CHEMOTHERAPY.pptx

(according to Lippincott´s Pharmacology, 2009)
Antimicrobial agents affecting cell wall synthesis
Agents affecting
the cell wall b-lactamase
inhibitors
b-lactam antibiotics Other antibiotics
Penicillins Cephalosporins Carbapenems Monobactams
1st generation 2nd generation 3rd generation 4th generation
Bacitracin
Vancomycin
Daptomycin
Clavulanic acid
Sulbactam
Tazobactam
Amoxicillin
Ampicillin
Dicloxacillin
Indanyl carbenicillin
Methicillin
Nafcillin
Oxacillin
Penicillin G
Penicillin V
Piperacillin
Ticarcillin
Ertapenem
Imipenem/cilastatin*
Meropenem
Aztreonam
Cefepime
Cefadroxil
Cefazolin
Cephalexin
Cefaclor
Cefprozil
Cefuroxime
Cefoxitin
Cefdinir
Cefixime
Cefotaxime
Ceftazidime
Ceftibuten
Ceftizoxime
Ceftriaxone
3

Antibacterial drugs that inhibit cell wall synthesis
• Are bactericidal
– selectively interfere with synthesis of the bacterial cell wall
a structure that mammalian cells do not possess
– The cell wall is a polymer called peptidoglycan that
consists of glycan units joined to each other by peptide
cross-links
• Require actively proliferating microorganisms to be maximally
effective thus they have little or no effect on bacteria that are
not growing
4

Penicillins
Mechanism of action
Inhibition of transpeptidase
Penicillins inactivate bacterial transpeptidases and prevent the cross-
linking of peptidoglycan polymers essential for bacterial cell wall
integrity. This results in loss of rigidity and a susceptibility to rupture.
Production of autolysins
• Gram positive cocci produce degradative enzymes, autolysins.
(autolysins participate in the remodeling of the bacterial cell wall)
• In the presence of penicillins , the degradative action of the
autolysins proceeds in the absence of cell wall synthesis and further
weakens the cell wall
[Penicillins are inactive against organisms that do not have
peptidoglycan structure in their cell wall (e.g. mycobacteria)]
5

Penicillins …. cont’d
Penicillin G and penicillin V: most gram-positive cocci, gram positive
rods (bacilli) and gram-negative cocci (gonococci and meningococci),
spirochetes and most anaerobes (except bacteroides fragilis)
Penicillinase resistant: methicillin, nafcillin, oxacillin, cloxacillin,
dicloxacillin, flucloxacillin (are resistant to the effects of penicillinase,
the enzyme that degrades penicillins; active against staphylococci)
Extended spectrum penicillins (aminopenicillins): ampicillin, amoxicillin
(activity similar to prototype penicillins but with greater gram negative
bacteria coverage)
Anti-pseudomonal penicillins: carbenicillin, ticarcillin, piperacillin
(more active against gram negative rods including pseudomonas
aeruginosa, but less active against other bacteria)
6

Beta-lactamase inhibitors
Clavulanic acid, sulbactam, tazobactam : contain a beta lactam
ring, but do not have significant antibacterial activity
Bind to and inactive beta-lactamases
By inactivating beta-lactamase these compounds enhance the
antibacterial activity when used in combination with other b-
lactam antibiotics
Examples of penicillin + beta-lactamase inhibitor combinations
• Amoxicillin + clavulanic acid (co-amoxiclav)
• Ticarcillin + clavulanic acid
• Piperacillin + tazobactam
• Ampicillin + sulbactam
7

Penicillins: adverse reactions
Hypersensitivity reactions (types I-IV):
The most important adverse reaction associated with penicillins.
The major cause is metabolite, penicilloic acid, which reacts with
proteins and serves as a hapten to cause an immune reaction.
There is cross allergic reactions among the beta-lactam
antibiotics
Other adverse effects
Diarrhoea, pseudomembraneous colitis (broad spectrum
penicillins), nephritis and neurotoxicity
8

Clinical uses of penicillins
• Bacterial meningitis caused by N. meningitidis, S. pneumoniae: penicillin G
(benzylpenicillin given IV in high does)
• Bone and joint infections caused by S. aureus: flucloxacillin
• Skin and soft tissue infections caused by S. pyogenes or S. aureus: benzylpenicillin,
flucloxacillin
• Animal bites: co-amoxiclav
• S. pyogenes pharyngitis: phenoxylmethyl penicillin (penicillin V)
• Otitis media caused by S. pyogenes and H. influenzae: amoxicillin
• Bronchitis (mixed infections common): amoxicillin
• S.Pneumoniae pneumonia: amoxicillin
• Urinary tract infections (e.g. with E. coli): amoxicillin
• Syphilis: procaine penicillin
• Endocarditis (e.g. with Streptococcus viridans or Enterococcus faecalis): penicillin G
• Serious infections with P. aeruginosa: piperacillin, carbenicillin, tircacillin
9

Cephalosporins
Beta-Iactam antibiotics that are closely related both structurally and
functionally to the penicillins (same mechanism of action as penicillins)
Antibacterial spectrum
• Classified as first, second, third and fourth generation
• Based largely on their bacterial susceptibility patterns and resistance
to beta-Iactamases
• All cephalosporins are ineffective against MRSA, Listeria
monocytogenes, Clostridium difficile and the enterococci
Adverse effects
Hypersensitivity reactions, nephrotoxicity and super-infection with gram
positive organisms and fungi
10

Cephalosporins …. cont’d
First generation
Include cephalexin, cephalothin, cefazolin and cefadroxil
Active mostly against gram positive bacteria
Resistant to the staphylococcal penicillinase
Have some activity against Proteus mirabilis, E. coli, and Klebsiella pneumoniae
Uses: E. Coli and klebsiella infections, penicillin and sulfonamide resistant urinary tract
infections and prophylaxis in various surgical procedures
Second generation
Include cefuroxime, cefoxitin, cefaclor and cefotetan
Greater activity against three additional gram negative organisms: H. influenzae,
Enterobacter aerogenes, and some Neisseria species
Effective against anaerobes including Bacteroides fragilis
Uses: Streptococcal, E.coli, klebsiella, proteus spp and anaerobe infections. Used in
the management of UTIs, RTIs, bone and soft tissue infections.
11

Cephalosporins …. cont’d
Third generation
Enhanced activity against gram-negative bacilli and most other enteric organisms plus
Serratia marcescens
Examples: ceftriaxone, cefotaxime, ceftazidime, cefoperazone and cefpodoxime
Uses: Pseudomonas aeruginosa infections (cefoperazone and ceftazidime), empiric
therapy for community acquired meningitis (ceftriaxone and cefotaxime), hospital
acquired gram negative infections (alone or in combination with an aminoglycoside),
Lyme disease, gonorrhoea (ceftriaxone) and gram negative septicaemia
Fourth generation
Include cefepime and cefpirom
Wide spectrum of activity: active against streptococci and staphylococci (but not
MRSA), aerobic gram negative organisms (enterobacter, E. coli, K. pneumoniae, P.
mirabilis, and P. aeruginosa)
Used for gram negative bacteria infections (including pseudomonas aeruginosa)
12

Beta-lactam related compounds
Carbapenems
• Include: imipenem-cilastatin, meropenem, ertapenem, doripenem
• Have broad-spectrum activity including penicillinase producing gram
positive and gram negative organisms, anaerobes and P. aeruginosa, and
are used to treat infections caused by these organisms
• Are relatively resistant to beta-lactamases
Aztreonam
• Highly resistant to the action of beta-lactamases
• Spectrum: active against P. aeruginosa and other gram negative bacteria
thus used for infections caused by these organisms
• Lacks activity against gram-positive organisms or anaerobes
• Used only for combination with other antibacterial drugs in empiric
therapy
13

Other inhibitors of bacterial cell wall biosynthesis
Glycopeptides
Include: vancomycin and teicoplanin
Mechanism of action: inhibit cell wall synthesis - prevents the
transglycosylation step in peptidoglycan polymerization
Are bactericidal
Indications: gram positive bacteria, MRSA, enterococcal infections
and pseudomembranous colitis caused by Clostridium difficile
Vancomycin acts synergistically with the aminoglycosides: the
combination can be used in the treatment of enterococcal
endocarditis individuals with prosthetic heart valves
14

