b p of pharm, aj-wk-09 - copy

7/25/2019 B P of Pharm, AJ-WK-09 - Copy

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Basic Principle

of Pharmacology

Pharmacology & Therapeutic Depart.

School of Medicine

Universitas Sumatera Utara

Drs. Admar Jas M.Sc. Apt

Senen !" #$t. %!!


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Topi$' Drug as a molecule

oMen(elas$an definisi o)at s)g *igand

oMen(elas$an peran chiral enantiomer danracemic.

omen(elas$an )entu$ dan u$uran ligand +drug

si,e & shape-.oonformation and chemistry of receptors and

ligands +men(elas$an pengertian reseptor-.oDrug receptor )inding +men(elas$an i$atan o)at

reseptor-'

!. /an der 0aals

%. 1ydrogen2. 3onic

4. ovalent

5. 1ydropho)ic


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36T7#DUT3#6 #8 P1A7MA#*#9:

The study of substances that interact with livingsystems:

1. Through chemical processes,

2. Especially by binding to regulatory molecules in

activating/ inhibiting normal body processes.

Pem)eri $uliah' A. Jas & 0a$idi ; BB2;

Blo$ Basic Biologi of ells TA %!=%!

Kuliah: Rb. 01-9-10

Pk. 10.00-11.00 Wib

Pk. 14.00-15.00 Wib

P1A7MA#*#9: D7U9S '

;Pharmaco$inetic > pharmacodymamic;1omeostatic


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Physical and chemistry properties of drugs

Sifat fisika-kimia obatnasib obat di dalam tubuh

kelarutannya di dalam tubuh membran sel, plasma darah!

metabolisme biotransformasi!

reaksi biologis reaksi biokimia " aktivitas farmakologi obat!

Pharmaco$inetic +ADM?-Pharmacodynamic;)inding

;interaction @ith receptor or @ithouth receptor

;actions +activation = inhi)iton-

Any su)stance that )rings a)out a change in )iologic

function through its chemical action


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Solid (cystals/crystalli! "o#d!r$

%i&uid

'as!ous

Asetosal paracetamol 6al

Atropine efedrin


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hemistry

0ea$ acid

0ea$ )ase

Ionization, esterification, hydrolisa, chelating

complex, redox, colour altering.

6ote'

This is importan for a)sorption ;; molecule across mem)rans cell

)y transport diffusion filtrasi vacuola etc.

K!bayaka obat-obata b!rsiat as l!ah

6i labu* tidak t!r3adi "!ruraia / ioisasi)

aka udah larut dala l!ak da !l!#ati

!bra s!l

!r3adi "!ruraia / ioisasi dala

labu*) obat aka b!rsiat "olar sh*

obat sulit !l!#ati !bra s!l.

#ydator

7edu$torR!do, "!ti* dala ra*ka"!ruraia da "!rubaha b!tuk

s!ya#


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D7U9 S3E?.

Molecular si,e ' M0 " +lithium to over M0 5 +throm)olytic en,ymes-

Molecular @eight ' ! >!

The lo@er limit of this narro@ range is pro)a)ly set )y the reFuirements for

spesificity of action.

To achieve sach selective )inding it appears that a molecule should in most

cases )e at least ! M0. The upper limit in molecular @eight is determinedprimarily )y the reFuirement that drug )e a)le to move @ithin the )ody.

Drug larger than M0 ! @ill not diffuse readly )et@een compartement of the

)ody. Therefore very large drugs +usually proteines- must )e administered

directily into the compartement @here they have their effect.

3n the case of alteplase a clor;dissolving en,yme the drug is administereddirectily into the vascular compartement )y intravenous infusion.


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Drug;7eceptor

May )e the Drug;receptor has )ind chemical sach as'

!. /an der @aals

%. 3$atan hydropho)

2. 1ydrogen4. 3onic

5. ovalen

Ad. !. 3$atan /an der @aalsgaya yg ter(adi antara atom yg memp $emampuan polarisasi $md

terindu$si asimetri$ dlm a@an ele$tron oleh inti yg )erde$atan leta$nya shg

ter(adi tari$ menari$ antara dua atom. Dayanya )er$urang se)anding dg (ara$

pang$at G ;;; !=7 G.

