In this chapter detail molecular mechanism of chemotherapeutic agents have been discussed

1. 1
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2. Objectives
At the end of this session you will able to
• Define chemotherapy and antibiotics
• List the class of antibiotics
• Explain the Mechanism of chemotherapeutics
• Explain the adverse effects of antibiotics
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By A.D

3. Introduction
a. Chemotherapy
• Use of drugs against invading organisms as
well as cancerous cells.
b. Antimicrobial agent
• Use of chemicals against invading organisms.
c. Antibiotic
• A drug that is produced by one microorganism
and has the ability to harm other microbes.
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4. Principles of antimicrobial
• Goal: Selective toxicity
 Ability to injure or kill an invading microorganism
without harming the cells of the host.
• How is selective toxicity achieved?
– Biochemical differences that exist between
microorganisms and human beings.
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5. Antimicrobials
1. Antibacterial
2. Antifungal
3. Antiviral
4. Antiparasites
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6. 6
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7. Therapeutic principle
Empiric therapy
• For a particular illness or the susceptibility to a particular
antimicrobial agent is known
• Often a broad-spectrum drug has to be used to cover all
likely pathogens
Definitive therapy
• Is typically narrower in coverage and is given for an
appropriate duration based on the results of clinical trials
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8. Selection of Antimicrobial Agents
• Selection of the most appropriate antimicrobial agent requires
knowledge of
1. The organism's identity
2. The organism's susceptibility to a particular agent
3. The site of the infection
4. Patient factors
5. The safety of the agent
6. The cost of therapy
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However, some critically ill patients require empiric therapy” that is, immediate
administration of drug(s) prior to bacterial identification and susceptibility testing.
By A.D

9. Classification
Based on bacterial coverage
• Narrow-spectrum antibiotics
Chemotherapeutic agents acting only on a single or a limited
group of microorganisms
E.g Isoniazide, Pen G
• Broad-spectrum antibiotics
 affect a wide variety of microbial species
E.g tetracycline, fluoroquinolones and carbapenems
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10. Combined use of antimicrobials
• More than one antimicrobial are frequently used
concurrently to treatment of infectious disease.
• Reasons for antimicrobial combinations
 To achieve synergism – e.g. Penicillin + Aminoglycoside
 To prevent emergence of resistance e.g. TB and H.pylori,
HIV and Leprosy Rx
 To broaden the spectrum of antimicrobial action e.g. Rx of
mixed infection
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11. Disadvantages of antimicrobial combinations
• Increased incidence and variety of adverse effects.
• Increased chances of super-infections
• If inadequate doses of non-synergistic drugs are used—
emergence of resistance may be promoted.
• Higher cost of therapy.
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12. Prophylactic use of antimicrobials
• Preventing the setting in of an infection or suppressing
contacted infection before it becomes clinically manifest.
• Prophylaxis against specific organisms e.g. Rheumatic
fever, TB, HIV…
• Prevention of infection in high risk situations e.g.
Dental extraction, Catheterization,
• Prophylaxis of surgical site infection
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13. Drug resistance
• Unresponsiveness of a microorganism to a drug,  akin to
the phenomenon of tolerance seen in higher organisms
Natural resistance
– microbes have always been resistant to certain AMAs  lack the
metabolic process or the target site
Acquired resistance
• Development of resistance by an organism (which was
sensitive before)
• Resistance may be developed by mutation or gene transfer
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14. Mutation
• It is a stable and heritable genetic change that occurs
spontaneously and randomly among microorganisms.
• Single step: A single gene mutation may confer high
degree of resistance; emerges rapidly.
• Multistep: A number of gene modifications are
involved sensitivity decreases gradually in a
stepwise manner
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15. Gene transfer
• Passage of the trait to daughter cells vertically transfer
• Resistance causing gene is passed from one organism to the
other horizontal transfer of resistance.
A. Conjugation
B. Transformation
C. Transduction
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16. A. Conjugation
• Sexual contact through the formation of a bridge or
sex pilus is common among gram-negative bacilli of
the same or another species.
• This may involve chromosomal or extrachromosomal
(plasmid) DNA.
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17. B. Transformation
• A resistant bacterium may release the resistance
carrying DNA into the medium and this may be
imbibed by another sensitive organism
becoming unresponsive to the drug
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18. C. Transduction
• The transfer of gene carrying resistance
through the agency of a bacteriophage
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19. Classification antibacterial agents
Based on mechanism of drug action
1. Disruption of bacterial cell wall synthesis
2. Inhibition of microbial protein synthesis
3. Inhibition of microbial nucleic acid synthesis
4. Inhibition of an enzyme required to synthesize
folic acid
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20. Cont…
1. Inhibition of cell wall synthesis
• Penicillins
• Cephalosporins
• Carbapenums
• Monobactams
• Vancomycin
• Bacitracin
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21. 21
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22. Cont..
2. Inhibition of protein synthesis
• Aminoglycosides
• Chloramphenicol
• Tetracycline
• Microlides
3. Inhibition of nucleic acid synthesis
• Rifampicin
• Fluoroquinolones
4. Antimetabolites
• Sulphonamides
• Trimethoprim
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23. 1. Inhibition of cell wall synthesis
1. Penicillin
Mechanism of action
• The penicillins interfere the bacterial cell wall
synthesis (transpeptidation or cross-linkage)
23
(X) Bond which is broken by
penicillinase.
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24. Penicillins
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25. Mechanism of bacterial resistance
1. Inactivation of antibiotic by -lactamase: common
2. Impaired penetration: from g-ves , absence of porins
3. Modification of target penicillin binding sites
4. Presence of efflux pump
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26. Natural penicillins
Penicillin G
a. Active against G +ve cocci except penicillinase
producing staphylococci
b. Active against some G +ve bacilli
c. G –ve cocci (N. meningitidis, N. Gonorrhea)
d. Spirochetes (T.pallidum)
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27. Therapeutic uses
1. Drug of choice for:
 Pneumonia or meningitis by Streptococcus pneumonia
 Pharyngitis by streptococcus pyogenes
 Infectious endocarditis by streptococcus viridians
2. Infection caused by G+ve bacilli
– Gangrene by Cl. Perfringes
– Tetanus by Cl. Tetani
– Anthrax by B. anthracis
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28. Cont..
3. First choice for meningitis by N. meningitides
4. Drug of choice for the treatment of syphilis
5. Prophylactic applications
 Syphilis in sexual partners
 Benzathine penicillin G monthly for life in recurrent
rheumatic fever  caused by GAS
 Bacterial endocariditis
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29. Pharmacokinetics
• Penicillin G is available as salts (Na+, K+, Procaine,
Benzathine penicillin G)
• Penicillin G is acid sensitive  not taken orally
• Penicillin G is mainly excreted by tubular secretion
• Excretion delayed by probenecid
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• Na and K Pen G = short acting
• Procaine Pen G = intermediate acting
• Benzathine penicillin G= Long acting
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30. Formulations of Pen-G
• Procaine penicillin fortified (PPF) – IM route
1 vial = 10 ml = 4,000,000 IU
• Byzantine Penicillin – IM route
1 vial =8 ml = 2,400,000 IU
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31. Penicillinase resistant penicillin
• These agents have side chains that protect the β-lactam ring
from attack by penicillinase.
• Cloxacillin
• Oxacillin
• Nafcillin
• Dicloxacillin
• Methicillin  not used as Rx rather for laboratory purpose
 Also an Inducer of penicillinase
 Acid sensitive  injected perentrally
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32. Penicillinase resistant penicillin
• Effective against staphylococcal bacteria (β-
lactamase producing bacteria )
• Are not effective for gram –ve infection
• Acid stable; orally and parenterally administered
• Absorption affected by food taken 2 hrs before
meal
• Mechanism of resistant (MRSA) is altered PBPs
• Use skin and soft tissue infection
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33. Aminopenicillins
• Ampicillin
• Amoxicillin
Antimicrobial spectrum
• Effective as penicillin G (G+ve bactreia)
• Plus G-ve bacilli (H.influenza, E.coli, Salmonella,
Shigella)
• But ineffective against -lactamase producing bacteria
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34. Ampicillin
Therapeutic use
 UTI, RTI
 Shigellosis (but not amoxicillin)
 Typhoid fever: less efficacious than ciprofloxacin
Adverse effects
a. Diarrhea (incompletely absorbed, irritate; alteration of
bacterial flora)
b. Rashes
 Reduce entro-hepatic circulation of oral contraceptives
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35. Amoxicillin
• Oral absorption is better
• Have less diarrheal effect than Ampicillin
• Less active against shigella
Therapeutic use
1. RTI like pneumonia, tonsillitis, pharyngitis
2. UTI
3. Typhoid fever
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36. Extended-spectrum penicillins
• Are antipseudomonal penicillins
 Pseudomonas aerugnosa infction most common in
immunocompromised host
• Activity against several gram-negative rods, including
Pseudomonas, Enterobacter, proteus and Klebsiella pneumoniae
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Carboxypenicillins
Carbenicillin
Ticarcillin
Ureidopenicillins
Piperacillin
Mezlocillin
Superior activity for Pseudomonas

