Central Nervous System

PHARMACOLOGY
ELLY NURUS SAKINAH

NEUROTRANSMITTER
Neurotransmitte
r
Asetilkolin
Dopamine

Kelebihan

Kekurangan

Delirium, psikosis
Psikosis,
sindrom
Tourette, chorea

Penyakit alzeimer
Parkinson, depresi

GABA

Depresi CNS, Sedasi

Glutamat

Kejangn
neuron

Kejang,
gangguan
gerak
Skizofren,
depresi,
gangguan kognitif

Norepinefrin

Ansietas,
panic,
anoreksia, insomnia

Depresi

Serotonin

Tidur,
halusinasi,
penurunan
nafsu
makan, ansietas

Depresi,
sensitive
nyeri,ansietas

degenerasi

TARGET MOLEKULAR FARMAKOLOGI

SISTEM SARAF PUSAT

SEDATIF HIPNOTIK
ELLY NURUS SAKINAH

PENGERTIAN
Anxiolytic (sedative) adalah obat yang

mengurangi gejala cemas, memberikan

efek menenangkan dengan sedikit atau
tanpa efek terhadap status mental atau
motorik.
Sedangkan hipnotik (sleep-inducing)
adalah obat yang menghasilkan efek
induksi tidur, mempengaruhi onset tidur
dan mempertahankan fase tidur.
Graded dose-dependent depression of
central nervous system function

Barbiturat dan
alkohol

Benzodia
zepin

Teori neurobiologi terjadinya

gangguan anxietas
Kelebihan serotonin (5-HT) dan kekurangan

NT noradrenergic
Kekurangan GABA
Kelebihan Glutamat
Penurunan BDNF (Brain-derived neurotropic
factor)

OBAT SEDATIF-HIPNOTIK
BENZODIAZEPINE (BZD)
BARBITURAT
Z DRUG
RAMELTEON
BUSPIRON

BENZODIAZEPINE
FARMAKOKINETIK
Rates of oral absorption : lipophilicity major role

drug enters the CNS

Triazolam, barbiturat, newer hypnotics more rapid
Clorazepate prodrug, active
desmethyldiazepam (nordiazepam)
Cross the placental barrier depression of neonatus
Also detectable in breast milk depressant effect of
nursing infant
Biotransformation
Phase 1 (CYP3A4), phase II (eventually excreted as

glucuronide conjugates in the urine)

Understanding of the importance of drug

half life in determining appropriate drug

therapy and minimizing adverse effects
Obat penenang ideal:
Menenangkan, day time sedation -,

ketergantungan fisik/psikis -, TI lebar

Obat tidur yg ideal:

Onset of sleep cepat, mempertahankan
kualitas dan lamanya tidur, hang over -,
ketergantungan fisik/psikis -

Drug

Tmax(hr)

T1/2 (hr)

Comments

Alprazolam

1-2

12-15

Rapid oral absorption

Chloediazepoxide

2-4

15-40

Active metabolite

Clorazepate

1-2
(nordiazepa
m)

50-100

Prodrug, hydrolized to active

form in stomach

Diazepam

1-2

20-80

Active metabolic

Eszoplicone

Minor active metabolites

Flurazepam

1-2

40-100

Active metabolite with long

half live

Lorazepam

1-6

10-20

No active metabolites

Oxazepam

2-4

10-20

No active metabolites

Temazepam

2-3

10-40

Slow oral absorption

Triazolam

2-3

Rapid onset, short DOA, is

affected by inhibitor and
inducer CYP3A4

Zaleplon

<1

1-2

Metabolized via aldehyde

dehidrogenase

Zolpidem

1-3

1,5-3,5

No active metabolite

Pharmacodynamics of
BZD
The GABAA-receptors is a ligand-gated ion

channel consisting of a pentameric

assembly of subunits

BZD: Mechanism of action, interaksi BZD dg reseptor

GABA frekuensi pembukaan kanal ion meningkat

BZD

BZD do not directly gate GABA-A receptor/ion channel

(in contrast to Barbiturate meningkatkan lama (durasi)
pembukaan

EFEK SAMPING
drowsiness, confusion, amnesia, impaired

coordination. Potensiasi efek sedasi dari alcohol,

long-lasting hangover.
Overdose depresi nafas, Flumazenil merupakan
antagonis kompetitif dari BZD, sehingga bs
digunakan untuk tatalaksana overdosis BZD.
Toleransi : pada dosis terapeutik tidak didapat efek
terapi. efek hipnotik lebih cepat hiang, rebound
insomnia.
Dependence /ketergantungan: terjadi ketika
penggunaan terapi jangka waktu yang lama.
Biasanya terjadi pada individu dengan riwayat
ketergantungan alcohol, personality disorder.

