11.

CHEMOTHERAPEUTICDRUGS

Antimicrobials
Antibacterials
Antifungals
Antivirals
Antiprotozoals
Antihelminthes?

Chemotherapy
Antineoplastics 1
Use of Anti-infective Agents
 Prophylactic therapy

 Empiric therapy

 Definitive therapy

Chemotherapy 2
 Antibacterial Agents
• Can be:
Narrow spectrum: INH, Cloxacillin,
Naldixic acid(quinolone), Pen-G
Broad spectrum:
spectrum CAF, TTCs, Rifamycins, FQs
 Bactericidal:
All cell wall synthesis inhibitors
Aminoglycosides
Rifamycins (Rifampicin/rifampin)
Fluoroquinolones
Metronidazole
Chemotherapy 3
 Antibacterial Agents . . .
 Bacteriostatic:

 Tetracyclines

 Macrolides

 Amphenicols

 Lincosamides

 Aminocyclitoles,
Chemotherapy 4
 Antibiotics…
Mechanisms of Antibacterial Actions
 Inhibit synthesis of cell wall
– Penicillins, Cephalosporins, Carbapens, Monobactams,
Cycloserine, poly peptides (Vancomycin, Bacitracin)
 Increase cell membrane permeability
– Polyene antibiotics, Polymixins.
 Inhibit protein synthesis
– Aminoglycosides, Tetracyclines, Macrolides, Amphenicols.

 Inhibit nucleic acid synthesis

– Rifamycins, Fluoroquinolones.
 Antimetabolites: Sulphonamides, Trimethoprim.
Chemotherapy 5
 Antibiotics…
• Drug resistance:
– unresponsiveness of microrganism to
antimicrobial agents
Can be innate/acquired

Chemotherapy 6
 Antibiotics…
Origin of Drug Resistance
 Chromosomal mutation & selection
 Acquisition of chromosomal or extra
chromosomal material
 Conjugation: sexual reproduction
 Transduction: phages
 Transformation: taking genetic
material from env’t or dead bacteria

Chemotherapy 7
Mechanisms of Bacterial Resistance
 Destruction of the drug by the microorganism.
– -lactamase inactivates penicillins.
 Development of altered drug receptor
– Aminoglycosides, Erythromycin, Penicillin.
 Decreased drug entry/cease active uptake:
Tetracycline
 Development of alternate metabolic pathway
– Sulphonamides
• Active efflux pumps: removing the antibiotic from
its site of action before it can act
Chemotherapy 8
Chemotherapy 9
Delaying the Emergence of Resistance

 Antimicrobials should be employed only

when actually needed.
 Narrow spectrum agents should be
employed whenever possible.
 Newer antibiotics should be reserved.

Chemotherapy 10
Systematic Approach for Selection of
Antimicrobials
 Confirm the presence of infection
– Careful history & physical examination
– Signs and symptoms
– Predisposing factors
 Identification of the pathogen
– Collection of infected material
– Stains
– Serologies
– Culture and sensitivity
 Host & Drug factors
Chemotherapy 11
Patient specific considerations
 Age: causative agents, contraindication.
 Disruption of host defenses(immunity):
 Compromised  cidal.
 Site of infection
 History of recent antimicrobial use
 Antimicrobial allergies
 Renal and/or hepatic function
 Concomitant administration of other medications
 Pregnant and nursing women
 Compliance

Chemotherapy 12
Drug-specific considerations
 Spectrum of activity,
 Effects on nontargeted microbial flora,
 Appropriate dose,
 Pharmacokinetic & Pharmacodynamic
properties,
 Adverse-effect & drug-interaction profile,
and
 Cost

Chemotherapy 13
Antimicrobial drug combinations
Indication
 Severe infection of unknown etiology
 Mixed infection
 Prevention of resistance
 Decreased toxicity
 Enhanced action [penicillin & aminoglycoside]
Disadvantages of antimicrobial combination
Increase risk of allergy
Antagonism of antimicrobial effect
Increase risk of super infection
Increased cost
Chemotherapy 14
 CELL WALL SYNTHESIS
INHIBITORS
B-LACTAMS
Penicillins
Cephalosporin
s
Carbapenems
Monobactams
Non B-Lactams
Chemotherapy 15
 B-LACTAMS

Chemotherapy 16
 PENICILLINS
MoA
 Inhibition of bacterial cell wall synthesis: inhibition of
transpeptidase.
transpeptidase
 Activation of autolysins: destruction of the existing
cell wall(by an enzyme produced by bacteria(:Gm+ cocci)
• Inactivates penicillin-binding protein, PBP
Bactericidal.

To be maximally effective, inhibitors of cell

wall synthesis require actively proliferating
microorganisms.
They have little or no effect on bacteria that
are not growing and dividing.
Chemotherapy 17
Chemotherapy 18
 NARROW SPECTRUM PENICILLINS
(penicillinase sensitive): Penicillin G, Pen.V
Active against:
 G+ve except penicillinase producing
staphylococci.
 G–ve cocci (N. menigitidis, N. gonorrhea).
 Spirochetes (T.pallidum, Borrelia, Leptospira).

Chemotherapy 19
Chemotherapy 20
 Therapeutic uses
 Drug of choice for:
– pneumonia or meningitis by Streptococcus pneumonia.
– Pharyngitis by streptococcus pyogenes.
– Infectious endocarditis by streptococcus viridians.
 Infection caused by G+ve bacilli:
– Gangrene by Cl. Perfringes.
– Tetanus by Cl. tetani.
– Anthrax by B. anthracis.
 First choice for meningitis by N. meningitides.
 Drug of choice for the treatment of syphilis.
 Prophylactic applications;
 Syphilis in sexual partners.
 Benzathine penicillin G monthly for life in
recurrent rheumatic fever.
fever
 Bacterial endocarditis.
endocarditis
Chemotherapy 21
Pharmacokinetics
 Penicillin G is available as salts [Na+, K+, Procaine,
Benzathine penicillin G].
 Penicillin G: orally ineffective due to the acid.
 Procaine & Benzathine salts are intermediate &
long acting respectively.
 Procaine & Benzathine salts absorbed from the
muscle slowly and referred to as repository form
of Pen G.
 Distributes well to most tissues; Inflammation
increases distribution into CSF, joints, and eye.
 Penicillin is eliminated by tubular secretion [90%].
 Excretion delayed by probenecid.
Chemotherapy 22
PHENOXYMETHYL PENICILLIN
[PENICILLIN V]
 Acid stable: given orally.

 Used in streptococcal pharyngitis,

prophylaxis of rheumatic fever.

Chemotherapy 23
PENICILLINASE RESISTANT
PENICILLINS
Cloxacillin, Dicloxacillin, Oxacillin, Methicillin, Nafcillin

 They have chains that protect the -lactam ring.

 Used against penicillinase producing strains of

staph.aureus & staph.epidermdis.
 Emergence of staphylococcal strains [methicillin
resistant]:

 Vancomycin is used
Chemotherapy 24
Methicillin
 Acid labile; allergic reaction; interstitial
nephritis.
 Due to its nephrotoxicity used only for drug
sensitivity testing.
Nafcillin
 Erratic & incomplete absorption from PO.
 Given IM or IV.
Isoxazolyl Penicillins
Oxacillin, Cloxacillin, Dicloxacillin
 Acid stable; orally & parenterally administered.
 Absorption affected by food.

Chemotherapy 25
 AMINOPENICILLINS
Ampicillin, Amoxicillin, Bacampicillin
 Antimicrobial spectrum as penicillin G; plus G-ve bacilli
[H.influenza, E.coli, Salmonella, Shigella].
 Ineffective against  lactamase producing bacteria.
 Ampicillin
Therapeutic use
 UTI, RTI
 Shigellosis [but not amoxicillin]
 Typhoid fever: less efficacious than ciprofloxacin
 Meningitis combined with 3rd gen. Cephalosporins.
Adverse effects: Diarrhea, Rashes
 Amoxicillin
– Oral absorption is better than ampicillin.
– Incidence of diarrhea is less than ampicillin.
– Less active against shigella.
 Bacampicillin: Prodrug of ampicillin.
Chemotherapy 26
Chemotherapy 27
 ANTIPSEUDUOMONAL PENICILLINS
Carboxypenicillins
 Carbenicillin
 Active against p.aeruginosa & Indole positive
proteus.
 Neither penicillinase resistant nor acid resistant.
 Ticarcillin
 2-4 times more potent against pseudomonas.
Ureidopenicillins:
 Piperacillin, Mezlocillin, Azlocillin
 Active against pseudomonas, Klebsiella
pneumoniae.

Chemotherapy 28
BETA-LACTAMASE INHIBITORS:
Clavulinic Acid, Sulbactam, Tazobactam

 Inhibits bacterial -lactamases.

 Most active against -lactamase produced

by: S. aureus, H.influenza, some
enterobacteriaceae, Bacteroid spp.

 Chromosomal -lactamases of Serratia spp,

Enterobacter spp, P. aeruginosa are not
inhibited.

Chemotherapy 29
 Amoxicillin-clavulinic acid (augmentin®)
 Available in 4:1 combination.
 250-750mg amoxicillin & 62.5-125mg clavulinic
acid.
Use:
 Skin infection: streptococci, staphylococci.
 Acute otitis media: H.infleunza
 Sinusitis, Lower RTI
 Diabetic foot infection: staphylococci, aerobic &
anaerobic G-ve.
 Ampicillin-Sulbactam (Unasym®)
 Combination is available 1:0.5
 Same spectrum of augmentin: used in mixed infection.
 Piperacillin-tozabactam (Zosyn®)
 Equivalent or superior to 3rd generation cephalosporin.
Chemotherapy 30
DRUG INTERACTION OF PENICILLINS:
Aminoglycosides: inactive precipitate is
formed.
Probenecid: inhibits the secretion of
penicillins by competing for active tubular
secretion via the organic acid transporter.

 Bacteriostatic antibiotics: due to antagonism.

 Ampicillin and oral contraceptives;
 Decreased enterohepatic circulation.

Chemotherapy 31
ADVERSE EFFECTS OF PENICILLINS
 Allergy;-including anaphylactic shock
 Diarrhea: Ampicillin
 Rash: Ampicillin
 Sodium overload, inhibition of platelet
function: Ticarcillin
 Antibiotic-associated colitis (Pseudo
membranous colitis): Ampicillin
 Seizures: patients with renal failure with
high doses
 Neurotoxic effects: due to GABA antagonis(high
dose of Iv)
Chemotherapy 32
 CEPHALOSPORINS
Pharmacodynamics:
 Inhibition of cell wall synthesis.
 Bactericidal

Chemotherapy 33
CLASSIFICATION

 Four generations PLUS advanced (5th Gen.)

 From 1st generation to 3rd generation

Increase activity against G-ve &

anaerobes.
Increase resistance against -lactamase.

Increase ability to reach CSF.

Chemotherapy 34
1st GENERATION CEPHALOSPORINS
 Relatively narrow spectrum (G+ve bacteria).
Selected 1st generation Cephalosporins;

Chemotherapy 35
 2nd GENERATION CEPHALOSPORINS
 True Cephalosporins: Cefaclor,
Cefamandole, Cefonicid, Cefuroxime,
Cefprozil, Cefpodoxime, Loracarbef &
Ceforanide.
 Have high activity against: H.infleunza,
N.meningitidis, N.gonorhoeae
 Cephamycins: Cefoxitin, Cefmetazole,
Cefotetan.
 Antibacterial against selected
enterobacteriaceae
Chemotherapy 36
3rd GENERATION CEPHALOSPORINS

Cefotaxime, Ceftriaxone, Ceftazidime,

Cefoperazone
 Less active than 1st generation against
G+ve cocci.
 More active against Enterobacteriaceae.

