CHEMOTHERAPY

GENERAL PRINCIPLES OF
ANTIMICROBIAL THERAPY

By Desta H.(B.Pharm in clinical pharmacy)

Hawassa University, Pharmacology Unit

1
 Definition
Antibiotics are antimicrobial substances produced by
various species of microorganisms that suppress the growth
of other microorganisms
Commonly the term extends to include synthetic
antimicrobial agents, such as sulfonamides and quinolones

Are antibiotics necessarily antibacterials ?

Differentiate chemotherapeutic agents, antimicrobials and
antibiotics

2
 General principles of antimicrobial therapy
 Definition:
Chemotherapy Use of drugs against invading organisms
as well as cancerous cells
Antimicrobial agent chemicals against invading
organisms
Antibiotic A drug that is produced by one microorganism
and has the ability to harm other microbes
Commonly the term extends to include synthetic
antimicrobial agents, such as sulfonamides and
quinolones
Goal: Selective toxicity: Ability to injure or kill an invading
microorganism without harming the cells of the host.
» More toxic to the invader and innocuous to the
host 3
• If they were as harmful to the host as they are to infecting
organisms, antimicrobials would have no therapeutic
utility
 How is selective toxicity achieved?
Biochemical differences that exist between
microorganisms and human beings.
Example: Disruption of bacterial cell wall synthesis by penicillins
 Due to differences between bacterial and human cells at four
major sites
 Cell wall
 Cell membrane
 Ribosomes
 Nucleic acids
• Few antiviral agents due to lack of selective toxicity 4
• Minimal inhibitory concentration (MIC): Lowest
concentration of antimicrobial drug capable of
inhibiting growth of an organism in a defined growth
medium
 Classification of Antimicrobial Drugs
 Antibacterial,
 Antifungal ,
 Antiviral,
 Miscellaneous (Antiprozoals, antihelmemthics/worms,
etc.)

5
 Classifications of Antibiotics

 Based on chemical structure and proposed MOA

1) Inhibition of cell wall synthesis
penicillin, cephalosporin, cycloserine, vancomycin,
bacitracin, carbapenems
2) Increase in cell membrane permeability
polyene antibiotics, polymixins, nystatin and
amphotericin B
3) Inhibition protein synthesis
aminoglycosides, chloramphenicol, tetracycline
4) Inhibition nucleic acid synthesis
rifamycins, fluoroquinolones
5) Antimetabolites
sulphonamides, trimethoprim
6
 Use of Anti-infective Agents
Antibiotics have three general uses
Empiric therapy: treatment of an infection before
specific culture information has been reported or
obtained
Antibiotic should cover all the likely pathogens
Either combination therapy or a single broad-
spectrum agent
Definitive therapy :treating the etiology of the infection with
antibiotics effective against that organism
Once the infecting microorganism is identified, a
narrow-spectrum, low-toxicity agent is instituted
Prophylactic therapy or preventive therapy : treatment with
antimicrobials to prevent an infection 8
Classification of antibacterials
Bacteriostatic vs. bactericidal
Bacteriostatic : arrest the growth and replication of
bacteria at serum levels achievable in the patient
• Bacteria may grow again when drug is withdrawn
• Host defenses are needed to kill bacteria
• In large doses may become bactericidal

Bactericidal : kill bacteria at drug serum levels achievable

in the patient
Useful in life-threatening infections and in patients with
low WBC count immunocompromised]
9
Drug resistance : Unresponsiveness of microorganism to antimicrobial agents
Mechanisms by which Resistance is acquired
A. Spontaneous mutation
B. Gene transfer
Biochemical alterations leading to antimicrobial
resistance include:
A. Destruction of the drug by the organism :β lactamase inactivates
penicillins
B. Development of altered drug receptor :Aminoglycosides,
erythromycin, penicillin
C. Decreased drug entry :Tetracycline
D. Development of alternate metabolic pathway :Sulphonamides
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 Misuses of Antimicrobial Drugs
A. Attempted Treatment of Untreatable Infection
B. Treatment of Fever of Unknown Origin
C. Improper Dosage—Too low or too high
D. Treatment in the Absence of Adequate Bacteriologic
Information
E. Omission of Surgical Drainage—Have limited efficacy in
presence of foreign material, necrotic tissue, or pus

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 12
Antimicrobial drug combinations
Indication
– severe infection of unknown etiology
– Mixed infection
– Prevention of resistance
– Decreased toxicity
– Enhanced action [penicillin & aminoglycoside]
Disadvantages of antimicrobial agents combination
– Increase risk of allergy
– Antagonism of antimicrobial effect
– Increase risk of superinfection
– Increased cost

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1. BETA-LACTAM ANTIBIOTICS AND OTHER INHIBITORS OF CELL WALL SYNTHESIS

14
BETA-LACTAM ANTIBIOTICS AND OTHER INHIBITORS OF CELL
WALL SYNTHESIS
 Mechanism of action
are bactericidal
– Inhibition of bacterial cell wall synthesis
• Inhibition of transpeptidase
• Activation of autolysins
 Cell lysis can then occur, either through osmotic pressure or through
the activation of autolysins.
 Mechanism of bacterial resistance
1) Inactivation of antibiotic by -lactamase: common
2) Impaired penetration: from G-ves, absence of porins
3) Modification of target penicillin binding sites
4) Presence of efflux pump
• Penicillinases (beta-lactamases) break lactam ring structure (e.g.,
staphylococci).
• Structural change in PBPs (eg, methicillin-resistant
Staphylococcus aureus [MRSA], penicillinresistant pneumococci)
• Change in porin structure (e.g., Pseudomonas) 16
Bacteria

17
 Penicillins

 Mechanism of action Inhibition of bacterial cell wall synthesis

by inhibition of transpeptidase.

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1.Penicillin G
 Antimicrobial spectrum/ AMS
a) G+ve cocci except penicillinase producing staphylococci
b) some G+ve bacilli
c) G –ve cocci [N. meningitidis, N. gonorrhea]
d) Spirochetes [T.pallidum]

Therapeutic uses
Drug of choice for
a) pneumonia or meningitis by Streptococcus pneumonia
b) Pharyngitis by streptococcus pyogenes
c) Infectious endocarditis by streptococcus viridians 19
 Infection caused by G+ve bacilli

a) Gangrene by Cl. Perfringes

b) Tetanus by Cl. Tetani

c) Anthrax by B. anthracis
C. First choice for meningitis by N. meningitides
D. Drug of choice for the treatment of syphilis
E. Prophylactic applications
a) Syphilis in sexual partners
b) Benzathine penicillin G monthly for life in
recurrent rheumatic fever
c) Bacterial endocariditis 20
 Pharmacokinetics Penicillin G
 is available as salts [Na+, K+, Procaine, Benzathine penicillin G]
– orally ineffective due to gastric acid / Procaine penicillin G
and benzathine penicillin G are administered IM and serve
as depot forms
– Distributes well to most tissues; Inflammation increases
distribution into CSF, joints, and eye
– Penicillin G is eliminated by tubular secretion [90%]
• Benzathine penicillin G-repository form (half-life of 2 weeks).
– Excretion delayed by probenecid
 phenoxymethyl penicillin [penicillin V]
Acid stable: given orally
Used for streptococcal pharyngitis, prophylaxis of rheumatic
fever
21
– Not for serious infections
2. PEPENICILLINASE RESISTANT NICILLINS / Antistaphylococcal
penicillins: Cloxacillin , dicloxacillin, oxacillin , methicillin,
nafcillin
• Their use is restricted to the treatment of infections caused by
penicillinase-producing strains of staph.aureus and
staph.epidermidis / They have chains that protect the -lactam
ring from being hydrolyzed

 Methicillin Acid labile; allergic reaction; interstitial nephritis

 Naficillin Eratic & incomplete absorption from P.O.
– Given i.m. or i.v
 Isoxazolyl penicillins [cloxacillin,dicloxacillin,oxacillin]
– acid stable; orally & parentrally administered
Emergence of staphylococcal strains [methicillin
resistant]: treated with vancomycin 22
3. AMINOPENICILLINS
 ampicillin, amoxicillin, bacampicillin
 Antimicrobial spectrum
-antibacterial spectrum similar to that of penicillin
G but are more effective against gram-negative
bacilli/ G-ve bacilli [H.influenza, E.coli, Salmonella,
Shigella]
-Ineffective against  lactamase producing bacteria
A. Ampicillin peutic use
1. UTI, RTI
2. Shigellosis [but not amoxicillin]
3. Typhoid fever: less efficacious than Ciprofloxacin
4. Meningitis combined with 3rd generation

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 Adverse effects
a. Diarrhea
b. Rashes
B. Amoxicillin
-Oral absorption is better
-Incidence of diarrhea is less
-Less active against shigella
C. Bacampicillin: prodrug of ampicillin

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4 . ANTIPSEUDUOMONAL PENICILLINS
• Formulation of ticarcillin or piperacillin with clavulanic
acid or tazobactam, respectively, extends the
antimicrobial spectrum of these antibiotics to include
penicillinase-producing organisms
 Carboxypenicillins
– Carbenicillin
» active against pseudomonas aeruginosa & Indole
positive proteus
– Ticarcillin
» 2-4 times more potent against pseudomonas
 Ureidopenicillins
– piperacillin, mezlocillin, Azlocillin
» active against pseudomonas, Klebsiella pneumoniae
25
 BETA-LACTAMASE INHIBITORS
 Clavulinic acid, sulbactam, tazobactam
• contain a  -lactam ring but, by themselves, do not have
significant antibacterial activity.
• Instead, they bind to and inactivate  -lactamases,
thereby protecting the antibiotics that are normally
substrates for these enzymes / Inhibits bacterial -
lactamases; have weak antibacterial effect
Most active against -lactamase produced by: S.aureus,
H.infleunza, some enterobacteriaceae, Bacteroid spp
 Restore antibacterial activity of amoxicillin, ampicillin,
piperacillin, mezlocillin

26
 Amoxicillin-clavulinic acid [augmentin®]
250-750mg amoxicillin & 125mg clavulinic acidpeutic use
- acute otitis media [H.infleunza; B.catarrhalis];
- Sinusitis
- Lower RTI
- Skin infection [streptococci, staphylococci];
- Diabetic foot infection [staphylococci, aerobic &
anaerobic G-ve]

27
• 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
DRUG INTERACTION PENICILLINS:
– Aminoglycosides
– Probenecid
– Bacteriostatic antibiotics
– Ampicillin and oral contraceptives [decreased
enterohepatic circulation]
• The antibacterial effects of all the  -lactam antibiotics
are synergistic with the aminoglycosides.
• Because cell wall synthesis inhibitors alter the
permeability of bacterial cells, these drugs can facilitate
the entry of other antibiotics (such as aminoglycosides)
that might not ordinarily gain access to intracellular
target sites.
ADVERSE EFFECTS OF PENICILLINS
allergy, diarrhea ( ampicillin), rash(ampicillin)
sodium overload, inhibition of platelet function
ticarcillin
antibiotic-associated colitis (pseudomembranous colitis)

29
 CEPHALOSPORINS
• Mechanism of action
– Inhibition of cell wall synthesis
• Bactericidal

7-aminocephalosporanic acid
 CEPHALOSPORINS
Related both structurally and functionally to the penicillins

Identical to penicillins in terms of mechanism of action

(bind to PBPs); are bactericidal and require the intact
beta-lactam ring structure for activity.
• However, they tend to be more resistant than the
penicillins to certain  -lactamases.
• Cephalosporins are ineffective against MRSA, L.
monocytogenes, Clostridium difficile, and the
enterococci

31
 Mechanism of action
- Inhibition of cell wall synthesis / Bactericidal
 Mechanisms of Bacterial Resistance
- Production of β-lactamases (cephalosporinases)
- Altered penicillin binding proteins (PBPs)
 Classification Four generation
• classified as first, second, third, or fourth generation,
based largely on their bacterial susceptibility patterns
and resistance to  -lactamases
• From 1st generation to 3rd generation
Increasing activity against G-ve & anaerobes
Increasing resistance to -lactamase destruction
Increasing ability to reach CSF 32
 FIRST GENERATION CEPHALOSPORINS
• are resistant to the staphylococcal penicillinase
• Activity includes gram-positive cocci (not MRSA), E. coli,
Klebsiella pneumoniae, and some Proteus species/
Proteus mirabilis
. Common use in surgical prophylaxis. None enter CNS.
Includes cefazolin, cephalexin, cephradine.
1. Excellent gram-positive coverage, some gram
negative coverage.
2. Do not cross the blood–brain barrier.
3. Useful for treating soft-tissue infections and for
surgical prophylaxis.
 Can often be used as an alternative to penicillin G.

