Insomnia 2

Terminology
Sedative state
Hypnotic state
Sedative H ypnotic D rugs

H M Bakhriansyah, dr., M.Kes., M.Med.Ed
Department of Pharmacology
Medical Faculty
Lambung Mangkurat University
Sleeping
Wakefulness
NREM
REM
4 phases
1 phase
Physical processes
Physical processes
decreased
increased
For relieving physical
For relieving mental
tiredness
tiredness
Non recalling of and non
Detail, non logical and
detail dream
bizarre dream
nightmare
Night terror and sleep
walking
Wakefulness
Driven by formation reticulare brain

steam and hypothalamus
Neurotransmitters:
5HT, adenosin, GABA
Excitation: NE, dopamine, histamine

Inhibition: 5HT, GABA, adenosine
ACh
Insomnia
Difficultly to fall into
sleep or sleep cycle
incompletely leading
to symptoms and life
disturbances
diminishing of
working ability, social
and daily life
Classification:
Transient insomnia : 2-3 days
Short term insomnia : 3 weeks
Long term insomnia : > 3 weeks
Initial insomnia
: difficult to fall into sleep
Delayed insomnia : easy to wake up and
difficult to gain into sleep again
Broken insomnia
: multiple awakening
Consideration
Initial insomnia
Short acting benzodiazepine
Anxiety
Delayed insomnia
Broken insomnia
Tricyclic and tetracyclic

anti depressants agents
Long acting benzodiazepine

Phenobarbital
Depression syndrome
Psychosocial stress
Given 15-30 minutes before night sleeping

Dose is increased gradually
Optimal dose is maintained for 1-2 weeks
followed by tapering off
Elderly: dose is reduced or given 2-3 times
per week
SEDATIVE HYPNOTIC AGENTS
BENZODIAZEPINE DERIVATES
BENZODIAZEPIN DERIVATES
BARBITURATE DERIVATES
OTHERS:
Bind to its receptors (close to GABA

receptors) inhibitory neurotransmitter
within the CNS
CHLORALHIDRATE
PARALDEHIDE
ANTIHISTAMINE: Diphenhidramine,
doxylamine
NEWER DRUGS: zolpidem, zaleplon, zolpiklon
BDZ
BARB
Intensify Cl conductance
mediated by GABA
Prolong GABA effects
The receptors-drugs interaction regulates

the entrance of Cl into the post synaptic
cells.
Commonly used: wide range of safety
Alprazolam
Bromazepam
Chlorazepate
Chlordiazepoxide
Diazepam
Estazolam
Flurazepam
Halazepam
Lorazepam
Midazolam
Nitrazepam
Oxazepam
Prazepam
Temazepam
Triazolam
Diminish synaptic transmission
Pharmacodynamic
Clinical Uses
Depression the CNS
Anxiety
Low therapeutic dose

Relief of anxiety, drowsiness, sluggishness
Increased dose
Muscle relaxation, hypnosis
Relatively safe: distinctive dose for therapy and

death
Side effects: minimal related to lacking of GABA
neurons in the periphery.
Pharmacotherapy
accomplished by
counseling
Using the lowest
effective dose and the
shortest duration
Chosen drug based on
half life unless for
depression based
anxiety
(ALPRAZOLAM)
Clinical Problems
Insomnia
Altering the normal distribution of REM phase and
NREM sleep.
Epilepsy and seizures (clonazepam, diazepam)

Sedation, retrograde amnesia and anesthesia
Muscle relaxant (diazepam)
Alcohol and sedative hypnotic withdrawal
(diazepam and chlordiazepoxide)
Cross tolerance
Dependency (physically and mentally)
Drug abuse
Withdrawal syndrome particularly for
barbiturate rebound insomnia, anxiety
BARBITURATES
Side effects are related to their ability to
produce CNS depression: excessive
sedation, confusion, impaired motor
coordination suppress breathing center,
allergy and death.
Accidental ingestion suicides

Having serious and lethal interaction with
other drugs
Depressing CNS: sedation general
anesthesia
Interaction: alcohol, other CNS

depressants
Clinical use: insomnia, anxiety, epilepsy,

seizure, anesthesia.
Other drugs
Side effects : laryngospasm
Interaction : oral contraceptive,
phenytoin, digitoxin, quinidine etc.
Azapirones such as buspirone (5HT)