(according to Lippincott´s
Pharmacology, 2009)
PROTEIN SYNTHESIS INHIBITORS
TETRACYCLINES
AMINOGLYCOSIDES
MACROLIDES/KETOLIDES
CHLORAMPHENICOL
CLINDAMYCIN
QUINUPRISTIN/DALFOPRISTIN
LINEZOLID
Demeclocycline
Doxycycline
Minocycline
Tetracycline
Amikacin
Gentamicin
Neomycin
Netilmicin
Streptomycin
Tobramycin
Azithromycin
Clarithromycin
Erythromycin
Telithromycin
15

Tetracyclines
Examples: tetracycline, doxycycline, demeclocycline, minocycline and
tigecycline
Mechanism of action: Bind reversibly to the 30s subunit of the bacterial
ribosome and block access of the amino acyl-tRNA to the mRNA-ribosome
complex at the acceptor site
Antimicrobial spectrum: Active against both gram positive and gram negative
bacteria and effective against intracellular bacteria - they are drugs of choice
against atypical bacteria - rickettsia, mycoplasma and chlamydial
Uses: Treatment of rickettsial infections, brucellosis, cholera, Lyme disease,
mycoplasma infections, chlamydial infections, acne vulgaris, helicobacter
pylori and malaria
Adverse effects: Nausea, vomiting and diarrhoea, epigastric distress;
deposition in the bone and primary dentition (occurs during calcification in
growing children and leads to discoloration and hypoplasia of the teeth and a
temporary stunting of growth), hepatotoxicity, phototoxicity and super-
infections
16

Aminoglycosides
Examples: amikacin, gentamicin, tobramycin, streptomycin,
neomycin, netilmicin and kanamycin
Mechanism of action: Bactericidal - inhibit bacterial protein
synthesis bind to the isolated 30S ribosomal subunit
Uses: Serious infections due to aerobic gram-negative bacilli,
tularemia, streptomycin and kanamycin can be used to treat
tuberculosis
Adverse effects: ototoxicity and nephrotoxicity, neuromuscular
paralysis, teratogenic and allergic reactions
17

Macrolides
Include: erythromycin, roxithromycin, azithromycin, clarithromycin,
telithromycin and spiramicin
MOA: Bind irreversibly to a 50S subunit of the bacterial ribosome and
inhibit the translocation step of protein synthesis. Are bacteriostatic.
Adverse effects: epigastric distress, diarrhoea
Inhibit cytochrome P450
Erythromycin
• Few indications where it is a drug of first choice
• Mostly used as an alternative to penicillin in allergy to beta-lactam
antibiotics (especially gram positive bacteria, spirochaetes and
N.gonorrhoae)
• Also used for Chlamydia, Mycoplasma, Legionella, Corynebacterium
diphtheriae, vibrio cholerae and staphylococcus aureus (not MRSA)
18

Macrolides …. cont’d
Clarithromycin
Similar to erythromycin, but it is also effective against H. influenzae
Has higher activity than erythromycin against intracellular pathogens
(e.g. Chlamydia, Legionella, Moraxella, Ureaplasma species) and
H.pylori
Azithromycin
Less active against streptococci and staphylococci than erythromycin
More active against respiratory infections due to H. influenzae and
Moraxella catarrhalis
The preferred therapy for urethritis caused by Chlamydia trachomatis
Telithromycin
Spectrum similar to azithromycin, and less vulnerable to resistance
19

Chloramphenicol
Broad-spectrum antibiotic active against a wide range of gram positive and gram
negative organisms, anaerobes, and some intracellular bacteria e.g. rickettsiae
Mechanism of action: Binds to the bacterial 50S ribosomal subunit to block the action
of peptidyl transferase and thus prevents amino acid incorporation into newly formed
peptides
Indications
Serious life-threatening infections such as H. influenzae, Bacteroides fragilis and
meningitis when beta-lactams cannot be used or no other appropriate antibiotic is
available, and in typhoid fever
Adverse effects: hemolytic anemia - in patients with low levels of glucose 6-phosphate
dehydrogenase, reversible anemia - dose-related and occurs concomitantly with
therapy, aplastic anemia (pancytopenia): idiosyncratic and usually fatal; is
independent of dose and may occur after therapy has ceased, GIT disturbances,
diarrhea (due to alteration of gut flora), hypovitaminosis B and K and gray baby
syndrome in neonates
Inhibits some cytochrome P450 enzymes
20

Clindamycin
Mechanism of action: as macrolides (antagonism occurs
when co-administered)
Uses: treatment of infections caused by anaerobic bacteria
(e.g. Bacteroides fragilis). Also active against non-
enterococcal gram-positive cocci (note: Clostridium difficile
is resistant to clindamycin)
Adverse effects: Skin rashes, GIT disturbances, impaired
liver function. The most serious adverse effect is potentially
fatal pseudomembranous colitis (caused by overgrowth of
Clostridium difficile; treated with vancomycin)
21

Metronidazole
A prodrug that is bactericidal against most anaerobic bacteria,
clostridium difficile and anaerobic protozoa (e.g. Trichomonas vaginalis
and Entamoeba histolytica)
MOA: Inhibition of DNA replication in anaerobic organisms
Indications: infections caused by Bacteroides fragilis, anaerobes in
abdominal and pelvic cavity, diarrhea by C. difficile, cerebral abscesses,
trichomonas infections, tetanus, H. pylori
Adverse effects: metallic taste, GIT disturbances, dizzines, vertigo ,
headache, depression, dark urine, disulfiram-like effect when taken
with alcohol
Tinidazole: similar to metronidazole but has a longer duration of action
22

Fusidic acid
• A narrow spectrum steroid antibiotic – active only against
staphylococci
• Active against gram positive bacteria by inhibiting protein
synthesis – prevents binding of tRNA to the ribosome
• Used mainly in penicillin-resistant staphylococcal infections (in
combination with another antistaphylococcal effective agent)
• Adverse effects: GIT disturbances, skin eruption, jaundice
23

Quinolones
Include: nalidixic acid, ciprofloxacin, levofloxacin, norfloxacin, ofloxacin,
moxifloxacin, gatifloxacin, lomefloxacin, gemifloxacin and sparfloxacin.
All are flouroquinolones except nalidixic acid
MOA: inhibit bacterial DNA gyrase (topoisomerase II) and topoisomerase
IV and thereby inhibit the replication of bacterial DNA. Are bactericidal.
Antibacterial spectrum
• Nalidixic acid: moderate activity against gram negative organisms
• Ciprofloxacin, ofloxacin, levofloxacin, norfloxacin and lomefloxacin are
highly active against gram negative bacteria and moderately active
against gram positive bacteria. Also have some activity against
atypical bacteria (mycoplasma, chlamydia, legionella). Ciprofloxacin is
active against bacillus anthracis.
• Moxifloxacin, gatifloxacin, sparfloxacin and gemifloxacin have an even
greater activity against gram positive organisms and activity against
some anaerobes, and improved activity against atypical bacteria
24

Fluoroquinolones …. cont’d
Adverse effects: nausea, vomiting, diarrhea; headache and
dizziness or light-headedness; phototoxicity and hepatotoxicity
Drug interactions
The effect of antacids and cations (aluminium, calcium and
magnesium) reduce absorption of flouroquinolones
Inhibit cytochrome P450 enzymes - may raise the serum levels of
warfarin, theophylline, caffeine, and cyclosporine
Cimetidine reduces the elimination of the fluoroquinolones
25

Folic acid antagonists
• Coenzymes containing folic acid are required for the synthesis of purines
and pyrimidines, and other compounds necessary for cellular growth and
replication
• In the absence of folic acid, bacteria cannot grow or divide
• Humans cannot synthesize folic acid and thus obtain preformed folate as a
vitamin from the diet
• Many bacteria are impermeable to folic acid, and must synthesize folate
de novo
Mechanisms by which folic acid antagonists act
• Inhibit the synthesis of folic acid by inhibiting the enzyme dihydropteroate
synthetase (e.g. sulfonamides) which is required for the synthesis of
dihydrofolate from para-aminobenzoic acid (PABA)
• Prevent the conversion of folic acid to its active, coenzyme form
(tetrahydrofolic acid) (e.g. trimethoprim) [the enzyme involved is
dihydrofolate reductase]
26