37. Extended spectrum ….
• Susceptible to constitutive pencillinase so that
combined with pencillinase inhibitors
• Are acid labile and hence administered parentrally (IV)
• These agents interferes platelet function thereby promote
bleeding
• Piperacillin is more pontent of all
• Ticarcilin is usually combined with Aminoglycosides
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38. Beta-lactamase inhibitors
• Clavulinic acid, Sulbactam, Tazobactam
• Inhibits bacterial -lactamases; have weak
antibacterial action
• Most active against -lactamase produced by:
S.aureus, H.infleunza, some enterobacteriaceae
• Not taken alone  taken in combination with
other Penicillin (e.g. Ampicillin + sulbactam)
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39. Cnt….
• Most active against Ambler class A β-lactamases (plasmid-encoded
transposable element β-lactamases)
– i.e. produced by staphylococci, H influenzae, N gonorrhoeae,
Salmonella, Shigella, E coli, and K pneumoniae
• They are not good inhibitors of class C β-lactamases, which typically
are chromosomally encoded and inducible
– i.e. produced by Enterobacter sp, Citrobacter sp, S marcescens,
and P aeruginosa,
• But they do inhibit chromosomal β-lactamases of B fragilis and M
catarrhalis.
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40. • The novel non-β- lactam β-lactamase inhibitor
avibactam is active against Ambler class A β-
lactamases
• But also active against Ambler class C and some
Ambler class D β-lactamases.
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41. Amoxicillin-clavulinic acid (augmentin)
 250-750mg amoxicillin and 125mg clavulinic acid
used in:
 Acute otitis media
 Sinusitis
 Lower RTI
 Skin infection (streptococci, staphylococci)
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42. Adverse effects of penicillins
• Allergy (even cross allergy) (how -?- next slide)
• Rash
• Diarrhea
• Antibiotic-associated colitis
 Pseudomembranous colitis
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43. 43
Inactive (Major Determinant)
Responsible for hypersensitivity
Active material
Raw material for other penicillin

44. Resistance
• The natural resistance to pencillines occur in bacteria
that lack peptidoglycan i.e. Mycoplasma pneumonia
• Impermeability to drugs
• Plasmid mediated B-actamase
• Alteration of PBPs
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45. B-lactamase
• Bacteria produce a large variety of B-lactamases
 some are specific for penicillins penicillinases.
 some are specific for other beta-lactam antibiotics (eg,
cephalosporins)
 Some act on several kinds of beta-lactam antibiotics
• Gram+ve bacteria secrete B-lactamase extracelluarly
• But Gram –ves produce B-lactamase in periplasmic spaces
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46. Cont….
• The genes that code for beta-lactamases are located
on chromosomes and on plasmids (extrachromosomal
DNA).
• The genes on plasmids may be transferred from one
bacterium to another,  thereby promoting the
spread of penicillin resistance
E.g. Staphylococcus aureus
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47. Cephalosporins
• Structurally and functionally similar to the penicillins
• There are 5 generations
• From 1st generation to 5th generation
– Increasing activity against G-ve and anaerobes
– Increasing resistance to destruction to -lactamase
– Increasing ability to reach CSF
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48. 1st generation cephalosporins
Generic Route
Half
life
(hr)
Properties
Cephalexin oral 0.9 - Active against G +ve
- Less active against
penicillinase producing
staphyccocus
Cefadroxil oral 1.2 Used in treatment of UTI
Cephradine Oral, iv/im 0.7 Similar to Cephalexin
Cefazolin Iv/im 1.8 - Good penetration to bone
- Preferred due to t1/2
Cephalothin iv 0.6 Used in severe staph. infection
E.g. endocarditis
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49. 1st generation
• Sensitive to B-lactamase destruction
• Effective for staphylococcci but are not for MRSA
• Anaerobic cocci, E.coli and K.pneumonia proteus
mirabilis sensitive
• Poor against P.aeruginosa and and entrobacter
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50. 2nd generation cephalosporins
• Improved activity against Haemophilus influenzae,
Neisseria species, and Moraxella catarrhalis.
• Cefoxitin and cefotetan have anaerobic activity and
are used in mixed soft-tissue infections
• Cefuroxime- is a popular oral cephalosporin
• Overall, this generation is of limited usefulness
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51. 3rd generation cephalosporins
• Improved gram-ive coverage
• Excellent activity against Neisseria gonorrhoeae, N.
meningitidis, H.influenzae and Moraxella catarrhalis
• Ceftriaxone has a long half-life that allows for once-
daily dosing.
• Cefotaxime has a shorter half-life but activity identical
to that of ceftriaxone
• Ceftazidime– best for community-acquired pneumonia
and bacterial meningitis
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52. Ceftriaxone
• Most potent; t1/2 8hrs once daily dose
• High efficacy in bacterial meningitis, multiresistant
typhoid fever
• Complicated UTI, abdominal sepsis, septicemias
• Majorly excreted via bile  preferred during renal
insufficient
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53. Cont…
• Cefotaxime and ceftazidime  less protein
bound  have good CSF penetration
• Ceftazidime more useful activity against
P.aeruginosa.
• Cefixim orally effective 3rd G.Cephalosporin
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54. 4th generation cephalosporins
a. More resistant to extended-spectrum β–
lactamases and β -lactamases.
b. Excellent gram+ve (staph.aureus) and gram-ve
coverage (Pseudomonas aeruginosa).
c. Excellent broad-spectrum; empiric therapy
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55. 5th generation cephalosporin
Ceftaroline
• Novel 5th generation cephalosporin
• Exhibits broad spectrum activity against G +ve
bacteria including MRSA and extensively resistant
strains i.e. Vancomycin Resistant S.aureus (VRSA)
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56. MRSA
• The only Beta lactam antibiotic effective for MRSA is Ceftaroline
fosamil (Prodcrug of Ceftaroline )
• But Ceftaroline is not effective for extended spectrum B-lactamase
producings
Ceftaroline is Useful for
• Skin and soft tissue infection
• Endocardtis
• Oesteomylitis
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57. Vancomycin
• It is a glycopeptide antibiotics  isolated from Amycolatopsis
orientalis
• Because of its molecular wt  effective only to G+ve
• Active against G+ve (staph.aureus and staph epidermidis)
• Effective for MRSA
• Backup drug for Clostridium difficle
• Not absorbed orally; given IV route
Adverse effect
• Nephrotoxicity and ototoxicity
• “Red man” syndrome  infusion-related flushing
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Teicoplanin and Telavancin are other glycopeptide

