Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman


Definition: It is the use of a drug (chemotherapeutic agent) to kill or stop growth and
multiplication of infective microbes (anti-microbial chemotherapy), or to kill cancer cells
(anti-cancer chemotherapy).
Anti-Microbial Chemothearpy:
Anti-microbial chemotherapeutics are further classified into:
a) Anti-Bacterial chemotherapy (including Anti-Tuberculous Drugs).
b) Anti-Fungal chemotherapy.
c) Anti-Viral chemotherapy.
d) Anti-Protozoal chemotherapy: include Anti-amoebic and Anti-malarial chemotherapy.
e) Anti-Helminthic chemotherapy.
Anti-Bacterial Chemotherapy
Scheme for studying anti-bacterial chemotherapy:
1) Source:
Chemotherapeutic agents are either:
a) Natural : from microorganism source as fungi = Antibiotics.
b) Semisynthetic.
c) Synthetic (sulphonamides and fluroquinolones).
2) Chemistry:
3) Pharmacokinetics:
a) Absorption:
I. Poorly absorbed chemotherapeutics as Aminoglycosides should be given
parenterally to treat systemic infections, but are given orally to treat local GIT
II. Broad spectrum antibiotics, especially if incompletely absorbed, lead to
Superinfection and Vitamin B and K deficiency (they affect bacterial flora).
III. Antacids containing Mg
and Al
reduce oral absorption of Quinolones and
IV. Food decreases absorption of penicillins especially Ampicillin.
in milk and other dairy products as well as oral iron preparations decrease oral
absorption of Tetracyclines.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

b) Distribution:
I. Plasma protein binding: Sulphonamides are highly bound to plasma proteins and
they displace other drugs as warfarin and oral hypoglycemics, and displace
bilirubin in neonates leading to hyperbilirubinemia (jaundice and Kernicterus may
II. Chemoterapeutics that pass BBB and achieve high level in CSF are useful in
treatment of meningitis. Some chemotherapeutics cannot penetrate normal
meninges but penetrate inflamed meninges in case of meningitis, as penicillins.
Drugs that cannot penetrate even inflamed meninges may be given intrathecal as
III. Some chemotherapeutics may be teratogenic (as Aminoglycosides, Tetracyclines,
Quinolones, Sulphonamides, and Chloramphenicol) whereas others are safely
used in pregnancy (as Penicillins and Erythromycin).
c) Fate:
I. Some chemotherapeutics are metabolized in the liver and are not effective in
treatment of urinary tract infections (UTIs), and are better avoided in patients
with hepatic insufficiency.
II. Other chemotherapeutics are excreted unchanged in urine (by glomerular
filtration or active secretion) and are accordingly useful in UTIs. They are better
avoided in renal impairment, or the dose may be adjusted according to renal
functions (creatinine clearance).
III. Few chemotherapeutics are excreted in bile and are very effective in treatment of
GIT infections as typhoid fever and in biliary tract infections. They usually undergo
"entero-hepac recycle" and have long duraon of acon, may be given once / 24
hours which results in excellent compliance.
4) Pharmacodynamics:
a) Action on bacteria: chemotherapeutics may be either:
I. Bactericidal: they kill "active growing and multiplying bacteria", e.g. β-lactam
antibiotics (penicillins-cephalosporins-monobactams-carbapenems), vancomycin,
co-trimoxazole, polypeptide antibiotics. They should be used in immuno-
compromised patients and in serious infections as endocarditis, septicemia, and
II. Bacteriostatic: they stop growth and multiplication of bacteria, e.g.
sulphonamides, chloramphenicol, tetracyclines, trimethoprim. Bacteriostatic
drugs should not be given to immuno-compromised patient (due to D.M., AIDS,
patients treated by immunosuppressive drugs as cortisone and cancer
N.B.: few chemotherapeutics may be bacteriostatic or bactericidal according to their
concentration or the state of activity of bacteria, e.g. erythromycin and isoniazid.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

b) Mechanism of action:
Chemotherapeutic agents may act by the following mechanisms:

Chemotherapeutic Mechanism of Action
1) β-Lactam antibiotics:
2) Vancomycin.
3) Cycloserine.
4) Bacitracin.
1-Inhibition of cell wall synthesis:
Polymyxins. 2-Interference with cell membrane:

1) Aminoglycosides.
2) Tetracyclines.

1) Chloramphenicol.
2) Macrolides (as Erythromycin)
and Clindamycin.
3-Inhibition of Protein synthesis:
A-Inhibion of 30 S ribosomal subunit:

B-Inhibion of 50 S ribosomal subunit:
Fluroquinolones. 4-Inhibition of DNA synthesis by
inhibition of DNA gyrase:
Rifampicin. 5-Inhibition of RNA synthesis by
inhibition of DNA –dependent RNA
1) Sulphonamides.
2) Trimethoprim.
3) Co-trimoxazole.
6-Inhibition of folic acid synthesis:

5) Spectrum of activity:
Chemotherapeutic agents are broadly classified according to spectrum of activity into:
a) Narrow Spectrum.: e.g. Aminoglycosides and some penicillins.
b) Broad (Wide) Spectrum: e.g. Chloramphenicol, Tetracyclines, and some penicillins.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

Infection Microorganism

a) Pyogenic infections; e.g. of skin
(abscess) and bone (osteomyelitis).
b) Endocarditis.

a) Upper respiratory tract infections
(RTIS): tonsillitis, pharyngitits, otitis,
b) Lower respiratory tract infections:
bronchitis and pneumonia.
c) Rheumatic fever.
Gram positive cocci


Tetanus and gas gangrene.


Gram positive bacilli

2-Corynebacterium diphtheria

3-Bacillus anthracis


Gram negative cocci:
1-Neisseria gonorrhea

2-Neisseria meningitidis
a) GIT infections (Typhoid, Bacillary
dysentery, Cholera).
b) Peptic ulcer (by H.pylori).
c) Urinary tract infections (UTIs).
d) Meningitis.
e) Septicemia.
f) Pneumonia.
g) Endocarditis.
Gram negative bacilli:
E.coli, Proteus, Klebsiella,
Pseudomonas, H.pylori,
Salmonella, Shigella, Vibrio
a) Pneumonia.
b) Uro-genital infections.
c) Eye infections (trachoma).
Pneumonia (Atypical). Mycoplasma:

T.B. Mycobacterium tuberculosis:

Syphilis. Treponema pallidum:

Pneumonia in AIDS. Pneumocystis cainii:
Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

6) Indications:
a) Treatment of infections: according to spectrum.
b) Prophylaxis against infections (Chemoprophylaxis): for example:
I. Prophylaxis against rheumatic fever (by benzathine penicillin).
II. Prophylaxis against endocarditis (by procaine penicillin or vancomycin).
III. Prophylaxis against meningococcal meningitis (by rifampicin).
7) Adverse (toxic) effects:

Adverse Effects Chemotherapeutic
Hypersensitivity (rash, urticaria, angioedema, and
anaphylactic shock).
1) Penicillins:
a) Hypersensitivity and cross allergy with penicillins.
b) Nephrotoxicity.
2) Cephalosporins:
a) Ototoxicity (damage of 8
cranial nerve)
b) Nephrotoxicity.
3) Aminoglycosides:
a) Gut upsets (nausea, vomiting, colics, and diarrhea).
b) Cholestatic hepatitis.
c) HME inhibition.
4) Erythromycin:
a) Bone marrow depression.
b) Grey baby syndrome.
c) Diarrhea and superinfection.
d) HME inhibition.
5) Chloramphenicol:
a) Gut upsets (nausea, vomiting, hyperacidity,
b) Chelation with Ca
in bone and teeth.
c) Fanconi syndrome (nephrotoxicity by outdated
d) Teratogenicity.
6) Tetracyclines:
a) Hypersensitivity reactions.
b) Crystalluria.
c) Blood dyscrasias (bone marrow depression and
hemolysis in paents with G6PD deficiency).
d) Hyperbilirubinemia and kernicterus (in neonates), and
displacement of other drugs from plasma proteins.
7) Sulphonamides:
a) Arthropathy (damage of growing articular cartilage).
b) HME inhibition.
c) Seizures especially with NSAIDs.
8) Fluroquinolones:
a) Red man syndrome
b) Ototoxicity -Nephrotoxicity.
9) Vancomycin:

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

8) Drug interactions:
a) Drug interaction before administration:
Anti-Pseudomonal penicillins (acidic) should not be mixed with Aminoglycosides
(basic) in the same syringe or infusion bottle to avoid chemical antagonism.
b) Pharmacokinetic interactions:
I. Absorption: see before.
II. Distribution: see before.
III. Metabolism:
1. Erythromycin, chloramphenicol, and fluroquinolones are HME inhibitors.
2. Rifampicin is a HME inducer.
IV. Excretion:
Probenicid decreases renal tubular secretion of penicillins and cephalosporins
leading to increased duration of action.
c) Pharmacodynamic interactions:
I. Bactericidal drug + Bactericidal drug → Synergism.
II. Bacteriostatic drug + Bacteriostatic drug → Synergism or Addion.
III. Bactericidal drug + Bacteriostatic drug → Antagonism (cidal drugs act on acve
growing and multiplying bacteria).
d) Benefits of Anti-microbial Combinations:
I. To achieve synergism (see before).
II. To reduce the incidence of bacterial resistance.
III. To reduce toxic effects of individual drugs.
IV. To broaden the spectrum.
V. To treat mixed infections.
VI. To treat serious infections as septicemia before diagnosis (empiric therapy).
Inhibitors of Cell Wall Synthesis:
I-β-Lactam Antibiotics:
They have the following common characteristics:
a) Contain β-Lactam ring which is essential for anti-bacterial activity. Bacteria producing β-
lactamases as Staph. aureus destroy β-lactam ring and show resistance to some
b) Bactericidal.
c) Inhibit cell wall synthesis by inhibition of transpeptidase enzyme.
They include:
I. Penicillins.
II. Cephalosporins (and Cephamycins).
III. Carbapenems.
IV. Monobactams.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