 Antipseudomonal activity from

Cefoperazone & Ceftazidime.
NB: CEFTAZIDIME and CEFOPERAZONE are the
only two drugs with useful activity against
P. aeruginosa
Chemotherapy 37
Ceftriaxone
 Most potent;t1/2=8hrsonce daily dose.
 High efficacy in bacterial meningitis, multiresistant
typhoid fever, complicated UTI, Abdominal sepsis,
Septicaemias.
Ceftazidime
 Excellent activity against G-ve including
p.aeruginosa.
 Penetrate CSF & txt of choice in meningitis due to
p.aeruginosa; given parenterally.
Cefoperazone
 Strong activity against pseudomonas; high PPB.
 Do not reliable penetrate into CSF.
 Indicated in severe urinary, respiratory, biliary
infection and septicaemia.
• Dose: t1/2: 2 hours &can be infused q 8–12 hours in a
dosage of 25–100 mg/kg/d.
Chemotherapy 38
4th Gen. Cephalosporins: Cefepime,
Cefpirome.

 Rapidly cross the outer membrane of G-ve.

 More resistant to hydrolysis [chromosomal

-lactamase: produced by enterobacter] &
lactamases that inactivate 3rd generation.

 Active against Enterobacteriaceae, P.

aeruginosa, H. influenza & Neisseria spp.

Chemotherapy 39
ADVANCED GENERATION: Ceftaroline
 Broad spectrum
 Administered IV as a Prodrug, Ceftaroline
fosamil.
 Active against MRSA.
 Used for the tXt of complicated skin &
skin structure infections and CAP.
 The unique structure allows Ceftaroline to
bind to PBP found with MRSA and
Streptococcus pneumoniae.

Chemotherapy 40
 In addition to its broad G+ve activity, it
also has similar G-ve activity to the 3rd
Gen(Ceftriaxone)
 Active against:
 P. aeruginosa,
 extended spectrum β-lactamase
(ESBL)-producing Enterobacteriaceae,
 Acinetobacter baumannii.
 The twice-daily dosing regimen also limits
use outside of an institutional setting.

Chemotherapy 41
Adverse effects of Cephalosporins
1. Allergic reactions
2. Antibiotic-associated colitis: super infection.
3. Bleeding: hypoprothrombinemia
(methylthioterazole/MTT containing group,3rd
generation).
4. Local effects: thrombophlebitis from IV
injection.
Drug interaction
 Probenecid
 Alcohol: Cephalosporins with MTT have disulfiram
like rxn.
 Drugs that promote bleeding.

Chemotherapy 42
 OTHER Β-LACTAM ANTIBIOTICS
I. CARBAPENEMS
- Imipenem, with Cilastatin (Primaxin); Meropenem
MOA: Inhibit bacterial cell wall synthesis
– -lactamase resistant
Imipenem (IV)
 Antimicrobial spectrum: G+ve and G-ve including P.
aeruginosa; & anaerobes.
 Distributed in CSF; metabolized in renal tubule by
dehydropeptidases which can be inhibited by cilastatin.
Adverse effect
– GIT: NVD in rapid IV infusion
– CNS: Seizure
– Hypersensitivity reaction
Therapeutic use
 Serious hospital acquired infection
 Treatment of mixed infections [aerobic & anaerobic].
Chemotherapy 43
II. MONOBACTAMS: Aztreonam.
MOA:
 Bind to PBP inhibit cell wall synthesis.
 Antimicrobial spectrum: narrow (G-ve aerobic
bacteria: H. Influenza, N. Meningitides, &
pseudomonas).
 -Lactamase resistant; no cross sensitivity with
other -lactam.
 Used as substitute to Aminoglycosides in UT,
lower RT, skin & soft tissue infection.

Chemotherapy 44
Other inhibitors of cell wall synthesis:
Cycloserine, Bacitracin, Vancomycin
VANCOMYCIN
MOA:
 Binding to peptidoglycan pentapeptide 
Transglycosylase inhibition  inhibition of
elongation of peptidoglycan & cross linking.
 Spectrum: against G+ve [staphylococcus aureus &
staph epidermidis including methicillin resistant,
& Cl.difficile].
 PKs: not absorbed orally; given IV except
antibiotic induced colitis.

Chemotherapy 45
 PROTEIN SYNTHESIS INHIBITORS
Aminoglycosides
Aminocyclitols
Tetracyclines
Macrolides
Amphenicols
Lincosamides
Streptogramins
Oxazolidinones
Chemotherapy 46
 Protein Synthesis

Simplified schematic of mRNA translation

Chemotherapy 47
 Protein synthesis inhibitors
• A protein synthesis inhibitor is a substance that stops
or slows the growth or proliferation of cells by
disrupting the processes that lead directly to the
generation of new proteins.
• While a broad interpretation of this definition could be
used to describe nearly any antibiotic, in practice, it
usually refers to substances that act at the ribosome
level (either the ribosome itself or the translation
factor), taking advantages of the major differences
between prokaryotic & eukaryotic ribosome structures.
• Toxins such as ricin also function via protein synthesis
inhibition. Ricin acts at the eukaryotic 60S.
• Examples: Neomycin, Geneticin, also called G418

Chemotherapy 48
 Mechanism
In general, protein synthesis inhibitors work
at different stages of 
prokaryotic mRNA translation into proteins,
like;
Initiation,
Elongation (including aminoacyl tRNA entry,
proofreading, peptidyl transfer, and 
ribosomal translocation) and
Termination

Chemotherapy 49
 AMINOGLYCOSIDES cidal
Includes: Streptomycin, Gentamycine, Kanamycin,
Amikacin, Tobramycin, Neomycin, Paramomycin

General properties:
 Composed of two or more amino sugars
connected by a glycoside linkage.
 At physiological pH, they are polycations.

 Are water soluble, stable in solution.

 Interact chemically with -lactam antibiotic.

Chemotherapy 50
MOA:
 Transport of aminoglycosides through outer membrane
by passive diffusion via porins; then they are actively
transported across the cell membrane. Low
extracellular pH & anaerobic conditions inhibit
transport by reducing the gradient
 The drug binds to 30s rRNA irreversibly 
• Interference with the initiation complex of peptide
formation;
• Misreading of mRNA, which causes incorporation of
incorrect amino acids into the peptide and results in a
non functional or toxic protein;
• Breakup of polysomes into non functional monosomes.

Chemotherapy 51
Antimicrobial spectrum
Aerobic, gram-negative organisms.
Pseudomonas, Klebsiella, E.coli, others.
Pharmacokinetics
 Absorbed very poorly from intact GIT [IM &
IV].
 Distribution limited to ECF;
Bind to renal tissue  nephrotoxicity.
Penetrate to perilymph & endolymph of inner
ear  ototoxicity.
Eliminated primarily by kidney.

Chemotherapy 52
 ONCE DAILY DOSING
 2-3 Equally divided doses (traditional).
 Once daily dosing may be preferred in certain
situations, since they have PAE & conc. dependent
killing
 Once daily dose;
 Efficacious as traditional multiple dose method.
 Lower but not eliminate: nephrotoxicity &
ototoxicity.
 Simple, less time consuming & cost effective.
 Does not worsen neuromuscular function.
 Exceptions: in pts with Enterococcal endocarditis;
further study in pediatrics.

Chemotherapy 53
Therapeutic uses
 Against G-ve enteric bacteria in bacterimia &
sepsis; TB.
 In combination with -lactam antibiotic to
increase coverage(G+ve) & synergism.

Chemotherapy 54
Chemotherapy 55
AMINOGLYCOSIDES…

Chemotherapy 56
Adverse Effects of Aminoglycosides
1. Ototoxicity
 Cochlear toxicity: tinnitus, high frequency
hearing loss.
– Neomycin, Kanamycin, Amikacin.
 Vestibular toxicity: vertigo, ataxia, loss of
balance.
– Streptomycin & Gentamycine.
2. Nephrotoxicity
 Injure cells of proximal renal tubule.
 Risk factors: older pts, renal disease, large
doses, frequent dosing interval, concomitant
drugs [Vancomycin, Frusemide, Clindamycin,
Piperacillin, Cephalothin, Foscarnet].

Chemotherapy 57
3. Neuromuscular blockade: rarely.
 Weakness of respiratory musculature.
 Risk is amplified in pts with tubocurarine,
succinylcholine.
 Aminoglycosides prevent internalization of Ca2+
in presynaptic axon  decrease release of
acetylcholine.

Chemotherapy 58
BACTERIOSTATIC INHIBITORS OF
PROTEIN SYNTHESIS
Aminocyclitols
Tetracyclines
Macrolides
Amphenicols
Lincosamides
Streptogramins
Chemotherapy
Oxazolidinones 59
 AMINOCYCLITOLS
Spectinomycin
 Structurally related to aminoglycosides.
 It lacks amino sugars & glycosidic bonds.
MOA: binds with 30s sub unit of rRNA.
 Active in vitro against many G+ve & G-ve organisms, but it is
used almost solely as an alternative treatment for drug-resistant
gonorrhea or gonorrhea in penicillin-allergic patients.
 The majority of gonococcal isolates are inhibited by 6 mcg/mL of
Spectinomycin.
 Strains of gonococci may be resistant to spectinomycin, but there
is no cross-resistance with other drugs used in gonorrhea.
 Spectinomycin is rapidly absorbed after IM injection.
 A single dose of 40 mg/kg up to a maximum of 2 g is given.
Side effects:
 Pain at the injection site &, occasionally, fever & nausea.
 Rarely nephrotoxicity & anemia.
Chemotherapy 60
 TETRACYCLINES
Includes: Oxytetracycline, Tetracycline,
Demeclocycline, Doxycycline, Minocycline.
Antimicrobial Spectrum: broad.
 G+ve & G-ve aerobic & anaerobic bacteria.
 Spirochetes, Mycoplasma, Rickettsia,
Chlamydia & some protozoa.

Chemotherapy 61
Chemotherapy 62
MOA:
 Enter microorganism by passive & active
transport.

Act by binding 30s ribosome reversibly  block

the binding of aminoacyl t-RNA on the mRNA-
ribosome complex.

This prevents addition of amino acids to the

growing peptide.

Chemotherapy 63
 Pharmacokinetics of Tetracyclines

Chemotherapy 64
Chemotherapy 65
 Adverse Effects of TTCs
 GI Irritation: oral therapy burning, cramps & NVD.
 Super infection
 Effect on bone & teeth;
 Yellow or brown discoloration of teeth.
 Suppression of long bone growth in infants.
Doxycycline bind less with Ca2+  less frequent
dental changes.
 Liver toxicity
 Kidney toxicity: in kidney impairment except
doxycycline.
 Photosensitization especially demeclocycline
 Vestibular reactions [vertigo, nausea & vomiting]
>100mg doses of doxycycline;
200-400mg of Minocycline.

Chemotherapy 66
 MACROLIDES  static
 Macro cyclic lactone ring to which deoxysugar is
attached.
 Includes: Erythromycin, Clarithromycin, Azithromycin.
MOA:

 Binding to 50s rRNA  inhibiting peptidyl

transfer, ribosomal translocation
(transpeptidation), premature dissociation of
peptidyl t-rRNA from the ribosome  inhibition
of protein synthesis
 Usually bacteriostatic, may be cidal @ high dose.

Chemotherapy 67
Erythromycin
Pharmacokinetics
Decreased by stomach acid  enteric
coating.
Stearate & esters: fairly acid resistant
 better absorbed.
Estolate salt best absorbed orally.
Administration: topical, PO, IM, IV
Excretion: Primarily bile & faces.

Chemotherapy 68
Chemotherapy 69
 Therapeutic uses

Chemotherapy 70
Chemotherapy 71
Adverse Effects of Erythromycin
 GI effects: NVD.
 Liver toxicity: estolate salts cause acute
cholestatic hepatitis due to hypersensitivity
reaction.
Drug Interaction
 Erythromycin metabolized to form inactive
complexes with CYP450  increase level of
Terfenadine or Astemizole.
 Increase bioavailability of digoxin by
interfering with its inactivation in gut flora.

Chemotherapy 72
Azithromycin & Clarithromycin
 Semisynthetic derivative of Erythromycin.
– Have better oral absorption.
– Longer t1/2.
– Fewer GI side effects.
 Are expensive.

Clarithromycin is similar with erythromycin with

respect to antibacterial activity & drug
interaction except:
– More active against M. avium complex.