33
 Selected 1st generation cephalosporins

Generic Route Half

life(h)

Cephalexin oral 0.9

Cefadroxil oral 1.2

Cephradine Oral,iv/im 0.7

Cefazolin Iv/im 1.8

Cephalothin iv 0.6

34
 SECOND GENERATION CEPHALOSPORINS
• Cefaclor, cefamandole,cefonicid, cefuroxime,cefprozil, loracarbef &
ceforanide; cephamycins [cefoxitin, cefmetazole, cefotetan]
• True cephalosporins provide high activity against: H.infleunza,
N.meningitidis, N.gonorhoeae
• Cephamycins: antibacterial against selected enterobacteriaceae;
most active against B.fragilis
• ? Gram-negative coverage, including some anaerobes. Most do not
enter CNS.
• Improved activity against Haemophilus influenzae, Neisseria species,
and Moraxella catarrhalis.
1) Activity against gram-positive organisms is weaker
2) Cefoxitin and cefotetan have anaerobic activity and are used in
mixed soft-tissue infections and pelvic inflammatory disease.
Includes cefutetan (Bacteroides fragilis) and cefaclor (H. influenzae,
Moraxella catarrhalis).
Cefuroxime– axetil is a popular oral cephalosporin
35
 Overall, this generation is of limited usefulness
 THIRD GENERATION CEPHALOSPORINS
Wider spectrum that includes gram-positive and gram-
negative cocci, plus many gram-negative rods.
• Most enter CNS (not cefoperazone).
• Important in empiric management of meningitis and
sepsis.
• Includes ceftriaxone (IM) and cefuime (PO) used in single
dose for gonorrhea, cefotaxime (has a shorter half-life
but activity identical to that of ceftriaxone and thus
active versus most bacteria causing meningitis), and
ceftizoxime (B. fragilis).
 Less active than first generation against gram positive
cocci
 Improved gram-negative coverage
36
 Excellent activity against Neisseria gonorrhoeae, N.
meningitidis, Haemophilus influenzae, and Moraxella
catarrhalis.B.Fragilis
 CEFTRIAXONE
 has a long half-life that allows for once-daily dosing.
 high efficacy in bacterial meningitis, multiresistant typhoid fever,
complicated UTI, abdominal sepsis, septicaemias
 CEFTAZIDIME given parenterally
Excellent activity against G-ve including p.aeruginosa
but reduced activity against Staphylococcus aureus.
Penetrate CSF & txt of choice in meningitis due to p.
aeruginosa
• Recommended for community-acquired pneumonia and
bacterial meningitis
37
• CEFOPERAZONE
– Strong activity against pseudomonas; high ppb
– Do not reliable penetrate into CSF
– Indicated in severe urinary, respiratory, biliary infection and
septicaemia
 FOURTH GENERATION CEPHALOSPORINS
 Cefepime & cefpirome
 Even wider spectrum, resistant to most beta-
lactamases. cefepime (IV).
a) More resistant to β–lactamases
b) Excellent gram-positive (including methicillin
sensitive Staphylococcus aureus) and gram
negative coverage (including Pseudomonas
aeruginosa).
• Excellent broad-spectrum empiric therapy.
Useful in nosocomial infections.
 ADVERSE EFFECTS OF CEPHALOSPORIN
1) Allergic reactions
2) Antibiotic-associated colitis: superinfection
3) Bleeding tendency: hypoprothrombinemia caused
by methylthioterazole/MTT containing group -
Cefoperazone, cefotetan, cefmandole, cefmetazole
]
4) Many of the cephalosporins must be administered IV or
IM because of their poor oral absorption. Local effects:
thrombophlebitis from iv injection, IM + pain.
5) Also disulfiram-like interactions with ethanol

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 1. Carbapenems
 Imipenem and meropenem
MOA : bind to PBPs with the same mechanism of action
as penicillins and cephalosporins , however, they are
resistant to beta-lactamases.
– are bactericidal
– Wide spectrum that includes gram-positive cocci,
gram-negative rods (e.g.,Enterobacter, Pseudomonas
sp.), and anaerobes.
Important in-hospital agents for empiric use in severe
life-threatening infections.
– Both drugs are used IV only

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II. MONOBACTAMS- Aztreonam
• Mechanism: 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
 OTHER INHIBITORS OF CELL WALL SYNTHESIS

1. Vancomycin
• has become increasingly important because of its
effectiveness against multiple drug-resistant organisms,
such as MRSA and enterococci
 Mechanism:
 Inhibit bacterial cell wall synthesis by binding to
peptidoglycan pentapeptide  Transglycosylase
inhibition  inhibition of elongation of peptidoglycan &
cross linking
 Spectrum: Activity is restricted to gram-positive cocci /
G+ve [staphylococcus aureus & staph epidermidis
including methicillin resistant MRSA (DOC) and
enterococci and the anaerobe Clostridium dificile (backup
drug).
43
Vancomycin (+I- rifampin) is also active against
pneumococci resistant to the penicillins.
 PKS:
 Not absorbed orally; given iv except antibiotic induced
colitis
• Used IV and orally (not absorbed) in colitis
enters most tissues (e.g., bone), but not CNS
2. Bacitracin
• is a mixture of polypeptides that also inhibits bacterial cell
wall synthesis.
• It is active against a wide variety of gram-positive
organisms. Its use is restricted to topical application
because of its potential for nephrotoxicity with systemic
use.]
44
2. BACTERIOCIDAL INHIBITORS OF PROTEIN
SYNTHESIS
A. AMINOGLYCOSIDES
 Includes: Streptomycin, Gentamicin, Kanamycin,
Amikacin, Tobramycin, Sisomycin
 General properties of Aminoglycosides
 Amino sugars attached through glycosidic
linkages to the aminocyclitols
 Are water-soluble, stable in solution, and more active at
alkaline than at acid pH
 Interact chemically with -lactam antibiotic
 Are rapidly bactericidal
 Have a post-antibiotic effect
• Mechanism of action
– Transport of aminoglycosides through outer membrane by
passive diffusion via porins; then they are actively
transported across the cell membrane
• The drug binds to 30s ribosomal subunit  Protein synthesis
inhibition
misreading and premature termination of mRNA
translation
 Hence, aberrant proteins produced and may be inserted
into the cell membrane, leading to altered permeability
 Bind to 30S ribosomal subunit and disrupt the normal
cycle of ribosomal function by interfering
 With the initiation of protein synthesis
 Misreading of the mRNA template
 Incorporation of incorrect amino acids into the growing
polypeptide chains
 Mechanisms of Bacterial Resistance
a) Production of enzyme that can inactivate
aminoglycoside [phosphorylate, acetylate or
adenylate the drug]
b) Alteration of drug target site
c) Altered drug transport
 Failure to penetrate intracellularly
 Low affinity of the drug for the bacterial ribosome
Antimicrobial spectrum
 E.g Pseudomonas, Klebsiella, E. coli, others
 Primarily active against aerobic g(-) bacilli
 Have little activity against anaerobic microorganisms or facultative
bacteria under anaerobic conditions.
Pharmacokinetics
 Very poorly absorbed from the GIT.

 Absorbed rapidly from IM sites of injection.

 In critically ill patients, especially those in shock, absorption of drug

may be reduced from intramuscular sites because of poor perfusion
• Bind to renal tissue  nephrotoxicity
• Penetrate to perilymph & endolymph of inner ear  ototoxicity
• Streptomycin and tobramycin can cause hearing loss in children
born to women who receive the drug during pregnancy.
• Eliminated primarily by kidney
 ONCE DAILY DOSING
Once daily dosing may be preferred in certain situations
lower but not eliminate : nephrotoxicity & ototoxicity
simple, less time consuming & cost effective
does not worsen neuromuscular function
 Therapeutic uses
 used against G-ve enteric bacteria in bacteremia &
sepsis; TB
 used in combination with -lactam antibiotic to increase
coverage (G+) and synergism
 Adverse Effects of Aminoglycosides
 Vestibular & auditory ototoxicity
 Vestibular and auditory dysfunction can follow the
administration of any of the aminoglycosides
i. Cochlear toxicity: tinnitus, high frequency hearing
loss
» Neomycin, kanamycin, amikacin,
ii. Vestibular toxicity: vertigo, ataxia, loss of balance

» Streptomycin and Gentamicin

 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]
 Neuromuscular Blockade
 And the associated apnea
 Decreasing potency for blockade: neomycin,
kanamycin, amikacin, gentamicin, and tobramycin.
– weakness of respiratory musculature
– Risk is amplified in pts with tubocurarine, succinylcholine
– Aminoglycosides prevent internalization of Ca2+ in
presynaptic axon  decrease release of acetylcholine
 Gentamicin
 First choice due to low cost and reliable activity against all but the
most resistant g(-) aerobes.
 Available for parenteral, ophthalmic, and topical
 Therapeutic Uses (Gentamicin, tobramycin, amikacin, and
netilmicin)
 Urinary Tract Infections
 Pneumonia
 Meningitis
 Bacterial Endocarditis
 Sepsis
• Tobramycin
 Therapeutic Uses
 Same as those for gentamicin
 The preferred aminoglycoside for treatment of
serious infections caused by P. aeuroginosa (usually
in combination with an antipseudomonal -lactam
antibiotic)
 Poor activity in combination with penicillin against
many strains of enterococci.
 Ineffective against mycobacteria
Amikacin
 Broadest spectrum of activity in the group
 Resistant to many of the aminoglycoside-inactivating
enzymes
 Therapeutic Uses
 The preferred agent for the initial treatment of serious
nosocomial g(-) bacillary infections in hospitals
 Active against the majority of aerobic g(-) bacilli in the
community and the hospital
 Less active than gentamicin against enterococci
 It is active against M. Tuberculosis
• Streptomycin
 Is generally less active than other members of the class
 Administered by deep IM or IV
 Dose adjustment in renal impairment
 Therapeutic Uses
 Bacterial Endocarditis
Streptomycin and penicillin in combination
 Tularemia
 Streptomycin (or gentamicin) is the drug of
choice
 Plague
 Tuberculosis
• BACTERIOSTATIC INHIBITORS OF PROTEIN
SYNTHESIS
Tetracyclines
 Macrolides
 Lincosamides
 Chloramphenicol
 Tetracyclines (TTCs)
 Includes: oxytetracycline, tetracycline,
demelocycline, doxycycline, minocycline
 Produced by different species of Streptomyces
 OxyTTC is a natural product elaborated by
Streptomyces rimosus
 TTC is a semisynthetic derivative of chlorTTC
 Demeclocycline is the product of a mutant strain
of Strep. Aureofaciens
 Methacycline, doxycycline, and minocycline are
semisynthetic derivatives.
 Chlortetracycline, the prototype of the class, was
introduced in 1948
• Effects on Pathogenic Microorganisms
 Are bacteriostatic antibiotics active against a wide range
of aerobic and anaerobic g(+) & g(-) bacteria
 Are also effective against Rickettsia, Coxiella burnetii,
Mycoplasma pneumoniae, Chlamydia spp., Legionella
spp., Ureaplasma, some atypical mycobacteria, and
Plasmodium spp., that are resistant to cell-wall-active
antimicrobial agents
- G+ve & G-ve aerobic & anerobic bacteria
- Spirochetes, Mycoplasma, Rickettsia, Chlamydia &
some protozoa
• Mechanism of Action
• TTCs inhibit bacterial protein synthesis by binding to the 30S bacterial
ribosome and preventing access of aminoacyl tRNA to the acceptor (A)
site on the mRNA-ribosome complex
• Act by binding 30s ribosome  prevent addition of aminoacid to growing
peptide

 The main resistance mechanisms

1. Decreased accumulation of tetracycline as a result of either
decreased antibiotic influx or acquisition of an energy-dependent
efflux pathway;
2. Production of a ribosomal protection protein that displaces
tetracycline from its target
3. Enzymatic inactivation of tetracyclines
 Pharmacokinetics
 Absorption
 Partially absorbed from the stomach and upper GIT
 Impaired by Food (all except doxycycline and minocycline)
 TTCs form insoluble chelates with calcium, magnesium, and
other metal ions  interfere with absorption
 Distribution
 Distributed throughout body tissues and fluids
Minocycline and doxycycline (highest lipid solubility),
oxyTTC (the least)
 Ellimination
 TTCs are excreted mainly in bile and urine
 10 to 50 % of various TTCs is excreted into the urine.
 Doxycycline is eliminated by non renal mechanisms TTC of
choice in renal insufficiency.
60
• Pharmacokinetics of tetracyclines
 Classification
 Based on serum half-lives, TTCs are Classified
 Short-acting
Serum half-life of 6-8 hours
ChlorTTC, TTC, oxyTTC
 Intermediate-acting)
Serum half-life of 12 hours
Demeclocycline and methacycline
 long-acting
Serum half-life of 16-18 hours
Doxycycline and minocycline
Almost complete absorption and slow excretion of these
drugs allow for once daily dosing.
62
 Therapeutic Uses
Are generally drugs of choice in infections with Mycoplasma
pneumoniae, chlamydiae, rickettsiae, Trachoma and some
spirochetes
Rickettsial Infections
 Doxycycline is the drug of choice
 Anthrax
 Doxycycline: for prevention or treatment of anthrax
 Bacillary Infections
 Brucellosis
Tetracyclines in combination with rifampin or streptomycin
 Tularemia
TTCs are effective, though streptomycin is preferable
 Cholera
63
Therapeutic uses of tetracyclines
 Adverse Effects of TTCs
1) GI Irritation: oral therapy burning, cramps & NVD
Administration of food with doxycycline or minocycline
ameliorate some of the symptoms
Supper infections : modificatinon the normal flora with overgrowth
of pseudomonas, proteus, staphylococci, resistant coliforms,
clostridia, and candida
2) Effect on bone & teeth: contraindicated in children under the
age of 8 years
– Yellow or brown discoloration of teeth
– Hypoplasia of enamel
– Suppression of long bone growth in infants
– Doxycycline bind less with Ca2+  less frequent dental
changes
3)Liver toxicity; contraindicated in pregnant women
4) Kidney toxicity: Aggravate azotemia in patients with renal
disease
5)Photosensitization especially demeclocycline
6)Vestibular reactions [vertigo, nausea & vomiting]
 Macrolides
 Contain a large 14 or 15 membered lactone ring to
which one or more deoxy sugars are attached.
 Include erythromycin, clarithromycin, azithromycin, and
oleandomycin
 Clarithromycin differs from erythromycin only by
methylation of the hydroxyl group at the 6 position,
 Azithromycin differs by the addition of a methyl-
substituted nitrogen atom into the lactone ring.
 Improve acid stability and tissue penetration and
broaden the spectrum of activity
 Antibacterial Activity
 Macrolide resistance is common among streptococci.
 Cross-resistance among macrolides is complete
 Macrolides are active against Campylobacter jejuni.
1.Erythromycin usually is bacteriostatic, but may be bactericidal in high
concentrations
- is inactive against most aerobic enteric gram-negative bacilli but is active against
M. Pneumoniae and Legionella pneumophila
-is most active in vitro against aerobic gram-positive cocci and bacilli.
Staphylococci are not reliably sensitive to erythromycin.
2. Azithromycin & Clarithromycin is more potent than erythromycin against
sensitive strains of streptococci and staphylococci, and has modest activity
against H. influenzae and N. gonorrhoeae.
 Azithromycin: less active than erythromycin against g(-) organisms and slightly
more active against H. influenzae and Campylobacter spp.
 Azithromycin & clarithromycin have enhanced activity against M. avium-
intracellulare & some protozoa (e.g., T. gondii, Cryptosporidium, and
Plasmodium spp.).
 Mechanism of Action
 Inhibit protein synthesis by binding reversibly to 50S ribosomal
subunit
 Inhibits the translocation step wherein a newly synthesized
peptidyl tRNA molecule moves from the acceptor site on the
ribosome to the peptidyl donor site.
 Increased antimicrobial activity at alkaline pH (more
permeabillity of the un-ionized form)
Mechanism of resistance
 Resistance to macrolides usually results from
1. Drug efflux by an active pump mechanism
2. Ribosomal protection by inducible or constitutive production of
methylase enzymes, which modify the ribosomal target and decrease
drug binding
3. Macrolide hydrolysis by esterases produced by Enterobacteriaceae
4. Chromosomal mutations that alter a 50S ribosomal protein
Pharmacokinetics
 Absorbed from the intestinal tract,
 Presence of food interferes with absorption
 Erythromycin is relatively more acid labile
 Serum levels of clarithromycin and azithromycin are low,
but they concentrate in tissue and reach high levels.
 Erythromycin and azithromycin are excreted primarily in
active form in bile
 Clarithromycin is metabolized to the biologically active
14-OH metabolite and is eliminated largely by the kidney.
 t½ : erythromycin (1.4 hours), clarithromycin (3 to 7),
azithromycin (68 hours).
Clinical uses
 Mycoplasma pneumonia infections
 A macrolide or TTC is the drug of choice
 Legionnaires’ Disease
 Azithromycin or a fluoroquinolone
 Chlamydial Infections
 Can be treated effectively with any of the macrolides
 Diphtheria
 erythromycin
 Pertussis
 Drug of choice for treatment & prophylaxis
 Streptococcal infections
 Alternatives in patients who are allergic to penicillin. Penicillin-
resistant strains of S. Pneumoniae are very likely to be resistant
to macrolides
 Campylobacter infections
 largely replaced by Fluoroquinolones in adults
 Erythromycin remains useful for treatment of
Campylobacter gastroenteritis in children.
 Tetanus
 Erythromycin may be given to eradicate Clostridium
tetani in patients allergic to penicillin
 Mycobacterial Infections
 Clarithromycin or azithromycin is recommended as
first-line therapy for prophylaxis and treatment of
disseminated infection caused by M. avium-
intracellulare in AIDS patients and for treatment of
pulmonary disease in non-HIV-infected patient
Adverse Effects
 The incidence of side effects associated with erythromycin
therapy is very low.
 Mild GI upset with nausea, diarrhea, and abdominal
pain (more common)
 Rashes are seen infrequently
 Thrombophlebitis may follow IV administration
 Transient impairment of hearing.
 Cholestatic hepatitis (characterized by fever, enlarged and
tender liver, hyperbilirubinemia, dark urine, eosinophilia,
elevated serum bilirubin, and elevated transaminase levels)
 The drugs induce hepatic microsomal enzymes and
interfere with the actions of various drugs
 LINCOSAMIDES:
Clindamycin
Mechanism: The binding site for clindamycin on the 50S subunit of the
bacterial ribosome similar to erythromycin
Therapeutic use
Infections that involve B. fragilis & penicillin resistant anaerobic
bacteria
with aminioglycosides/ cephalosporins to treat penetrating wounds of
the abdomen
Infections on female genital tract
• Septic abortions
• Pelvic abscess
• Aspiration pneumonia
Recommended instead of erythromycin for prophylaxis of
endocariditis
Clindamycin + Primaquine in tXt of moderate or severe PCP
alternative to cotrimoxazole
Clindamycin + Pyrimethamine for AIDS related toxoplasmosis
Adverse effects
nausia, diarrhrea & skin rashes
 Clindamycin

