1.
BASIC PRINCIPLES
OF
CHEMOTHERAPY
Mr. Vijay Salvekar
Dept. of Pharmacology
GRY Institute of Pharmacy, Borawan

2.
CHEMOTHERAPY:
Is a term that applies to the use of both natural
and synthetic chemicals to interfere with the
functioning of the foreign cell population.
The Synthetic chemical substances used to
inhibit or destroy microorganisms. (ie bacteria).
The term is used for both treatment of cancer
and treatment of Infection.

3.
19th Century
LOUIS PASTEUR & ROBERT KOCH: Identified
bacteria as causative agent of disease. (Germ theory)
(Now know what is causing disease, need to find out how
to stop it)
1877 Pasteur: Soil bacteria injected into animals
made Anthrax harmless
1888 de Freudenreich: Isolated product from bacteria with
antibacterial properties. Toxic and
The Development of Chemotherapy

4.
 Early 20th century
 1904: Paul Ehrlich is pioneer researcher found that
the dye trypan red was effective against Trypanosoma
(sleeping sickness)
 Arspheniamine against syphilis
 1st antibacterial, only cured syphilis.
 Systemic infection : Blood stream
 Enunciated : 1906 Therapia Sterilizans Magna
 Published :Magic Bullet

5.
Paul Ehrlich:
Quinine : Malaria
Various Dyes (Gentian Violet); Disinfectants
Heavy Metals : Antimicrobial Agents
Fight against systemic infection and acknowledged
as the Father Of Chemotherapy

6.
 Sulfa drugs:
 1927: Domagk discovered that the dye Prontosil
Red was effective against staphlococcal and
streptococcal infections; later in 1935 it was found
that Protonsil red was converted to sulfonamide in
the body
 Penicillin
 Produced by Penicillium notatum
 Discovered in 1928 by Fleming
 Method of mass production developed in late 1930s
- early 1940s by Chain and Florey

7.
 Streptomycin
 Produced by Streptomycin griseous
 Discovered in 1944 by Waksman after screening
10,000 soil isolates
 Following its discovery was the discovery of other
antibiotics produced by soil microbes, including
chloramphenicol, neomycin, terramycin, and
tetracyclin by the early 1950s

8.
•Selective toxicity
•Ability of chemical strike selectively at
foreign cell and harm them without
causing significance damage to host
cells.
•Drug must inhibit microorganism at
lower concentrations than those that
produce toxic effects in humans
•No Chemotherapy is completely safe

9.
CHEMOTHERAPEUTIC INDEX:
•Maximally Parasitotropic
•Minimally Organotropic

10.
Antibiotic : A chemical that is produced by one
microorganism and has the ability to harm other
microbes.
Bacteriostatic activity: Ability of compound to
inhibit the growth and multiplication of organism.
Bacteriocidal activity: Actually killing effect on
the microorganism
Antibiotic spectrum:
Broad
Narrow

11.
 Selective toxicity
 Therapeutic dose
 Toxic Dose
 Therapeutic Index
 Side Effects
 Narrow-Spectrum
 Broad Spectrum
 Cidal vs Static
 Minimal Inhibitory Concentration
 Minimal Lethal Concentration

12.
 1- Wrong Diagnosis
2- Wrong Choice Of Drug
3- Wrong Dose
4- Development Of Resistance
5- Infections With More Than One Organism
6- Presence of Pus ,Blood ,Necrotic Tissues .

