OBAT-OBAT PSYCHIATRY

Dimas P.Nugraha
KJF farmakologi dan Terapi FK UNRI
DRUGS USED IN THE TREATMENT OF
PSYCHOSES
The neuroleptic drugs (also called antipsychotic
drugs, or major tranquilizers) are able to reduce
psychotic symptoms in a wide variety of
conditions :
 including schizophrenia,
 bipolar disorder,
 psychotic depression,
 senile psychoses,
 various organic psychoses, and
 drug-induced psychoses.
Antipsychotic drugs able to :
 improve mood and
 reduce anxiety and sleep disturbances,
 but they are not the treatment of choice when
these symptoms are the primary disturbance
in nonpsychotic patients.
 The immediate goal of antipsychotic treatment is a
decrease in acute symptoms that induce patient distress,
particularly behavioral symptoms (e.g., hostility, agitation)
that may present a danger to the patient or others.
 For schizophrenia and schizoaffective disorder,
the goal of antipsychotic treatment is to
maximize functional recovery by
 decreasing the severity of positive symptoms
and their behavioral influence,
 improving negative symptoms,
 decreasing social withdrawal, and
 remediating cognitive dysfunction
Delusional disorder, schizophrenia,
and schizoaffective disorder are
chronic diseases that require
long-term antipsychotic treatment
Neuroleptic agents

First Generation
Antypsychotic
(FGA)

Second Generation
Antypsychotic
(SGA)
Mechanism of action

 Dopamine receptor blocking activity in the

brain
All of the older and most of the newer
neuroleptic drugs block dopamine receptors in
the brain and the periphery
 Serotonin receptor blocking activity in the
brain
Neuroleptic drugs block at dopaminergic and serotonergic
receptors as well as at adrenergic, cholinergic, and
histamine-binding receptors.
 Therapeutic uses
Treatment of schizophrenia:
 The neuroleptics are considered to be the only
efficacious treatment for schizophrenia

 The traditional neuroleptics are most effective in treating

positive symptoms of schizophrenia (delusions,
hallucinations, thought processing, and agitation)

 The newer agents with 5-HT2A receptor blocking

activity may be effective in many patients who are
resistant to the traditional agents, especially in treating
the negative symptoms of schizophrenia (social
withdrawal, blunted emotions, ambivalence, and
reduced ability to relate to people).
Prevention of severe nausea and vomiting:
 The older neuroleptics (most commonly
prochlorperazine) are useful in the treatment of drug-
induced nausea
Other uses:
 The neuroleptic drugs can be used as tranquilizers to
manage agitated and disruptive behavior secondary to
other disorders.
 Neuroleptics are used in combination with narcotic
analgesics for treatment of chronic pain with severe
anxiety.
 Chlorpromazine is used to treat intractable hiccups.
Pimozide is primarily indicated for treatment of the
motor and phonic tics of Tourette's disorder.

However, risperidone and haloperidol are also

commonly prescribed for this tic disorder.

risperidone is now approved for the management of

disruptive behavior and irritability secondary to autism.
 Chemical Structures, Dosages for Acute Psychosis and
Schizophrenia Maintenance, and Metabolic Risk Profilea
 Actions
Antipsychotic actions:
All of the neuroleptic drugs can reduce the
hallucinations and delusions associated with
schizophrenia (positive symptoms) by blocking
dopamine receptors in the mesolimbic system of the
brain
Pharmacotherapy Algorithma for Schyzophrenia
Extrapyramidal effects:
Dystonias (sustained contraction of muscles leading to
twisting distorted postures),
parkinson-like symptoms,
akathisia (motor restlessness),
tardive dyskinesia (involuntary movements of the
tongue, lips, neck, trunk, and limbs) occur with chronic
treatment
Antiemetic effects:
With the exceptions of aripiprazole and
thioridazine, most of the neuroleptic drugs
have antiemetic effects that are mediated by
blocking D2-dopaminergic receptors of the
chemoreceptor trigger zone of the medulla.
Antimuscarinic effects:
Some of the neuroleptics, particularly thioridazine,
chlorpromazine, clozapine, and olanzapine, produce
anticholinergic effects, including blurred vision, dry
mouth (exception: clozapine increase salivation),
confusion, and inhibition of gastrointestinal and
urinary tract smooth muscle, leading to constipation
and urinary retention.