• Mechanism of Action and Resistance

 Clindamycin inhibits protein synthesis by interfering with the
formation of initiation complexes and with aminoacyl
translocation reactions.
 The binding site for clindamycin on the 50S subunit of the
bacterial ribosome is identical with that for erythromycin.
 Resistance to clindamycin, which generally confers cross-
resistance to other macrolides, is due to
i. mutation of the ribosomal receptor site
ii. modification of the receptor by a constitutively expressed methylase
iii. Enzymatic inactivation of clindamycin
 G(-) aerobic species are intrinsically resistant because of poor
permeability of the outer membrane.
 Clindamycin is not a substrate for macrolide efflux pumps
• Antibacterial Activity

 Streptococci, staphylococci, and pneumococci are inhibited by clindamycin

 Enterococci and g(-) aerobic organisms are resistant (in contrast to their
susceptibility to erythromycin).
 Bacteroides species and other anaerobes, both g(+) and g(-), are usually
susceptible.
 Clostridium difficile is resistant.

Pharmacokinetics
 Absorption
 Nearly completely absorbed following oral administration
 Food in the stomach does not reduce absorption significantly
 Distribution
 Widely distributed in many fluids and tissues
 Readily crosses the placental barrier

 Excretion
 10% is excreted unaltered in the urine, and small quantities are found in
the feces.
 Inactivated by metabolism to N-demethylclindamycin and clindamycin
sulfoxide, which are excreted in the urine and bile
Therapeutic Uses
 Treatment of severe anaerobic infection caused by bacteroides and other
anaerobes that often participate in mixed infections.
 In combination with aminoglycoside or cephalosporin,
 To treat penetrating wounds of the abdomen and the gut
 Clindamycin plus primaquine is an effective alternative to co-trimoxazole
for moderate to moderately severe Pneumocystis carinii pneumonia in
AIDS patients.
 Also used in combination with pyrimethamine for AIDS-related
toxoplasmosis of the brain. 76
 Untoward Effects
 Diarrhea (in 2% to 20% subjects)
 Pseudomembranous colitis caused by the toxin from C.
difficile
 Characterized by abdominal pain, diarrhea, fever, and mucus
and blood in the stools.
 It may be lethal
 Discontinuation of the drug, combined with administration of
metronidazole orally or intravenously usually is curative
 Skin rashes, Stevens-Johnson syndrome, impaired liver
function, granulocytopenia, thrombocytopenia, and
anaphylactic reactions
 Local thrombophlebitis with IV administration
 Can inhibit neuromuscular transmission and may
potentiate the effect of a neuromuscular blocking 77
 Chloramphenicol
Mechanism
 binds 50s ribosome subunit  inhibiting peptidyl transferase
steps of protein synthesis (Bacteriostatic)
Antimicrobial spectrum: Broad spectrum and covers both aerobic
&anaerobic G+ve & G-ve and Rickethisiae ,Mycoplasma, and
Chlamydia spp.
Also effective against most anaerobic bacteria, including Bacteroides
fragilis.
Pharmacokinetics
 Crystalline CAF is rapidly and completely absorbed After oral administration

 widely distributed to virtually all tissues and body fluids, including the CNS

 Most of the drug is inactivated either by conjugation with glucuronic acid or

by reduction to inactive aryl amines
Therapeutic uses of CAF
Adverse drug reactions
a) GI disturbance: NVD
b) Effects on hematopoietic system: Bone marrow disturbances
and Aplastic anemia(Idiosyncratic reaction)
 Bone marrow depression is dose related and is characterized by
anemia, leukopenia or thrombocytopenia, but it is reversible
on discontinuation of CAF.
 Aplastic anemia is usually fatal. The mechanism is not known,
but it occurs most frequently with oral or ocular administration
C) superinfection: including oropharyngeal candidiasis
d) Newborn infants cannot adequately conjugate CAF to form the
glucuronide
ÞHigh levels of free CAF cause the gray baby syndrome.
 Abdominal distention, vomiting, progressive cyanosis, irregular
respiration, hypothermia, and vasomotor collapse
 Drug interaction of CAF

1. CAF inhibits hepatic CYP450s and prolongs the t½ of

drugs metabolized by this system (warfarin, dicumarol,
phenytoin, chlorpropamide, antiretroviral protease
inhibitors, rifabutin, and tolbutamide)
2. Drugs like Phenobarbital, rifampin potently induce CYPs
and shorten the t½ of CAF
 Anti metabolites
1. Sulfonamides
 Susceptible microorganisms require extracellular PABA
to form dihydrofolic acid (Humans cannot synthesize
folic acid and must acquire it in the diet)
 Competitively inhibit dihydropteroate synthase (DHPS)
and block folic acid synthesis  are bacteriostatic
 Inhibit both G(+) and G(-) bacteria, nocardia, Chlamydia
trachomatis, Some enteric bacteria ( E coli, klebsiella,
salmonella, shigella, and enterobacter), and some
protozoa.
83
Rapidly Absorbed and Eliminated Sulfonamides
 Sulfamethoxazole
 A close congener of sulfisoxazole with slower rates of enteric
absorption and urinary excretion
 Crystalluria may occur (high %age of the acetylated, relatively
insoluble form in the urine).
 A component of the fixed-dose combination cotrimoxazole
(with trimethoprim)

 Sulfadiazine
 Sulfadiazine given orally is absorbed rapidly from the GI tract,
and excreted quite readily by the kidney in both the free and
acetylated forms
 About 15% to 40% of the excreted sulfadiazine is in acetylated
form.
 Risk of crystal (ensure adequate fluid intake or sodium
bicarbonate)
 Poorly Absorbed Sulfonamides

 Sulfasalazine
 Used in ulcerative colitis and regional enteritis
 Broken down by intestinal bacteria to sulfapyridine and 5-
aminosalicylate
 5-Aminosalicylate effective in inflammatory bowel disease,
whereas sulfapyridine is responsible for most of the toxicity.
 Toxic reactions include acute hemolysis in patients with
glucose-6-phosphate dehydrogenase deficiency, and
agranulocytosis.
 Sulfonamides for Topical Use
 Silver Sulfadiazine
 Used topically to reduce microbial colonization and the
incidence of infections of wounds from burns
 It should not be used to treat an established deep infection.
 Silver is released slowly from the preparation in concentrations
that are selectively toxic to the microorganisms.
 One of the agents of choice for the prevention of burn
infection.
• Long-Acting Sulfonamides
 Sulfadoxine
 Has long half-life (7 to 9 days)
 Used in combination with pyrimethamine (500 mg sulfadoxine
plus 25 mg pyrimethamine as FANSIDAR) for the prophylaxis and
treatment of malaria caused by mefloquine -resistant strains of
Plasmodium falciparum
 Adverse effects
Sulfonamides of
1. Hypersensitivity
(All sulfonamidesreactions
and their
derivatives are cross-
1

allergenic).
a) Mild [rash, fever,
photosensitivity]
b) Severe
Johnson [stevens-
syndrome:
lesion
mucus of skin &
membrane,
fever, malaise]
2.Haematologic effect
a) Hemolytic
[Glucose 6 anemia
phosphate
dehydrogenase
deficiency]
Agranulocytosis:
b) leucopenia &
thrombocytopenia
urine (at neutral
producing or acid pH)
crystalluria,
hematuria,
obstructionor even
4. Kernicterus:
bilirubin by displacing
from plasma
protein crosses
Not given in 2 Monthsthe BBB;
age
Trimethoprim
 Structural analogue of the pteridine portion of DHF acid
 Competitively inhibits dihydrofolate reductase (DHFR)
 The bacterial enzyme is 20,000 to 60,000 times more sensitive
than its mammalian enzyme
 exhibits broad-spectrum activity (Active against most g(+) and g(-))
 Little activity against anaerobic bacteria
Pharmacokinetics
 Usually given orally, alone or in combination with
sulfamethoxazole
 Absorbed efficiently from the gut and distributed widely in
body fluids and tissues, including CSF
 Trimethoprim (a weak base of pKa 7.2) concentrates in
prostatic and vaginal fluids, which are more acid than plasma.
Clinical use
 In acute urinary tract infections(100 mg twice daily) .
 Most community-acquired organisms tend to be susceptible to the
high concentrations that are found in the urine.
Co- trimoxazole [Trimethoprim + Sulfamethoxazole (TMP-
SMX)]
 The combination shows synergistic effect as the two affect
different points in the folic acid synthetic pathway
 The incidence of bacterial resistance is less than that observed
when the drugs are used individually.
 Oral preparation
 Effective for P. jiroveci pneumonia, shigellosis, systemic
salmonella infections, complicated UTI, prostatitis, many
respiratory tract pathogens (including the pneumococcus,
haemophilus species, Moraxella catarrhalis, and Klebsiella
pneumoniae)
Useful alternative to -lactams in URTI and community-
acquired bacterial pneumonia
 Parentheral preparations
 Agent of choice for moderately severe to severe pneumocystis
pneumonia.
 If patient can not take the oral preparation
FLUOROQUINOLONES
 Nalidixic acid: the first quinolone
 Used for many years in treatment of UTIs
 Fluorinated 4-quinolones
 Broad antimicrobial activity
 Effective after oral administration for the treatment of a wide variety of
infectious diseases
 Relatively few side effects
 Microbial resistance does not develop rapidly
MOA
 The quinolone antibiotics target bacterial DNA gyrase and topoisomerase
IV
 DNA replication or transcription  double-helical DNA separation 
overwinding or excessive positive supercoiling
 DNA gyrase introduces negative supercoils
 An ATP-dependent reaction requiring that both strands of the DNA be cut to
permit passage of a segment of DNA through the break; the break then is
 Topoisomerase IV separates interlinked (catenated)
daughter DNA molecules that are the product of DNA
replication.
 Eukaryotic cells
 Do not contain DNA gyrase
 Have type II DNA topoisomerase
 Quinolones inhibit eukaryotic type II topoisomerase
only at much higher concentrations

93
 Classification of Quinolones
 Often classified into generations (1st through 4th) with
spectrum of specificity and unique pharmacological
properties
 First: nalidixic acid and cinoxacin;
 Second: norfloxacin, ciprofloxacin, ofloxacin,
enoxacin, and lomefloxacin;
 Third: levofloxacin, sparfloxacin, gatifloxacin;
 Fourth: trovafloxacin and moxifloxacin

94
 First-generation
 Oldest quinolones
 Exhibit limited g(-) activity
 Nalidixic acid and cinoxacin restricted to therapy of bladder
infections caused by urinary pathogens, such as E. coli and
Klebsiella and Proteus spp.
 Use is restricted by resistance.

95
 Second-generation
 Demonstrate activity against g(-) organisms including
Enterobacteriaceae. Haemophilus spp.and STD
agents are also susceptible.
 The piperazine moiety is responsible for the
antipseudomonal activity of some of these drugs
 Resistance is becoming more prevalent.

96
 The third and fourth generations possess significantly
greater activity against g(+), such as S. pneumoniae
 The fourth-generation quinolones also possess activity
against anaerobes.

97
 Pharmacokinetics
 Fluoroquinolones are well absorbed (bioavailability of
80–95%) after oral administration
 Distributed widely in body fluids and tissues.
 Oral absorption is impaired by divalent cations
 Most are eliminated by renal mechanisms (tubular
secretion or GF. Dose adjustment required in renal
impairment.

98
 Mechanism of Resistance
 Via mutations in the bacterial chromosomal genes
encoding DNA gyrase or topoisomerase IV or by active
transport of the drug out of the bacteria.
 No quinolone-modifying or -inactivating activities have
been identified in bacteria
 Resistance has increased in Pseudomonas,
staphylococci, Salmonella, N. gonorrhoeae, and S.
pneumoniae

99
 Clinical Uses
 UTI by even MDR bacteria, eg, Pseudomonas.
 Norfloxacin, ciprofloxacin, and ofloxacin
 Also for bacterial diarrhea caused by shigella, salmonella, E
coli, or campylobacter.

