Interaksi Farmakokinetik dan

Farmakodinamik dan Target

Kerja Obat Terhadap Sel
dr. Pandu Indra Bangsawan, M.Kes
Departemen Farmakologi
FK UNTAN
2013

Logika berpikir Kombinasi

Obat

Ilmu Sains : 1 + 1 = 2
Ilmu Farmakologi 1 + 1 2
1+1=0
1+1=5
1+1=-5
Mengapa?

Antagonisme Obat
Antagonisme Obat adalah suatu keadaan
dimana efek suatu obat dikurangi atau
dihapus oleh efek obat lainnya.
Contoh :
Chemical Antagonism
Ex: Antasid dan Susu tidak boleh diberikan
secara bersamaan dengan tetrasiklin
absorbsi tetrasiklin menurun
Farmakokinetik Antagonism
Ex : Rifampisin dan obat Kontrasepsi Oral
efek kontrasepsi menurun

 Competitive Antagonism
Reversible : Histamin dan Anti Histamin
berebut ikatan dengan reseptor histamin
mengurangi efek histamin
Irreversible : Blocker dan Adrenalin
mengatasi hipertensi hebat akibat adrenalin.
Non Competitive Antagonism
Ex : Calsium antagonis dan Adrenalin
menghambat kerja adrenalin
Physiological Antagonism
Ex : Adrenalin dan Histamin pada anafilaktik
syok saling bersifat antagonis tidak
mempunyai efek.

Interaksi Farmakokinetik
Interaksi Farmakokinetik adalah Kemampuan
suatu efek obat yang dapat mengurangi atau
meningkatkan efek obat lain dengan cara
meningkatkan atau menurunkan kadar obat di
tempat kerjanya.
Contoh :
Fenilbutazon ( anti radang usus) dan warfarin
Fenilbutazon afinitednya lebih besar terhadap
albumin plasma daripada warfarin warfarin
terusir dari albumin warfarin free meningkat
dalam darah toksisitas warfarin meningkat.
Fenilbutazon menghambat metabolisme warfarin
RESIKO PENDARAHAN MENINGKAT

 Ciprofloxacin dan theophyllin

Ciprofloxacin merupakan inhibitor enzim
mikrosomal.
Ciprofloxacin menghambat enzim-enzim
metabolisme theophyllin meningkatkan
kadar theophyllin dalam darah EFEK
TOKSIKnya meningkat antara lain
Cardiac Aritmia (Stimulasi Jantung)
dan susah tidur sampai kejang
(Stimulasi Otak).

Efek therapy tidak terganggu tapi

efek sampingnya meningkat.

Interaksi Farmakodinamik
Interaksi Farmakodinamik adalah
interaksi dua macam obat dimana
efek obat pertama dapat
menurunkan atau meningkatkan efek
obat kedua tanpa menurunkan atau
meningkatkan kadar obat di tempat
kerjanya.

 Contoh :
Yang menguntungkan :
Sulfonamid dan Trimetropim

Enzim dihidrofolat sintetase

Enzim dihidrofolat reductase

PABA ---------------------------------- dihidrofolat ------------------------- tetrahidrofolat

Sulfonamid menghambat Enzim dihidrofolat
sintetase sedangkan trimetropim
menghambat Enzim dihidrofolat reductase
dimana kedua dapat saling menguatkan
efek anti bakteri.

 Yang merugikan :
NSAID dan Anti Hipertensi
NSAID menurunkan produksi
prostaglandin (dibutuhkan untuk
vasodilatasi terutama pembuluh darah
ke glomerulus) retensi air dan
garam cairan extracell meningkat
edema (NSAID melawan efek Anti
Hipertensi).

Interaksi Obat Berbahaya

Sildenafil ( Viagra ) dan Isosorbid
dinitrat
Beta Blocker dan Verapamil
Ketokonazol dan terfenadin
Ciprofloxacin dan teofilin

Ada yang bisa menjelaskan ?