58. Vancomycin
Mechanism
• Inhibits cell wall by binding to D-Ala-D-Ala terminus of
nascent peptidoglycan
• This inhibits Transglycosilase  limit further elongation and
cross link
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Does not bind PBPs
Resistance to vancomycin in enterococci is due to modification of the d-Ala-d-Ala binding
site of the peptidoglycan building the terminal d-Ala is replaced by d-lactate

59. Fosfomycin
• Antimetabolite inhibitor of cytosolic enolpyruvate
transferase  prevent formation of N-acetylmuramic
acid
• Disrupting cell wall by Inhibiting an enzyme UDP-N-
acetyleglucosamine enolpyruvate transferase
• Used for women with uncomplicated UTI caused by
E.coli
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60. Bacitracin
• Produced from bacillus subtilis
• Inhibits cell wall by interfering dephosphorylation in cycling
of lipid carrier that transfers peptidoglycan subunit to the
growing cell wall
• Nephrotoxic in systemically so limited to topical use
• Poor absorption orally
• Effective for  Staph, Strep, C.difficile, Neisseria and
H.influenza
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61. Cycloserine
• Produced by streptomyces orchidaceous
• Water soluble but unstable in acidic ph
• Inhibit both G-Ve and G+ve organism
• But it is used mostly for second line TB
• It is analog of D-alanine and inhibits incorporation of
D-alanine into Peptidoglycan  by inhibiting Alanin
Racemase which convert L-ananine to D-alanine
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62. Daptomycin
• Novel cyclic lipopeptides
• Active against Vancomycin resistant strains
• Effective only for G+ve bacteria
• Also effective for Entrobacter and Staph.
• Has Myopathy need creatinine Phosphokinase
monitoring
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63. Daptomycin
MOA-
• Has a novel mechanism of action
• Inserts its lipid tail via Ca+2 defendant mechanism into the
bacterial cell membrane,  forms channels that permit efflux
of intracellular potassium (and other ions)
• Loss of ions has two effects
 Depolarizes the membrane
 Inhibits synthesis of DNA, RNA and proteins  cell death
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64. 64
Daptomycin first binds to the cytoplasmic membrane (step 1) and then forms complexes in
a calcium-dependent manner (steps 2 and 3). Complex formation causes a rapid loss of
cellular potassium, possibly by pore formation, and membrane depolarization. This is
followed by arrest of DNA, RNA, and protein synthesis resulting in cell death. Cell lysis
does not occur.

65. Carbapenems
Ertapenem, Imipenem, Meropenem,Doripenem
• Resistant to beta-lactamase
• Beta-lactam antibiotics that have very broad
antimicrobial spectra
• Effective for G-ve rods (P.aeruginosa), G+ve and
Anaerobes
• None is active against methicillin-resistant
Staphylococcus aureus.
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66. Inactivation
• Imipenem is inactivated by Dehydropeptidase in
renal tubules combined with Cilastatin
• Meropenem and Doripenem not significantly
inactivated by Dehydropeptidase no inhibitor needed
• Ertapenem does not have appreciable effect on
P.aeruginosa
• Also not degraded by Dehydropeptidase
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67. Monobactams
Aztreonam
• Contain a monocyclic β-lactam ring  but resistant to B-lactamase of
Pseudomonas, Klebsiella
• Binds to PBP3 inhibit cell wall synthesis, and thereby promotes cell
lysis.
• It penetrates well into the cerebrospinal fluid.
• Limited to aerobic Gram-negative organisms (including P aeruginosa).
• The drug is not effective for G+ve and anaerobes
• Because of its structural similarity to ceftazidime, there is potential for
cross-reactivity;
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68. Protein synthesis inhibitors
• Interfere the bacteria growth by targeting bacterial
ribosomes and inhibiting bacterial protein synthesis.
• Bacterial ribosomes differ structurally from
mammalian cytoplasmic ribosomes  minimizes
potential adverse consequences
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69. Protein synthesis inhibitors
1. Aminoglycosides
─ Gentamicin, Streptomycin, Amikacin, Neomycin,
Tobramycin
2. Tetracyclines
─ Doxycycline, Demeclocycline, Minocycline, Tetracycline
3. Macrolides/ketolides
─ Azithromycin, Clarithromycin, Erythromycin
4. Chloramphenicol
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70. Aminoglycosides
• MOA- Bind to specific 30S-subunit ribosomal proteins
 Interfere the initiation complex of peptide formation
 Misreading of mRNA non-functional protein
• Effective for the majority of aerobic gram-ve bacilli, including
those that may be multidrug resistant
– such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and
Enterobacter sp.
• Aminoglycosides are often combined with a β-lactam antibiotic to
employ a synergistic effect
• Highly polar-absorbed very poorly from intact GIT  (I.M. and
I.V.) 70
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71. Mechanism of resistance
• The principal cause is production of transferase enzymes that
can inactivate aminoglycosides  by adenylylation,
acetylation, or phosphorylation
• Impaired penetration or via efflux pump
• Receptor protein on the 30S ribosomal subunit may be deleted
or altered as a result of a mutation.
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72. Indications
• Used against G-ve enteric bacteria in
bacteremia and sepsis,
• TB –i.e. Streptomycin, amikacin
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73. Why Amino glycosides active only for aerobics
• Transport of aminoglycoside into the bacterial cell is a multistep process.
• They diffuse across the outer coat of gram-negative bacteria through porin channels.
• Entry from the periplasmic space across the cytoplasmic membrane is carrier
mediated which is linked to the electron transport chain.
• Thus, penetration is dependent upon maintenance of a polarized membrane and on
oxygen dependent active processes (energy dependent phase I or EDP1 entry).
• These processes are inactivated under anaerobic conditions; anaerobes are not
sensitive
• More active for gram-negative bacteria than g+ve – so combined with pen to cover
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74. Cidal mechanism of Aminoglycosides
• Binds to ribosome  misreading of mRNA –
termination of translation
• Allow to produce aberrant proteins and inserted in the
Cell membrane  further aminoglycoside enters --
energy-dependent phase II
 Progressive disruption of the cell envelope
74

75. • Amikacin
• Nitilmaycin
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sensitive for most Aminoglycoside resistant

76. Adverse effects
• Ototoxicity
• Nephrotoxicity
• Neuromuscular paralysis
• Allergic reactions
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CI During pregnancy: late in pregnancy may result in accumulation of drug
in fetal plasma and amniotic fluid.