 Infections of soft tissues, bones, and joints and in intra-

abdominal and RTI
– All fluoroquinolones except norfloxacin,

100
 Clinical Uses (cont’d)

 Gonococcal infection (Ciprofloxacin and ofloxacin)

 Chlamydial urethritis or cervicitis (ofloxacin).
 Occasionally in the treatment of TB (Ciprofloxacin or
levofloxacin)

101
 Adverse Effects
 Extremely well tolerated.
 Most common: nausea, vomiting, and diarrhea
 Occasionally, headache, dizziness, insomnia, skin rash, or
abnormal liver function tests develop.
 Acute hepatitis and hepatic failure (Trovafloxacin)
 Photosensitivity (lomefloxacin and pefloxacin)
 QT prolongation
 Arthropathy and Cartilage deterioration in immature animals :
not recommended in child  18 yrs; & lactating & pregnant
woman

102
 ANTIMYCOBACTERIAL AGENTS

 DRUGS FOR TUBERCULOSIS

 Treating mycobacterial infection present problems:
 they are slow growing microbes
 can also be dormant; resistant to many drugs
 lipid rich cell wall is impermeable to many agent
 a substantial portion is intracellular
-Needs prolonged treatment
-Drug toxicity & poor patient compliance
-High risk of emergency of resistant bacteria

103
 individual antituberculous agents
 First line drugs: superior efficacy & acceptable toxicity
• isoniazide, rifampin, pyrazinamide,
ethambutol, streptomycin
Second line drugs: less efficacy, greater toxicity or
both.
– Used in combination with 1st line drug to treat
dissiminated TB & TB caused by resistant
organism
» PAS, kanamycin, capreomycin,
ethionamide, cycloserine

104
 ISONIAZID (INH/Isonicotinic hydrazide)
 Mechanism
– block mycolic acid synthesis
– bactericidal
 Pharmacokinetics
– Well absorbed p.o. or i.m.
– Distributed widely: CSF  20% of plasma
conc. Increased in meningeal inflammation
– Metabolised by acetylation
» Fast acetylation t1/2  1hr
» Slow acetylation t1/2  3hr

105
 Therapeutic Uses
1) component of all TB chemotherapeutic regimens
2) alone is used to prevent
a) transmission to close contact at high risk of
disease
b) progression of infection in recently infected,
asymptomatic individuals
c) development of active TB in immunodeficient
individuals

106
 Adverse effects
 Allergic reactions (fever, skin rashes)
Drug induced hepatitis: high risk age, rifampin, alcohol
Peripheral neuropathy (Reversed by administration of vit B6)
due to relative pyridoxine deficiency: increased vit B6 excretion
& interference with vit B6 utilization
Likely to occur in slow acetylators & pts with predisposing
factor [malnutrition, alcoholism, diabetes, AIDS & Uremia]
Convulsion
Optic neuritis reversed by vit. B6
Psychosis
Drug interaction
» reduces metabolism of phenytoin
» absorption of INH is impaired by Al(OH)3 107
 RIFAMPICIN
 Mechanism: binds to the -subunit of bacterial DNA dependent
RNA polymerase  inhibits RNA synthesis
bactericidal for both intracellular and extracellular mycobacteria,
including M. tuberculosis
Pharmacokinetics
- well absorbed; distributed throughout the body
- excreted mainly through liver into bile
Therapeutic uses
a)Prophylaxis of meningococcal carriers & H.influenza type b
b)Mycobacterial infection
c) TB: Bacteriocidal for intra & extracellular bacteria
d) Leprosy
108
 Adverse effects
1) Hepatitis in pts with
– Preexisting liver disease, high dose, alcoholics, elderly

2) Hypersensitivity reactions
– Fever, flushing, pruritis, thrombocytopenia,
interstitial nephritis
3. Miscellaneous adverse reaction
– Harmless orange color appearing in urine, saliva,
tears, sweat
 Drug interaction
– is a microsomal enzyme inducer; enhances its own metabolism
as well as other drugs [warfarin, OTC, Steroids, HIV protease
inhibitors & ketoconazole] 109
 ETHAMBUTOL
 Mechanism: Inhibits cell wall synthesis by blocking
arabinosyl transferase  bacteriostatic
 Therapeutic use: TB
 Adverse effects
– optic neuritis
– Loss of visual acuity & red-green color blindness
– GI intolerance
– Hyperuricemia due to deceased uric acid
excretion

110
 PYRAZINAMIDE
-Converted to pyrazinoic acid, active form of drug
 Therapeutic use: TB
 Adverse effects
-GI intolerance, hepatotoxicity, hyperuricemia

111
 leprosy
• Bacilli from skin lesions or nasal discharges of infected
patients enter susceptible individuals via abraded skin or
the respiratory tract.
• Drugs for leprosy
 Dapsone
MOA : structurally related to the sulfonamides
inhibits folate synthesis via dihydropteroate
synthetase inhibiton
 is bacteriostatic for Mycobacterium leprae
• resistant strains are encountered

112
 Pharmacokinetics
 well absorbed from the gastrointestinal tract and is
distributed throughout the body, with high levels
concentrated in the skin.
 undergoes hepatic acetylation
 Both parent drug and metabolites are eliminated through
the urine
Therapeutic use / leprosy
 also employed in the treatment of pneumonia caused by
Pneumocystis jiroveci in patients infected with the HIV
Adverse effects
 hemolysis, especially in patients with glucose 6-
phosphate dehydrogenase deficiency
 peripheral neuropathy
113
 Clofazimine
 MOA
– binds to DNA and prevents it from serving as a
template for future DNA replication
– May also generate cytotoxic oxygen radicals that
are also toxic to the bacteria
– is bactericidal to M. leprae
 Pharmacokinetics
– Following oral absorption, the drug accumulates
in tissues
– it does not enter the CNS
– Adverse effect
– Patients may develop a red-brown discoloration
of the skin
114
 Rifampin
 MOA
– blocks transcription by interacting bacterial DNA-
dependent RNA polymerase
 Therapeutic uses
• TB
• is the most active antileprosy drug at present
– to delay the emergence of resistant strains, it is
usually given in combination with other drugs
Adverse effects
Tears may permanently stain
soft contact lenses : orange-red

115
ANTIPROTOZOAL DRUGS

116
• Introduction:
 Examples of protozoal diseases :- malaria, amebiasis,
leishmaniasis, trypanosomiasis, trichomoniasis,
toxoplasmosis and giardiasis
 unicellular eukaryotic protozoal cells have metabolic
processes closer to those of the human
 Protozoal diseases are thus less easily treated than
bacterial infections and
 many of the antiprotozoal drugs cause serious toxic
effects in the host particularly on cells showing high
metabolic activity, such as neuronal, renal tubular,
intestinal, and bone marrow stem cells.
- Most antiprotozoal agents have not proved to be safe for
pregnant patients

117
 TREATMENT OF MALARIA

- Malaria is an acute infectious disease caused by four

species of the protozoal genus Plasmodium
P. vivax, P. malariae, P. ovale, and P. falciparum.
-P. falciparum and P. vivax malaria are the two most
common forms
-P falciparum causes most of the serious
complications and deaths.
- effectiveness of antimalarial agents varies between
parasite species and between stages in their life cycles.

118
119
 Parasite Life Cycle
human blood that contains parasites in the sexual form
(gametocytes) is fed by the mosquito
Sporozoites develop in the mosquito from gametocytes and then
inoculated into humans at its next feeding

I. Exoerythrocytic stage
– the sporozoites multiply in the liver to form tissue schizonts
then, parasites escape from the liver into the bloodstream as
merozoites
II. Erythrocytic stage

– Merozoites multiply to form blood schizonts, and finally rupture

the red blood cells, releasing new merozoites.

– merozoites either invade erythrocytes or become gametocytes

120
 P .falciparum and P. malariae
– have only one cycle of liver cell invasion and
multiplication, and liver infection ceases spontaneously
in less than 4 weeks.
– Then multiplication is confined to the red blood cells
So, treatment that eliminates these species from the
red blood cells four or more weeks after inoculation of
the sporozoites will give cure.
 P.vivax and P.ovale
– Sporozoites also induce in hepatic cells the dormant
stage (the hypnozoite) that causes subsequent
recurrences (relapses) of the infection.
Therefore, treatment that eradicates parasites from
both the red blood cells and the liver is required to cure
these infections.
121
Drug Classification
The antimalarial drugs are classified by their
selective actions on the parasite's life cycle.
1. Tissue schizonticides:
– Eliminate tissue schizonts or hypnozoites in the liver
(e.g.; primaquine)
– prevents the maturation of sporozoites in the liver,
So that the liberation of merozoits from the liver is
prevented
2. Blood schizonticides:
– Act on blood schizonts (e.g., chloroquine, proguanil,
pyrimethamine, mefloquine, quinine) . 122
3. Gametocides
– destroy gametocytes in the blood (eg, primaquine
for P falciparum and chloroquine for P vivax, P
malariae and P ovale
4. Sporonticidal agents
– make gametocytes non infective in the mosquito
(eg, pyrimethamine, proguanil).

123
 1. Chloroquine
has been the mainstay of antimalarial therapy
 Pharmacodynamics : exact mechanism of action has not
been known
 Mainly by inhibition of heme polymerase
• binding to heme ( released from hemoglobin by the
parasite) and prevention of its polymerization in to less
toxic hemozoin causes parasite death and hemolysis
 blood schizonticidal: highly effective for all except
resistant falciparum species
 Gametocidal : moderately effective against
gametocytes of P. vivax, P. ovale, and P. malariae
but not against those of P falciparum
not active against the preerythrocytic plasmodium and
124
does not effect radical cure.
 Pharmacokinetics: half-life of the drug is 6 to 7 days
– rapidly and almost completely absorbed from GIT
 more concentrated in parasitized cells:
 concentration in normal erythrocytes is 10-20 times that in
plasma;
 in parasitized erythrocytes, its concentration is about 25 times
that in normal erythrocytes.
– is rapidly distributed to the tissues including across the placenta
and also permeates the CNS
– Distributed widely and is extensively bound to body tissues
e. g in the liver: 500 times the blood concentration

125
 Clinical uses
Acute Malaria Attacks
– Chloroquine is effective for acute attacks of P vivax, P ovale,
and P malariae and of malaria due to nonresistant strains
of P falciparum
Chemoprophylaxis
– Chloroquine is the preferred drug for prophylaxis against
all forms of malaria except in regions where P falciparum is
resistant to it
 also effective in the treatment of extraintestinal amebiasis
and photoallergic reactions
• occasional used in treatment of rheumatoid arthritis
and lupus erythematosus b/c of its antiinflammatory effect

126
 Adverse Effects:
– Gastrointestinal symptoms, mild headache, pruritus,
anorexia, malaise, blurring of vision, and urticaria
» an ophthalmologic examination should be
routinely performed
– depigmentation or loss of hair
 Contraindications:
– in patients with a history of liver damage, alcoholism,
or neurologic or hematologic disorders, psoriasis or
porphyria
»it may precipitate acute attacks of these diseases

127
 2. Primaquine

 Primaquine is the least toxic and most effective of the 8-

aminoquinoline antimalarial compounds.
 Pharmacodynamics:
» Has a metabolite that inhibits the coenzyme Q–
mediated respiratory chain of the exoerythrocytic
parasite
» The metabolites also cause hemolysis as toxicity
Against exoerythrocytic form
» eradicates primary exoerythrocytic forms of P.
falciparum and P. vivax and the secondary
exoerythrocytic forms of recurring malarias (P.
vivax and P. ovale).
 Primaquine is the only agent that can lead to radical
cures of the P. vivax and P. ovale malarias 128
 Gametocidal
• Destroys the sexual (gametocytic) forms of all four
plasmodia in the plasma or
• Prevents the gamectocytes from maturing later in the
mosquito
 NB:- Primaquine is not effective against the erythrocytic
stage of malaria
 is often used in conjunction with a blood schizonticide, such
as chloroquine, quinine, mefloquine, or pyrimethamine
 Pharmacokinetics:
– usually well absorbed after oral administration
– half-life is short, and daily administration is usually
required for radical cure and prevention of relapses.
129
 Clinical Uses:
– Terminal prophylaxis of vivax and ovale malaria.
– Radical cure of acute vivax and ovale malaria.
– Pneumocystis carinii pneumonia
 Adverse Effects: generally well tolerated
– infrequently causes nausea, epigastric pain,
abdominal cramps, and headache
» abdominal discomfort, especially when
administered in combination with chloroquine
– agranulocytosis is rare
– drug-induced hemolytic anemia in patients with
genetically low levels of glucose-6-phosphate
dehydrogenase can be lethal
130
 3. Quinine

 Pharmacodynamics: Mechanisms of its antimalarial

activity is not known
– It may be poison to the parasite’s feeding mechanism
– interferes with heme polymerization
blood schizonticide
-rapidly acting, highly effective blood schizonticide
against the four malaria parasites
gametocidal
-for P vivax and P ovale but not very effective
against P falciparum gametocytes
 reserved for severe infestations and for malarial strains
that are resistant to other agents, such as chloroquine
131
 Pharmacokinetics:
– Oral route- rapidly absorbed and is widely distributed in body
tissues , also given IV
• metabolized in the liver and excreted for the most part in the
urine. Excretion is accelerated in acid urine
 Clinical Uses:
1. Parenteral Treatment of Severe falciparum malaria
2. Oral treatment of falciparum malaria resistant to
Chloroquine
3. Prophylaxis
4. Quinine sulfate is also used for the prevention and
treatment of night time leg cramps such as those resulting
from arthritis, diabetes, and varicose veins.
132
 Adverse Effects: often causes nausea, vomiting, hypoglycemia
(Quinine is a potent stimulus to insulin secretion, irritates GIT
mucosa)
- less common : headache, slight visual disturbances, dizziness,
and mild tinnitus - subside as treatment continues.
» are reversible and should not be reasons for
suspending therapy
 Severe toxicity: fever, skin eruptions, GI symptoms, deafness,
visual abnormalities, CNS effects (syncope, confusion)
 severe hypotension may follow its rapid intravenous
administration.
– Quinine treatment should be suspended if a positive Coombs'
test for hemolytic anemia occurs.
 Contraindications: haemoglobinuria, optic neuritis and in
patients hypersensitive to quinine or quinidine

133
 4. Proguanil and Pyrimethamine

Pharmacodynamics: are dihydrofolate reductase inhibitors

 Parasites cannot use preformed folic acid and therefore must
synthesize this compound
 blood schizonticides : are slow acting blood schizonticides
against susceptible strains of all four malarial species.
 Proguanil (but not pyrimethamine) has a marked effect on the
primary tissue stages of susceptible P falciparum
 Pyrimethamine also acts as a strong sporonticide in the
mosquito's gut when the mosquito ingests it with the blood
of the human host

