Central Nervous System

PHARMACOLOGY
ELLY NURUS SAKINAH
NEUROTRANSMITTER
Neurotransmitter Kelebihan Kekurangan
Asetilkolin Delirium, psikosis Penyakit alzeimer
Dopamine Psikosis, sindrom Parkinson, depresi
Tourette, chorea
GABA Depresi CNS, Sedasi Kejang, gangguan
gerak
Glutamat Kejangn degenerasi Skizofren, depresi,
neuron gangguan kognitif
Norepinefrin Ansietas, panic, Depresi
anoreksia, insomnia
Serotonin Tidur, halusinasi, Depresi, sensitive
penurunan nafsu nyeri,ansietas
makan, ansietas
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 50-100 Prodrug, hydrolized to active form

(nordiazepam) in stomach
Diazepam 1-2 20-80 Active metabolic

Eszoplicone 1 6 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 1 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
 Efek toleransi muncul dengan cepat
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
• Kerja langsung pada kanal ion Cl – reseptor GABA
Penguatan transmisi • Benzodiazepine, barbiturate.
GABA-ergik • Inhibitor GABA-T (metabolisme GABA) : vigabatrin
• Inhibitor GABA transporter (GAT-1) : tiagabine
(inhibitorik) • Analog GABA : Gabapentin

• Penyekatan reseptor AMPA

Pengurangan • Phenobarbital, topiramate
transmisi Glutamat- • Penyekatan reseptor NMDA
ergik (eksitatorik) • Remacemide , carbamazepine,
valproate

Modifikasi • Blok kanal Na : phenytoin, carbamazepine,

konduktans ion (Na lamotrigine dan zonisamide
dan Ca) • Blok Kanal Ca : Ethosuximide, valproate
 Drug of choice in the Tx Epilepsi
Type of seizure First line Second line
Partial Seizure •Phenytoin •Phenobarbital, primidone
•Carbamazepine •Clonazepam / clobazam
•Valproate •Gabapentin
•Lamotrigine
•Vigabatrin
•topiramate
•Zonisamide

Generalized seizure
Tonic clonic Carbamazepine Phenobarbital / primidone
Valproate Vigabatrine
Lamotrigine Phenytoin
Phenytoin
Myoclonic Valproate
Ethosuximide
Clonazepam
absence Ethosuximide Clonazepam
Valproat 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
 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

www.nwabr.org/.../pictures/whthppns.jpg
treatment strategies: can ↑
DA or  Ach
Drugs for Parkinson’s disease

Meningkatkan Dopamin Menghambat perusakan

 Dopamine precursor Dopamin
 levodopa/carbidopa  COMT inhibitors
 Dopamine agonists  entacapone, tolcapone
 bromocriptine  MAO-B inhibitor
 pergolide  Selegiline
 pramipexole
 ropinerole
Menurunkan ACh
 Anticholinergics
 Dopamine Releaser  trihexyphenidyl (Artane)
 amantadine
 benztropine (Cogentin)
 Bromocriptine,
pergolide
Levodopa

Amantadine
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 (D2- Well tolerated, nausea,fatigue
selective)
PRAMIPEXOLE DA agonis (D2- Well tolerated, nausea,fatigue
selective)
SELEGILINE MAO-B inhibitor Meningkatkan ES dari levodopa, ansietas,
insomnia
RASAGILINE = selegiline = selegiline
ENTACAPONE/ COMT inhibitor Jarang mnimbulkan masalah hati serius,
TOLCAPONE nausea, dizziness, drowsiness
TRIHEXYPHENIDYL Antagonis Efek Antimuscarinik dry mouth, inability to
muskarinik 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
• A.Phenothiazine Derivatives
TYPICAL DRUGS/ • Aliphatic Derivative: CHLORPROMAZINE
• Piperidine Derivative: THIORIDAZINE
classic drug (D2 • Piperazine Derivative: FLUPHENAZINE,
PERPHENAZINE, TRIFLUOPERAZINE
reseptor affinity) • B. Thioxanthene Derivative:
• C. Butyrophenone: HALOPERIDOL
THIOTHIXENE

ATYPICAL • CLOZAPINE
• LOXAPINE

DRUGS/ newer • RISPERIDONE

• MOLINDONE

agent (5HT2 • SERTINDOLE

• ZIPRASIDONE
• OLANZAPINE
receptor affinity) • QUETIAPINE
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 D4 BLOCK α1 5HT2 BLOCK M BLOCK H1 BLOCK
BLOCK BLOCK
Most ++ _ ++ + + +
phenothiazin
e dan
tioxanthine
Thioridazine ++ - ++ + +++ +

Haloperidol +++ _ + - - -

Clozapine - ++ ++ ++ ++ +

Molindone ++ - + - + +

Olanzapine + - + ++ + +

Risperidone ++ - + ++ + +
 ADVERSE EFFECT
• Gejala Parkinson • gerakan berulang involunter
• Acute dystonia pada lidah, wajah,
mulut/rahang dan anggota
• akathisia gerak.

EPS TD

• Altered Mental Status

• Muscle Rigidity NMS OTHERS • Metabolic side effect
• Fever:> 38°C , > 40°C is • Antagonis muscarinic
common (cholinergic)
• Autonomic Instability • Antagonis α adrenergik
• Anatagonis H1
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]:13–25.)
• 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 thyrotropin-releasing
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
neurotransmitters] in
the synapse by one
of several
mechanisms
 Anti Depresan

• Trisiklik : amitriptilin, doksepin, imipramin,

Heterocyclic desipramin
• Tetrasiklik : amoksapin. maprotiline

SSRI (selective
serotonin • Fluvoxamin, fluoxetine, paroxetin, sertralin
inhibitor)

MAOI (monoamin • Fenelzin, tranylcypromine

oksidase inhibitor)
 Mekanisme kerja
• block the reuptake of monoamine
neurotransmitter (serotonin, NE, Dopamin)
Heterocyclic • and also interact with muscarinic, cholinergic, alpha1-adrenergic,
and histaminic receptors, which results in their characteristic side-
effect profile

• block serotonin reuptake into presynaptic nerve

SSRI terminals, leading to enhanced serotonergic
neurotransmission

• irreversibly inhibit the enzyme,monoamine oxidase,

MAOI located in the central nervous system,gut and platelets,
leading to lack of degradation ofmonoamines
 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 (inhibition
of liver enzymes – low specificity)
Drug interaction