3. History
• The term antibiotics coming from the word
”antibiosis” which mean against life,
• Antibiosis were first described in 1877 by the
French “ Louis Pasteur”, then was renamed as
antibiotics by the American “Selman
Waksman” in 1942.
5. Classification (cont)
• II. biological activity:
• -bactericidal: kills the bact.
• -bacteriostatic: slow or
stall bacterial growth
6. Bacteriocidal:
• The beta-lactams Which interfere with
cell wall homeostasis,
• quinolones which are topoisomerase
inhibitors.
7. Beta lactam:
• contain four rings in which steric constrains or
chemical substituents activate the beta-lactam
bond,
• Mechanism of Action:
• Beta-lactams act mainly by blocking the synthesis
of peptidoglycan, a component of the cell wall
formed of parallel glycase strands cross-linked by
peptides. Peptidoglycan synthesis includes
cytoplasmic rections to form precursors, catalyzed
transglycolase, and cross-linking of peptide
components catalyzed
8. Mechanism of Action (cont)
• by transpeptidase. The transpeptidase step is
specifically and irrevrsibly inhibited by beta-lactams.
They attack multiple targets called
penicillin binding proteins (PBPs), of which
transpeptidase is the main example.
9.
10.
11. Mechanisms of resistance against the beta
lactams
• include altered PBPs and
production of beta-lactamases.
PBPs in Streptococcus
pneumoniae, methicillin-resistant
Staph.
aureus, Enterococcus
faecium and E. hirae often bind
pooly to beta-lactamase (50% of
the strains may be resistant).
Production of beta-lactamases in
the primary mechanism of
resistant in S. aureus, Moraxella
catarrhalis and Neisseria
goonorrhea.
12. Beta lactam classification:
• The beta-lactams are classified
according to their chemical
structures as either penicillins or
cephalosporins.
• -The penicillins include penicillin G,
penicillin V, nafcillin, amoxicillin and
ampicillin.
• -The cephalosporins include
cefazolin, ceftazidine, ceftriaxone
and imipenem
13. Pencillins indication:
• -Parenteral penicillin G is indicated to tret S.
pneumoniae, non-penicillinase strains of S.
aureus, oral anaerobes, Neisseria meningitidis,
and Treponema pallidum
• -Parenteral nafcillin is indicated to treat
penicillinase-producing S. aureus.
14. • Oral penicillin V is indicated to treat S. pneumoniae,
non-penicillinase strains of S. aureus,
and Enterococci.
• -Oral amoxicillin is indicated to treat B. fragilis (in
combination wit clavulanic acid), H. influenzae
(alone or in combination with clavulanic acid), and
P. mirabilis (in combination with clavulanic acid.
Clavulanic acid is a beta-lactamase inhibitor that
potentiates the action of amoxicillin against beta-lactamase
producing strains
15. Cephalosporins indication:
• Parenteral cefazolin is indicated to treat Escherichia
coli, Klebsiella pneumoniae and P. mirabilis
• Parenteral ceftazidine is indicated to treat E. coli, K.
pneumoniae, P. mirabilis and P aeruginosa.
• Parenteral ceftriaxone is indicated to treat S.
pneumoniae, N. meningitidis, N. gonorrhea, H.
influenzae, E. coli, K. pneiumoniae, Enterobacter,
and P. mirabilis.
16. Side effects:
• GI irritation is common with the
amoxicillin/clavulanic acid
combination.
• Oral penicillin V& Amoxicillin may
block estrogen, thus antagonizing
oral contraceptives.
• biliary sludging (pain, nausea,
vomoting) with ceftriaxone
17. Quinolone
• The representative quionolone agents are
nalidixic acid, ciproflaxin and levoflaxin the
last 2 drugs contain a fluorine atom attached
to the reactive quinolone ring.
18. Mechanism of action:
• are bactericidals of rapid effectys that inhibit
baterial topoisomerases II and IV.
Topoisomerase II is the primary target,
promoting double-strand breaks in bacterial
DNA. By inhibitin topoisomerase IV,
ecadenation of daughter bacterial cells is
blocked. The quinolones will also inhibit
mammalian topoisomerases I and II, but at
much higher concentration than needed to
inhibit baterial topoisomerases.
19. Quinolone indications:
• -Nalixilic acid is an older agent that does not
differentiate much between bacterial and hosts
targets, and is useful only to treat urinary
infections (where it accumulates).
• -Ciproflaxin and levoflaxin are indicated for
urinary track infections, pneumonia and
bronchitis caused by gram-negative aerobes.
• -Ciproflaxin is also indicated in N. gonorrhea and
Pseudomonas.
• -Levoflaxin is indicated for community-aquired
pneuminia.
20. Side effect of quinolones
• As ciproflaxin distributes to the CNS
,the main adverse reactions are due
to CNS stimulation: headache,
dizziness, insomnia and nervousness.