134
 Pharmacokinetics:
– slowly but adequately absorbed from the GIT
– Pyrimethamine has a half-life of about 4 days
 Clinical uses:
– Chemoprophylaxis
– Treatment of Chloroquine-resistant P. falciparum
malaria
– Toxoplasmosis (10 to 20X higher dose than that
employed in malaria)
 Adverse Effects:
– In the high doses, pyrimethamine causes
megaloblastic anemia, agranulocytosis and
thrombocytopenia
» leucovorin calcium is given concurrently 135
 5. Sulfones and Sulfonamides

 Pharmacodynamics: inhibit dihydrofolic acid synthesis

– blood schizonticidal
» against P falciparum
» weak effects against P vivax
– are not active against the gametocytes or liver stages
of P falciparum or P vivax
 Sulfonamide/sulfone + pyrimethamine has synergistic
blockade of folic acid synthesis in susceptible plasmodia
- most used combinations are:-
Sulfadoxine with pyrimethamine (Fansidar)
dapsone with pyrimethamine (Maloprim)

136
 6. Pyrimethamine – sulfadoxine (Fansidar)

 Pharmacodynamics:
effective against falciparum malaria
• Fansidar is only slowly active. Hence quinine must be
given concurrently in treatment of seriously ill
patients
not effective in the treatment of vivax malaria
 Pharmacokinetics:
– is well absorbed when given orally
– Average half-lives are about 170 hours for sulfadoxine
and 80-110 hours for pyrimethamine

137
 Clinical uses:
– Treatment of Chloroquine-Resistant Falciparum
– Fansidar is no longer used in prophylaxis because of
severe reactions
 Adverse Effects:
– sulfonamide allergy including the hematologic
(agranulocytosis) , thrombocytopenia,
photosensitivity , hepatitis, megaloblastic anemia etc
 Contraindications:
–contraindicated in patients who have had adverse
reactions to sulfonamides, pregnancy, in nursing womenor
in children less than 2 months of age.
Fansidar should be used with caution in those with severe
allergic disorders, and bronchial asthma 138
 7. Mefloquine

 is chemically related to quinine

 like quinine, it can apparently damage the parasite's
membrane
 Pharmacodynamics:
- blood schizonticidal - against all plasmodia species
as it concentrates in the liver and lung
 Pharmacokinetics:
- It can only be given orally because intense local
irritation occurs with parenteral use.
- absorbed well after oral administration
- cleared in the liver
- elimination half-life varies from 13 days to 33 days
139
 Clinical uses:
For treatment of chloroquine-resistant and
multidrug-resistant falciparum malaria
also effective in prophylaxis against P. vivax, P. ovale,
P. malariae, and P. falciparum
 Adverse Reactions:
– frequency and intensity of reactions are dose-related
– In prophylactic doses
» GI disturbances, headache, dizziness, syncope,
and transient neuropsychiatric events
(convulsions, depression, and psychoses).

140
 – In treatment doses
» the incidence of neuropsychiatric symptoms
(dizziness, headache, visual disturbances,
tinnitus, insomnia, restlessness, anxiety,
depression, confusion, acute psychosis, or
seizures) may increase
 Contraindications:
– A history of epilepsy, psychiatric disorders,
arrhythmia, sensitivity to quinine and the first
trimester of pregnancy

141
 9. Atovaquone

 MOA
 involves inhibition of the mitochondrial electron
transport system in the protozoa
 is effective against erythrocytic and exoerythrocytic P.
falciparum
 has good activity against the blood but not the
hepatic stage of P. vivax and P. ovale
 pharmacokinetics
– poorly absorbed from the gastrointestinal tract, but
absorption is increased with a fatty meal
– Fecal excretion
– elimination half-life is 2 to 3 days
142
 Therapeutic use
 the combination of atovaquone and proguanil is used
for the treatment and prophylaxis of P. falciparum
malaria
» Atovaquone and proguanil are synergistic and
are highly effective when combined and no
atovaquone resistance is seen
 atovaquone is also used for the treatment and
prevention of P. carinii pneumonia
 Adverse effect
– Atovaquone is well tolerated
– rare instances of nausea, vomiting, diarrhea,
abdominal pain, headache, and rash of mild to
moderate intensity
143
10. Doxycycline
– is generally effective against multidrug-resistant P
falciparum
– is active against the blood stages of Plasmodium
species but not against the liver stages
– In the treatment of acute malaria, it is used in
conjunction with quinine

144
11. Halofantrine
– is an oral schizonticide for all four malarial species
– Excretion is mainly in the feces

12. Lumefantrine:
– Availabe in fixed dose combination with artemether
as Coartem
– T 1/2  4.5 hrs
– Coartem is very effective for Rx of P falciparum

145
 Artemisinin and its derviatives

– artemisinin, artemether, arteether, artesunate, artlinic

acid
– are potent and rapidly acting antimalarial drugs that
show relatively low human toxicity
 Mechanism of action
Act by interacting with heme to produce carbon-
centered free radicals that alkylate protein & damage
microorganelle & membranes of the parasites
– active against blood stages, especially in patients with
severe manifestations, such as cerebral malaria and
chloroquine-resistant malarial infections
– have no effect on exoerythrocytic stage of the parasite

146
 Therapeutic use
- are most useful in treating life-threatening cerebral
edema
- for the treatment of severe, multidrug-resistant P.
falciparum malaria
 pharmacokinetics
- Oral, rectal, and IV preparations are available
- the short half-lives preclude their use in
chemoprophylaxis
- metabolized in the liver and are excreted primarily in
the bile

147
 Adverse effects
– include nausea, vomiting, abdominal pain and
diarrhea, but overall, artemisinin is remarkably safe.
– Extremely high doses may cause neurotoxicity and
prolongation of the QT interval.

148
 Summary of Treatment and prevention of malaria
 All plasmodium species except chloroquine resistant P falciparum
Chloroquine
 chloroquine resistant P falciparum
Quininine + (pyrimethamine-sulfadoxine or doxycycline )
Alternaive is mefloquine
 Prevention of relapses: P vivax and P ovale only
Primaquine

 Prevention of malaria
 Chloroquine sensitive areas
chloroquine
 Chloroquine resistant areas
mefloquine
 In pregnancy
149
Chloroquine or mefloquine
 Prophylactic Measures for Use in Endemic Areas
Chloroquine
– only in areas where chloroquine-sensitive P. falciparum
organisms are present
atovaquone–proguanil
– first choice for chemoprophylaxis for travel to areas of
chloroquine resistance
 Treatment of an Acute Uncomplicated Attack
 Chloroquine phosphate administered orally
– In non-resistant areas
 mefloquine or atovaqone-proguanil combination
– Orally for uncomplicated infections resistant to
chloroquine

150
 acute attack of malaria caused by chloroquine-resistant P.
falciparum complicated by renal failure or cerebral
manifestations
parenteral quinidine gluconate alone or with oral
pyrimethamine and sulfadiazine

 Prophylactic drugs, such as chloroquine or mefloquine, should

be started 2 to 4 weeks prior to travel and continued for 6 to 8
weeks after leaving the endemic areas.
 The atovaquone–proguanil combination is the exception in
that it is started 1 to 2 days prior to departure and is continued 1
week after return.

151
 Drugs used in amebiasis

 Amebiasis/also called amebic dysentery is infection of the

intestinal tract by the protozoan parasite Entamoeba histolytica
 The parasite exists in two forms:
Cysts: can survive outside the body
Trophozoites: labile but invasive and do not persist outside
the body
 Trophozoites multiply in intestine and either invade and ulcerate
the mucosa of the large intestine or simply feed on intestinal
bacteria
» Adding antibiotics, such as tetracycline, to the
treatment regimen is one strategy for treating luminal
amebiasis

152
- The infection may present as:
Intestinal - a severe intestinal infection (dysentery), a mild
to moderate symptomatic intestinal infection, an
asymptomatic intestinal infection
extraintestinal - liver abscess, or other type of
extraintestinal infection
 All of the antiameobic drugs act against Entamoeba histolytica
trophozoites, but most are not effective against the cyst stage.

153
Drug classification
•The choice of drug depends on the clinical presentation and on the
desired site of drug action, i.e, in the intestinal lumen or in the
tissues.
•Antiamebic drugs are classified as luminal, systemic, or mixed
(luminal and systemic) ameobicides according to the site where the
drug is effective
I. luminal amebicides - act on the parasite in the lumen of the
bowel. Eg paromomycin, iodoquinol
II. systemic amebicides - are effective against ameobas in the
intestinal wall and liver. Eg chloroquine, emetine,
dihydroemetine
III. Mixed amebicides - are effective against both the luminal
and systemic forms of the disease
• But luminal concentrations are too low for single-drug
treatment Eg metronidazole and tinidazole
154
 Tissue amebicides
 eliminate organisms primarily in the bowel wall, liver, and other
extraintestinal tissues
 are not effective alone against organisms in the bowel lumen
– Metronidazole, and tinidazole are highly effective against
ameobas in the bowel wall and other tissues.
– Emetine and dehydroemetine also are effective on
organisms in the bowel wall and other tissues
– Chloroquine - active principally against ameobas in the liver.

155
 Luminal Amebicides
 act primarily in the bowel lumen
– Diloxanide furoate
– Iodoquinol
– Tetracyclines, paromomycin and erythromycin

156
 Treatment of Ameobiasis
Asymptomatic Intestinal Infection:
The drugs of choice, diloxanide furoate and
iodoquinol
Alternatives are metronidazole plus iodoquinol
or diloxanide.
Intestinal Infection:
The drugs of choice, metronidazole and a
luminal ameobicide.

157
Hepatic Abscess:
The treatment of choice is metronidazole
- An advantage of metronidazole is its effectiveness
against anaerobic bacteria, which are a major cause of
bacterial liver abscess.
Diloxanide furoate or iodoquinol should also be given to
eradicate intestinal infection whether or not organisms
are found in the stools.
Dehydroemetine and emetine are potentially toxic
alternative drugs.

158
Ameoboma or Extraintestinal Forms of Amebiasis:
Metronidazole is the drug of choice
Dehydroemetine is an alternative drug;
chloroquine cannot be used because it does not
reach high enough tissue concentrations to be
effective (except in the liver).
A simultaneous course of a luminal ameobicide
should also be given.

159
 Metronidazole

 Mechanism of Action:
• The nitro group of metronidazole is able to serve as an
electron acceptor, forming reduced cytotoxic
compounds that bind to proteins and DNA, resulting
in cell death.
• the nitro group is chemically reduced by the enzyme
pyruvate-ferredoxin oxidoreductase
» Reduced metronidazole disrupts replication and
transcription and inhibits DNA repair.
– Is both luminal and systemic ameobicide

160
 Pharmacokinetics:
– Oral metronidazole is readily absorbed
– Has good distribution including the CSF, breast milk, alveolar
bone, liver abscesses, vaginal secretions, and seminal fluid.
– The drug and its metabolites are excreted mainly in the urine
Clinical Uses:
• Metronidazole is the most effective agent available for the
treatment of individuals with all forms of amebiasis, with
perhaps the exception of the person who is asymptomatic but
continues to excrete cysts.
• That situation calls for an effective intraluminal ameobicide, such
as diloxanide furoate, paromomycin sulfate, iodoquinol or
diiodohydroxyquin.
• This combination provides cure rates of greater than 90 percent

161
– Metronidazole is active against ameobiasis,
urogenital trichomoniasis, giardiasis
– anaerobic infections (gram –ve cocci, baciili, eg
Bacteroides species)
– drug of choice for the treatment of
pseudomembranous colitis by anaerobic gram +ve
bacili C difficile)
– also effective in the treatment of brain abscesses
caused by the above organisms

162
 Adverse effects:
– nausea, headache, dry mouth, or metallic tastes occur
commonly
– oral moniliasis (yeast infection of the mouth)
– rare adverse effects include vomiting, diarrhea, insomnia,
weakness, dizziness, stomatitis, rash, urethral burning, vertigo,
and paresthesias
• The drug is not recommended for use during pregnancy.
• Alcohol should be forbidden during metronidazole
therapy,because it causes disulfiram like side effect.
• Ethanol alchohol dehydrogenase Acetaldehyde aldehyde
dehydrogenase CH3COOH (acetic acid)

• metronidazole (inhibitor of aldehyde dehydrogenase 

disulfiram like effect 163
 Other Nitroimidazoles
• with the exception of tinidazole, the other nitroimidazoles
have produced poor results than metronidazole in the
treatment of amebiasis
 Tinidazole
• is a second-generation nitroimidazole that is similar to
metronidazole in spectrum of activity, absorption, adverse
effects and drug interactions
– is as effective as metronidazole, with a shorter course of
treatment, yet is more expensive than generic
metronidazole.
• Is a 5-nitroimidazole closely related to metronidazole, is
effective against vaginal trichomoniasis resistant to
metronidazole.

