Basic Principle

of Pharmacology
Drs. Admar Jas M.Sc. Apt
Senen, 17 Okt. 2011

Pharmacology & Therapeutic Depart.

School of Medicine
Universitas Sumatera Utara

Topik: Drug as a molecule

o Menjelaskan definisi obat sbg Ligand
o Menjelaskan peran chiral, enantiomer dan
racemic.
o menjelaskan bentuk dan ukuran ligand (drug
size & shape).
o Conformation and chemistry of receptors and
ligands (menjelaskan pengertian reseptor).
o Drug receptor binding (menjelaskan ikatan obat
reseptor):
1. Van der Waals
2. Hydrogen
3. Ionic
4. Covalent
5. Hydrophobic

Pemberi kuliah: A. Jas & Wakidi - BBC3-K12 (R.k. Histologi 1)

Blok Basic Biologi of Cells TA 2010/2010

Kuliah: Rb. 01-9-10

Pk. 10.00-11.00 Wib
Pk. 14.00-15.00 Wib

INTRODUCTION OF PHARMACOLOGY
-Pharmacokinetic pharmacodymamic
-Homeostatic

PHARMACOLOGY DRUGS :
The study of substances that interact with living
systems:
1. Through chemical processes,
2. Especially by binding to regulatory molecules in
activating/ inhibiting normal body processes.

Physical and chemistry properties of drugs

Sifat fisika-kimia obat nasib obat di dalam tubuh
kelarutannya di dalam tubuh ( membran sel, plasma darah)
metabolisme (biotransformasi)
reaksi biologis (reaksi biokimia & aktivitas farmakologi obat)
Any substance that brings about a change in biologic
function through its chemical action

Pharmacokinetic (ADME)
Pharmacodynamic
-binding
-interaction with receptor or withouth receptor
-actions (activation / inhibiton)

Asetosal, paracetamol, NaCl

Physics:

Solid (cystals/crystalline powder)

Liquid
Gaseous

Atropine, efedrin, KMnO4

Phenobarbital

Ethanol, glycerol, aceton, aether

Nitrous oxide, O2

Physics of drugs is important in route of administration

Water (room temperature),hot water , organic & anorganic solven, melting point,
molecule weight, Hygroscopis, Koefisien Partisi.

Physical

Solubility
Flammability
Explosivity
Stability (thermolability, Redoxybility)
Odourless, colourless, taste,

Koef. Partisi

P = [obat] lemak / [obat] air

Konst. kesetimbangan kosentrasi obat di dlm dua fase, yi: lemak & air.
Salah satu parameter obat. (fisika-kimia).

Berpengaruhi thd karakteristik transpor obat jalan mencapai tempat aksi

dari tempat aplikasi. Mis. Tempat inj., saluran cerna dll. Obat biasanya
didistribusikan mel. darah, oleh karena itu mesti mengadakan penetrasi
melintasi membran sel untuk mencapai tepat aksi sampai di keluarkan dari
tubuh.
Sifat fisika-kimia obat berpengaruh thd:
-BSO
-Cara pemberian obat
-Efek farmakologi
-Penanggulangan intoksikasi

Chemistry

Weak acid

Weak base

Ionization, esterification, hydrolisa, chelating

complex, redox, colour altering.
Kebanyakan obat-obatan bersifat as lemah
Di lambung tidak terjadi peruraian / ionisasi,
akan mudah larut dalam lemak dan melewati
membran sel
Terjadi peruraian / ionisasi dalam
lambung, obat akan bersifat polar shg
obat sulit melewati membran sel.

Oxydator
Reduktor

Redox penting dalam rangka

peruraian dan perubahan bentuk
senyaw

Note:
This is importan for absorption -- molecule across membrans cell
by transport, diffusion, filtrasi, vacuola etc.

DRUG SIZE.
Molecular size : MW 7 (lithium to over MW 50,000 (thrombolytic enzymes)
Molecular weight : 100 1000

The lower limit of this narrow range is probably set by the requirements for
spesificity of action.
To achieve sach selective binding, it appears that a molecule should in most
cases be at least 100 MW. The upper limit in molecular weight is determined
primarily by the requirement that drug be able to move within the body.
Drug larger than MW 1000 will not diffuse readly between compartement of the
body. Therefore, very large drugs (usually proteines) must be administered
directily into the compartement where they have their effect.
In the case of alteplase, a clor-dissolving enzyme, the drug is administered
directily into the vascular compartement by intravenous infusion.

