Principles of Drug Action
Prinsip-prinsip aksi obat
Sugiyanto
Lab. Farmakologi & Toksikologi
Fak. Farmasi UGM
1
3/16/2016
General Overview
 A few drugs act by virtue of their physicochemical properties, e.g.
laxative agent (MgSO4), general anesthetics (based on its lipid
solubility (?), osmotic diuretics (mannitol)
 Some drugs act as false substrates (sulphonamides) or
inhibitor for certain transport systems (cardiac glycosides) or enzymes
(NSAIDs)
 Most drugs produce their effects by acting on specific protein
molecules, usually located in the cell membrane. These proteins
are called receptors
2
3/16/2016
Prinsip aksi obat
3
3/16/2016
Receptor, Agonist & Antagonist
 Receptors normally respond to endogenous chemicals in
the body.
 These chemicals are either synaptic transmitter
substances (neurotransmitters) or hormones, for
example acetylcholine, epinephrine, insulin, aldosterone
etc.
 Chemicals or drugs that activate receptors and produce a
response are called agonist.
 Drugs or chemicals that combine to receptors but do
not activate them are called antagonist
4
3/16/2016
Receptors
 They are protein molecules which are normally activated by
neurotransmitters or hormones.
 Many receptors have now been cloned and their amino acid
sequences determined.
 The 4 main type of receptors are:
 1. Agonist-gated receptors are made up from subunits
which form a central ion channel (e.g. nicotinic receptor)
 2. G-protein-coupled receptors form a family of receptors
with seven membrane-spanning helices
5
3/16/2016
Receptors
 3. Nuclear Receptors (Intracellular receptors, Protein
Synthesis-regulating Receptors) for steroid hormones and
thyroid hormones
 4.Kinase-linked receptors (Ligand-regulated Enzymes)
adalah reseptor permukaan membran yg biasanya
mempunyai aktivitas kinase tirosin intrinsik, sebagai
contoh: reseptor insulin, reseptor sitokin dan reseptor
faktor pertumbuhan
6
3/16/2016
Reseptor asetilkolin nikotinik :
 Suatu protein pentamer yang terdiri dari 5
subunit yaitu 2βγδ
 Terkait dengan kanal Na+
 berlokasi di neuromuscular junction, ganglia
otonom, medula adrenal, dan CNS
 pertama kali dikarakterisasi dengan
kemampuannya mengikat nikotin
3/16/2016
7
Reseptor GABA
8
3/16/2016
Contoh reseptor terkopel protein G
 Reseptor asetilkolin muskarinik
 Reseptor adrenergik
 Reseptor dopamin
 Reseptor angiotensin
Reseptor terkopel Protein G
 merupakan keluarga terbesar reseptor permukaan sel
 menjadi mediator dari respon seluler berbagai molekul,
seperti: hormon, neurotransmiter, mediator lokal, dll.
 merupakan satu rantai polipetida tunggal, keluar masuk
menembus membran sel sampai 7 kali  disebut
memiliki 7 transmembran
Some examples of Nuclear Receptor (Protein
synthesis-regulating Receptors)
Receptor
Location (Unliganded)
Thyroid Hormone
100% Nucleus
Retinoic Acid
~95% Nucleus
Vitamin D
75% Nucleus
Estrogen
95% Nucleus
Glucocorticoid
90% Cytosol
Androgen
90% Nucleus
Mineralocorticoid
~40% Nucleus
Contoh Kinase-linked Receptor (Ligandregulated Enzymes)
12
Reseptor Insulin
3/16/2016
Drug-receptor Interactions
 The activation of receptors by an agonist is coupled to
the physiological or biochemical responses by
transduction mechanisms that often (but not always)
involve molecules called second messengers (for example
Ca2+, inositol triphosphate, diacylglycerol and cAMP)
 The interaction between a drug and the binding site of
the receptor depends on the complementary of “fit” of
the 2 molecules.
 The closser the fit and the grater the number of bonds (usually
non-covalent), the stronger will be the attractive forces between
them, and the higher the affinity of the drug for the receptor.
13
3/16/2016
Aktivasi GPCR (G protein-coupled receptor) melalui
sistem fosfolipase
 merupakan salah satu mekanisme transduksi signal yang penting
 diawali dg pengikatan suatu ligan pada reseptor  mengaktivasi
enzim fosfolipase C  membelah PIP2 menjadi IP3 dan DAG
 PIP2 = fosfatidil inositol bis-fosfat  merupakan hasil degradasi
fosfatidil inositol pada membran sel dg bantuan enzim PI kinase
 IP3 = inositol trifosfat  berikatan dengan reseptor spesifik pada
retikulum endoplasmik yang tekait dg kanal Ca++  memicu
pelepasan kalsium intrasel  kontraksi sel, pelepasan
hormon/neurotransmiter, eksositosis
 DAG = diasil gliserol  mengaktivasi protein kinase C 
memfosforilasi residu serine/threonin kinase pada sel target
Signal molecule
G-protein linked
receptor
Activated
Phospholipase C
Activated G
 subunit
PI 4,5-biphosphate
(PI(4,5)P2)
inositol
1,4,5-triphosphate
(IP3)
diacylglycerol
Activated
PKC
Ca++
Open IP3-gated
Ca++ channel
lumen of
endoplasmic
reticulum
Cara kerja reseptor insulin dlm
pengambilan glukosa
16
3/16/2016
Specificity & selectivity
 The ability of a drug to combine with one particular type
of receptor is called specificity.