Target Utama Kerja Obat

Bila ditinjau dari aspek Farmakologi molekuler, ada 4 target utama

kerja obat (mekanisme molekuler) :
Obat yang bekerja pada enzim-enzim
Contoh :
Obat anti inflamasi (aspirin,diclofenac,aspirin) menghambat enzim
cyclooksigenase sehingga menghambat terbentuknya prostaglandin.
Captopril dan Enalapril (ACE Inhibitor ) menghambat kerja
Angiotensin Converting Enzym sehingga tidak terjadi perubahan
dari angiotensin 1 angiotensin 2 VASODILATASI
Obat yang bekerja pada Carrier (Molekul Pembawa)
Contoh :
Amiptriptilin (Trisiklik Anti Depresan) menghambat carrier reuptake
serotonin (5 hidroksi triptamin) dan nor adrenalin (nor
epineprin) untuk kembali ke ujung syaraf sehingga terjadi akumulasi
nor adrenalin dan serotonin (monoamine) nor adrenalin dan
serotonin bisa bekerja lebih lama pada celah sinaptik di otak
Keadaan ini sangat menguntungkan karena pada keadaan depresi
monoamin berkurang di otak.

 Obat yang bekerja pada Ion Channels

Calsium Channel Blocker (nipedipin, verapamil)
menghambat pembukaan Ca Channel jadi Ca ga bisa
masuk ke intrasel otot polos pembuluh darah sehingga
membran makin negatif hiperpolarisasi, terjadi
relaksasi otot polos vaskuler dan menurunkan
kontraksi otot jantung baik digunakan sebagai anti
angina dan anti hipertensi.
Obat yang bekerja pada Reseptor
Contoh :
Salbutamol (Agonis 2) Aktivasi perangsangan 2 pada
paru sehingga menimbulkan bronkodilatasi th/
simptomatik bronkospasme
blocker ( Antagonis 2) Tidak mengaktifkan dan
menghambat kerja agonis lain pada resptor tersebut.
Prazosin ( blocker/ 1 antagonis) mengikat reseptor 1
tapi tidak mengaktifkannya vasodilatasi

Ligand-gated ion channels

These are sometimes called
ionotropic receptors. They are
involved mainly in fast synaptic
transmission
Ligand binding and channel opening
occur on a millisecond timescale
Eamples : nACh-receptors, GABA
type A (GABAA) receptors, 5-HT3receptors.

G-protein-coupled receptors
(metabotropic receptors)

All are monomers comprising 7 membrane-spanning segments

One of the intracellular loops is larger than the others and
interacts with the G-protein
The G-protein is a membrane protein comprising 3 subunits (),
the -subunit possessing GTPase activity.
When the trimer binds to agonist-occupied receptor, the -subunit
dissociates and is then free to activate an effector (a membrane enzyme or
ion channel). In some cases the -subunit may be the activator species.
Activation of the effector is terminated when the bound GTP molecule is
hydrolysed, which allows the -subunit to recombine with .
There are several types of G-protein, which interact with different receptors
and control different effectors.
Examples : mACh-receptors, adrenoceptors and neuropeptide receptors.

Effectors controlled by Gproteins

Two key pathways are controlled by receptors, via
G-proteins. Both can be activated or inhibited by
pharmacological ligands, depending on the nature
of the receptor and G-proetin.
These include : 1) the adenylate cyclase/cAMP
system, and 2) the phospholipase C/inositol
phosphate system
Receptor-linked G-proteins also control:
1)phospholipase A (and thus the formation of
arachidonic acid and eicosanoids), 2) ion channels
(e.g. K+ and Ca++ channels, thus affecting
membrane excitability, transmitter release,
contractility, etc.)

Adenylate cyclase(AC) /cAMP

system
AC catalyses the formation of the
intracellular messenger cAMP
cAMP activates various protein kinases, which control cell function in
many different ways by causing
phosphorylation of various enzymes,
carriers & other proteins.