77. Why toxicity of Aminoglycosides
• Persistent concentration of Aminoglycosides in the fluids of ear and slowly
removed from this site  vestibular or the cochlear toxicity
Nephrotoxicity
• Aminoglycosides attain high concentration in the renal cortex (proximal
tubules) and toxicity
• Aminoglycosides also interfere with the production of PGs in the kidney
How Neuromuscular blockade??
• Antagonizing Ca2+ used for vesicular fusion of ACH to nerve terminal --
interfere with ACH release
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78. Tetracyclines
• MOA: bind on 30S ribosomal subunit and blocks the binding of
aminoacyl-tRNA to the acceptor site on the mRNA-ribosome
complex
• Bacteriostatic antibiotics effective against a wide variety of
organisms, including gram+ve and gram-ve bacteria, protozoa
• Are adequately absorbed after oral ingestion
• Dairy products or other substances that contain divalent and trivalent
cations (Ca, Mg and Al antacids or iron supplements) decreases
absorption
• Main Resistance to tetracyclines is an efflux pump
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79. Mechanism of resistance
• Impaired influx or increased efflux by an active transport
protein pump;
• Ribosome protection due to production of proteins that
interfere with tetracycline binding to the ribosome
• Enzymatic inactivation.
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Efflux pump-expressing Gram-negative species are resistant to the older
tetracyclines, doxycycline, and minocycline. They are susceptible, however, to
tigecycline, which is not a substrate of these pump

80. Pharmacokinetics
• Tigecycline is poorly absorbed orally and must be
administered intravenously.
• Tetracycline and demeclocycline should be administered on an
empty stomach
• While doxycycline and minocycline absorption is not impaired
by food.
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81. Indications
1. Chlamydial infections
• Conjunctivitis
• Trachoma
• Acute epididymitis
2. Ricketisial infections
• Typhoid fever
3. Others
• Relapsing fever
• Cholera
• Arthritis
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82. Adverse effects
• Effects on calcified tissues-- in bone and teeth
• Phototoxicity-- demeclocycline
• Contraindications: The tetracyclines should not be used
• In pregnant
• Breast-feeding women
• In children less than 8 years of age.
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83. Macrolides
• Contain macrocyclic lactone ring
• Why are they called macrolides?  Because they are very big
molecules.
• Erythromycin is the oldest member of the family.
• All of the newer macrolides azithromycin, clarithromycin,
dirithromycin, and troleandomycin
• MOA: Bind on 50S Ribosomal subunit
– Inhibiting translocation steps of protein synthesis  interfere
transpeptidation) 83
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84. Macrolides …
• Erythromycin-- Effective against many of the same
organisms as penicillin G.
• Therefore, it may be used in patients with penicillin allergy.
• Clarithromycin- similar to erythromycin, but it is also
effective against Haemophilus influenzae.
• Azithromycin-- less active against streptococci and
staphylococci than erythromycin, azithromycin is far more
active against respiratory infections due to H. influenzae
5/19/2023 By A.D 84

85. Ketolides (telithromycin)
• Used to treat MDR S. pneumoniae
ketolides neutralize the common macrolide resistance mechanisms
 3-keto function converts a methylase-inducing macrolide into a non-inducing
ketolide…also prevents drug efflux
 The carbamate substitution at C11-C12 enhances binding to the ribosomal
target site, even when the site is methylated
• Inducible and constitutive methylase-producing strains of S. pneumoniae are
therefore telithromycin-susceptible.
• However, constitutive methylase-producing strains of S. aureus and S.
pyogenes are telithromycin-resistant because the strength of the ketolide
interaction with the fully methylated ribosomal binding site is insufficient to
overcome resistance
85

86. Chloramphenicol
• Halt protein synthesis by blocking peptidyl transferase
• Broad-spectrum antibiotic, is restricted to life-
threatening infections
• Primarily bacteriostatic
• Use: Typhoid fever, Streptococcus pneumoniae
• S/E Gray baby syndrome, Hemolytic anemia
• C/I for child less than 3 months
86
5/19/2023 By A.D

87. • Why Chloramphenicol inhibit mitochondrial protein synthesis
in mammalian cells ?
• Because mitochondrial ribosomes resembles to bacterial
ribosomes (both are 70S) more than they do the 80S
cytoplasmic ribosomes of mammalian cells
• This is the possible Mechanism of toxicity
5/19/2023 By A.D 87

88. Spectinomycin
• Selectively inhibits protein synthesis in gram-negative bacteria
by binding to and affecting the 30S ribosomal subunit.
• It does not cause misreading of messenger RNA and is not
bactericidal.
• Resistance develops frequently.
• Active against a number of gram-negative bacteria
• Preferred for gonorrhea in patients who cannot tolerate preferred
drugs
• Spectinomycin is administered by IM injection
5/19/2023 88
By A.D

89. Clindamycin
• Chlorine-substituted derivative of lincomycin, an antibiotic that is
elaborated by Streptomyces lincolnensis.
• MOA: like erythromycin, inhibits protein synthesis by interfering with the
formation of initiation complexes and with aminoacyl translocation
reactions.
– Binding site for clindamycin is the 50S subunit
• Streptococci, staphylococci, and pneumococci are inhibited by clindamycin
• Use: for skin and soft tissue infection caused by streptococci and
staphylococci
– It is primarily for anaerobic infections outside the CNS
• Side effect: promote severe antibiotic-associated pseudomembranous
colitis By A.D 89

90. Clinical Use
• Clindamycin is recommended for prophylaxis of endocarditis
in patients with specific valvular heart disease who are
undergoing certain dental procedures and Penicillin allergies.
• Clindamycin plus primaquine  for moderate to moderately
severe Pneumocystis jiroveci pneumonia in AIDS
• Combination with pyrimethamine for AIDS-related
toxoplasmosis of the brain
5/19/2023 By A.D 90

91. Oxazolidinone
Linezolid
• Active against Gram-positive organisms including staphylococci,
streptococci, enterococci, Gram-positive anaerobic cocci, and Gram-
positive rods such as corynebacteria, Nocardia sp, and
L.monocytogenes
• It is primarily a bacteriostatic agent but is bactericidal against
streptococci.
• It is also active against Mycobacterium tuberculosis.
• Linezolid is 100% bioavailable after oral administration
5/19/2023 By A.D 91

92. Mechanism of action
• Linezolid Preventing formation of the ribosome complex that
initiates protein synthesis.
• Its unique binding site, located on 23S ribosomal RNA of the
50S subunit, results in no cross-resistance with other drug
classes.
• Resistance is caused by mutation of the linezolid binding site
on 23S ribosomal RNA
5/19/2023 By A.D 92

93. Clinical Uses
• Linezolid is approved for
 Vancomycin-resistant E faecium infections,
 Health care–associated pneumonia,
 Community-acquired pneumonia, and
 Both complicated and uncomplicated skin and soft tissue
infections caused by susceptible G+ve bacteria.
• Off-label uses  multidrugresistant tuberculosis and Nocardia
infections.
5/19/2023 By A.D 93

94. Antimetabolite drugs
Sulphonamides and Trimethoprim
• Inhibit bacterial growth by interfering with microbial folic acid
synthesis
• Inhibit competitively the incorporation of PABA into
tetrahydropteroate
• Cotrimoxazole =sulphamethoxazol + Trimethoprim
94
5/19/2023 By A.D
Inhibit both Gram-positive bacteria, such as Staphylococcus sp and Gram-negative
enteric bacteria
Pseudomonas aeruginosa is intrinsically resistant

95. 95
5/19/2023 By A.D

96. Therapeutic uses
 UTI Caused by E.coli, Klebsiella, Enterobacter, P.mirabilis
 PCP: Treatment of choice
 Drug of choice for shigellosis
 Alternative for typhoid fever
 HIV patients with PCP
96
5/19/2023 By A.D
Rickettsiae are not inhibited by sulfonamides but are instead stimulated in their growth
Rickettsia lack this enzyme target, and thus possess a natural resistance to the antibiotic.
As tetrahydrofolate is an essential compound, it is believed that Rickettsia possess an
alternative enzymatic process which is not susceptible to sulfonamides, or the bacteria
simply acquire the compound (or its immediate precursors) from their environment.

