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 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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 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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 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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◦ 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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 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 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
 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
Reseptor Insulin
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 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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 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
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 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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 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 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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 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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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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 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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Kinetics, effect and fate

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 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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 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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 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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 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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