Sulfonamides
Spectrum: active against selected enterobacteriaceae, chlamydia
and nocardia
Adverse effects: nephrotoxicity, hypersensitivity reactions,
hemolytic anemia in patients with glucose 6-phosphate
dehydrogenase deficiency, granulocytopenia, thrombocytopenia
can also occur, nausea, vomiting, headache, mental depression
and kernicterus
Drug interactions: Displacement of some drugs from serum
albumin – results in transient potentiation of the hypoglycemic
effect of oral anti-diabetic drugs (e.g. tolbutamide) and the
anticoagulant effect of warfarin
27

Sulfonamides: clinical uses
• Urinary tract infections – sulfadimidine, sulfisoxazole, co-
trimoxazole (sulfamethoxazole-trimethoprim)
• Nocardiosis (high doses) – co-trimoxazole
• Toxoplasmosis (sulfadiazine in combination with pyrimethamine)
• Trachoma (as alternatives to tetracyclines which are the drugs of
choice) – sulfacetamide, co-trimoxazole
• Lymphogranuloma venereum and chancroid (as alternatives to
tetracyclines) – co-trimoxazole
• Malaria (sulfadoxine is used with pyrimethamine in chloroquine
resistant P.falciparum malaria)
• Bacterial conjunctivitis (sulfacetamide)
• Ulcerative colitis (sulfasalazine)
28

Trimethoprim
MOA: inhibits bacterial dihydrofolate reductase
Antibacterial spectrum similar to sulfonamides
May be used alone in the treatment of acute UTIs, and in the
treatment of bacterial prostatitis and vaginitis
Mostly compounded with sulfamethoxazole (the combination is
called co-trimoxazole)
Adverse effects : folic acid deficiency leading to megaloblastic
anemia, leukopenia, granulocytopenia, nausea, vomiting and
skin rashes
29

Co-trimoxazole
Co-trimoxazole is a combination of trimethoprim and
sulfamethoxazole
The ratio of trimethoprim:sulfamethoxazole is 1:5 to attain the
optimum plasma concentration
The combination of trimethoprim with sulfamethoxazole is synergistic
Active against several gram positive and gram negative bacteria
Susceptible organisms include: meningococci, gonococci, E.coli,
Yersinia, Shigella, Salmonella, C. diphtheriae, H. influenzae,
Staphylococcus aureas (including methicillin resistant organisms),
streptococci and Pneumocystis jirovecii
Development of resistance to the combination is slower when
compared to either drugs given alone
30

Co-trimoxazole: clinical indications
• Urinary tract infections: (1) uncomplicated infection of the
lower urinary tract infection (2) chronic and recurrent urinary
tract infections (including enterobacteriaceae)
• Bacterial prostatitis and bacterial vaginitis
• Respiratory tract infections: including bronchitis, sinusitis and
otitis media
• Drug of choice for pneumocystis jiroveci pneumonia
(prophylaxis and treatment)
• Gastroenteritis due to Shigella and E.coli
• Ampicillin- or chloramphenicol-resistant systemic salmonella
infections
• Chancroid (co-trimoxazole is the drug of choice)
31

Urinary tract antiseptics
• About 80% of UTIs are caused by E. Coli. The rest are caused
by Staphylococcus saprophyticus, Klebsiella pneumoniae and
Proteus mirabilis
• Urinary antiseptics are those antibacterial agents which are
concentrated in urine but do not achieve systemic
antibacterial concentrations. Their use is restricted to
treatment of UTIs.
• Some antibacterial agents treatment of UTIs are known as
urinary antiseptics
• They include: methenamine, nalidixic acid, norfloxacin and
nitrofurantoin
32

Topical antibacterial agents
Bacitracin
• A mixture of polypeptides - inhibits bacterial cell wall synthesis
• Spectrum - gram-positive organisms
• Use is restricted to topical application because of its nephrotoxicity
Polymyxin B and colistin (polymyxin E)
• Basic polypeptides that act to disrupt cell membrane functions
• Bactericidal and active against gram negative bacteria
(pseudomonas, coliforms)
• Not absorbed from GIT
• Adverse effect: neurotoxicity and nephrotoxicity
• Indications: gut sterilisation (given orally), eye, ear and skin
infections (topical application) and pseudomonas aeruginosa
infection in cystic fibrosis (by inhalation)
33

Mupirocin
• Rapidly inactivated after absorption (thus very low systemic
concentrations)
• Narrow spectrum antibiotic: active against staphylococci
including methicillin-resistant S. aureus (more than 95% of
hospital staphylococcal isolates are still susceptible)
• MOA: inhibits staphylococcal isoleucyl tRNA synthetase
• Used as an ointment for topical treatment of minor skin
infections (e.g. impetigo)
34

Drugs used in tuberculosis (TB)
First line drugs
• Isoniazid, rifampicin, pyrazinamide, ethambutol and
streptomycin
• Good efficacy, less toxicity and well tolerated for most
patients
Second line drugs
• Ethionamide, protionamide, para-amino salicylic acid
(PAS), amikacin, fluoroquinolones, capreomycin,
cycloserine, rifabutin, kanamycin and terizidone
• Less efficacious and/or more toxic than first line drugs
• Used as alternatives to the first-line drugs when drug
resistance occurs, or in certain circumstances such as drug
toxicity to first-line drugs
37

Isoniazid (INH, H)
Effective against both intracellular and extracellular organisms
It is the most active drug for the treatment of tuberculosis
MOA: inhibits the synthesis of mycolic acids (mycolic acids are
unique to mycobacteria). Active against mycobacterium
tuberculosis only
Administered in combination with other anti-TB drugs for
treatment of TB. For prophylaxis, INH is used alone.
Adverse effects: Peripheral neuritis - due to interference with
utilisation and increased excretion of pyridoxine, hepatitis,
psychosis, anorexia, GI discomfort, fever, allergic reactions and
haemolysis in patients with G-6-P-D deficiency
Drug interactions: Inhibits cytochrome P450 thereby reducing
metabolism of some drugs (e.g. phenytoin)
38

Rifampicin (R)
Bactericidal to M.tuberculosis, M.leprae and atypical mycobacteria. Also
inhibits most gram positive and gram negative bacteria. Acts on both
intra- and extracellular organisms.
MOA: inhibits DNA-dependent RNA polymerase thus inhibits RNA
synthesis
Uses: Tuberculosis, leprosy and atypical mycobacterial infections,
prophylaxis of Haemophilus influenzae, treatment of resistant
staphylococcal infections, brucellosis and eradication of carrier state of
N. meningitidis, H. influenzae and S. aureus
Adverse effects: Hepatotoxicity, epigastric distress, nausea, vomiting,
abdominal cramps, diarrhoea, flu-like syndrome (more common with
intermittent dosing), headache, drowsiness, dizziness, ataxia, confusion,
peripheral neuropathy, hypersensitivity reactions and stains sweat, tears,
saliva and urine an orange red colour
Induces cytochrome P450 enzymes (hence accelerates metabolism of
many drugs)
39

Rifampicin analogues
Include rifapentine and rifabutin
Rifapentine
• Its pharmacology is similar to rifampicin
• Used once weekly in TB treatment after sputum cultures
convert to negative (during the continuation phase of TB
therapy)
Rifabutin
• More active against atypical mycobacteria than rifampicin
• Less cytochrome P450 induction than rifampicin
• Can be used in place of rifampicin in patients receiving
ARVs that are substrates for cytochrome P450 (e.g.
protease inhibitors)
40

Pyrazinamide (PZ, Z)
MOA: inhibits mycolic acid synthesis
Active only against Mycobacterium tuberculosis
Active against intracellular bacilli
Adverse effects: hepatotoxicity, hyper-uricaemia with
precipitation of gout (reduces excretion of uric acid),
arthralgia, anorexia, vomiting and rashes
Streptomycin
Acts only against extracellular organisms
Adverse effects: ototoxicity and nephrotoxicity
Contraindications: pregnancy
41

