Chapter 10

CHEMOTHERAPY

By: Desta H. (Msc)

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 CHEMOTHERAPY
Chemotherapeutic agents: Compounds used in
treatment of infectious diseases and cancer
Antimicrobial agents: Chemical that kills or inhibits the
growth of microorganisms
Categories of antimicrobial agents
• Antibiotics : biologically produced by microbes
• Semi-synthetic : other chemical groups are added to
a nucleus of antibiotic
• Synthetic : synthesized by using structural activity
relationship
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 CHEMOTHERAPY
Antibiotic: Chemical produced by a microorganism
that kills or inhibits the growth of another
microorganism
Empiric therapy: treatment of an infection before
specific culture information has been reported or
obtained

Prophylactic therapy: treatment with antimicrobials to

prevent an infection

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 CHEMOTHERAPY
Bactericidal: Agents that kill bacteria . Useful in life-
threatening infections and in patients with low WBC
count [immunocompromised]
Bacteriostatic: Agents that inhibit but do not kill
bacteria

• Bacteria may grow again when drug is withdrawn

• Host defences are needed to kill bacteria

• In large doses may become bactericidal

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Bacteria

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 Characteristics of Antibacterial Agents
1. Selective Toxicity
• [Aldrien and Albert in 1951]
• Inhibit growth of bacteria without damage to host
• Due to differences between bacterial and human cells at
four major sites
• Cell wall
• Cell membrane Few antiviral agents
• Ribosomes due to lack of
• Nucleic acids selective toxicity

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 Characteristics of Antibacterial Agents
1. Spectrum of Activity
Broad Spectrum:
• Active against both gram-positive and gram-
negative bacteria e.g. tetracycline, quinolones
Narrow spectrum:
• Active against one or very few types of bacteria
Vancomycin for Staph. & Enterococci.
• Metronidazole- antiamoebic and antiprotozoal

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 Antimicrobials Mechanisms of Action

1. Inhibitors of cell wall synthesis

2. Inhibitors of cell membrane functions

3. Inhibitors of protein synthesis

4. Inhibitors of mycolic acid synthesis

5. Inhibitors of nucleic acids synthesis

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 INHIBITORS OF CELL WALL SYNTHESIS

• These agents require actively-dividing microorganisms

• They have no or little effect on non growing bacteria

• Have no effect on organisms devoid of cell wall

• Less toxic on human cells (mammalian cell has no cell

wall)

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11
 β-LACTAMS
Mechanism of action:
 Inhibit transpeptidation reactions or cross linkinings
of peptidoglycan chains (last step in bacterial cell
wall synthesis), through binding to penicillin binding
protein (PBPs)
 Increase activity of autolysins produced by some
bacteria leading to cell wall lysis
 Bactericidal

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 β-lactam ring
β-lactam ring is a common structure for:

• Penicillins

• Cephalosporins

• Monobactams

• Carbapenems
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 PENICILLINS
• Gram positive organisms have cell walls susceptible to the
action of penicillins

• The cell walls of gram negative micro-organisms have an

impermeable outer membrane(envelop)

• β-lactam antibiotics cross the outer membrane and enter

gram negative organisms via outer membrane protein
channels (porins)

• Lack of these porins in pseudomonas aeruginosa makes

them resistant to many antibiotics
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 PENICILLINS
• Preparations of penicillins
• Penicillins differ from each other due to different groups
attached to β-lactam ring
These differences include:
• Spectrum
• Stability to gastric acidity
• Susceptibility to β-lactamase or penicillinases (secreted by
some bacteria leading to inactivation of β-lactam →
resistance)

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 PENICILLINS
1. Natural penicillin's: penicillin G (benzyl penicillin) &
penicillin V

• Narrow spectrum (gram +ve cocci and gram –ve cocci)

 Penicillin V is acid-stable (so can be used orally)but not

used for treatment of bacteremia because of higher
minimum bactericidal concentration

 Penicillin G is less stable to acid (so given parentrally)

• Inactivated by β-lactamase
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 PENICILLINS
2. Anti staphylococcal
Penicillins
3. Broad spectrum
• Narrow spectrum as
natural penicillins • Broad spectrum
• Stable to gastric acidity
• Stable to gastric acidity
• Stable to β-lactamase
• Nafcillin is effective in • Inactivated by β –lactamase
treatment of penicillinase
producing staph (may be combined with β-

• Oxacillin, cloxacillin, lactamase inhibitors

dicloxacillin,, methicillin • Ampicillin, amoxicillin

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 PENICILLINS
4. Anti-pseudomonal penicillins

Ticarcillin, Carbenicillin, Azlocillin, Mezlocillin, Piperacillin

 Broad spectrum including pseudomonas aeruginosa and

many gm -ve bacilli

 Not effective against klebsiella

 Unstable to gastric acidity

 Inactivated by β-lactamase (may be combined with β-

lactamase inhibitors)
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 Depot IM preparations
penicillin G procaine & penicillin G benzathine

• are drugs that release penicillin G slowly from the area

in which they are injected and produce relatively low but
persistent concentrations of penicillin G in the blood

e.g. benzathine penicillin given monthly as prophylactic

against rheumatic fever

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 Pharmacokinetics of penicillin's
Absorption: most preparations are incompletely absorbed orally,
however Amoxicillin is almost completely absorbed.

o Absorption of all the penicillinase resistant penicillin is

affected by the presence of food in stomach

Distribution: Cross placenta & BBB only in case of inflamed

meninges

Excretion: Renal elimination through organic acid tubular secretory

mechanisms and by glomerular filtration.

• Probenicid inhibits renal tubular secretion of penicillin.