Jara$ antara atom dimana gaya /an der 0aals masih ada ' 4;G nm.


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Ad. 2. 3$atan 1ydrogenstabilitas itra struktur dala ol!kulya.

7kata ii t!r3adi it!raksi !l!ktrostatik dari "asa*a !l!ktro suyi dari ato

+) S) s!ba*ai door da ato 8 sb* aks!"tor (k!kura*a !l!ktro$)

is: -S8 -+8 -8 8--8 d* sudut 104)5 o

'aya ii akibat dari "olritas air ya* ti**i s!hi**a t!r3adi sudut ikata 104)5

Ad. %. 3$atan hydropho) +seny non polar )erintera$si dg mol air-. 7kata atara ol o "olar (ba* hidrocarbo$ y* tidk a"u !b!tuk

ikata hidro*! d* ol air) sh* ol air l!bih t!ratur l!takya d!kat ol!kul tsb

!b!tuk "!rukaa atara diti*kat ol. is:

-Ratai sa"i* l!usi dari "rot!i d!*a air. -S!ya#a ali;atis/ aroatis d!*a air

-Stabilisasi koorasi "rot!i

-ras"ort li"ida "ada "rot!i "lasa

-P!*ikata st!roid "ada r!s!"tor


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Ad. 4. 3$atan 3onic

7kata ya* t!r3adi atara uata io ya* b!rla#aa) it!raksi !l!ktrostatik sa*at kuat) !l!bihi k!kuata

it!raksi "ada ikata ko;al!. is. : +a +a=l

Ad. 5. 3$atan


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SB% KK) 15 +PR 0C (=D-K1 B.Eas-WK$

EF6F%: BS7= PR7+=7P% G P8BRB=%'H


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3


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Pem)eri $uliah' Datten Bgn & A(as

Jumat 2 = !!;G p$. H;!. 0i)

Pharmacology molecular concept

!. Drugs that do not fit the drug;receptor model

%. 3npact of drug )inding on reseptor conformation

2. Processing of signals resulting from drug;receptor interactions

4. elluler regulation of drug;receptor interactions

5. Moleculler and celluler determinants of drug selectivity

Senya@a o)at atau senya@a )ioa$tif umumnya di$elompo$an men(adi % golongan a.l'

!. Senya@a o)at = )ioa$tif )erstru$tur $has yaitu a$tivitasnya sangat tergantung pada

stru$tur mole$ulnya.

%. Senya@a o)at = )ioa$tif yang )erstru$tur tida$ $has yaitu a$tivitas )iologinya tida$

tergantung pada stru$tur mole$ulnya.

!ori k!r3a bat diti*kat ol!kul:Untu$ menerang$an )agaimana antara$si o)at dengan reseptor ada )e)erapa teori al'

!. Pendudu$an reseptor +lar$ & 9addum-

%. Ariens & Stephenson

2. *a(u rea$si

4. harniere

5.


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Ad. 3. Drugs that do not fit the drug;receptor model

Bti;ity by ot r!c!"tor as !diat!d !chais. Structur! o s"!ciic dru*s ar! thos!

i #hich th! "haracolo*ical actio is ot dir!ctly d!"!d!t o th! ch!ical structur!

o th! dru*) !,c!"t that structur! !!cts "hysico-ch!ical "ro"!rti!s. Structural o

s"!ciic dru*s act by "hysico-ch!ical "ross!s!ss.,a"l!s:

-osotic diur!tics

-atacids

-ch!lati* a*!t

-la,at (lubricat$

-!oli!t

Bd. 77. 3npact of drug )inding on receptor conformation

1. h! si"l! actio or "roduc! a !!ct

,a"l!s: sy"athoi!tic ad "arasy"athoi!tic dru*s

-adr!!r*ic

-choli!r*ic

The first massenger I 7 I 9;protein ;;;; M79 I effector ;;;; the second massenger @ill )e

7eleased.


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D. =ha*!s i r!c!"tor cooratio

D.1. haci* th! aiity o th! dru* or th! r!c!"tor ------ iduc!t it

r!c!"tor alt!ri* th! actio o th! r!c!"tor.