Ethambutol (E)
Also effective against atypical mycobacteria
MOA: inhibits the incorporation of mycolic acids into the
mycobacterial cell wall (inhibits arabinosyl transferases
involved in this process)
Adverse effects: reversible optic (retrobulbar) neuritis
resulting in reduced visual acuity and inability to
differentiate red from green
Avoid in children because it is not easy to reliably test for
visual acuity in them
Other adverse effects: nausea, anorexia, headache, fever,
allergic reactions and gout precipitation (decreases excretion
of uric acid)
42

Second-line drugs
Ethionamide
• An analogue of isoniazid, and acts by inhibiting synthesis
of mycolic acid
• Does not exhibit cross-resistance with INH
• Effective against both intra- and extracellular organisms
• Also effective in atypical mycobacteria
• Poorly tolerated
• Adverse effects: anorexia, nausea, metallic taste,
hepatitis, skin rashes, peripheral neuritis (prevent with
prophylactic pyridoxine)
43

Second-line drugs …. cont’d
Cycloserine
• An analogue of d-alanine
• Inhibits cell wall synthesis
• Also effective against some gram positive organisms
• Adverse effects: headache, psychosis, tremors and seizures
• Only used in TB resistant to first-line drugs
Para amino salicylic acid
• PABA analogue, structurally related to sulfonamides and
inhibits synthesis of folic acid. Has narrow spectrum of activity
because it only penetrates mycobacteria.
• Rarely used because it is poorly tolerated
• Adverse effects: nausea, anorexia, epigastric pain, vomiting,
diarrhoea, allergic reactions and hepatitis
44

Second-line drugs …. cont’d
Amikacin, kanamycin and capreomycin
• Inhibit protein synthesis
• Given parenterally
• Are ototoxic and nephrotoxic
• Used only in cases resistant to first-line drugs
• Amikacin is also effective against atypical mycobacteria
Fluoroquinolones
• The fluoroquinolones recommended for TB treatment are
gatifloxacin, moxifloxacin, levofloxacin and ofloxacin
• Inhibit tubercle bacilli and atypical mycobacteria
• Useful in multi-drug resistant TB in combination with other drugs
45

Drugs used for Mycobacterium avium complex (MAC)
• Drugs that are effective in MAC include: rifampicin,
rifabutin, macrolides (clarithromycin and azithromycin),
fluoroquinolones, ethambutol, clofazimine, amikacin and
ethionamide
• The macrolides are highly effective and are the first choice
drugs in MAC
• Preferred regimen: macrolide + ethambutol ± rifabutin
(life-long treatment) [the macrolide mostly used is
clarithromycin]
• Rifabutin or a macrolide are used for prophylaxis
46

Drugs used in the treatment of leprosy
Dapsone
Inhibits dihydropteroate synthetase, therefore inhibits synthesis of
folic acid
Also used as a second-line drug in the treatment of pneumocystis
pneumonia
Adverse effects: anorexia, nausea, vomiting, hepatitis,
agranulocytosis, haemolysis in G-6-P-D deficiency
Erythema nodosum leprosum
An inflammatory process that develops during dapsone therapy of
lepromatous leprosy. Suppressed by corticosteroids or
thalidomide.
47

Drugs used in the treatment of leprosy …. cont’d
Rifampicin
• Rapidly bactericidal to M. leprae and is highly effective – a
single dose of 1500mg can kill 99% of the lepra bacilli
• It can be given once monthly
• Used in combination with dapsone
Clofazimine
• A dye that has weak bactericidal actions against M. leprae
• Has anti-inflammatory properties which is useful in suppressing
lepra reactions
• Adverse effects: reddish-black discoloration of the skin, dryness
of the skin, pruritis and photo-dermatitis
48

Other drugs used in leprosy treatment
Fluoroquinolones: ofloxacin is lepricidal and is used in
multidrug regimens along with rifampicin
Minocycline (a tetracycline found to be active against
against M. leprae): used in combination regimens to shorten
the duration of treatment
Clarithromycin: has bactericidal activity against M. leprae
Ethionamide: bactericidal to M.leprae, but more toxic than
dapsone. Used in multidrug regimen in patients who cannot
tolerate clofazimine.
49

ANTI-PROTOZOAL, ANTI-HELMINTH AND
ANTI-FUNGAL DRUGS

Drugs used in the treatment of African trypanosomiasis
Suramin
• It acts by inhibiting enzymes of energy metabolism including glycerol
phosphate dehydrogenase
• It does not penetrate into the CNS, thus it is only used in early
trypanosomiasis before the CNS is involved
• Given IV
• Adverse effects: vomiting, shock, loss of consciousness, rash, neuropathy,
haemolytic anaemia and agranulocytosis
Melarsoprol
A trivalent arsenical
MOA: reacts with sulfhydryl groups in proteins
Use: meningo-encephalitic stage of African trypanosomiasis
Adverse effect: fever, vomiting, arthralgia, reactive encephalopathy
53

Drugs used in the treatment of African trypanosomiasis ….
cont’d
Eflornithine
MOA: inhibits ornithine decarboxylase
Used for both haemolymphatic and CNS stages of African trypanosomiasis
Adverse effects: diarrhoea, vomiting, anaemia, thrombocytopaenia,
leukopenia and seizures
Pentamidine
Active against trypanosomiasis, leishmaniasis and pneumocystis jiroveci
MOA: interfere with synthesis of RNA, DNA and proteins
Administered IV or aerosol (in PCP)
Has many adverse effects which include hypotension, nephrotoxicity,
hypoglycaemia, cardiac arrhythmias, pancreatitis, thrombocytopaenia,
hallucinations, dyspnoea, hypocalcaemia
54

Drugs used in the treatment of Chaga’s disease (caused by
Trypanosoma cruzi)
Nifurtimox
It acts by generating superoxide and hydrogen peroxide radicals which are
toxic to the trypanosomes
Orally well absorbed
Adverse effects: nausea, vomiting, abdominal, fever, rash, restlessness,
insomnia, neuropathy, seizures
Benznidazole
Similar efficacy to nifurtimox in acute Chaga’s disease
Has limited availability currently
Adverse effects: peripheral neuropathy, rash, GIT symptoms and
myelosuppression
55

Drugs used in the treatment of Leishmaniasis
Drugs active against leishmaniasis are sodium stibogluconate,
pentamidine and amphotericin B
Sodium stibogluconate
• A pentavalent antimonial
• First line drug for visceral and cutaneous leishmanisais
• It acts by inhibiting glycolysis and fatty acid oxidation
• It is administered IM or IV
• Adverse effects: GIT symptoms, fever, myalgias, arthralgias,
rash, cardiac arrhythmias and nephrotoxicity
56

Drugs used in the treatment of toxoplasmosis
First line treatment: pyrimethamine in combination
with sulfadiazine
Alternative treatment: co-trimoxazole
Pyrimethamine
• MOA: inhibits dihydrofolate reductase (thus inhibits
the conversion of DHF to THF)
• Adverse effects: megaloblastic anaemia and folate
deficiency at high doses
57

Drugs used in the treatment of amoebiasis (Entamoeba
histolytica infections)
Classification of amoebicidal drugs
Are classified as luminal, systemic or mixed (luminal and systemic)
amoebicides according to the site where the drug is effective
Luminal amoebicides
Diloxanide furoate, iodoquinol and paromomycin: act on the parasite in the
lumen of the bowel
Systemic amoebicides
Chloroquine, dehydroemetine and emetine: effective against amoeba in the
intestinal wall and liver
Mixed amoebicides
Metronidazole: effective against both the luminal & systemic forms of the
disease, although luminal concentrations are too low for single drug
treatment
58

Treatment of specific forms of amoebiasis
Asymptomatic intestinal infection
Asymptomatic carriers are treated with a luminal amebicide
Amoebic colitis
Metronidazole plus a luminal amebicide is the treatment of
choice for colitis & dysentery. Tetracycline & erythromycin are
alternative drugs
Extra-intestinal infections
The treatment of choice of liver abscesses is metronidazole plus
a luminal amebicide. If initial therapy fails, then the addition of
chloroquine to a repeat course of metronidazole may be helpful.
Dehydroemetine and emetine are alternative drugs (but are very
toxic – cardiotoxicity, nausea and vomiting).
59