• Nafcillin is excreted via biliary route(preferred in renal 20

 penicillin's
Therapeutic uses Adverse Drug Reactions
1. Streptococcal infections (ADR)
2. Staphylococcal infections 1. Penicillins are considered
3. Pneumococcal infections among the safest antibiotics

4. Syphilis and gonorrhea • Hypersensitivity

5. Meningococcal meningitis 1. Cross allergy may occur

6. Diphtheria, tetanus between β-lactam

antibiotics
7. Prophylaxis
2. Diarrhea:

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 A. CEPHALOSPORINS
• β- lactam antibiotics similar to penicillins in their mode
of action but are more resistant to β-lactamase

• There is cross allergy and cross resistance with

penicillins → should be avoided in patients allergic to
penicillin or infections resistant to penicillins

• Cephalosporins are ineffective against MRSA

(methicillin resistant staph aureus)

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 Cephalosporins
First Generation Second Generation Third Generation Fourth Generation

Cefadroxil Cefaclor Cefdinir Cefepime

Cefazolin Cefamandole Cefoperaxone
Cefalexin Cefonicid Cefotaxime
Cephalothin Ceforanide Ceftazidime
Cephaprin Cefotetan Ceftibuten
Cephradine Cefoxitin Ceftizoxime
Cefuroxime Ceftriaxone
moxalactam
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 First Generation Cephalosporins
• Broad spectrum especially against gm+ve organisms

• Not effective against pseudomonas

• Resistant to β-lactamase enzyme

• Do not cross the meninges so not effective in

meningitis

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 Second Generation Cephalosporins
• Broader spectrum than first generation

• Extended spectrum against gram –ve organisms

• Do not penetrate meninges

• All second generation cephalosporins are less active

against gm+ve bacteria than first generation
cephalosporins except cefoxitin and cefotetan

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 3rd generation cephalosporins

• Have increased activity against resistant gram –ve

organisms

• Decreased coverage against Gram +ve

• Cross BBB (most agents)

• Used in serious infections, e.g. meningitis(ceftriaxone

or cefotaxime)

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 Cephalosporin's: PK
• Some members are absorbed orally, but most are given
parenterally

• 1st and 2nd generations can't cross BBB, while the 3rd
can cross (except cefoperazone) → useful in meningitis

• Elimination is mainly renal →adjust dose in renal

dysfunction

• Cefoperazone & cefotriaxone are excreted mainly in

bile 27
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Cephalosporin's: adverse effects
• Hypersensitivity reactions. Should not be used in
patients that had anaphylactic reaction with penicillin
• Local irritation: severe pain after IM injection and
thrombophlebitis after IV administration
• Nephrotoxicity especially when used with
aminoglycosides
• Platelet dysfunction
• Disulfiram-like action
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 β-lactamase inhibitors
Clavulanic acid, Sulbactam, Tazobactam

• Some bacteria produce b-lactamase- enzyme that

breaks the critical β-lactam ring

• They don't have significant antibacterial effect

• Inhibit β-lactamase, so protect antibiotics which are

inactivated by this enzyme

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 β-lactamase inhibitors

• Combinations of β-lactamase inhitors with β-lactam

antibiotics are effective against β-lactamase
producing organisms
 Amoxicillin + clavulanic acid
 Ampicillin + sulbactam
 Ticarcillin + clavulanic acid
 Piperacillin + tazobactam

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 GLYCOPEPTIDES
Vancomycin
Mechanism of action: Inhibits cell wall synthesis at an
earlier stage than β-lactam antibiotics (inhibits
transglycosylation step in peptidoglycan
polymerization)
Antibacterial spectrum: affect gram +ve organisms

• PK: cross inflamed meninges, renal dose adjustment

needed, given IV

• Drug of choice in MRSA

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 PROTEIN SYNTHESIS INHIBITORS
• Ribosomes caries out protein synthesis

• Eukaryotic & prokaryotic ribosome's differ in size &

structure Selectivity toxicity

• There are two major subunits of the ribosome:

– 30S subunit
• 50S subunit
• Both are critical in reading codons and initiating protein
synthesis

• The 50S also forms peptide bonds between amino acids34

 1. TETRACYCLINES
Tetracycline, Doxycycline, Minocycline, Demeclocycline

Mechanism of action:

• Reversibly bind to 30 S ribosomal bacterial subunits

leading to inhibition of binding of t-RNA and inhibition
of protein synthesis

• They are bacteriostatic

• ADR: teeth discoloration, photosensitivity

• Contraindicated in pregnant and lactating woman

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 Tetracycline: Pk
Absorption: Absorption is decreased by food due to formation of
non absorbable chelates of tetracyclines with Ca++, Mg++, Al+++
and iron.

Distribution: Concentrated in bone and teeth →deformities in

children (up to 8 years).

 Cross the placenta and affect fetal bones and teeth

Metabolism and excretion:

• Metabolites and parent drug are excreted via kidney except

doxycycline which is excreted in bile and so can be used in renally
compromised patients
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 2. AMINOGLYCOSIDES
Gentamycin, Streptomycin, Neomycin, Tobramycin, Amikacin,
Netilmicin

Mechanism of action:
• Irreversibly bind with 30 S ribosomal bacterial
subunits leading to inhibition of protein synthesis by:
Inhibition of formation of initiation complex
Misreading of mRNA leading to formation of abnormal
proteins
Breaking down of polysomes into non-functional
monosomes

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 AMINOGLYCOSIDES
Antibacterial spectrum:

• Bactericidal

• Ineffective against anaerobes due to lack of oxygen-

dependent transport mechanism as they needs oxygen-
dependent process to be transported across cell membrane

