FARMAKOLOGI

Senyawa Bioaktif pada Sistem

Syaraf Otonom
Kuliah Program Sarjana dan Pasca Sarjana
Fakultas Farmasi
Universitas Gadjah Mada
Universitas Ahmad Dahlan

Oleh:
Prof. Sugiyanto, S.U., Ph.D., Apt

09/23/18 1
References:
1. Neal, M.J., 2002, Medical Pharmacology at A Glance, 4th Edition,
Blackwell Science, London

2. Stringer, J.L., 2001, Basic Concepts in Pharmacology: A Student’s

Survival Guide, 2nd Edition, McGraw-Hill International Editions,
Boston

3. Lullmann, H., Mohr, K., Ziegler, A., and Bieger, D., 2000, Color Atlas of
Pharmacology, 2nd Edition, Thieme Stuttgart

4. Hardman, J.G., Limbird L.E., Molinoff, P.B., Ruddon, R. W., and

Gilman, A. G., 1996, Goodman and Gilman’s The Pharmacological
Basis of Therapeutics, 9th Edition, McGraw-Hill Co., New York

09/23/18 2
DRUGS ACTING ON AUTONOMIC
NERVOUS SYSTEM
NERVOUS SYSTEM:
A. Central Nervous System (CNS)
B. Peripheral Nervous System (PNS):
1. somatic nervous system
2. autonomic nervous system

09/23/18 3
Autonomic nervous system (ANS)
Comprises of:
Sympathetic nervous system (adrenergic),
postganglionic nerve release noradrenaline
(norepinephrine)
Parasympathetic nervous system (cholinergic),
postganglionic nerve release acetylcholine

09/23/18 4
09/23/18 5
09/23/18 6
Farmakologi obat-obat yang beraksi
pada sistem syaraf otonom
Senyawa simpatomimetik:
Agonists adrenergik (direct-acting sympathomimmetic)
Indirect-acting sympathomimmetic
Senyawa simpatolitik (antagonis adrenergik)
α-blocker
β-blocker
Parasimpatomimetik
Agonis reseptor muskarinik dan nikotinik
Inhibitor asetilkholinesterase
Parasimpatolitik
09/23/18 7
SYMPATHETIC (adrenergic) SYSTEM
Noradrenaline (norepinephrine)
Adrenaline (epinephrine)
Adrenoreceptors (adrenoceptors)
Sympathomimetic
Sympatholytic

09/23/18 8
09/23/18 9
Effects of sympathetic stimulation
1. pupillary dilatation (more light reaches the
retina)
2. bronchiolar dilatation
3. heart rate and force are increase, blood pressure
rises
4. Vasoconstriction on skin and viscera and
vasodilatation in skeletal muscle
5. Contraction of spleen
6. Provide extra energy
7. GI tract and urinary bladder relax

09/23/18 10
09/23/18 11
Adrenergic receptors
(adrenoceptors)
α-receptors: excitatory effect
ß-receptors: inhibitory effect
Exception for the smooth muscle of the gut: α-
stimulation is inhibitory, ß-stimulation is excitatory

09/23/18 12
Adrenergic receptors
(adrenoceptors)
α-adrenoceptors have been divided into two
classes, originally depending on their location:
post-synaptic (α1) and pre-synaptic (α2)
Stimulation of pre-synaptic α2-receptors by
synaptically released NA reduces further
transmitter release (negative feedback)
It is now known that post-synaptic α2-receptors
occur in a few tissues, e.g. brain

09/23/18 13
Adrenergic receptors
(adrenoceptors)
ß-receptors is not homogenous.
NE is an effective stimulant of cardiac ß–receptors, but
has little or no action on the ß–receptors mediating
vasodilatation
Classified as ß1 (heart, intestinal smooth muscle and
ß2 (bronchial, vascular and urine smooth muscle)