164
Chloroquine
– Chloroquine reaches high liver concentrations
– is used in combination with metronidazole and diloxanide
furoate to treat and prevent ameobic liver abscesses
– Chloroquine is not active against luminal organisms
Dehydroemetine and Emetine
– inhibit protein synthesis by blocking chain elongation
– the use of these drugs is limited by their toxicities
(dehydroemetine is less toxic than emetine)
– They should not be taken for more than 5 days

165
 Pharmacokinetics:
– IM injection is the preferred route
– stored primarily in the liver, lungs, spleen, kidneys
– slowly metabolized and excreted, and can accumulate
– are eliminated slowly via the kidneys
– half-life in plasma is 5 days
 Clinical Uses:
– Severe Intestinal Disease (Amebic Dysentery)

 Adverse Effects:
– Sterile abscesses, pain, tenderness, and muscle
weakness in the area of the injection are frequent
– They should not be used during pregnancy.
166
Diloxanide Furoate
– is directly ameobicidal, but its mechanism of action is not
known
– Diloxanide furoate is the drug of choice for asymptomatic
infections.
– For other forms of ameobiasis it is used with another drug

167
Iodoquinol
– It is thought to inactivate essential parasite enzymes
– Iodoquinol is effective against organisms in the bowel lumen
but not against trophozoites in the intestinal wall or
extraintestinal tissues.
 Adverse Effects:
– Reversible severe neurotoxicity (optic atrophy, visual loss, and
peripheral neuropathy).
– Long-term use of this drug should be avoided

168
 Antibiotics

 Erythromycin and tetracycline

– Do not have a direct effect on the protozoa
» Act on the normal flora
 Paromomycin
– is directly and indirectly ameobicidal

169
Paromomycin Sulfate
– an aminoglycoside antibiotic, (is an alternative luminal drug
used concurrently with metronidazole)
– only effective against the intestinal (luminal) forms of E.
histolytica and tapeworm
It can be used only as a luminal ameobicide and has no effect in
extraintestinal amebic infections.
» b/c not significantly absorbed from the gastrointestinal
tract
– Paromomycin is an alternative drug for the treatment of
asymptomatic ameobiasis.
– is both directly and indirectly ameobicidal
– Direct effect- leakage on cell membranes
170
 Summary of amoeba treatment
 Assymptomatic cyst carriers
– Iodoquinol /diloxanide or paromomycin
 Diarhea/dysentry- extraintestinal
– Metronidazole + Iodoquinol/diloxande/paromomycin
 Amebic liver abscess
– Chloroquine + metronidazole/emetine

171
 Giardiasis

–Infection is due to ingestion, usually from contaminated

drinking water
• Caused by Giardia lamblia
• has only two life-cycle stages:
– Trophozoite and the drug-resistant -cyst
– The trophozoites exist in the small intestine and divide
by binary fission.
– severe diarrhea can occur, which can be very serious in
immune-suppressed patients.
 Metronidazole- is a drug of choice
 Tinidazole – alternatetive
– Tinidazole 2 g given once
172
• Nitazoxanide [nye-ta-ZOX-a-nide], a nitrothiazole
derivative structurally similar to aspirin, was recently
approved for treatment of giardiasis.
• Nitazoxanide is also equally efficacious as
metronidazole and, in comparison, has a 2 day shorter
course of therapy

173
 Trichomoniasis

– It is a genital infection produced by the protozoan

Trichomonas vaginalis
– Metronidazole – the drug of choice
– tinidazole - alternate drug
• Relapses occur if the infected person’s sexual
partner is not treated simultaneously

174
 Leishmaniasis

 There are three types of leishmaniasis: cutaneous, mucocutaneous,

and visceral (kala-azar)
– L. donovani causes visceral leishmaniasis
– L. tropica and L. major produce cutaneous leishmaniasis
– L. braziliensis causes South American mucocutaneous
leishmaniasis.
 leishmaniasis is transmitted by the bite of infected sandflies
- the protozoa is taken by macrophages, multiply and kill the
macrophages

175
  sodium antimony gluconate (sodium stibogluconate)
» the drug of choice
 amphotericin B and pentamidine - alternative drugs
• Amphotericin B is injected slowly intravenously.
– Patients must be closely monitored in hospital,
because adverse effects may be severe.
- Treatment of leishmaniasis is difficult
» because of drug toxicity, the long courses of
treatment, treatment failures, and the frequent need
for hospitalization.

176
 Sodium stibogluconate
 Exact mechanism is unknown
– Thought to inhibit glycolysis in the parasite
 is not effective in vitro (prodrug)
– Hence it is proposed that reduction to the trivalent
antimonial compound is essential for activity
 it is not absorbed on oral administration
– must be administered parenterally
 Adverse effects include pain at the injection site,
gastrointestinal upsets, and cardiac arrhythmias.

177
 Trypanosomiasis

 refers to two chronic and, eventually, fatal diseases

caused by species of Trypanosoma:
 African sleeping sickness
• Trypanosoma brucei gambiense and Trypanosoma
brucei rhodiense
• invades the CNS, causing an inflammation of the
brain and spinal cord that produces eventually
continuous sleep
American sleeping sickness/Chagas' disease
 caused by Trypanosoma cruzi and occurs in South America

178
 Melarsoprol
• first-line therapy for advanced CNS African trypanosomiasis
• is the agent of choice in the treatment of T. brucei rhodesiense,
which rapidly invades the CNS, as well as for meningoencephalitis
caused by T. brucei gambiense.
• Mechanism of action: drug reacts with sulfhydryl groups of various
substances, including enzymes
• The parasite's enzymes may be more sensitive than those of the
host
• Pharmacokinetics: slowly administered IV even though it is absorbed
from the GIT
– in contrast to pentamidine, adequate trypanocidal concentrations
appear in the CSF.
– The host readily oxidizes melarsoprol to a relatively nontoxic
– very short half-life and is rapidly excreted into the urine 179
 Adverse effects:
– CNS toxicities are the most serious side effects
– Encephalopathy may appear soon after the first course of
treatment but usually subsides.
– It may, however, be fatal
– Hypersensitivity reactions and fever may follow injection
– GI disturbances, such as severe vomiting and abdominal
pain, can be minimized if the patient is in the fasting state
during drug administration
– Hemolytic anemia has been seen in patients with glucose 6-
phosphate dehydrogenase deficiency.

180
 Pentamidine isethionate
• active against T. brucei gambiense
• used to treat and prevent the organism's hematologic stage
• also active against Pneumocystis carinii, and leishmaniasis
unresponsive to pentavalent antimonials
• However, some trypanosomes, including T. cruzi, are resistant

 Mechanism of action: the drug binds to the parasite's DNA and

interferes with the synthesis of RNA, DNA, phospholipid, and
protein by the parasite.
– Also may act by inhibiting dihydrofolate reductase

181
 Pharmacokinetics: is not well absorbed from GIT
– Fresh solutions of pentamidine are administered IM or as an
aerosol
» intravenous route is avoided because of severe adverse
reactions, such as a sharp fall in blood pressure and
tachycardia
– Because it does not enter the CSF, it is ineffective against the
meningoencephalitic stage of trypanosomiasis
– The drug is not metabolized, and is excreted very slowly into
the urine.
– Its half-life in the plasma is about 5 days

182
 to treat and prevent the hematologic stage of trypanosomiasis
by T. brucei gambiense
• an alternative drug in the treatment of visceral leishmaniasis
especially when sodium stibogluconate has failed or is
contraindicated
treatment of systemic blastomycosis (caused by the fungus
Blastomyces dermatitidis)
treating infections caused by Pneumocystis jiroveci
» For patients who failed to respond to trimethoprim-
sulfamethoxazole or allergic to sulfonamides

183
 Adverse effects:
– Serious renal dysfunction may occur, which reverses on
discontinuation of the drug.
• Other adverse reactions are hypotension, dizziness, rash, and
toxicity to beta 2 cells of the pancreas(Changes in blood sugar
(hypoglycemia or hyperglycemia) necessitate caution in its use,
particularly in patients with diabetes

184
 Nifurtimox(suppressive, not curative)
• has found use only in the treatment of acute T.
cruzi infections (Chagas' disease)
• undergoes reduction and, eventually, generates
intracellular oxygen radicals, such as superoxide
radicals and hydrogen peroxide
• highly reactive radicals are toxic to T. cruzi, which
lacks catalase
• is administered orally, and it is rapidly absorbed
Adverse effects are common following chronic
administration, particularly among the elderly.
• toxicities include immediate hypersensitivity
reactions anaphylaxis, delayed dermatitis , and GI
problems that may be severe enough to cause
weight loss.
• Peripheral neuropathy is relatively common, and
disturbances in the CNS may also occur. 185
 Suramin
– Used primarily in the early treatment and, especially, the
prophylaxis of African trypanosomiasis
» it is the drug of choice
• It is very reactive and inhibits many enzymesinvolved in energy
metabolism /parasite specific –glycerophosphate oxidase,
thymidylate synthetase, dihydrofolate reductase, and protein
kinase but not on host enzymes.e.g, glycerol phosphate
dehydrogenase
– not absorbed from the intestinal tract and must be injected
intravenously
– It binds to plasma proteins and remains in the plasma for a long
time, accumulating in the liver and in the proximal tubular cells
of the kidney.

186
• Although the initial high plasma levels drop rapidly,
suramin binds tightly to and is slowly released from
plasma proteins, and so it persists in the host for up to 3
months.
• The severity of the adverse reactions demands that the
patient be carefully followed, especially if he or she is
debilitated.
 adverse reactions include:
– nausea and vomiting (which cause further debilitation
of the patient),
– shock and loss of consciousness,
– neurologic problems, including paresthesia,
photophobia, palpebral edema (edema of the eyelids)
– Albuminuria tends to be common
– hematuria may occur and treatment should cease. 187
 Benznidazole
 inhibits protein synthesis and ribonucleic acid synthesis
in the T. cruzi cells
 It is an alternative choice for treatment of acute phases
of Chagas’ disease
 benznidazole is recommended as prophylaxis for
preventing infections caused by T. cruzi among
hematopoietic stem cell transplant recipients because
treatment in potential donors is not always effective.

188
 Toxoplasmosis

– caused by Toxoplasma gondii

– transmitted to humans when they consume raw or
inadequately cooked, infected meat
– An infected pregnant woman can transmit the
organism to her fetus.
– Cats are the only animals that shed oocysts, which
can infect other animals as well as humans.

189
 Pyrimethamine
– The treatment of choice
– At the first appearance of a rash, pyrimethamine should be
discontinued, because hypersensitivity to this drug can be
severe.
 sulfadiazine –pyrimethamine
– is also efficacious
– Leucovorin is often administered to protect against folate
deficiency
• Other inhibitors of folate biosynthesis, such as trimethoprim and
sulfamethoxazole, are without therapeutic efficacy in
toxoplasmosis.

190
 ANTIFUNGAL AGENTS
 Fungal infections have increased in incidence and
severity in recent years
due to increase in the use of broad-spectrum
antimicrobials and the HIV epidemic
 antifungal drugs fall into two groups:
antifungal antibiotics- Amphotericin B, Nystatin,
Griseofulvin
synthetic antifungals- Flucytosine, Azoles
(imidazoles and triazoles)

191
1. amphotericin B
– is antifungal antibiotic
– is a broad-spectrum antifungal agent
» against yeasts including; Candida albicans and
Cryptococcus neoformans; molds, Aspergillus
fumigatus
 MOA
– binds to ergosterol (a cell membrane sterol) and alters the
permeability of the cell by forming amphotericin B-associated
pores in the cell membrane
– The pore allows the leakage of intracellular ions and
macromolecules, eventually leading to cell death.

192
 pharmacokinetics
• is poorly absorbed from the GIT (by slow IV injection)
• also used topically (mycotic corneal ulcers and keratitis can be
cured with topical drops).
• Oral amphotericin B is thus effective only on fungi within the
lumen of the GI tract
- widely distributed in tissues, but only 2-3% of the blood level is
reached in CSF, thus occasionally necessitating intrathecal
therapy for certain types of fungal meningitis
 Therapeutic use
– drug of choice for nearly all life-threatening mycotic infections
– as the initial induction regimen for serious fungal infections
(immunosuppressed patients, severe fungal pneumonia, and
cryptococcal meningitis with altered mental status).

193
 Adverse Effects
– fever, chills, muscle spasms, vomiting, headache,
hypotension (related to infusion), renal damage
associated with decreased renal perfusion (a reversible)
and renal tubular injury (irreversible).
– Anaphylaxis, liver damage, anemia occurs infrequently.

194
2. Nystatin
– active against most Candida species
– is antifungal antibiotic
 MOA
– has similar structure with amphotericin B and has
the same pore-forming mechanism of action
 Pharmacokinetics
– too toxic for systemic use and is only used topically
– is not absorbed from skin, mucous membranes, or
the gastrointestinal tract
 Therapeutic use
– most commonly used for suppression of local
candidal infections
» in the treatment of oropharyngeal thrush,
vaginal candidiasis, and intertriginous candidal
infections. 195
3. Griseofulvin
 MOA
– is a fungistatic
– is antifungal antibiotic
 Pharmacokinetics
– fatty foods increase its absorption
– is deposited in newly forming skin where it binds to
keratin, protecting the skin from new infection
 Therapeutic use
– used is in the treatment of dermatophytosis
– must be administered for 2-6 weeks for skin and hair
infections to allow the replacement of infected keratin
by the resistant structures
– Nail infections may require therapy for months to
allow regrowth of the new protected nail and is often
followed by relapse. 196
 Adverse effects
– allergic syndrome much like hepatitis
– drug interactions with warfarin and phenobarbital.
 Griseofulvin has been largely replaced by newer antifungal
medications such as itraconazole and terbinafine.

197
4. Flucytosine
– synthetic antifungal agent
– spectrum of action is much narrower than that of
amphotericin B
» Active against Cryptococcus neoformans, some Candida
species, and the dematiaceous molds that cause
chromoblastomycosis
 MOA
– is related to fluorouracil (5-FU)
– inhibit DNA and RNA synthesis after being changed

198
 Pharmacokinetics : well absorbed orally
– penetrates well into all body fluid compartments including the
CSF
 Therapeutic use
– with amphotericin B for cryptococcal meningitis
– with itraconazole for chromoblastomycosis (chronic fungal
infection of the skin, producing wart like nodules)
 Adverse effects
– Bone marrow toxicity with anemia, leukopenia, and
thrombocytopenia are most common
• Toxicity is more likely to occur in AIDS patients and in the presence
of renal insufficiency

199
 Azoles anti fungals
– synthetic compounds
 Classification
– can be classified as imidazoles and triazoles
imidazoles (ketoconazole, miconazole, and clotrimazole)
Triazoles (itraconazole and fluconazole)
 MOA
– reduction of ergosterol synthesis by inhibition of fungal
cytochrome P450 enzymes
– Have greater affinity for fungal than for human cytochrome
P450 enzymes
» Imidazoles exhibit a lesser degree of specificity than
the triazoles

200
 Antifungal spectrum
– active against many Candida species, Cryptococcus
neoformans, the endemic mycoses (blastomycosis,
coccidioidomycosis), the dermatophytes, and, Aspergillus
infections (itraconazole)
 Adverse Effects
– azoles are relatively nontoxic
– most common adverse reaction is minor GI upset
– Most azoles cause abnormalities in liver enzymes

201
Ketoconazole
– limited use because of the drug interactions,
endocrine side effects, and of its narrow
therapeutic range
 Therapeutic use
– in treatment of mucocutaneous candidiasis
and nonmeningeal coccidioidomycosis
(mainly affects the lung)
– also used in the treatment of seborrheic
dermatitis and pityriasis versicolor (Topical/
shampoo)
 Adverse Effects
– Interferes with biosynthesis of adrenal and
gonadal steroid hormones
– Endocrine effects such as
gynecomastia, infertility, and menstrual
irregularities
– Inhibits hepatic enzyme cytochrome p450 202
 Clotrimazole and miconazole
 often used for vulvovaginal candidiasis
 Oral clotrimazole troches are available for treatment of oral
thrush and are a pleasant-tasting alternative to nystatin
– In cream form, both agents are useful for dermatophytic
infections, including tinea corporis, tinea pedis, and tinea
cruris
– Absorption is negligible, and adverse effects are rare.