Penggunaan maksimal 4 minggu ,

penggunaan obat yang memiliki long acting

dapat meminimalisasi efek dependence.
Lorazepam merupakan BZD yg poten tetapi
memiliki DOA yang pendek sehingga
meningkatkan risiko withdrawal.
Gejaa withdrawal : ansietas, agitasi, sensitive
terhadap cahaya dan suara, parestesia.kram
otot, gangguan tidur. Penggunaan dalam
jangka waktu yang lama akan menyebabkan
kejang, delirium.

II. BARBITURAT
Mekanisme kerja: potensiasi efek GABA,

berikatan dengan reseptor GABAA pada

sisi yang berbeda dengan BZD. Setelah
berikatan dengan reseptor GABA , akan
memperlama waktu pembukaan kanal
Cl.
Efek samping dari barbituratL
Hangover, dependensi,toleransi,

Penggunaan barbiturate sebagai

hipnotik sedative sudah tidak

direkomendasikan , oleh karena:
Memiliki indeks terapi yang sempit

III. Benzodiazepine-like drugs: 'Z

'drugs
Zaleplon, zolpidem,
Mekanisme kerja: berikatan dengan

subtype reseptor GABA

Kelebihan : tidak ada rebound insomnia ,
low potential for tolerance, dependence or
abuse

IV. New non-benzodiazepine:

Ramelteon
Ramelteon (Rozerem): approved by FDA

late 2005. Mechanism of action: Melatonin

receptor agonist.
Melatonin is the hormone that regulates
circadian rhythm in mammals.
Well tolerated: minimal somnolence,
fatigue, dizziness compared to placebo.
No abuse potential shown; not a controlled
substance

V. 5-HT receptor agonist

Buspirone
Slow onset (1-2 weeks) of anxyolytic effect.

Minimal psychomotor impairment, no

additive CNS depression
PK : oral activity, forms active metabolite,
short half life
Toxicity : tachycardia, paresthesia, GI
disorder

ANTI SEIZURE DRUGS

ELLY NURUS SAKINAH

MEKANISME KERJA
Penguatan

Epilepsi
Type of seizure

First line

Second line

Partial Seizure

Phenytoin
Carbamazepine
Valproate
Lamotrigine
topiramate

Phenobarbital, primidone
Clonazepam / clobazam
Gabapentin
Vigabatrin
Zonisamide

Tonic clonic

Carbamazepine
Valproate
Lamotrigine
Phenytoin

Phenobarbital / primidone
Vigabatrine
Phenytoin

Myoclonic

Valproate
Ethosuximide
Clonazepam

absence

Ethosuximide
Valproat

Generalized seizure

Clonazepam
lamotrigine

Adverse effect antiseizure

drug
Drug

Adverse effect

BZD

Sedasi, toleransi, dependence

Carbamazepine

Diplopia, g3 kognitif, pusing, ataxia, SJS, teratogenik, blood

dyscrasia

Ethosuximide

GI distress, letargi, headache, gangguan perilaku

Gabapentin

Dizzines, sedasi, ataxia, nistagmus

Lamotrigine

Dizzines, ataxia, nausea, rash, SJS

Phenobarbital

Sedasi, g3 kognitif, toleransi, dependence, induksi enzim

metabolisme di hepar

Phenytoin

Nistagmus, diplopia, sedasi, hiperplasi gingiva, hirsutism,

anemia, neuropati, osteoporosis, induksi enzim di hepar

Tiagabine

Abdominal pain, nausea, dizzines, tremor, astenia

Topiramate

Drowsiness, dizzines, ataxia, kelemahan psikomotor,

gangguan memori, parestesi, weight loss, miopia

Valproate

Drowsiness, nausea, tremor, hair loss, weight gain,

hepatotoksik (infant), menghambat enzim di hepar

Drug interactions among

anticonvulsant
Carbamazepine (inducer p450)
Can lower plasma concentration of : clobazam,