– Also activity against M. leprae, H.pylori,

Toxoplasma gondii.
Chemotherapy 73
Azithromycin is similar to clarithromycin
except:
 Less active against staphylo-& strepto-
cocci.
 Slightly more active against H.
influenza.
 Highly active against Chlamydia.
 Long t1/2 [3days] permit once daily
dosing.
 Free of drug interaction.

Chemotherapy 74
Chemotherapy 75
 AMPHENICOLES
Chloramphenicol (CAPH)
MOA:
 Binds 50s rRNA of bacteria & mitochondria 
inhibiting peptidyl transferase (
peptidyl transfer step
transfer of elongation) steps of
protein synthesis.
 Bacteriostatic
 Antimicrobial spectrum: broad
– Both aerobic & anaerobic G+ve & G-ve.
– Rickettsia.

Chemotherapy 76
Chemotherapy 77
 ADRs of CAPH
1. GI disturbance: NVD.
2. Bone marrow disturbances.
Suppression of RBC production: dose related.
Hemolytic anemia: in G6PD deficiency.
Aplastic anaemia: idiosyncratic reaction.
3. Super infection: including oropharyngeal candidiasis.
4. Gray baby syndrome (vomiting, cyanosis, abdominal
distension, circulatory collapse & death).
Result from decreased conjugation & excretion.
Drug Interactions: CAF inhibits some of the hepatic mixed-function
oxidases &, thus, blocks the metabolism of drugs such as
warfarin and phenytoin, thereby elevating their concentrations
and potentiating their effects.
Chemotherapy 78
 DNA SYNTHESIS INHIBITORS
FLUOROQUINOLONES (FQs)  cidal
 Related chemically to Nalidixic acid.
 Active against broad spectrum of bacteria:
mainly G-ve, some G+ve & mycoplasma.
MOA:
 Block DNA replication by inhibiting
– Topoisomerase II (DNA gyrase); 1⁰ target in
G-ve bacteria  relaxation of super coiled
DNA, promoting DNA strand breakage. &
– Topoisomerase IV; 1⁰ target in G+ve
bacteria  impacts chromosomal stabilization
during cell division, thus interfering with the
separation of newly replicated DNA.
Chemotherapy 79
Antimicrobial Spectrum
 Norfloxacin is the least active of flouroquinolones
against G+ve and G-ve.
 Ciprofloxacin, Enoxacin, Lemofloxacin, Ofloxacin,
Pefloxacin, Levofloxacin, Moxifloxacin, Gemifloxacin, &
Gatifloxacin:
– Possess excellent activity against G-ve including
enterobacteriaceae, pseudomonas, haemophilus spp.,
Neisseria spp., Campylobacter.
– Possess moderate to good activity against G+ve:
methicillin susceptible strains of staph; streptococci
& enterococci tend to be less susceptible.
 Flouroquinolones also have activity against Mycoplasma
& Chlamdiae; Legionella spp. & Mycobacteria.

Chemotherapy 80
Pharmacokinetics
 Absorption
– Well absorbed, food does not reduce absorption.
 Distribution
– Vd is high.
– Concentration in prostate, kidney, bile, lung,
 Elimination
– Ofloxacin & lomefloxacin: predominantly by kidney.
– Pefloxacin, sparfloxacin, trovafloxacin: nonrenal
pathway.
– Most others have mixed excretion: renal & nonrenal.
Drug interaction
– With di or trivalent cations: cation-quinolone complex.
– Inhibit CYP1A2: increase serum methylxanthine.
– Can elevate levels of warfarin [PT time monitored].

Chemotherapy 81
Chemotherapy 82
 Therapeutic uses
 UTI: complicated & uncomplicated, prostatitis.
 GIT infection;
Diarrhea caused by shigella, salmonella,
toxigenic E.coli, campylobacter.
Peritonitis.
 STIs; N.gonorrhea, C.trachomatis, H.ducreyi.
 RTIs:
 RTI: H.influenzae, M.catarrhalis & Enteric G-ve.
 Atypical pneumonia:
 M.pneumoniae
 Exacerbation of chronic bronchitis.
 Skin & soft tissue infection.
 Others: mycobacterial(TB), for nontubercular
mycobacteria, typhoid fever.
Chemotherapy 83
Adverse effect
 GIT: NV & Abdominal discomfort.
 CNS: Head ache, dizziness, insomnia.
 Cartilage deterioration in immature animals:
not recommended in child 18yrs; & lactating
& pregnant woman.

Chemotherapy 84
 Antimetabolites  static
Sulphonamides & Pyrimidines
MOA:

Pteridine + PABA
Sulphonamides compete with
Dihydropteroate synthetase
PABA
Dihydropteroic acid
Dihydrofolate synthetase
Dihydrofolic acid
Dihydrofolate reductase TMP & Pyrimethamine
Tetrahydrofolic acid

Purines Pyrimidines

Chemotherapy
DNA RNA Proteins/Enzymes
85
 Classification of Sulphonamides
1.Systemic Sulphonamides;
– Short acting agents: Sulfacytine, sulfisoxazole &
Sulfamethizole .
– Intermediate acting: Sulfadiazine, Sulphamethoxale,
Sulfapyridine
– Long acting: sulfadoxine
2.Sulphonamide limited to GIT;
Succinylsulfathiazole & Sulfasalazine
3.Topical Sulphonamides:
Mafenide acetate
Silver sulfadiazine
Sulfacetamide

Chemotherapy 86
 Therapeutic uses
UTI: Sulfisoxazole: high solubility, achieve
effective concentration & less expensive.
Other uses;
1. Nocardiosis (nocardia-G+ve).
2. Trachoma (Sulfacetamide).
3. Sulphadiazine/Sulfadoxine + Pyrimethamine OR
(FANSIDAR®=Sulfadoxine + Pyrimethamine): to
treat toxoplasmosis.
4. Ulcerative colitis: sulfasalazine.

Chemotherapy 87
 Adverse effects
1. Hypersensitivity reactions: Sulphur content
 Mild [rash, fever, photosensitivity].
 Severe (Steven’s Johnson Syndrome): lesion
of skin & mucus membrane, fever, malaise &
toxemia.
2. Hematologic effect
 Hemolytic anemia[Glucose 6 phosphate dehydrogenase
deficiency].
 Agranulocytosis: leucopenia & thrombocytopenia.
3. Kernicterus: by displacing bilirubin from plasma
protein crosses the BBB; Not given in 2 months
age.
4. Renal damage: they form crystal urea.

Chemotherapy 88
 Antimetabolites  static
Sulphonamides & Pyrimidines
MOA:

Pteridine + PABA
Sulphonamides compete with
Dihydropteroate synthetase
PABA
Dihydropteroic acid
Dihydrofolate synthetase
Dihydrofolic acid
Dihydrofolate reductase TMP & Pyrimethamine
Tetrahydrofolic acid

Purines Pyrimidines

Chemotherapy
DNA RNA Proteins/Enzymes
89
 COTRIMOXAZOLE (TMP+SMX)
 Trimethoprim & Sulphamethoxazole.
 Shows synergism  Cidal
 Selected because of similarity in pharmacokinetics.
MOA: inhibition of two sequential steps.
Therapeutic Uses
 UTI: caused by E.coli, Klebsiella, Enterobacter,P.mirabilis.
 PCP: Txt of choice.
 Drug of choice for shigellosis.
 Other infections;
– Acute otitis media & chronic bronchitis
[H. infleunza, streptococcus pneumonia].
– Urethritis & pharyngitis due to penicillinase
producing N. gonorrhoe.
– Alternative to CAF for typhoid fever.
Chemotherapy 90
Pharmacokinetics
 TMP concentrates in the relatively acidic milieu
of prostate & vaginal fluids  effective.
 TMP (1part) & SMZ (5part).
Adverse effects
 Dermatologic
 GI: NV & stomatitis
 Hematologic:
– megaloblastic anemia; Leukopenia;
thrombocytopenia.
 HIV pts with PCP: drug induced fever, rashes,
diarrhea.
Chemotherapy 91
 Drugs For the RX of Tuberculosis &
Leprosy
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
agents.
– A substantial portion is intracellular;
Needs prolonged treatment.
Drug toxicity & poor patient compliance.
High risk of emergency of resistant
bacteria.
Chemotherapy 92
 The objective of therapy is: to eliminate
symptoms & prevent relapse.
 To accomplish this goal tXt must kill actively
dividing & resting mycobacteria.
 Since the response of mycobacterial infections to
chemotherapy is slow, tXt is prolonged.
 Combination of drugs are required to prevent the
emergence of resistance.
TB resistance can be:
 Mono drug resistance
 Multi drug resistance (MDR-TB)
 Extensively drug resistance (XDR-TB)
 Total drug resistance (TDR-TB India, Iran, Italy)

Chemotherapy 93
Individual Antituberculous Agents
 First-line agents (in order of preference):
 Superior efficacy & acceptable toxicity.
 Isoniazid: 300 mg/day
 Rifampin: 600 mg/d
 Pyrazinamide: 25 mg/kg/d
 Ethambutol: 15–25 mg/kg/d
 Streptomycin: 15 mg/kg/d
 Dosage: adult dose in normal renal function

Chemotherapy 94
 XDR= extensively drug-resistant TB

Definition

Resistance to at least rifampicin and isoniazid,

in addition to any fluoroquinolone, and to at
least one of the three following injectable
drugs used in anti-TB treatment:
capreomycin, kanamycin and amikacin.

Chemotherapy 95
Second-line agents: adult dose in normal renal function
Amikacin: 15 mg/kg/d
Aminosalicylic acid (PAS): 8–12 g/d
Capreomycin: 15 mg/kg/d
Ciprofloxacin: 1500 mg/d, divided
Clofazimine: 200 mg/d
Cycloserine: 500–1000 mg/d, divided
Ethionamide: 500–750 mg/d
Kanamycin:
Levofloxacin: 500 mg/d
Rifabutin: 300 mg/d OR
 150 mg/d if used concurrently with a protease inhibitor
Rifapentine: 600 mg once or twice weekly

Chemotherapy 96
 ISONIAZID (INH/Isonicotinic hydrazide)-H
MOA:
 H inhibits synthesis of mycolic acid, which is an
essential component of mycobacterial cell wall.
 H is a prodrug that is activated by KatG, the
mycobacterial catalase-peroxidase.
 The activated form of H forms a covalent
complex with an acyl carrier protein (AcpM) &
KasA, a beta-ketoacyl carrier protein
synthetase, which blocks mycolic acid synthesis
& kills the cell  cidal

Chemotherapy 97
Pharmacokinetics
 Well absorbed PO or IM.
 Distributed widely: CSF  20% of plasma conc.
Increased in meningeal inflammation.
 Metabolized by acetylation;
– Fast acetylation: hepatotoxicity
– Slow acetylation: peripheral neuropathy
 Acetylation status does not generally affect the
outcome with daily therapy.
Therapeutic Uses
1. Component of all TB chemotherapeutic regimens.
2. Alone is used to prevent TB.

Chemotherapy 98
Adverse effects
 Allergic reactions (fever, skin rashes)
 Direct toxicities
1. Drug induced hepatitis: high risk age, rifampin, alcohol.
2. Peripheral neuropathy;
– Due to relative pyridoxine deficiency
 Promotes excretion of pyridoxine
– Likely to occur in slow acetylators & pts with
predisposing factor [malnutrition, alcoholism, diabetes,
AIDS & Uremia].
 Reversed by administration of vitamin B6.
1. Other adverse effect  reversed by vitamin B6.
– Convulsion, optic neuritis, psychosis.
Drug interaction
– Reduces metabolism of phenytoin.
– Absorption of INH is impaired by Al(OH)3.
Chemotherapy 99
 RIFAMPICIN(R)
MOA: binds to the -subunit of bacterial DNA
dependent RNA polymerase  inhibits RNA

synthesis (transcription)  cidal

Pharmacokinetics
– Well absorbed; distributed throughout the
body.
– Excreted mainly through liver into bile.