 No drug is truly specific but many have a relatively
selective action on one type of receptor.
 Drugs are prescribed to produce a therapeutic effect but
they often produce additional unwanted effects which
range from the trivial (slight nausea) to the fatal (aplastic
anaemia)
17
3/16/2016
Neurotransmitters
 Neurotransmitter substances are chemicals released from nerve
terminals which diffuse across the synaptic cleft and bind to the
receptors.
 The neurotransmitter activates receptors, presumably by changing
their conformation, and triggers a sequences of post-synaptic
events resulting in, for example, muscle contraction or glandular
secretion.
 Following its release, the transmitter is inactivated by either
degradation (e.g. acetylcholine) or reuptake (e.g. norepinephrine,
GABA).
 Many drugs act by either reducing or enhancing synaptic
tranmission.
18
3/16/2016
Hormones
 Hormones are chemicals released into bloodstream; they produce
their physiological effects on tissues possessing the necessary
specific hormone receptors.
 Drugs may interact with the endocrine system by inhibiting (e.g.
antithyroid drugs) or increasing (e.g. oral antidiabetic agents)
hormone release.
 Other drugs interact with hormone receptors which may be
activated (e.g. steroidal anti-inflammatory drugs) or blocked (e.g.
oestrogen antagonists).
 Local hormones (autacoids) such as histamine, serotonin (5-HT),
kinins and prostaglandins are released in pathological processes.
19
3/16/2016
Hormones
 Propil tio urasil (PTU) obat antitiroid
 Glimepirid dan glibenklamid, obat golongan sulfonilurea,
digunakan untuk memacu skresi hormon insulin
(abtidiabetik)
 Efek dari histamin dapat dihambat oleh antihistamin
 Beberapa obat dapat menghambat biosintesis prostaglandin
(obat-obat anti inflamasi non-steroid, NSAIDs)
20
3/16/2016
Neurotransmitter Asetilkholin
Asetilkholin:
 molekul pertama yang diidentifikasi sebagai neurotransmitter
 aksinya pada sistem syaraf otonom di perifer maupun CNS
 Di sistem syaraf perifer:
 Neurotransmitter sistem syaraf parasimpatik (kholinergik)
 memiliki 2 macam reseptor yaitu nikotinik dan muskarinik
 Di sistem syaraf pusat (CNS):
 berperan antara lain dalam regulasi belajar (learning), memori,
kontrol gerakan, dan mood (perasaan)  contoh: penyakit
Alzheimer (pikun) disebabkan karena degenerasi sistim kolinergik
21
3/16/2016
Reseptor kanal ion (ionotropik)
 Teraktivasi sebagai respon terhadap ligan spesifik
 Selektif terhadap ion tertentu
 Terlibat dalam signaling sinaptik yang cepat (yang lambat
: melalui reseptor protein G)
 Contoh :
reseptor asetilkolin nikotinik
reseptor GABAa
reseptor glutamat (NMDA)
reseptor serotonin (5-HT3)
3/16/2016
22
DRUG-receptor INTERACTION
Kinetics, effect and fate
23
3/16/2016
Kinetics of drug-receptor interaction
24
3/16/2016
Kinetics……..
 A+R
[AR]
Response
 Rate of association= k1 [A][R]
 Rate of dissociation = k2 [AR]
 At equilibrium:
 Rate of association = rate of dissociation
 k1 [A][R] = k2 [AR]
 k2/k1 = [A][R]/ [AR] = kD
25
3/16/2016
Kinetics…. (some assumptions)
 1.reaksi antara agonis dan reseptor adalah reversibel
 2. kedua reaktan tersedia dalam bentuk bebas atau
terikat dan tidak termasuk bentuk lain, mis hasil
degradasi yang tidak terlibat dalam reaksi tersebut
 3. Semua tempat di reseptor mempunyai affinitas yg
sama terhadap agonis dan independen
26
3/16/2016
Plot terhadap waktu….
 d([AR]/dt = k1[A][R] – k2[AR]
 Plotting of [AR] as function of time yields an hyperbolic curve and
asymptotic relationships for the formation of [AR] as equilibrium
was approach
27
3/16/2016
DRUG-RECEPTOR INTERACTION
28
3/16/2016
29
3/16/2016
Difference in configuration
30
3/16/2016
31
3/16/2016
Protein binding & drug effect
32
3/16/2016
33
3/16/2016
Agonist & Antagonist
34
3/16/2016
Affinity & efficacy
35
3/16/2016
Competitive antagonism
36
3/16/2016
Type of antagonism
 Competitive antagonism: atropine, ipratropium, hyoscine for
ACTH-receptor
 Irreversible antagonism: phenoxybenzamine for α-
adrenoceptor
 Non-competitive antagonism: Ca-channel blockers
 Chemical antagonism: protamine vs heparin
 Physiological antagonism: prostacyclin against thromboxane
A2
37
3/16/2016
Kinetics of drug-receptor interaction
38
3/16/2016
Type of receptors
39
3/16/2016
40
3/16/2016
41
3/16/2016
Activation of receptor
42
3/16/2016
The role of Second messengers
43
3/16/2016
Farmacokinetics
44
3/16/2016
45
3/16/2016
46
3/16/2016
Adverse effect of drugs
47
3/16/2016
Adverse effect of drugs
48
3/16/2016
Adverse effect of drugs
49
3/16/2016