Chemotherapeutic Agent

8/10/2019 Chemotherapeutic Agent

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Chemotherapeutic Agent

= are compounds that destroys pathogenic microorganism

or inhibit their growth.= one of the most valuable method of treating infection= most common agents used are: antibiotics, microbial

products or their derivatives that are capable ofkilling susceptible microorganism or inhibiting their

growth

Antibiotics:= are naturally occurring metabolic products of primarily

soil bacteria & fungi= these substances functions to limit microbial growth in

soil environment by killing or inhibiting their growth= some are semi-synthetic in which the natural active

component in the molecule is combined with asynthetic group


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Desirable Properties of Chemotherapeutic Agent:

1. Selective toxicity2. Bactericidal rather than bacteriostatic3. Should not be allergenic4. It should remain active in the presence of plasma,

body fluids and exudates5. Should have broad-spectrum activity6. Water soluble and stable7. Susceptible organism should not become resistant

8. Cheap


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Antibiotic producing organism:A) Bacteria

a.1. Bacillus

a.2. Streptomyces

B) Fungib.1. Penicillium

b.2. Cephalosporiumb.3. Micromonospora

Mech. of action:1. Interfere with cell wall synthesis2. Interfere with cell membrane function3. Interfere with Protein synthesis4. Interfere with nucleic acid metabolism


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I. Cell Wall Inhibitors:

1.1. B lactam antibiotics

A. Penicillin= product of the green mold penicillium notatum= basic structure consist of thiazolidine ring joined

to a B-lactam ring= MOA: affect bacteria by interfering with the

normal maintenance and synthesis ofbacterial cell wall

= inhibit the transpeptidation enzyme involve in cellwall synthesis

= have a B-lactam ring structure that is inactivatedby B-lactamase which are genetically coded insome bacterial DNA and some R plasmid

= reacts with penicillin-binding protein= active against both gram positive and gram

negative bacteria


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a.1. Natural occurring Penicillin

Benzylpenicillin / Penicillin G= first antibiotic to be widely used in medicine= administered parenterally= inactivated by acidic pH of gastric juice= destroyed by B-lactamase

= highly effective against gram positive and lesseffective against gram negative bacteria

Phenoxymethylpenicillin / Penicillin V= similar to penicillin G= more stable in acid medium= can be given orally


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a.2. Semisynthetic Penicillin= are derivative of 6-aminopenicillamic acid

= most crucial feature is the B-lactam ring which

appears to be essential for biologic activity1) Penicillinase-resistant penicillin

1.1. Includes: Methicillin and Nafcillin= drug of choice for penicillinase-resistant organism

= penicillinase, the enzyme synthesized by manypenicillin-resistant bacteria which destroysactivity by hydrolyzing a bond in the ring

= less active than penicillin G= acid-labile

1.2. Isoxazolyl PCN (Oxacillin, Cloxacillin & Dicloxacillin)= resistant to B-lactamase and gastric acid= drug of choice for PCN-resistant S. aureus and

S. epidermides


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2) Extended-spectrum penicillin

2.1. Ampicillin, Amoxicillin, Aminopenicillin= administered orally= has a broad-spectrum of activity= highly active against gram positive and

gram negative bacteria

= acid-stable and B-lactamase sensitive

2.2. Carbenicillin and Ticarcillin= both have broad spectrum activity

= active against gram negative bacteriaincluding (P. aeruginosa & Proteus)= acid-stable= not well tolerated by the intestine


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B. Cephalosporins= isolated from fungus cephalosporium= mechanism of action similar to penicillin in inhibiting

the transpeptidation reaction during peptidoglycan

synthesis= all these drugs are derivatives of the 7-amino-

cephalosporamic acid= contain a B-lactam ring structure similar to penicillin

= inactivated by B-lactamaseFirst GenerationCephalothin, Cefazolin and Cephalexin

bactericidal against most gram (+) bacteria

Second GenerationCefamandole, Cefuroxime and Cefaclor bactericidal against gram negative bacilli

Third GenerationCefotaxime, Ceftazidime and Cefoperazoneless active against gram (+) but more active

against gram (-) bacteria


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C. Other B-lactam antibodies= MOA similar to penicillin= have a B-lactam ring and is resistant to B-lactamase

a) Monobactam - Aztreonam= has excellent activity against aerobic gram (-)

organism such as the Enterobacteriaceae,

Pseudomonas, Gonococci and Hemophilus

b) Thienamycin - Carbapenem compounds= active against all medically important organism

including organism frequently resistant to

other B-lactam antibiotics

c) B-lactamase inhibitors - Clavulamic acid, Sulbactam


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II. Cycloserine= produced by specie of steptomyces= broad-spectrum antibiotic used to treat patient with TB= inhibit peptidoglycan synthesis