Phospholipase C/
inositoltriphosphate
(IP3)/diacylglycerol (DAG)
Catalyses the formation
of two intracellular
system

messengers, IP3 and DAG, from membrane

phospholipid
IP3 acts to increase free cytosolic Ca++ by
releasing Ca++ from intracellular compartments
Increased free Ca++ initiates many events,
including contraction, secretion, enzyme
activation and membrane hyperpolarisation
DAG activates protein kinase C, which controls
many cellular functions by phosphorylating a
variety of proteins.

Effectors controlled by Gproteins

Adenylate cyclase(AC)/ cAMP : AC catalyses formation of the

intracellular messenger cAMP. cAMP activates various protein
kinases, which control many cell functions by causing
phosphorylation of various enzymes, carriers and other proteins.
Phospholipase C / IP3/ DAG : -PC catalyses the formation of 2
intracellular messengers, IP3 and DAG, from membrane
phospholipid; -IP3 acts to increase cytosolic Ca2+ from intracellular
compartments; -increased free Ca2+ initiates many events,
including contraction, secretion, enzyme activation and membrane
hyperpolarization; -DAG activates protein kinase C, which controls
many cellular functions by phosphorylating a variety of proteins.
Receptor-linked G-proteins also control: -phospholipase A (and
thus the formation of AA and eicosanoids; -ion channels (e.g. K +
and Ca++ channels, thus affecting membrane excitability,
transmitter release, contractility, etc.)

Type 3 : Kinase-linked and

related receptors

Receptors for insulin &growth hormones incorporate tyrosine kinase

in their intracell.domain
Cytokine receptors have an intracell.domain that binds and activates
cytosolic kinases when it is occupied.
All receptors share a common architecture, with a large
extracell.ligand-binding domain connected to intracell.domain by a
single -helix .
Signal transduction involves dimerisation of receptors, followed by
autophosphorylation of tyrosine residues. The phosphotyrosine
residues act as acceptors for the SH2 domains of a variety of
intracell.proteins, thereby allowing control of many cell functions.
They are involved in events controlling cell growth & differentiation;
they also act indirectly by regulating gene transcription.
Two important pathways are : 1)the Ras/Raf/MAP kinase pathway,
which is important in cell division, growth & differentiation; 2)the
Jak/Stat pathway, which is activated by many cytokines and which
controls the synthesis & release of many imflammatory mediators.

Protein phosphorylation in
signal transduction

Many receptor-mediated events involve protein

phosphorylation, which controls the functioning & binding
properties of intracell.proteins.
Receptor-linked tyrosine kinase, cyclic nucleotide-activated
tyrosine kinases, & intracell.serine/threonine kinases
comprise a kinase cascade mechanism that leads to
amplification of receptor-mediated events.
There are many kinases, with different substrate
specificities, allowing specificity in the pathways activated
by different hormones.
Desensitisation of G-protein-coupled receptors occurs as a
result of phosphorylation by specific receptor kinases,
causing the receptor to become non-functional and to be
internalised.
There is a large family of phosphatases that act to reverse
the effects of kinases.

Receptors that control gene

transcription (nuclear
receptors)
Ligands include steroid hormones, thyroid hormones, Vit. D &

retinoic acid, as well as certain lipid-lowering & antidiabetic drugs.

Receptors are intracell.proteins, so ligands must first enter cells.
Receptors consist of conserved DNA binding domain attached to
variable ligand-binding and transcriptional control domains.
DNA-binding domain recognises specific base sequences, thus
promoting or repressing particular genes.
Pattern of gene activation depends on both cell type & nature of
ligand, so effects are highly diverse.
Effects are produced as a result of altered protein synthesis and,
therefore, are slow in onset.
One type of nuclear receptor is responsible for the increased
expression of drug-metabolising enzymes induced by many
therapeutic agents.

Ion Channels as Drug

Targets

Ions cannot penetrate the cell membrane & can get across
only with the help of membrane-spanning proteins in the
form of channels or transporters.
Ion channels consist of protein molecules designed to form
water-filled pores that span the membrane, and they can
switch between open & closed states.
The rate and direction of ion movement through the pore is
governed by the electrochemical gradient for the ion in
question, which is a function of its concentration on either
side of the membrane, and of the membrane potential.
Ion channels are characterised by : 1).their selectivity for
particular ion speciesg; 2).their gating properties ; 3).their
molecular architecture.