97. Sulfasalazine
• It is Non-absorbable
• Widely used in ulcerative colitis, enteritis, and other inflammatory
bowel disease. How??
5/19/2023 By A.D 97
It metabolizes by intestinal bacteria into two compounds:
• 5-aminosalicylic acid (5-ASA) and sulfapyridine
• 5-ASA  reducing inflammation by inhibiting
prostaglandin synthesis & inflammatory cells
• Sulfapyridine  responsible for adverse effects.

98. Cont…
Sulfacetamide
• Ophthalmic solution or ointment is effective in
the treatment of bacterial conjunctivitis and as
adjunctive therapy for trachoma.
5/19/2023 By A.D 98

99. Adverse effect
• Hypersensitivity reactions
• Hemolytic anemia
• Kernicterus: by displacing bilirubin from
plasma protein  crosses the BBB
 Not given in 2 months age
99
5/19/2023 By A.D

100. DNA synthesis inhibitors
Fluoroquinolones
• Block DNA synthesis
 By inhibiting bacterial topoisomerase II (DNA gyrase)
and topoisomerase IV.
• All the fluoroquinolones are bactericidal
• Active against broad spectrum of bacteria: mainly G-ve, some
G+ve and mycoplasma
• Well absorbed; food does not reduce absorption
i.e Ciprofloxacin, norfloxacin, levofloxacin 100
5/19/2023 By A.D

101. How bactericidal effect
• Gyrase – induce negative supercoiling  nick DNA ---transcription
done
• And also induce positive supercoiling after transcription  seal
• Up on FQs bind – inhibit nicking and sealing – damaged
• The bactericidal action results from digestion of DNA by
exonucleases whose production is signalled by the damaged DNA.
• In humans there is Top II which prevents positive supercoiling -
very low affinity for FQs-- the low toxicity to host cells
5/19/2023 By A.D 101

102. Indications
1. UTI: complicated and uncomplicated
2. GI infection and abdominal infection
 Diarrhea caused by shigella, salmonella, toxigenic E.coli
3. Sexually transmitted diseases
 N.gonorrhea
 C.trachomatis
 H. ducreyi
4. RTI
102
5/19/2023 By A.D
Trovafloxacin
Be reserved for treatment of life-threatening
infections because it causes Complete liver
failure

103. Urinary tract antiseptics
• Four urinary tract antiseptics are available
1. Nitrofurantoin
2. Methenamine
3. Nalidixic acid
4. Cinoxacin
5/19/2023 By A.D 103
These drugs are used
only for UTIs.
All four become concentrated in the urine, and are active against
the common urinary tract pathogens.

104. Nalidixic acid
• Earlier quinolones
• Did not achieve systemic antibacterial levels and were useful
only in the treatment of lower urinary tract infections.
• Active against most gram-negative urinary tract pathogens,
including E. coli, Klebsiella, Enterobacter, and Proteus species
• MAO: inhibits replication of bacterial DNA, thereby causing
DNA degradation and cell death.  target DNA gyrase
• Use: approved only for UTIs
5/19/2023 By A.D 104

105. Nitrofurantoin
• Broad-spectrum antimicrobial drug
• Bacteriostatic in low concentrations and bactericidal in high
concentrations.
MAO:
• It injures bacteria by damaging DNA.
– However, in order to damage DNA, the drug must first be converted to a
reactive form
– Selectively toxic to bacteria because, unlike mammalian cells, bacteria
possess relatively high levels of the enzyme that activates the drug
• It can cause serious adverse effects.
5/19/2023 By A.D 105

106. Metronidazole
• Used for protozoal and obligate anaerobic bacteria infections
– Lethal to anaerobic organisms only. WHY??
• To exert bactericidal effects, it must first be taken up by cells and then
converted into its active form (reduced);  Only anaerobes can perform
the conversion.
• The active form interacts with DNA to cause strand breakage and loss of
helical structure,
 Effects that result in inhibition of nucleic acid synthesis and, ultimately, cell death.
• Since aerobic bacteria are unable to activate metronidazole, they are
insensitive to the drug.
106

107. Drugs for tuberculosis
Drugs for tuberculosis
• Treating mycobacterial infection present problems:
 They are slow growing microbes
 Can also be dormant; resistant to many drugs
 Lipid rich cell wall is impermeable to many agent
 A substantial portion is intracellular
• Needs prolonged treatment
• Drug toxicity and poor patient compliance
• High risk of emergency of resistant bacteria
107
5/19/2023 By A.D

108. Treatment
• First line drugs: superior efficacy & acceptable
toxicity
• Isoniazid (H)
• Rifampin (R)
• Pyrazinamide (Z)
• Ethambutol (E)
108
5/19/2023 By A.D

109. Cont.
• Second line drugs: less efficacy, greater toxicity or
both.
• Used in combination with first line drugs to treat
disseminated TB and TB caused by resistant organism
• Streptomycin (S)
• Kanamycin
• Capreomycin
• Ethionamide
• Cycloserine
109
5/19/2023 By A.D

110. Isoniazid (H)
• Isoniazid inhibits synthesis of mycolic acids, which are essential
components of mycobacterial cell walls.
• It is a prodrug that is activated by KatG, the mycobacterial catalase-
peroxidase.  deletion of the katG gene leads resistance
• Readily absorbed from the gastrointestinal tract
• Reduce the peak concentration when taken with a fatty meal.
• Metabolism of isoniazid, especially acetylation by liver N-acetyltransferase
• Causes Neuropathy due to a relative pyridoxine deficiency
• Pyridoxine supplementation is recommended for all pregnant or
breastfeeding women taking isoniazid
5/19/2023 110
By A.D

111. Rifampin (R)
• Semisynthetic antibiotic produced by Streptomyces
mediterranei.
• It is active against gram+ve and gram-ve cocci, some
enteric bacteria, and mycobacteria
• Effective against S. aureus, N. meningitidis, H.
influenzae, E. coli, Klebsiella, Pseudomonas.
5/19/2023 111
By A.D

112. Rifampin
• MOA: interrupts RNA synthesis by binding to β
subunit of mycobacterial DNA-dependent RNA
polymerase and blocking its polymerizing function.
• Selective toxicity on bacteria  that mammalian
RNA polymerase does not avidly bind rifampin.
5/19/2023 112
By A.D

113. Rifampin…
• Other uses of rifampin
 Leprosy
 Prophylaxis of Meningococcal and H. influenzae
meningitis
• Increases several CYP450 isoenzymes has many drug
interaction
• Route of excretion liver
• Adverse effects
– Hepatotoxicity
5/19/2023 113
By A.D

114. Pyrazinamide (Z)
• The mechanism of action of Z is not well established
But probably
– Disrupting mycobacterial cell membrane and transport functions
– Inhibiting mycolic acid synthesis
– Interacting with a different fatty acid synthase
• A/E: Hepatotoxicity is the most important dose related
adverse effect
5/19/2023 114
By A.D

115. Ethambutol (E)
• The mechanism of action is not fully understood
– However, proposed to be involved in arabinogalactan
synthesis thereby interfering with mycolic acid
incorporation in mycobacterial cell wall.
• Selectively tuberculostatic
• Fast multiplying bacilli are more susceptible
• Dose dependant A/E is loss of visual acuity, due to
optic neuritis
5/19/2023 115
By A.D