III. Vancomicin= produced by specie of streptomyces= used as alternative drug for serious infection in patient

who are allergic to B-lactam agents caused bymethicillin resistant S. aureus

= drug of choice for antibiotic-associated colitissecondary to Cl. defficile infection

IV. Bacitracin=polypeptide antibiotic produced by strain of B. subtilis= bactericidal for many gram (+) organism and pathogenic

neisseria

= highly toxic: used for topical application only


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II. Protein Synthesis Inhibitors= protein synthesis is the end results of 2 major processes

1) DNA dependent RNA synthesis (transcription)

2) RNA dependent protein synthesis (translation)Inhibitors of transcription:1) Actinomycin

= active against gram (+) and gram (-) bacteria aswell as mammalian cells

= toxic; with limited clinical use2) Rifampicin

= are compounds which contain an aromatic ringsystem

Rifampin = most useful member of the group= effective against gram (+) organism

and mycobacteria= major drug for the treatment of

tuberculosis, leprosy & as prophylaxisagainst meningococcal meningitis


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Inhibitors of translation:= translation of mRNA into protein are divided into 3

major phases

a) initiation- starts with association of mRNA in the 30sribosomal subunit to form a 30s initiation

complex

b) elongation- ribosome is the target site for proteinsynthesis

c) termination of polypeptide chain-enzyme catalyzingpeptide formation (peptidyl transferase)


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Inhibitors of the 30s Ribosomal subunit:1) Aminoglyside antibiotics

(Streptomycin, Neomycin, Kanamycin, Tobramycin)Gentamicin and Amikacin

Streptomycin - bactericidal for gram (+), gram (-)bacteria and M. tuberculosis

- drug of choice F. tularensis andY. pestis infection

Gentamicin, Tobramycin and Amikacin - activeagainst gram (-) bacteria incl. Pseudomonas

= synthesized by the genus streptomyces= Gentamicin synthesized by micromonospora purpuriae

= MOA: binds to 30s ribosomal subunits and inhibitprotein synthesis= may irriversively block initiation of translation or

cause mRNA misreading or both= toxic and can cause renal and eight cranial nerve

damage, neuromuscular paralysis


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2)Tetracylines

= Oxytetracycline and Chlortetracycline,Demethylchlotetracycline

= naturally produce by specie of the genusstreptomyces

= inhibit protein synthesis by combining with the 30ssubunits of the ribosome= active against gram (+) and gram (-) bacteria

including Mycoplasma, Rickettsia and Chlamydia= Semi-synthetic: Doxycycline, Minoccycline

- both are lipophilic and are absorbed completelyin the GIT


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3) Nitrofurans

Nitrofurantoin (synthetic derivative)= used clinically to treat urinary tract infection

especially patient unable to tolerateSulfonamide

= most active against E. coli, Klebsiella,Enterobacter and S. faecalis

= at present, it is recommended only foruncomplicated UTI


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Inhibitors of the 50s Ribosomal Subunit:

1) Chloramphenicol

= produce from cultures of streptomyces venezuelae= binds to the 23s RNA on the 50s ribosomal

subunits and inhibit peptide bond formation(similar to erythromycin)

= bacteriostatic for gram positive and gram negativebacteria including Rickettsia and Chlamydia

= maybe inactivated by the enzyme chloramphenicolacetyltransferase which is carried by the Rplasmid

= very toxic, can cause allergic & neurotoxic reaction= used only in serious and life-threathening situation= most common side effect is bone marrow

depression leading to aplastic anemia and

decreased blood leukocytes


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2) Macrolide antibiotics (Erythromycin)= synthesize by streptomyces erythraeus= binds to the 50s ribosomal unit to inhibit peptide

chain elongation during protein synthesis= most frequently used antibiotic in patient allergic

to penicillin= primarily bacteriostatic, but may be bactericidal for

some organism= effective against gram positive bacteria, mycoplasmaand few gram negative organism

3) Clindamycin / Lincomycin

= similar activity spectrum with Erythromycin butchemically unrelated= active against group A strept., Pneumococci and

Penicillinase producing staphylococci


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4. Puromycin= not clinically useful but has an inhibiting effect on

growth of both procaryotic and eucaryoticorganism

5. Fusidic acid= steroidal antibiotic with narrow antibacterial spectrum= active against gram (+) bacteria= no significant activity against gram (-) organism

Fucidin (salt of fusidic acid)

= used in the treatment of various seriousstaphylococcal infection


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Inhibitors of Protein Assembly

Griseofulvin= a fungistatic agent specific for fungi whose cell

wall contains chitin

= no effect on fungi with cellulose cell wall bacteriaand yeast

=given orally and clinically useful in treating chronicdermatophyte infection


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Inhibitors of Tetrahydrofolate Synthesis (Folic acid synthesis)