203
 Itraconazole
– available in an oral formulation
– absorption is increased by food and by low gastric pH
 is the azole of choice in the treatment of dermatophytoses
and onychomycosis
– is the only agent with significant activity against Aspergillus
species.

204
 Fluconazole (has a wide therapeutic window)
– has good CSF penetration
– given IV or PO
– has the least effect on hepatic microsomal enzymes
– is the azole of choice in the treatment and secondary
prophylaxis of cryptococcal meningitis
– also effective for mucocutaneous candidiasis.

205
 TREATMENT OF HELMINTHIC INFECTIONS
 Three major groups of helminths (worms) the nematodes,
trematod, and cestodes infect humans
 Anthelmintic drugs are used to eradicate or reduce the numbers
of helminthic parasites in the intestinal tract or tissues of the
body.
 Most anthelmintics are active against specific parasites; thus,
parasites must be identified before treatment is started.

206
 Drugs for the Treatment of Nematodes
 Nematodes : are elongated roundworms
– cause infections of the intestine as well as the blood and
tissues.

207
Roundworms (nematodes)
– Ascaris lumbricoides (roundworm)
• First choice
– Albendazole/pyrantel pamoate/ mebendazole
• Alternative
– Piperazine
– Trichuris trichiura (whipworm)
• First choice
– Mebendazole/albendazole
• Alternative
– Oxantel/pyrantel pamoate

208
– Necator americanus (hookworm); Ancylostoma
duodenale (hookworm)
• First choice
– Pyrantel pamoate/mebendazole/ albendazole
– Strongyloides stercoralis (threadworm)
• First choice- Ivermectin
• Alternative - Thiabendazole, albendazole
– Enterobius vermicularis (pinworm)
• First choice- Mebendazole/pyrantel pamoate
• Alternative- Albendazole

209
– Trichinella spiralis (trichinosis)
• First choice - Mebendazole
– add corticosteroids for severe infection
• Alternative - Albendazole
– add corticosteroids for severe infection
– Trichostrongylus species
• First choice - Pyrantel pamoate/mebendazole
• Alternative - Albendazole

210
– Cutaneous larva migrans
» First choice - Albendazole or ivermectin
» Alternative - Thiabendazole (topical)
– Visceral larva migrans
» First choice - Albendazole
» Alternative - Mebendazole
– Angiostrongylus cantonensis
» First choice - Thiabendazole
» Alternative – Albendazole/mebendazole

211
– Wuchereria bancrofti (filariasis); Brugia malayi
(filariasis); tropical eosinophilia; Loa loa (loiasis)
» First choice - Diethylcarbamazine
» Alternative - Ivermectin
– Onchocerca volvulus (onchocerciasis)
• Ivermectin
– Dracunculus medinensis (guinea worm)
» First choice - Metronidazole
» Alternative – Thiabendazole/mebendazole

212
 Mebendazole

 synthetic benzimidazole compound, is effective against a

wide spectrum of nematodes.
 drug of choice in the treatment of infections by:
– whipworm (Trichuris trichiura)
– pinworm (Enterobius vermicularis)
– hookworms (Necator americanus and Ancylostoma
duodenale) and
roundworm (Ascariasis lumbricoides)
Mebendazol – 100mg twice daily for 3 days (90 – 100%
cure).

213
 Mechanism of action:
– bind to and interfere with the assembly of the parasites'
microtubules and also by decreasing glucose uptake
– Mebendazole is nearly insoluble in aqueous solution.
– Little of an oral dose (that is chewed) is absorbed by the body,
unless it is taken with a high-fat meal.
– undergoes first-pass metabolism to inactive compounds
– is relatively free of toxic effects, although patients may
complain of abdominal pain and diarrhea.
– It is, however, contraindicated in pregnant women

214
 Pyrantel pamoate
 MOA- acts as a depolarizing, neuromuscular-blocking agent,
causing persistent activation of the parasite's nicotinic receptors
- The paralyzed worm is then expelled from the host's
intestinal tract
• along with mebendazole, is effective in the treatment of
infections caused by roundworms (500mg to be taken in the
morning on an empty stomach), pinworms, and
hookworms(250mg twice daily for 3days).
- poorly absorbed orally and exerts its effects in the intestinal tract
- Adverse effects are mild and include nausea, vomiting, and
diarrhea.

215
 Thiabendazole
 affects microtubular aggregation
- is effective against strongyloidiasis caused by
Strongyloides stercoralis (threadworm), cutaneous
larva migrans, and early stages of trichinosis (caused
by Trichinella spiralis)
- the drug is readily absorbed on oral administration.
- It is hydroxylated in the liver and excreted in the
urine

216
 adverse effects
– most often encountered are dizziness, anorexia,
nausea, and vomiting
– central nervous system (CNS) symptoms
– erythema multiforme and Stevens-Johnson
syndrome that can be fatal
 contraindicated during pregnancy

217
 Ivermectin

 Acts on the parasite's glutamate-gated Cl- channel

receptors
– Chloride influx is enhanced, and hyperpolarization
occurs, resulting in paralysis of the worm.
 drug of choice in the treatment of :
– onchocerciasis (river blindness) caused by
Onchocerca volvulus
– cutaneous larva migrans and strongyloides.

218
 The drug is given orally
 It does not cross the blood-brain barrier
– it is contraindicated in patients with meningitis,
because their blood-brain barrier is more
permeable and CNS effects might be expected
 also contraindicated in pregnancy
 The killing of the microfilaria can result in a Mazotti-
like reaction (fever, headache, dizziness, somnolence,
and hypotension)

219
 Diethylcarbamazine
 used in the treatment of filariasis
– because of its ability to immobilize microfilariae
and render them susceptible to host defense
mechanisms.
 Combined with albendazole, diethylcarbamazine is
effective in the treatment of Wucheria bancrofti and
Brugia malayi infections
 It is rapidly absorbed following oral administration
with meals and is excreted primarily in the urine.

220
 Adverse effects
– are primarily caused by host reactions to the killed
organisms.
– The severity of symptoms is related to the parasite
load and include fever, malaise, rash, myalgias,
arthralgias, and headache.
– Most patients have leukocytosis
 Antihistamines or steroids may be given to ameliorate
many of the symptoms

221
Drugs for the Treatment of Trematodes
 trematodes (flukes)
– are leaf-shaped flatworms
– generally characterized by the tissues they infect.
For example, they may be categorized as liver,
lung, intestinal, or blood flukes

222
– Schistosoma haematobium (bilharziasis)
– First choice - Praziquantel
– Alternative - Metrifonate
– Schistosoma mansoni
– First choice - Praziquantel
– Alternative - Oxamniquine
– Schistosoma japonicum
» Praziquantel
– Clonorchis sinensis (liver fluke); Opisthorchis
species
» Praziquantel and alternative is Albendazole

223
– Paragonimus westermani (lung fluke)
• First choice - Praziquantel
• Alternative - Bithionol
– Fasciolopsis buski (large intestinal fluke)
» Praziquantel or niclosamide
– Heterophyes heterophyes; Metagonimus
yokogawai (small intestinal flukes)
» Praziquantel or niclosamide

224
 Praziquantel
– Permeability of the cell membrane to calcium is
increased, causing contracture and paralysis of the
parasite
 Trematode infections are generally treated with
praziquantel
– an agent of choice for the treatment of all forms
of schistosomiasis and other trematode infections
and for cestode infections like cysticercosis.

225
 pharmacokinetics
– rapidly absorbed after oral administration and
distributes into the cerebrospinal fluid
– The drug is extensively metabolized, resulting in a
short half-life
– The metabolites are inactive and are excreted
through the urine and bile
 adverse effects
– Commonly include drowsiness, dizziness, malaise,
and anorexia, as well as gastrointestinal upsets.

226
– The drug is not recommended for pregnant
women or nursing mothers.
– contraindicated for the treatment of ocular
cysticercosis, because destruction of the organism
in the eye may damage the organ

227
 Drugs for the Treatment of Cestodes
 The cestodes, or true tapeworms
– typically have a flat, segmented body and attach to
the host's intestine
– Taenia saginata (beef tapeworm)
• First choice - Praziquantel or niclosamide
• Alternative - Mebendazole
– Diphyllobothrium latum (fish tapeworm)
– Praziquantel or niclosamide
– Taenia solium (pork tapeworm)
– Praziquantel or niclosamide
228
– Cysticercosis (pork tapeworm larval stage)
• First choice - Albendazole
• Alternative - Praziquantel
– Hymenolepis nana (dwarf tapeworm)
• First choice - Praziquantel
• Alternative
– Niclosamide
– Echinococcus granulosus (hydatid disease);
Echinococcus multilocularis
– Albendazole

229
 Niclosamide
– inhibits the parasite's mitochondrial phosphorylation
of adenosine diphospate
– Anaerobic metabolism may also be inhibited
 the drug of choice for most cestode (tapeworm)
infections.
 Niclosamide (0.5g table) – 2 tabs to be crushed in the
mouth and swallowed in the early morning on an empty
stomach and then after 1hr 2 more tabs are to be taken
in a similar ways.
 Saline purgative/laxative administered after 2hrs to
assist in expulsion of the worm..
 Alcohol should be avoided within 1 day of niclosamide.
230
Alternative treatments for tape worm infestation
• Praziquantel 10mg/kg in a single dose
• Mebendazole 300mg 3 times a days for 3 days

231
 Albendazole
 inhibits microtubule synthesis and glucose uptake in
nematodes
– primary therapeutic application, however, is in the
treatment of cestodal infestations, such as
cysticercosis (caused by Taenia solium larvae) and
hydatid disease (caused by Echinococcus
granulosis).
• 400mg single dose (mostly 400mg/d for 3days

232
 Pharmacokinetics
– Albendazole is erratically absorbed after oral
administration, but absorption is enhanced by a
high-fat meal.
– It undergoes extensive first-pass metabolism
– Albendazole and its metabolites are primarily
excreted in the urine

233
 Adverse effect
– When used in short-course therapy (3 days) for
nematodal infestations, adverse effects are mild and
transient and include headache and nausea.
– Treatment of hydatid disease (3 months) has a risk
of hepatotoxicity and, rarely, agranulocytosis
– Medical treatment of neurocysticercosis is
associated with inflammatory responses to dying
parasites in the CNS, including headache, vomiting,
hyperthermia, convulsions, and mental changes.
– should not be given during pregnancy or to children
under 2 years of age.

234
 ANTIVIRAL DRUGS
• Viruses are obligate intracellular parasites that consist of
either double- or single-stranded DNA or RNA enclosed in
a protein coat called a capsid
• Most viruses contain or encode enzymes essential for viral
replication inside a host cell, and they seize the metabolic
machinery of their host cell
• Effective antiviral agents inhibit virus-specific replicative
events or preferentially inhibit virus-directed rather than
host cell-directed nucleic acid or protein synthesis

235
236
237
238
 Antiviral Drugs

• A virus consists of nucleic acid enclosed in a shell of

protein.
• It does not have a cell wall or enzymes as present in
bacteria.
• Viruses are of two types (not contain both RNA & DNA)
– DNA containing viruses
– RNA containing viruses (HIV)
• For varicela zoster – eg-Acyclovir
• For Influenza Virus- eg- Amantadine
• For Hepatitis Virus – eg- Interferons

239
1. Antiherpes & Anticytomegalo virus agents
• Eg. Acyclovir, ganciclovir, famciclovir, vidarabine, Indoxucridine
These drugs are pyrimidine and purine analogues and inhibit DNA
virus replication by competitive antagonism.
2. Anti-influenza agents
• Eg. Amantadine, Rimantadine, Ribavirin. (are a tricyclic primary amine).
Amantadine is effective for chemoprophylaxis of influenza A during out
break of an epidemic but not effect against influenza B. It is also
effective against rubella, if given within 48hrs of the onset of
symptoms.
Ribavirin:- is a guanosine analogue
- interferes with synthesis of viral mRNA and viral DNA – dependent RNA
polymerase
• Effective against both RNA & DNA viruses, including influenza A & B,
respiratory syncytial virus (RSV).

240
 Retrovirus
• Infectious particle containing an RNA genome closed in a protein
capsid surrounded by a lipid envelope.
• This envelope contains polypeptides acting as receptors mediating
entry & infection
• Reverse Transcriptase - vRNA codes for DNA.
• This DNA is inserted into host genome (integrase)
• Propagation –
• 1} new virons &
• 2} copied as part of host cell DNA when cell divides

241
 Life cycle of human immuno-deficiency virus (HIV)
• HIV binds to CD4 and chemokine co-receptors and enters
by fusion
• Genome is reverse transcribed into DNA in the cytoplasm
and integrated into the nuclear DNA
• Transcription and translation of the genome occur in a
fashion similar to that of human T-lymphotropic virus
• Virus assembles at the plasma membrane and matures after
budding from the cell

242
243
 HIV life cycle

Fusion-Inhibitors

Gray = blood
Blue circle = CD4 cell
Purple circle = CD4 cell nucleus
Fusion Inhibitors
HIV Replication Cycle
• Once HIV has bound to and invaded the host cell, part of
the virus, an enzyme called reverse transcriptase (RT)
translates HIV’s genetic material (single stranded RNA)
into a form compatible with human DNA (double stranded
DNA, the building block of all human cells).
• This viral DNA can then become part of the CD4 cell’s DNA
within the nucleus and transform the cell into a factory for
making more HIV (think of the viral DNA combined with
the host cell’s DNA like a complete blueprint for making
new virus).
• The complete DNA (i.e., the blueprint) undergoes
translation and creates complex HIV proteins.

246
• These new HIV proteins are not infectious until the
protease enzyme cuts each complex protein chain into
smaller functional proteins that can be used to build the
new virus (e.g., the core, the envelope).
• These smaller functional proteins are then stuck
together to form new HIV virus.
• These complete virus can then leave the CD4 cell and
enter the plasma to infect new host cells.