a) Source:
I. Natural from fungi (moulds): benzyl penicillin (penicillin G) and phenoxymethyl
penicillin (penicillin V).
II. Semi-synthetic.
b) Chemistry:
I. Derivaves of 6-Amino Penicillanic acid.
II. Contain β-Lactam ring.
c) Pharmacokinetics:
I. Absorption:
1) Some penicillins are "Acid-Sensitive": destroyed by gastric acidity and
accordingly not given orally; e.g. benzyl penicillin –procaine penicillin –
benzathine penicillin – methicillin –carbenicillin.
2) Other penicillins are "Acid-Resistant": not destroyed by HCl and are given
orally; e.g. phenoxymethyl penicillin- ampicillin- amoxycillin.
3) Ampicillin is incompletely absorbed orally especially in the presence of food.
II. Distribution:
1) Bound to plasma proteins.
2) Pass placental barrier and are safe in pregnancy.
3) Penicillins cannot penetrate normal meninges but penetrate well inflamed
meninges in case of meningitis. They can also be given intra-thecal but may
cause convulsions.
III. Fate:
Penicillins are excreted unchanged (active) in urine by tubular secretion mainly
and to a much lesser extent by glomerular filtration.
1) They are effective in treatment of UTIs.
2) The dose should be adjusted in cases of renal impairment according to kidney
3) Benzyl penicillin is rapidly excreted and has short duration of action. Probenicid
reduces the rate of urinary excretion and accordingly prolongs the duration of
action of penicillins.
4) Nafcillin is excreted in bile and undergoes entero-hepatic circulation and has
long duration of action.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

IV. Antibacterial Activity:
1) Action on bacteria: Bactericidal.
2) Mechanism of action:
a) Penicillins bind to specific penicillin binding proteins (PBPs) → inhibion of
transpeptidase enzyme→ inhibion of cross linking between pepdoglycan
layers → inhibition of cell wall synthesis.
b) Penicillins activate bacterial autolytic enzymes (autolysins) → cell wall lysis.
c) Bacteria imbibe water by its high osmotic pressure leading to rupture and
cell death.
N.B.: penicillins act on active growing bacteria not on resting ones.
3) Selectivity: Penicillins have selective toxicity, they act on bacteria but do not
affect human cells due to the lack of peptidoglycan cell wall in human cells.
4) Resistance: resistance shown by some microorganisms to penicillins may be:
a) Natural: due to absence of peptidoglycan cell wall as in Mycoplasma.
b) Acquired (plasmid-mediated) by:
I. Synthesis of enzymes that destroy the β-lactam ring of penicillins, these
enzymes are known as "β-lactamases" or penicillinases.
II. Alteration in the binding site of penicillins (PBP).
III. Decreased permeability (influx) to penicillins.
IV. Increased efflux (extrusion) of the antibiotic from the inside of the
bacterial cells to the outside.
Give reason:
1) Penicillins have "selective toxicity" and are considered safe antibiotics.
2) Penicillins are inactive against Mycoplasma, Mycobacteria, Fungi, and Viruses.
d) Spectrum:
Penicillins are classified according to their spectrum into:
1) Narrow spectrum penicillins.
2) Broad spectrum penicillins.
3) Extended spectrum penicillins (known as Anti-Pseudomonal penicillin).

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

Examples Active Against Type of Penicillin
a) Benzyl penicillin.
b) Procaine penicillin.
c) Phenoxymethyl penicillin.
d) Benzathine penicillin.
a) Gram positive bacteria
(cocci and bacilli).
b) Gram negative cocci
Not active against Gram
negative bacilli.
1) Narrow spectrum:
a) Ampicillin.
b) Ampicillin esters =
Ampicillin prodrugs = Pro-
ampicillins: Bacampicillin,
Talampicillin, Epicillin.
c) Amoxycillin.
a) Gram positive bacteria
(cocci and bacilli).
b) Gram negative cocci.
c) Gram negative bacilli
Except Pseudomonas,
Proteus, and Klebsiella.
d) Broad spectrum:
a) Carbenicillin.
b) Carbenicillin indanyl.

a) Ureido-penicillins:
b) Piperacillin.
c) Azlocillin.
d) Mezlocillin.
e) Ticarcillin.
a) Gram positive bacteria
(cocci and bacilli).
b) Gram negative
bacteria (cocci and
bacilli including
Proteus, and
e) Extended spectrum

N.B.: Penicillins are also active against anaerobes except β-lactamase producing Bacteroides
fragilis, Spirochaetes (Treponema pallidum and acute ulcerative gingivitis), and Actinomyces
israelii (actinomycosis).
e) Indications:
I. Chemoprophylaxis:
1) Prophylaxis against streptococcal infections in patients with rheumatic fever by
benzathine penicillin (1,200.000 units IM every month for 5 years or unl
reaching 20 years of age; which is ever longer. Some physicians advise life-long
2) Prophylaxis against endocarditis in patients with valve disease or prosthetic
valves before dental procedures. Procaine penicillin (300,000 – 600,000 units
IM) is used.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

II. Treatment of:
1) Respiratory tract infections: pharyngitis, tonsillitis, otitis, sinusitis, bronchitis,
and pneumonia.
2) Urinary tract infections.
3) GIT infections as typhoid fever and bacillary dysentery and eradication of
H.pylori in peptic ulcer.
4) Meningitis.
5) Gonorrhea.
6) Pyogenic infections as abscess, osteomyelitis.
7) Endocaditis.
8) Diphtheria, tetanus, gas gangrene, anthrax.
9) Actinomycosis.
10) Syphilis.

f) Adverse effects: (Penicillins are among the safest antibiotics)
I. Hypersensitivity (allergic reactions):
1) It is due to "penicilloic acid" which acts as a hapten.
2) It is manifestsed as rash, urticaria, angioedema, or anaphylactic shock (treated
by adrenaline IM, cortisone IV, and antihistaminics).
3) It is prevented by asking the patient for previous history and by skin test.
4) The patient should never re-use penicillins.
5) There is "cross allergy" between penicillins and other β-lactam antibiotics as
cephalosporins in about 10% of populaon , due to similarity in the chemical
6) Ampicillin causes "maculopapular rash" in case of:
a) Allergy.
b) Leukemia.
c) Infectious mononucleosis (diagnostic test).
d) Patients treated by allopurinol.
II. Diarrhea and superinfection especially with ampicillin. Superinfection may be
caused by monilia (candida) and is treated by Nystatin orally, or by Staph. or by
Clostridium difficile which is treated by oral Vancomycin or Metronidazole.
III. Local pain and induration due to IM injection (benzathine penicillin), and
thrombophlebitis after IV injection.
IV. Seizures and epileptic fits in case of large doses or intrathecal injection.
V. Penicillins are given in the form of Na
or K
salts, which may lead to
hypernatremia or hyperkalemia especially in cardiac and renal patients.
VI. Platelet dysfunction leading to bleeding (by carbenicillin, ticarcillin, and rarely
benzyl penicillin).
VII. Acute interstitial nephritis by methicillin (not used clinically).
Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

VIII. Jarisch-Herxheimer reaction: due to release of toxins from dead Treponema in
syphilitic paents treated by 1
dose of penicillin. The manifestations are similar
to allergic reactions and are treated by cortisone. In contrast to allergy; penicillin
therapy should be continued.
g) Contraindications:
I. Allergy.
II. Epilepsy.

h) Penicillin Preparations (Classification):
I. Benzyl Penicillin (Penicillin G):
1) Natural.
2) Acid-sensitive: not given orally, given by IV and IM injection.
3) β-Lactamase (penicillinase)-sensitive: inactive against bacteria that produce β-
lactamase as Staph.aureus.
4) Narrow spectrum (see before).
5) Short acting due to rapid excretion in urine.
II. Long-Acting Penicillins:
1) Procaine Penicillin.
2) Fortified Procaine Penicillin: combination of benzyl penicillin (rapid onset) and
procaine penicillin (long duration).
3) Benzathine Penicillin: used only for chemoprophylaxis against Rheumatic fever,
and not for treatment of infections.
They all have the following characteristics:
a) Acid-sensitive.
b) β-Lactamase-sensitive.
c) Narrow spectrum.
III. Acid-Resistant Penicillin: Phenoxymethyl Penicillin (Penicillin V):
1) Natural.
2) β-Lactamase-sensitive.
3) Narrow spectrum.
4) Short duration of action.
IV. β-Lactamase (Penicillinase) Resistant Penicillins:
1) Oxacillin.
2) Cloxacillin.
3) Dicloxacillin.
4) Flucloxacillin.
5) Nafcillin: excreted in bile and has entero-hepatic circulation.
Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