09/23/18 14
09/23/18 15
Nasib neurotransmiter NE
Norepinephrine (NE) menstimulasi syaraf simpatik
melalui interaksi dengan reseptor adrenergik ( alpha
atau betha)
NE kemudian akan di re-uptke oleh ujung syaraf
disimpan di vakuole penyimpan di axoplasma
Sebagian dari NE bebas di aksoplasma akan
dimetabolisir oleh enzim monoamin oksidase (MAO)
atau oleh enzi catechol ortho methyl transferase
(COMT)

09/23/18 16
Nasib neurotransmiter NE
Inhibisi MAO akan menyebabkan kadar NE bebas
meningkat. Demikian pula metabolisme dopamin
akan terhambat, sehingga lebih banyak dopamin yang
akan disintesis menjadi NE. Bila ada impuls datang
maka akan lebih banyak NE yang disekresikan.
Pada CNS penghambatan MAO akan berpengaruh
tidak hanya pada ketersediaan NE, tetapi juga
dopamin dan serotonin

09/23/18 17
Identification of Responses from
Adrenergic receptors (adrenoceptors)
Responses mediated by α–receptors and ß–
receptors can be distinguished by:
1. phentolamine, a selective α-blocker, and propranolol,
a selective ß-blocker
2. the relative potencies on different tissues of
norepinephrine (NE), epinephrine (E) and isoprenaline
(I). Excitatory (α)response >>> NE>E>I; Inhibitory
(ß)response >>> I>E>NE

09/23/18 18
Adrenergic Agonist
Receptor α1 in most vascular smooth muscle
Agonists contract
Receptor β1 in the heart
Agonists increase rate & force
Receptor β2 in respiratory and uterine smooth
muscle
Agonists relax

 Seorang pasien penderita asma kronis juga mempunyai riwayat

hipertensi. Apa saran anda apabila membutuhkan obat untuk
mengobati asmanya yg lagi kambuh ?

09/23/18 19
09/23/18 20
Direct-acting Agonist
Epinephrine & norepinephrine activate both α and β receptors
Norepinephrine has a relatively low affinity for β2 receptors
Phenylephrine, α1 agonist, nasal decongestant
Clonidine, α2 agonist, decreases blood pressure through a
central action
Dobutamine, β1 agonist, increases heart rate & cardiac output
Isoproterenol, β1 and β2 agonist
albuterol, terbutaline, β2 agonist, relieve bronchoconstriction

09/23/18 21
Structure activity relationship (SAR)

09/23/18 22
Relative affinity toward adrenoceptors
phenylephrine clonidine
α1
α2

norepinephrine
epinephrine

dobutamine terbutaline
β1 β2
isoproterenol

09/23/18 23
Dopamine
Dopamine is a catecholamine and is precursor to
norepinephrine.
Dopamine receptors are located throughout the body
and in the CNS
At low doses causes renal & coronary vasodilatation
Also activates β1 receptors in the heart
 In the treatment of shock, dopamine increase heart rate & cardiac
output while simultaneously dilating the renal and coronary arteries.
 The action in the renal vascular bed is useful in attempts to preserve
renal blood flow and function in the presence of overall decreased
tissue perfusion (shock).

09/23/18 24
Efek pada otot polos
Efek berlawanan karena stimulasi resptor α dan β-
adrenergik disebabkan karena perbedaan mekanisme
transduksinya.
Stimulasi reseptor α1 akan meningkatkan pelepasan ion
Ca2+ intraseluler melalui jalur inositol trifosfat (IP3). Ion
Ca 2+ ini bersama calmodulin menyebabkan aktivasi
kinase miosin yang akan memfosforilasi protein
kontraktil miosin sehingga akan meningkatkan tonus
otot, menyebabkan vasokonstriksi
Peningkatan c-AMP, terkait dengan stimulasi reseptor
β2, menghambat aktivitas kinase miosin sehingga tidak
terjadi fosforilasi miosin, mengakibatkan vasodilatasi
09/23/18 25
09/23/18 26
Efek pada otot jantung
Stimulasi reseptor β1 pada otot jantung
menyebabkan aktivasi enzim adenilat siklase
sehingga kadar c-AMP meningkat
mengakibatkan meningkatnya fungsi jantung
meliputi: systolic force (positive inotropism),
velocity of shortening (pos. clinotropism),
sinoatrial rate (pos. chronotropism), conduction
velocity (pos. dromotropism) dan axcitability
(pos. bathmotropism).