Drug-Receptor
May be the Drug-receptor has bind chemical, sach as:
1. Van der waals
2. Ikatan hydrophob
3. Hydrogen
4. Ionic
5. Covalen
Ad. 1. Ikatan Van der waals,
gaya yg terjadi antara atom yg memp kemampuan polarisasi, kmd
terinduksi asimetrik dlm awan elektron oleh inti yg berdekatan letaknya shg
terjadi tarik menarik antara dua atom. Dayanya berkurang sebanding dg jarak
pangkat 6 --- 1/R 6.
Jarak antara atom, dimana gaya Van der Waals masih ada : 0,4-0,6 nm.

Ad. 2. Ikatan hydrophob (seny non polar berinteraksi dg mol air).

Ikatan antara mol non polar (bag hidrocarbon) yg tidk mampu membentuk
ikatan hidrogen dg mol air, shg mol air lebih teratur letaknya dekat molekul tsb &
membentuk permukaan antara ditingkat mol. Mis:
-Rantai samping leusin dari protein dengan air.
-Senyawa alivatis/ aromatis dengan air
-Stabilisasi konformasi protein
-Transport lipida pada protein plasma
-Pengikatan steroid pada reseptor

Ad. 3. Ikatan Hydrogen,

stabilitas intra struktur dalam molekulnya.
Ikatan ini terjadi interaksi elektrostatik dari pasangan elektron sunyi dari atom
N, S, O sebagai donor dan atom H sbg akseptor (kekurangan elektron),
Mis: -SH; -NH; -OH
H-O-H dg sudut 104,5 o
Gaya ini akibat dari polritas air yang tinggi sehingga terjadi sudut ikatan 104,5

Ad. 4. Ikatan Ionic

Ikatan yang terjadi antara muatan 2 ion yang berlawanan, interaksi elektrostatik sangat kuat, melebihi kekuatan
interaksi pada ikatan kovalen. Mis. : Na + + Cl- ------> NaCl

Ad. 5. Ikatan Kovalen

Ikatan yang terjadi karena pasangan elektron sunyi menjadi kepunyaan bersama.
..
-N
dg H2SO4 atau HCl , membentuk garam.
!

Relative Strength of bonds between Receptors and Drugs

Bond Type

Mechanism

Bonds strength

Van der Waals

Shifting electron density in areas of a molecule, or in a molecule

as a whole result in the generation of transient positive or
negative charges. The areas interact with transient areas of
oposite charge on anather molecule.

hydrogen

Hydrogen atoms bound to nitrogen or oxygen became more

positively polarized, allowing them to bond to more negatively
polarized atom such as oxygen, nitrogen or sulfur.

++

ionic

Atoms with an excess of electrons (imparting an overall

negative charge on the atom) are attracted to atoms with a
deficiency of electrons (imparting an overall positive charge on
the atom)

+++

covalent

Two bonding atoms share electrons

++++

SOAL KBK, 15 NOPEMBER 07 (BBC3-K12 A.Jas-WK)

JUDUL: BASIC PRINCIPLE OF PHARMACOLOGY

IKD 4.3: 9.00 10.00 WIB

DATTEN B DAN A. JAS

Pemberi kuliah: Datten Bgn & Ajas

Jumat, 3 / 11-06 pk. 9-10.00 Wib

Pharmacology molecular concept

1. Drugs that do not fit the drug-receptor model
2. Inpact of drug binding on reseptor conformation
3. Processing of signals resulting from drug-receptor interactions
4. Celluler regulation of drug-receptor interactions
5. Moleculler and celluler determinants of drug selectivity
In order to have a good fit to only one type receptor a drug molecule must be
sufficiently unique in shape, charge, structure, etc, to prevent its binding to other receptors.
Senyawa obat atau senyawa bioaktif umumnya dikelompokan menjadi 2 golongan, a.l:
1. Senyawa obat / bioaktif berstruktur khas, yaitu aktivitasnya sangat tergantung pada
struktur molekulnya.
2. Senyawa obat / bioaktif yang berstruktur tidak khas, yaitu aktivitas biologinya tidak
tergantung pada struktur molekulnya.