This anticholinergic property may actually assist in

reducing the risk of EPS with these agents.
Therapeutic application of
antiemetic agents
 Adverse effects
Extrapyramidal side effects
 The inhibitory effects of dopaminergic neurons
are normally balanced by the excitatory actions
of cholinergic neurons in the striatum.
 Blocking dopamine receptors alters this balance,
causing a relative excess of cholinergic
influence, which results in extrapyramidal motor
effects.
The maximal risk of appearance of the movement
disorders is time and dose dependent, with
dystonias occurring within a few hours to days of
treatment, followed by akathisias (the inability to
remain seated due to motor restlessness) occurring
within days to weeks.

Parkinson-like symptoms of bradykinesia, rigidity,

and tremor usually occur within weeks to months
of initiating treatment. Tardive dyskinesia, which
can be irreversible, may occur after months or
years of treatment
Tardive dyskinesia:

Long-term treatment with neuroleptics can

cause this motor disorder. Patients display
involuntary movements, including lateral jaw
movements andof the tongue.

A prolonged holiday from neuroleptics may

cause the symptoms to diminish or disappear
within a few months. However, in many
individuals, tardive dyskinesia is irreversible
and persists after discontinuation of therapy.
 Tardive dyskinesia is postulated to result
from an increased number of dopamine
receptors that are synthesized as a
compensatory response to long-term
dopamine-receptor blockade

 This makes the neuron supersensitive to the

actions of dopamine, and it allows the
dopaminergic input to this structure to
overpower the cholinergic input, causing
excess movement in the patient.
 Neuroleptic malignant syndrome

This potentially fatal reaction to neuroleptic drugs is

characterized by muscle rigidity, fever, altered mental status
and stupor, unstable blood pressure, and myoglobinemia.

Treatment necessitates discontinuation of the neuroleptic

and supportive therapy.

Administration of dantrolene or bromocriptine may be

helpful.
Other effects:

Drowsiness occurs due to CNS depression and

antihistaminic effects, usually during the first few weeks
of treatment. Confusion is sometimes encountered.

Those neuroleptics with potent antimuscarinic activity

often produce dry mouth, urinary retention, constipation,
and loss of accommodation.

Others may block α-adrenergic receptors, resulting in

lowered blood pressure and orthostatic hypotension.

The neuroleptics depress the hypothalamus, affecting

thermoregulation, and causing amenorrhea,
galactorrhea, gynecomastia, infertility, and impotence.
Significant weight gain is often a reason for noncompliance.

It is also recommended that glucose and lipid profiles be

monitored in patients taking antipsychotics due to the
potential for the atypical agents to increase these
laboratory parameters and the possible exacerbation of
preexisting diabetes mellitus or hyperlipidemia.
Adverse effects commonly observed in individuals
treated with neuroleptic drugs
Cautions and contraindications
 Acute agitation accompanying withdrawal from
alcohol or other drugs may be aggravated by the
neuroleptics. Stabilization with a simple
sedative, such as a benzodiazepine, is the
preferred treatment.

 All antipsychotics may lower the seizure

threshold, and chlorpromazine and clozapine are
contraindicated in patients with seizure
disorders. Therefore, the neuroleptics can also
aggravate preexisting epilepsy, and they should
be used with caution in patients with epilepsy.
The high incidence of agranulocytosis with
clozapine may limit its use to patients who
are resistant to other drugs.

All of the atypical antipsychotics also carry

the warning of increased risk for mortality
when used in elderly patients with
dementia-related behavioral disturbances
and psychosis
 Maintenance treatment

Patients who have had two or more psychotic

episodes secondary to schizophrenia should receive
maintenance therapy for at least 5 years, and some
experts prefer indefinite therapy.

There has been a greater emphasis in research and

practice on identifying and aggressively managing
first-episode psychosis to determine the benefits of
antipsychotic agents in this population.