,a"l!s: isuli aalo* --- stiulat! all th! isuli r!c!"tor to th! sa! !,t!t

d!s"it! sli*htly di!r!t aio acid s!&u!c!

. Pr!;!ti* th! r!c!"tor to bid #ith its !do*!ous li*ad) #ithout cha*i* th!

cooratio

,a"l!s: =urar!


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Transmem)rane 3on hannels

9 P7#T?36 and Second Messenger

3npact of drug )inding on receptor conformation


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2.%. 3nhi)iting ;;;;;; inactivation

Ad. 333. Processing of signals resulting from drug;receptor interactions

1. !ss!*!r : =at!cholai!s

. !ss!*!r : c. BP ,. %1 < R -------> '- "rot!i ---------------> B =5 ------ c. BP

% < R -------> '- "rot!i ---------------> B =i ----->?? c BP

!. lar$ dan 9addum:

7t!sitas !!k b!rbadi* la*su* d* 3l r!s!"tor ya* dit!"ati ol!h s!ya#a obat. Btaraksi obat-

r!s!"tor

s!suai d!*a huku aksi asa s!"!rti "!rsaaa ii:K1

R < ----------------> R ---------->

I--------------

k

El r!s!"tor y* dit!"ati obat t*t "ada kos!trasi obat "ada ko"art!! r!s!"tor da 3ul k!s!luruha

r!s!"tor da !!k obat l!bih kuat bila 3l r!s!"tor y* dit!"ati s!aki bayak. !ori ii tidak da"at

!3!laska ada obat t!rt!tu b!k!r3a sb* a*ois da obat lai d* struktur ya* saa b!k!r3a sb* ata*ois.

%. Teori Ariens dan Stephenson

Btaraksi obat d!*a r!s!"tor !caku" dua taha") yaitu

a. P!b!tuka ko"l!ks obat-r!s!"tor

b. !u3ukka !!k

P!rsyarataya) a.l :

1. S!ya#a obat harus "uya aiitas kuat thd r!s!"tor

. Bkti;itas itriksikD. Struktur s"!siik


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R!c!"tor !diat!d acti;atio o a ' "rot!i ad

th! R!sultat !ctor it!ractio

a$ 7 th! r!sti* stat!) th! ad subuits o ' "rot!i ar! associat!d #ith o! aoth!r)ad '6P is boud to subuit.

b$ idi* o a !,trac!llular li*ad (a*oist$ to a ' "rot!i-cou"l!d r!c!"tor !,cha*!o 'P or '6P o th! subuit.

c$ h! subuit dissociat!s ro th! subuit) #hich dius!s to it!ract #ith !!ctor"rot!is. 7t!ractio o th! 'P-associat!d subuit #ith a !!ctor acti;at!s th!!!ctor.

o 7 so! cas!s ) th! subuit ca also acti;at! !!ctor "rot!is.

o 6!"!di* o th! r!c!"tor subty"! ad th! s"!siic 'isoor) 'ca also ihibit th! acti;ity o a !!ctorol!cul!.

o h! subuit "oss!s!s itrisic 'Pas! acti;ity) #hich l!ads to hydrolysis o 'P to '6P. his l!ads tor!associatio o th! subuit #ith th! subuit ad th! cycl! ca b!*i a*ai.


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Ad. 3/. elluler regulation of drug;receptor interactions

6ru* ---- Gor!i* body to our c!lls) "risi"l! ho!ostatis

!. 6o of receptors

-u"r!*ulatio --b!ta-block!r

-do# r!*ulatio --- =B (tricyclic acid$ --- atid!"r!ssat

,. "iat ------ tol!rasi

%. Tachyphylais --- tol!rasi c!"at t!r3adi

-r!duc! !!ct "roduc!d at!r r!"!at!d adiistratio

2. Teori harniere

Menerang$an mengapa suatu agonis mes$ipun td$ dapat menggeser antagonis dari resep

tornya dapat )ersaing dg antagonis sesuai dengan hu$um a$si masa. 7eseptor mempunyai

dua $edudu$an a. l'

!.