Teori kerja Obat ditingkat molekul:

Untuk menerangkan bagaimana antaraksi obat dengan reseptor, ada beberapa teori a,l:
1. Pendudukan reseptor (Clark & Gaddum)
2. Ariens & Stephenson
3. Laju reaksi
4. Charniere
5. Kesesuaian yang terimbas
6. Penggangguan makromolekul

Ad. I. Drugs that do not fit the drug-receptor model

Ativity by not receptor as mediated mechanism. Structure non specific drugs are those
in which the pharmacological action is not directly dependent on the chemical structure
of the drug, except that structure effects physico-chemical properties. Structural non
specific drugs act by physico-chemical prossesess.
Examples:
-osmotic diuretics
-antacids
-chelating agent
-laxant (lubricant)
-emolient
Ad. II. Inpact of drug binding on receptor conformation
The first massenger + R + G-protein ---- MRG + effector ---- the second massenger will be
Released.

1. The simple action for produce an effect

Examples: sympathomimetic and parasympathomimetic drugs
-adrenergic
-cholinergic

2. Preventing the receptor to bind with its endogenous ligand, without changing the
conformation
Examples: Curare
3. Changes in receptor conformation
3.1. Enhancing the affinity of the drug for the receptor ------ inducet fit
receptor altering the action of the receptor.
Examples: insulin analog --- stimulate all the insulin receptor to the same extent
despite slightly different amino acid sequence

Inpact of drug binding on receptor conformation

Transmembrane Ion Channels

G PROTEIN and Second Messenger

3.2. Inhibiting ------ inactivation

Ad. III. Processing of signals resulting from drug-receptor interactions

1. Messenger : Catecholamines
2. Messenger : c. AMP
Ex. L1 + R
-------> G- protein ---------------> A C5 ------ c. AMP
L2 + R
-------> G- protein ---------------> A Ci ----->!! c AMP
1. Clark dan Gaddum:
Intensitas efek berbanding langsung dg jml reseptor yang ditempati oleh senyawa obat. Antaraksi obatreseptor
sesuai dengan hukum aksi masa seperti persamaan ini:
K1
R + O
---------------->
RO ----------> E
<-------------k2
Jml reseptor yg ditempati obat tgt pada konsentrasi obat pada konpartemen reseptor dan juml keseluruhan
reseptor dan efek obat lebih kuat bila jml reseptor yg ditempati semakin banyak. Teori ini tidak dapat
menjelaskan ada obat tertentu bekerja sbg agonis dan obat lain dg struktur yang sama bekerja sbg antagonis.

2. Teori Ariens dan Stephenson

Antaraksi obat dengan reseptor mencakup dua tahap, yaitu
a. Pembentukan kompleks obat-reseptor
b. Menunjukkan efek
Persyaratannya, a.l :
1. Senyawa obat harus punya affinitas kuat thd reseptor
2. Aktivitas intriksik
3. Struktur spesifik

Receptor mediated activation of a G protein and

the Resultant Effector interaction

a) In the resting state, the and subunits of G protein are associated with one another,
and GDP is boud to subunit.
b) Binding of an extracellular ligand (agonist) to a G protein-coupled receptor exchange
of GTP for GDP on the subunit.
c) The subunit dissociates from the subunit, which diffuses to interact with effector
proteins. Interaction of the GTP-associated subunit with an effector activates the
effector.
o
o
o

In some cases , the subunit can also activate effector proteins.

Depending on the receptor subtype and the spesific G isoform, G can also inhibit the activity of an effector
molecule.
The subunit posseses intrinsic GTPase activity, which leads to hydrolysis of GTP to GDP. This leads to
reassociation of the subunit with the subunit and the cycle can begin again.