Chemotherapy 100
Therapeutic uses
 Mycobacterial infection;
TB: cidal for intra & extracellular bacteria.
In TB prevention as an alternative to H.
Leprosy
Atypical mycobacteria.
 Prophylaxis in contacts of children with
H.influenzae type b disease(meningitis).
 In combination with other agents;
– To eradicate staphylococcal carriage.
– For Rx of serious staphylococcal infections;
Osteomyelitis
Prosthetic valve endocarditis.
Chemotherapy 101
Adverse effects
– Hepatitis
– Hypersensitivity reactions
Fever
Flushing
Pruritus
Thrombocytopenia
Interstitial nephritis
– Miscellaneous adverse reaction
Harmless orange color appearing in urine,
saliva, tears, sweat & soft contact lenses.
GI upset

Chemotherapy 102
 ETHAMBUTOL(E)
MOA:
 Inhibits mycobacterial arabinosyl transferases,
which are encoded by the embCAB operon.
 Arabinosyl transferases are involved in the
polymerization reaction of arabinoglycan, an
essential component of the mycobacterial cell wall
  bacteriostatic.

Chemotherapy 103
Therapeutic use: TB.
Adverse effects
– Retrobulbar neuritis (optic neuritis)
Loss of visual acuity & red-green color
blindness.
– GI intolerance.
– Hyperuricemia due to deceased uric acid
excretion.

Chemotherapy 104
 PYRAZINAMIDE(Z)
 Synthetic pyrazine analogue of nicotinamide.
 Converted to pyrazinoic acid, active form of drug.
 Largely Bacteriostatic, but can be cidal on actively
replicating mycobacteria.
MOA: the specific drug target is unknown
 Disrupts cell membrane metabolism & transport
functions  static
 Inhibit fatty acid synthase(FAS) I, which is
required to synthesise fatty acids.
 In acidic media pyrazinoic acid accumulated ->
disrupts membrane potential & interferes with
energy production necessary for survival of
M.tuberculosis at acidic site of infection.
Chemotherapy 105
Therapeutic use: for RX of TB only.
 Sterilizing agent in IP of therapy
 Allows total duration of therapy to be shortened
to 6 months
 M.bovis & M.leprae are innately resistant to
Pyrazinamide.
Adverse effects
 GI intolerance,
 Joint pains (arthralgia),
 The most hepatotoxic agent
 Hyperuricemia.

Chemotherapy 106
 ANTI-TB DRUGS
 Drugs available in FDC in Ethiopia:

ERHZ – 275/150/75/400 mg

RHZ – 150/75/400 mg

RH – 150/75 mg

EH – 400/150 mg
 TB medicines available as loose form are:
– Ethambutol 400mg,
– Isoniazid 300mg,
– Streptomycin sulphate vials 1gm.
Chemotherapy 107
 PHASES OF CHEMOTHERAPY
 There are two phases:
1. Intensive (initial) phase(IP)
 Consists of 4 or more drugs.
 Duration;
8 wks for new cases, and
12 wks for re-treatment cases.
 The drugs must be swallowed daily under DOT.
 Rapid killing of actively growing & semi dormant
bacilli.
 It renders the patient non infectious ( 2wks).
 Protects against the development of resistance.
Chemotherapy 108
2. Continuation phase
Immediately follows the intensive phase.

Consists of 2 or 3 drugs.

Duration is 4 – 6 months.

Except for re-treatment cases drugs must be

collected every month.
Eliminates bacilli that are still multiplying.

Reduces failures and relapses.

Chemotherapy 109
 1. New Patients
 New patients presumed or known to have drug-
susceptible TB, pulmonary TB: 2HRZE/4HR.
Alternatives:
1. 2HRZE/4(HR)3 (a daily intensive phase followed by
three times weekly continuation phase, provided that
each dose is directly observed). OR
2. 2(HRZE)3/4(HR)3 (Three times weekly dosing
throughout therapy, provided that every dose is
directly observed and the patient is NOT living with
HIV or living in an HIV-prevalent setting).
 Settings with high levels of INH resistance in
new patients: 2HRZE/4HRE.
Chemotherapy 110
 2. Previously Treated Patients
 Specimens for culture and drug susceptibility
testing (DST) should be obtained from all
previously treated TB patients at or before the
start of treatment.
 DST should be performed for at least Isoniazid
and Rifampicin.
 Recommendation: 2HRZE(S)/1HRZE/5HRE.

Chemotherapy 111
 2nd line agents
Ethionamide
Chemically related to H & similarly blocks the
synthesis of mycolic acid.
Poorly water soluble & available only in oral form.
Metabolized by the liver.
Capreomycin
Is a peptide protein synthesis inhibitor antibiotic
obtained from Streptomyces capreolus.
Aminosalicylic Acid (PAS)
A folate synthesis antagonist that is active almost
exclusively against M tuberculosis .
It is structurally similar to PABA & sulfonamides112
Chemotherapy
 Drugs active against atypical Mycobacterium
 M.avium: cause disseminated TB in late stages
of AIDS.
 Azithromycin or Clarithromycin plus
Ethambutol: well tolerated regimen.
 Rifabutin and Clarithromycin: prevent M.avium
complex bacterimia in AIDS patients.

Chemotherapy 113
 ANTILEPROTIC DRUGS
 Leprosy(Hansen’s disease) caused by M.leprae.
There are two types of leprosy;
1. Lepromatous Leprosy
– Severe
– Rapidly progress
– Marked ulceration
– Tissue destruction & nerve damage
– TXt lasts at least 2yrs with Dapsone + Rifampicin+
Clofazimine.
2. Tuberculoid Leprosy
- Mild infection.
- Slow in progress & loss of sensation.
- TXt lasts 6months(Dapsone + Rifampicin).
Chemotherapy 114
 DAPSONE/SULFONES
 The primary drug (effective, low in toxicity &
inexpensive).
MOA: inhibition of folate synthesis.
 Pharmacokinetics: given orally, well absorbed.
– Widely distributed.
– Enterohepatic recycling.
– Excreted as metabolites renally.
 Adverse effects
– Rashes
– GI disturbance
– Show erythema nodusom ( Inflammatory rxn).

Chemotherapy 115
 CLOFAZIMINE
 Weakly bactericidal.
MOA: not known, may involve DNA binding
 Has anti-inflammatory action.
 Used together with or as an alternative to
Dapsone in sulfone-resistant leprosy or when
patients are intolerant to sulfones.
 A common dosage is 100 mg/d orally.
Adverse effects
– Red brown to nearly black discoloration of the
skin & conjunctiva.
– GI intolerance (occasionally)

Chemotherapy 116
 ANTIFUNGAL
AGENTS

Chemotherapy 117
 ANTIFUNGAL AGENTS
 Fungal infection termed as mycosis.
– Superficial infection (affecting skin, nails, scalp or
mucous membranes).
– Systemic infection (affecting deeper tissue & organ).
 Superficial fungal: dermatomycosis & candidiasis.
– Dermatomycosis: skin, hair, & nail caused by
Trichophyton, Microsporum & Epidermophyton
spp.,these causes various types of ring worms &
tinea.
Tinea capitis: scalp; Tinea pedis: foot
Tinea cruris: groin, thigh; Tinea barbae: beard
Tinea corporis: body.
– Superficial candidiasis: mucous membrane of
mouth (thrush), vagina or skin.
Chemotherapy 118
 Systemic fungal disease:
– Systemic candidiasis; other more serious
cryptococcal meningitis or endocarditis,
pulmonary aspergillosis,& rhino cerebral
mucormycosis.

Chemotherapy 119
 AMPHOTERICIN
 Amphotericin A & B are antifungal antibiotics
produced by Streptomyces nodosus.
 Amphotericin A is not in clinical use.

Amphotericin-B
MOA: binds to sterols in the fungal cell membrane 
alters the permeability by forming amphotericin B-
associated pores  Loss of intracellular K+.
– Greater avidly to ergosterol.

– Enhances antifungal effect of flucytosine.

Chemotherapy 120
Pharmacokinetics
Amphotericin B is an amphoteric polyene macrolide
(polyene =containing many double bonds; macrolide =
containing a large lactone ring of 12 or more atoms).
It is nearly insoluble in water & is therefore prepared
as a colloidal suspension of amphotericinB & sodium
desoxycholate for intravenous injection.
Absorption from GIT is negligible: effective on fungal
in lumen.
Antifungal activity;
– Systemic fungal infections.
– Aspergillus, Candida, Cryptococcus.
– Against protozoa Leishmania braziliensis.

Chemotherapy 121
Therapeutic uses
 Intrathecal infusion in meningitis caused by
coccidioides.
 IV administration of amphotericin B treatment
choice for mucormycosis, aspergillosis,
extracutaneous sporotrichosis, cryptococcosis,
trichosporonosis & penicilliosis morneffei.
 Bladder irrigation: in candida cystitis.
 Topical amphotericin B in cutaneous candidiasis.
 Oral tablet to decrease colonization of intestine
by candida.

Chemotherapy 122
Adverse effects
 Infusion related toxicity (immediate reactions)
 Nearly universal & consist of fever, chills, muscle
spasms, vomiting, headache, and hypotension.
 They can be ameliorated by slowing the infusion rate or
decreasing the daily dose.
 Premedication with antipyretics, antihistamines,
meperidine, or corticosteroids can be helpful.
 Cumulative Toxicity
 Renal damage
 Anemia due to reduced erythropoietin production by
damaged renal tubular cells.
 Seizures & chemical arachnoiditis after intrathecal
therapy
 Abnormalities of liver function tests (occasionally)
Chemotherapy 123
 FLUCYTOSINE
MOA:
Is taken up by fungal cells via the enzyme cytosine
permease.
It is converted intracellularly first to 5-FU & then
to 5-FdUMP & FUTP, which inhibit DNA and RNA
synthesis, respectively. (inhibit thymidylate
synthetase)
Human cells are unable to convert the parent drug
to its active metabolites, resulting in selective
toxicity

Chemotherapy 124
 Pharmacokinetics
 Given by IV infusion, also be given orally.
 90% excreted renally unchanged.
 Combined with amphotericin for severe
infections such as cryptococcal meningitis.
 Side effects are infrequent: anaemia,
neutropenia, thrombocytopenia & alopecia;
reversed when therapy ceases.

Chemotherapy 125
 AZOLES
According to the number of nitrogen atoms in the five-
membered azole ring they can be;
Triazole(3-N) Imidazole(2-N)
– Fluconazole - Clotrimazole
– Itraconazole - Miconazole
– Terconazole - ketoconazole
– Voriconazole - Oxiconazol
– Posaconazole - Sulconazole
- Econazole

Chemotherapy 126
 AZOLES…
MOA: reduction of ergosterol synthesis by inhibition of
fungal cytocrome P450 enzymes.
 Greater affinity for fungal than for human CYP450
enzymes.
 Imidazoles exhibit a lesser degree of selectivity than
the triazoles, accounting for their higher incidence of
drug interactions and adverse effects.
Therapeutic uses
– Systemic fungal infections;
• Cryptococcal meningitis (fluconazole).
– Vaginal candidiasis.
– Severe recalcitrant cutaneous dermatophyte
infections.
Chemotherapy 127
 KETOCONAZOLE
 Drug interactions
– Inhibit CYP450: inhibit metabolism of protease
inhibitors, TCAs, benzodiazepines, warfarin.
 Adverse effects
– Primarily GI effects, hepatotoxicity.

Chemotherapy 128
 ITRACONAZOLE (PO)
Pharmacodynamics
 Absorption reduces in fasting, reduced gastric
acidity,
 Itraconazole concentration are decreased by
concomitant therapy with rifampin, phenytoin &
carbamazepine, as well as by drugs that reduce
gastric acidity- H2 antagonist & proton pump
inhibitor.
Therapeutic use:
 Preferred over ketoconazole for txt of nonmeningeal
hystoplasmosis.
 Cryptococcus may respond better with amphotericinB or
fluconazole.
Untoward effect: occasionally, hepatotoxicity & rash.

Chemotherapy 129
 FLUCONAZOLE
 Completely absorbed, not affected by food,
gastric acidity.
 Diffuses readily into body fluids.
Drug interaction:
 Increase plasma levels of phenytoin, zidovudine,
Rifabutin, cyclosporine, sulfonylureas & warfarin.