Other anti-protozoal drugs
Nitazoxanide
Used in the treatment of intestinal protozoa: cryptosporidium parvum and
giardia lamblia
Other susceptible strains include: E. histolytica, H. pylori, A. lumbricoides and
Fasciola hepatica
MOA: its metabolite, tizoxanide, inhibits the pyruvate:ferrodoxin oxido-
reductase pathway, thus interferes with anaerobic metabolism
Active against metronidazole resistant protozoal strains
Adverse effects: abdominal pain, diarrhea, anorexia, nausea, vomiting,
allergy, increased ALT and anemia
60

Classification of Antifungal Drugs
Antifungal Antibiotics
• Griseofulvin
• Polyene macrolide : amphotericin B & nystatin
Synthetic
• Imidazoles: ketoconazole , miconazole
• Triazoles : fluconazole , itraconazole
• Flucytosine
• Squalene epoxidase inhibitors : e.g. terbinafine & naftifine
62

Classification according to route of administration
Systemic
Griseofulvin , amphotericin B , ketoconazole , fluconazole ,
terbinafine
Topical
• Imidazoles : ketoconazole, miconazole, clotrimazole
• Triazoles : terconazole
• Polyene macrolides : nystatin , amphotericin B
• Terbinafine
63

Amphotericin B
MOA: disrupts fungal cell membrane by binding to ergosterol , so alters the
permeability of the cell membrane leading to leakage of intracellular ions &
macromolecules (causing cell death )
Broad spectrum fungicidal drug
Poorly absorbed orally
Given orally for fungal infection of gastrointestinal tract
For systemic infections given as slow IV infusion
Clinical uses
• The drug of choice for life-threatening mycotic infections e.g. cryptococcal
meningitis
• For induction regimen for serious fungal infection
• Chronic therapy and preventive therapy of to prevent relapse
• In cancer patients with neutropenia who remain febrile on broad –
spectrum antibacterial agents
64

Amphotericin B …. cont’d
Adverse effects
Immediate reactions (infusion–related toxicity): fever, muscle spasm,
vomiting ,headache, hypotension. Can be reduction by slowing the infusion,
decreasing the daily dose and premedication with antipyretics,
antihistamines and corticosteroids. Give a test dose before giving the full
dose.
Slower toxicity: most serious is renal toxicity (nearly in all patients ),
hypokalemia, hypomagnesaemia, impaired liver function, thrombocytopenia
and anemia
Liposomal preparations of amphotericin B
Amphotericin B is packaged in a lipid- associated delivery system to reduce
binding to human cell membrane , so reducing nephrotoxicity and infusion
toxicity
More effective and more expensive
65

Nystatin
It is a polyene macrolide ,similar in structure & mechanism to
amphotericin B
Too toxic for systemic use
Used only topically and is available as creams, ointment,
suspensions, suppositories & other topical preparations
Not significantly absorbed from skin, mucous membrane and GIT
Clinical uses
Prevention or treatment of superficial candidiasis of mouth,
esophagus, intestinal tract
Vaginal candidiasis
66

Azoles (imidazoles and triazoles)
A group of synthetic fungistatic agents with a broad spectrum of activity
They have anti-bacterial, anti-protozoal anti-helminthic and anti-fungal
activity
Are teratogenic
Mechanism of action
• Inhibit the fungal cytochrome P450 enzyme, (α-demethylase), which is
responsible for converting lanosterol to ergosterol (the main sterol in
fungal cell membrane)
• Inhibition of mitochondrial cytochrome oxidase leading to accumulation of
peroxides that cause autodigestion of the fungus
• Imidazoles alter RNA & DNA metabolism
67

Imidazoles
Include: ketoconazole, miconazole and clotrimazole
Miconazole and clotrimazole are only used topically
Ketoconazole
Clinical uses: Used topically or systematic (oral route only ) to treat oral
and vaginal candidiasis, dermatophytosis, systemic mycoses,
mucocutaneous candidiasis and seborrhoeic dematitis
Adverse effects: Nausea, vomiting ,anorexia, hepatotoxic and inhibits
synthesis of adrenal & gonadal steroids
Contraindications: Pregnancy, lactation, hepatic dysfunction
Drug interactions: Ketoconazole is a cytochrome P450 inhibitor.
Histamine H2 blockers and antacids decrease its absorption
68

Triazoles
Itraconazole
Used orally in dermatophytosis & vulvo-vaginal candidiasis and IV in serious
infections. Effective in AIDS-associated histoplasmosis.
Adverse effects: nausea, vomiting, hypokalemia, hypertension, edema,
inhibits the metabolism of many drugs e.g. warfarin
Fluconazole
Clinical uses: mucocutaneous candidiasis, cryptococcus meningitis,
histoplasmosis, blastomycosis and dermatophytoses
Adverse effects: nausea, vomiting, headache, skin rash , diarrhea, abdominal
pain , reversible alopecia, hepatic impairment
Voriconazole
Used for the treatment of invasive aspergillosis & other serious mycotic
infections
Adverse effects: reversible visual disturbances
69

Topical azoles
Ketoconazole, itraconazole, clotrimazole and miconazole are
used topically in dermatophyte infections and mucocutaneous
candidiasis
Both can cause mild irritation at the site of application
Clotrimazole: used as lotion, cream and vaginal pessaries
Miconazole: used as ointment, gel, cream, lotion and vaginal
suppository
Ketoconazole is also used as a shampoo for seborrheic dermatitis
70

Flucytosine
Converted within the fungal cell to 5-fluorouracil (but not in human
cell), that inhibits thymidylate synthetase enzyme resulting in
inhibition of DNA synthesis
Synergistic with amphotericin B (amphotericin B increases cell
permeability to flucytosine), allowing more flucytosine to penetrate
the cell, they are synergistic.
Uses: severe deep fungal infections such as crytococcal meningitis
Given with amphotericin B for cryptococcal meningitis
Adverse effects: nausea, vomiting , diarrhea, severe enterocolitis,
reversible neutropenia, thrombocytopenia, bone marrow depression,
alopecia, elevation in hepatic enzymes
71

Caspofungin
• Inhibits the synthesis of fungal cell wall by inhibiting the
synthesis of a glucose polymer which is an important
component of the fungal cell wall, leading to lysis & cell death
• Effective in aspergillosis, candidiasis and pneumocystis
jirovecii
• Second line for those who have failed to respond to or cannot
tolerate amphotericin B or itraconazole
• Adverse effects : nausea, vomiting, flushing (release of
histamine from mast cells)
72

Griseofulvin
MOA: Inhibits fungal mitosis by interfering with microtubule function
Used to treat dermatophyte infections (ring worm of skin, scalp, nails)
Taken selectively by newly formed skin and concentrated in the
keratin, and protects the skin from getting newly infected
Should be given for 2-6 weeks for skin & hair infections to allow
replacement of infected keratin by the resistant structure
Not effective in subcutaneous or deep mycosis
Given orally (absorption increases with fatty meal)
Adverse effects: peripheral neuritis, mental confusion, fatigue, vertigo,
GIT upset and blurred vision
Increases alcohol intoxication
Induces cytochrome P450 enzymes
73

Terbinafine
Inhibits fungal squalene epoxidase, thus decreases the synthesis
of ergosterol. Accumulation of squalene, which is toxic to the
organism causes death of fungal cell
Active against candida albicans & dermatophytes
Effective for treatment of onychomycoses
Given both orally and topically
Accumulates in skin and nails
Adverse effects: diarrhea, abdominal pain, nausea, taste
disturbance, visual disturbance and hepatotoxic
Accumulate in breast milk therefore avoid in lactating mothers
74

Other squalene epoxidase inhibitors
Tolnaftate
• Effective in most cutaneous mycosis
• Ineffective against candida
• Used as cream, gel, powder, topical solution for
dermatophytoses
Naftifine
• Broad spectrum fungicidal
• Available as cream or gel
• Effective for treatment of tinea cruris
75