Low doses of antipsychotic drugs are not as effective

as higher-dose maintenance therapy in preventing
relapse
Summary of neuroleptic agents
 Drug Therapy of Depression and
Anxiety Disorders
Antidepressant Drugs
 Selective Serotonin Reuptake Inhibitors (SSRI’s)
 Serotonin-Norepinephrine Reuptake Inhibitors
(SNRIs)
 Atypical Antidepressan
 Tricyclic Antidepressan
 Monoamine oxidase inhibitor
 Drug Used to treat mania and Bipolar disorder
Selective Serotonin Reuptake
Inhibitors
 Actions
The SSRIs block the reuptake of serotonin,
leading to increased concentrations of the
neurotransmitter in the synaptic cleft and,
ultimately, to greater postsynaptic neuronal
activity
mechanism of action of selective serotonin re-
uptake inhibitors (SSRI) and tricyclic
antidepressant (TCA) drugs
The prototype SSRI → fluoxetine

Fluoxetine and paroxetine are

potent inhibitors of the CYP2D6
isoenzyme, and this contributes
to potential drug interactions
Therapeutic uses
 The primary indication for SSRIs is depression,
 obsessive-compulsive disorder (the only
approved indication for fluvoxamine),
 panic disorder,
 generalized anxiety disorder,
 posttraumatic stress disorder,
 social anxiety disorder,
 premenstrual dysphoric disorder,
 bulimia nervosa (only fluoxetine is approved for
this last indication).
Pharmacokinetics

 All of the SSRIs are well absorbed after oral

administration.
 Peak levels are approximately 2 to 8 hours
on average
Adverse effects
 Serotonin-Norepinephrine
Reuptake Inhibitors (SNRIs)
Action
 selectively inhibit the re-uptake of both
serotonin and norepinephrine
 mechanism of action of selective
serotonin/norepinephrine re-uptake inhibitor
antidepressant drugs.
 Adverse Effect
 The most common side effects of venlafaxine
are nausea, headache, sexual dysfunction,
dizziness, insomnia, sedation, and
constipation. At high doses, there may be an
increase in blood pressure and heart rate.
 Gastrointestinal side effects are common with
duloxetine, including nausea, dry mouth, and
constipation. Diarrhea and vomiting are seen
less often. Insomnia, dizziness, somnolence,
and sweating
 Atypical Antidepressants

 The atypical antidepressants are a mixed

group of agents that have actions at several
different sites
 Bupropion
 acts as a weak dopamine and norepinephrine
reuptake inhibitor to alleviate the symptoms of
depression
 Bupropion is unique in that it assists in decreasing
the craving and attenuating the withdrawal
symptoms for nicotine in tobacco users trying to
quit smoking
 Side effects may include dry mouth, sweating,
nervousness, tremor, a very low incidence of sexual
dysfunction, and an increased risk for seizures at
high doses.
 Mirtazapine

 This drug enhances serotonin and

norepinephrine neurotransmission via
mechanisms related to its ability to block
presynaptic 2 receptors
 It is a sedative because of its potent
antihistaminic activity
 Increased appetite and weight gain frequently
occur
 Nefazodone and trazodone

 weak inhibitors of serotonin reuptake.

 Their therapeutic benefit appears to be related
to their ability to block postsynaptic 5-HT2A
receptors
 Both agents are sedating, probably because of
their potent H1-blocking activity.
 Trazodone has been associated with causing
priapism, and nefazodone has been associated
with the risk for hepatotoxicity.
 Tricyclic Antidepressants

Mechanism of Action
 The tricyclic antidepressants (TCAs) block
norepinephrine and serotonin reuptake into the
neuron
 TCAs also block serotonergic, α-adrenergic,
histaminic, and muscarinic receptors
 the prototype drug→imipramine
 The TCAs elevate mood, improve mental
alertness, increase physical activity, and
reduce morbid preoccupation in 50 to 70
percent of individuals with major depression.
The onset of the mood elevation is slow,
requiring 2 weeks or longer
Therapeutic uses

 The TCAs are effective in treating moderate to

severe major depression.
 Some patients with panic disorder also
respond to TCAs.
 The TCAs, particularly amitriptyline, have been
used to treat migraine headache and chronic
pain syndromes (for example, neuropathic•
pain) in a number of conditions for which the
cause of the pain is unclear.
Adverse Effect
Drugs interacting with tricyclic
antidepressants
Monoamine Oxidase Inhibitors

Monoamine oxidase (MAO) is a mitochondrial

enzyme found in nerve and other tissues, such
as the gut and liver.

