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Matrikulasi UKAI 2015

Farmakokimia- Infeksi, Endokrin & THT Non Infeksi dan
Pernafasan

Agustina Setiawati, M.Sc., Apt

Tujuan Pembelajaran
1. Mahasiswa mampu memahami aspek kimia
medisinal obat anti infeksi meliputi antibakteri dan
antivirus
2. Mahasiswa mampu memahami aspek kimia
medisinal obat yang bekerja pada sistem endokrin
3. Mahasiswa mampu memahami aspek kimia
medisinal dalam sistem pernafasan

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Referensi
Patrick, G.L., 2005, An Introduction to Medicinal
Chemistry, 3rd edition, Oxford University Press.

Pendahuluan
Paul Ehrlich bapak kemoterapi (menggunakan senyawa
kimia untuk mengobati infeksi)
Prinsip kemoterapi: chemicals could directly interfere the
microorganism at the concentration tolerated by the host
Konsep: MAGIC BULLET
The process: selective toxicity the chemicals has greater
toxicity to the microorganism than to the host cells
Chemotherapeutic index= minimum effective dose of
drug/maximum dose can be tolerated by the host

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Paul Ehrlich
Developed in 1910
Effective to kill protozoal disease
of sleeping sickness
(trypanosomiasis)
It was not wide used to treat wide
range of bacterial infection
Replaced by penicillin

ANTIBACTERIA

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Antibacteria Target

Mechanism of antibacterial action

1.
2.
3.
4.
5.

Inhibition of cell metabolism : sulphonamide

Inhibition of bacterial cell wall synthesis: -lactam
Interaction of plasma membrane
Disruption of protein synthesis
Inhibition of nucleic acid transcription and
replication

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Inhibition of cells metabolism

SULFONAMIDES
1935 red dye discovery called protonsil has in
vivo antibacterial, but not in vitro
Protonsil metabolized to be sulfanilamide by gut
bacteria pro drug
Sulfanilamide synthesis in lab treat thyphoid
against Salmonela

Structure-Activity Relationship
p-amino is essential for
activity
Aromatic ring & sulfonamide
functional group is
important
Aromatic ring must be para
subtitude

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Analogue of sulphonamide with reduced toxicity

Sulfathiazole (an early sulfonamide) form insoluble metabolite

and can prove fatal if it can block kidney
Chinese & Japanese metabolite more higher than American
Strategy: replacing thiazole group with more electron
withdrawing group
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Analogue of sulphonamide with reduced toxicity

More active than sufadiazine

Used to prevent topical infection

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Analogue of sulphonamide with reduced toxicity

So stable in the body, intake once a week

Penicillin superseded sulfonamide, still use in present
medication to treat urinary tract infection, eye,
mucous & gut infection
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Mechanism of Action

Dihydropteroat synthase is important enzyme to

produce tetrahydrofolate a percusore of folic acid-(necessary to bacterial survival)
Why does sulfonamide spesific to kill bacteria cells
without harmful to human cells?
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Sulfonamide prevent PABA binding to

dihydropteroat synthase

Sulfonamide acts as an inhibitor by mimicking PABA-normal

substrate of dihydropteroat synthetase (similar structure)
Reversible-competitive enzyme inhibitor level of
concentration is determined the action
Resistance of sulfa, caused by mutation of target enzyme
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Other antimetabolite-Trimethoprim

Given in combination with sulfamethoxazole

(COTRIMOXAZOLE)
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Key point
Principle of chemotherapy:
design of chemicals with
selective toxicity against
bacterial cells rather than
mamalia cells
Bacterial cells are differ from
mamalian cells so that selective
target can be addressed to drug
development

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INHIBIT CELL WALL SYNTHESIS-Penicillin

Biosynthesis of penicillin percusor

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Important fact about penicillin

Bactericidal than bacteriostatic!
Sensitives to beta-lactamase
Active against dividing bacteria
May causes allergic reactionrash to anaphylactic
reaction
Ineffective if given orally acid degradation in
stomach