All are acid-resistant.
6) Methicillin: acid-sensitive -nephrotoxic (causes acute interstitial nephritis) –
obsolete- some strains of Staph. aureus became resistant to methicillin and are
known as MRSA. They are treated by vancomycin.
V. Broad Spectrum Penicillins:
Active against Gram positive and Gram negative bacteria except Pseudomonas,
Proteus, and Klebsiella.
1) Ampicillin:
a) Acid-resistant (given orally).
b) β-Lactamase-sensitive (inactive against Staph.).
c) Incompletely absorbed orally especially in the presence of food, causing
diarrhea and superinfection.
d) May cause maculo-papular rash (see adverse effects).
2) Ampicillin Esters (Pro-Ampicillins = Ampicillin Prodrugs):
a) They are better absorbed orally than ampicillin and accordingly cause
minimal diarrhea and superinfection.
b) They are de-esterified in the liver and gut mucosa into "active" ampicillin.
c) They include: Bacampicillin – Talampicillin – Pivampicillin.
3) Amoxycillin:
a) Acid-resistant (given orally).
b) β-Lactamase sensitive.
c) Absorption is much better than ampicillin and not affected by food.
VI. Extended Spectrum = Anti-Pseudomonal Penicillins:
a) They are active against Gram positive and negative bacteria including
b) They are β-lactamase sensitive.
c) They are acid sensitive (except carbenicillin indanyl).
d) They are given with aminoglycosides in treatment of serious infections to
achieve synergism but should not be mixed in the same syringe or bottle
e) They are subdivided into:
Carboxypenicillins: Carbenicillin – Carbenicillin indanyl.
Ureidopenicillins: Azlocillin – Mezlocillin – Piperacillin – Ticarcillin.
How To Treat β-Lactamase Producing Bacteria?:
1) By β-Lactamase resistant penicillins as oxacillin, cloxacillin, dicloxacillin, and nafcillin.
2) By combination of β-lactamase resistant penicillin with broad spectrum penicillin, e.g.:
Ampicillin + Cloxacillin =Ampiclox

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

3) By combination of broad spectrum penicillin or anti-pseudomonal penicillin with β-
lactamase inhibitors (suicide inhibitors) as clavulanic acid- sulbactam – tazobactam:
Examples: Ampicillin + sulbactam = Unasyn
Amoxycillin + clavulanic acid = Augmentin
2. Cephalosporins:
a) Source: Natural and semisynthetic.
b) Chemistry: β-Lactam antibiotics.
c) Pharmacokinetics:
I. Absorption: they may be given orally and parenterally (IV and IM).
II. Distribution: bound to plasma proteins-pass placental barrier and are safe in
pregnancy- 1
and 2
generaons cannot pass BBB whereas 3
Cefoperazone) and 4
generations easily penetrate BBB into CSF.
III. Fate: most cephalosporins are excreted unchanged in urine mainly by tubular
secretion and adding probenicid prolongs their action (as penicillins).
Ceftriaxone and Cefoperazone are excreted in bile and undergo entero-hepatic
circulation (long duration and very effective in GIT infections as typhoid fever).
d) Pharmacodynamics: As penicillins:
I. Action on bacteria: Bactericidal.
II. Mechanism of action: Inhibit cell wall synthesis.
e) Spectrum:
Gram positive, Gram negative, and anaerobes (especially Cefoxitin).
I. Activity on Gram positive: 1
generaon > 2
generaon > 3
and 4

II. Activity on Gram negative: 3
and 4
generaons > 2
generaon > 1

III. Β-Lactamase Resistance: all cephalosporins are resistant to β-lactamases but
resistance increases from 1
to 4
f) Indications:
I. Respiratory tract infections.
II. Urinary tract infections.
III. Meningis (3
and 4
generations except cefoperazone).
IV. Gonorrhea.
V. Typhoid fever (especially cefoperazone and ceftriaxone).
VI. Anaerobic infections (especially cefoxitin).
VII. Pyogenic infections especially if due to penicillin-resistant bacteria.
VIII. Serious infections by Gram negative bacteria as endocarditis and septicemia.
IX. Prophylaxis against surgical wound infections.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

g) Adverse effects:
I. Hypersensitivity: allergy to cephalosporins is less frequent than penicillins. In
about 10% of people there is "cross allergy" with penicillins.
II. Nephrotoxicity; especially if given with aminoglycosides (also nephrotoxic) and
with loop diuretics (increase renal concentration of cephalosporins).
III. Diarrhea and superinfections with oral administration.
IV. Pain and induration after IM injection.
V. Thrombophlebitis after IV injection.
VI. Hypoprothrombinemia and bleeding due to vitamin K deficiency (by
cefoperazone and cefamandole).
VII. Disulfiram-like action in alcoholic patients (disulfiram inhibits aldehyde
dehydrogenase leading to accumulation of acetaldehyde after alcohol injestion
causing nausea, vomiting, bronchospasm, and hypotension).
h) Classification of Cephalosporins:


Generation 2
Generation 1
Generation Character
Broad: as

Broad:more active on G-
ve than on G+ve.
Broad:more active on
G-ve and less on
Broad: G+ve > G-
than 3

More resistant than 2

More resistant than
Resistant. Resistance to β-
across BBB.
Excellent passage except
Cannot pass BBB Cannot pass BBB Passage across
only IV.
a) Oral:

b) Parenteral:
I. Cefoperazone
(cannot pass BBB,
excreted in bile)
II. Ceftriaxone
(excreted in bile)
III. Cefotaxime
IV. Moxalactam.
a) Oral:

b) Parenteral;
a) Cefamandole
b) Cefoxitin
(most active
a) Oral:
) –

b) Parenteral:

Routes of
Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

4. Carbapenems:
a) Examples: Imipenem – Meropenem – Ertapenem.
b) Source: Synthetic.
c) Chemistry: β-Lactam antibiotics.
d) Pharmacokinetics:
I. Given IV.
II. Pass BBB during meningitis.
III. Pass placental barrier (safe in pregnancy).
IV. Excreted unchanged in urine by tubular secretion. Imipenem is metabolized in
renal tubular cells of PCT by "dihydropeptidase" into an inactive and
nephrotoxic metabolite. That is why imipenem should be combined with a
dihydropeptidase inhibitor as cilastatin.
(Imipenem + Cilastatin = Tienam
N.B.: the dose should be adjusted in renal impairment.
e) Action on bacteria:
f) Mechanism of action:
Inhibit cell wall synthesis (as penicillins).
g) Spectrum:
Active on Gram positive, Gram negative (including Pseudomonas), and anaerobes.
h) Indications:
I. Respiratory tract infections.
II. Urinart tract infections.
III. Anaerobic infections.
IV. Mixed infections.
V. Serious and resistant infections.
i) Adverse effects:
I. Nausea, vomiting, and diarrhea.
II. Seizures (in large doses).
III. Neutropenia and eosinophilia.
IV. Skin rash.
5. Monobactam:
a) Aztreonam
I. Source: synthetic.
II. Chemistry: β-lactam antibiotic.
III. Pharmacokinetics: given IM and IV-excreted in urine.
IV. Pharmacodynamics: bactericidal- inhibits cell wall synthesis.
V. Spectrum: active on Gram negative only (including Pseudomonas), inactive
against Gram positive and anaerobes.
Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

VI. Adverse effecst: thrombophlebitis- superinfection with Staph.-elevates hepatic
serum transaminases- skin rash.
b) Vancomycin:
a) Source: natural.
b) Pharmacokinetics:
I. Not absorbed orally, given by IV infusion to treat systemic infection but is
given orally to act locally on GIT.
II. Poorly penetrates BBB except in meningitis.
III. Passes placental barrier and may cause deafness of fetus.
IV. Excreted unchanged in urine by passive glomerular filtration (useful in UTIs
and dose should be adjusted in renal impairment).
c) Pharmacodynamics:
I. Action on bacteria: bactericidal.
II. Mechanism of action: inhibits cell wall synthesis.
d) Spectrum: Gram positive bacteria (including MRSA and Clostridium difficile).
e) Indications:
I. Chemoprophylaxis against endocarditis in penicillin- allergic patients.
II. Treatment of pseudomembranous colitis (given orally).
III. Treatment of MRSA infections.
IV. Urinary tract infections.
f) Adverse effects:
I. Ototoxicity.
II. Nephrotoxicity.
III. "Red man syndrome": rapid IV infusion leads to histamine release causing V.D.
of cutaneous blood vessels and flushing.
IV. Allergy: rash and fever.
V. Thrombophlebitis.
6. Bacitracin:
a) Polypeptide antibiotic (ineffective orally).
b) Bactericidal-inhibits cell wall synthesis.
c) Spectrum: Gram positive bacteria especially Staph. aureus (β-lactamase
d) Indications: used topically only in treatment of skin and wound infections; never
used systemically because it is extremely nephrotoxic.
7. Cycloserine:
a) Bactericidal by inhibition of cell wall synthesis.
b) Used as a 2
line drug in T.B.
c) adverse effects: CNS manifeststions as headache, drowsiness, convulsions and
toxic psychosis.
Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

Inhibitors of Protein Synthesis
A- Aminoglycosides:
a) Source: most aminoglycosides are natural.
b) Chemistry: Polar (highly ionized and poorly lipid soluble) –strongly basic.
c) Pharmacokinetics:
a) Absorption: poorly absorbed orally, given orally only for treatment of GIT
infections and bowel sterilization. They must be given IM or IV for treatment of
systemic infections. They may be also given topically as skin ointments, by
inhalation in treatment of respiratory tract infections, and intra-thecally in
treatment of meningitis.
b) Distribution:
I. Minimal plasma protein binding (only 10%).
II. Cannot pass BBB even in meningitis (and cannot enter the eye).
III. Concentrated in renal cortex and in endolymph of inner ear.
IV. Pass placental barrier and may induce fetal deafness.
c) Fate:
Aminoglycosides are excreted unchanged in urine mainly by glomerular filtration.

d) Pharmacodynamics:
I. Action on bacteria:
Bactericidal (but bacteriostatic on T.B. bacilli).
II. Mechanism of action:
1) Aminoglycosides diffuse into bacterial cell by an active oxygen-dependent
2) They bind to 30 S ribosomal subunit leading to inhibition of the codon-
anticodon recognition (interfere with the initiation complex of peptide
formation) and misreading of m-RNA with consequent inhibition of protein
1) Aminoglycosides are more active in alkaline medium.
2) Aminoglycosides are inactive against anaerobes (why?).
3) β-Lactam antibiotics enhance diffusion of aminoglycosides.