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4. 7acti;astio

%oss o ability a r!c!"tor to r!s"od) to stiulatio by a dru*

5. R!ractory

Bt!r a r!c!"tor is stiulat!d) a "riod o ti! is r!&uir!d b!or! th! !,t dru*-r!c!"tor

it!ractio ca "roduc! a !!ct.

Ad. /. Moleculler and celluler determinants of drug selectivity

6ru* 2 r!c!"tor it!ractios

S"!ciicity : tissu!) syst!s) or*a #h!r! r!c!"tors ar! distribut!d (co"art!!t$

,. Bdr!!r*ic ad choli!r*ic

S!l!cti;ity : dru* it!racts "r!!r!tially o "articular r!c!"tor ty"!s or sub ty"!s.,. Pro"aolol: o s!l!cti;! ---- ata*oist o !ad J

Bt!olol : !2s!l!cti;!) %l!ss !rbutali : a*oist o %

6!t!riat :

h! ch!ical structur! ay b! ;!ry uch di!r!t) y!t th! "haracolo*ical actio ar!siilar.B sli*ht odiicatio i ch!ical structur!do!s ot "roduc! a draatic cha* i "haracolo*icalactio. Structural s"!ciic dru*s ar! thos! i #hich th! "haracolo*ical actio d!"!d!t dir!ctly

o th! ch!ical structur! o th! dru*) #ichh attach!s its!l to a three;dimensionalstructur! o a

r!s!"tor i th! bio"has!. Pr!r!&uisit!s o th! bidi* o a dru* to r!c!"tor ar!: ch!ical) r!acti;ity

"r!s!c! o u*sioal *rou"s) !l!ctoic distributio ad to"o*ra"hic irror-lik! ia*! o th!

r!c!"tor.


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Stereoisomers

8a;! th! sa! ol!cular orula ad th! sa! ord!ro attach!t o th!ir atos (th! sa! co!cti;ity$)

but di!r!t thr!!-di!sioal ori!tatios o th!ir

atos i s"ac!.

2 !,a"l!: th! cis-tras iso!rs o cycloalka!s

cis-1,4-Dimethyl- cyclohexane

and

H

CH3

CH3

HCH3

H

CH3

H

trans-1,4-Dimeth cyclohexane


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6ru*s siilar "haracolo*ical actio ha;! usually so! coo structural caract!ristics

#ith uctioal *rou"s i siilar s"atial dir!ctio. B sli*ht odiicatio i ch!ical

structur! ay "roduc! draatic cha*! i "haracolo*ical actio (ro icr!s!d acti;ity

to ata*ois.

R!c!"tor ar! all s"!ciic ol!cul!s) ol!cul! co"l!,!s or "art o th!s!) #hich bid

th! dru* ch!ically ad this co"l!, !,!rts a "haracolo*ical actio.


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Kos!" Garakolo*i ol!kular

bat adl Aat akti ya* sudah t!rbukti b!r*ua utuk "!uliha k!s!hata) tidak s!ua Aat akti da"at di*uaka

s!ba*ai obat.

Gokus: !kais! k!r3a obat-obat t!rutaa it!raksi obat d* r!s!"tor sh* t!r3adi suatu !!k.

9am)ar' peru)ahan $onformasi suatu en,im yg diim)as oleh su)stratnya

Pada *abar ii t!r3adi *aya ataraksi atara ratai "rot!i) ol!kul substrat da io-io ya* ada dala

laruta dib!ri tada 8 utuk *aya hidroob < da 2 utuk *aya !l!ktrostatik. Ko"l!ks "rot!i-substrat

ya* t!rb!tuk da"at b!rdissosiasi da "rot!i t!rli"at k!bali k! koorasi s!ula.

bat diba*i dala k!lo"ok b!sar) yaitu:1. Struktur s"!siik) utk b!k!r3a !butuhka r!s!"tor --- "!rubaha "ada sist!!!ktor) ada !!k da

da"at diaati.

. Struktur o s"!siik) tidak butuh r!s!"tor ---- tidak ada !!k.

is: Btacida) laksa osotik / *ara (*S4$) *lis!ri) +aD P4

6iur!tik osotik

b p of pharm, aj-wk-09 - copy

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