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.