Seizures are rare but may occur in
sensitive patients or those using
alcohol or theophilline.
• Pain, nausea, vomiting, tendonitis
and tendon rupture are also
common.
• Unpredictable acute liver failure is
associated with certain quinolones.
• Renal impairment as they are
eliminated mostly in urine.
23. Drug interaction:
-The beta lactam group have many
drug interactions.
-Bacteriostatic antibiotics
(chloramphenicol, macrolides
and tetracyclines) interfere with
the action of beta-lactams.
- The aminoglycoside antibiotics
have synergistic antibacterial
action but are chemically
incompatible with the beta-lactams.
-
24. Drug interaction:
Low pH and destroxe solution
inactivates beta lactams.
-Probenecid bloks their excretion
thus prolonging effective blood
levels of most beta-lactams
(excepts a few cephalosporins).
- Drugs containing metals
decrease the absorption of
quinolones
- Warfarinm may havee greater
anticoaguant effects with
fluoroquinolones
25.
26. Bacteriostatic
• bacteriostatic antibiotics include
• the macrolides,
• tetracyclines,
• aminoglycosides
• chloramphemnicol
• and clindamycin
27. Mode of action
• They inhibit bacterial protein synthesis by acting on
bacterial ribosomal units. In addition to the
bacteriostatic activity.
• Each drug class has other characteristic
mechanisms:
• Macrolides: accumulate in gram-positive bateria and some
mammalian cells
• Tetracyclines: pumped into bacterial cells
• Aminoglycosides and Aminociclitols: are also bactericidal
• Chloramphenicol: also affects mitochondrial protein synthesis
• Clindamycin: passively enters bacteria and concentrates in
macrophages
28. Indication
• Macrolides: they include azithromycin and
erythromycin
• They are indicated to treat atypical pneumonias caused
by Mycoplasma pneumoniae and Legionella
pneumoniae. Other patogens like Streptococcus
pneumonia, H. influenzae and M. avium readily develop
resis
• Azithromycin is also indicated to treat H. influenzae,
bronchitis and Chlamydia tance by either increasing
drug eflux from bacterial cells or by altering drug
binding targets.
• Erythromycin is also indicated to treat otitis media in
combination with sulfisoxazole.
29. Indications (cont)
• Chloramphenicol is indicated to treat H.
influenzae, Salmonella, Ricketsia, Chlamydia and
anaerobic absesses, especially in the brain, or
meningitis.
• Clindamycin isindicated in anaerobic bacteria or
sites, like bone and abdomen. Other indications are
against gram-positive bateria and Pneumocystis
carinni (in combination with primaquine).
•
30. Indications (cont)
• Tetracyclines: they are indicated to
treat Rickettsia, Chlamydia, Mycoplasma, Lyme
disease, relapsing fever, and selected gram-positive
and gram-negative bacteria
• Aminoglycosides and Aminocyclitols: they include;
amikacin, gentamycin, kanamycin, netilmycin,
streptomycin, neomycin and paromomycin. The
only amynociclitol in use is spectinomycin.
31. Indications (cont)
-These agents are indicated against gram-negative
aerobic bacteria like E. coli, Enterobacter, Proteus
and Klessiella. Anmikacin, gentamicin, netlmicin and
tobramycin are active against Ps. aeruginosa.
-They are also used against gram-positive aerobicbacteria like
Strep. viridans, Strep. agatactae and Enterococus.
Aminoglycosides are used in combination with beta-lactams
to treat serious gram-positive infections.
- Streptomycin is indicated against M. tuberculosis and
spectinomycin against N. gonorrhea.
32. Side effects:
• The macrolides concentrate in tissue and inflammatory cells, but CNS levels
are too low to be effective. They are metabolized in the liver and excreted
primarily in bile. May cause stomach cramps, nausea, vomiting and diarrhea
by overstimulation of the GI muscles
• The tetracyclines are contraindicated in children less than 9 years old and
pregnant women because they interfere with bone and teeth development.
They are also contraindicated in patients with renal impairment.
• The aminoglycosides cause dose-dependent ototoxicity (may be
permanent), renal toxicity and neuromuscular blockade due to atypical
absortion.
• Chloramphenicol will cause reversible bone marrow supression (dose-related),
aplastic anemia (rare and fatal, not dose related, may occur weeks
or months after therapy), and gray baby syndrome.
• Clindamycin may cause diarrhea, antibiotic associated colitis and
pseudomembramous colitis
33.
34. Drug interaction:
- Chloramphenicol and clindamycin antagonize the
antibiotic effect of macrolides.
- Tetracyclines antagonize the antibiotic effects of
penicillins
-The beta-lactams and aminoglycosides inactivate each
other in sdolution but act synergistically when used
sequentially.