e) Spectrum:
1) Gram negative bacilli including Pseudomonas.
2) Some Gram positive cocci especially Staph.aureus and Strept.viridans and fecalis
(cauing endocarditis).
3) Mycobacteria T.B.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

f) Indications:
1) Endocarditis.
2) Meningitis.
3) Respiratory tract infections.
4) Urinary tract infections.
5) Septicemia.
6) T.B. by streptomycin (1
line) and kanamycin, viomycin, and amikacin (2
7) Gentamycin is used topically in wound and burn infection and to prevent catheter
8) GIT infections by neomycin and streptomycin orally.
9) Neomycin is used:
a) Orally: Treatment of GIT infection-Bowel sterilization before surgery and
endoscopy-Treatment of ammonia encephalopathy in hepatic insufficiency
(hepatic coma). It was used orally to decrease cholesterol absorption in
treatment of hyperlipidemia.
b) Topically on skin: treatment of wound infections.
c) Inhalation: treatment of respiratory tract infection.
g) Toxic effects:
I. Ototoxicity: aminoglycosides achieve high levels in endolymph and cause damage
of 8
cranial nerve leading to deafness and vertigo, especially if given frequently
for long periods and with other ototoxic drugs as loop diuretics (frusemide).
II. Nephrotoxicity: aminoglycosides are concentrated in renal cortex and may cause
renal impairment or acute tubular necrosis, especially if given frequently for long
periods and with other nephrotoxic drugs as cephalosporins.
III. Skeletal muscle weakness due to inhibition of acetylcholine release from somatic
nerves and decreased sensitivity of N
-receptors (curare-like action). This was
particularly dangerous after intra-pleural and intra-peritoneal injection of
streptomycin in treatment of T.B. as it lead to respiratory paralysis.
IV. Neomycin is extremely toxic and is used locally (never used systemically) and may
cause contact dermatitis-when applied to skin-and diarrhea and malabsorption if
given orally.

Examples of Aminoglycosides:
Streptomycin. Gentamicin. Amikacin (used in gentamicin-resistant bacteria).
Tobramycin. Kanamycin. Viomycin.
Paromomycin (amoebicidal). Netilmicin.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

h) Precautions to reduce toxicity:
I. Adjust the dose in patients with renal impairment.
II. Prolong the intervals between doses (40 mg. / 12 hours is less toxic than 20 mg. /
8 hours).
III. Avoid using other nephrotoxic drugs as cephalosporins.
IV. Avoid loop diuretics because they are ototoxic and also increase the level of
aminoglycosides in renal cortex.
V. Follow up by frequent kidney function tests and frequent audiogram in cases of
long duration of treatment with aminoglycosides.
VI. Never use aminoglycosides in pregnancy.

Give Reason:
Aminoglycosides are usually combined with extended spectrum penicillins in treatment of
serious infections but should not be mixed in the same syringe or container?
B- Macrolides:
1. Erythromycin:
a) Source: natural.
b) Pharmacokinetics:
I. Absorbed orally but is destroyed by gastric acidity (acid-sensitive) and is
given"enteric coated" with estolate ester. It may be given IV.
II. Poor penetration of BBB into CSF.
III. Passes placental barrier and is safe in pregnancy.
IV. Extensively metabolized by the liver and metabolites are excreted in urine and
c) Pharmacodynamics:
I. Mechanism of action:
Macrolides bind reversibly to 50 S ribosomal subunits and inhibit translocaon
of amino acids, thus inhibiting protein synthesis.
They are more active in alkaline medium.
II. Action on bacteria:
Macrolides are bacteriostatic or bactericidal according to their concentration.
d) Spectrum:
I. Gram positive bacteria; both cocci and bacilli.
II. Gram negative cocci and some Gram negative bacilli as H.influenza and
III. Mycoplasma pneumoniae, Chlamydia, and Spirochaetes.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

e) Indications:
I. Treatment of Respiratory tract infections: diphtheria, atypical pneumonia
caused by Mycoplasma and Legionella especially in pregnant and neonates
(tetracyclines are contraindicated).
II. Treatment of Chlamydia infections: pneumonia, uro-genital, and eye infections.
III. Treatment of sexually transmitted diseases: gonorrhea and syphilis.
IV. Alternative to penicillin in penicillin-allergic patients as in cases of prophylaxis
in rheumatic fever and endocarditis.
V. Topically in treatment of Acne vulgaris.
VI. Erythromycin acts as "prokinetic" in cases of diabetic gastroparesis by
stimulating "motilin" receptors in GIT.
f) Adverse effects:
I. GIT disturbances: anorexia, nausea, vomiting, epigastric pain, colics and
II. Cholestatic hepatitis (jaundice) caused by estolate ester.
III. Allergic reactions: fever, rash, and eosinophilia.
IV. Drug interactions: Erythromycin (and Clarithromycin but not Azithromycin)
inhibit CYP 450 3A4 and decreases clearance of theophylline and warfarin and
may cause toxicity by these drugs.
g) Contraindications: liver diseases.
2. Clarithromycin:
a) As erythromycin but more active against atypical bacteria.
b) Better oral absorption and less gut upset.
c) Used in peptic ulcer to eradicate H.pylori.
d) HME inhibitor (as erythromycin).
3. Azithromycin (Zithromax
a) As erythromycin but more active on mycobacteria and Chlamydia and less active
on Staph. and Strept.
b) High tissue concentration (exceeding blood concentration) except CSF then slowly
released from the ssues leading to long t 1/2 and long duraon of acon, and is
given once daily.
c) Not HME inhibitor.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

C- Ketolides:Telithromycin
a) Semi-synthetic macrolide.
b) Given orally once daily due to high tissue concentration.
c) Active against Gram positive, Gram negative, and Chlamydia.
d) HME inhibitor (inhibits CYP 450 3A4 as erythromycin and clarithromycin).
e) Useful in cases of bacterial resistance to macrolides.
D- Lincocamines:
Clindamycin and Lincomycin
a) Pharmacokinetics:
I. Absorbed orally and can be given IV.
II. Highly bound to plasma proteins.
III. Poor penetration into CSF but highly concentrated in teeth and bone.
IV. Metabolized by the liver and excreted in urine and bile.
b) Mechanism of action:as macrolides.
c) Spectrum: as macrolides but much more active against anaerobes except Clostridium
d) indications:
1) Treatment of anaerobic infections as dental infections (usually with
2) Prophylaxis against endocaditis.
3) Tretment of intra-abdominal and female genital infections in combination with
aminoglycosides or cephalosporins.
4) Combined with primaquine (anti-malarial) in treatment of Pneumocystis carinii
pneumonia as alternative to Co-trimoxazole (drug of choice).
e) Adverse effects:
1) Superinfection by Clostridium difficile leading to serious and may be fatal
pseudomembranous colitis treated by oral vancomycin and metronidazole.
2) GIT disturbances.
3) Impaired liver functions.
4) Allergy: skin rash.
5) Neutropenia.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

V- Broad Spectrum Antibiotics:
1) Chloramphenicol:
a) Source: natural.
b) Pharmacokinetics:
I. Well absorbed orally, and may be given by injection and topically.
II. Passes BBB and attains high level in CSF.
III. Fate: mainly metabolized by the liver by conjugation with glucuronic acid,
excreted in urine mainly as metabolite.
c) Pharmacodynamics:
I. Action on bacteria: Bacteriostatic.
II. Mechanism of action:
Binds to 50 S ribosomal subunit and inhibits pepdyl transferase leading to
inhibition of protein synthesis.
d) Spectrum: Gram positive, Gram negative, Rickettsia, and anaerobes.
e) Indications:
I. Respiratory tract infections.
II. Typhoid fever (in acute stage and not in carriers).
III. Meningitis (especially H.influenza).
IV. Rickettsial infections as Typhus.
V. Anaerobic infections (as brain abscess).
VI. Topically in eye and ear infections.
f) Adverse effects:
I. Bone marrow depression (blood dyscrasias): usually in the form of
agranulocytosis, and is either:
1. Toxic = Dose-Dependent: chloramphenicol inhibits mitochondrial protein
synthesis in bone marrow. It is usually reversible after stoppage of the drug.
2. Idiosyncratic = Dose-Independent: is irreversible and may be fatal.
II. Gray Baby Syndrome: occurs in newborn and especially if premature due to
failure to conjugate chloramphenicol. It is characterized by ash color of the skin,
vomiting, hypothermia, hypotension, collapse and shock (treated by HME
inducers as phenobarbitone).
III. Diarrhea, superinfection, and vitamin K deficiency.
IV. HME inhibition and decreases clearance of theophylline, warfarin, phenytoin, and
oral hypoglycemic drugs as tolbutamide.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