Benzimidazoles
Include: albendazole, mebendazole and thiabendazole
MOA: (1) inhibit microtubule synthesis by binding to β-tubulin (2) inhibit glucose
uptake in the parasite
Should be avoided in pregnancy: are teratogenic and embryotoxic
Albendazole
• Broad spectrum oral anti-helmintic: active against hydatid, tapeworms, hookworm,
roundworm, whipworm, pinworm, strongyloidiasis, trichinella, filaria, giardia
• Drug of choice for treatment of hydatid disease and cysticercosis
• Penetrates well into tissues including hydatid cyst
• Adverse effects: mild abdominal pain, diarrhea, nausea, headache, fatigue and
dizziness. Long term use with high doses: increased liver enzymes, jaundice, fever,
weakness, alopecia and pancytopenia.
• Contraindications: Hypersensitivity to benzimidazoles and children under 2 years
77

Mebendazole
Active against roundworm, hookworm, pinworm, whipworm, guineaworm
and hydatid
Adverse effects: nausea, abdominal pain, diarrhoea. Large doses cause
headache, dizziness, alopecia, elevation of liver enzymes and
granulocytopenia
Use with caution under 2 years of age - may cause convulsion
Thiabendazole
More toxic than other benzimidazoles. Has more frequent adverse effects:
dizziness, anorexia, vomiting, diarrhoea, drowziness, paraesthesia,
bradycardia, hypotension, convulsions, liver damage
Drug of choice for Trichinella spiralis infection
Used as an alternative to albendazole in strongyloidiasis and cutaneous larva
migrans
78

Other anti-helminthic drugs
Pyrantel pamoate
MOA: depolarization neuromuscular blocker – paralyzes the worms, and the paralyzed
worms are passed in faeces
Active against roundworms, pinworms and hookworms
Adverse effects: abdominal pain, headache, dizziness, rash ,fever
Contraindications: pregnancy and children under 2 years of age
Piperazine citrate
MOA: neuromuscular junction blockade resulting in flaccid paralysis of the worms
Active against roundworms and pinworms
Adverse effects: GI symptoms, headache and dizziness
Levamisole
Stimulates nicotinic receptors at the neuromuscular junction resulting in spastic
paralysis
Active against roundworms and hookworms
Adverse effects: mild nausea and vomiting.
79

Other anti-helminthic drugs
Niclosamide
MOA: kills worms by inhibition of oxidative phosphorylation
Poorly absorbed from gut
Active against most tapeworms (not effective in hydatid and cysticercosis)
Adverse effects: abdominal discomfort, pruritis and rashes
Alcohol consumption should be avoided
Contraindicated in children under 2 years of age and in pregnancy
Praziquantel
MOA: increases cell membrane permeability to calcium resulting in
contraction followed by paralysis and the worms are expelled
Active against schistosomes of all species and tapeworms
Used in schistosomiasis and tapeworm infections
Adverse effects: GI disturbances, headache, dizziness, drowsiness, rashes and
myalgia
80

Diethylcarbamazine (DEC)
• Drug of choice for the treatment of filariasis and tropical
eosinophilia
• Immobilizes microfilariae and alters their surface structure,
displacing them from tissues & making them susceptible to
destruction by host defense mechanisms. Kills both
microfilariae in the peripheral circulation and adult worms in
the lymphatics
• Adverse effects: anorexia, nausea, vomiting, dizziness,
headache, allergic reactions with rashes, itching and fever due
to release of antigens from dying worms. Antihistamines are
given with DEC to minimize allergic reactions.
81

Ivermectin
Paralyses worms increasing chloride influx (hyperpolarization
occurs) by enhancing GABA- mediated transmission of signals in
peripheral nerves
Active against many nematodes, arthropods and filariae that
infect animals and human beings
Drug of choice for onchocerciasis
Also used for treatment of lymphatic filariasis, strongyloidiasis,
cutaneous larva migrans, roundworm, scabies and lice
Adverse effects: nausea, vomiting, drowsiness and allergic
reactions resulting from dying microfilariae (Mazzotti reaction)
Avoid concomitant use with other drugs that enhance GABA
82

Classification of antimalarial agents
Drugs acting on intrahepatic stages
• Causal prophylactic drugs: inhibit liver stage from initiating
erythrocytic stage (tetracyclines, primaquine, proguanil,
atovaquone-proguanil, pyrimethamine)
• Hypnozoitocidal: destroy exo-erythrocytic hypnozoites of P. vivax
and P. ovale after treatment of acute erythrocytic phase to produce
radical cure (primaquine)
Drugs acting on erythrocytic stages
• Clinical cure: fast action on erythrocytic stages (artemisinin
derivatives and quinolines)
• Suppressive therapy: slower suppressive action on erythrocytic
stages (anti-folates, tetracyclines, clindamycin)
86

Classification of antimalarial agents …. Con’t’d
Gametocytocidal drugs
Destroy sexual forms of the parasite in erythrocytes preventing
transmission to mosquito (artemisinin derivatives, primaquine)
Sporonticidal drugs
Destroy sporozoites (primaquine, pyrimethamine, proguanil)
Chemoprophylaxis
• Causal prophylaxis: inhibit liver stage from initiating erythrocytic
stage (atovaquone-proguanil, primaquine, chloroquine,
pyrimethamine, proguanil, doxycycline)
• Clinical or suppressive prophylaxis: inhibit development of
merozoites in erythrocytes (atovaquone-proguanil, proguanil,
pyrimethamine, primaquine, dapsone)
87

Five broad groups based on mechanism of action
1. Quinolines: Inhibit polymerisation of haem to haemozoin
2. Artemisinins: 1. Binds haem iron and generate oxygen
radicals which damage proteins in the parasite 2. Damages
Ca2+ ATPase (calcium transporter)
3. Anti-folates: Inhibit DNA synthesis (pyrimethamine,
proguanil, sulfonamides)
4. Atovaquone: inhibit electron transport chain in the
mitochondria
5. Protein synthesis inhibitors (ribosome inhibition) -
tetracyclines, clindamycin
88

Quinoline derivatives
• Include chloroquine, amodiaquine, quinine, quinidine,
mefloquine, primaquine, lumefantrine and halofantrine
• These drugs have activity against the erythrocytic stage of
infection (primaquine also kills intrahepatic forms and
gametocytes)
• The drugs act by accumulating in the parasite food vacuole
and forming a complex with haem
• They inhibit haem polymerase activity resulting in
accumulation of cytotoxic free haem (haem polymerase
polymerises haem to the non-toxic haemozoin)
90

Quinoline derivatives …. cont’d
Quinine and quinidine
Mostly used as second-line treatment and for severe falciparum malaria
Adverse effects: Cinchonism - tinnitus, high tone hearing impairment, vertigo,
nausea, vomiting, abdominal pain, dysphoria, headaches, dizziness and
disturbed vision
Other adverse effects: hypoglycaemia, blackwater fever,hypersensitivity
reactions, neurotoxicity and cardiotoxicity
Mefloquine
Used in the treatment of acute malarial infections and prophylaxis of
chloroquine-resistant P. falciparum malaria
Adverse effects: nausea, vomiting, diarrhoea, abdominal pain and dizziness,
neuropsychiatric manifestations (affective and anxiety disorders,
hallucinations, sleep disturbances, nightmares, psychosis, toxic
encephalopathy, convulsions and delirium), bradycardia and sinus arrhythmia
91

Chloroquine
Widespread resistance in most malaria-endemic countries has led to decline
in its use for the treatment of P. falciparum
Used in the treatment of acute malaria for chloroquine-sensitive malaria
strains (P. ovale, P. malariae, and some strains of P. vivax) and
chemoprophylaxis for susceptible strains of plasmodium
Adverse effects: headaches, dizziness, abdominal discomfort, vomiting,
diarrhea, rashes, pruritus, neuromyopathy, retinopathy, idiosyncratic
reactions, such as erythema multiforme and bone marrow toxicity, and can
provoke psoriasis
Amodiaquine
Treatment of chloroquine-resistant infections, in combination with artesunate
Adverse effects: GIT effects, hepatotoxicity and agranulocytosis
92