13.
Microbs: Bacteria, viruses, fungi,
Parasites: Protozoa, helminths
Living Organism Are Classified :
Prokaryotic : Cell Without Nuclei. Ex. Bacteria
Eukaryotic : Cell With Nuclei ex. Protozoa,
fungi,helminths


14.
Bacteria cause more infectious disease than any other parasites.
Simplicity well-developed cell structure .

15.
•Synthesis Of The Main Type Of Macromolecules

16.
BIOCHEMICAL REACTION AS POTENT TARGETS
Class I reaction: Not Promising Targets : 2 Reason
1st :- No Diffence b/w Bacteria And Human Cell
Mechanism for Obtaining Energy {Glucose}
ex. By EMP Pathway And TCA Cycle
2nd :- Glucose Pathway Blocked and Other Coumpound
Used By Bacteria{ AA , Lactate}

17.
Class II Reaction : Better / Potent Target
• Essential Amino Acid Responsible For Growth
Ex. Synthesis Of Folate : Required For DNA Synthesis
In Human: Obtain From Diet/Not Sythesise
In Bacteria: Synthesis Own Folate

18.
CLASS III REACTION :
Good Target { Macromolecules }With Selective Toxicity
Formation of skeleton ,
Protect from osmotic disruption{3 to 5 times}

19.
1.Inhibition of bacterial cell wall synthesis/Peptidogylcan

20.
Bacterial Cell Wall: Peptidoglycan

21.
www.uccs.edu/

22.
Cell Membrane semipermiable Function With Very
Selective Permiability
{ Tripple Layered Lipoprotien Structure }
Locate: b/w cytoplasm and cell wall
Function:maintain Osmotic Pressure And Barrier
Rapid Release Of Small Molecules From Interior Barrier
b/w External ATM
Increase Permiability :Result Cell {Disorganizing Cell
Function}

23.
Protein synthesis
DNA mRNA Protein
transcription translation
Ribosome is a protein factory in bacteria takes mRNA
in and produces proteins from them.
Bacterial ribosome has 2 parts:
30S binds to mRNA to translate mRNA into amino
acids, which form Proteins
50S required for Peptide Elongation

24.
• 3 phases from mRNA to protein
Initiation
Elongation
Termination
Disruptive effect on many essential bacterial functions
leading to cell death

25.
1. Inhibition The Synthesis of The Nucleotides:
for class II reaction
2.Altering The Base Pairing Properties of The Templet:
Framshaft mutation= misreading addition of extra base

26.
3.Inhibiting Either DNA or RNA Polymerase:
Drugs bind to Guanine in DNA and block the movement of
RNA polymerase prevent transcription leads to inhibit
protein synthesis
4.Inhibition Of DNA Gyrase:
chromosome fold around RNA core
Supercoiling by DNA gyrase {Topoisomerase II}

27.
5.Direct Effect On DNA Itself:
covalent bond with base{Prevent Replication}
Only for cancer chemo. Not for antibacterial agents

28.
 Ability of the drug to reach the site of infection
 Route of administration
 Rate at which the drug is eliminated from the
body
 Susceptibility of the pathegen to the drug
 Level of the drug must exceed the pathogen’s
MIC value at the site of infection

29.
1. Allergic Reactions: some people develop
hypersensitivities to antimicrobials
2. Toxic Effects: some antimicrobials toxic at
high concentrations or cause adverse effects
3. Suppression of normal flora: when normal
flora killed, other pathogens may be able to
grow to high numbers

30.
 Selectively toxic to microbe but nontoxic to host.
 Soluble in body- tissue distribution .
 Remains in body long enough to be effective -
resists excretion and breakdown.
 Shelf life.
 Does not lead to resistance.
 Cost not excessive.
 Hypoallergenic.
 Microbiocidal rather than microbiostatic.