• Act mainly against gm –ve organisms

• Gentamycin is also effective against staph infections

• Have synergistic action with β-lactam (should not be mixed

in the same infusion fluid →inactive complex) 38
 AMINOGLYCOSIDES: PK
Absorption:
• Not absorbed orally thus have to be given parentrally
• They have concentration-dependent killing
Distribution:

• They don't cross BBB even when meninges are inflamed,

but cross the placental barrier

• Concentrated in renal cortex & endolymph of inner ear

→ nephrotoxicity and ototoxicity
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 3. MACROLIDES
Include: Erythromycin, Clarithromycin , Azithromycin
Mechanism of action:
• Irreversibly bind to 50 S ribosomal subunits inhibiting
protein synthesis

• Prevent movement of ribosome along mRNA

 Bacteriostatic

 May be bactericidal at higher doses

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 Erythromycin:Pk .

• It is unstable in acid medium, oral administration is in

the form of enteric coated
• Food interferes with the absorption of erythromycin
• It is widely distributed throughout the body fluids
except the CSF
• It traverses the placenta and reaches the fetus
• It is extensively metabolized in the liver and excreted in
the bile and lost in feces, and only 5% is excreted in the
urine
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 Clarithromycin
• It is a methylated form of erythromycin

• The methoxy group allows Clarithromycin to be stable

to gastric acidity and be readily absorbed

• Food increases the absorption of Clarithromycin

• widely distributed in the body

• metabolized in the liver and eliminated by the

kidney

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 Azithromycin
It has the longest half life and the largest volume of
distribution
It is rapidly absorbed and well tolerated orally
Food decreases its bioavailability
It penetrates into most tissues and phagocytic cells
extremely well except CSF, with tissue concentrations
exceeding serum concentrations
It does not affect liver microsomal enzymes, and it is
relatively free of drug interactions
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MACROLIDES: Adverse effects:
1. Epigastric pain and GIT distress

2. Cholestatic jaundice (erythromycin estolate)

3. Ototoxicity: transient deafness with erythromycin

4. Thrombophlebitis if erythromycin given IV

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MACROLIDES: Drug interactions:
1. Erythromycin and Clarithromycin is enzyme inhibitor,
increasing levels of drugs metabolized by the same enzyme
2. Increases digoxin level (inhibits intestinal flora that
inactivate digoxin)
Contraindications:
All should be avoided or used cautiously in liver
dysfunction

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 A. CLINDAMYCIN (lincosamides)
• Similar to macrolides (bacteriostatic with the same
mechanism)

• Used specifically against anaerobic infections

• Used in bone infections (good penetration into bone)

Adverse effects:

-Pseudomembranous colitis -Liver dysfunction

-Skin rash -Diarrhea

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 CHLORAMPHENICOL
• Reversibly binds to 50 S ribosomal subunits leading to
inhibition of protein synthesis
• It blocks the action of peptidyl transferase step of protein
synthesis
• It also inhibits mitochonderial protein synthesis of
mammalian cells
• Broad spectrum drug and has great activity against
anaerobes
• Completely absorbed after oral administration
• Distributed all over the body and reaching CSF
• Metabolized in liver, inhibits microsomal hepatic enzymes

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 CHLORAMPHENICOL: Adverse effects
• The most important adverse effect of chloramphenicol is
bone marrow depression

• GIT upsets and superinfection

• Gray baby syndrome:
• This adverse effect occurs in newborn, as they lack an
effective glucoronic acid conjugation mechanism for the
degradation and detoxification of chloramphenicol
• The drug will accumulate to levels that interfere with the
function of mitochondrial ribosomes
• This leads to poor feeding, vomiting, flaccidity,
hypothermia, gray colour, shock, collapse and death 48
Drug interactions:
– As chloramphenicol is an enzyme inhibitor,
increasing blood levels of other drugs.

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50
 NUCLEIC ACID SYNTHESIS
INHIBITOR
• Target enzymes required for nucleic acid synthesis

• Fluoroquinolones: Prevents the relaxation of

positively supercoiled DNA that is required for
normal transcription and replication

• Rifamycins: block prokaryotic RNA polymerase

from initiating transcription

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 A. FLUOROQUINOLONES
• Intracellularly they block the replication of bacterial
DNA by inhibiting Topoisomerase II (DNA-gyrase)
and Topoisomerase IV
• Inhibit DNA gyrase (topoisomerase II (significant in
gram -ve organism as E.coli)
• DNA- gyrase causes relaxation of positively
supercoiled DNA.
• Topisomerase IV causes separation of replicated
chromosome during cell division DNA
• Also inhibit topoisomerase IV (significant in gram +ve
as staph organisms)
• They are bactericidal 52
Generation Drug Names Spectrum
Nalidixic acid Gram- ve
1st Cinoxacin

Norfloxacin Gram- (including Pseudomonas

Ciprofloxacin species), some Gram+ (S. aureus)
2nd Enoxacin and some atypical
Ofloxacin

Levofloxacin Same as 2nd generation with

Sparfloxacin extended Gram+ and atypical
3rd Moxifloxacin coverage Some anaerobes
Gemifloxacin

Trovafloxacin Same as 3rd generation with broad

Moxifloxacin anaerobic coverage
4th
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 FLUOROQUINOLONES: PK
• Not completely absorbed when orally administered
• Parenteral preparations are available
• Absorption of quinolones is affected by sucralfate,
antacids and dietary supplement containing iron, zinc
and calcium
• Well distributed into all tissues
• Penetration to CSF is low except for ofloxacin
• Excretion is via renal route
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FLUOROQUINOLONES: Adverse effects:
• GI disturbances: the most common
• Phototoxicity (can cause interruption of therapy)
• Nephrotoxicity