116. Phases of Chemotherapy
• There are two phases:
• The treatment of TB is 6-8 months
1. Intensive /initial/phase – for 2 month with direct observation
therapy – to cure the bacilli
• Rapid killing of actively growing bacilli
2. Continues phase – for 4 -6 months
– Eliminates bacilli that are still multiplying.
– Helps to avoid relapse after completion of treatment.
116
5/19/2023 By A.D

117. Rx
• New patients with pulmonary TB should
receive a regimen containing 6 months of
rifampicin: 2HRZE/4HR
117
5/19/2023 By A.D

118. Dose
• The fixed dose combination (FDC) medicines
available for adults and adolescents are:
• RHZE 150/75/400/275mg
• RHZ 150/75/400mg
• RH 150/75mg
• EH 400/150mg
118
5/19/2023 By A.D

119. 5/19/2023 119
By A.D

120. Non-tuberculous mycobacteria
• Agents such as macrolides, sulfonamides, and tetracyclines, which are not
active against M tuberculosis, may be effective for infections caused by
nontuberculous mycobacteria
• M avium complex (MAC) and M intracellulare
• Less susceptible than M tuberculosis to most antituberculous drugs
• Combination of drugs is needed
– Azithromycin/day OR clarithromycin BID PLUS ethambutol 15 mg/kg/d,
• Azithromycin and clarithromycin are the prophylactic drugs of choice for
preventing disseminated MAC in AIDS patients
5/19/2023 By A.D 120

121. Hansen’s disease/leprosy/
• Caused by slow growing bacteria called
Mycobacterium leprae
• Affects nerves, skin, eye and lining of nose
• Has been considered incurable in ages
– Due to availability of effective antileprotic drugs
now, it is entirely curable
– But deformities/defects already incurred may not
reverse.
5/19/2023 121
By A.D

122. Treatment
Objectives
• Cure leprosy by rapidly eliminating the bacilli
• Prevent the emergence of medicine resistance
• Prevent relapse
• Prevent disability
5/19/2023 122
By A.D

123. Treatment
Drugs
• Dapsone
• Clofazimine
• Rifampin
• Moxifloxacin
• Minocycline
• Clarithromycin
5/19/2023 123
• Treated with a combination of two or
more medicines in the form of Multi-
Medicine Therapy (MDT)
• MDT by combination of
 Rifampacin, Clofazimine and/or
Dapsone
Taken for at least 12 months
By A.D

124. Dapsone
• Chemically related to sulfonamides
• Has the same mechanism of action, i.e. inhibition of PABA
incorporation into folic acid by folate synthase
• Dapsone is active against certain protozoa as well.
– Combined with pyrimethamine, it was an alternative to
sulfadoxine-pyrimethamine for P. falciparum and Toxoplasma
gondii infections.
• C/I: severe anaemia (Hb < 7 g/dl) and G-6-PD deficiency
5/19/2023 124
Currently not used for malaria
By A.D

125. Clofazimine (Clo)
• Has leprostatic and antiinflammatory properties.
• Mechanisms of antileprotic action
– Interference with template function of DNA in M.leprae
– Alteration of membrane structure and its transport function.
– Disruption of mitochondrial electron transport chain.
• A/E: reddish-black discolouration of skin
• C/I: avoid during early pregnancy and liver or kidney problem
5/19/2023 125
By A.D

126. 126
5/19/2023 By A.D

127. Quiz -10%
1. What is chemotherapy ? 1pt
2. What is antibiotics ? 1pt
3. list the class of antibacterial agents based on their
mechanism 2 pt
4. Why Pen G is not administered via IV route? 1pt
5. Why Pen G is not administered via Oral route? 1 Pt
6. What is the specific mechanism of resistant of
Amoxacillin ? 1 pt

128. Cont…
7. Which one is beta lactamase inhibitor ? 1 Pt
A. Pen G C. Cephalosporins
B.Clavulanic acid D. Cloxacillin
8. Which one is Natural Pen --- 1pt
A. Ampicillin C Benzantine Pen
B.Claxacillin D. Vancomycin
9. Which one is effective against S.aureus 1Pt
A. Ampicillin C Cloxacillin
B. Pen V D. Amoxacillin

129. Antiviral Agent
Non-HIV viral infections
• Efforts to develop safe and effective antiviral drugs have been less
successful
• The reason for lack of success is due to the process of viral replication
– Viruses are obligate intracellular parasites that use the biochemical machinery
of host cells to reproduce
– It is difficult to suppress viral replication without doing significant harm to the
host.
• The antiviral drugs used clinically act by suppressing biochemical
processes unique to viral reproduction.
5/19/2023 By A.D 129

130. Life cycle of virus
• First step process is facilitated by polypeptide binding sites on
the envelope or capsid, interacting with receptors on the host
cell
• Receptors’ are normal membrane constituents:
– E.g. receptors for cytokines, neurotransmitters or hormones, ion channels,
integral membrane glycoproteins
• Some host cell receptors utilized by particular viruses
• Following attachment, receptor–virus complex enters the cell (often by
receptor-mediated endocytosis)  then virus uncoated by host cell enzymes
5/19/2023 By A.D 130

131. Life cycle…
• Virus then uses the host cell’s machinery to synthesize nucleic acids and proteins
– But differs between DNA and RNA viruses.
• Replication in DNA viruses
• Viral DNA enters the host cell nucleus, where transcription into mRNA occurs
catalyzed by the host cell RNA polymerase
• Then Translation to virus-specific proteins.
• These proteins are enzymes may be used to/as
 Synthesize more viral DNA
 Structural proteins comprising the viral coat and envelope
• After assembly of coat proteins around the viral DNA complete virions are
released by budding or after host cell lysis
5/19/2023 By A.D 131

132. Replication in RNA viruses
• Enzymes within the virion synthesize its mRNA from the viral
RNA template
• Then Translated by the host cell into various enzymes,
including RNA polymerase
• Also into structural proteins of the virion
• Then Assembly and release
5/19/2023 By A.D 132

133. Replication in retroviruses
• Virion in retroviruses contrains a reverse transcriptase enzyme (virus
RNA-dependent DNA polymerase)
– makes a DNA copy of the viral RNA.
• This DNA copy is integrated into the genome of the host cell
– Then it is termed a provirus.
• Provirus DNA is transcribed into both new viral genome RNA as well
as mRNA for translation in the host into viral proteins,
• The completed viruses are released by budding.
• Many retroviruses can replicate without killing the host cell
5/19/2023 By A.D 133

134. Drug targets in viral infection
5/19/2023 By A.D 134
Interferon alfas are speculated to have multiple sites of action

135. Herpes simplex viruses (HSV) and varicella zoster
virus (VZV)
• Members of the herpesvirus group
• HSV causes infection of the genitalia, mouth and face, and
other sites.
• VZV is the cause of varicella (chickenpox) and herpes zoster
(shingles)
a painful condition resulting from reactivation of VZV that had been
dormant within sensory nerve roots.
• Acyclovir, Valacyclovir and Famciclovir
– Have similar mechanisms of action
5/19/2023 By A.D 135