31.
 Mechanisms of Drug resistance
 Origin of Drug Resistance in a microbial population
 Drug resistance genes on chromosomes and plasmids
 Transmission of resistance genes between bacteria

32.
30S
1 3
2 GTP
1 2 3 GTP
Initiation
Factors
mRNA
3
1
2 GTP
30S
Initiation
Complex
f-met-
tRNA
Spectinomyci
n
Aminoglycoside
s
1
2
GDP + Pi
50S
70S
Initiation
Complex
AP

33.
GTP
AP
Tu GTP Tu GDP
Ts
Ts
Tu
+
GDP
Ts
Pi
P A
Tetracycline
AP
Erythromyci
n
Fusidic Acid
Chloramphenico
l
G GTP
G GDP + Pi
G
GDP
AP
+
GTP

34.
 Chemicals used to treat microbial infections
 Before antimicrobials, large number of people died
from common illnesses
 Now many illnesses easily treated with antimicrobials
 However, many antimicrobial drugs are becoming less
useful

35.
 Chemotherapeutic agent=
 Antimicrobial drug=
 Different types of antimicrobial drugs:
 Antibacterial drugs
 Antifungal drugs
 Antiprotozoan drugs
 Antihelminthic drugs

36.
 Most modern antibiotics come from species of
microorganisms that live in the soil
 To commercially produce antibiotic:
1. Select strain and grow in broth
2. When maximum antibiotic concentration reached,
extract from medium
3. Purify
4. Chemical alter to make it more stable

37.
 Cause greater harm to microorganisms than to host
 Chemotherapeutic index: lowest dose toxic to patient
divided by dose typically used for therapy

38.
 Bacteriostatic: inhibit growth of microorganisms
 Bactericidal: Kill microorganisms

39.
 Antimicrobial medications vary with respect to the
range of microorganisms they kill or inhibit
 Some kill only limited range : Narrow-spectrum
antimicrobial
 While others kill wide range of microorganisms:
Broad-spectrum antimicrobial

40.
 Combinations are sometimes used to fight infections
 Synergistic: action of one drug enhances the activity of
another or vice versa.
 Antagonistic: activity of one drug interferes with the
action of another.

41.
1. Allergic Reactions: some people develop
hypersensitivities to antimicrobials
2. Toxic Effects: some antimicrobials toxic at high
concentrations or cause adverse effects
3. Suppression of normal flora: when normal flora
killed, other pathogens may be able to grow to high
numbers

42.
 Some microorganisms inherently resistant to effects of
a particular drug
 Other previously sensitive microorganisms can
develop resistance through spontaneous mutations or
acquisition of new genes (more later).

43.
 Selectively toxic to microbe but nontoxic to host.
 Soluble in body- tissue distribution – BBB.
 Remains in body long enough to be effective -
resists excretion and breakdown.
 Shelf life.
 Does not lead to resistance.
 Cost not excessive.
 Hypoallergenic.
 Microbiocidal rather than microbiostatic.
 Concerns suppression of normal flora - antibiotic
associated colitis with Clostridium difficule and it’s
toxins or Candida albicans.

44.
1. Inhibit cell wall synthesis
2. Inhibit protein synthesis
3. Inhibit nucleic acid synthesis
4. Injury to plasma membrane
5. Inhibit synthesis of essential metabolites

45.
 Irreversibly inhibit enzymes involved in the final steps
of cell wall synthesis
 These enzymes mediate formation of peptide bridges
between adjacent stands of peptidoglycan
 b-lactam ring similar in structure to normal substrate
of enzyme
 Drug binds to enzyme, competitively inhibit
enzymatic activity

46.
 Some bacteria produce b-lactamase- enzyme that
breaks the critical b-lactam ring
 b-lactam drugs include: penicillins and
cephalosporins

47.
 Acid-labile.
 Gram+ bacteria.
 So, take phenoxymethylpenicillin.
 Large Vd, but penetration into brain: poor, except when
the meninges are inflammed.
 Broad spectrum penicillins: amoxicillin and ampicillin
are more hydrophillic and therefore, are active against
gram- bacteria.

48.
Penicillinase-resistant penicillins – Flucloxacillin
Indicated in infections caused by penicillinase-
producing pen-resistant staphlococci.
Has an isoxazolyl group at R1  sterically hinders
access of the enzyme to the β-lactam ring.
Less effective than benzylpen.
So, should be used only for pen-resistant infections.
Well-absorbed orally, but in severe infections,
should be i.v. and not alone.
Staphlococci aureas-resistant strains to flucloxicillin
and MRSA (methicillin-resistant Staph aureas) –
increasing problem.