• Arthropathy (in children less than 18 years)

Drug interactions:
• Absorption is affected by antacids and cations
• Cimetidine interferes with elimination of quinolones
• Metabolism of theophylline is inhibited by ciprofloxacin
• While 3rd and 4th generations increase concentrations of
warfarin, caffeine and cyclosporine 55
FLUOROQUINOLONES: Contraindications:

 Pregnancy

 Lactation

 patients less than 18 years (may lead to arthropathy)

 Sparfoxacin, levofloxacin, and moxifloxacin may prolong

QT interval and should not be used in patients
predisposed to arrhythmias

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 B. RIFAMYCINS
• Inhibits DNA-dependent RNA polymerase
• Active against Gram-positive bacteria (including
Mycobacterium tuberculosis) and some Gram-negative
bacteria
• Binds to the beta subunit of the polymerase and blocks
the entry of the first nucleotide which is necessary to
activate the RNA polymerase, thereby blocking mRNA
synthesis
• Effective orally and penetrates the cerebrospinal fluid
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 A. SULPHONAMIDES
• They are synthetic of P-Amino benzene
sulphonamide (sulphanilamide)
Mechanism of action:
 Structural analogues of PABA

 compete with PABA for the enzyme dihydropteroate

synthase, leading to inhibition of folate synthesis with
inhibition of DNA and RNA synthesis

 Bacteriostatic
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N.B: Human cells utilize already formed folic acid

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 Classification:
1.Orally absorbable agents:
• Sulphisoxasol, sulphamethoxazole: Short to medium
acting
• Used to treat urinary tract infections
 Sulphaiadiazne: achieves therapeutic conc. in CSF

 Sulphadoxine: the only available long acting

sulfonamide, when combined with pyrimethamine
is used in the treatment of malaria
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 2.Orally non-absorbable agents:
Sulfasalazine - used in the treatment of inflammatory bowel
diseases

3.Topical agents:
Sodium sulphacetamide - ophthalmic solution used in the
treatment of bacterial conjunctivitis and in trachoma
Marfenide - is used in prevention of bactreial infection of
burn wounds
Silver sulphadiazine - it is much less toxic so, preferred in
burn wounds. 61
Pharmacokinetics:
 High pp bound , cross BBB and placental barrier
 Acetylated in liver (slow acetylators are liable to toxicity of
sulfapyridine) into metabolites which causes crystalluria (at
neutral and acidic pH)
 Excreted by glomerular filtration
Adverse effects:
 Crystalluria
 Hypersensitivity
 Hemolytic anemia
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Drug interaction:
 Potentiates oral hypoglycemics leading to hypoglycemia
Potentiates warfarin
Displaces methotrexate leading to bone marrow aplasia

Contraindications:
Infants less than 2 months
Pregnancy and lactation
Patients with impaired renal functions.

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 A. TRIMETHOPRIM
Mechanism of action:
 Inhibition of dihydrofolate reductase enzyme

 Trimethoprim is about 50,000 times less efficient in

inhibition of mammalian dihydrofolic acid reductase

Adverse effects:
 Megaloblastic anemia due to folate deficiency
 Granulocytopenia
 leucopenia (especially in pregnant women)

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 A. COTRIMOXAZOLE
• It is a combination of sulfamethoxazole (400 mg) +
trimethoprim (80 mg) 5:1
• Bactericidal
Mechanism of action:
• Synergistic combination due to inhibition of two
subsequent steps in the synthesis of folic acid
• Advantages:
• More potent, Synergistic combination.
• Less and delayed bacterial resistance.
• Wider spectrum against urinary and respiratory
infections

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Adverse effects:
1. Megaloblastic anemia due to folate deficiency

2. Granulocytopenia and leucopenia

3. Hemolytic anemia in G-6-phosphate deficient patients

4. GIT disturbances

5. Interactions with phenytoin, methotrexate and warfarin

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 INHIBITION OF CELL MEMBRANE
FUNCTION
• Those agents lead to disruption of the functional
integrity of cell membrane leading to leak of
intracellular protein molecules & cell damage
 Polymyxins
 Amphotericin B

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68
 ANTIMYCOBACTERIAL DRUGS
 Second Line Agents
 First Line Agents
– Amikacin
– Isoniazid (INH)
– Aminosalicylic acid
– Rifampine
– Capreomycin
– Pyrazinamide
– Ciprofloxacin
– Ethambutol
– Clofazimine
– Streptomycin
– Cycloserine
– Ethionamide
– Levofloxacin
– Rifabutin
– Rifapentine 69
 Anti-TB agents
• Combination drug therapy is the rule to delay or prevent
the emergence of resistance and to provide additive
[possibly synergistic] effect against mycobacterium
tuberculosis.
• Isoniazid–rifampicin combination administered for 9
months will cure 95-98% of cases
• Addition of pyrazinamide for this combination for the
first 2 months allows total duration to be reduced to 6
months
• Never use a single drug therapy 70
 Isoniazid
• Inhibits synthesis of mycolic acid is which an essential
components of mycobacterial cell wall

• Bacteriostatic at low conc. & bactericidal at high conc.