09/23/18 27
Efek pada otot jantung
Pada pace maker fiber depolarisasi diastolik
tertunda sehingga nilai ambang untuk
potensial aksi tercapai lebih cepat (pos.
chronotropic effect)
Efek kardiostimulan dari β-simpatomimetik ini
dimanfaatkan untuk penanganan pada kasus cardiac
arrest.
Penggunaan β-simpatomimetik pada kasus gagal
jantung memungkinkan terjadinya cardiac
arrhythmias.

09/23/18 28
09/23/18 29
Metabolic effect
Β-adrenoseptor memediasi pengubahan glikogen
menjadi glukosa baik di hepar maupun di otot skelet,
sehingga kadar glukosa darah meningkat.
Di adiposa terjadi peningkatan lipolisis, trigliserid
dihidrolisis menjadi asam lemak (diperentarai oleh
reseptor β3)
Efek terhadap metabolisme ini tidak mempunyai arti
penting secara terapetik

09/23/18 30
Indirect-acting agents
The indirect-acting sympathomimetic agents act by
releasing stored norepinephrine
Their effects are widespread & nonspecific.
Ephedrine and phenylpropanolamine are nasal
decongestants
Phenylpropanolamine also has been used to suppress
appetite
Amphetamine and methylphenidate are CNS
stimulants used to treat attention deficit hyperactivity
disorder in children.
09/23/18 31
Therapeutic use
Vasoconstriction: Local application of α-sympathomimetics:
Infiltration anesthesia (cocaine, indirect
sympathomimetic)
Nasal decongestion (naphazoline, tetrahydrozoline,
xylometazoline)
Systemic application: for combating hypotension in
anaphylactic shock (epinephrine)
Bronchodilatation: ß2-adrenoceptor mediated
bronchodilatation with terbutaline, fenoterol or
salbutamol plays important role in the treatment of
bronchial asthma

09/23/18 32
Therapeutic use
Relaxant effects of ß1-adrenoceptors stimulation by
terbutaline or fenoterol may prevent premature labor
Cause hypotension that results in tachycardia reflect
which in part due to ß1-stimulation, too.

09/23/18 33
Therapeutic use
Cardio stimulant effects of ß-sympathomimetics, such
as epinephrine and dobutamine is exploited in the
treatment of cardiac arrest
ß-Stimulation carries the risk of cardiac arrythmias

09/23/18 34
09/23/18 35
Therapeutical use
Dopamin dan serotonin ini potensial berperan pada fungsi
CNS yang ditunjukkan secara konsisten dengan timbulnya
efek stimulan pada pemakaian obat-obat inhibitor MAO,
sebagai anti depresan.
Tranilsipromin digunakan untuk pengobatan penyakit
depresi (berpengaruh thd MAOa &b)
Meklobemid inhibitor MOAa (reversible), sbg
antidepresan pula
Selegilin , inhibitor MAOb sebagai obat parkinson

09/23/18 36
09/23/18 37
09/23/18 38
09/23/18 39
Adrenergic antagonists
The effect of the sympathetic nervous system can be
blocked by:
 decreasing sympathetic outflow from the brain
Suppressing release of norepinephrine from nerve
terminals, or
By blocking postsynaptic receptors
Adrenergic antagonists reduce the effectiveness of
sympathetic nerve stimulation and the effects of
exogenously applied agonists.