1) Sulfonamide (analogue of PABA)

= generic name for derivatives of para-aminobenzenesulfonamide or sulfanilamide

= first administered as a red dye Prontosil (Sulfanilanide)= effective chemotherapeutic agent used systematically

as prevention and cure of bacterial infection in huma = MOA: interfere with synthesis of folic acid (required for

the synthesis of purine & pyrimedine) precursor of

RNA and DNA= useful in the treatment of uncomplicated UTI


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2) Sulfones

= analogue of PABA and is most useful clinically= derivatives of the diaminodiphenylsulfone (dapsone)

= primarily used to treat leprosy

3) Para-aminosalicylic Acid (PAS)

= highly specific for M. tuberculosis

= used primarily as a second-line drug in the treatmentof tuberculosis


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Inhibitors of dihydrofolate reductase

1) Trimethoprim

= antifolic acid agent= very potent and a selective inhibitor of bacterial

dihydrofolate reductase= spectrum of activity similar to sulfonamide= are bactericidal and act synergistically with sulfonamide

or sulfamethoxazole

= useful in the treatment of recurrent or chronic UTIand Pneumocystis infection= also effective against bronchitis shigellosis and Ty fever


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2) Isoniazed (INH)= hydrazide of isonicotinic acid

= highly specific for M. tuberculosis= hepatotoxic= most potent anti-TB drug= never given as single drug

3. Flucytosine= flourine analogue of cytosine= an antifungal agent which is a true antimetabolite= effective against most systemic deep-seated fungal

infection= drug of choice for chromomycosis= toxic effect: skin rashes, diarrhea, liver damage and

aplastic anemia


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III. Cell Membrane Inhibitors

1) Polymixin= produced by Bacillus polymxa= MOA: binds specifically to the outer surface of cell

membrane, altering their structure and osmoticproperties

= spectrum of activity is restricted to gram (-) organism= reserved drug for the treatment of severe

Pseudomonas infection when organism is resistant

to other antibiotics


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2) Polyenes= macrolide antibiotics, most important antifungal agent:

Amphotericin B and Nystatin

= MOA: binds to sterol in fungal membrane causingdisruption of membrane permeability resulting toleakage of cell content

= active against yeast, fungi and other eucaryotic cellsbut inhibitory to procaryotic organism

= selectively inhibit org. whose membrane contain sterols

Amphotericin B - cornerstone of antifungal therapy= active agent most deep-seated fungi infection

= toxic and used only for serious life-threateninginfection

Nystatin - use to treat candida infection of the skin,vagina and alimentary tract


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3) Azoles

3.1) Imidazoles: Ketaconazole, Miconazole, Clotrimazole

= acts by interfering ergosterol synthesis by thefungal cell or disrupt fungal membranepermeability and inhibit sterol synthesis

= blocks demethylation of ergosterol precursor

lanosterol= broad-spectrum antifungal agent active against

dermatophytes, dimorphic fungi and yeast= Miconazole and Clotrimazole are administered

topically only as a treatment of cutaneousand vaginal candidiasis

= Ketoconazole given orally, very effective forsuperficial and deep mycotic infection inhuman


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3.2) Triazoles:Itaconazole, Fluconazole

= are substitute of imidazoles with antifungalspectrum

= MOA same with Imidazole

= better tolerated when given orally= effective in the treatment of deep mycosesand opportunistic infection


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Inhibitors of DNA Function= MOA: inhibit cross-linkage and intercalation between

the stacked bases of the double helix DNA

1) Mitomycin (synthetic antibacterial agent)= converted enzymatically to a highly reactive

hydroquinone derivatives that acts as a bifunctionalalkalyting agent

= acts on the guanine residues of DNA and under certaincondition blocks the synthesis of host cell DNA

2) Quinolones= all agents in the quinolone class are synthetic products

Nalidixic acid - first to be introduced as derivative ofnaphthyridine compound

= blocks DNA replication= bactericidal and use in the management of

uncomplicated UTI


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Newer QuinolonesNorfloxacin and Ciprofloxacin

= most useful flourinated compounds

= spectrum of activity includes Enterococci,Staphylococci and PseudomonasCiprofloxacin - most potent of the quinolones

= active against gram (-) and gram (+) bacteria= used to treat UTI

3) Metronidazole= effective antimicrobial agent for infection caused by

anaerobes and some protozoans= no effect on facultative and aerobic organism

4) Novobiocin= bactericidal especially among gram positive bacteria= target site is the subunit B component of the DNA gyrase

= no valid therapeutic used at present

Chemotherapeutic Agent

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