-clindamycin and may interact with anesthetics,
neuromuscular blockers (enhance block), antidiarrheals
(block absorption), and will antagonize the antibiotic
effects of chloramphenicol and the macrolides.
35. Chemotherapy
• The word "chemotherapy"
without a modifier usually
refers to cancer treatment.
• The first modern
chemotherapeutic agent
was arsphenamine, an
arsenic compound
discovered in 1909 and
used to treat syphilis.
36. Sidney Farber is regarded as the father of
modern chemotherapy.
Sidney Farber, M.D. - founder of Children's Hospital Cancer Research
Foundation in the 1950's and 1960's.
37. Mechanism of action
• Most chemotherapeutic drugs
work by impairing mitosis (cell
division), effectively
targeting fast-dividing cells.
• As these drugs cause damage
to cells, they are termed
cytotoxic.
• Some drugs cause cells to
undergo apoptosis (so-called
"self-programmed cell death").
38. • Drugs affect "younger" tumors (i.e., more differentiated)
more effectively, because mechanisms regulating cell growth
are usually still preserved.
• With succeeding generations of tumor cells, differentiation is
typically lost, growth becomes less regulated, and tumors
become less responsive to most chemotherapeutic agents.
• Near the center of some solid tumors, cell division has
effectively decreased, making them insensitive to
chemotherapy. Another problem with solid tumors is the fact
that the chemotherapeutic agent often does not reach the
core of the tumor.
Solutions to this problem include radiation
therapy ( brachytherapy & teletherapy) and surgery.
39. Cancer cell they fight back!
• Over time, cancer cells become more resistant to
chemotherapy treatments.
• Recently, scientists have identified small pumps on
the surface of cancer cells that actively move
chemotherapy from inside the cell to the outside.
• Research on p-glycoprotein and other such
chemotherapy efflux pumps is currently ongoing.
• Medications to inhibit the function of
p-glycoprotein are undergoing testing as of 2007 to
enhance the efficacy of chemotherapy.
40. Mechanisms of resistance
• One way is to pump drugs out of cells by increasing the
activity of efflux pumps, such as ATP-dependent transporters.
• Resistance can occur as a result of reduced drug influx a
mechanism reported for agents that 'piggyback' on
intracellular carriers or enter the cell by means of
endocytosis.
• In cases in which drug accumulation is unchanged, activation
of detoxifying proteins, such as cytochrome P450 mixed-function
oxidases, can promote drug resistance. Cells can also
activate mechanisms that repair drug-induced DNA damage.
• Finally, disruptions in apoptotic signaling pathways (e.g. p53
or ceramide) allow cells to become resistant to drug-induced
cell death.
41.
42. Depending on your type of cancer and how
advanced it is, chemotherapy can:
• Cure cancer - when chemotherapy destroys cancer cells
to the point that your doctor can no longer detect them
in your body and they will not grow back.
• Control cancer - when chemotherapy keeps cancer
from spreading, slows its growth, or destroys cancer
cells that have spread to other parts of your body.
• Ease cancer symptoms (also called palliative care)
- when chemotherapy shrinks tumors that are
causing Pain or pressure.
43. Other uses
• Certain chemotherapeutic agents also have a role
in the treatment of other conditions, including
• ankylosing spondylitis,
• multiple sclerosis,
• Crohn's disease,
• psoriasis, psoriatic arthritis,
• rheumatoid arthritis,
• and scleroderma.
44. Chemotherapy may be given in many ways.
• Injection. The chemotherapy is given by a
shot in a.
• Intra-arterial (IA). The chemotherapy goes
directly into the artery that is feeding the
cancer.
• Intraperitoneal (IP). The chemotherapy goes
directly into the peritoneal cavity.(Ovarian
tumor)
• Intravenous (IV). The chemotherapy goes
directly into a vein.
• Topically. The chemotherapy comes in a
cream that you rub onto your skin.(BCC)
• Orally. The chemotherapy comes in pills,
capsules, or liquids that you swallow.
(Tamoxifen)
45.
46. • Traditional chemotherapeutic agents act by
killing cells that divide rapidly, (one of the
main properties of most cancer cells.)
• This means that chemotherapy also harms
cells that divide rapidly under normal
circumstances:
• cells in the bone marrow,
• digestive tract,
• and hair follicles.
47. • Newer anticancer drugs (for example,
various monoclonal antibodies) are not
indiscriminately cytotoxic, but rather target proteins
that are abnormally expressed in cancer cells and
that are essential for their growth.
• Such treatments are often referred to as targeted
therapy (as distinct from classic chemotherapy) and
are often used alongside traditional
chemotherapeutic agents in antineoplastic
treatment regimens.