09/23/18 40
Adrenergic antagonists: reduce
sympathetic outflow from the brain
Central blocker:
α2 agonists reduce sympathetic nerve activity and
are used to treat hypertension
α2-receptors activation inhibits both sympathetic
outflow from the brain and release of NE from
nerve terminals
For example: clonidine, guanfacine, guanabenz
α-methyl-DOPA is metabolized to α-
methylnorepinephrine, is also α2 agonist

09/23/18 41
Adrenergic antagonists: blocking
postsynaptic receptors
Alpha blocker:
Most of the α antagonists cause vasodilatation, thus
decrease blood pressure.
Activation of α-receptors results in vasoconstriction
Blocked of α-receptors will produce vasodilatation
 This is particularly true when the sympathetic nervous system
is firing (“more active”).
 For example, the sympathetic n.s. is more active in maintaining blood
pressure when a person is standing than when lying down.
 This is why α-blockade results in a greater decrease in blood pressure
in the standing position (postural hypotension)

09/23/18 42
Adrenergic antagonists: blocking
postsynaptic receptors
The side effects of the α-blockers are directly related
to their α-blocking activity
The antipsychotics have α-antagonist properties
(postural hypotension, hypothermia) (clozapine,
risperidone, chlorpromazine)
The other side effect is reflex tachycardia.
Prazosin, terasozin, doxasozin, trimasozin, and
phenoxybenzamine are α1-blockers
Phentolamine, tolazoline are α1 & α2-blockers
Yohimbine is α2-blocker (have no clinical
significance).
09/23/18 43
Adrenergic antagonist
Most of the α-adrenoceptor antagonist allow
vasodilatation and, thus decrease blood
pressure

α1 ⇌ α2
phenoxybenzamine
Prazosin Pentolamine yohimbine
Terazosin tolazoline
Doxazosin
trimazosin

09/23/18 44
Adrenergic antagonist
Semua antagonist reseptor α adalah inhibitor yg
reversibel kecuali fenoksibenzamin yang
bersifat inhibitor irreversibel
Prazosin, terazosin, doxazosin, dan trimazosin
digunakan dalam terapi untuk mengobati
hipertensi

09/23/18 45
09/23/18 46
Antagonist reseptor β-adrenergik
Reseptor β1 ada di jantung. Aktivasi reseptor ini
mengakibatkan apa ?
Reseptor β2 terdapat di otot polos saluran nafas,
uterus, dan otot polos pembuluh darah.
Aktivasi reseptor ini berakibat apa ?
Antagonis reseptor β1 akan menurunkan
frekuensi denyut jantung dan kontraktilitasnya
Antagonis reseptor β2 akan menyebabkan
konstriksi saluran nafas maupun uterus dan
pembuluh darah
09/23/18 47
Antagonist reseptor β-adrenergik
Efek inhibisi terhadap reseptor β2 dapat
membahayakan pasien asma
Aktivasi reseptor α1 akan menyebabkan
vasokonstriksi, aktivasi reseptor β2
menyebabkan relaksasi otot polos di pembuluh
darah (dan juga di bronkhus). Tetapi
penggunaan β-blocker secara rutin dapat
menurunkan tekanan darah dengan mekanisme
yg belum diketahui. Mungkin peran
penghambatan reseptor β1 lebih dominan.

09/23/18 48
Antagonist reseptor β-adrenergik
Senyawa β-blocker banyak digunakan secara
klinis untuk penatalaksanaan cardiac
arrhythmia, angina, dan hipertensi.
Senyawa β-blocker juga digunakan untuk
pengobatan hipertiroidisme, glaucoma, migrain,
dan ansietas (kegelisahan)
 Penggunaan β-blocker bersama-sama dengan obat
antidiabetika perlu kehatia-hatian, sebab pemeberian β-
blocker dapat menghilangkan tanda-tanda penurunan gula
darah berupa denyut jantung dan kadar gula darah tetap
rendah (efek metabolik stimulasi reseptor β menyebabkan
naiknya gula darah). Kemungkinan terjadi hipoglikemia.
09/23/18 49
Antagonist reseptor β-adrenergik
Antagonist selektif terhadap reseptor β1 disebut
cardioselective.

