b Princ of Antimicrobial & Antineoplastic Phar
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Transcript of b Princ of Antimicrobial & Antineoplastic Phar
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