Chemotherapy 130
Therapeutic use
 Candidiasis: oropharyngeal, esophageal, vaginal
candidiasis, deep candidiasis.
 Cryptococcosis: to prevent relapse cryptococcal
meningitis in AIDS patient whose infection has
been controlled by amphotericin B.
 Treatment choice for coccidioidal meningitis
because of much lesser morbidity than with
amphotericin B.
Untoward effect:
 Nausea & Vomiting: antiemetic drug may be used.

Chemotherapy 131
 GRISEOFULVIN
 Active against the dermatophytes: Microsporum,
Epidermophyton & Trichophyton.
MOA: Fungistatic by interacting with microtubule
& interfering with mitosis.
 To treat dermatophyte infections of skin & nail.
 Treatment need very prolonged.
 Given orally.
 Deposited in keratin precursor cells.

Chemotherapy 132
Therapeutic uses
 Mycotic disease of skin, hair & nails.
 Infection of hair (tinea capitis).
 Ringworm of the glabrous skin.
 Tinea cruris & tinea corporis.
 Tinea of hand & bread.
 Athlete’s foot.
 Not effective in subcutaneous or deep mycosis.

Chemotherapy 133
 RX of Superficial Fungal Infections
 Diseases include;
Dermatophytosis(ring worm),
Candidiasis,
Tinea versicolor,
Tinea nigra &
Fungal keratitis.

Chemotherapy 134
A. Clotrimazole
 Available as: 1% cream (body, vaginal), lotion &
solution, 10mg troches.
 Skin apply BID.
 Vagina: - 100mg/day at bed time for 7days.
» 500mg tab only once.
» Troches five times a day for 14days.
B. Miconazole
 Therapeutic use: 2% vaginal cream, 100mg
suppository at bed time for 7days (vulvovaginal
candidiasis).
 In txt of tinea pedis, tinea cruris & tinea
versicolor.
 ADR: vaginal application  burning, itching or
irritation.
Chemotherapy 135
C. Nystatin
MOA: binds to fungal sterols.
Therapeutic uses
– Candidiasis of intestine, mouth, skin, etc.
Adverse effects
– Nausea
– Bitter taste

Chemotherapy 136
D. Undecylenic Acid (UDA)
 11 carbon, unsaturated compound.
MOA:
 Possibly, inhibition of enzymes involved in lipid
metabolism  interfere with the alkalinization
of the cytoplasm which accompanies germ tube
formation  inhibits morphogenesis in candida
 Useful in txt of various dermatomycosis,
especially tinea pedis.
 The formulation is not irritant (Zn)
 Fungistatic
 Cure rate is 50% lower than Imidazole.

Chemotherapy 137
E. Benzoic Acid & Salicylic Acid (Whitfield’s
Ointment)
 Fungistatic -benzoic acid(6%) &
keratolytic -salicylic acid(3%).
 Used in the txt of tinea pedis.
 Txt ends for several weeks to months.
 Mild irritation at site of application.

Chemotherapy 138
 Antiviral
Agents
Chemotherapy 139
 INTRODUCTION TO VIRUSES
Viruses;

Are obligate intracellular parasites

Lack both cell wall & cell membrane

Do not carry out metabolic processes

Use much of the host’s metabolic machinery

Chemotherapy 140
 Introduction…
Few drugs are selective enough to prevent viral
replication without injury to the infected host
cells.
Therapy for viral diseases is further
complicated by the fact that the clinical
symptoms appear late in the course of the
disease, at a time when most of the virus
particles have replicated.
At this stage of viral infection, administration
of drugs that block viral replication has limited
effectiveness.
However, some antiviral agents are useful as
prophylactic
Chemotherapy
agents 141
 Classification of Viruses
DNA Viruses
 Adenoviruses (URTIs)
 Herpes simplex (genital herpes)
 Cytomegalovirus(CMV)
 Hepatitis-B(HBV)
 Varicella(chikenpox) & Varicella-zoster (shingles)
 Smallpox
RNA Viruses: influenza A & B.
RNA retroviruses:
Human Immunodeficiency Virus (HIV)
Chemotherapy 142
 VIRAL REPLICATION STEPS
 Attachment of the virus to receptors on the
host cell surface
 Entry of the virus through the host cell
membrane
 Uncoating of viral nucleic acid
 Synthesis of early regulatory proteins, eg,
nucleic acid polymerases
 Synthesis of new viral RNA or DNA
 Synthesis of late structural proteins
 Assembly (maturation) of viral particles
 Release from the cell
Chemotherapy 143
MoA: Treatment of Influenza
A. Amantadine (Symmetrel)
MOA: block the M2 protein ion channel of the
virus particle and inhibit uncoating of the viral
RNA within infected host cells, thus preventing
its replication.
Therapeutic use:
 Prophylaxis & treatment of Influenza A only
due to resistance
Adverse Effects:
 GI upset
 Headache
 Nervousness
Chemotherapy 144
B. Neuraminidase inhibitors
Zanamivir (Relenza), Oseltamivir (Tamiflu)
MOA: inhibit viral neuraminidase.
Therapeutic use
 Treatment of influenza A &B.
 Prophylaxis: Oseltamivir.
Adverse Effects
 Nausea, Vomiting, diarrhea, neutropenia.
 Bronchospasm & respiratory function.

Chemotherapy 145
Chemotherapy 146
 Virus-specified enzymes
Acyclovir (thymidine kinase, UL97)
Penciclovir Monophosphate
Ganciclovir
(‘Ovirs’) & Trifluridine Host kinases
NRTIs Cidofovir

Diphosphate

Triphosphate
Foscarnet, NNRTIs
Incorporation into viral
DNA
Competitive inhibition
of viral DNA polymerase

Chain termination
Inhibition of viral
DNA synthesis
Chemotherapy 147
 Rx of Varicella Zoster & Herpes Simplex
Acyclovir: Nucleoside analog.
MOA: inhibit viral DNA polymerase.
Therapeutic uses:
 HSV(1&2)
 VZV since they have thymidine kinase
Adverse Effects
 Rash, headache, N/V, diarrhoea,
nephrotoxicity.

Chemotherapy 148
 Treatment of CMV infection
A. Ganciclovir (Cytovene)
MOA: inhibits viral DNA polymerase.
Incorporation into viral DNA.
Therapeutic uses: treatment of
 CMV retinitis in HIV infected patients
 CMV infection in transplant patients.
Adverse Effects
 Bone marrow suppression
 Infertility
 Teratogenic in animals

Chemotherapy 149
B. Foscarnet (Foscavir): non nucleoside
MOA: inhibits viral DNA & RNA polymerase.
Therapeutic uses:
 CMV retinitis.
 Herpes Simplex infections.
 Acyclovir resistant
Adverse Effects
 Fever, nausea, diarrhea, headache.
 Nephrotoxicity
 Electrolyte & mineral imbalances.
Chemotherapy 150
Antiretroviral Drugs
 HIV Replication Cycle

Chemotherapy 152
Chemotherapy 153
 STEPS IN HIV REPLICATION
1. Binding of Gp120 to CD4 and co-receptor on the
cell surface  Attachment.
2. Fusion of the viral envelope with the cell
membrane.
3. Release & 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.

Chemotherapy 154
 STEPS IN HIV REPLICATION...
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 & maturation occurs outside the
cell by the protease enzyme, rendering the HIV virion
infectious.

Chemotherapy 155
 The goals of therapy are to;
Maximally & durably suppress HIV RNA replication,
Restore & preserve immunologic function,
Reduce HIV-related morbidity & mortality,
Improve quality of life.
The preferred initial therapy is;
2NRTIs + 1PI/NNRTI/integrase inhibitor.
Selection of the appropriate combination is based on;
1.Avoiding the use of 2agents of the same nucleoside
analog
2.Avoiding overlapping toxicities & genotypic & phenotypic
characteristics of the virus
3.Patient factors (symptoms & concurrent illnesses)
4.Impact of drug interactions
5.Chemotherapy
Ease of adherence to the regimen. 156
 STEPS IN HIV REPLICATION...
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.

Chemotherapy 157
Chemotherapy 158
Chemotherapy 159
 Mechanism of Action
1. Inhibition of Binding of GP120 to CD4 receptor by
“neutralizing antibodies” [?]
2. Fusion inhibition “Pentafuside T20”-Infuvertide
(binds with gp41 & inhibits fusion of HIV-1 to CD4+
cells) & Maraviroc (CCR5 antagonist).
3. Reverse Transcriptase Inhibition
“NRTIs & NNRTIs”
4. Integrase inhibition - integrase strand transfer
inhibitors.
5. Protease Inhibition “Protease inhibitors”
 Currently therapy based mainly on 3 & 5 above.

Chemotherapy 160
 Introduction to Antiretroviral Drugs
Class Drugs Viral target Mode of action
Nucleoside Zidovudine Reverse Phosphorylated by
Reverse Didanosine Transcriptase cellular enzymes
Transcriptase Zalcitabine Competitively
Inhibitor Stavudine inhibits viral DNA
(NRTI) Lamivudine synthesis or
Abacavir causes chain
Tenofovir termination
Emtricitabine

Chemotherapy 161
Introduction to Antiretroviral Drugs…
Class Drugs Viral target Mode of action
Non Nevirapine Reverse Not
Nucleoside Delavirdine Transcriptase phosphorylated
Reverse non
Efavirenz
Transcriptase Competitive
Inhibitor Etravirine inhibition of viral
(NNRTI) Rilpivirine DNA synthesis.
Binds directly to
enzyme

Chemotherapy 162
Introduction to Antiretroviral Drugs…
Class Drugs Viral target Mode of action
Protease Saquinavir Protease Binds to
Indinavir
Inhibitor Ritonavir protease active
Nelfinavir site, thereby
Amprenavir
Lopinavir inhibiting
Atazanavir function
Tipranavir
Darunavir
Fosampreinavir

Chemotherapy 163
 The Adverse Effects of Antiretroviral
Drugs
 Hyperglycemia, new onset of diabetes mellitus,
exacerbation of pre-existing diabetes, and diabetic
ketoacidosis have been reported in those on ART.
Disorder in lipid and CHO metabolism  central
adiposity, insulin resistance
 Hyperlipidemia has been most strongly, but not
exclusively, associated with protease inhibitor
therapy (Nelfinavir, Saquinavir, Ritonavir > Indinavir,
Amprenavir).
 Lipodystrophy: Morphologic Changes Definitions.
–Protease inhibitor and/or Nucleoside RT inhibitor
effects on adipocytes.
–Nucleoside RT inhibitor-induced mitochondrial toxicity.
Chemotherapy 164
 ADRs of ART…
 Lactic acidosis:
– Inhibition of mitochondrial DNA polymerase 
Mitochondrial drop out during cell division.
Zalcitabine(ddc) >
Stavudine(d4T) >
(AZT)Zidovudine(ZDV), Didanosine(ddI) >
Lamivudine(3TC), Abacavir(ABC)
– Other effects on mitochondria
• Inhibition of Krebs cycle --> Lactic acid.

Chemotherapy 165
 ADRs of ART…
 Peripheral Neuropathy
– Usually due to Nucleoside RT Inhibitors:
Zalcitabine [ddc] (17-36%) > Stavudine [d4T] (5-
24%) > Didanosine [ddI] (5-24%).

Chemotherapy 166
 Adverse Effects of Antiretroviral Drugs:
Particular to Individual Drugs
1.Efavirenz (EFV): CNS Effects [Dizziness,
impaired concentration, somnolence, abnormal
dreams, insomnia, ataxia, emotional lability].
2.Indinavir (IDV): Nephrolithiasis.
3.Nevirapine (NVP): rash, SJS, or Toxic
Epidermal Necrolysis.
4.Abacavir (ABC): Hypersensitivity reaction.
5.Zidovudine (ZDV): Bone Marrow Suppression.
6.Tenofovir (TDF): Renal toxicity (proximal
tubule), impairs lipid profile.
Chemotherapy 167
 Characteristics of Antiretroviral Agents
 The CYP450 3A4 subset is the major enzymatic
route of metabolism of the PIs & NNRTIs.
 The following table shows characteristics of ART
drugs.