Especially against actively growing bacteria

• Structurally similar to pyridoxine

• Penetrates macrophages so it is effective against intra and

extracellular organisms

• Metabolized in liver by acetylation

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 Rifampin
• A semisynthetic derivative of rifamycin
• Bactericidal
• There is no cross-resistance to other classes of
antimicrobial drugs, but there is cross-resistance to other
rifamycin derivatives like, rifabutin and rifapentine.
Mechanism of action:
• Binds strongly to β subunit of bacterial DNA-dependent
RNA polymerase leading to inhibition of RNA synthesis
 Penetrates macrophages so affect extra and
intracellular organisms

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 Ethambutol
• Inhibits mycobacterial cell wall synthesis by inhibiting
arabinosyl transferase

• Bacteriostatic

• Active against intra & extracellular bacilli

• Well absorbed from gut

• 20% excreted in feces and 50% in urine in unchanged form.

• Crosses BBB in meningitis

• Used only in mycobacterial infections

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 Pyrazinamide
• It is converted to pyrazinoic acid ,the active
form (prodrug)
• Mechanism is unknown.
• Bactericidal
• Acting on intracellular organisms.
• Well absorbed orally ,metabolized in liver
,excreted mainly through kidney .

74
 Streptomycin
• Life threating forms of TB ( meningitis,
disseminated disease).
• Resistant cases (Multidrug resistance
tuberculosis at least to INH & rifampicin ) .
• Amikacin can be used as alternative to
streptomycin.
• Both active mainly against extracellular bacilli.

75
 Indication of 2 line treatment
nd

• Resistance to the drugs of 1st line.

• Failure of clinical response
• Increase of risky effects.
• Patient is not tolerating the first line drugs.

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 B.DRUGS USED IN LEPROSY
Dapsone
• Inhibits folate synthesis
• Well absorbed orally, widely distributed
• Half-life 1-2 days, tends to be retained in skin,
muscle, liver and kidney
• Excreted into bile and reabsorbed in the intestine
• Excreted in urine as acetylated
• It is well tolerated 77
 Clofazimine
• It is a phenazine dye.
• Unknown mechanism of action ,may be DNA
binding.
• Antiinflammatory effect.
• Absorption from the gut is variable.
• Given orally , once daily.
• Excreted mainly in feces.
• Stored mainly in reticuloendothelial tissues and
skin
• Half-life 2 months
• Delayed onset of action (6 weeks). 78
 Treatment of TB in pregnant women
• INH ( pyridoxine should be given )

• Rifampicin , ethambutol

• Pyrazinamide is given only if :

– Resistant to other drugs is documented

– Streptomycin is contraindicated

• Breast feeding is not contraindication to receive drugs ,

but caution should be observed

79
 ANTIFUNGAL DRUGS

• Human fungal infections have increased dramatically in

incidence and severity in recent years due mainly to:

• Advances in surgery

• Cancer treatment

• Critical care accompanied by increased use of

broad spectrum antibiotics

80
 Antıfungal drugs by mode of action

1. Membrane disrupting agents

Polyene antibiotics (Amphotericin B, nystatin,

natamycin)

1. Nucleic acid inhibitor

Flucytosine

1. Ergosterol synthesis inhibitors

Azoles, allylamines

1. Anti-mitotic (spindle disruption)

Griseofulvin 81
A. POLYENE ANTIBIOTICS (Membrane disrupting agents)
1. Amphotericin B

• It is a naturally occurring polyene macrolide antibiotic

• Despite its potential toxicity, it is the drug of choice in life

threatening systemic mycoses,

Mechanism of action:

• Binds selectively to ergosterol → disturbance in cell

membrane permeability and transport → leakage of
intracellular ions & enzymes →cell death (fungicidal)
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 2. Nystatin
 Similar to amphotericin B

 Used topically for treatment of candida infection because

of its systemic toxicity

 It is not absorbed systemically →when orally

administered it acts locally in GIT to treat oral
candidiasis..

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 A. NUCLEİC ACİD İNHİBİTOR

FLUCYTOSINE
• Narrow spectrum antifungal drug

• Fungistatic

Mechanism of action:

Converted within the fungal cell (not the human cell) into 5-
flurouracil (5-FU), then to F-dUMP and FdUTP which
inhibit DNA & RNA synthesis respectively

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N.B.

Flucytosine & amphotericin B are synergistic

 as amphotericin B ↑cell permeability allowing more 5-FC

to enter the cell

 This combination is used in the treatment of candidiasis or

cryptococcosis

 Also it is combined with itraconazole for treating

chromoblastomycosis

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A. ERGOSTEROL SYNTHESİS İNHİBİTORS

Squalene
Allylamines
Squalene epoxide

Lanosterol
Azoles
14-Demethyllanosterol

Zymosterol

Fecosterol

Ergosterol Polyenes

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 I.AZOLES
• Broad spectrum fungistatic

• Less toxic than amphotericin B

• Sub groups:

1. IMIDAZOLES 2.TRIAZOLES
Clotrimazole
Itraconazole
Econazole topical Fluconazole
 Miconazole voriconazole
 Ketoconazole ←systemic
87
Mechanism of action:

 Inhibit synthesis of fungal cell membrane through

inhibition of cytochrome P450-dependent C14- α
demethylase enzyme which is essential for
conversion of lanosterol to ergosterol

 Depletion of ergosterol alters the fluidity and

function of fungal cell membrane → inhibition of
cell growth
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 1-Ketoconazole
• The 1st broad spectrum oral antifungal

• Broad spectrum against superficial and systemic fungal

infections as candida, not aspergillus and fungal meningitis
(does not cross BBB).