247
 Antiretrovirals

Antiretroviral drugs are classified as:

1. Nucleoside reverse transcriptase inhibitors (NRTIs)
2. Non-nucleoside reverse transcriptase inhibitors
(NNRTIs)
3.Protease inhibitors (PIs)
4.Integrase inhibitor
5.Fusion inhibitor

248
 Current Antiretroviral Medications
NRTI PI Fusion Inhibitor
·Abacavir ·Atazanavir · Enfuvirtide
·Didanosine ·Darunavir
CCR5 Antagonist
·Emtricitabine ·Fosamprenavir
· Maraviroc
·Lamivudine ·Indinavir
·Stavudine ·Lopinavir
Integrase Inhibitor
·Tenofovir ·Nelfinavir
· Raltegravir
·Zidovudine ·Ritonavir
·Saquinavir
NNRTI ·Tipranavir
·Delavirdine
·Efavirenz
·Etravirine
·Nevirapine
 NUCLEOSIDE & NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS
• Compete with cellular nucleotides and prevent completion
of reverse transcription
– zidovudine (AZT)
– didanosine (ddI )
– zalcitabine (ddC)
– stavudine (d4T)
– lamivudine (3TC)
– Abacavir (ABC)
– Tenofovir (TDF)

250
Mechanism of action of NRTIs
• NRTI’s compete with the normal physiological
nucleosides used for DNA synthesis.
• They differ from the normal substrates only by a minor
modification in the sugar (ribose) molecule.
• Acting as "false building blocks“, nucleoside analogs
incorporate themselves, preventing DNA synthesis,
because normal bridges can no longer be built to build
the double strand.
• Thus they prevent the development of functional viral
DNA

251
 Nucleoside Reverse
Transcriptase Inhibitors (NRTIs)

RNA DNA
Nucleus
Host Cell
 A. ZIDOVUDINE (AZT, ZDV) *

• It is a deoxythymidine analog
Mechanism of Action: It is phosphorylated 3 times to the active
metabolite, zidovudine 5’-triphosphate.
• Phosphorylated by cellular thymidine kinase
• Zidovudine triphosphate interferes with HIV vRNA-dependent DNA
polymerase
• incorporated into DNA chain and terminates synthesis
• Zidovudine was the first ARV approved in 1987 when monotherapy
was the standard of care. In the 1980s, AZT was dosed 5 times daily
and the toxicities were much greater. Now, the drug is better
tolerated, though it does still have significant side effects (nausea,
anemia),
• well absorbed from the gut and distributed to most body tissues and
fluids, including the cerebrospinal fluid
• The most common adverse effect is myelosuppression, resulting in
macrocytic anemia 253
• Dosing: 300mg BID
• Food Interactions
– None – with or without food is ok
– Food decreases AZT-related nausea
• T1/2: 1 hour
• Intracellular T1/2 (NRTIs exert their effect intracellulary, duration of
action is based on intracellular half-life): 3 hours

254
• Nausea
• Nausea is most common side effect for AZT, eating prior to dose
helps reduce nausea
• Bone Marrow Suppression (Anemia , Neutropenia )
• Anemia means a shortage of red blood cells. Red blood cells
transport oxygen around the body, so anaemia can cause
symptoms of tiredness and breathlessness.
Anemia may occur within 4 to 6 weeks. In severe cases, blood
transfusion may be needed.
• Headaches
• Myalgias/ Myopathy
• Insomnia
• Pigmentation of nail beds
• Lactic acidosis, fatty Liver

255
 ZDV-Related Fingernail Discoloration

Nail Hyperpigmentation
Can be seen on hands and feet after 2-6 weeks, usually dark bluish-black vertical-line
discoloration.
More common among African population.
This is NOT an indication to stop AZT
 Lamivudine(3TC)
• a cytosine analog
• Mechanism of Action: It is phosphorylated 3 times by thymidine
kinase to the active metabolite, 3TC-triphosphate
• long T1/2
• Lower risk of peripheral neuropathy (versus didanosine or zalcitabine)
• Best tolerated of all antiretrovirals. 3TC is recommended to be included in
all first line regimens
• active against Hepatitis B virus (HBV), possibly drug of choice in those
with HIV & HBV
• bioavailability increases when it is co-administered with
trimethoprim-sulfamethoxazole
• Dosing: 150mg BID or 300mg QD
• Food Interactions: no food interactions
• Toxicity : very rare
• Part of all first line regimens
• Also indicated for Hep B, dose=100-300mg qd; but high rate of HBV resistance
257
Use for Hep B: 3TC is a potent inhibitor of HBV, good for
patients with co-infection. The dose for HBV only is
100mg QD. For HIV/HBV co-infection, dose is 300mg QD.
HBV develops resistance at a rate of 20%-25% per year.
Tenofovir is active against 3TC-resistant HBV.
• FDA Approval: November 1995
• T1/2: 3-6 hours
• Intracellular T1/2: 12 hours

258
 Emtricitabine (FTC)

• Nucleoside Analog:Cytosine analogue

• Emtricitabine is the flourinated version of lamivudine.
• The flourinated version was designed to reduce toxicity and
prolong drug half-life, but clinically there does not appear to be
any difference between the 2 drugs.
• Mechanism of Action: It is phosphorylated 3 times to the active
metabolite, emtricitabine 5’-triphosphate
• FTC has demonstrated activity against Hepatitis B, but it is not
FDA approved for this indication
• Dosing: 1 x 200mg capsule QD
• Food Interactions: no food interactions
• Toxicity
– Mild abdominal discomfort , Occasional nausea
• T1/2: 8-9 hours
• Intracellular T1/2: > 20 hours
 Stavudine (d4T) *

• Nucleoside Analog: Thymidine analogue

Mechanism of Action: It is phosphorylated 3 times, first by thymidine
kinase, 2nd by thymidylate kinase, and 3rd by pyrimidine
diphosphate kinase to the active metabolite, stavudine
triphosphate.
• Dosing 30 mg BID
• Food Interactions: None
• Toxicity
– Peripheral Neuropathy (5-15%, pain, tingling, and
numbness in extremities)
– Lactic acidosis, fatty liver *
– Pancreatitis *
– Lipoatrophy *
– Hypertriglyceridemia
Removed from market because of toxicity
• Stavudine is a “D” drug – side effect profile is similar for
all “D” drugs
• Side effects: Peripheral neuropathy and pancreatitis are
dose-related side effects. Use lower dose to reduce risk
of S/E development for patients.
• Peripheral Neuropathy: is usually after 2-6 months of
therapy. If patient develops peripheral neuropathy
discontinue d4T at onset (or reduce dose.
• If provider does not discontinue therapy (or reduce dose)
at onset, peripheral neuropathy will become permanent
and increasingly painful and debilitating.
• Pancreatitis: If develops, discontinue therapy. When
symptoms resolve, do not re-challenge with stavudine
261
Facial Lipoatrophy Also known as facial wasting.
• The look is distinct. It is characterized by thinning in
cheeks.
• This has become concerning to patients as they fear
that the lipoatrophy will enable other people to
recognize that they have HIV.
• Appears to be most common with long-term stavudine
use, but difficult to determine because combination
therapies are typically used.
• If facial lipoatrophy develops, discontinue the offending
agent and use an alternate medication.
• Facial wasting is usually not reversible, but by changing
medications, it prevents progression of the side effect.
Facial Lipoatrophy Also known as facial wasting.
 Abacavir (ABC)
• Nucleoside Analog: Guanine analogue
• Mechanism of Action: It is phosphorylated 3 times to the active
metabolite
Dosing: 1 x 300mg tablet BID
Pediatric Dose: 8mg/kg BID
Dose does not need to be adjusted for compromised renal function.
No data on hepatic failure, use usual dose.
• Food Interactions: no food interactions
Toxicity
• Abacavir is generally well tolerated. Patients should be counseled about
abacavir hypersensitivity reaction
– Hypersensitivity reaction - 5% *
– Occurs within first 6 weeks of therapy
– Pregnancy: (Category C) Crosses placenta.
• T1/2: 1.5 hours
• Intracellular T1/2: > 12 hours
 Tenofovir disoproxil fumarate n(TDF) *

• An acyclic nucleoside phosphonate (ie, nucleotide) analog of adenosine

• The only nucleotide analog currently marketed for the treatment of
HIV infection
TDF is different from nucleosides in that it has already been
phosphorylated once.
Mechanism of Action: Tenofovir disoproxil fumarate is a pro-drug of
tenofovir. After oral administration, TDF is rapidly cleaved by
nonspecific extracellular carboxyesterases into tenofovir. Once inside
cells tenofovir is metabolized by adenylate cyclase and nucleoside
diphosphate kinase to the active moiety, tenofovir diphosphate .
• Dosing: 1 x 300mg tablet QD(Dose 300 mg QD
• Also has activity against Hepatitis B (Active vs. Lamivudine resistant HBV strains)
• Food Interactions: no important effect
• Toxicity
– Renal insufficiency – Fanconi syndrome (rare) *
– Must dose adjust with renal failure
2. Non-Nucleoside Reverse Transcriptase Inhibitors
• They bind directly to HIV-1 reverse transcriptase
resulting in blockade of RNA- and DNA-dependent DNA
polymerase
• Unlike the NRTI agents, NNRTIs neither compete with
nucleoside triphosphates nor require phosphorylation to
be active
• They hook on to the actual enzyme (reverse
transcriptase) and stop it from working.
• The result is the same as the NRTIs: the DNA copy of
viral RNA cannot be made and therefore cannot be
integrated into the nucleus.

266
• NNRTIs
1st generation: Nevirapine (NVP), Efavirenz (EFV)
Delavirdine (DLV)(not in ethiopia),
2nd generation : Etravirine
• All substrates for CYP3A4 and can act as
inducers (nevirapine), inhibitors (delavirdine),
or mixed inducers and inhibitors (efavirenz)

267
 Nevirapine (NVP, Nevipan®)

• Dosing: 200 mg QD x 2 weeks, then 200 mg BID

• Food Interactions: None
• Toxicity: two serious ADRs in first 6 weeks & more common with
CD4 > 300 (female >250 ,male >400)
1.Rash – Maculo Papular (17%); Steven Johnson
Syndrome (1%) When initiating therapy, gradual dose
escalation over 14 days is recommended to decrease
the incidence of rash
2. Hepatitis – liver necrosis
• Drug interactions: Few
• Metabolic side effects: None
• Hepatotoxicity that occurs in the first 8 weeks appears to be a
hypersensitivity reaction and may be accompanied by DRESS:
Drug rash, eosinophilia and systemic symptoms
• The risk of hepatitis is greatest in the first 6 weeks of therapy. .
 NNRTI Rash

• Often diffuse, slightly raised, itchy

• Vary in redness and distribution
• Can be severe - Steven’s Johnson Syndrome
 Efavirenz (EFV, Stocrin®)
• Dosing: 600 mg tab QHS
• Food Interactions
– Take on empty stomach or with low-fat meal
• High-fat meals increase absorption 50% 
increases side effects
• Drug Interactions: Rifampin ↓ EFV by 25%
• Side Effects: CNS changes are very common (noted in 52%
of patients), but require discontinuation in a much smaller
percentage (2%-5%). Onset is usually at initiation of
therapy and usually resolves after 2 to 4 weeks.
Include: confusion, abnormal thinking, impaired
concentration, abnormal dreams (Very vivid, bizarre
dreams, most concerning if they are nightmares. Some
patients enjoy the dreams and are not worried at all by
them.) and dizziness.
• Others are drowsiness, insomnia, amnesia, hallucinations,
and euphoria may usually resolve after 2 to 4 weeks.
• Avoiding high-fat meals at time of dose consumption
reduces side effect intensity or taking the dose at bedtime
so that pt sleep through the peak of the side effects.
271
• In addition, patients should use caution if operating a car
or other heavy machinery during the day or night if they
experience these symptoms to prevent accidents,
especially during the first 2 weeks of therapy.
• patients that experience insomnia (which can be
associated with the peak level), should take their dose 1 to
2 hours prior to going to bed.
• some patients experience severe psychiatric symptoms
including delusions, manic episodes and severe depression
, particularly common in people with a history of mental
illness or recreational drug abuse.
They may even become suicidal and require anti-psychotic
medication.
For these pts , only use EFV if no other options are available.
272
• Co-Formulated Reverse Transcriptase Inhibitors – FDC
– AZT/3TC
(Combivir, Duovir, Virocomb, Zidolam )
– D4T/3TC
(Lamivir-S, Viro LIS, Lamistar)
– Abacavir/AZT/3TC
(Trizivir or Trisivir, Generic Brands: Virol LZ )
– Nevirapine/d4T/3TC
(Generic Brands: Triomune, Viro LNS, Nevilast)
– Nevirapine/AZT/3TC
(Generic brand: Duovir-N)
– Efavirenz/ddI/3TC
(Generic brand: Odivir Kit)
– Atripla (TDF,FTC,EFV)

273
 3. PROTEASE INHIBITORS
• Protease inhibitors – prevent viral protease enzyme from
cleaving the polyprotein precursor to viral coat protein and
reduces activation of critical viral proteins/enzymes
• Thus new virons are formed, but are defective and cannot
infect other cells
• Use of PIs is associated with a syndrome of redistribution
and accumulation of body fat that results in central obesity
to the exception of atazanavir

274
 Characteristics of Antiretroviral Agents

The P450 3A4 subset is the major enzymatic route of metabolism

of the PIs and NNRTIs

Antiretroviral agent Metabolism Effect on cytochrome P450

Zidovudine Hepatic glucuronidation, -

Renal
excretion
Other NRTIs Renal excretion
-
Nevirapine Cytochrome P450
Modest Induction
Delavirdine Cytochrome P450
Modest Inhibition
Efavirenz Cytochrome P450
Modest Induction and Inhibition
Ritonavir Cytochrome P450
Potent Inhibition
Amprenavir, Cytochrome P450
 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 zidovudine and stavudine, or zalcitabine and
lamivudine.
• Combination of zidovudine and stavudine caused a decline in CD4+
T cell counts as compared with baseline values prior to therapy.
• Combinations of didanosine + zalcitabine, and stavudine +
zalcitabine, are not recommended due to overlapping potential for
the development of peripheral neuropathy.
Strongly recommended
Stavudine and Didanosine
Stavudine and Lamivudine
Zidovudine and Didanosine
Zidovudine and Lamivudine
Alternative combinations
Didanosine and Lamivudine
Zidovudine and Zalcitabine
 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
• Saquinavir ( soft gel ) usually 1200mg q8h ( or 6 capsules q8h) or
hard gel 600mg ( 3 caps ) q8h.
• With ritonavir this is reduced to 2 caps every 12 hours
• Hence studies are underway to determine whether the same effects can be
achieved with lower ritonavir doses.
Interactions Between PIs and 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 to ensure trough plasma concentrations of the
PIs are above the minimum inhibitory concentration.
For example, Indinavir may be increased from 800 mg tds to
1000mg tds, and nelfinavir may be increased from 750 mg
to 1000 mg tds.
Interactions Between Antiretroviral Agents and
Other Drugs
Hepatic metabolism:
Macrolide antibiotics, azole antifungals and H-2 blockers are
P450 inhibitors and hence interact with PIs and NNRTIs.
– Pi doses need to be reduced or azole doses reduced, when
given with azole antifungals such as ketoconazole
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.
Anti-tuberculosis Agents and ARVs

Rifampin
– 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.