Selectivity of ion channels

They are generally either cation or
anion selective.
Cation-selective channels may be
selective for NA+, Ca2+ or K+ or may
be non-selective & permeable to all
three.
Anion channels are mainly permeable
to Cl-, though other types also occur.

Gating properties of ion

channels

Voltage-gated channels open when the cell membrane is depolarised. The

most important channels are selective Na+, K+, or Ca2+ channels
Ligand-gated channels are activated by binding of a chemical ligand to a
site on the channel molecule. Fast neurotransmitters, such as glutamate,
ACh, GABA, & ATP act in this way, binding to sites on the outside of the
membrane
Some ligand-gated channels in the plasma membrane respond to
intracell.signals. For examples : 1).Ca2+-activated K+ channels, which open
& hyperpolarise the cell, when intracell. Ca2+ level increases;2)ATPsensitive K+ channels, which open when the intracell.ATP conc. falls
because the cell is short of nutrients
Ca release channels : are present on the endoplasmic/ SR. The main ones,
IP3 & ryanodine receptors, are a special class of ligand-gated Ca channels
that control the release of Ca2+ from intracell.stores.
Store-operated Ca channels : when the intracell. Ca2+ stores are depleted,
channels in the plasma membrane open to allow Ca2+ entry. The opening of
SOCs allows intracell.Ca to remain elevated even when the stores are
running low,and they also provide a route to replenish the stores.

Pharmacology of ion
channels

Ligands that bind directly to the channel protein.These include

many neurotransmitters & drugs & toxins that act in different
ways, for example, by blocking the channel or by affecting the
gating process, thereby either facilitating or inhibiting the opening
of the channel.
Mediators & drugs that act indirectly, mainly by activation of
GPCRs.This involves the production of 2nd messengers that
activate protein kinases. The opening of the channel may be
facilitated or inhibited, depending on which residues are
phosphorylated. Drugs such as opioids & beta-agonists affect Ca ++
& K+ channel function in this way, producing a wide variety of
cellular effects.
Intracell.signals, particularly Ca++ & nucleotides such as ATP and
GTP. Many ion channels possess binding sites for these
intracell.mediators. Increased inracell. Ca++ levels open certain
type of potassium channels and inactivates voltage-gated Cachannels. Intracell.Ca++ is itself affected by the function of ion
channels &GPCRs. Drugs of the SU class act selectively on ATPgated K+- channels.

Receptors and disease (1)

Autoantibodies directed against receptor
protein: myasthenia gravis(inactivation of
nAChR), hyperthyroidism(activation of
thyrotrophin receptors),severe hypertension(activation of -adrenoceptors),
cardiomyopathy(activation of -adrenoseptor), some epilepsy and neurodegenerative disorders(glutamate receptors)

Receptors and disease (2)

Inherited mutations of genes encoding GPCRs
account for various disease states, such as
permanently switched-on of receptors in the
absence of agonist (e.g.thyrotrophin
receptors), adrenoceptor polymorphism
(reduced efficacy of -adrenoceptor agonists
in treating asthma).
Mutations of the genes encoding growth factor
receptors and many other proteins involved in
signal transduction can result in malignant
transformation of cells.

Soal Diskusi
Jelaskan mengapa diazepam (sangat
larut dalam lipid) dengan cepat dapat
mencapai sel-sel otak,sedangkan
gentamisin (larut dalam air dan tidak
larut dalam lipid) tidak bisa mencapai
sel-sel otak. Jelaskan juga mengapa
diazepam sulit dikeluarkan dari tubuh,
sedangkan gentamisin dieksresikan
dengan cepat melalui ginjal?