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Mechanism of Action

Inhibit cross-linking formation in cell wall structure

by inhibit transpeptidase enzyme

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Structure of bacteria cell membran

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Penicillin inhibit transpeptidase

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Inhibition of transpeptidase

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Resistance to penicillins
Is happened in gram
negative or positive?
Porin transport penicillins
pass through cell
membrane
In gram negative bacteria,
there are -lactamase in
membran layer

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Penicillin degradation

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Penicillin resistance

High level of transpeptidase enzyme

Cells effluks
Low affinity to transpeptidase enzyme
Mutation or genetic factor (plasmid)

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Structure-activity relationship
-lactam ring is important to the
activity
Free carboxylic acid is essential bind
to ammonium ion of lysin
Bicyclic ring is important
Acylamino is essential while sulfur is
ussual but not essential

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Why dose penicillin easily degraded by

acid?
Ring strain five member ring fused to four member
rings

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OTHER - LACTAM: CEPHALOSPORINS

First discovered; cephalosporin C isolated from
Acremonium chrysogenum
Less potency than penicillin G but it can employ both
in gram positive or negative bacteria

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Mechanism of Action

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First generation of cephalosporine

Less effective in gram negative
bacteria due to penicillinase
Steric shield is successful to
increase stability to penisillinase
but decrease activity in
transpeptidase enzyme
Cephalotin, cephaloridine,
cefalexin, cefazoline

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Second generation of cephalosporin

Iminomethoxy group increases stability due to -lactamase

stability

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Third & Fourth generation

Iminomethoxy group increases stability due to -lactamase

stability
Zwitter ion in body radically enhances the activity to
penetrate cell membrane of gram negative bacteria
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Fifth generation

Treat Streptococcus pneumonia

Ceftaroline fosamil is prodrug for ceftaroline

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Other Inhibitor of Cell Wall Synthesis

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Other Inhibitor of Cell Wall Synthesis

Monobactam

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Other Inhibitor of Cell Wall Synthesis

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Other Inhibitor of Cell Wall SynthesisVancomycin

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Inhibit protein translation

Aminoglycoside: streptomycin
Tetracycline
Chloramphenicol
Macrolide (eq: erythromycin)
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Inhibit nucleic acid transcription &

replication

Stabilize the complex of DNA-topoisomrease IV,

fluroquinolon DNA gyrase
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Inhibit nucleic acid transcription &

replication

Inhibit DNA-dependent RNA polymerase

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ANTIVIRUS

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Virus Structure
Capsid (core protein), consist of
subunit called protomer.
Protomer form capsid by self
assembly
Nucleic acid is protected by
capsid form structure:
nucleocapsid
Nucleocapsid may contain enzyme
to replicate in host cell (RNAdependent RNA polymerase)

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VIRAL LIFE CYCLE

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Antiviral drug against DNA

viruses

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1. Inhibitor of DNA virus polymerase-Acyclovir

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Acyclovir
Metabolite of acyclovir is
nucleoside-like structure
& has similar base structure
to deoxyguanosine
Nucleoside triphosphate is
percusore for DNA
synthesis/replication
Inhibit DNA polymerase

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Acyclovir
Inhibit DNA polymerase by two mechanism:
1) Acyclovir triphosphate bind to DNA polymerase
and inhibit it
2) DNA polymerase attach acyclovir triphosphate to
growing DNA acyclovir as chain terminator
Does acyclovir stop proliferation in normal
and infected cells?

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Acyclovir analogues
Bioavailabililty of acyclovir is
low has to be developed!
Valaciclovir (prodrug) has L-valyl
ester group Absorbed effective in
gut wall than acyclovir
Polarity and ionization of valaciclovir
is similar to acyclovir no more able
to cross the gut wall by passive
transport
How to solve this?