• Used in advanced androgen-dependent prostate cancer

(inhibits gonadal and adrenal steroid synthesis)

• Available topically (shampoo or cream) as well as tablets

89
Drug interactions:

 H2 blockers, antacids block its absorption

 Enzyme inhibition (cytochrome P450) →↑levels & toxicity

of drugs such as phenytoin, warfarin and tolbutamide

 Ketoconazole and amphotericin B should not be given

together because the decrease in ergosterol of fungal
membrane reduces fungicidal action of amphotericin B

 Should be avoided in pregnancy

90
 2-Fluconazole

 Broad spectrum, given orally or IV

 The drug of choice in Cryptococcus neoformans

which cause menigitis

 Given prophylactically in recipients of bone

marrow transplants

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Differs from ketoconazole in:

1. Its absorption does not depend on gastric acidity

2. Excellent bioavailability and CSF penetration

3. Minimal pp binding & metabolism

4. Excretion via kidney (dose adjustment in renal

dysfunction)

5. Lack of endocrine adverse effects

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 3-Itraconazole
 Broad spectrum, given orally or IV

 Like ketoconazole: its absorption needs gastric acidity,

extensively pp bound & metabolized, doesn't penetrate BBB

 It doesn't inhibit androgen synthesis

 More potent than ketoconazole with less adverse effects

 Drug of choice for blastomycosis, aspergillosis, &AIDS-

associated histoplasmosis(unlike ketoconazole)…

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 4. Miconazole, clotrimazole
 used in Candidiasis

 Miconazole is a potent enzyme inhibitor, resulted in

bleeding in patients taking warfarin even if applied
topically

 Topical use is associated with contact dermatitis, vulvar

irritation &edema

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 II. ALLYLAMINES

TERBINAFINE
 Better tolerated, shorter duration of therapy (3 months) and more
effective than either griseofulvin & itraconazole

Mechanism of action:

Selectively inhibits fungal squaline epoxidase enzyme, which is

involved in ergosterol synthesis from squalene in fungal cell
membrane →accumulation of toxic squalene within the cell→
cell death

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 ANTİ-MİTOTİC (SPİNDLE DİSRUPTİON)
GRISEOFULVIN

 Narrow spectrum oral antifungal

 Absorption is affected by size of particles and increased

by presence of fat in food

Mechanism of action:

 It prevents fungal growth by Inhibition of microtubules

→inhibition of mitosis so it leads inhibition of fungal
mitosis
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 ANTIPROTOZOAL DRUGS

Protozoa
 Eukaryotes and unicellular organisms
 They have metabolic process close to human host
 less easily treated than bacterial and fungal
infections

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 PROTOZOAL INFECTIONS
• Sporozoa
– Malaria, Toxoplasmosis
• Amoeba
– Amoebic dysentery
• Flagellates
– Giardiasis, leishmaniasis, Sleeping sickness

• Ciliata
– Balantidial dysentery

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 ANTI-MALARIAL DRUGS

• Four species of plasmodium:

– P. Falciparam
one cycle of liver infection
– P. Malariae

– P. Vivax
Have dormant stage
– P. Ovale

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100
 Antimalarial Agents
• Quinoline group:
– quinine, quinidine, chloroquine, Mefloquine,
primaquine, amodiaquine
• Anti-folate:
– pyrimethamine, proguanil, chloroproguanil,
trimethoprim
 Artemisinin analog:
– artemisinin, artisunate, artemether, artether,
dihyroartemisinin
 Some antibiotics like:
– tetracycline, Clindamycin, macrolides (azithromycin),
atovaquone
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 Mechanisms of Action of Anti-Malarials:
1. Inhibition of Heme catabolism: chloroquine,
quinine, mefloquine, artemisinin

2. Electron transport inhibition: primaquine,

atovaquone

3. Folate synthase inhibition: sulfadoxine,

pyrimethamine

4. Protein translation blockers: clindamycin,

doxycycline and tetracycline 102
Drugs for Acute Attack (Blood schizonticides)
• Used for clinical cure (suppressive)

• Act on Erythrocytic form of plasmidium

• Used as cure for P. falciparum and P. malariae(no

exoerythrocytic stage)

• Agents:

– Quinine, quinidine, chloroquine, mefloquine,

halofantrine, sulphones, pyrimethamine, atovaquone,
doxycycline, Artemisinin analogs
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Agents Used for Prophylaxis
Agents for Radical Cure
– Prevents malaria attack by
• Cause a radical cure
blocking the link between
(eradication) of dormant
Pre-erythrocytic and stage in the liver of P
Erythrocytic stages vivax, P ovale
• Chloroquine • Tissue schizonticides
• Mefloquine • PRIMAQUINE
• Doxycycline

• Atovaquone/Proguanil

• Dapsone

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 Drug Used to Prevent Transmission(Gametocides)
• These agents destroy gametocytes and prevent transmission
by mosquito

• Not used alone for this action, usually combined with other

agents

• Agents:
– Primaquine

– Pyrimethamine

– Proguanil 105
 ANTI-AMEBIASIS

• Amebiasis is infection with Entamoeba histolytica

• spread by ingestion of the mature cysts in water or
food that is contaminated with human faeces
• The infectious cysts pass into the colon, where they
develop into trophozoites.
• The trophozoite lyses the colonic mucosal cells
• The trophozoites may also migrate through the
damaged intestinal tissue into the portal blood and
liver
 Chemotherapy for Amebiasis

• Metronidazole
• Tinidazole
• Chloroquine
• Emetine
• Dehydroemetine
• Paramomycin
Metronidazole
PK ADR
• Metallic, bitter taste
– Oral metronidazole is
• Minor gastrointestinal
readily absorbed and disturbances
permeates all tissues • Dizziness, headache,
sensory neuropathies
by simple diffusion
• Interferes with alcohol
• Cross blood brain metabolism
barrier Contraindication:
• Pregnancy
• Metabolizing in liver
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Chemotherapy for Leishmaniasis & Trypanosomiasis