2) Tetracyclines:
a) Source: natural and semisynthetic.
b) Pharmacokinetics:
I. Absorption:
1) Tetracycline-Chlortetracycline-Oxytetracycline are incompletely absorbed
orally especially in the presence of food.
2) Doxycycline is completely absorbed orally and not affected by food.
3) All tetracyclines are "chelated" with Ca
(in milk and other dairy products and
in some antacids), Al
(in most antacids), Mg
(in most antacids), and iron (in
oral iron preparations used in treatment of iron deficiency anemia). This
decreases absorption and oral bioavailability of tetracyclines (and iron).
II. Distribution:
1) Poor penetration of BBB except Minocycline which may reach an adequate CSF
concentration and was used in eradication of meningococci in meningococcal
carriers (Rifampicin is better).
2) Pass placental barrier and are teratogenic.
3) Tetracyclines are concentrated bone and teeth, and in calcified tumors, where
they are precipitated with Ca
. Tetracyclines are also concentrated in liver and
III. Fate:
1) All tetracyclines are excreted mainly unchanged in urine (useful in treatment of
UTIs but the dose should be adjusted in renal impairment) except Doxycycline
which is eliminated in bile and can be used in renal impairment without dose
adjustment. Doxycycline undergoes entero-hepatic circulation and is given
once daily.
2) All tetracyclines are excreted in breast milk and are accordingly contraindicated
during lactation.
c) Pharmacodynamics:
I. Action on bacteria: Bacteriostatic.
II. Mechanism of action: Bind to 30 S ribosomal subunit and inhibit protein synthesis
by inhibition of aminoacyl t-RNA from reaching
III. m-RNA –ribosomal complex.
d) Spectrum:
Tetracyclines have the broadest spectrum but are not commonly used because of
serious toxic effects.
I. Gram positive and Gram negative bacteria (very active against vibrio cholera).
II. Chlamydia, Mycoplasma, and Rickettsia.
III. Spirochaetes (Treponema pallidum).
IV. Amoeba (luminal amoebicidal).
Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

e) Indications:
I. Respiratory tract infections: especially if caused by Chlamydia and Mycoplasma
(Atypical Pneumonia) but are contraindicated in newborn and pregnant females
II. Urinary tract infections (except doxycyline).
III. GIT infections as Cholera and eradication of H.pylori in peptic ulcer and amoebic
IV. Minocycline was used in eradication of meningococci in meningococcal carriers
but is now replaced by rifampicin.
V. Demiclocycline decreases renal action of ADH and is used in patients with
excessive ADH release known as Syndrome of Inappropriate ADH (SIADH).
f) Toxicity:
1. GIT disturbances: anorexia, nausea, vomiting, hyperacidity, esophagitis,
esophageal ulcerations and bleeding.
2. Diarrhea, superinfection (by candida, Staph. or Clostridium difficile), and vitamin K
and B deficiency especially with poorly absorbrd tetracyclines.
3. Teratogenicity.
4. Chelation with Ca
in bone and teeth leading to defective growth (enamel
hypoplasia), yellow-brown discoloration, and dental caries.
5. Allergy: rash and photosensitivity.
6. Hepatotoxicity and pancreatic toxicity is more common in pregnant
7. Fanconi syndrome: the use of outdated (expired) tetracyclines causes
nephrotoxicity (glucosuria, aminoaciduria, polyuria, proteinuria).
8. Minocycline causes CNS disturbances as dizziness and vertigo.
9. Demiclocycline causes nephrogenic diabetes insipidus.
10. Thrombophlebitis.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

Inhibitors of Nucleic Acid Synthesis
1. Quinolones:
a) Source: all quinolones are synthetic.
b) Chemistry: all quinolones are 4-fluorinated except Nalidixic acid and Cinoxacin.
c) Pharmacokinetics:
I. Absorption:
Quinolones are well absorbed except in the presence of antacids containing Al

II. Distribution:
1) Bound to plasma proteins.
2) Poor passage across BBB and thus they have low CSF levels.
3) Pass placental barrier and are contraindicated in pregnancy as they may cause
fetal arthropathy (see adverse effects).
4) Highly concentrated in prostate.

III. Fate:
1) Nalidixic acid and cinoxacin have very low blood levels and very high urine levels
because they are rapidly excreted unchanged in urine.
2) Fluoroquinolones are partly metabolized by the liver and mainly excreted
unchanged in urine, and are excreted in breast milk.
d) Pharmacodynamics:
1) Action on bacteria: bactericidal.
2) Mechanism of action: inhibit DNA synthesis by inhibition of DNA gyrase
(Topoisomerase II) which is responsible for supercoiling of bacterial DNA.
e) Spectrum:
1) Nalidixic acid and cinoxacin are active against Gram negative bacteria causing
urinary tract infections as Pseudomonas and Hemophilus.
2) Old fluoroquinolones are active against Gram negative cocci (gonococci), Gram
negative bacilli (Pseudomona, Hemophilus, Salmonella, Shigella, E.coli, Proteus),
Mcoplasma, Chlamydia, Mycobacteria T.B., some Gram positive cocci as Staph.
but are inactive against Strept. and anaerobes. Examples: Ofloxacin Norfloxacin
3) New fluoroquinolones have similar spectrum to old fluoroquinolones and are
more active against Gram positive including Strept. and MRSA, and are active
against anaerobes.
Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

4) Examples: Levofloxacin Gatifloxacin Moxifloxacin Sparfloxacin (may cause
phototoxicity and cardiac arrhythmias as prolonged QT)
5) Trovafloxacin (hepatotoxic).

f) Indications:
1) Urinary tract infections.
2) Prostatitis.
3) Gonorrhea.
4) GIT infections as Typhoid fever and bacillary dysentery.
5) Respiratory tract infections including Mycoplasma pneumonia.
6) Chlamydial infections.
7) Multi-drug resistant T.B.
8) Pyogenic infections of skin, soft tissues, and bones.

g) Adverse effects:
1) Arthropathy (damage of growing articular cartilage of bones), tendonitis, and joint
2) Allergy: skin rash and photosensitivity.
3) Gut upsets: nausea, vomiting, and abdominal pain.
4) CNS disturbances: headache, dizziness, and seizures which may occur if given with
5) Hepatotoxicity: with trovafloxacin.
6) Phototoxicity and prolonged QT interval in ECG: with sparfloxacin.

h) Drug interactions:
1) HME inhibition: decreases clearance of theophylline.
2) Seizures in some patients treated with NSAIDs.

i) Contraindications:
1) Pregnancy and lactation.
2) Pre-pubertal children.
3) Allergy.
4) Epilepsy.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

Interference with metabolic pathway:
1. Sulphonamides:
a) Source: synthetic.
b) Chemistry: derivatives of Para-Amino Benzene Sulphonamide (Sulphanilamide) which is
structurally similar to Para Amino Benzoic Acid (PABA).
Different sulphonamides are obtained by substitution at N
and N
c) Pharmacokinetics:
I. Absorption:
a) Some sulphonamides are poorly absorbed and are used for local GIT diseases, e.g.
Sulphaguanidine used in bacillary dysentery, and Sulphasalazine (Salazopyrine)
used as anti-inflammatory in treatment of ulcerative colitis.
b) Other sulphonamides are well absorbed orally and used in treatment of systemic
infections (see later).
II. Distribution:
a) Sulphonamides are highly bound to plasma proteins leading to serious drug
interactions, and may lead to displacement of bilirubin causing
hyperbilirubinemia, jaundice, and Kernicterus if used before labor and in
b) They pass BBB.
c) They pass placental barrier and may lead to hyperbilirubinemia and
"Kernicterus" if given in late pregnancy.
III. Fate:
Sulphonamides used for treatment of systemic infections are partly excreted
unchanged in urine (are used in treatment of UTIs, need dose adjustment in renal
impairment, and are more soluble and more active in alkaline urine), and partly
metabolized in the liver by acetylation. The acetylated metabolite is inactive and
insoluble in acidic urine leading to "crystalluria". This is avoided by proper hydration
and by urine alkalinizers as NaHCO
d) Classification on Sulphonamides:
Sulphonamides are classified according to their pharmacokinetic properties into:
I. Poorly Absorbed Sulphonamides:
Sulphaguanidine, Sulphathalidine,Sulphasuxidine: treat bacillary dysentery.
Sulphasalazine (Salazopyrine): Anti-inflammatory in Ulcerative colitis.

II. Rapidly (Completely) Absorbed Sulphonamides:
They are subdivided according to rate of excreon and t 1/2 into:
a) Short Acting (Rapidly excreted): are given every 6 hours and include:Sulphadiazine
and Sulphisoxazole.
b) Intermediate Acting: are given every 12 hours and include:
c) Sulphamethoxazole.
Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

d) Long Acting: are given every 24 hours and include:
e) Sulphadoxine and Sulphamethoxypyridazine.

N.B.: Short acting are bound to plasma proteins, intermediate acting are more bound, and
long acting are the most bound.
III. Sulphonamides for Topical Use:
Silver Sulphadiazine: used as ointment for treatment of burn infections.
Sulphacetamide: used as eye drops in treatment of eye infections.
Mafenide: used as ointment in treatment of wound infections but is ineffective in the
presence of pus which contains high level of PABA which antagonizes sulphonamides.

e) Pharmacodynamics:
I. Action on bacteria: bacteriostatic.
II. Mechanism of action:
Sulphonamides compete with bacterial PABA (due to structural similarity) for
bacterial dihydropteroate synthetase leading to inhibition of folic acid synthesis.

dihydropteroate dihydrofolate
PABA----------------------------► dihydrofolic acid ----------------------►tetrahydrofolic acid
synthetase reductase

Inhibited by sulphonamides inhibited by:
- Pyrimethamine.
N.B. human cells get preformed dihydrofolic acid in diet which is converted into "active"
tetrahydrofolic acid (folinic acid) necessary for synthesis of purines which are in turn
required for DNA and RNA synthesis.

III. Synergism: by drugs that inhibit dihydrofolate reductase: trimethoprim,
pyrimethamine and proguanil (anti-malarial drugs).