Chemotherapy 168
Antiretroviral agent Metabolism Effect on CYP450

Zidovudine Hepatic glucuronidation,

Renal excretion
-
Other NRTIs Renal excretion -
Nevirapine Cytochrome P450 Modest Induction
Delavirdine Cytochrome P450 Modest Inhibition
Efavirenz Cytochrome P450 Modest Induction &
Inhibition
Ritonavir Cytochrome P450 Potent Inhibition
Amprenavir, Cytochrome P450 Modest Inhibition
Indinavir,
Nelfinavir
Saquinavir Cytochrome P450 Weak Inhibition
Chemotherapy 169
 FIRST LINE REGIMEN: ETHIOPIAN
ART PROGRAM 2008

Preferred:
1) TDF EFV
2) AZT

3TC/FTC

Alternatives:
1) d4T
NVP
2) ABC
REGIMENS:
PREFERRED
1. TDF+FTC+EFV
2. ZDV+3TC+EFV
3. ZDV+3TC+NVP

ALTERNATIVES
1. D4T+3TC+NVP
2. TDF+3TC+NVP
3. D4T+3TC+EFV
4. ABC+3TC+NVP
5. ABC+3TC+EFV
Chemotherapy 6.ABC+3TC+ZDV 170
 Combining NRTIs
 Interactions between NRTIs occur due to competition
for the same intracellular phosphorylating enzymes, or
due to overlapping toxicities.
 Nucleoside analogues that are activated by the same
intracellular enzymes include ZDV & d4T, or ddc &
3TC.
 Combinations of ddI + ddc, d4T + ddI & d4T+ ddc,
are not recommended due to overlapping potential for
the development of peripheral neuropathy.
 Recommended ART regimen(2014):
TDF + FTC + EFV Preferred
TDF + 3TC + EFV/NVP
ZDV + 3TC + EFV/NVP alternatives
ABC + 3TC + EFV/NVP
ABC + 3TC + ZDV

Chemotherapy 171
 Second-line Regimens(2014)
1. A boosted protease inhibitor (bPI) + 2NRTIs
are recommended for 2nd line ART.
2. ATV/r and LPV/r are the preferred bPIs for
second-line ART.
 If TDF + FTC/3TC + EFV/NVP is 1st line
therapy
ZDV ± 3TC + LPV/r or ATV/r OR
ZDV + ABC + LPV/r or ATV/r
 If ZDV + 3TC + EFV/NVP is 1st line therapy
 TDF + 3TC ± ZDV + LPV/r or ATV/r OR
 ABC + ddI + LPV/r or ATV/r
 If ABC + 3TC + ZDV is 1st line therapy
 EFV or NVP + LPV/r or ATV/r
Chemotherapy 172
 Preferred & alternative 1st-line regimens for
children according to the 2013 WHO
consolidated guidelines

Age group Preferred first-line Alternative first-line

regimens regimens

Children<3 ABC/AZT + 3TC + LPV/r ABC/AZT + 3TC + NVP

years

Children 3–9 ABC + 3TC + EFV ABC/AZT/TDF + 3TC/FTC

years & + NVP/EFV
adolescents
<35 kg

Adolescents TDF + 3TC/FTC + EFV ABC/AZT/TDF + 3TC/FTC

(10–19 yrs) + NVP/EFV
≥35 kg
Chemotherapy 173
 Interactions Between NRTIs & PIs
No significant alterations.
 One important interaction involves didanosine
and indinavir, or didanosine and nelfinavir.
 The neutralising agents in the oral formulations
of didanosine result in increased gastric pH.
 Optimal absorption of indinavir and nelfinavir
requires an acidic pH.
 It is recommended that these drugs are given at
least one hour apart from didanosine.

Chemotherapy 174
 Saquinavir – Ritonavir
 The combination reduces the pill burden (from
1200 mg tid to 400mg/400 mg bd). Hence, may
also improve adherence and reduce costs of
therapy.
 PI “Boosting” Using Ritonavir.

Chemotherapy 175
 Interactions Between PIs & NNRTIs
NNRTIs alter the kinetics of PIs:
 Nevirapine induces hepatic enzymes, reducing
the plasma concentrations of some protease
inhibitors.
– The dose of indinavir or nelfinavir may be
increased to accommodate for decreased
AUCs when administered with Niverapine.

Chemotherapy 176
 Interactions Between Antiretroviral Agents &
Other Drugs
Hepatic metabolism:
Macrolide antibiotics, azole antifungals and H-2
blockers are P450 inhibitors and hence interact
with PIs and NNRTIs.
Rifamycin derivatives, alcohol and anticonvulsants
are P450 inducers and hence also interact with
PIs and NNRTIs.
Simvastatin and lovastatin are potent inducers,
and other agents such as atorvastatin and
pravastatin are less likely to interact and are
recommended for use.
Chemotherapy 177
 Anti-tuberculosis Agents & ARVs
Rifampicin
– is the most potent P450 inducer, and results in
significant reductions in PI and NNRTI plasma
concentrations.
Rifabutin
– is a less potent inducer, and current guidelines
suggest that it may be used with agents such
as indinavir or nelfinavir with appropriate
dosage adjustments.

Chemotherapy 178
 PMTCT
ART options recommended for HIV-infected
pregnant women who are eligible for treatment
Maternal ART + infant ARV prophylaxis
Mother: Maternal ante partum daily ART,
starting as soon as possible irrespective of
gestational age, and continued during
pregnancy, delivery and thereafter.
Infant: Daily NVP or twice-daily AZT from
birth until 4 to 6 weeks of age (irrespective of
the mode of infant feeding).

Chemotherapy
179
 Post-Exposure Prophylaxis
Use of therapeutic agent to prevent
establishment of infection following exposure to
pathogen
HIV occupational exposure: An “occupational
exposure” to HIV when an individual is exposed
to blood or bodily fluids during the course of the
individual’s duty of work.

Chemotherapy
180
 Indications on Eligibility of PEP
Knowing the Source status and exposure status is
used to decide on eligibility of an exposed person
for PEP
Source status
1=Assymptomiatic, or stage 1 and 2
2=Stage 3 and 4

Chemotherapy
181
 Exposure code (mucous membrane & non-
intact skin exposure)
Status
code
EC 1 EC 2 EC 3

SC 1 2-drug PEP 2-drug PEP 3-drug

PEP

SC 2 2-drug PEP 3-drug PEP 3-drug

PEP

SC no PEP no PEP* no PEP*

unknown
182
Chemotherapy
No PEP No PEP warranted No PEP
 ARV drugs for PEP use in Ethiopia

2-Drug PEP 3-Drug PEP

ZDV/3TC ZDV/3TC + LPV/r or EFV
d4T/3TC d4T/3TC + LPV/r or EFV
TDF/3TC TDF/3TC + LPV/r or EFV

 Should be given in the shortest time possible

(within the first 1-4 hours of exposure).
 Do not consider PEP beyond 72 hours.

183
Chemotherapy
NEW & INVESTIGATIONAL ANTIRETROVIRAL
AGENTS
New therapies are continually being sought that exploit
other HIV targets, have activity against resistant viral
strains, have a lower incidence of adverse effects, and
offer convenient dosing.
Newly approved agents and those currently in advanced
stages of clinical development include the NRTI agents
elvucitabine, racivir, & apricitabine; the NNRTI agent
rilpivirine; entry inhibitors such as the CCR5 receptor
antagonists vicriviroc & PRO 140, the fusion inhibitor
TNX-355 (ibalizumab); and integrase inhibitors such as
elvitegravir. In addition, new drug classes such as
maturation inhibitors (bevirimat) are under investigation.

Chemotherapy 184
 ANTIPROTOZOAL AGENTS

Chemotherapy 185
 Introduction
Protozoal infections are;
Common among people in underdeveloped
tropical & subtropical countries, where;
Sanitary conditions,
Hygienic practices, &
Control of the vectors of transmission are
inadequate.
However, with increased world travel,
protozoal diseases are no longer confined to
specific geographic locales.

Chemotherapy 186
 Introduction…
Protozoas are unicellular eukaryotes
Have metabolic processes closer to those
of the human host than to prokaryotic
bacterial pathogens.
Less easily treated than bacterial
infections,
Serious toxic effects in the host,
particularly on cells showing high metabolic
activity.
Most antiprotozoal agents have not proven
to be safe for pregnant patients.
Chemotherapy 187
 MALARIA
 Caused by protozoa of the genus plasmodium.
 Affects > 5million people; killing > 2 million each
year.
 Life cycle of malaria parasite: takes place in
two hosts.
In human (asexual reproduction) &
Female anopheles (sexual reproduction)
Types of malaria
 Caused by five different species of plasmodium
(P.Vivax, P.Falciparum, P.Ovale, P.Malariae, P.Knowlesi).

Chemotherapy 188
Chemotherapy 189
Chemotherapy 190
 Chemotherapy of Malaria
Considered in relation to the biology of infection.
1.  Drugs active against Sporozoites:
– True causal prophylaxis.
 No drug is yet available.
2.  Drugs active against Pre or Primary Exo-
erythrocytic Stage;
– Causal prophylaxis [primary tissue schizonticides]
 Proguanil & Pyrimethamine
 Kill the parasites before RBCs are invaded.
 Primaquine has causal prophylaxis activity especially
against P.falciparum but its use is unsafe.

Chemotherapy 191
 Chemotherapy of Malaria…
3.  Drugs active against the secondary exo-
erythrocytic stage (persistent liver cycle,
hypnozoite).
 Secondary tissue schizonticides.
 Primaquine acts on hypnotic of P.Vivax.
4.  Drugs active against the erythrocytic stage
(blood schizonticides)
 Suppression or clinical prophylaxis.
 Chloroquine, Proguanil, Mefloquine.
 Used for temporary prevention of clinical symptoms.
 Kill blood schizonts, but the tissue schizonts are not
destroyed.
 Falciparum promptly cured.

Chemotherapy 192
Clinical cure:
A.4-aminoquinolines: Chloroquine, Amodiaquine
B. Quinoline methanol: Quinine, Quinidine, Mefloquine
C. Arthmisinine compounds:
Dihyddroartemisinin, Artemether, Artesunate
 Interrupt the erythrocytic cycle of the malaria
parasite.
5. Drugs active against the sexual stage
A.  Gametocidal: Primaquine
B.  Sporontocides: Proguanil & Pyrimethamine
A. Gamates become incapable of forming sporozoite.

Chemotherapy 193
 Therapeutic Objective

Chemotherapy 194
 CHLOROQUINE
MOA:
 Acts by concentrating in parasite food vacuoles,
preventing the bio-crystallization of the
haemoglobin breakdown product, heme, into
hemozoin, and thus eliciting parasite toxicity due
to the build up of free heme.
 Inhibition of heme polymerase

Chemotherapy 195
Therapeutic uses
 Malaria:
 A highly effective blood schizonticide for all forms
 Moderately gametocidal for P vivax, P ovale, and P
malariae but not against those of P falciparum.
 Chloroquine is not active against liver stage parasites
(hypnozoites)
 Chemoprophylaxis
 Amebic liver abscess: with metronidazole.
 Rheumatoid arthritis.
 Discoid lupus erythromatous.

Chemotherapy 196
Adverse effects
 CVS (parenteral dose): vasodilation, hypotension,
decrease myocardial infarction, ECG changes.
 Oral route can cause (high dose)
– Visual disturbance
– Urticaria
– Head ache
– GI upset
 Rare reaction include hemolysis in pts with G6PD
deficient.
 High daily doses of chloroquine: irreversible
ototoxicity & retinopathy.
Contraindication: psoriasis, porphyria cutanea tarda
it may precipitate acute attacks of these diseases.
Chemotherapy 197
 QUININE & QUINIDINE
 Derived from the bark of cinchona.
MOA: unknown;
Pharmacological effects
– Quinine acts primarily as blood schizonticidal.
• Gametocidal for P.Vivax, P.Ovale, P.Malariae
• Not effective liver stage parasite.
– Quinine is the drug of choice for severe illness
due to chloroquine resistant & MDR strains of
P.falciparum.
– Potentiation of neuromuscular blocking drugs.