49.
 Ampicillin and amoxicillin – very active against non-β-
lactamase-producing gram+ bacteria.
 Because they diffuse readily into Gram- bacteria, also very
active against many strains of E. coli, H. influenzae, and
Salmonella typhimurium.
 Orally, amoxicillin is better because absorption is better.
 Ineffective against penicillinase-producing bacteria (e.g., S.
aureus, 50% of E. coli strains, and up to 15 % of H.
influenzae strains.
 Many baterial β-lactamases are inhibited by clavulaic acid
± amoxicillin (co-amoxiclav)  antibiotic is effective
against penicillinase-producing organisms.
 Co-amoxiclav indicated in resp and UT infections, which
are confirmed to be resistant to amoxicillin.

50.
 Used for treatment of meningitis, pneumonia, and
septicemia.
 Same mech and p’col as that of pens.
 May  allergic rxn and cross-reactivity to pen.
 Similar to pens in broad-spectrum antibacterial activity.
Cedadroxil (for UTI) in case of antibact resist.
Cefuroxime (prophylactic in surgery) – Resistant to
inactivation by β-lactamases and used in severe infections
(others ineffective).
Ceftazidine – wide range of activity against gram- including
Pseudomonas aeruginosa), but is less active than
cefurozime against gram+ bact (S aureus).
Used in meningitis (CNS-accessible) caused by gram-
bacteria.

51.
 Not well absorbed orally.
 Inhibits peptidoglycan formation.
 Active against most gram+ organisms.
 I.v. treatment for septicemia or endocarditis caused by
MRSA.
 Used for pseudomembranous colitis (superinfection of
the bowel by Clostridium difficile – produces a toxin
that damages the colon mucosa)

52.
Antibacterial Drugs that Inhibit Cell Wall Synthesis

53.
 Target ribosomes of bacteria
 Aminoglycosides: bind to 30S subunit causing it to
distort and malfunction; blocks initiation of
translation
 Tetracyclines: bind to 30S subunit blocking
attachment of tRNA.
 Macrolides: bind 50S subunit and prevents protein
synthesis from continuing.

54.
 Against many gram- and some gram+.
 Narrow TI – very potentially toxic.
 Most important adverse side-effect: VIIIth cranial n.
(ototoxicity) and kidney damage.
 Resistance – several mechs: inactivation of the drug
by acetylation, phos, or adenylation, Δ envellope to
prevent drug access, and Δ the binding site of the 30S
subunit (streptomycin only).

55.
 Gentamicin – used for acute, life-thretening gram-
infections. Has synergism with pen and van and combo.
 Amikacin – used for bact that are gent-resistant.
 Netilmicin – less toxic than gentamicin.
 Neomycin – too toxic for parenteral use. Used for topically
for skin infections and orally for sterilizing bowel before
surgery.
 Streptomycin – active against Mycobacterium tuberculosis.
But bec of its ototoxicity, rifampicin replaces.
 Rifampicin – resistance develops quickly alone; so, with TB,
combine with isoniazid, ethambutol, and pyrazinamide for
the 1st 2 mos of treatment, followed by another 4 mos with
rifampicin and isoniazid.