3. Teori Charniere
Menerangkan mengapa suatu agonis, meskipun tdk dapat menggeser antagonis dari resep
tornya, dapat bersaing dg antagonis sesuai dengan hukum aksi masa. Reseptor mempunyai
dua kedudukan a. l:
1. Kedudukan kritis atau yang khas, yaitu berinteraksi dg ggs kromofor senyawa agonis.
2. Kedudukan non kritis atau tidak khas, yaitu membentuk kompleks dg ggs nonpolar
senyawa antagonis.
Menurut Chaniere, baik agonis maupun antagonis terikat pada kedudukan yg khas dg ikatan
lemah secara reversibel. Dsp itu antagonis juga terikat secara tidak khas melalui ikatan hidrofob
dan Van der Waals serta transfer muatan. Persaingan agonis dg antagonis terjadi pada kedu
dukan yg khas dg reseptor.

Ad. IV. Celluler regulation of drug-receptor interactions

Drug ---- Foreign body to our cells, prinsiple homeostatis
1. No of receptors
-upregulation -- beta-blocker
-down regulation --- TCA (tricyclic acid) --- antidepressant
Ex. Opiat ------ toleransi
2. Tachyphylaxis --- toleransi cepat terjadi
-reduce effect produced after repeated administration

3. Desensitization (Ketidak pekaan)

-homologous ----- decrease response of a single class of receptor
-heterologous ---- multiple class

4. Inactivastion
Loss of ability a receptor to respond, to stimulation by a drug
5. Refractory
After a receptor is stimulated, a priod of time is required before the next drug-receptor
interaction can produce an effect.
Ad. V. Moleculler and celluler determinants of drug selectivity
Drug receptor interactions
Specificity : tissue, systems, organ where receptors are distributed (compartement)
Ex. Adrenergic and cholinergic
Selectivity : drug interacts preferentially on particular receptor types or sub types.
Ex. Propanolol: non selective ---- antagonist of 1 and 2
Atenolol : 1 selective, 2 less
Terbutalin : agonist of 2

Determinant :

The chemical structure may be very much different, yet the pharmacological action are similar.
A slight modification in chemical structuredoes not produce a dramatic chang in pharmacological
action. Structural specific drugs are those in which the pharmacological action dependent directly
on the chemical structure of the drug, wichh attaches itself to a three-dimensional structure of a
reseptor in the biophase. Prerequisites of the binding of a drug to receptor are: chemical, reactivity,
presence of fungsional groups, electonic distribution and topographic mirror-like image of the
receptor.

Stereoisomers

Have the same molecular formula and the same order

of attachment of their atoms (the same connectivity),
but different three-dimensional orientations of their
atoms in space.
example: the cis-trans isomers of cycloalkanes

CH3

CH3

CH3

CH3

and
H
H
cis-1,4-Dimethylcyclohexane

trans
-1,4-Dimethylcyclohexane

Drugs similar pharmacological action have usually some common structural caracteristics
with functional groups in similar spatial direction. A slight modification in chemical
structure may produce dramatic change in pharmacological action (from incresed activity
to antagonism.
Receptor are all specific molecules, molecule complexes or part of these, which bind
the drug chemically and this complex exerts a pharmacological action.

Konsep Farmakologi molekular

Obat adl zat aktif yang sudah terbukti berguna untuk pemulihan kesehatan, tidak semua zat aktif dapat digunakan
sebagai obat.
Fokus: Mekanisme kerja obat-obat terutama interaksi obat dg reseptor shg terjadi suatu efek.

Obat dibagi dalam 2 kelompok besar, yaitu:

1.
2.

Struktur spesifik, utk bekerja membutuhkan reseptor --- perubahan pada sistemefektor, ada efek dan
dapat diamati.
Struktur non spesifik, tidak butuh reseptor ---- tidak ada efek.
mis: Antacida, laksan osmotik / garam (MgSO4), gliserin, Na3 PO4
Diuretik osmotik

Gambar: perubahan konformasi suatu enzim yg diimbas oleh substratnya

Pada gambar ini terjadi gaya antaraksi antara rantai protein, molekul substrat dan ion-ion yang ada dalam
larutan diberi tanda H untuk gaya hidrofob + dan untuk gaya elektrostatik. Kompleks protein-substrat
yang terbentuk dapat berdissosiasi dan protein terlipat kembali ke konformasi semula.