Cardioselective Non-cardioselective
Acebutolol Propranolol
Atenolol Carteolol
Betaxolol Levobunolol
Esmolol Nadolol
metoprolol Penbutolol
Pindolol
Timolol

09/23/18 50
09/23/18 51
09/23/18 52
Parasympathetic Nervous system
Acetylcholine released by:
1. All preganglionic autonomic nerves (both sympathetic
and parasympathetic)
2. All post-ganglionic parasympathetic nerves
3. Some post-ganglionic sympathetic nerves
(thermoregulatory sweet glands and skeletal muscle
vasodilator fibers)
4. Nerve to adrenal medulla
5. Somatic motor nerves at the neuro-muscular junction
6. Some neuron in the CNS

09/23/18 53
Parasympathetic (cholinergic) Nervous
system
Acetylcholine
Acetylcholinesterase
Muscarinic receptors
Nicotinic receptors
Parasympathetic nervous system

09/23/18 54
Acetylcholine receptors
Divided into nicotinic and muscarinic receptors

Acetylcholine released at the end of postganglionic

parasympathetic nerves acts on muscarinic receptors can be
blocked selectively by atropine

Three subtypes of muscarinic receptors: M1, M2 and M3

M1-receptors occur in the brain and gastric parietal cells
M2-receptors occur in the heart
M3-receptors occur in the smooth muscle and glands
Clinically useful muscarinic agonists and antagonists show little or
no selectivity for the different subtypes of muscarinic receptors,
except for pirenzepine which selectively blocks M1-receptors:
administered to reduce acid secretion
09/23/18 55
Acetylcholine receptors
Nicotinic receptors occur in autonomic ganglia and in the
adrenal medulla where the effect of acetylcholine (or
nicotine) can be blocked selectively by hexamethonium
The nicotinic receptors at the skeletal muscle
neoromuscular junctions are not blocked by
hexmethonium, but are blocked by tubocurarine
Nicotinic-receptors at ganglia and neuromuscular
junctions are different, although both types are stimulated
by nicotine

09/23/18 56
Actions of acetylcholine
Muscarinic effects are mainly parasympatomimetic (except
sweating and vasodiltation); in general are the opposite to
those caused by sympathetic stimulation
Include:
 constriction of the pupil
 Accommodation for near vision
 Profuse watery salivation
 Bronchiolar constriction
 Bronchosecretion
 Hypotension (due to bradicardia and vasodilatation)
 Increase in GI motility and secretion
 Contraction of the urinary bladder and sweating

09/23/18 57
09/23/18 58
Actions of acetylcholine
Nicotinic effects include stimulation of all autonomic
ganglia
The action of acetylcholine on ganglia is relatively weak
compared with its effect on muscarinic receptors >>> thus
parasympathetic effects predominate.
The nicotinic action on the parasympathetic system can be
demonstrated by blocking the muscarinic receptors with
atropine. High i.v. dose of acetylcholine then cause a rise
in blood pressure because stimulation of ganglia and
adrenal medulla result in vasoconstriction and tachycardia

09/23/18 59
09/23/18 60
09/23/18 61
Cholinergic agonists
Direct-acting cholinergic agonists mempunyai aksi
langsung pada reseptor asetilkholin.
Beberapa obat berinteraksi hanya dengan reseptor
muskarinik, beberapa yang lain berinteraksi dengan
reseptor nikotinik (spesifisitas obat).
Reseptor nikotinik ada di semua ganglion syaraf otonom
Reseptor nikotinik juga terdapat di neuromuscular junction.
Reseptor muskarinik ada di semua organ target dari syaraf
parasimpatis (post synaptic nerve release acetylcholin)
Ada juga reseptor kholinergik di CNS dan di kelenjar keringat
yang diinervasi oleh syaraf simpatis.
09/23/18 62
Cholinergic agonists
Indirect-acting cholinomimmetics beraksi dengan
menghambat metabolisme asetilkholin oleh enzim
asetilkholinesterase.
Senyawa ini akan meningkatkan keberadaan
asetikholin di semua sinapsis.