56.
 Very safe drugs.
 Ususally given orally.
 Erythromycin and clarithomycin
 Effective against gram- bact and can be used as an alt to
pen-sensitive patients, esp in infections caused by
streptococci, staphylococci, pneumococci, and clostridia.
 Don’t cross the BBB – ineffective against meningitis.
 Resistance- occurs bec of plasmid-controlled Δ of their
receptor on the 50S subunit.
 Erythromycin – in high doses, may cause nausea and
vomiting (less so with clarithromycin and azithromycin).
 Azithromycin – very long t1/2 (~40-60 hr) and a single dose
is as effective in treating chlamydial non-specific urethritis
as tretracycline admin over 7 days,

57.
 Broad-spectrum.
 Penetrate microorganisms well.
 Sensitive organisms accumulate it through partly passive
diffusion and partly through active transport.
 Resistant organisms develop an efflux pump and do not
accumulate the drug.
 Genes for tet-resistance transmitted by plasmids.
 Closely assoc with those for other drugs to which the
organisms will also be resistant (e.g., sulphonamides,
aminoglycosides, chloramphenicol).
 Tets bind to Ca in growing bones and teeth  can discolor
teeth. So, should be avoided in children < 8 yrs old.

58.
 Broad-spectrum.
 Serious side-effects: bone marrow aplasia,
suppression of RBCs, WBCs, encephalopathy, optic
neuritis.
 So, periodic blood counts required, esp in high
doses.
 Large Vd, including CNS.
 Inhibits the actions of other drugs and may incr
the actions of phenytoin, sulphonlureas, and
warfarin.
 Neonates cannot met the drug rapidly  accum 
‘grey baby’ syndrome (pallor, abdominal
distension, vomiting, and collapse).

59.
Antibacterial
Drugs that Inhibit
Protein Synthesis

60.
 Target enzymes required for nucleic acid synthesis
 Fluoroquinolones: inhibit enzymes that maintain the
supercoiling of closed circular DNA
 Rifamycins: block prokaryotic DNA-dependent RNA
polymerase from initiating transcription

61.
 Sulfadiazine well-absorbed orally. Used to treat
UTIs.
 But many strains of E. coli are resistant.
 So, use less toxic drugs instead.
 Adverse effects: allergic rxns, skin rashes, fever.
 Trimethoprin – used for UTIs and Resp TIs
 Co-trimoxazole (trimethoprin +
sulfamethoxazole) – used mostly for pneumonia,
neocarditis, and toxoplasmosis.

62.
 Sulfonamides (Sulfa drugs)
 Inhibit folic acid synthesis
 Broad spectrum
Figure 5.7

63.
Figure 20.13

64.
 Inhibit DNA gyrase.
 Nalidixic acid – used only for UTIs.
 Ciprofloxin (6-fluoro substituent) that greatly
enhances its effectiveness against both gram- and
gram+ bacteria.
Well-absorbed both orally and i.v.
Eliminated largely unchanged by the kidneys.
Side-effects (headache, vomiting, nausea) are rare;
but convulsions may occur.

65.
 Wide-spectrum
 Metronidazole – against anaerobic bacteria and
protozoan infections.
 Tinidazole – longer duration of action.
 Diffuses into the organism where the nitro group is
reduced  chemically reactive intermediates are
formed that inhibit DNA synthesis and/or damage
DNA.

66.
 Polymyxin B: binds to membrane of G- bacteria and
alters permeability
 This leads to leakage of cellular contents and cell death
 These drugs also bind to eukaryotic cells to some
extent, which limits their use to topical applications

67.
 Competitive inhibition by substance that resembles
normal substrate of enzyme
 Sulfa drugs

68.
 Very few antiviral drugs approved for use in US
 Effective against a very limited group of diseases
 Targets for antiviral drugs are various points of viral
reproduction

69.
 Amantadine – interferes with replication of influenza A by
inhibiting the transmembrane M2 protein that is essential
for uncoating the virus.
- Has a narrow spectrum; so, flu vaccine is usually
preferable.
 Zanamivir – inhibits both influenza A and B
neuraminadase. Decr duration of symptoms if given
within 48 hr of the onset of symptoms. Prophylactic in
healthy adults.
 Immunoglobulins – Human Ig contains specific Abs
against superficial Ags of viruses  can interfere with their
entry into host cells. Protection against hepA, measles, and
rubellla (German measles).