Primaquine
Used to achieve radical cure of P.ovale and P. vivax (prevents relapse of P. ovale
and P. vivax malaria by eliminating dormant hypnozoites) - given in conjunction
with chloroquine
Also used as a gametocytocidal drug in P. falciparum infections to prevent
transmission (in conjunction with another effective blood schizonticidal drug)
Adverse effects: Anorexia, nausea, vomiting, abdominal cramps, chest weakness,
anaemia, bone marrow suppression, haemolysis in people with glucose-6-
phosphate dehydrogenase deficiency
Halofantrine
Use: treatment of multidrug resistant P. falciparum malaria
Adverse effects: ventricular arrhythmias (prolongation of PR and QT interval) – has
been associated with death. Cardiotoxicity has limited its use.
Other adverse effects include nausea, abdominal pain, diarrhea, and pruritus
93

Lumefantrine
Active against most chloroquine-resistant parasites although there is
cross-resistance with halofantrine and mefloquine
Lumefantrine is a long-acting drug always given in combination with
artemether in a widely used fixed-dose combination (Zambia has
adopted this combination as first line antimalarial)
The bioavailability is highly variable and increases up to three-to-four
fold when taken with a high fat meal
Lumefantrine is well tolerated, with rare mild adverse reactions such
as diarrhea, nausea, abdominal pain and vomiting
There is no evidence of significant cardiotoxicity associated with
lumefantrine use
94

Antimalarial activity and use of the anti-folates
Antimalarial activity
• Have activity on sporozoites (proguanil and pyrimethamine), tissue
schizonts (proguanil, pyrimethamine) and blood schizonts (all the anti-
folates)
• Are slow acting compared to quinolines and artemisinins
• Combination of pyrimethamine with sulfonamide or dapsone is synergistic
Uses
• Treatment of malaria (pyrimethamine-sulfonamide combination)
• Chemoprophylaxis (dapsone, proguanil, pyrimethamine-dapsone)
• Intermittent preventive therapy in pregnancy (pyrimethamine-
sulfadoxine)
Sulfonamides are not recommended for chemoprophylaxis because of severe
skin reactions experienced by some individuals
95

Atovaquone-proguanil
• Atovaquone inhibits electron transport in mitochondria
resulting in the inhibition of key metabolic enzymes
responsible for the synthesis of nucleic acids and ATP
• Acts on hepatic schizonts and merozoites
• It is used for treatment and chemoprophylaxis of P. falciparum
malaria (always in combination with proguanil)
• It is administered orally with meals (absorption is significantly
increased with a high-fat meal)
• Adverse effects include: abdominal pain, vomiting, diarrhea,
headache and pruritus and transient increases in
transaminases
96

Artemisinin derivatives
Include: dihydroartemisinin, artemether, artesunate and arte-ether
Artemisinins act by binding iron, leading to the generation of free oxygen radicals that
damage parasite proteins. Binds and inhibits Ca2+ ATPase (calcium transporter).
They act rapidly, killing blood stages of all plasmodium species
Artemisinins have the fastest parasite clearance times of all antimalarials currently used
Artemisinins act primarily on the trophozoite phase and are also active against
gametocytes
WHO recommends the use of artemisinins (in combination with other anti-malarials) as
first line drugs for the treatment of P. falciparum malaria
Also used for treatment of severe malaria: IV/IM artesunate (it is superior to quinine for
treatment of severe malaria with respect to clearing parasitemia and reducing mortality)
Adverse effects that have been associated with artemisinins include headaches, nausea,
vomiting, abnormal bleeding, dark urine, itching, drug fever, transient neurological
abnormalities (nystagmus and disturbances in balance) and Type 1 hypersensitivity
reactions
97

Artemisinin-based combination therapies (ACTs)
It is recommended that artemisinins are used in combination with other anti-
malaria drugs, to prevent emergence of drug resistance and to shorten the
duration of treatment
ACTs combine the highly effective short-acting artemisinins with a longer-
acting partner to protect against artemisinin resistance and to facilitate
dosing convenience
ACTs are typically administered for 3 days and are often available in fixed-
dose tablets
Five ACTs are recommended by the WHO for the treatment of uncomplicated
malaria: (1) artemether-lumefantrine (2) artesunate-amodiaquine (3)
artesunate-mefloquine (4) artesunate-sulfadoxine-pyrimethamine (5)
dihydroartemisinin plus piperaquine
98

Tetracyclines and clindamycin
Tetracyclines and clindamycin act on the trophozoite stage
(erythrocytic)
Tetracyclines also act on tissue schizonts
The tetracyclines used in malaria treatment are tetracycline and
doxycycline
They have slow antimalarial activity and thus not to be used as
monotherapy for malaria
They are used in combination (with quinine or artemisinin
derivatives) for the treatment of acute cases of P. falciparum
infections
Doxycycline is also used for malaria chemoprophylaxis
99

The major sites of antiviral drug action
102

Viruses controlled by current antiviral therapy
• Cytomegalovirus (CMV)
• Hepatitis B and C viruses (HBV & HCV)
• Herpes viruses 1 and 2 (HSV-1 & HSV-2)
• Varicella-zoster virus (VZV)
• Human immunodeficiency virus (HIV)
• Influenza viruses
• Respiratory syncytial virus (RSV)
• Epstein-Barr virus (EBV)
• Human papilloma virus (HPV)
• Human herpes virus 6 (HHV-6)
103

Aciclovir, valaciclovir, famciclovir & penciclovir
Are guanosine analogues
Phosphorylated by viral thymidine kinase then metabolised by
host cell kinases to a nucleotide analogue. The nucleotide
analogue inhibits viral DNA synthesis by inhibiting DNA
polymerase
Only actively replicating viruses are inhibited
Clinical uses
• Aciclovir: HSV-1, HSV-2 and VZV infections
• Famciclovir and penciclovir: HSV-1, HSV-2, VZV, EBV and HBV
infections
104

Idoxuridine, trifluridine and vidarabine
Idoxuridine and trifluridine
MOA: uracil nucleoside analogues converted by cellular enzymes
to their triphosphate analogs which inhibits viral DNA
polymerase
Uses: ocular, oral, genital HSV infections. Administered topically.
Vidarabine
MOA: adenine nucleoside analogue converted by cellular
enzymes to its triphosphate analog which inhibits viral DNA-
polymerase
Uses: HSV keratoconjunctivitis (topical), neonatal herpes, VZV
infections in immunocompromised patient
105

Ganciclovir, valganciclovir and cidofovir
Ganciclovir and valganciclovir
Ganciclovir is an acyclic guanosine analogue and
valganciclovir is a prodrug of ganciclovir
MOA: inhibit viral DNA polymerase
Uses: HSV-1, HSV-2, VZV, EBV and CMV infections
Cidofovir
A cytosine analogue that inhibits viral DNA polymerase
Uses: CMV, HSV-1, HSV-2, VZV, EBV, HHV-6, adenovirus and
HPV infections
106

Foscarnet, fomivirsen and adefovir
Foscarnet
An inorganic pyrophosphate that directly inhibits viral DNA
polymerase, RNA polymerase, and HIV reverse transcriptase
Uses: HSV, VZV, CMV, EBV, HHV-6 and HBV infections
Fomivirsen
An oligonucleotide that binds to mRNA and inhibits protein
synthesis and viral replication
Uses: CMV retinitis
Adefovir
An analogue of adenosine monophosphate that competitively
inhibits HBV DNA polymerase
Uses: hepatitis B infection
107

Anti-influenza anti-viral agents
Amantadine and rimantadine
Are cyclic amines that inhibit the uncoating of viral RNA therefore inhibiting
replication
Use: prevention and treatment of Influenza A (no effect on Influenza B and
C)
Zanamivir and oseltamivir
The influenza virus contains an enzyme neuraminidase which is essential
for the replication of the virus
Zanamivir and oseltamivir inhibit the enzyme neuraminidase thereby
preventing the release of new virions and their spread from cell to cell
They are active against influenza types A and B
Can be used for both prophylaxis and acute treatment of influenza A and B
108

Ribavirin
A guanosine analogue that Inhibits the synthesis of nucleic
acids (DNA and RNA)
Active against a wide range of DNA and RNA viruses are
susceptible, including influenza A, B and C viruses,
parainfluenza viruses, measles virus, HSV-1, HSV-2, CMV, and
RSV
Uses
Ribavirin is the drug of choice for (1) RSV bronchiolitis and
pneumonia in hospitalized children (given by aerosol) (2) Lassa
fever
Ribavirin is an alternative drug for: influenza, parainfluenza and
measles virus infection in immunocompromised patients
109