clonazepam, lamotrigine, tiagabine, topiramat, valproate

Phenobarbital dan primidone (inducer p450)
Can lower plasma concentration of carbamazepine,

clonazepam, lamotrigine, tiagabine, phenytoin, valproate

Phenytoin (inucer p450)
Can lower plasma concentration of carbamazepine,

clonazepam, lamotrigine, tiagabine, valproate

Valproate (inhibition p450)
Increase plasma concentration of : phenobarbital,

lamotrigine, phenytoin

Anti Parkinson

PARKINSON

Pathophysiology: degeneration of
substantia nigra neurons, which results in
loss of dopamine (DA) to striatum

Cardinal symptoms: bradykinesia (slowed

movement), rigidity, resting tremor, postural
instability

Imbalance between dopamine and

acetylcholine in striatum
treatment strategies:
can DA or Ach

www.nwabr.org/.../pictures/whthppn

s.jpg

D rugs for Parkinsons disease

Meningkatkan Dopamin
Dopamine precursor
levodopa/carbidopa

Dopamine agonists
bromocriptine
pergolide
pramipexole
ropinerole

Dopamine Releaser
amantadine

Menghambat
perusakan Dopamin
COMT inhibitors
entacapone, tolcapone

MAO-B inhibitor
Selegiline

Menurunkan ACh
Anticholinergics
trihexyphenidyl (Artane)
benztropine (Cogentin)

Levodo
pa

Bromocript
ine,
pergolide

Amanta
dine

1. Levodopa
Mechanism:
(1) Because dopamine does not cross the blood-brain
barrier, levodopa the precursor of dopamine, is given
instead.
(2) Levodopa itself has minimal pharmacologic activity,
in contrast to its decarboxylated product, dopamine.
(3) Levodopa is rapidly decarboxylated in the
gastrointestinal tract. Prior to the advent of
decarboxylase inhibitors (carbidopa), large oral
doses of levodopa were required; thus, toxicity from
dopamine was a limiting factor.

Adverse effect
DRUG

MOA

COMMENT & SIDE EFFET

LEVODOPA

DA precursor

Diberikan scr kombinasi dg

decarboksilase inhibitor (carbidopa), ES:
nausea, halusinasi, confusion

BROMOCRIPTINE

Agonis DA parsial

Hipertensi,nausea, fatigue

PERGOLIDE

DA agonis (D1/D2)

Hipertensi,nausea, fatigue

ROPINIROLE

DA agonis (D2selective)

Well tolerated, nausea,fatigue

PRAMIPEXOLE

DA agonis (D2selective)

Well tolerated, nausea,fatigue

SELEGILINE

MAO-B inhibitor

Meningkatkan ES dari levodopa, ansietas,

insomnia

RASAGILINE

= selegiline

= selegiline

ENTACAPONE/
TOLCAPONE

COMT inhibitor

Jarang mnimbulkan masalah hati serius,

nausea, dizziness, drowsiness

TRIHEXYPHENIDYL

Antagonis
muskarinik

Efek Antimuscarinik dry mouth, inability

to sweat, impaired vision, urinary
retention, constipation, drowsiness,
confusion. , sedasi,

Levodopa

Adverse effect:
On-off phenomena
On-off Effect fluctuations in clinical response to
levodopa.
Off = marked akinesia.
On = improved mobility but marked dyskinesia.
Thought to be related to fluctuations in levodopa
plasma concentrations.
Fluctuations can be smoothed out by
incorporating a dopamine receptor agonist into
pharmacotherapy.
Pramipexole.
Ropinirole.
Apomorphine.
Selegiline
tolcapone

Anti Psikosis

ANTI
PSYCHOTIC
TYPICAL

Dopamine Pathways
Mesolimbic dan mesokortikal efek psikologis
Nigrostriatal voluntary movement
Tuberoinfundibular hambat pelepasan prolaktin

DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA

Overactive dopamine system pada mesolimbik
dan mesokortikal
Reseptor Dopamin : Klas D1 (D1 dan D5); klas D2
(D2,D3 dan D4)
Obat yang menghambat resptor klas D2 lebih
efektif untuk antipsikosis
Douglas L. Geenens, D.O. 2000