70.
 Acyclovir- used to treat genital herpes
 Cidofovir- used for treatment of cytomegaloviral
infections of the eye
 Lamivudine- used to treat Hepatitis B

71.
 HSV and VZV contain a thymidine kinase (TK)
that  acyclovir to a monophosphate
phosphorylated by host cell enzymes to
acycloguanosine triphosphate, which inhibits viral
DNA pol and viral DNA synthesis.
 Selectively toxic (TK of uninfected host cells
activates only a little of the drug).
 Viral enzymes have a much higher affinity than the
host enzymes for the drug.
 Effective against HSV, but does not eradicate them.
 Need high doses to treat shingles.

72.
 Quite toxic (neutropenia) –so, given only for severe
CMV infections in immunosuppressed patients.
 CMV is resistant to acyclovir because it does not code
for TK.

73.
 Currently implies a drug used to treat HIV
 Tenofovir- nucleotide reverse transcriptase inhibitor
 Zidovudine- nucleoside analog – inhibits RT of HIV and is
only used orally for AIDS.
- Activated by triple phosphorylation and then binds RT
(with100X affinity than for cellular DNA pols).
- Incorporated into the DNA chain, but lacks a 3’OH; so
another nucleoside cannot form a 3’-5’-phosphodiester
bond  DNA chain elongation is terminated.
-Severe adverse effects: anemia, neutropenia, myalgia,
nausea, and headaches.
 Stavudine, didanosine, zalcitabine – among other NRTIs.
 Nevirapine, efavirenz – Non nucleoside RTIs - denature RT.

74.
Life Cycle of
HIV

75.
HIV gp41-mediated fusion and enfuvirtide (T-20) action – Prohibits HIV entry

76.
 Zanamivir (Relenza) and Oseltamivir phosphate
(Tamiflu)- inhibitors of the enzyme neuominidase
 Used to treat influenza
 Indinavir- protease inhibitors. Inhibit the synthesis of
essential viral proteins (e.g., RT) by viral-specific
proteases.

77.
 Cells infected by a virus often produce interferon,
which inhibits further spread of the infection
 Alpha-interferon - drug for treatment of viral hepatitis
infections

78.
1. Bacteria spread on surface of agar plate
2. 12 disks, each with different antimicrobial drug,
placed on agar plate
3. Incubated- drugs diffuse outward and kill
susceptible bacteria
4. Zone of inhibition around each disk
5. Compare size of zone to chart

79.
 Drug resistance limits use of ALL known
antimicrobials
 Penicillin G: first introduced, only 3% of bacteria
resistant
 Now, over 90% are resistant

80.
1. Inactivating enzymes that destroy the drug (e.g., β-
lactamases).
2. Decreased drug accumulation (e.g., tet).
3. Altering the binding sites (e.g., aminoglycosides and
erythromycin).
4. Development of alternative metabolic pathways
(sulphonamides ( dihydropteroate synthease) and
trimethoprim (dihydrofolate reductase).

81.
1. Spontaneous Mutation: happen as cells replicate –
Within a pop, there will be some bact with acquired
resistance. The drug then elim the sensitive
organisms, while the resistant ones proliferate.
2. Gene Transfer or Transferred resistance: Usually
spread through conjugative transfer of R plasmid (
may be virally mediated).

82.
1. Responsibilities of Physicians: must work to identify
microbe and prescribe suitable antimicrobials, must
educate patients
2. Responsibilities of Patients: need to carefully follow
instructions

83.
3. Educate Public: must understand appropriateness and
limitations of antibiotics; antibiotics not effective
against viruses
4. Global Impacts: organism that is resistant can quickly
travel to another country
- in some countries antibiotics available on non-
prescription basis
- antibiotics fed to animals can select for drug-
resistant organisms

84.
 Scientists work to find new antibiotic targets in
pathogens
 Discovery of new and unique antibiotics is necessary