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Acyclovir analogues
Add D-valine group instead of L-valine to valaciclovir
These peptide drive prodrug is transported to the cells by
active transport
Protein transport: human intestinal proton-dependent
oligopeptide transporter-1 (hPET-1) & human intestinal
di/tri-peptide transporter (HPT-1)
Once valaciclovir is absorbed, it is hydrolized to acyclovir in
liver & gut wall

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Acyclovir analogues
Desciclovir, prodrug of acyclovir
which has no carbonyl in C6 position
Purine structure is oxidized by
xanthine oxidase to form acyclovir

Ganciclovir, analogue of acyclovir, has

hydroxymethylene group
Valganciclovir ganciclovir prodrug

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Acyclovir analogues
Penciclovir is ganciclovir analogue
Famciclovir is penciclovir analogue,
has 2 alcohol group masked by ester
group less polar better absorption
Once absorbed, acetyl group are
hydrolysed by esterase & in liver
purine group oxidized by aldehyde
oxidase form penciclovir

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Antiviral drug against RNA

viruses: HIV

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Structure and life cycle of HIV

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Inhibitor of viral reverse transcriptase

NUCLEOSIDE REVERSE TRANCRIPTASE INHIBITOR (NRTI)
Reverse transcriptase is DNA polymerase
Challenge: how to make the drug selective only to inhibit it in
virus not in host cell?
Nucleoside-like structure, need 3 phosphorylation to get
active nucleotide triphosphate
Difference: cellular enzyme are needed to do phosphorylation

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Zidovudin

First, approved as anti-HIV

Analogue deoxythimidine 3-hydroxil replaced by azido group
Analogue deoxycytidine
Inhibit chain growing of DNA: chain terminator

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Inhibitor of viral reverse transcriptase

NON NUCLEOSIDE REVERSE TRANCRIPTASE INHIBITOR (NNRTI)
Hydrophobic molecule that bind to allosteric binding site that
hydrophobic in nature
Non-competitive & reversible inhibitor

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NON NUCLEOSIDE REVERSE TRANCRIPTASE INHIBITOR

(NNRTI)
Rapid emergence case mutation K103N in binding
site
Strategy: combine NRTI & NNRTI
Nevirapine
Lead compound: 2 wings:
1stvan der walls
interaction with aromatic
rings
2nd --aliphatic

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Obat yang bekerja pada Endokrin

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Hormone-based therapy (Anti-estrogen)

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Estrogen stimulate breast cells growth

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Obat yang bekerja pada THT dan

pernafasan

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Introduction
The important player in adrenergic nervous is
adrenaline and noradrenaline
Noradrenaline = norephinephrine
neurotransmitter released by symphatetic nervous
which feed smooth muscles and cardiac muscles
Adrenaline = ephinephrine hormone released
along with noradrenaline from adrenal medula

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Selectivity for and Receptor

Receptor has hydrophobic pocket

Distribution and effect of adrenoreceptor

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Useful 2 Agonist to Treat Asthma

Isoprenaline
Selective to receptor than -receptor because it has
isopropyl on its structure
Use to treat asthma but it interact to 1 receptor in hearth
and leading cardiovascular side effect
Next challenge: selective 2 receptor agonist, inhaled, long
acting

Useful 2 Agonist to Treat Asthma

Isoetharine

Add alkyl on nitrogen atom

Result: selective 2 receptor but it
has short acting
It was metabolized by COMT to
produce inactive ether

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Useful 2 Agonist to Treat Asthma

Next strategy: modify meta phenol group : soterenol &
salbutamol (altenerol)
R-enantiomer of salbutamol has 68 times activity than
its S-enantiomer R-enantiomer: levalbuterol
Duration: 4 hour (short time)

Useful 2 Agonist to Treat Asthma

Salmefamol is 1.5 times more effective than salbutamol
extension strategy
Salmefamol inhalation & intravenous route (emergency
case)
Other strategy: increase lipophilicity of drug salmeterol
Indicaterol: used in COPD

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Useful 2 Agonist to Treat Asthma