Ester kholin Alkaloid

Bethanechol Arecoline
Carbachol Muscarine
Methacholine Pilocarpine

09/23/18 63
Cholinergic agonists
Ester kholin strukturnya terkait dengan struktur
asetilkholin
Alkaloid strukturnya tidak terkait dengan asetikholin,
biasanya merupakan senyawa dari tumbuhan.
Alkaloid karena strukturnya tidak mirip asetilkholin,
mereka tidak dimetabolisme oleh asetilkholinesterase.
Ada enzim lain yang disebut pseudokholinesterase
sebuah esterase yang tidak spesifik dan banyak
ditemukan di hepar

09/23/18 64
09/23/18 65
Cholinergic agonists
Effects of all of those cholinergic agonists are exclusively
muscarinic.
Bethanecol paling banyak digunakan secara klinis
Bethanecol digunakan untuk mengobati urinary
retention. (mis. Pada waktu pasca pembedahan atau
karena sebab neurogenic bladder)
Efek sampingnya terkait dg reseptor muskarinik a.l. sweating
(increased secretion), salivation, GI distress and cramps (due to
increased motility)
Nikotin adalah agonis reseptor nikotinik ,useful to stop
smoking
09/23/18 66
09/23/18 67
Cholinesterase inhibitors
Klasifikasinya seringkali berdasarkan strukturnya:
mon0-quaternary amine, bis-quarternary amine,
carbamate, and organophospahtes.
Pada kesempatan ini pembagiannya menjadi dua ialah
inhibitor yang reversibel (umumnya larut dalam air)
dan inhibitor yang irreversibel (umumnya larut dalam
lipid, mis. Senyawa organofosfat).
Inhibitor reversibel meliputi senyawa karbamat dan amina
kuarterner.
Inhibitor reversibel berkompetisi dengan asetikholin
dalam berikatan dengan sisi aktif enzim.
09/23/18 68
Cholinesterase inhibitors
Reversible inhibitors Irreversible inhibitors
Edrophonium Diisopropyl fluorophospahte
Neostigmine Echothiophate
Physostigmine Isofluorophate
Pyridostigmine Malathion
Ambenonium Parathion
demecarium Sarin
soman

Semua senyawa ini menunjukkan aksi dan efek samping yg sama dg direct-
acting cholinergic agonists (muscarinic). Why ?

09/23/18 69
09/23/18 70
Cholinesterase inhibitors
Edrofonium, aksinya pendek, digunakan untuk diagnosis
myasthenia gravis
Neostigmin , piridostigmin, dan ambenonium, aksinya
panjang/lama, digunakan untuk mengobati myasthenia
gravis
Myasthenia gravis adalah penyakit imunitas dimana
pasien tersebut tidak mempunyai reseptor nikotinik di
neuromuscular junction, menyebabkan terjadinya
kelemahan dan kelelahan otot skelet.
Pada orang sehat obat ini menyebabkan fasikulasi dan
kelemahan otot skelet.
09/23/18 71
Cholinesterase inhibitors
Pemakaian lain dari inhibitor kholinesterase adalah
untuk mengobati glucoma and the reversal of
nondepolarizing neuromuscular blockade after surgery.
Inhibitor irreversible tidak mempunyai manfaat untuk
terapi, sebagai insectisida atau gas syaraf (senjata
kimia pada masa lalu, dan masa kini mungkin?)
Keracunan insektisida organofosfat dapat diobati
menggunakan pralidoksim dan/atau atropin.
Atropin adalah prototipe antagonist reseptor
muskarinik
09/23/18 72
09/23/18 73
09/23/18 74
09/23/18 75
09/23/18 76
09/23/18 77
09/23/18 78
09/23/18 79
09/23/18 80
09/23/18 81
 Agonist adrenergic receptors
Alpha-1(α1), most vascular smooth muscle; agonist
contract
Beta-1 (β1), heart; agonist increase rate
Beta-2(β2), respiratory & uterine smooth muscle;
agonist relax
Pasien 65 th penderita asma kronis. Tapi dia juga punya
riwayat serangan jantung. Maka dipilih obat yang
selektif thd reseptor β2, dan tidak mempengaruhi
reseptor β1.
Ada efek-efek lain selain efek di atas
09/23/18 82