BAGIAN FARMAKOLOGI DAN TERAPEUTIK ,

FAKULTAS KEDOKTERAN UNIVERSITAS SUMATERA UTARA

BASIC PRINCIPLE OF RESISTANCE &

MECHANISM

D.S. Hidayat

PRINCIPLES OF ANTIMICROBIAL & ANTINEOPLASTIC PHARMACOLOGY

INTRODUCTION MECHANISM OF SELECTIVE TARGETING

(UNIQUE DRUG TARGET, SELECTIVE INHIBITION OF SIMILAR TARGETS, COMMON TARGETS )

PATHOGEN, CANCER CELL BIOLOGY, AND DRUG CLASSES ( BACTERIA, VIRUSES, FUNGI AND PARASITES, CANCER CELLS

MECHANISM OF DRUG RESISTENCE : 1. ( GENETIC CAUSES OF DRUG RESISTANCE, REDUCED

INTRACELLULAR DRUG CONCENTRATION, ALTERED TARGET, INSENSITIVITY TO APOPTOSIS; BACTERIA, VIRUSES, FUNGI AND PARASITES, CANCER CELLS)

2. ( NON GENETIC CAUSES OF TREATMENT FAILURE)

METHOD OF TREATMENT CONCLUSION AND FUTURE DIRECTIONS

INTRODUCTION

INFECTIOUS DISEASES AND CANCER HAVE DIFFERENT UNDERLYING ETIOLOGY

PHARMACOLOGY PRESPECTIVE OF TREATMENT: SIMILAR

MECHANISM OF SELECTIVE TARGETING

THE GOAL OF ANTIMICROBIAL AND ANTINEOPLASTIC DRUG TERAPI IS SELECTIVE TOXICITY

HOW TO BE REALIZED SELECTIVITY HOW ABOUT DIFFERENCES HOW ABOUT THE RATIO OF THE TOXIC

DOSES TO THERAPEUTIC DOSES WHAT IS THE MEANING OF

THERAPEUTIC INDEX

THE GOAL OF ANTIMICROBIAL AND ANTINEOPLASTIC DRUG TERAPI

IS SELECTIVE TOXICITY INHIBITING PATHWAYS OR TARGET

THAT ARE CRITICAL FOR PATHOGEN OR CANCER CELL SURVIVAL AND REPLICATION ( at concentration of DRUG LOWER THAN THOSE TO AFFECT HOST PATHWAY )

SELECTIVITY can be realized by :1. Attacking targets unique to the pathogen

or cancer cell ( that are not present in the host)

2. Attacking targets in the pathogen or cancer cell that are similar but not identical to those in host

3. Attacking targets in the pathogen or cancer cell that are shared by the host, but that vary in importance between pathogen and host and thus impact selectivity

THE SELECTIVITY TARGETED DIFFERENCES CAN BE :

AS GREAT AS PROTEINS that are unique to the pathogen or

AS SLIGHT AS THE DIFFERENCES in cell cycling and growth rates between some cancer cells and normal cells.

IN PRINCIPLE : drugs exhibited the least toxicity to the host when they target unique differences and most toxicity when they target common pathways.

FOR THIS REASON many antineoplastic are more toxic to the host than many antimicrobial drugs

THERAPEUTIC INDEX or THERAPEUTIC WINDOW

THE RATIO OF THE TOXIS DOSES TO THE THERAPEUTIC DOSES OF DRUG

An indication of how selective the drug is in producing the desired effects

A hight selective such as penicillin, can often be safely because of the large difference between its therapeutic and toxic concentrations.

The margin of safety in less selective drugs, such as the anti cancer drug methotrexat , is much lower because of its low therapeutic index.

