Principles of Drug Action

Prinsip-prinsip aksi obat

Sugiyanto
Lab. Farmakologi & Toksikologi
Fak. Farmasi UGM

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 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

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 Prinsip aksi obat

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 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

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 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

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 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

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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
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 Reseptor GABA

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 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 (Ligand-
regulated Enzymes)

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 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.

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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 PI 4,5-biphosphate
G-protein linked (PI(4,5)P2)
receptor Activated
Phospholipase C diacylglycerol

Activated
Activated G PKC
inositol
 subunit 1,4,5-triphosphate
Ca++
(IP3)
Open IP3-gated
Ca++ channel

lumen of
endoplasmic
reticulum
 Cara kerja reseptor insulin dlm
pengambilan glukosa

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 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)

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 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.

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 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.

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 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)

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 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

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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)

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 DRUG-receptor INTERACTION

Kinetics, effect and fate

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 Kinetics of drug-receptor interaction

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 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

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 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

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 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

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 DRUG-RECEPTOR INTERACTION

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 Difference in configuration

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 Protein binding & drug effect

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 Agonist & Antagonist

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 Affinity & efficacy

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 Competitive antagonism

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 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

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 Kinetics of drug-receptor interaction

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 Type of receptors

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 Activation of receptor

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 The role of Second messengers

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 Farmacokinetics

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 Adverse effect of drugs

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 Adverse effect of drugs

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 Adverse effect of drugs

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