Jawaban
Susunan sel endotel otak sangat rapat. Obat yang
mampu berdifusi pasif melalui sel endotel otak harus
bersifat lipid soluble
diazepam merupakan obat yang sangat larut lipid,
obat-obatan yang larut dalam lipid dapat
menembus sawar darah otak, karena kelarutan
diazepam dalam lipid yang tinggi maka diazepam
dengan cepat dapat mencapai sel-sel otak.
Sedangkan obat yang larut dalam air dan tidak larut
lipid seperti gentamisin tidak mampu berdifusi pasif
melalui sel endotel otak karena untuk berdifusi obat
harus larut terlebih dahulu di dalam lapisan lemak
sel endotel otak dan pada sel endotel otak tidak
terdapat aqua channel, karena itu gentamisin tidak
bisa menembus sawar darah otak.

Jawaban
Sedangkan obat yang dapat dengan
cepat dieksresikan melalui ginjal adalah
obat yang larur dalam air(polar) dan
tidak larut dalam lipid misalnya
gentamisin.
Sebaliknya diazepam yang sangat larut
dalam lipid akan difiltrasi melalui glomerulus
dan akan berdifusi secara pasif masuk
kembali melewati sel-sel epitel tubuli ginjal
sehingga terjadi reabsorbsi obat secara pasif
dan akan dieksresikan secara lambat sekali.

 Waktu paruh obat A = 6 jam

Obat A memerlukan waktu 6 jam untuk mencapai
kadar obat dalam plasma 50% dari sebelumnya.
pKa aspirin = 3,5
Pada pH 3,5 aspirin akan terionisasi menjadi 50%
Steady State Concentration
Fase dimana kadar obat yang diminum sama
dengan kadar obat yang dikeluarkan
First Pass Metabolisme
Metabolisme yang dialami obat ketika pertama
kali melewati hati.

Soal
Jelaskan dengan singkat faktor apa
saja yang mempengaruhi absorbsi
obat yang diberikan per oral.

Jawab

Jawab :
Kelarutan di dalam lambung/ usus.
Motilitas daripada lambung/usus.
Terionisasi/tidak semakin banyak terionisasi
semakin sedikit diabsorpsi.
Vaskularisasi dari lambung/usus seberapa
banyak aliran darah yang mengalir ke
lambung/usus.
Kepatuhan pasien
Kelarutan dalam lemak semakin larut dalam
lemak semakin mudah diabsorpsi.

Soal
Mengapa isosorbid dinitrat atau nitroglisrin
atau gliseril trinitrat obat anti angina
pektoris harus diberikan secara sublingual?
Jawab : Karena Obat ini mengalami first pass
effect atau first pass metabolism yang
hebat oleh hepar sehingga kadar yang
seharusnya menjadi efek terapi menjadi
tidak bermakna karena bioavaibility yang
kecil sehingga tidak memiliki efek terapi.
Cth obat lain : Salbutamol , Morfin

Soal
Apa yang dimaksud dengan
metabolit, ketersediaan hayati
(bioavailability), first order kinetik,
zero order kinetik dan free drug

Jawab
Jawab :
Metabolit suatu hasil reaksi metabolisme suatu obat
yang bersifat aktif atau non aktif.
Bioavailability Fraksi/% obat yang kita telan yang
sampai ke sirkulasi sistemik.
First Order Kinetik Jumlah obat yang dikeluarkan
persatuan waktu menurut suatu konstanta /fraksi yang tetap
sesuai kadar dalam plasma darah, semakin tinggi kadar
dalam plasma maka semakin banyak jumlah obat yang
dieksresikan persatuan waktu.
Zero Order Kinetik Jumlah obat yang dieksresikan
persatuan waktu akan tetap karena aktivitas enzim di dalam
hati sudah dalam kejenuhan dalam kadar yang relatif rendah
sehingga bila kadar obat dinaikkan dapat memberikan efek
toksik.
Free Drug Obat yang tidak terikat dengan protein plasma
dan bisa memberikan efek.

Apa terapan G protein?

G protein stimulator : aktivasi kontraksi
jantung
G protein inhibitor : penekanan
kontraksi atrium
Cth obat : G protein stimulator :
adrenalin
Gprotein inhibitor : M2 Receptor yang
berfungsi mengontrol kontraksi atrium
pada atrial fibrilasi.