IMATINIB mesylate is a highly specific anticancer agent

AS MORE IS LEARNED ABOUT THE BIOLOGY OF PATHOGENS AND CANCER CELLS, DRUGS CAN BE DISIGNED AGAINS MORE SELECTIVE TARGETS

That targets the product of the novel gene rearranggement present in chronic myelogenous leukemia cells but not in normal cells

UNEXPLOITED POTENTIAL TARGET many known potential target remain unexploited because of the toxic side effects, unfavorable pharmacokinetic properties, or prohibitive cost associated with experimental drugs that have been developed to date against these targets

AS MORE IS LEARNED ABOUT

THE BIOLOGY OF PATHOGENS AND CANCER CELLS,

DRUGS CAN BE DISIGNED AGAINS MORE SELECTIVE TARGETS

MECHANISMS OF SELECTIVE TARGETTING UNIQUE DRUG TARGET SELECTIVE INHIBITION OF SIMILAR

TARGETS COMMON TARGETS

UNIQUE DRUG TARGETS, include: METABOLIC PATHWAY ENZYMES MUTATED GENES AND GENES

PRODUCTS THAT PRESENT IN THE PATHOGEN OR CANCER CELLS BUT LACKING IN THE HOST

One common target for bacterial drugs is the bacteral peptidoglycan cell wall, unique and essential for the survival of growing bacteria

COMMON TARGETS IF THE HOST AND PATHOGEN OR

CANCER SHARE COMMON BIOCHAMICAL AND PHYSIOLOGIC PATHWAY ,

A BASIS FOR SELECTIVITY MAYBE FOUND IF THE PATHOGEN OR CANCER REQUIRES A METHABOLIC ACTIVITY OR IS AFFECTED BY ITS INHIBITION GREATER DEGREE THEN THE HOST

IN CANCER PHARMACOLOGY- NARROW THERAPEUTIC INDECES OF THIS DRUGS

PATHOGENS , CANCER CELL BIOLOGY AND DRUG

CLASSIS SITE OF ACTION OF ANTIBACTERIAL

DRUG CLASSIS STAGES OF THE VIRAL LIFE CYCLE

TARGETED BY ANTIVIRAL DRUG CLASSIS

50S

30S mRNA

protein

replication

translation

Cell membranePolymixin B

Cell wallBeta-lactam

Anti-metabolitesEthambutolIsoniazidPASSulfonamide

Nucleic acidLevofloxacin

Nucleic acidRifampicin

transcription

Protein synthesisStreptomycin

ChloramphenicolMacrolides

The mechanism of action of antibiotics

Folic acid Sulfonamide & trimethoprim

Mechanism Of ANTI CANCER drugs

MG2

SINTESA KOMPONEN MITOSIS

G1

SINTESAKOMPONEN UNTUK SINTESA DNA

S SINTESA DNA

G0

Inhibitor mikrotubul

( vincristin & vinblastine) antibiotik (bleomicin)

inhibitormikrotubul

(etoposide)

Antimetabolit ( 6-merkaptopurin)

neuklotida neuklotida

purin pirimidin

Mercaptopurin,

Tioguanin

azasitidin

Methotrexate

riboneuklotida

hydroxyurea

deoksineuklotida

fluorouracil

cytarabine

DNA

FARMAKODINAMIK

precursor

DNA

mRNA

protein

Purine biosynthesis

precursor

Pyrimidine biosynthesis

RIBONUCLEOTIDES

DESOXYRIBONUCLEOTIDES

Asam amino

6 M Purine

Hydroksi Urea

1. ALKYLATING AGENT

2. ANTIBIOTICS

3. CISPLATIN

4. ETOPOSIDE

5. SEX STEROID, citosolic reseptor

6. Topoisomerase Inhibitor

Vinca alkaloidsTaxane

Nitrosoureas

methotrexate

6 M Purine

asparaginase

RadiasiKarsinogen

Sel normal sel mutasi (p53 normal) atau hilang

Fungsi p53

Kerosakan DNA kerosakan DNA

Aktivasi p53 p53 tidak aktif

Tiada peng- tiada p21 GADD45 bax hentian siklus perbaikan DNA (CDK inhibitor) (DNA repair) (gen apoptosis)

Sel memperbanyak dan bermutasi

Sel normal apoptosis tumor

Mekanisme kerja Sulfonamida & Trimethoprim