

4. Valproic Acid (Valproate; Depakene, Depakote):

• Adverse Effects:
• Weight gain (30-50%)
• Dose-related tremor
• Transient hair loss
• Polycystic ovary syndrome and menstrual disturbances
• Bone loss
• Ankle swelling
 NA+ CHANNEL INHIBITORS

5. Lamotrigine (Lamictal):
• Other Mechanism of Action:
• May inhibit synaptic release of glutamate.
• Indications:
• Adjunct therapy (ages 2 & up):
• Simple & complex partial seizures
• Generalized seizures of Lennox-Gastaut Syndrome
• Monotherapy (adults):
• Simple & complex partial seizures
• Contraindications:
• May make myoclonic seizures worse.  
Lennox-Gastaut syndrome
• is the most distressing of childhood epilepsies.
• The children suffer frequent fits of many different types,
and experience gradual mental deterioration.
• Infantile spasms often evolve into Lennox-Gastaut
syndrome, and the age of onset is from 1 to 8 years,
peaking at 3 to 5 years.
 NA+ CHANNEL INHIBITORS

5. Lamotrigine (Lamictal):

• Adverse Effects:
• Rash (10%)
• Rare progression to serious systemic illness
• Increased alertness
 NA+ CHANNEL INHIBITORS

6. Topiramate (Topamax):
• Other Mechanism of Action:
• Enhances post-synaptic GABAA receptor currents.
• Kainate receptor antagonist (blocks a certain type of
glutamate channel)

• Indications:
• Adjunct therapy for partial and primary generalized
• seizures in adults and children over 2.
• Decreases tonic and atonic seizures in children with
Lennox-Gastaut syndrome.
• Contraindications:
• History of kidney stones
 NA+ CHANNEL INHIBITORS

6. Topiramate (Topamax):

• Drug Interactions:
• CBZ, phenytoin, phenobarbital, & primidone decrease blood
levels

• Adverse Effects:
• Nervousness & paresthesias
• Psychomotor slowing, word-finding difficulty, impaired
concentration, interference with memory
• Weight loss & anorexia
• Metabolic acidosis
 NA+ CHANNEL INHIBITORS

7. Zonisamide (Zonegran):
• is a sulfonamide derivative that has a broad spectrum
of action
• Other Mechanism of Action:
• Inhibits T-type Ca2+ currents.
• Binds to GABA receptors.
• Facilitates dopaminergic and serotonergic neurotransmission.
 NA+ CHANNEL INHIBITORS

7. Zonisamide (Zonegran):
• Indications:
• Approved for adjunct treatment of partial seizures in adults.
• Appears to have a broad spectrum:
• Myoclonic seizures
• Infantile spasms
• Generalized & atypical absence seizures
• Lennox-Gastaut Syndrome
• Drug Interactions:
• Phenytoin and carbamazepine decrease its half-life by half.
 NA+ CHANNEL INHIBITORS

7. Zonisamide (Zonegran):

• Adverse Effects:
• Weight loss
• Abnormal thinking
• Nervousness
• Agitation/irritability
• Usually well tolerated
II. ENHANCEMENT OF GABA INHIBITION
 ENHANCEMENT OF GABA INHIBITION

1. Barbiturate drugs:

A. Phenobarbital (Luminal)
B. Primidone (Mysoline)

• Mechanism of Action:
• Increases the duration of GABAA-activated
Cl- channel opening.
 ENHANCEMENT OF GABA INHIBITION

A. Phenobarbital (Luminal):

• Indications:
• Second choice for partial and generalized tonic-clonic seizures.
• Rapid absorption has made it a common choice for seizures in
infants, but adverse cognitive effects cause it to be used less in older
children and adults.
• Status epilepticus
• Contraindications:
• Absence Seizures
 ENHANCEMENT OF GABA INHIBITION

B. Primidone (Mysoline):

• Indications:
• Adjuvant or monotherapy for partial and generalized tonic-clonic
seizures
• May control refractory generalized tonic-clonic seizures
• Contraindications:
• History of porphyria
 ENHANCEMENT OF GABA INHIBITION

• Phenobarbital (Luminal) & Primidone (Mysoline):

• Drug Interactions:
• Other CNS depressants
• Increased metabolism of vitamin D and K
• Phenytoin increases the conversion of primidone to phenobarbital.
 ENHANCEMENT OF GABA INHIBITION

• Phenobarbital (Luminal) & Primidone (Mysoline):

• Adverse Effects:
• Agitation and confusion in the elderly.
• Worsening of pre-existing hyperactivity and aggressiveness in
children
• Sexual side effects
• Physical dependence
 ENHANCEMENT OF GABA INHIBITION

2. Benzodiazepine drugs:

 Diazepam (Valium)
 Lorazepam (Ativan)
 Clonazepam (Klonopin)
 Clorazepate (Transxene-SD)

• Mechanism of Action:
• Increases the frequency of GABAA-activated Cl- channel opening.
 Enhancement of GABA Inhibition