Relative receptor blocking

DRUG

D2
BLOCK

D4
BLOCK

1
BLOCK

5HT2
BLOCK

M
BLOCK

H1
BLOCK

Most
phenothia
zine dan
tioxanthin
e

++

++

Thioridazi
ne

++

++

+++

Haloperido +++
l

Clozapine

++

++

++

++

Molindone

++

Olanzapin
e

++

++

Risperidon ++
e

ADVERSE EFFECT
Gejala
akathisia
Gejala
Acute
Acute
akathisia

Antidepressants drugs

Elly Nurus Sakinah, dr

Department of Pharmacology
2012

Pathophysiology of
depression
Neurotrophic Hypothesis
Monoamines and other
neurotransmitters
Neuroendocrine factors

The neurotrophic hypothesis

(Redrawn, with permission, from Nestler EJ: Neurobiology of depression.
Neuron 2002;34[1]:1325.)

brain-derived
neurotrophic
factor (BDNF)
nerve growth factors
regulation of neural
plasticity, resilience,
and neurogenesis
depression is
associated with the
loss of neurotrophic
support atrophic
structural changes in
the hippocampus,
frontal cortex, anterior
cingulate

Monoamine
hypothesis
depression is
related to a
deficiency in the
amount or
function of
cortical and
limbic serotonin
(5-HT),
norepinephrine
(NE), and
dopamine
(DA)
(Redrawn, with permission, from Belmaker
R, Agam G:
Major
depressive disorder. N Engl J Med 2008;358:59.)

Neuroendocrine Factors in the

Pathophysiology of Depression
MDD is associated with elevated cortisol levels
25% of depressed patients are reported to
have abnormal thyroid function blunting of
response of thyrotropin to thyrotropinreleasing hormone, and elevations in
circulating thyroxine during depressed states
Estrogen deficiency states, which occur in the
postpartum and postmenopausal periods, are
thought to play a role in the etiology of
depression in some women

 The purpose of
antidepressants
is the increase
the [monoamine
neurotransmitter
s] in the synapse
by one of several
mechanisms

Anti Depresan
Heterocyclic

Mekanisme kerja
Heterocyclic

How to choose an
antidepressant
Rationale should be based on side
effects, not efficacy

Norepinephrine uptake blockade

Possible clinical consequences

Tremors
Tachycardia

Serotonin reuptake blockade

Possible clinical consequences

Gastrointestinal disturbances
Anxiety (dose dependent)
Sexual dysfunction

Dopaminergic uptake blockade

Possible clinical consequences

Psychomotor activation
Antiparkinsonian effects
Psychoses
Increased attention/concentration

Histamine H1 blockade
Possible clinical consequences

Sedation, drowsiness
Weight gain
hypotension

Muscarinic receptor blockade

possible clinical consequences

Blurred vision
Dry mouth
Sinus tachycardia
Constipation
Urinary retention
Memory dysfunction

alpha 1 receptor blockade

possible clinical consequences

Postural hypotension
Reflex tachycardia
Dizziness

Interaction with food

The most serious problem of this class of drugs (MAO-I)
Much less important in novel RIMA (Reversible
Inhibitors of MAO-A) drugs like moclobemide
Tyramine cheese and wine reaction
tyramine
a natural indirect sympathomimetic produced by fermentation
some food contain high amounts
normally metabolized by MAO in the gut and liver.

After MAOI treatment bioavailability of tyramine is

significantly higher
hypertensive crisis, severe headache and potentially fatal
intracranial hemorrhage or other organ damage.
Dietary restrictions: maturing cheeses, wine, beer,
yogurts, bananas etc.

This risk is minimal with modern RIMA drugs.

Interaction with drugs

Hypertension & hypertensive crisis
TCA wash-out period (2 weeks) when switching
these antidepressants! Lower risk in RIMA.
levodopa (catecholamine precursor),
sympathomimetics
Serotonin syndrome (SSRI, TCA, opioids e.g.
pethidin)
confusion, agitation and excitation, tremor, fever,
sweating, nausea, diarrhea, sleep disruption
prolongs and profounds the effect of:

benzodiazepines, antihistamines, alcohol

Drug interaction