IV. Antagonism: by PABA, Pus (has high content of PABA), and drugs that release PABA
as Procaine.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

f) Spectrum:
1. Sulphonamides are active mainly against Gram positive bacteria.
2. They are active against some Gram negative bacteria as Hemophilus and E.coli.
3. Spectrum also involves: Spirochaetes (Treponema), Chlamydia, and Nocardia.
4. Combination with pyrimethamine → acvity against Toxoplasma and malaria.
g) Indications:
1. Urinary tract infections.
2. GIT infections as bacillary dysentery (use poorly absorbed sulphonamides as
3. Ulcerative colitis by sulphasalazine.
4. Respiratory tract infections.
5. Treatment and prophylaxis of meningococcal meningitis (by sulphadiazine); but
rifampicin is considered the drug of choice in prophylaxis.
6. Prophylaxis against streptococcal infections in rheumatic fever as an alternative to
penicillin as in penicillin allergic patients.
7. Locally in treatment of eye infections by sulphacetamide.
8. Locally for treatment of wound and burn infections by mafenide and silver
9. Treatment of Toxoplasmosis, malaria, chlamydial infections, and nocardiosis.
h) Adverse effects:
1. Hypersensitivity reactions: rash, photosensitivity, urticaria, angioedema, erythema
(Stevens-Johnson syndrome), fever, anaphylaxis.
2. There is cross allergy between sulphonamides and thiazides and some loop diuretics
as frusemide and sulphonylureas (oral hypoglycemics).
3. Blood dyscrasias: Bone marrow depression (leucopenia or thrombocytopenia) and
idiosyncratic hemolytic anemia in patients with favism due to G-6-PD deficiency.
4. Crystalluria due to precipitation of acetylated metabolites in acidic urine causing
renal colics, hematuria, and anuria. It is prevented by proper hydration and
alkalinization of urine by NaHCO
, or by using a mixture of soluble sulphonamides.
5. GIT disturbances: nausea, vomiting, diarrhea, and superinfection.
6. Hyperbilirubinemia, jaundice, and kernicterus in newborn.
7. Hepatotoxicity.
i) Drug interactions:
Sulphonamides (especially long acting) displace other drugs as oral anticoagulants, oral
sulphonylureas hypoglycemics, and digitoxin from plasma protein binding sites and may
cause serious toxic effects of such drugs.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

j) Contraindications:
1. Allergy to sulphonamides.
2. Favism.
3. Newborn and pregnancy especially last 2 weeks.
II- Trimethoprim:
a) Source: synthetic.
b) Pharmacokinetics:
I. Absorbed orally.
II. Bound to plasma proteins.
III. Concentrated in prostate and vaginal fluid.
IV. Excreted in urine and is intermediate acting.
c) Pharmacodynamics:
I. Action on bacteria: bacteriostatic.
II. Mechanism of action:
Inhibits dihydrofolate reductase and inhibits synthesis of folinic acid with
consequent inhibition of purines, DNA, and RNA synthesis.
d) Spectrum:
I. Gram negative cocci (Neisseria gonorrhea and meningitides) and bacilli (E.coli,
Hemophilus, Proteus, Salmonella, Shigella, Legionella)
II. Pneumocystis carinii (causing fatal pneumonia in AIDS patients).
e) Indications:
I. Urinary tract infections.
II. Respiratory tract infections.
III. GIT infections as typhoid fever.
IV. Gonorrhea.
V. Pneumocystis carinii pneumonia.
f) Adverse effects:
Megaloblastic anemia due to folinic acid deficiency.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

III-Co-Trimoxazole (Sutrim
a) Combination of Sulphamethoxazole (intermediate sulphonamide) and Trimethoprim
in a rao of 5 : 1 (400 mg. sulpha + 80 mg. trimethoprim in adults, and 100 mg.
sulpha + 20 mg. trimethoprim in children. Given every 12 hours).
b) Action on bacteria: bactericidal.
c) Mechanism of action:
Sulphamethoxazole inhibits dihydropteroate synthetase and trimethoprim inhibits
dihydrofolate reductase; leading to sequential block of the enzymes responsible for
synthesis of folinic acid.
d) Spectrum:
I. Sulphamethoxazole is active mainly on Gram positive, Chlamydia, Spirochaetes,
and Nocardia.
II. Trimethoprim is active mainly on Gram negative bacteria and Pneumocystis
Accordingly Co-trimoxazole acts on all the previous microorganisms.
e) Indications:
I. Drug of choice in Pneumocystis carinii in AIDS.
II. Typhoid fever (both acute stage and carriers).
III. Respiratory tract infections.
IV. Urinary tract infections.
V. Gonorrhea.
VI. Prostatitis.
VII. Chlamydial infections.
VIII. Treatment of Nocardiosis.
f) Adverse effects:
As sulphonamides but less toxic + megaloblastic anemia.
g) Benefits of Combination:
I. Achieves synergism: each drug alone is bacteriostatic but co-trimoxazole is
II. Broadens the spectrum.
III. Reduces toxicity caused by each drug alone.
IV. Reduces the incidence of bacterial resistance.
V. Treatment of mixed infections.
Treatment of Typhoid Fever:
Acute Stage:Co-Trimoxazole, Ciprofloxacin, Ceftriaxone and Cefoperazone (third
generation cephalosporins excreted in bile)are the first choice drugs. Ampicillin and
Amoxycillin are the second choice drugs. Chloramphenicol is the third choice due to
toxicity and bacterial resistance.
Carrier Stage: Ampicillin, Amoxycillin, or Co-trimoxazole.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

Special Chemotherapy
I. Anti-Tuberculous Drugs
Drugs used for chemotherapy against T.B. are classified into 2 lines:
a) First Line Drugs: are more effective and less toxic than second line drugs and include:
1) Isoniazid (Isonicotinic acid hydrazide = INH).
2) Rifampicin.
3) Ethambutol.
4) Pyrazinamide.
5) Streptomycin.
b) Second Line Drugs: are less effective and more toxic than the first line drugs and are
used as alternative to first line drugs especially in case of development of bacterial
resistance, they include:
1) Para amino salicylic acid (PAS).
2) Ethionamide.
3) Cycloserine.
4) Aminoglycosides: viomycin, kanamycin, amikacin, and capreomycin.
5) Fluoroquinolones as ciprofloxacin or ofloxacin in "multi-drug resistant T.B".
6) Clofazimine.
First Line Drugs:
1) Rifampicin:
A. Pharmacokinetics:
I. Absorption:
Well absorbed orally but absorption is affected by food, so it is given on empty
stomach (before breakfast).
II. Distribution:
Distributed to all tissues including CSF.
III. Fate:
Partially metabolized by the liver and partially excreted in: bile (undergoes entero-
hepatic circulation and has long duration so it is given once daily) – urine – sweat
– saliva – tears (causes orange-red discoloration of all these fluids).
B. Pharmacodynamics:
I. Action on Mycobacteria: bactericidal (tuberculocidal). It acts both intra- and extra-
II. Mechanism of action: inhibits DNA-dependent RNA polymerase leading to
inhibition of RNA synthesis.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

C. Spectrum:
I. Mycobacteria T.B.
II. Mycobacteria leprae.
III. Gram negative bactertia as meningococci and H.influenza.
IV. Gram positive bacteria as Staph.
V. Pox viruses.
D. Indications:
I. T.B. (combined with isoniazid ± pyrazinamide or ethambutol).
II. Leprosy.
III. Chemoprophylaxis against meningococcal meningitis; rifampicin is the drug of
choice and has replaced sulphonamides.
IV. To eradicate memingococci in carriers, rifampicin has replaced minocycline (a
V. Treatment of endocarditis by Staph., in combination with a β-lactam antibiotic or
E. Adverse effects:
1. Cholestatic hepatitis and jaundice.
2. Flu-like syndrome at the start of treatment.
3. CNS disturbances: headache, confusion, and ataxia.
4. GIT disturbances.
5. Allergy: fever, rash, and blood dyscrasias (thrombocytopenia).
6. Orange-red discoloration of urine.
7. Drug interaction: rifampicin is a hepatic microsomal enzyme inducer and thus
increases clearance of theophylline, warfarin, oral hypoglycemics, digitoxin, and
oral contraceptives.
2) Isoniazid (I.N.H.):
a) Pharmacokinetics:
I. Absorption:
Well absorbed orally but Al
-containing antacids decrease its absorption.
II. Distribution:
Distributed to all tissues including CSF.
III. Fate:
Mainly metabolized in the liver by acetylation which is genetically determined;
patients are either slow or fast acetylators. Metabolites are excreted in urine.
b) Pharmacodynamics:
I. Action on Mycobacteria: bacteriostatic in resting bacteria (stationery phase) and
bactericidal in active rapidly dividing bacteria. It acts both intra- and extra-cellular.
II. Mechanism of action: inhibits mycolic acid synthesis leading to inhibition of cell
wall synthesis.
Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

c) Spectrum: Mycobacteria T.B. only.
d) Indications: treatment of T.B. (in combination with rifampicin ± pyrazinamide or
e) Adverse effects:
1. Peripheral neuritis especially in slow acetylators due to competition between
vitamin B
(pyridoxine) and INH-due to structural similarity- which impairs
myelination of peripheral nerves. That is why B
should be prescribed
prophylactically with INH.
2. Hepatitis and hepatotoxicity especially in fast acetylators.
3. Hemolysis is patients with G-6-PD deficiency (idiosyncracy).
4. Allergy: rash, fever, blood dyscrasias.
5. Drug interaction: INH inhibits metabolism of phenytoin and may lead to toxicity.
3) Ethambutol:
a) Pharmacokinetics:
Absorbed orally – distributed to all tissues including CSF – excreted in urine and
decreases uric acid excretion.
b) Pharmacodynamics:
1. Action on Mycobacteria: bacteriostatic.
2. Mechanism of action: unknown.
c) Toxicity:
1. Optic neuritis which decreases visual acuity and failure to discriminate between
red and green.
2. Hyperuricemia and may precipitate gouty attacks.
4) Pyrazinamide:
a) Pharmacokinetics:
Absorbed orally – distributed to all tissues including CSF – extensively metabolized by
the liver and metabolite is excreted in urine and decreases uric acid excretion
b) Pharmacodynamics:
1. Action on Mycobacteria: bactericidal.
2. Mechanism of action: unknown.
c) Toxicity:
1. Hepatotoxicity.
2. Hyperuricemia and may precipitate gouty attacks.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