Sodium Stibogluconate
• The mechanism of action is not clear, but the drug may
increase production of oxygen free radicals, which are
toxic to the parasite
• Not stable orally so given by parental route
• Distribute extravascular compartment
• Metabolism is minimal
• Excreted in urine

Adverse effects:
• Pain at inj .site, G.I upset, Cardiac arrhythmia
 SURAMIN
• It is the first-line therapy trypanosomiasis but
because it does not enter the central nervous system,
it is not effective against advanced disease
• The drug's mechanism of action is unknown
• It is administered intravenously and displays
complex pharmacokinetics with very tight protein
binding
• It has a short initial half-life but a terminal
elimination half-life of about 50 days
• The drug is slowly cleared by renal excretion.
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 Toxoplasmosis
• One of the most common infections in man is caused by the
protozoan, Toxoplasma

• which is transmitted to humans when they consume raw

infected meat

• Lymph nodes get swallowed

• cause Enlarged spleen

• May cause psychiatric disorders

• Treatment is needed when the patient is imunocompromised

 Chemotherapy for Toxoplasmosis

• The treatment of choice for this condition is the

antifolate drug, pyrimethamine

• A combination of sulfadiazine and

pyrimethamine is also efficacious.
 GARDIASIS

• Usually occurs from contaminated drinking water, leads

to infection in form of trophozoites.

• The trophozoites exist in the small intestine

• Occasionally, cysts are formed that pass out in the stool

• Though some infections are asymptomatic, severe

diarrhea can occur which can be very serious in immune-
suppressed patients.
 CHEMOTHERAPY OF GIARDIASIS

• Very serious in immune-suppressed patients

• The treatment is usually either quinacrine or

metronidazole

• Quinacrine is primarily used in the treatment of

giardiasis, but is also effective against tapeworm and
malaria, and topically, against leishmaniasis.
 ANTHELMINTIC DRUGS
May act by causing :

1. Paralysis of the worm

2. Damaging the worm leading to partial digestion or

rejection by immune mechanisms

3. Interfere with the metabolism of the worm.

 ALBENDAZOLE

• Broad spectrum oral anthelmintic

• Drug of choice for treatment of hydatid disease and

cysticercosis

• It is also used for the treatment of ascariasis,

tricurasis and strongyloidiasis, pinworm,
hookworm
 Mechanism Of Action

• Inhibits microtubule synthesis by binding to β –

tubulin

• Inhibits mitochondrial reductase causing reduced

glucose transport.. Intestinal parasites are immobilized
and die slowly

• larvicidal in hydatid ,cysticercosis , ascariasis and hook

worm infections

• Ovicidal in ascariasis, hookworm , trichuriasis

 MEBENDAZOLE
• Synthetic benzimidazole

• Wide spectrum and low incidence of adverse

effects

Mechanism of action:

 Inhibits microtubule synthesis

 It kills hookworm, pin worm , ascaris and trichuris

eggs
 Adverse Effects & Precautions

• Short term therapy, Mild GI disturbance

• High dose: hypersensitivity reactions,

agranulocytosis, alopecia, elevation of liver enzymes

• Used with caution under 2ys of age may cause

convulsion.

Contraindicated in pregnancy

• Enzyme inducers and inhibitors affect plasma level of

the drug
 PIPERAZINE
• Only recommended for the treatment of
ascariasis cure rate 90% for 2 days treatment
• Readily absorbed orally and excreted mostly
unchanged in urine
Mechanism of action:
• Causes paralysis of ascaris by blocking
acetylcholine at myoneural junction, the live
worms expelled by normal peristalsis
Adverse Effects

• GI disturbance

• Neurotoxicity, allergic reactions .

Contraindications:

• Epilepsy or a history of epilepsy

• Impaired liver or kidney functions

• pregnancy

• Chronic neurologic disease

 NICLOSAMIDE
• Second-line drug for treatment of most tapeworm
infections

Mechanism of action:

• Adult worm( not ova) is rapidly killed by

inhibition of oxidative phosphorylation

Pharmacokinetics:

• Poorly absorbed from gut & excreted in urine

 Clinical Uses

• Treatment of most forms of tapeworms

• Not effective against cysticercosis or hydatic

disease

• Given in the morning on empty stomach

• Purgative is necessary to purge all dead segments

& prevent liberation of ova
 Adverse effects & Contraindications

• Mild, infrequent and transitory GI disturbance

• Alcohol consumption should be avoided

• Not indicated in children under 2 years of age or

in pregnancy
 IVERMECTIN
• Drug of choice for treatment of strongyloidiasis

• Macrocyclic lactone ring

• Given only orally

• Rapidly absorbed

• Does not cross BBB

• Excretion is mainly in feces

 Mechanism of action

• Acts on the parasites glutamate-gated Cl- channel

receptors

• Chloride influx increased, hyperpolarization

occurs , resulting in paralysis of the worm Or

• Paralyze nematodes by intensifying GABA-

mediated transmission of signals in peripheral
nerves
 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
128
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129
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130
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131
 Retrovirus
• Infectious particle containing an RNA genome c/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

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 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
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134
 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

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 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)
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 A. ZIDOVUDINE
• It is a deoxythymidine analog

• Phosphorylated by cellular thymidine kinase

• Zidovudine triphosphate interferes with HIV vRNA-

dependent DNA polymerase

• incorporated into DNA chain and terminates synthesis

• 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 137
 B. Didanosine

• a synthetic analog of deoxyadenosine

• competitive inhibition-RT & chain termination

• Prolonged ICF presences

• Penetrates CNS

• food interferes with absorption

• dose-dependent pancreatitis

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 C. Lamivudine

• a cytosine analog

• long T1/2

• Lower risk of peripheral neuropathy (versus didanosine or

zalcitabine)