Chemotherapy 198
Therapeutic use
 Rx malaria
– Cure of chloroquine resistant & MDR
P.falciparum.
– Rx nocturnal leg cramps.
Toxicities & side effects
– Commonly causes:
Tinnitus
Nausea
Head ache Cinchonism
Dizziness
Flushing

Chemotherapy 199
Toxicities & side effects…
 Hyperinsulinema- severe hypoglycemia.
 Stimulate uterine contraction.
 Black water fever:
Marked hemolysis & hemoglobinuria.
Due to hypersensitivity reaction to the drug.
Contraindications
 Hypersensitivity reaction to quinine.
 Severe Cinchonism.
Drug interactions
 Absorption blocked by aluminum containing
antacids.
 Should not be given concurrently with Mefloquine
(cardiac arrest).
Chemotherapy 200
 MEFLOQUINE
MOA:
– Effective blood schizonticidal.
Therapeutic use
 Chemoprophylaxis: nonimmune travelers
 Treatment: for malaria caused by chloroquine
resistant & MDR P.falciparum.
For severe or complicated malaria: Quinine or
Quinidine are selected.

Chemotherapy 201
Adverse effects
– NVD; Abdominal pain, dizziness, dysphoria
– Higher doses cause
• Neuropsychiatric toxicity [disorientation,
seizure, encephalopathy].
• Alter cardiac conduction, arrhythmias &
bradycardia.
Contraindications
– History of seizure & neuropsychiatry.
– Combination with quinine & Quinidine 
Arrhythmia.

Chemotherapy 202
 PRIMAQUINE
Chemistry: synthetic 8-aminoquinoline.
MOA: not completely understood
 Metabolites of primaquine are believed to act
as oxidants that are responsible for the
schizonticidal action as well as for the
hemolysis & methemoglobinemia encountered as
toxicities.
 Active against hepatic stages of all human
malarial parasite.
 Gametocidal.

Chemotherapy 203
Therapeutic uses:
 Reserved primarily for radical cure of vivax
& ovale malarias.
 Occasionally to interrupt malarial
transmission by rendering plasmodial
gametocytes noninfectious to mosquitoes.
 Primaquine +Clindamycin: an alternative
regimen for PCP.

Chemotherapy 204
 PRIMAQUINE…
Adverse effects: generally tolerated
 Infrequently causes: nausea, epigastric pain,
abdominal cramp, head ache.
 Hemolysis & methehemoglobinemia especially in
persons with G6PD deficiency.
Contraindication
 Granulocytopenia.
 Methemoglobinemia.
 Pregnancy as the fetus is deficient in G6PD.

Chemotherapy 205
 ARTEMISININ & ITS DERIVATIVES
 Artemisinin or Qinghaosu was isolated in 1972 from
Artemisia annua L.
 Has been used in traditional Chinese medicine.
 Derivatives: Artemether, Arteether, Artesunate,
Artlinic acid.
MOA:
 Production of free radicals that follows the iron-
catalyzed cleavage of the artemisinin endoperoxide
bridge in the parasite food vacuole or from inhibition
of a parasite calcium ATPase.
In contrast to other antimalarials:
 Artemisinins have very fast action.
 Parasite clearance times are short.
 Unlike most of the antimalarials work at the late
trophozoite & schizont stage; Artemisinin & its
derivatives also acts at the early trophozoite.
Chemotherapy 206
Therapeutic uses
 Active against all plasmodium species.
 Should be administered in combination in order
to:
– Reduce recrudescence.
– Prevent or slow development of resistance.
 Uncomplicated malaria.
 Due to short t1/2, they are not useful for
chemoprophylaxis.
Adverse effect: safe & well tolerated.
 NVD.
 Avoided in pregnancy if possible.

Chemotherapy 207
 INHIBITORS OF FOLATE SYNTHESIS
PYRIMETHAMINE, PROGUANIL
MOA: Inhibit dihydrofolate reductase of plasmodia.
Therapeutic uses
 With sulphonamide.
 Not 1st line because it is slow to act.
 Suppressive Rx of chloroquine resistant
P.falciparum.
 Given concurrently with sulfadiazine for Rx of
toxoplasmosis.
Adverse effect
 Erythema multiform
 Steven’s Johnson syndrome
 Toxic epidermal necrosis
Chemotherapy 208
 PROGUANIL
 Prodrug metabolized to an active metabolite,
cycloguanil.
MOA: inhibits DHFR
– Inhibition of DNA synthesis.
– Depletion of folate co-factors.
 Slow antimalarial action.
Therapeutic uses:
– With chloroquine used as alternative to
Mefloquine for prophylaxis.
– Not suitable for acute attack.
– Considered safe for use during pregnancy.

Chemotherapy 209
 HALOFANTRINE & LUMEFANTRINE
HALOFANTRINE:
 Effective against erythrocytic stages of all for
human malaria species.
 Oral absorption is variable & is enhanced with
food.
 Plasma t 1/2  4 days.
ADRs:
 Generally well tolerated.
 Abdominal pain, Diarrhea, Vomiting, Cough, rash
& head ache, Altered cardiac conduction.

Chemotherapy 210
LUMEFANTRINE:
 Available in fixed dose combination with
artemether as Coartem.
 T 1/2  4.5 hrs
COARTEM®: very effective for Rx of P.falciparum.

Chemotherapy 211
 Drugs for Amebiasis
Amebiasis: infestation with E.hystolytica.
 Usually asymptomatic, when symptoms are
present the most characteristics are:
– Diarrhea & abdominal pain.

Chemotherapy 212
Chemotherapy 213
A. Asymptomatic Intestinal Infection(Cyst)
 In nonendemic areas they are treated by luminal
amebicide.
Diloxanide furoate, Iodoquinol, Paramomycin.
 Therapy with a luminal amebicide is also required
in the Rx of all other forms of amebiasis.
B. Amebic colitis
 Metronidazole PLUS luminal amebicide is the Rx
of choice for colitis & dysentery.
 TTC & erythromycin are alternative for
moderate colitis.
 Dehydroemetine or emetine can also be
used(toxic).
C. Extra-intestinal infections
 Rx of choice are metronidazole + a luminal
amebicide.
Chemotherapy 214
 Classification of Antiamebic agents
Luminal Amebicides
– Diloxanide
– Idoquinol
– TTCs
– Paramomycin(an aminoglycoside)
Tissue Amebicides
– Both intestinal & extraintestinal
Metronidazole
Tinidazole
Emetine & Dihydroemetine
– For extraintestinal only
Chloroquine
Chemotherapy 215
 METRONIDAZOLE
MOA:
 Amebas possess ferredoxin-like, low-redox-
potential, electron transport proteins that
participate in metabolic electron removal
reactions.
 The nitro group of metronidazole is able to serve
as an electron acceptor, forming reduced
cytotoxic compounds that bind to proteins and
DNA  death of the E. histolytica trophozoites.

Chemotherapy 216
 Pharmacokinetics
Absorption: complete & rapid after PO
Distribution: well throughout the body.
 Therapeutic levels can be found in vaginal and
seminal fluids, saliva, breast milk & CSF.
Metabolism: depends on hepatic oxidation of its side
chain by mixed-function oxidase, followed by
glucuronidation. Therefore, concomitant treatment with
inducers of the cytochrome P450 enhances the rate of
metabolism & inhibitors prolong the plasma half-life of
metronidazole.
 The drug accumulates in patients with severe hepatic
disease.
Excretion: via urine (parent drug & its metabolites)

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Therapeutic uses
1. Amebiasis
 For all symptomatic tissue infections: used with
luminal amebicide. Combination provides cure
rates of > 90%
2. Gardiasis: highly effective, lower dosage than for
amebiasis
3. Trichomoniasis: highly effective, can be given
topically
4. Anaerobic(G-/+ve) bacterial infection;
– Bacteriodes, Clostridium (pseudomembranous
colitis), Fusobacterium.
5. H. pylori (PUD): with other ABX
6. To facilitate extraction of guinea worm in
drancunculiasis.

Chemotherapy 218
Adverse effects
 Common: head ache, nausea, dryness of mouth,
metallic taste, dizziness.
 Has a disulfiram like effect copious vomiting,
flushing, palpitation, head ache.
 Used with caution in pts with active disease of CNS.
 Its use during 1st trimester is not recommended.
Drug Interaction
 With alcohol: disulfiram like effect.
 Inhibits inactivation of oral anticoagulant.
 Phenobarbitone: enhaced metabolism of metronidazole.
 Cimetidine: reduces metabolism of metronidazole.

Chemotherapy 219
 TINIDAZOLE
 2nd generation nitroimidazole.
 Similar to Metronidazole.
 Differ in: better toxicity profile & higher t½.

Chemotherapy 220
 DILOXANIDE FUROATE
Useful in the Rx of:
 Asymptomatic passers of cyst.
 In conjugation with metronidazole in the Rx of
intestinal & systemic amebiasis.
 90% absorbed & the nonabsorbed is effective.
Adverse effect
– Flatulence
– Dryness of mouth
– Pruritus

Chemotherapy 221
 EMETINE & DEHYDROEMETINE
MOA: inhibits protein synthesis by blocking chain
elongation.
 IM is the preferred route, since it is an irritant
when taken orally.
 Due to its toxicity, it has largely been replaced
by metronidazole.
Use: as alternative agent
Adverse effects
– Pain at the site of injection
– Transient nausea & vomiting
– Cardio toxicity [arrhythmia, CHF]
– Neuromuscular weakness
– Dizziness & rash.

Chemotherapy 222
 Drugs For Pneumocystis Jiroveci Pneumonia (PCP)
– Cotrimoxazole
– Pentamidine
– Trimethoprim + Dapsone
– Primaquine + Clindamycin
DRUGS FOR TRICHOMONIASIS
– Metronidazole
– Tinidazole
DRUGS FOR TOXOPLASMOSIS
– Pyrimethamine + Sulfadoxine = (FANSIDAR®)
– Pyrimethamine + Sulfadiazine

Chemotherapy 223
 DRUGS FOR LEISHMANIASIS
 Has three different forms:
Cutaneous leishmaniasis
Mucocutaneous leishmaniasis
Visceral leishmaniasis [kalazar]
 Drugs include:
– Pentavalent antimony(Sb)
• Sodium Stibogluconate (SSG): 1st line agent
• Meglumine antimonite(MA)
– Allopurinol + SSG
– Miltefosine: visceral
– Amphotericin-B
– Ketoconazole
Chemotherapy 224
 DRUGS FOR TRYPANOSOMIASIS
(AFRICAN SLEEPING SICKNESS)
Caused by:
A. Trypanosomia brucei gambiense
- Slow to enter CNS
- Causes sleeping sickness
Suramine & Pentamidine are used in early stage of
the disease [hemolymphatic stage]
 Pentamidine interferes with parasite synthesis
of RNA, DNA, phospholipids & proteins.
Enflornithine: used in early stage or CNS
involvement.

Chemotherapy 225
B. Trypanosomia brucei rhodesiense
- Early invasion of the CNS
- Usually fatal if not treated
Melarsoprol:
 A trivalent arsenical compound
MOA: reacts with sulfhydryl groups of various
substances, including enzymes in both the
organism and host
Use: involvement of CNS in both ‘a’ & ‘b’

Chemotherapy 226
 CHAGA’S DISEASE [AMERICAN TRYPANOSOMIAS]
- Caused by Trypanosoma cruzi.
- Parasites invade cardiac cells & neurons of
myenteric cause cardiomyopathy & mega colon
 death.
Rx options:
- Nifurtimox &
- Benznidazole22:

Chemotherapy 227
Chemotherapy 228
 Benznidazole22
Nitroimidazole derivative
MOA: similar to nifurtimox.
Better tolerated than nifurtimox
An alternative for the treatment of Chagas
disease

Chemotherapy 229
 Helminthic Infestation
&

Drugs of Choice

Chemotherapy 230
 ANTHELMINTICS
 Helminthes: Parasitic worms.
 Classification of parasitic worms;

Chemotherapy 231
NEMATODE INFESTATION [INTESTINAL]
1. ASCARIASIS (Giant round worm infestation)
 Most prevalent helminthic infestation.
 Adult worm inhabit the intestine
heavy infestation  intestinal blockade.
Drug of choice: Albendazole
Mebendazole
Pyrantel pamoate
Alternative drug: Piperazine citrate 4g stat
Levamisole??