In the neuron, MAO functions as a safety valve•

to oxidatively deaminate and inactivate any
excess neurotransmitter molecules
(norepinephrine, dopamine, and serotonin)
that may leak out of synaptic vesicles when
the neuron is at rest
Mechanism of action of monoamine
oxidase (MAO) inhibitors
Therapeutic uses
 The MAO inhibitors are indicated for
depressed patients who are unresponsive or
allergic to TCAs or who experience strong
anxiety.
 Patients with low psychomotor activity may
benefit from the stimulant properties of the
MAO inhibitors.
 These drugs are also useful in the treatment
of phobic states
Adverse effects

 Severe and often unpredictable side effects

due to drug-food and drug-drug interactions
limit the widespread use of MAO inhibitors
 drowsiness, orthostatic hypotension, blurred
vision, dry mouth, dysuria, and constipation
Treatment of Mania and
Bipolar Disorder
 Lithium salts are used prophylactically for treating
manic-depressive patients and in the treatment of
manic episodes and, thus, is considered a mood
stabilizer

 •Lithium is effective in treating 60 to 80 percent of

patients exhibiting mania and hypomania

 Lithium is believed to attenuate signaling via

receptors coupled to the phosphatidylinositol
bisphosphate (PIP2) second-messenger system.
Common adverse effects may include
headache, dry mouth, polydipsia,
polyuria, polyphagia, gastrointestinal
distress (give lithium with food), fine
hand tremor, dizziness, fatigue,
dermatologic reactions, and sedation.

Adverse effects due to higher plasma

levels may include ataxia, slurred
speech, coarse tremors, confusion,
and convulsions. [Note: The diabetes
insipidus that results from taking
lithium can be treated with amiloride
SEDATIVE-HYPNOTIC
Oleh :
Dimas P Nugraha
KJF Farmakologi FK UR
 SEDATIVE ( ANXIOLYTIC)

An effective sedative (anxiolytic) agent should

reduce anxiety and exert a calming effect.

The degree of central nervous system depression

caused by a sedative should be the minimum
consistent with therapeutic efficacy
A hypnotic drug should produce drowsiness and
encourage the onset and maintenance of a state of
sleep

Hypnotic effects involve more pronounced depression

of the central nervous system than sedation, and this
can be achieved with many drugs in this class simply by
increasing the dose.
The benzodiazepines are widely used
sedative-hypnotics
The chemical structures of some older and less commonly
used sedative-hypnotics, including several barbiturates
Chemical structures of newer hypnotics
 Pharmacokinetics
The rates of oral absorption of sedative-hypnotics differ
depending on a number of factors, including lipophilicity.

All sedative-hypnotics cross the placental barrier during

pregnancy.

If sedative-hypnotics are given during the predelivery

period, they may contribute to the depression of neonatal
vital functions.

Sedative-hypnotics are also detectable in breast milk and

may exert depressant effects in the nursing infant.
Biotransformation of benzodiazepines
Pharmacokinetic Properties of Some
Benzodiazepines and Newer Hypnotics in Humans
Pharmacodynamics of Benzodiazepines,
Barbiturates, & Newer Hypnotics

bind to molecular components of the GABAA

receptor in neuronal membranes in the
central nervous system

This receptor, which functions as a chloride

ion channel, is activated by the inhibitory
neurotransmitter GABA
Comparison of the durations of action of the
benzodiazepines
 Clinical Pharmacology of Sedative-
 Relief of anxiety Hypnotics

Insomnia

 Sedation and amnesia before and during medical and surgical

procedures

Treatment of epilepsy and seizure states

As a component of balanced anesthesia (intravenous administration)

For control of ethanol or other sedative-hypnotic withdrawal states

For muscle relaxation in specific neuromuscular disorders

As diagnostic aids or for treatment in psychiatry

Anxiety disorders:

Benzodiazepines are effective for the treatment of :

• the anxiety symptoms secondary to panic disorder

•generalized anxiety disorder
•social anxiety disorder
•performance anxiety
•posttraumatic stress disorder
•obsessive-compulsive disorder
•extreme anxiety sometimes encountered with specific phobias,
such as fear of flying.