EVALUASI MAHASISWA
Latihan soal format UKAI sesuai dengan materi
yang diajarkan

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Latihan 1
Seorang pasien perempuan, berusia 32 tahun, didiagnosis
kanker payudara stadium III. Setelah biopsi ringan
didapatkan informasi histologi sel kanker payudara pasien
mempunyai ER yang berlebihan. Kemoterapi yang tepat
diresepkan untuk pasien tersebut adalah .....
a. Doxorubicin
b. 5-Flurourasil
c. Tamoxifen
d. Bevacizumab
e. Paclitaxel
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Latihan 2
Sebuah industri farmasi mengembangkan sediaan sirup obat
antibiotik baru untuk kasus infeksi penyebab diare pada suatu
daerah. Bagian riset dan pengembangan obat industri tersebut
melakukan uji kultur pada bakteri penyebab infeksi dan
disimpulkan bakteri tersebut resisten terhadap golongan laktam. Obat apakah yang diformulasikan industri farmasi
tersebut?
A. Sefiksim
B. Sefriakson
C. Amoksisilin
D. Eritromisin
E. Aztreonam

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Latihan 3
Seorang pria, 27 tahun, mengalami demam tinggi dan lesi
urtikaria pada kulitnya. Pemeriksaan klinis sampel darah pasien
disimpulkan bahwa wanita tersebut terinfeksi adenovirus. Dokter
meresepkan tablet gangsiklovir yang mempunyai target aksi
nukleotida virus tersebut. Apakah proses pada sel yang
dipengaruhi oleh obat tersebut?
A. Transkripsi DNA
B. Translasi
C. Replikasi DNA
D. Modifikasi protein
E. Pematangan mRNA
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Latihan 4
Sebuah industri farmasi mengembangkan formulasi sediaan obat
oral berupa analog hormone estrogen untuk indikasi kanker
payudara. Manakah pernyataan berikut ini yang sesuai untuk
obat tersebut?
A. Meningkatkan konsentrasi protein kinase A di sitoplasma
B. Obat terikat pada reseptor di sitoplasma
C. Obat meningkatkan fosforilasi tirosin pada reseptor
D. Obat mengaktifkan enzim adenilat siklase
E. Obat mengaktifkan diasil gliserol

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Latihan 5
Seorang wanita berumur 25 tahun datang ke rumah sakit dengan
keluhan jerawat bernanah. Dokter meresepkan sirup doksisiklin
pada pasien tersebut. Apakah target aksi antibiotik tersebut?
A. Menghambat replikasi DNA
B. Menghambat sintesis Mrna
C. Menghambat sintesis protein
D. Merusak membran sel
E. Menghambat sintesis dinding sel

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Latihan 6
Seorang bapak, berusia 45 tahun, menjalani perawatan di
sebuah Rumah Sakit akibat infeksi saluran kencing. Dokter
memberikan kotrimoksazol untuk pengobatan. Apakah target
aksi dari obat tersebut?
A. Metabolisme sel
B. Replikasi DNA
C. Transkripsi
D. Translasi
E. Pembelahan sel

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Latihan 7
Seorang pria, 40 tahun, positif terinfeksi HIV. Berdasarkan data
hematologi, jumlah sel T tipe CD4+ turun signifikan. Pria tersebut
dirujuk berobat ke dokter spesialis bedah onkologi. Dokter
tersebut memberi pasien tersebut injeksi obat untuk
menghambat aktivitas enzim dalam virus. Apakah obat yang
diinjeksikan oleh dokter tersebut?
A. Asiklovir
B. Gangsiklovir
C. Zidovudin
D. Valgansiklovir
E. Desiklovir
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Latihan 8
Seorang bapak, berusia 45 tahun, dibawa ke IGD sebuah Rumah
Sakit karena sesak nafas akibat COPD. Dokter memberikan injeksi
salmefamol, suatu agonis reseptor adrenergik, pada pasien
tersebut. Apa reseptor tipe apakah obat tersebut bekerja?
A. 1
B. 2
C. 1
D. 2
E. 3

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TERIMA KASIH

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