5) Streptomycin: (see Aminoglycosides).
N.B.: all first line drugs –except streptomycin- may cause liver impairment and follow up
by liver function tests is required.
Second Line Drugs:
1) Para Amino Salicylic acid (PAS):
a) Pharmacokinetics:
Absorbed orally – metabolized by acetylation- metabolite is excreted in urine and is
insoluble in acidic urine causing crystalluria (as sulphonamides).
b) Pharmacodynamics:
1. Action on Mycobacteria: bacteriostatic.
2. Mechanism of action:competes with PABA and inhibits folic acid synthesis (as
c) Toxicity:
1. Hepatotoxicity.
2. Allergy.
3. Gut upsets.
4. Crystalluria (prevented by proper hydration and alkalinization of urine by
2) Ethionamide:
a) Chemically related to INH.
b) Given orally and passes into CSF.
c) Toxicity: peripheral neuropathy –optic neuritis- allergy –gut upsets.
3) Aminoglycosides: Kanamycin- Capreomycin – Viomycin – Amikacin.
a) Given IM.
b) Toxicity: Ototoxic and nephrotoxic.
4) Cycloserine:
a) Inhibits cell wall synthesis.
b) Toxicity: CNS manifeststions as headache, drowsiness, vertigo, seizures, and toxic
5) Fluoroquinolones: Ciprofloxacin- Ofloxacin
Used in multi-drug resistant T.B. (see Quinolones).
6) Clofazimine:
Inhibits DNA.
Other actions: Anti-leprotic and Anti-inflammatory.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

Regimens of treatment of T.B.:
1) Rifampicin + INH + Pyrazinamide or Ethambutol for 6 months.
2) Rifampicin + INH for 9 months.

Treatment of Leprosy:
1) Rifampicin.
2) Clofazimine.
3) Sulphones as Dapsone: compete with PABA (as sulphonamides).
4) All are given orally.
II. Anti-Amoebic Drugs
Drugs used in treatment of amoebiasis are classified into:
a) Luminal Amoebicides: they kill cyst form and include:
1. Diloxanide furoate.
2. Paromomycin (aminoglycoside antibiotic).
3. Tetracyclines.
4. Halogenated hydroxyquinolines.
b) Tissue Amoebicides: they kill trophozoits causing intestinal and hepatic amoebiasis
and include:
1. Nitroimidazoles: Metronidazole and Tinidazole.
2. Chloroquine.
3. Emetine and dehydroemetine.
Metronidazole (Flagyl
a) Pharmacokinetics:
 Absorption:
Absorbed orally and also given by IV infusion.
 Distribution:
1) Passes BBB and may cause serious CNS disturbances.
2) Passes placental barrier and induces teratogenicity.
3) Concentrated in vagina, seminal fluid, and saliva.
 Fate:
Metabolized by the liver and is excreted in breast milk.
b) Pharmacodynamics:
1. Action on bacteria and protozoa: cidal (bactericidal and amoebicidal)
2. Mechanism of action:
Metronidazole is reduced inside bacteria and protozoa by ferrodoxin into an
active metabolite which binds to DNA and inhibits nucleic acid synthesis.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

c) Spectrum:
1. Amoeba (tissue more than luminal).
2. Giardia.
3. Trichomonas vaginalis.
4. H.pylori.
5. Anaerobic bacteria including Clostridium difficile.
d) Indications:
1. Treatment of amoebiasis especially acute tissue amoebiasis (intestinal and
2. Treatment of giardiasis.
3. Treatment of uro-genital trichomoniasis in females and males.
4. Eradication of H.pylori in peptic ulcer.
5. Treatment of anaerobic infections as acute ulcerative gingivitis, peritonitis, female
genital tract infections, brain abscess, septic shock.
6. Treatment of pseudomembranous colitis caused by antibiotics as clindamycin,.
Metronidazole is usually given with oral vancomycin.
e) Adverse effects:
1. GIT disturbances: anorexia, nausea, vomiting, and metallic taste.
2. Allergic reactions.
3. Teratogenicity.
4. CNS disturbances: headache, dizziness, parasthesia. If vertigo occurs the drug
should be stopped to avoid CNS toxicity.
5. Intensification of moniliasis (candidiasis) which should be treated by nystatin.
6. Dark color of urine.
7. Disulfiram-like action in alcoholics.
f) Drug interactions:
HME inhibitor and decreases clearance of warfarin.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

III. Anti-Malarial Drugs
Anti-malarial drugs can be classified according to the chemical structure and according
to their action on malaria.
A-Chemical classification:
Anti-malarial drugs are classified chemically into:
1) Aminoquinolines: Chloroquine – Amodiaquine.
2) Aminoquinolines: Primaquine.
3) Pyrimethamine and Proguanil.
4) Quinine
5) Mefloquine.
B- Classification according to action:

Indication in malaria Action in malaria Drugs
1-Clinical cure.
2-Suppressive prophylaxis.
3-Radical cure in P.falciparum
and P.malariae (no relapse).
Blood shizonticidal (act on
erythrocytic stage).
Chloroquine and
1-Causal prophylaxis (unsafe).

2-Radical cure and Anti-relapse
in P.ovale and P.vivax.

3-Prevents transmission.
1-Primary tissue shizonticidal
exo-erythrocytic stage).
2-Secondary tissue
schizoncidal (2
erythrocytic stage).

1-Causal prophylaxis.

2-Suppressive prophylaxis.

3-Prevents transmission.

1-Primary tissue
2-Blood shizonticidal (much
weaker than chloroquine).

Proguanil and
As 4-Aminoquinolines. Blood shizonticidal. Quinine.
(for chloroquine-
resistant P.falciparum).

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

N.B.: there is no "true prophylaxis" against malaria because no drug can kill sporozoits
injected by bite of female Anopheles mosquito.
a) Chemistry: 4-aminoquinoline.
b) Pharmacokinetics:
I. Absorbed orally.
II. Passes BBB and cause CNS disturbances.
III. Passes placental barrier and is teratogenic.
Concentrated in liver, RBCs, retina, kidney, and spleen.
Excreted in urine, excretion is enhanced by acidification of urine.
c) Pharmacodynamics:
 Mechanism of action:
Binds to and inhibits synthesis of DNA and RNA.
 Pharmacological actions:
1) Anti-malarial: blood shizonticidal.
2) Antiamoebic.
3) Anti-giardiasis.
4) Anti-inflammatory.
d) Therapeutic uses:
1. Malaria: clinical cure – suppressive prophylaxis – radical cure in P.falciparum and
malariae (no secondary tissue shizont and accordingly no relapse).
2. Treatment of hepatic amoebiasis.
3. Treatment of giardiasis.
4. Anti-inflammatory in RA and SLE (given in large doses and for long periods).
e) Adverse effects:
1. GIT upsets.
2. Blood dyscrasias (bone marrow depression).
3. Teratogenic.
4. Retinopathy: blurred vision, retinal vasoconstriction, and macular degeneration.
5. Skin manifestations: eruption, dermatitis, alopecia, graying of hair, and pruritus.
6. CNS disturbances: headache, peripheral neuritis.
7. (Adverse effects are more common in patients treated with chloroquine in cases
of RA and SLE).
f) Contraindications:
1. Pregnancy.
2. Psoriasis.
3. Porphyria.
4. With gold salts (used in RA) and phenylbutazone (NSAIDs also used in RA) to avoid
severe dermatitis.
Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

2- Primaquine:
a) Chemistry: 8-Aminoquinoline.
b) Pharmacokinetics:
Absorbed orally – Metabolized by the liver into 6-hydroxy derivative (active
metabolite) and then into quinonimine which causes hemolysis in G-6-PD deficiency.
c) Pharmacodynamics:
 Mechanism of action: unknown.
 Actions: Antimalarial by: primary tissue shizonticidal – secondary tissue
shizonticidal (in P. ovale and vivax) – gametocidal.
d) Therapeutic uses:
I. Causal prophylaxis of malaria (unsafe).
II. Radical cure and anti-relapse in P. ovale and vivax.
III. Prevention of spread by gametocidal action.
IV. Combined with clindamycin as an alternative to co-trimoxazole in treatment of
pneumocystis carinii in AIDS.
N.B.: primaquine is not used in treatment of acute malarial attacks because it is not blood
e) Adverse effects:
1. GIT upsets.
2. Blood dyscrasiasis: Methemoglobinemia- hemolytic anemia in favism (G-6-PD
N.B.: Toxicity of primaquine increases if combined with proguanil.
3- Proguanil and Pyrimethamine:
a) Pharmacodynamics:
 Mechanism of action: inhibit dihydrofolate reductase leading to inhibition of
folinic acid synthesis.
 Actions:
1) Primary tissue shizonticidal.
2) Sporontocidal: inhibits sexual cycle inside mosquito.
3) Blood shizoncidal (much less potent than 4-aminoquinolines and act before
rupture of RBCs).
b) Therapeutic uses:
1) Causal prophylaxis.
2) Prevention of spread.
3) Suppressive prophylaxis.
4) (Pyrimethamine + sulphdoxine = Fansidar).
5) Pyrimethamine + sulphdiazine in treatment of toxoplasmosis.
Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

c) Adverse effects:
1. GIT disturbances.
2. Blood dyscrasias: megaloblastic anemia – granulocytopenia.
4- Quinine:
a) Plant origin: from cinchona bark (as quinidine).
b) Blood shizonticidal used in clinical cure in chloroquine-resistant malaria.
c) Adverse effects: Cinchonism (headache, nausea and vomiting, blurred vision, and
tinnitus) – Gut upset – Blood dyscrasias as hemolysis – Abortion due to oxytocic
5- Mefloquine:
Blood shizonticidal – used for suppressive prophylaxis and clinical cure in chloroquine-
resistant P. falciparum.
IV. Anti-Bilharzial Drugs :
Metrifonate Oxamniquine Praziquantel
Irrevesible anti-
s compound) leading
to paralysis of the
Inhibit DNA in male
worm leading to
hepatic shift and
death. Female
worms fail to lay
Increases Ca
into worm leading to
severe contraction and
spastic paralysis.
Mechanism of
S. hematobium only. S.mansoni only. 1) S.hematobium.
2) S.mansoni.
3) Taeniasis.
4) Hymenoepis nana.
5) Heterophes.
1) Colics and
2) Vertigo.
3) Increases action
1) Convulsions and
2) Orange-red
discoloration of
urine and
3) Low grade fever.
1) Abdominal pain,
anorexia, and
2) Headache and
3) Fever, pruritus
arthralgia, and
myalgia (due to
release of dead
worm contents).
Adverse effects:
Pregnancy. Pregnancy.
Pregnancy. Contraindications
Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

