Sedative H ypnotic D rugs

H M Bakhriansyah, dr., M.Kes., M.Med.Ed

Department of Pharmacology
Medical Faculty
Lambung Mangkurat University

Terminology

Sedative state Hypnotic state

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Sleeping
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 

Night terror and sleep nightmare
walking
Wakefulness

5HT, adenosin, GABA
ACh

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Wakefulness

Driven by formation reticulare brain

steam and hypothalamus

Neurotransmitters:
Excitation: NE, dopamine, histamine
Inhibition: 5HT, GABA, adenosine

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Insomnia

Difficultly to fall into
sleep or sleep cycle
incompletely leading
to symptoms and life
disturbances 
diminishing of
working ability, social
and daily life

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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

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 Initial insomnia Delayed insomnia Broken insomnia

Tricyclic and tetracyclic • Long acting benzodiazepine

Short acting benzodiazepine
anti depressants agents • Phenobarbital

Anxiety Depression syndrome Psychosocial stress

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Consideration

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

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SEDATIVE – HYPNOTIC AGENTS

BENZODIAZEPIN DERIVATES

BARBITURATE DERIVATES

OTHERS:
CHLORALHIDRATE
PARALDEHIDE
ANTIHISTAMINE: Diphenhidramine,
doxylamine
NEWER DRUGS: zolpidem, zaleplon, zolpiklon

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BENZODIAZEPINE DERIVATES

Bind to its receptors (close to GABA

receptors)  inhibitory neurotransmitter
within the CNS

The receptors-drugs interaction regulates

the entrance of Cl into the post synaptic
cells.

Commonly used: wide range of safety

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 BDZ BARB

Intensify Cl conductance
Prolong GABA effects
mediated by GABA

Diminish synaptic transmission

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Alprazolam
Lorazepam

Bromazepam
Midazolam

Chlorazepate
Nitrazepam

Chlordiazepoxide
Oxazepam

Diazepam
Prazepam

Estazolam
Temazepam

Flurazepam
Triazolam

Halazepam

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Pharmacodynamic

Depression the CNS

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.
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Clinical Uses

Anxiety
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)

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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)

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Clinical Problems

Cross tolerance

Dependency (physically and mentally)

Drug abuse

Withdrawal syndrome particularly for
barbiturate  rebound insomnia, anxiety

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Side effects are related to their ability to
produce CNS depression: excessive
sedation, confusion, impaired motor
coordination  suppress breathing center,
allergy and death.

Interaction: alcohol, other CNS

depressants

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BARBITURATES

Accidental ingestion  suicides

Having serious and lethal interaction with
other drugs

Depressing CNS: sedation – general
anesthesia

Clinical use: insomnia, anxiety, epilepsy,

seizure, anesthesia.
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Side effects : laryngospasm

Interaction : oral contraceptive,
phenytoin, digitoxin, quinidine etc.

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Other drugs

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.

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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).

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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

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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
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Treatment flowchart for status

epilepticus

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Medications
Fenitoin
Lamotrigin
Karbamazepin

Na Glutamate

STATUS EPILEPTICUS

GABA Ca

Barbiturat Fenitoin
Benzodiazepin Karbamazepin
Asam valproat Asam valproat
Gabapentin Etosuksimid
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Karbamazepin Fenitoin

Stabilize neural
Difenilhidantoin
membrane by derivate
decreasing Na, Ca
Mechanism of actions
and K flows through are similar to
it. Karbamazepin

avoid to be given
Could be given orally,
with MAO inhibitor intra venous and intra
consecutively muscular

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Valproic Acid Etosuksimid

Increasing GABA
Mechanism of action
transmission is unknown

Sedation effect is
Probably by
minimal inhibiting Ca channel

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Phenobarbital Primidon

Stimulating GABA
Mechanism of actions
receptor are unknown

SE: sedation,
Its active metabolit
nistagmus, ataxia and has long half life
allergy

Inducing enzym P450

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Gabapentin Lamotrigin

GABA agonist
Stabilizing neuron

Adjuvant therapy and affecting
glutamate release

Adjuvant therapy

SE: rash (prominent)

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Klonazepam Felbamat

Stimulating GABA
Stimulating GABA
receptor receptor and
inhibiting NMDA
receptor

Used un-frequently

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Parkinson disease

A progressive
neurodegenerative
disorder associated
with loss of
dopaminergic
nigrostriatal neurons.

Distinctive features:
Resting tremor,
rigidity, bradikinetia,
and postural instability

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Principle therapy

To facilitate action of dopaminergic To suppress action of cholinergic

Increasing the synthesis
Blocking muscarinic/

and release of cholinergic receptor
dopamine (L- (trihexiphenidile,
dopa+karbidopa, benzathropine,
amantadin) diphenhidramine)

Inhibiting dopamin
metabolism
(selegilin/deprenil)

Activating dopamine
receptor
(bromocriptine,
pergolide) HaMBa - 2008
Protocol of therapy
Anti cholinergic
Amantadine

L-dopa+karbidopa

Dopamine agonists drugs

MAO B inhibitors

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L-dova (levodopa)
Interaction:

Dopamine precursor piridoxine increases
 inactive form decarboxilated

Activated by reaction.
decarboxilase
On/off phenomenon
enzyme; (+) after 3-5 years
Brain application 
Lever & kidneys  can mechanism ???
not pass through BBB Desensitization of
 bioavailability  dopamine receptor
countered by
karbidopa/benserazide
Not a first line
. therapy
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Selegiline (deprenil) Bromociptine & Pergolide

Instead of inhibiting
Dopamine receptor
metabolism of dopamine: agonists
 Stimulating dopamine
Action: Lesser than L-
release. dopa
 Neuro-protective effect

As a single therapy at the

+ MOA inhibitors  early stage
crisis of hypertension.

Combination with L-
dopa at the moderate and
late stage.

Tapering dose
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Trihexiphenidile & Diphenhidramine

benzotropine
Anti cholinergic effect

Action: less than L- at central level
dopa
Anti histamine

Adjuvant therapy

Tapering dose

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Amantadine
Early stage:

Anti virus  Anti cholinergic or

Mechanism: ??? May be  Amantadine
by facilitating dopamine
When early stage therapy
release is not effective, L-

Action: dopa+karbidopa are
 Less than L-dopa
started.
 Better than anti
Final stage: dopamine
cholinergic agonists medications and
MAO inhibitors.

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