136. Acyclovir
• The agent of first choice for most infections caused by HSV and VZV.
• The drug can be administered topically, orally, and IV
MOA
• Suppresses synthesis of viral DNA
• Acyclovir must first undergo activation
– conversion of acyclovir to acyclo-GMP by thymidine kinase  then acyclo-GTP,
• Acyclo-GTP suppresses DNA synthesis by
1. Inhibiting viral DNA polymerase and
2. Incorporated into the growing strand of viral DNA, which blocks further strand growth
• The selectivity of acyclovir is based on the ability of viruses to activate the
drug.
136
Cytomegalovirus: inherently resistant to the drug
 because acyclovir is a poor substrate for the form of thymidine kinase
Mechanism of Resistance
 Decreased production of thymidine kinase

137. • Valacyclovir
• prodrug form of acyclovir
• Famciclovir  prodrug of penciclovir.
5/19/2023 By A.D 137

138. Drugs for Cytomegalovirus (CMV)
Ganciclovir
• Active against herpesviruses, including CMV
• Serious adverse effects, especially granulocytopenia and
thrombocytopenia
MOA:
• It is Converted to its active form, ganciclovir triphosphate, inside infected cells
• It suppresses replication of viral DNA by
 Inhibiting viral DNA polymerase and
 Undergoing incorporation into the growing DNA chain,
By A.D 138
Foscarnet & Cidofovir Also other agents for CMV
Foscarnet is active against all known herpesviruses

139. Antiretroviral Agents
• Human immunodeficiency virus (HIV), the microbe that causes
acquired immunodeficiency syndrome (AIDS).
• HIV promotes immunodeficiency by killing CD4 T lymphocytes
(CD4 T cells) which are key components of the immune
system
• As a result of HIV-induced immunodeficiency patients are at
risk of opportunistic infections and certain neoplasms.
• Retroviruses lack the machinery needed for self replication, and
hence are obligate intracellular parasites
5/19/2023 By A.D 139

140. 1. Binding of gp120 to CD4 and co-receptor on the cell surface
2. Fusion of the viral envelope with the cell membrane
3. Release and disassembly of the viral core in the cytoplasm
4. Reverse transcription (Reverse transcriptase enzyme translates HIV’s single stranded RNA into a provirus made of
double stranded DNA)
5. Viral DNA moves into cell nucleus
6. Viral DNA is integrated (by Integrase enzyme) into host genome to form HIV provirus
7. HIV provirus DNA is transcribed back to both viral genomic RNA and viral mRNA, the latter which is translated to
HIV polyproteins.
8. The RNA virus and polyproteins are assembled beneath the cell membrane
9. The assembled package becomes enveloped in the host cell membrane as it buds off to form an HIV virion.
10. Further assembly and maturation occurs outside the cell by the protease enzyme, rendering the HIV virion
infectious.
140
Steps in HIV replication are illustrated in the diagram

141. 141

142. Mechanism and classification of antiretroviral drugs
1. Inhibition of Binding of GP120 to CD4 receptor by
“neutralizing antibodies”
2. Fusion Inhibition “Pentafuside T20”
3. Reverse Transcriptase Inhibition “NRTIs & NNRTIs”
4. Protease Inhibition “Protease Inhibitors”
5. Intergrase Inhibition
142

143. NRTIs
Zidovudine (ZDV)
• Prototype drug in the group
• Analog of thymidine, a naturally occurring nucleoside
MOA
• Inhibits HIV replication by suppressing synthesis of viral DNA.
• To do this, ZDV must first undergo intracellular conversion to its active form
triphosphate (ZTP)
• ZTP, the drug acts as a substrate for reverse transcriptase  it prevents reverse
transcriptase from adding more bases for growth of the strand
• ZTP Also binding to the active site of reverse transcriptase
• S/E: Severe anemia and neutropenia are the principal toxic effects
5/19/2023 By A.D 143

144. Didanosine
• Dideoxyinosine (ddI), is an analog of inosine
• Its active form is dideoxyadenosine triphosphate (ddATP)
– Causing premature termination of the growing DNA strand
– Its oral absorption affected by gastric acidity  formed enteric-coated
S/E
• Pancreatitis
• Lactic Acidosis  lipodystrophy
• peripheral neuropathy
5/19/2023 By A.D 144

145. Zalcitabine
• Also known as dideoxycytidine (ddC), is an analog of cytidine
• Undergoes conversion to its active form (ddC triphosphate)
within host cells
• Owing to a high incidence of peripheral neuropathy
 withdraw from the market
5/19/2023 By A.D 145

146. Stavudine
• Didehydrodoxythymidine (d4T) is an analog of thymidine
• It is converted to its active form, stavudine triphosphate
S/E
• Peripheral Neuropathy
• Pancreatitis
• Lactic Acidosis with Hepatic Steatosis lipodystrophy,
5/19/2023 By A.D 146

147. Lamivudine
• Known as dideoxy 3′-thiacytidine (3TC), is an analog of cytidine
• Uptake by cells, the drug is converted to its active form, lamivudine
triphosphate
• Approved for HIV infection and also for hepatitis B
S/E
• Lamivudine is the best tolerated of all.
• Small risk of potentially fatal lactic acidosis
• Common headache, diarrhea, nausea, and rash
5/19/2023 By A.D 147

148. Tenofovir disoproxil fumarate
• It is Nucleotide reverse transcriptase inhibitor not a
nucleoside reverse transcriptase inhibitor
• TDF undergoes conversion to tenofovir  then tenofovir
diphosphate, its active form
• Small risk of potentially fatal lactic acidosis with hepatic
steatosis
5/19/2023 By A.D 148

149. Abacavir
• Known as ABC, is an analog of guanine
• Taken up by host cells, where it undergoes conversion to its active
form, carbovir triphosphate
• Has good oral bioavailability
• It is converted to inactive metabolites by alcohol dehydrogenase.
– So concurrent alcohol use may increase ABCserum levels
Adverse Effects
• Hypersensitivity Reactions
5/19/2023
By A.D
149

150. Emtricitabine
• Fluorinated derivative of lamivudine
• Like lamivudine, emtricitabine is active against HIV and
hepatitis B virus (HBV)
• Following uptake by cells, emtricitabine is converted to
emtricitabine triphosphate, its active form
S/E
• Well tolerated
• Common headache, diarrhea, nausea, and rash
5/19/2023 By A.D 150

151. NNRTIs
• Differ from the NRTIs in structure and mechanism of action
• Not structurally analogous to naturally occurring nucleosides.
MOA
• They are non-competitive inhibitors
• Allosteric inhibition of RNA- and DNA-dependent DNA polymerase activity.
• NNRTIs binds directly to the active center of reverse transcriptase, and
thereby cause direct inhibition
• NNRTIs are active as it is  no activation process required
• It does not inhibit reverse transcriptase of HIV-2.
• Have high cross-resistnce
5/19/2023 By A.D 151

152. Cont..
• As a class, NNRTI agents tend to be associated with varying
levels of gastrointestinal intolerance and skin rash
• All NNRTI agents are substrates for CYP3A4 and can act as
 Inducers (nevirapine)
 Inhibitors (delavirdine), or
 Mixed inducers and inhibitors (efavirenz, etravirine)
5/19/2023 By A.D 152

153. Efavirenz
• The drug is effective and, because of its long half-life, can be
administered once a day
• Increased metabolism of two protease inhibitors—saquinavir
and indinavir is of particular concern
S/E
• Most common are dizziness, insomnia, impaired
consciousness, drowsiness, vivid dreams, and nightmares
5/19/2023 By A.D 153