• 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
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 D. Stavudine

• Thymidine analog, phosphorylated

• Inhibits RT and chain termination

• High oral bioavailability (86%) that is not food-

dependent

• Associated with peripheral neuropathy,

pancreatitis, arthralgias

• Removed from market because of toxicity

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 E. ABACAVIR
• A guanosine analog

• Well absorbed following oral administration

(83%) and unaffected by food

• Hypersensitivity reactions, occasionally fatal,

have been reported in approximately 5% of
patients receiving abacavir

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 F. TENOFOVIR

• An acyclic nucleoside phosphonate (ie, nucleotide) analog

of adenosine

• The only nucleotide analog currently marketed for the

treatment of HIV infection

• Like the nucleoside analogs, tenofovir competitively

inhibits HIV reverse transcriptase and causes chain
termination after incorporation into DNA

• Oral bioavailability increases with a high-fat meal

142
 2. NONNUCLEOSIDE 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

• All substrates for CYP3A4 and can act as inducers (nevirapine),

inhibitors (delavirdine), or mixed inducers and inhibitors
(efavirenz)

143
 A. EFAVIRENZ
• should be taken on an empty stomach because high-fat meal
increase toxicity

• metabolized by CYP3A4 and CYP2B6 to inactive metabolites

• It is highly bound to albumin (~ 99%)

• The principal adverse effects: dizziness, drowsiness, insomnia,

headache, confusion, amnesia, agitation, delusions, depression,
nightmares, euphoria and Skin rash

• Safe in pregnant women

• It is both inducer and an inhibitor of CYP3A4

144
 B. NEVIRAPINE

• Oral bioavailability (90%) is not food-dependent

• It is extensively metabolized by the CYP3A isoform

• Rash occurs in approximately 17% of patients

• When initiating therapy, gradual dose escalation over 14

days is recommended to decrease the incidence of rash

• Hepatotoxicity occurs in about 4% of patients

• A moderate inducer of CYP3A metabolism

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 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
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 A. AMPRENAVIR

• Rapidly absorbed and can be taken with or without

food

• However, high-fat meals decrease absorption

• common adverse effects: nausea, diarrhea, vomiting,

perioral paresthesias, depression &rash

• Amprenavir is both an inducer and an inhibitor of

CYP3A4
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 B. LOPINAVIR/RITONAVIR

• Combination in which subtherapeutic doses of ritonavir

inhibit the CYP3A-mediated metabolism of lopinavir

• Ritonavir is acting as a pharmacokinetic enhancer rather

than an antiretroviral agent

• Absorption of lopinavir is enhanced with food

• Lopinavir is extensively metabolized by the CYP3A

isozyme

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 C. RITONAVIR
• An inhibitor of HIV-1 and HIV-2 proteases

• Bioavailability increases with food

• Metabolism to an active metabolite occurs via the

CYP3A and CYP2D6 isoforms

• A potent inhibitor of CYP3A4

• CYP3A4 inhibitory properties exploited to prolong

the half-life of more potent and less toxic PI agents

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 4. FUSION INHIBITORS
A. ENFUVIRTIDE

• It is a fusion inhibitor that blocks entry into the cell

• A synthetic 36-amino-acid peptide

• Prevent the conformational changes required for the fusion

of the viral and cellular membranes

• Administered by subcutaneous injection

• Enfuvirtide lacks cross-resistance to the other currently

approved antiretroviral drug classes
150
 B.MARAVIROC

• Binds selectively to coreceptors necessary for entrance of

HIV into CD4+ cells, thus blocking entry of HIV

• The absorption is rapid but variable

• Penetration into the cervicovaginal fluid almost four times

higher than the corresponding concentrations in blood
plasma

• No cross-resistance with drugs from any other class,

including enfuvirtide
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 5. INTERGRASE INHIBITORS:
A. RALTEGRAVIR
• A pyrimidine analog that binds integrase
• By doing so, it inhibits strand transfer, the third and
final step of the provirus integration, thus interfering
with the integration of reverse-transcribed HIV DNA
into the chromosomes of host cells
• Bioavailability does not appear to be food-dependent
• Metabolized by glucuronidation

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 TREATMENT RECOMMENDATIONS FOR HIV

• The use of antiretrovirals as monotherapy is limited largely by

the rapid development of viral resistance

• Typically this involves combining two NRTIs with one or two

protease inhibitors, or two NRTIs with a NNRT

153
Some Possible ART combinations
• TDF + 3TC + EFV/NVP

• ZDV + 3TC + EFV/ NVP

• DDI + 3TC + EFV

• ABC + ZDV + 3TC

• TDF + 3TC + LPV/r

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 ANTIMICROBIAL RESISTANCE
• Relative or complete lack of effect of antimicrobial
against a previously susceptible microbe
• Increase in minimum inhibitory concentration (MIC)
Promoting factors for antimicrobial resistance
• Exposure to sub-optimal levels of antimicrobial
• Exposure to microbes carrying resistance genes

155
 Causes of resistance:
1. Widespread use of antimicrobial drug
2. Interrupted or inadequate antimicrobial treatment of infection
3. Type of bacteria – gram-negative strains have higher rates of resistance
4. Re-occurring infections
5. Condition of the host
6. Location – critical care areas
Mechanisms of Antibiotic Resistance
• Enzymatic destruction of drug
• Prevention of penetration of drug
• Alteration of drug's target site
• Rapid ejection of the drug
• Mutations
• Resistance genes on plasmids or transposons can be transferred between
bacteria

156
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157