Antihistamines such as diphenhidramine,
promethazine, hydroxyzine, etc
B-adrenergic blocking agents such as
propranolol, particularly somatic anxiety
controversy.
Antipsychotic and antidepressants such as
chlorpromazine and amitriptyline.
Status Epilepticus
SE :
Continues seizures
occuring 30 minutes
(epilepsi foundation)
More than 30 minutes
of continues seizures
activity or 2 or more
sequential seizures
without full recovery of
consciousness between
seizures (Dodson,
1993).
Systemic and primary brain changes related

to morbidity and mortality rates
Decreasing GABA inhibition.
Increasing blood pressure (early stage) decreasing
Acidosis (+)
Pulmonary edema
Hyperthermia
Mild leukocytosis
GABAergic mechanism fails
Treatment flowchart for status

epilepticus
Goal of therapy: to treat the epilepsy and to
minimalise the side effects
Principal therapy:
Monotherapy is better than polypharmacy
Dosage is increased until the therapeutic effect
or toxicity effect are met.
Polypharmacy is introduced when monotherapy
does not work
Avoiding the sudden withdrawal
Medications
Fenitoin
Karbamazepin
Lamotrigin
Na
Glutamate
STATUS EPILEPTICUS
GABA
Barbiturat
Benzodiazepin
Asam valproat
Gabapentin
Ca
Fenitoin
Karbamazepin
Asam valproat
Etosuksimid
Karbamazepin
Stabilize neural
membrane by
decreasing Na, Ca
and K flows through
it.
avoid to be given
with MAO inhibitor
consecutively
Fenitoin
Difenilhidantoin
derivate
Mechanism of actions
are similar to
Karbamazepin
Could be given orally,
intra venous and intra
muscular
Valproic Acid
Increasing GABA
transmission
Sedation effect is
minimal
Etosuksimid
Mechanism of action
is unknown
Probably by
inhibiting Ca channel
Phenobarbital
Stimulating GABA
receptor
SE: sedation,
nistagmus, ataxia and
allergy
Inducing enzym P450
Primidon
Mechanism of actions
are unknown
Its active metabolit
has long half life
Gabapentin
GABA agonist
Adjuvant therapy
Lamotrigin
Stabilizing neuron
and affecting
glutamate release
Adjuvant therapy
SE: rash (prominent)
Klonazepam
Stimulating GABA
receptor
Felbamat
Stimulating GABA
receptor and
inhibiting NMDA
receptor
Used un-frequently
Parkinson disease
Principle therapy
A progressive
neurodegenerative
disorder associated
with loss of
dopaminergic
nigrostriatal neurons.
To facilitate action of dopaminergic
Distinctive features:
Resting tremor,
rigidity, bradikinetia,
and postural instability
Increasing the synthesis

and release of
dopamine (Ldopa+karbidopa,
amantadin)
Inhibiting dopamin
metabolism
(selegilin/deprenil)
Activating dopamine
receptor
(bromocriptine,
pergolide)
To suppress action of cholinergic
Blocking muscarinic/
cholinergic receptor
(trihexiphenidile,
benzathropine,
diphenhidramine)
Protocol of therapy
Anti cholinergic
Amantadine
L-dopa+karbidopa
Dopamine agonists drugs

MAO B inhibitors
Selegiline (deprenil)
Instead of inhibiting
metabolism of dopamine:
Stimulating dopamine
release.
Neuro-protective effect
+ MOA inhibitors
crisis of hypertension.
Bromociptine & Pergolide

Dopamine receptor
agonists
Action: Lesser than Ldopa
As a single therapy at the
early stage
Combination with Ldopa at the moderate and
late stage.
Tapering dose
L-dova (levodopa)
Dopamine precursor
inactive form
Activated by
decarboxilase
enzyme;
Brain
Lever & kidneys can
not pass through BBB
bioavailability
countered by
karbidopa/benserazide
.
Trihexiphenidile &
benzotropine
Action: less than Ldopa
Adjuvant therapy
Tapering dose
Interaction:
piridoxine increases
decarboxilated
reaction.
On/off phenomenon
(+) after 3-5 years
application
mechanism ???
Desensitization of
dopamine receptor
Not a first line
therapy
Diphenhidramine
Anti cholinergic effect
at central level
Anti histamine
Amantadine
Anti virus
Mechanism: ??? May be
by facilitating dopamine
release
Action:
Less than L-dopa
Better than anti
cholinergic
Early stage:
Anti cholinergic or
Amantadine
When early stage therapy

is not effective, Ldopa+karbidopa are
started.
Final stage: dopamine
agonists medications and
MAO inhibitors.

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Terminology

Sedative H ypnotic D rugs

Driven by formation reticulare brain

5HT, adenosin, GABA

Excitation: NE, dopamine, histamine

Short acting benzodiazepine

Tricyclic and tetracyclic

Long acting benzodiazepine

Given 15-30 minutes before night sleeping

SEDATIVE HYPNOTIC AGENTS

Bind to its receptors (close to GABA

Prolong GABA effects

The receptors-drugs interaction regulates

Diminish synaptic transmission

Depression the CNS

Low therapeutic dose

Relatively safe: distinctive dose for therapy and

Epilepsy and seizures (clonazepam, diazepam)

Accidental ingestion suicides

Interaction: alcohol, other CNS

Clinical use: insomnia, anxiety, epilepsy,

Azapirones such as buspirone (5HT)

Systemic and primary brain changes related

Treatment flowchart for status

To facilitate action of dopaminergic

Increasing the synthesis

To suppress action of cholinergic

Dopamine agonists drugs

Bromociptine & Pergolide

When early stage therapy

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