Chemotherapy 232
 ALBENDAZOLE
MOA: produce many biochemical changes.
 Inhibition of mitochondrial fumarate reductase.
 Uncoupling of oxidative phosphorylation.
 Inhibits microtubule polymerization 
irreversibly impairing glucose uptake 
immobilized & slowly die.
Pharmacokinetics:
– Erratically absorbed PO.
– Rapidly undergoes 1st pass metabolism in liver
to albendazole sulfoxide.
–  absorption when taken with fatty meal.

Chemotherapy 233
Therapeutic uses of albendazole:
– Broad antiparasitic spectrum.
1. Effective as single dose for the Rx of;
 A.lumricoides
 Hookworm: Ankylostoma.duodenalis(A.duodenalis) & N.
americanus
 Trichuris.trichuria(T.trichuria)
2. Also effective against:
– E.vermicularis
– T.spiralis
– S.sterocoralis [invermectin is superior]
3. High dose in Rx of hydatid disease.
4. Useful for Rx of neurocycticercosis [Superior
to praziquantel].
 Corticosteroids: used to control inflammatory
response.
Chemotherapy 234
 Albendazole…
Adverse effects
– Fewer ADR when used for short term therapy
abdominal pain
Diarrhea
Nausea & dizziness
Head ache
– With protracted therapy
GI pain
Severe head ache
Fever
Fatigue
Loss of hair
 in serum transaminase
Leucopenia & thrombocytopenia
Chemotherapy 235
 MEBENDAZOLE
MOA: prevents uptake of glucose 
Immobilization & death.
Therapeutic use: drug of choice for most
intestinal round worms [pin worm, hookworm,
whipworm, Giant worm].
Pharmacokinetics: Only 5-10% is absorbed &
rapidly metabolized.
Adverse effect:
– Transient abdominal pain & diarrhea[massive
infestation].
– Embryocytotoxic & teratogenic in rats.
Chemotherapy 236
 PYRANTAL PAMOATE
MOA: depolarizing neuromuscular blocker.
Therapeutic uses:
– Alternative to mebendazole for infestation
with: hookworm, pinworm, Giant worms.

PIPERAZINE CITRATE

MOA: paralysis of ascaris by blocking Ach

Therapeutic uses:
– Alternative to albendazole or mebendazole in
the Rx of ascariasis.
Adverse effect: NVD, Dizziness & headache
Chemotherapy 237
2. ENTEROBIASIS (Pinworm infestation)
 Most common helminthic.
 Serious infections are rare but may cause
intense perineal itching.
 It is readily transmissible; family members
should be treated.
Drugs of choice: Albendzole
Mebendazole
Pyrantel pamoate

Chemotherapy 238
3. ANCYLOSTOMIASIS & NECATORIASIS
(Hookworm infection)
 Common in rural area (barefoot)
 Adult worm attach to intestine chronic blood loss
anemia.
 Nausea, vomiting & abdominal pain
– Albendazole, Mebendazole, Pyrantel pamoate.
4. TRICHURIASIS (Whipworm infestation)
 Mebendazole[drug of choice].
 Albendazole
5. STRONGLOIDIASIS (Threadworm infestation)
– Larva & adult inhabit small intestine
Drug of choice: Ivermectin
Albendazole
Thiabendazole
Chemotherapy 239
 THIABENDAZOLE
MOA: inhibit helminth specific fumarate
reductase.
Therapeutic use: alternative drug against
– Strongloidiasis
– Trichinosis
Adverse effect: incidence is high, most common
includes:
 GIT: Anorexia, nausea & vomiting
 Neurological: dizziness & drowsines

Chemotherapy 240
NEMATODE INFESTATION (Extra intestinal)
1. TRICHINOSIS (Pork roundworm infestation)
 Acquired by eating uncooked pork infested with
encycted larva of T.spiralis.
 Adult worm reside in intestine; Lareva migrate to
skeletal muscle & become encysted.
Symptoms include:
– Muscle pain
– Sore throat
Potential lethal complications:
Heart failure, meningitis, & neuritis.
Drugs of choice: Mebendazole
Albendazole
 Prednisolone is included to reduce inflammation
during larva movement.
Chemotherapy 241
2. WUCHERERIASIS & BRUGLASIS (Lymphatic
filarial infestation)
 W.bancrofti & B.malayi invade the lymphatic
system.
 Heavy infestation  lymphatic destruction 
Elephantiasis.
Drug of choice: Diethylcarbamazine.

Chemotherapy 242
 DIETHYLCARBAMAZINE
Pharmacokinetics:
– Readily absorbed & extensively metabolized.
Therapeutic uses:
 Drug of choice for filarial infestations;
– Destroys microfilariae of W.bancrofti,
B.malayi & Loa loa.
– Onchocerciasis: but it does not kill the adult
worm.

Chemotherapy 243
Adverse effects
 Reactions caused directly by DEC are minor:
Headache, Dizziness, Nausea, Vomiting.
 Occurring secondary to death of the parasite
are more serious:

 These can be decreased by pretreatment with

glucocorticoids.
Chemotherapy 244
 ONCHOCERCIASIS (River blindness)
 O.volvulus is found in stream & rivers.
 Heavy infestation causes:
– Dermatologic
• Nodules
• Pruritic dermatitis
– Opthalmic
• Occular lesions,
– The drug of choice is Ivermectin.

Chemotherapy 245
 IVERMECTIN
MOA: disrupts nerve traffic & muscle function in target
parasite.
Pharmacokinetics:
– Administered p.o.
– Distribution to CNS is poor
Therapeutic uses: onchocerciasis, intestinal
strongloidiasis.
 Used extensively in veterinary medicine.
Adverse effects:
 Mazotti reaction (fever, urticarial, swollen &tender
lymph nodes, tachycardia, hypotension ,edema,
athralgias) when used for onchocerciasis.
 Due to allergic & inflammatory response to death of
microfilariae.
 No data on pregnant women; teratogenic in mice,
rats, rabbits[ cleft palate].
Chemotherapy 246
 CESTODE INFESTATIONS
1. TAENIASIS [beef & pork tape worm]
 Treated by: praziquantel
Niclosamide
2. DIPHYLLOBOTHRIASIS [Fish tapeworm infestation]
 Worms are killed by: praziquantel
Niclosamide

Chemotherapy 247
 NICLOSAMIDE
MOA: inhibits mitochondrial oxidative
phosphorylation in tapeworm  cessation of ATP
production  death.
Therapeutic uses:
– Alternative to praziquantel in Rx of Cestode
infestation.
Adverse effects:
– Absorption is poor  systemic ADR is minimal.
– GIT: NV.

Chemotherapy 248
 PRAZIQUANTEL
MOA: absorbed by helminthes.
 At low concentration  spastic paralysis 
detachment of worms.
 At high concentration  disruption of the
tegument of the worm  rendered vulnerable to
lethal effect of host defenses.
Therapeutic uses:
– Active against cestodes and trematodes.
Adverse effects:
Transient headache
Abdominal discomfort
Drowsiness

Chemotherapy 249
 TREMATODE INFESTATION
1. Schistosomiasis (blood fluke infestation)
– For both acute & chronic phase, praziquantel is
the drug of choice.
2. FACILIASIS (Liver fluke infestation)
– Praziquantel is the drug of choice
– Bithionol is the alternative
3. FASCIOLOPSIASIS (Intestinal fluke infestation)
– Praziquantel is Rx of choice

Chemotherapy 250
ANTINEOPLASTICS
Cancer:
 Uncontrolled multiplication and spread within
the body of abnormal forms of body's own
cells.
Neoplasm
– A mass of tissue formed as a result of
• Abnormal
• Excessive
• Uncoordinated
• Autonomous and
• purposeless
Proliferation of cells.
Chemotherapy 252
 Why term Chemotherapy???
• Like infective disease;
– Some malignant cells can be cultured
– Some malignancies can be transmitted by
inoculation.

Chemotherapy 253
Cancer chemotherapy is not as successful as
antimicrobial chemotherapy because;
 Metabolism in parasite differs qualitatively from
host cells, while metabolism in cancer cells differ
only quantitatively from normal host cells.
– Hence selective toxicity is more difficult in
cancer.
– There is no substantial immune response.
– Diagnostic complexity: delay in institution of
treatment.

Chemotherapy 254
 Modalities of treatment in cancer
 Surgery 1/3 of patients can be cured,
effective when tumor has not
 Radiotherapy metastasized.
 Chemotherapy: 50% of the patients can be
treated with chemotherapy contributing to
cure in 15-20% of patients.

Chemotherapy 255
 Cancer chemotherapy can be curative in;
 Acute Leukemia
 Wilm’s Tumour In children
 Ewing’s Sarcoma
 Choriocarcinoma
 Hodgkin’s Disease
 Non Hodgkin’s Disease
 Burkitts lymphoma
 Testicular Teratomas
 Seminomas

Chemotherapy 256
Chemotherapy can have only Palliative effect in;
 Breast Cancer
 Ovarian Cancer
 Endometrial Cancer
 Prostatic Cancer
 Chronic Lymphatic Leukemia
 Chronic Myeloid Leukemia
 Head & Neck Cancer
 Lung (small cell) Cancer

Chemotherapy 257
 Chemotherapy is less sensitive in;
 Colorectal Cancer
 Carcinoma Stomach
 Carcinoma of esophagus
 Renal carcinoma
 Hepatoma
 Bronchogenic (non small cell) carcinoma
 Malignant Melanoma
 Sarcoma

Chemotherapy 258
Chemotherapy 259
 Classification of Anticancer Agents-I
A. Cell Cycle Specific (CCS) agents
1. Antimetabolites (S phase): Capecitabine, Clofarabine,
Cytarabine, Fludarabine, 5-Fluorouracil (5-FU), Gemcitabine, 6-
Mercaptopurine (6-MP), Methotrexate (MTX), 6-Thioguanine (6-
TG)
2. Epipodophyllotoxin (topoisomerase II inhibitor) (G1–S
phase): Etoposide
3. Taxanes (M phase): Albumin-bound paclitaxel, Paclitaxel
4. Vinca alkaloids (M phase): Vinblastine, Vincristine,
Vinorelbine
5. Antimicrotubule inhibitor (M phase): Ixabepilone
6. Antitumor antibiotics (G2–M phase): Bleomycin
Kills actively dividing cells.
Chemotherapy 260
 Classification-I...
B. Cell Cycle Nonspecific (CCNS) agents
1.Alkylating agents: Carmustine, Chlorambucil,
Cyclophosphamide, Dacarbazine, Lomustine
2.Antitumor antibiotics: Dactinomycin, Mitomycin
3.topoisomerase I inhibitors: Irinotecan,
Topotecan
4.Platinum analogs: Carboplatin, Cisplatin,
Oxaliplatin
5.Anthracyclines: Daunorubicin, Doxorubicin,
Epirubicin
Kills resting cells & dividing cells.
Chemotherapy 261
 CLASSIFICATION-II:
Depending on mechanism at cell level
Directly acting Cytotoxic drugs:
drugs Indirectly acting- by
 Alkylating agents altering the hormonal
mileau:
 Antimetabolites  Corticosteroids
 Natural products  Estrogens & ERMs
– Antibiotics  5 alpha reductase
– Vinca alkaloids inhibitors
– Taxanes  GnRH agonists
– Epipodophyllotoxins  Progestins
– Camptothecin analogs
– Enzymes
– Biological response
modifiers
 Miscellaneous: Cisplatin,
Carboplatin
Chemotherapy 262
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General toxicity of Cytotoxic Drugs
 Nausea & Vomiting
 Bone marrow depression
 Alopecia
 Gonads: Oligospermia, impotence, ↓ ovulation
 Foetus: Abortion, foetal death, teratogenicity
 Carcinogenicity
 Hyperuricemia
 Immunosupression: Fludarabine
 Hazards to staff

Chemotherapy 272
 Chemotherapeutic Agents…

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T H E
H N
E N D ATE /2020!!!

Chemotherapy 275