Other Anthelmintic Drugs:
1) Mebendazole and 2) Albendazole
They decrease glucose uptake and inhibit microtubular synthesis.
3) Pyrantel pamoate: depolarizing neuro-muscular blocker.
a) Used in round worms-pinworms-hookworms-taeniasis-hydatid disease-
b) They are contraindicated in pregnancy.
c) They are known as Broad-spectrum anthelmintics.
4) Levamisole:
a) Anthelmintic against round worm by depolarizing neuromuscular blocking action.
b) Immunostimulant.
V. Anti-Fungal Drugs
I. Polyene Antibiotics:
1-Amphotericin B:
a) Chemistry: Polyene antibiotic.
b) Pharmacokinetics:
1. Not absorbed orally, given by I.V. infusion, intra-thecal, and topical on eye,
nose, intra-articular, and to irrigate the bladder.
2. Cannot pass BBB, so must be given intra-thecal in fungal meningitis.
3. Excreted in bile and urine.
c) Pharmacodynamics:
 Action on fungus: Fungicidal.
 Mechanism of action: binds to ergosterol in the fungal cell membrane leading
to formation of channels and leakage of fungal cell content as electrolytes. This
causes death of fungal cells.
(Human cell membrane contains cholesterol not ergosterol).
d) Therapeutic uses:
Systemic fungal infections.
e) Adverse effects:
"Amphotericin has low therapeutic index" so start by small dose.
1. Allergic reactions and anaphlaxis.
2. Fever and chills.
3. Convulsions especially if given intra-thecal.
4. Hypokalemia and nephrotoxicity.
5. Bone marrow depression (aplastic anemia).
6. Thrombophlebitis.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

a) Chemistry: Polyene antibiotic.
b) Pharmacokinetics:
Nystatin should never be given systemically because of its toxicity especially
nephrotoxicity. It is given orally (not absorbed) and locally on skin and vagina.
c) Pharmacodynamics:
 Action on fungus: Fungicidal.
 Mechanism of action: as amphotericin.

d) Therapeutic uses:
Nystatin is the drug of choice in treatment of candidiasis (moniliasis) which is
common in D.M., due to steroids (oropharyngeal candidiasis in asthmatics treated by
inhaled steroids) and due to superinfection by antibiotics.
II. Azoles:
A- Azoles for Systemic Fungal Infections:
1) Ketoconazole (Nizoral
a) Pharmacokinetics:
I. Absorbed from the stomach (in the presence of HCl), absorption is
impaired in the presence of food and by drugs that decrease gastric
acidity as antacids and anti-secretory drugs as cimetidine and
II. Cannot pass BBB.
III. Extensively metabolized by the liver,metabolites are excreted in bile.
b) Pharmacodynamics:
 Action on fungus: Fungicidal.
 Mechanism of action:Inhibits synthesis of cell membrane by inhibition of
ergosterol synthesis.
CYP 450
N.B.: ketoconazole inhibits synthesis of testosterone and cortisol.
c) Therapeutic uses:
1. Systemic fungal infections but not in fungal meningitis.
2. Local fungal infections as hair dandruff (nizoral shampoo).

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

d) Adverse effects:
1. Hepatotoxicity.
2. Inhibits synthesis of testosterone leading to gynecomastia, impotence,
loss of libido, and infertility.
3. Allergy.
4. Gut upsets.
e) Drug interactions:
I. Ketoconazole is a hepatic microsomal enzyme inhibitor and reduces
clearance of theophylline and cyclosporine (immunosuppressive drug
used after renal transplantation).
II. Azoles as ketoconazole antagonize polyene antibiotics (how?).
III. Antacids, H
-blockers (as cimetidine), and Proton pump inhibitors (as
omeprazole) decrease oral bioavailability of ketoconazole.
2) Itraconazole: as ketoconazole but less adverse effects.
3) Fluconazole: as ketoconazole but:
a) Absorption is not affected by food or drugs.
b) Passes BBB and is the drug of choice in fungal meningitis in immunocompromised
c) Less hepatic toxicity.
d) No inhibition of testosterone synthesis and accordingly no gynecomastia or
e) Not HME inhibitor.
B- Azoles for Topical Use:
1) Miconazole.
2) Clotrimazole.
They are never used systemically because of severe toxicity and are used only
for local fungal infections including moniliasis.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

III. Flucytosine:
a) Pharmacokinetics:
Absorbed orally – passes BBB – excreted in urine.
b) Pharmacodynamics:
 Action on fungus: Fungicidal.
 Mechanism of action: converted inside fungal cell into 5-Flurouracil which
inhibits DNA synthesis.
c) Therapeutic uses:
Systemic fungal infections.
d) Adverse effects:
1. Bone marrow depression: thrombocytopenia and neutropenia.
2. Hepatotoxicity.
3. Gut upsets and severe entero-colitis.
e) Drug interaction:
Flucytosine + Azoles → synergism (both are fungicidal and act by different
IV. Griseofulvin:
a) Pharmacokinetics:
Absorbed orally especially in the presence of fats in diet – Concentrated in
keratinized tissues: hair and nails – Extensively metabolized by the liver.
b) Pharmacodynamics:
1. Action on fungus: Fungistatic.
2. Mechanism of action: Binds to and inhibits microtubular protein of the
mitotic spindle and accordingly inhibits mitosis.
3. It inhibits infection of newly synthesized keratin of hair and nails but does
not affect already infected tissues which must be shed. This requires long
term therapy before cure.
c) Therapeutic uses:
Treatment of muco-cutaneous fungal infection of hair and nail
d) Adverse effects:
1. Hepatotoxicity.
2. Teratogenicity.
3. Gut upsets.
4. Headache.
5. Precipitation of acute porphyria.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

e) Contraindications:
1. Pregnancy.
2. Porphyria.
f) Drug interaction:
Griseofulvin is a HME inducer.
V. Terbenafine:
a) Action on fungus: Fungicidal.
b) Mechanism of action: inhibits ergosterol synthesis and thus inhibits cell
membrane synthesis (as azoles but by a different mechanism).
c) Therapeutic uses: Treatment of muco-cutaneous infections of hair and nails, it is
given orally and topically.
d) Adverse effects: Rash – Headache – Gut upsets (it is much safer than griseofulvin).
Anti-Viral Drugs
I. Inhibitors of DNA-Polymerase:
1) Acyclovir (Zovirax
a) Given orally, IV, and topical on eye and skin.
b) Drug of choice in herpes simplex infection (HSV) of: skin, cornea (keratitis),
genitals, and encephalitis. Used also in varicella-zoster viral infections (VCV). Not
effective against cytomegalovirus (CMV) and Epstein Barr virus (EBV).
c) Adverse effects: nephrotoxicity – gut upset- local irritation.
2) Vidarabin: used topically in HSV infections.
3) Idoxuridine: used only topically in HSV keratitis and never used systemically because
of its toxicity.
4) Gancyclovir: used in treatment of cytomegalovirus (CMV) infection of respiratory
system in immunocompromised patients.
5) Foscarnet: as gancyclovir but inhibits both DNA and RNA polymerases.

II. Reverse Transcriptase Inhibitors (RTIs):
a) They inhibit reverse transcriptase = RNA-dependent DNA polymerase in HIV.
b) They are used in treatment of AIDS.
c) They include:
d) Nucleoside RTIs as Zidovudine which causes bone marrow depression and viral
resistance has developed.
e) Non-Nucleoside RTIs as Nevirapine which is less toxic and less virus resistance.

Chemotherapy 2011/2012

Dr.Ahmed Abdel Rahman

III. HIV Protease Inhibitors:
a) They inhibit HIV protease enzyme necessary for synthesis of mature proteins of
virus coat.
b) They are combined with RTIs in treatment of AIDS.
c) Examples: Indinavir –Saquinavir –Ritonavir.
d) They may cause bone marrow depression (thrombocytopenia).
IV. Other Anti-viral drugs:

1) Amantadine:
a) Anti-viral: in prophylaxis of influenza A by inhibition of viral uncoating.
b) Anti-parkinsonian: by stimulation of release and inhibition of reuptake of
c) Ataxia and Ankle edema are characteristic adverse effects.

2) Rimantadine: as amantadine but has no CNS actions (not antiparkinsonian and no

3) Neuraminidase inhibitors: inhibit neuraminidase enzyme leading to inhibition of viral
assembly (clumping) - used in treatment of avian flu - examples include Oseltamivir
and Zanamivir.

4) Ribavirin: inhibits DNA and RNA viruses – used in treatment of hepatitis C virus
(HCV)–causes bone marrow depression, hepatotoxicity, and teratogenicity.

5) Rifampicin: inhibits pox virus by inhibition of assembly and release.

6) Interferons:
a) Polypeptides, so are not given orally, but must be given by injection.
b) Types: alpha, beta, and gamma interferons.
c) Inhibit m-RNA and viral protein synthesis.
d) Used with ribavirin in HCV.
e) Toxicity: bone marrow depression – alopecia – flu like syndrome- anorexia and
weight loss – confusion, ataxia, and seizures.