The benzodiazepines are also useful in treating

the anxiety that accompanies some forms of depression and
schizophrenia
Muscular disorders:

Diazepam is useful in the treatment of skeletal

muscle spasms, such as occur in muscle strain, and
in treating spasticity from degenerative disorders,
such as multiple sclerosis and cerebral palsy.
Anesthesia:

The shorter-acting agents are often employed as premedication for

anxiety-provoking and unpleasant procedures, such as endoscopic,
bronchoscopic, and certain dental procedures as well as angioplasty.

They also cause a form of conscious sedation, allowing the

person to be receptive to instructions during these procedures.

Midazolam is an injectable-only benzodiazepine also used for

the induction of anesthesia.
Diazepam, lorazepam, and midazolam are used
in anesthetic procedures. The primary indication
is for premedication because of their sedative,
anxiolytic, and amnestic properties, and to
control acute agitation

Compared with the intravenous barbiturates,

benzodiazepines produce a slower onset of
central nervous system depressant effects which
reach a plateau at a depth of sedation that is
inadequate for surgical anesthesia
Using large doses of benzodiazepines to
achieve deep sedation prolongs the
postanesthetic recovery period and can
produce a high incidence of anterograde
amnesia

Because it possesses sedative-anxiolytic

properties and causes a high incidence of
amnesia (> 50%), midazolam is frequently
administered intravenously before patients
enter the operating room. Midazolam has a
more rapid onset, a shorter elimination half-
life (2–4 hours)
Seizures:

Diazepam and lorazepam are the drugs of choice in terminating grand mal
epileptic seizures and status epilepticus .

Due to cross-tolerance, chlordiazepoxide , clorazepate diazepam, and oxazepam

are useful in the acute treatment of alcohol withdrawal and reducing the risk of
withdrawal-related seizures.
Sleep disorders
Flurazepam: This long-acting benzodiazepine
significantly reduces both sleep-induction time and the
number of awakenings, and it increases the duration of
sleep. Flurazepam has a long-acting effect and causes
little rebound insomnia

Temazepam: This drug is useful in patients who

experience frequent wakening. Temazepam is useful for
insomnia caused by the inability to stay asleep

Triazolam: This benzodiazepine has a relatively short

duration of action and, therefore, is used to induce sleep
in patients with recurring insomnia. Triazolam is effective
in treating individuals who have difficulty in going to
sleep
Dosages of Drugs Used Commonly for
Sedation and Hypnosis
 Adverse effects

Many of the common adverse effects of sedative-

hypnotics result from dose-related depression of
the central nervous system.

Relatively low doses may lead to drowsiness,

impaired judgment, and diminished motor skills,
sometimes with a significant impact on driving
ability, job performance, and personal relationships
Drowsiness and confusion:
These effects are the two most common side effects of
the benzodiazepines.

Ataxia occurs at high doses and precludes activities

that require fine motor coordination, such as driving an
automobile

Cognitive impairment (decreased long-term recall and

acquisition of new knowledge) can occur with use of
benzodiazepines.
Barbiturates

The barbiturates were formerly the mainstay of

treatment to sedate the patient or to induce
and maintain sleep

Today, they have been largely replaced by the

benzodiazepines, primarily because
barbiturates induce tolerance, drug-
metabolizing enzymes, physical dependence,
and are associated with very severe withdrawal
symptoms.
 Mechanism of action

The sedative-hypnotic action of the

barbiturates is due to their interaction with
GABAA receptors, which enhances GABAergic
transmission
 Therapeutic uses
Anesthesia:
Selection of a barbiturate is strongly influenced by the desired duration of
action. The ultrashort-acting barbiturates, such as thiopental, are used
intravenously to induce anesthesia

Anticonvulsant:
Phenobarbital is used in long-term management of tonic-clonic seizures,
status epilepticus, and eclampsia. Phenobarbital has been regarded as the
drug of choice for treatment of young children with recurrent febrile
seizures. However, phenobarbital can depress cognitive performance in
children, and the drug should be used cautiously