48. Types
• The majority of chemotherapeutic
drugs can be divided in to
• alkylating agents( Cisplatin and carboplatin),
• Antimetabolites(azathioprine, mercaptopurine),
• anthracyclines,
• plant alkaloids,
• topoisomerase inhibitors,
• and other antitumor agents.
• All of these drugs affect cell
division or DNA synthesis and
function in some way.
49.
50. Side effects
• Depression of the immune system
• Gastrointestinal distress (Chemotherapy-induced
nausea and vomiting (CINV) Up to 20% of patients
receiving highly emetogenic agents in this era
postponed, or even refused, potentially curative
treatments.
• Hair loss These are most often temporary effects: hair
usually starts to regrow a few weeks after the last
treatment.
51. • Infertility: Patients may choose between several methods
of fertility preservation prior to chemotherapy,
including cryopreservation of semen, ovarian tissue, oocytes, or
embryos.
• Secondary neoplasm: Development of secondary neoplasia
after successful chemotherapy and/or radiotherapy treatment can
occur. The most common secondary neoplasm is
secondary acute myeloid leukemia, which develops
primarily after treatment with alkylating agents or topoisomerase
inhibitors.
• Survivors of childhood cancer are more than 13 times as likely to
get a secondary neoplasm during the 30 years after treatment
than the general population.
• Not all of this increase can be attributed to chemotherapy!
52.
53. Newer agents do not directly interfere with
DNA.
• These include monoclonal antibodies and the
new tyrosine kinase inhibitors, which directly
targets a molecular abnormality in certain types of
cancer
• Eg. (chronic myelogenousleukemia, gastrointestinal
stromal tumors).
• In addition, some drugs that modulate tumor cell
behaviour without directly attacking those cells may
be used. Hormone treatments fall into this category
54. Newer and experimental approaches
Isolated infusion approaches
• Isolated limb perfusion (often used in melanoma), or
isolated infusion of chemotherapy into the liver or the
lung have been used to treat some tumours.
• The main purpose of these approaches is to deliver a
very high dose of chemotherapy to tumor sites without
causing overwhelming systemic damage. These
approaches can help control solitary or limited
metastases,
• but they are by definition not systemic, and, therefore,
do not treat distributed metastases
or micrometastases.
55. Targeted delivery mechanisms
• Specially targeted delivery vehicles aim to increase effective levels of
chemotherapy for tumor cells while reducing effective levels for other cells.
This should result in an increased tumor kill and/or reduced toxicity.
• Specially targeted delivery vehicles have a differentially higher affinity for
tumor cells by interacting with tumor-specific or tumor-associated
antigens.
• Specially targeted delivery vehicles vary in their stability, selectivity, and
choice of target, but, in essence, they all aim to increase the maximum
effective dose that can be delivered to the tumor cells.
• Reduced systemic toxicity means that they can also be used in sicker
patients, and that they can carry new chemotherapeutic agents that would
have been far too toxic to deliver via traditional systemic approaches.
56. Nanoparticles
• Nanoparticles have emerged as a useful vehicle for
poorly soluble agents such as paclitaxel. Protein-bound
paclitaxel (e.g., Abraxane) or nab-paclitaxel
was approved by the U.S. Food and Drug
• Administration (FDA) in January 2005 for the
treatment of refractory breast cancer. This
formulation of paclitaxel uses human albumin as a
vehicle
• Nanoparticles made of magnetic material can also
be used to concentrate agents at tumour sites using
an externally applied magnetic field.
57. Electrochemotherapy
• Electrochemotherapy is the combined treatment in which
injection of a chemotherapeutic drug is followed by application
of high-voltage electric pulses locally to the tumor.
• The treatment enables the chemotherapeutic drugs, which otherwise
cannot or hardly go through the membrane of cells (such as bleomycin and
cisplatin), to enter the cancer cells.
• Clinical electrochemotherapy has been successfully used
for treatment of cutaneous and subcutaneous tumors
irrespective of their histological origin.
• Recently, new electrochemotherapy modalities have been developed for
treatment of internal tumors using surgical procedures, endoscopic routes
or percutaneous approaches to gain access to the treatment area.[
58. Monoclonal antibodies
• Several are in development and a few have been licenced
by the FDA:
• Rituximab (marketed as MabThera or Rituxan) targets CD20 found on B
cells. It is used in non Hodgkin lymphoma
• Trastuzumab (Herceptin) targets the Her2/neu (also known as ErbB2)
receptor expressed in some types of breast cancer
• Cetuximab (marketed as Erbitux) targets the epidermal growth factor
receptor. It is used in the treatment of colon cancer and non-small cell lung
cancer.
• Bevacizumab (marketed as Avastin) targets circulating VEGF ligand. It is
approved for use in the treatment of colon cancer, breast cancer, non-small
cell lung cancer, and is investigational in the treatment of sarcoma. Its use
for the treatment of brain tumors has been recommended