2. Benzodiazepine drugs:

• Indications:
• Only clonazepam & clorazepate approved for long-term treatment.
• Clorazepate
• In combination for partial seizures
• Clonazepam
• Lennox-Gastaut Syndrome, myoclonic, atonic, and absence seizures
• Tolerance develops after about 6 months
 ENHANCEMENT OF GABA INHIBITION

2. Benzodiazepine drugs:

• Indications:
• Diazepam and lorazepam are used in treatment of status epileticus.
• Diazepam is painful to inject; lorazepam is more commonly used in
acute treatment.
• Diazepam
• Intermittent use for control of seizure clusters
• Diazepam frequently combined with phenytoin.
 ENHANCEMENT OF GABA INHIBITION

2. Benzodiazepine drugs:
• Contraindications:
• Diazepam in children under 9
• Narrow angle glaucoma
• Adverse Effects:
• Hypotonia, Dysarthria (Difficulty in articulating words, caused by
impairment of the muscles used in speech)
• Muscle in-coordination (clonazepam)
• Behavioral disturbances (especially in children)
• Aggression, Hyperactivity, Irritability and Difficulty concentrating
 ENHANCEMENT OF GABA INHIBITION

3. Tiagabine (Gabitril):

• Mechanism of Action:
• Inhibition of GABA transporter (GAT-1) – reduces reuptake of
GABA by neurons and glial cells.
• Indications:
• Approved in 1998 as an adjunct therapy for partial seizures in
patients at least 12 years old.
• Contraindications:
• Absence seizures
 ENHANCEMENT OF GABA INHIBITION

3. Tiagabine (Gabitril):

• Interactions:
• Blood levels decreased by CBZ, phenytoin, phenobarbital, &
primidone

• Adverse Effects:
• Asthenia (weakness)
• Abdominal pain
 III. CALCIUM CHANNEL BLOCKERS

inhibit low-threshold (T-type) Ca 2+

currents, especially in thalamic
neurons that act as pacemakers to
generate rhythmic cortical discharge.
 VOLTAGE-GATED CA2+ CHANNEL T CURRENTS

1. Ethosuximide (Zarontin):

• Mechanism of Action:
• Reduces low -threshold Ca2+ currents (T currents) in the
thalamic neurons.
• Half-life is ~60 hr in adults; ~30hr in children.
• Indications:
• First line for absence seizures
• Contraindications:
• May exacerbate partial & tonic-clonic seizures
 VOLTAGE-GATED CA2+ CHANNEL T CURRENTS

1. Ethosuximide (Zarontin):
Adverse Effects:
• Psychotic behavior
• Blood dyscrasias
• Persistent headaches
• Anorexia
• Hiccups
• Lupus-like syndromes

• Toxicity:
• parkinson-like symptoms
• photophobia
 BLOCKADE OF CALCIUM CHANNELS ()

1. Gabapentin (Neurontin):
• Mechanism of Action:
• Originally designed to be a centrally acting GABA agonist.
• Selective inhibition of v-g Ca2+ channels containing the α2δ1
subunit.

• Indications:
• adjunct therapy in adults and children with partial & secondarily
generalized seizures.
• Also effective as monotherapy.
 BLOCKADE OF CALCIUM CHANNELS ()

• Gabapentin (Neurontin):

• Contraindications:
• Can exacerbate myoclonic & absence seizures.
• Adverse Effects:
• Weight Gain (5%) with ankle edema
• Irritability
• Behavioral problems in children (6%)
• Has been associated with movement disorders.
 BLOCKADE OF CALCIUM CHANNELS ()

2. Pregabalin (Lyrica):
• Mechanism of Action:
• Same as gabapentin
• Indications:
• Approved in 2005
• Adjunct therapy for partial & secondarily generalized seizures
• Other uses:
• Prescribed for neuropathic pain, fibromyalgia (A syndrome
characterized by chronic pain in the muscles of soft tissues surrounding
joints, fatigue, and tenderness at specific sites in the body)
 OTHER/UNKNOWN MOA

• Levetiracetam (Keppra):

• Indications:
• Approved in 1999 as an adjunct therapy for adults with partial
seizures.
• Some patients have success with monotherapy
 OTHER/UNKNOWN MOA

• Levetiracetam (Keppra):

• Contraindications:
• Renal dysfunction

• Adverse Effects:
• Asthenia
• Infection
• Behavioral problems in children
 Block the N-methyl-D-aspartate (NMDA)
glutamate receptor.

• Felbamate

• Felbamate has a broad spectrum of anticonvulsant action.

• The drug has multiple proposed mechanisms including
1) blocking voltage-dependent sodium channels
2) competing with the glycine-coagonist binding site on the N-methyl-
D-aspartate (NMDA) glutamate receptor
3) blocking calcium channels
4) potentiation of GABA actions.

• It is reserved for use in refractory epilepsies (particularly Lennox-Gastaut

syndrome) because of the risk of aplastic anemia (about 1:4000) and
hepatic failure.