154. Nevirapine
• Binds directly to HIV reverse transcriptase, causing
noncompetitive inhibition of the enzyme.
• Nevirapine is selective for HIV-1.
• It does not affect HIV-2, and does not inhibit human
DNA polymerase
• Well absorbed (over 90%)
• The most common adverse effect is rash,
5/19/2023 By A.D 154

155. Delavirdine
• similar to efavirenz in actions and uses
5/19/2023 By A.D 155

156. Protease inhibitors (PIs)
• PIs were generally well tolerated, although they did cause GI
disturbances
• Widespread use of these drugs has revealed additional side effects
– Fat maldistribution, hyperglycemia and diabetes
• All of the PIs can inhibit cytochrome P450
• Ritonavir common PI to boost other Pis
• St. John's wort, an herbal supplement taken for depression, can
decrease levels of all PIs  by enzyme induction
• Garlic supplements can decrease levels of saquinavir,
5/19/2023 By A.D 156

157. Integrase inhibitor
Raltegravir & dolutegravir
• Binds integrase, a viral enzyme essential to the replication of
both HIV-1 and HIV-2.
• Interfering with the integration of reverse-transcribed HIV
DNA into the chromosomes of host cells
5/19/2023 By A.D 157

158. Fusion inhibitors
Enfuvirtide
• Synthetic 36-amino-acid peptide fusion inhibitor that blocks HIV entry into
the cell
• Binds to the gp41 subunit of the viral envelope glycoprotein
 Preventing the conformational changes required for the fusion of the viral and cellular
membranes
• Must be administered by subcutaneous
• Resistance to enfuvirtide can result from mutations in gp41
• Adverse effects are local injection site reactions
5/19/2023 By A.D 158

159. Entry inhibitors
Maraviroc
• It binds specifically and selectively to the host protein CCR5  one of
two chemokine receptors necessary for entrance of HIV into CD4+
cells
• Since maraviroc is active against HIV that uses the CCR5 co-receptor
exclusively, and not against HIV strains with CXCR4, dual or mixed
tropism
– Co-receptor tropism should be determined by specific testing before
maraviroc is started
5/19/2023 By A.D 159

160. Interferons
• Are host cytokines that exert complex antiviral,
immunomodulatory, and antiproliferative actions
Example
• Interferon alfa appears to function by induction of intracellular
signals following binding to specific cell membrane receptors
– Resulting in inhibition of viral penetration, translation, transcription,
protein processing, maturation, and release
5/19/2023 By A.D 160

161. 5/19/2023 By A.D 161

162. Fungal infection
• Fungi are eukaryotic cells
• Some fungi are parasitic, others are commensals
• Fungal infections can be:
 Systemic
 Superficial
• Drugs used for fungal infections are also classified:
 Systemic
 topical antifungal
162

163. Drugs of systemic mycoses
• Systemic mycoses can be subdivided into two
1. Opportunistic infections and
2. Nonopportunistic infections
• Opportunistic mycoses  candidiasis, aspergillosis,
cryptococcosis, and mucormycosis
 are seen primarily in debilitated or immunocompromised hosts
• In contrast, nonopportunistic infections can occur in any host
5/19/2023 By A.D 163

164. Systemic antifungal drugs
• Divided into four classes:
1. Polyene antibiotics
2. Azoles
3. Echinocandins,
4. Pyrimidine analogs
5/19/2023 By A.D 164

165. Polyene Antibiotic
• Amphotericin B, Nystatin,
• Known as polyene antibiotics,  so named because their
structures contain a series of conjugated double bonds
• Amphotericin B  an important but dangerous drug (Toxic)
is active against a broad spectrum of pathogenic fungi and a
drug of choice for most systemic mycoses
Amphoteric polyene macrolide
5/19/2023 By A.D 165

166. Amphotericin B
• Amphotericin B is available in two formulations
 Conventional formulation
 Lipid-based formulations
• The lipid-based formulations are as effective as the
conventional formulation and cause less toxicity
 but are much more expensive.
• Poorly absorbed from the gastrointestinal tract.
5/19/2023 By A.D 166

167. Amphotericin B
Mechanism of Action
• Binds to components of the fungal cell membrane, thereby
increasing permeability
• Amphotericin B binds to ergosterol in the plasma membranes of
sensitive fungal cells
– Ergosterol, a cell membrane sterol, in membrane of fungi
– whereas the predominant sterol of bacteria and human cells is
cholesterol
167

168. Amphotericin B..
• Amphotericin binds more strongly to ergosterol than it does to
cholesterol, and hence fungi are hurt more than human cell
– Binding to ergosterol and alters the permeability of the cell
by forming pores in the cell membrane
• The pores disrupt membrane function
– Allowing electrolytes (particularly potassium) and small
molecules to leak from the cell resulting in cell death.
• Its toxicity  Nephrotoxicity, hypokalemia, bone marrow
suppression
5/19/2023 By A.D 168

169. Nystatin
• Polyene antibiotic used only for candidiasis
• Nystatin can be administered orally and topically.
• There is no significant absorption from either
route
• It is not used parenterally due to systemic toxicity
5/19/2023 By A.D 169

170. Azoles
• Broad-spectrum antifungal drugs
• Lower toxicity and can be administered by mouth than
polynes.
• Inhibit hepatic P450enzymes
5/19/2023 By A.D 170
Itraconazole, ketoconazole, fluconazole, voriconazole,
and posaconazole

171. Pyrimidine Analog
Flucytocine
• Are antimetabolite
• Narrow antifungal spectrum
– Employed for serious infections caused by susceptible
strains of Candida and Cryptococcus neoformans
• Because of resistance is common, it is most
combined with amphotericin B.
5/19/2023 By A.D 171

172. MOA
• Taken up by fungal cells, which then convert it to 5-
fluorouracil (5-FU), a powerful antimetabolite
Disruption of fungal DNA and RNA synthesis.
• Relatively harmless to us because mammalian cells lack
cytosine deaminase, the enzyme that converts
flucytosine to 5-FU.
5/19/2023 By A.D 172

173. Echinocandins
• Newest class of antifungal drugs
• Disrupt the fungal cell wall.
• Cannot be dosed orally,
• Narrow spectrum  limited to aspergillus and candida
species
5/19/2023 By A.D 173
Caspofungin, micafungin, and anidulafungin.

174. Heterocyclic benzofuran
Griseofulvin
• Fungistatic for most dermatophytes, including
Epidermophyton, Trichophyton, Microsporum
• But not against Candida and other fungi causing deep
mycosis.
• Inactive against systemic mycoses
5/19/2023 By A.D 174
Contraindicated in pregnancy and patients

175. Griseofulvin
MOA:
• Griseofulvin interferes with mitosis
– By binding to components of microtubules, the structures that
form the mitotic spindle.
• Deposited in the keratin precursor cells of skin, hair, and
nails
• Absorption from GIT is irregular because of its very low
water solubility
– Its absorption improved by taking it with fats
5/19/2023 By A.D 175

176. Allylamine
Terbinafine
• Inhibits squalene epoxidase with resultant inhibition
of ergosterol synthesis
• Highly active against dermatophytes, and less active
against Candida
5/19/2023 By A.D 176

177. Topical antifungals
• Useful for superficial fungal infection
• Not effective for fungal infections of the hair,
nail and subcutaneous tissues
177

178. Topical antifungals
• Indication for topical use are:-
 Ring worm (dermatophyte infection)
 T. versicolor
 Mucocutaneous candidiasis
• Preparation for topical use
 Clotrimazole
 Ketoconazole
 Miconazole
 Teroconazole
178

179. 179
5/19/2023 By A.D