Anxiety:
Barbiturates have been used as mild sedatives to relieve anxiety, nervous
tension, and insomnia. When used as hypnotics, they suppress REM sleep
more than other stages. However, most have been replaced by the
benzodiazepines.
Barbiturates classified according to their
durations of action
Adverse effect of barbiturates
 Other Hypnotic Agents
Zolpidem
 The hypnotic zolpidem is not a benzodiazepine
in structure, but it acts on a subset of the
benzodiazepine receptor family, BZ1.
 Zolpidem has no anticonvulsant or muscle-
relaxing properties
 Adverse effects of zolpidem include nightmares,
agitation, headache, gastrointestinal upset,
dizziness, and daytime drowsiness.
Zaleplon
 Zaleplon is very similar to zolpidem in its
hypnotic actions, but it causes fewer residual
effects on psychomotor and cognitive
functions compared to zolpidem or the
benzodiazepines
Eszopiclone
 Eszopiclone is an oral nonbenzodiazepine hypnotic
(also utilizing the BZ1 receptor similar to zolpidem
and zaleplon) and is also used for treating insomnia

 Eszopiclone been shown to be effective for up to 6

months compared to a placebo

 Adverse events reported with eszopiclone include

anxiety, dry mouth, headache, peripheral edema,
somnolence, and unpleasant taste.
Ramelteon
 Ramelteon is a selective agonist at the MT1
and MT2 subtypes of melatonin receptors

 Stimulation of MT1 and MT2 receptors by

melatonin in the suprachiasmatic nucleus
(SCN) is able to induce and promote sleep
and is thought to maintain the circadian
rhythm underlying the normal sleep-wake
cycle
 Ramelteon is indicated for the treatment of
insomnia in which falling asleep (increased
sleep latency) is the primary complaint

 Common adverse effects of ramelteon

include dizziness, fatigue, and somnolence

 Ramelteon may also increase prolactin levels.

Chloral hydrate
 Chloral hydrate is a trichlorinated derivative
of acetaldehyde that is converted to the
active metabolite, trichloroethanol, in the
body.

 The drug is an effective sedative and hypnotic

that induces sleep in about 30 minutes and
the duration of sleep is about 6 hours
Antihistamines
 Nonprescription antihistamines with sedating
properties, such as diphenhydramine and
doxylamine, are effective in treating mild
types of insomnia.
Ethanol
 Ethanol (ethyl alcohol) has anxiolytic and sedative
effects, but its toxic potential outweighs its benefits

 Ethanol synergizes with many other sedative agents

and can produce severe CNS depression with
benzodiazepines, antihistamines, or barbiturates

 Chronic consumption can lead to severe liver

disease, gastritis, and nutritional deficiencies.
Cardiomyopathy is also a consequence of heavy
drinking.
 The treatment of choice for alcohol
withdrawal are the benzodiazepines.
Carbamazepine is effective in treating
convulsive episodes during withdrawal.
Therapeutic disadvantages and advantages of some anxiolytic
and hypnotic agents
 SEKIAN
TERIMA KASIH !!

‫ور‬ ُ
‫د‬ ُّ
‫الص‬ ‫ي‬ِ ‫ف‬ ‫َا‬
‫م‬ ِ ‫ل‬ ٌ
‫ء‬ ‫ا‬‫ف‬َ ‫ش‬
ِ ‫و‬َ ْ
‫م‬ ُ ِ‫ن َرب‬
‫ك‬ ْ ‫م‬ِ ٌ
‫ة‬ َ ‫ظ‬ ‫ع‬ ِ ْ
‫و‬ َ
‫م‬ ْ
‫م‬ ‫ك‬ُ ‫اس َق ْد جَا َء ْت‬
ُ ‫ن‬َّ ‫ال‬ ‫َا‬
‫ه‬ ُّ‫يَا أَي‬
ِ
َ‫م ْؤ ِمنِين‬ُ ‫َة لِ ْل‬
ٌ ‫حم‬ ْ ‫َه ًدى َو َر‬ ُ ‫و‬
Hai manusia, sesungguhnya telah datang kepadamu pelajaran dari
Tuhanmu dan penyembuh bagi penyakit-penyakit (yang berada)
dalam dada dan petunjuk serta rahmat bagi orang-orang yang
beriman (QS. Yunus: 57)