Interferons
Interferons are inducible endogenous cytokines
The three major classes of human interferons (IFN) are:
1. IFN-alpha (human leukocyte IFN), induced by viruses
2. IFN-beta (human fibroblast IFN), induced by viruses
3. IFN-gamma (human immune IFN), induced by antigens
Mechanism of antiviral action: Bind to membrane receptors
on cell surface and (1) Induce host cell enzymes that inhibit
viral RNA translation (2) Cause degradation of viral mRNA and
tRNA. They also inhibit viral penetration, uncoating, mRNA
synthesis, and translation, and virion assembly and release.
Antiviral spectrum: Includes HBV, HCV, HDV, HSV, VZV, CMV
and human papillomavirus (HPV)
110

Interferons …. cont’d
Therapeutic uses
• Chronic HBV and HCV
• VZV infection in cancer patients
• CMV infections in renal transplant patients
• Refractory condylomata acuminata
• Hairy cell leukemia (in combination with zidovudine)
• AIDS related Kaposi’s sarcoma
111

Treatment of HPV ano-genital warts
Imiquimod
An immunomodulator: activates immune cells (monocytes,
macrophages, NK cells) which then produces antiviral cytokines
(IFN-α, TNF-α and various interleukins)
Administered topically
Podophyllotoxin and podophyllin
Exact mechanism not known
Administered topically
112

There are five classes of ARVs, each of which targets one of
four viral processes:
1. Nucleoside and nucleotide reverse transcriptase
inhibitors (NRTIs)
2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
3. Protease inhibitors
4. Entry inhibitors
5. Integrase inhibitors
Classes of ARVs
115

118
NRTIs
Mechanism of action of NRTIs
• Competitively inhibit reverse transcriptase thereby inhibiting viral
replication
• Are additive or synergistic with each other and with other classes of
ARVs
Major adverse effects
• All NRTIs: lactic acidosis
• Zidovudine: bone marrow depression, myopathy, cardiompyopathy
• Tenofovir: nephrotoxicity
• Stavudine: lipodystrophy, neuropathy
• Abacavir: hypersensitivity reactions
• Lamivudine: pancreatitis

119
NNRTIs
Include nevirapine (NVP), efavirenz (EFV) and etravirine
Mechanism of action
• Are non-competitive inhibitors of reverse transcriptase – they bind near
the catalytic site and denature it
• They do not inhibit HIV-2 reverse transcriptase
Major adverse effects
• Hepatotoxicity: NVP, EFV (NVP has greatest potential)
• Nervous system (insomnia, somnolence, dizziness, nightmares,
neuropathy, anxiety, psychosis, seizures etc): EFV
• Skin reactions (rashes including SJ syndrome): NVP, EFV (NVP has
greatest potential)
Drug interactions
NVP and EFV are inducers of cytochrome P450 enzymes (with NVP being the
more potent inducer)

Etravirine
• Etravirine is an NNRTI specifically designed to be less
susceptible than other NNRTIs to resistance mutations
• In contrast to other NNRTIs, more than one resistance
mutation needs to develop, in order to bring about
resistance to etravirine
• Etravirine is indicated for treatment-experienced adults
who have evidence of viral replication and HIV strains
resistant to an NNRTI and other ARVs
• Adverse effects: skin reactions
• It is a potent inducer of cytochrome P450 enzymes
120

121
Protease inhibitors
Include: lopinavir (LPV), ritonavir (RTV), atazanavir (ATV) and
darunavir (DRV)
Mechanism of action
• In HIV, the mRNA transcribed from the provirus is translated
into large inactive polyprotein precursors
• The HIV protease enzyme cleaves the precursor
polyproteins to release the structural proteins and enzymes
needed to produce mature infectious virions
• Protease is needed to form a fully mature, functional virus
that is able to replicate and produce more virus
• In the absence of a functional protease, viral particles are
produced, but they are immature and are not infectious

122
Protease inhibitors …. cont’d
• Protease inhibitors cause a syndrome of altered body fat
distribution (lipodystrophy), insulin resistance, and hyper-
lipidemia
• Other adverse effects include fatigue, GI effects (nausea,
vomiting, diarrhoea) and pancreatitis
• They all inhibit cytochrome P450
• RTV is a very potent inhibitor of cytochrome P450 and
inhibits the metabolism of other PIs - it is used as a
pharmaco-enhancer (booster) to raise & maintain plasma
concentrations of other PIs

Darunavir
• A protease inhibitor designed to be active against HIV
resistant to the current 'first-generation' protease
inhibitors
• Darunavir is active against HIV with high-level resistance to
other protease inhibitors
• Resistance to darunavir develops more slowly than with
other protease inhibitors
• Adverse effects: diarrhoea, nausea, skin reactions,
headache. DRV has been associated with drug-induced
hepatitis in patients with pre-existing liver disease.
123

Entry inhibitors
Include enfuvirtide and maraviroc
Entry inhibitors prevent HIV from entering human immune cells
Enfuvirtide
• It binds to the glycoprotein gp41 (a protein on the viral
membrane), preventing fusion of the viral and cellular membranes
and thereby inhibits entry of HIV into the CD4 cell
• Has additive to synergistic effects when combined with drugs of
other ARV classes
• Indications: HIV infection in combination with other ARVs for
resistant infection or for patients intolerant to other ARV
regimens
• Adverse effects: Local injection site reactions, hypersensitivity
reactions, headache, insomnia, anorexia, asthenia, peripheral
neuropathy, depression, pancreatitis
124

Maraviroc
• Maraviroc is an entry inhibitor that binds to the CCR5
receptor on the membrane of human cells such as CD4
cells. This binding prevents the interaction of HIV-1 gp120
and human CCR5 which is necessary for entry into the cell.
• HIV can also use another co-receptor, CXCR4, which
maraviroc does not affect. Maraviroc does not prevent
HIV-1 entry into CXCR4-tropic or dual-tropic cells.
• A tropism test must therefore be performed to determine
if the drug will be effective
125

Maraviroc …. cont’d
• Maraviroc is indicated for CCR5-tropic HIV infection (in
combination with other ARVs) in patients previously
treated with ARVs
• Maraviroc is not recommended in patients who have
dual/mixed tropic or CXCR4-tropic virus
• Adverse effects: hepatotoxicity (may be preceded by a
systemic allergic reaction, pruritic rash and eosinophilia),
dizziness, postural hypotension, increased risk of cardiac
ischaemic events (e.g. myocardial infarction)
126

Raltegravir
MOA: Inhibits the enzyme integrase – thus inhibits the final
step in integration of strand transfer of the viral DNA into
host cell DNA
Indication: raltegravir (in combination with other ARVs) is
approved for therapy of treatment-experienced patients
with evidence of viral replication despite ongoing
antiretroviral drug therapy
Adverse effects: nausea, headache and diarrhea, myalgia,
myopathy and rhabdomyolysis
127

Goals of cancer treatment
Primary goal
Cure the patient i.e. eradicate the cancer (render the patient clinically
and pathologically free of disease and return their life expectancy to
that of healthy individuals of the same age and sex)
Current therapies do not offer cures for all patients
The best alternative goal
To prolong survival while maintaining the patient's functional status
and quality of life (amelioration of symptoms and preservation of
quality of life, while striving to extend life)
The third goal
Relieve symptoms such as pain for patients in whom the likelihood of
cure or prolonged survival is very low
130

Modalities of cancer therapy
The major modalities of therapy are
1. Surgery (for local and local-regional disease)
2. Radiation therapy (for local and local-regional disease)
3. Chemotherapy (for systemic disease)
Other important methods include
• Hormonal therapy (for selected cancers, e.g. prostate, breast,
endometrium)
• Biologic therapy: immunotherapy (monoclonal antibodies,
interferons, and other biologic response modifiers and tumor
vaccines)
131

Mechanisms of action of cancer
chemotherapeutic drugs (cytotoxic drugs)
• Inhibition of DNA and RNA synthesis
• Disruption of DNA structure and function
• Inhibition of protein synthesis
• Inhibition of microtubule function
132

Mechanisms of action of anti-cancer drugs
Mechanism of action Drugs acting by this mechanism
Alkylation of DNA (covalent
bond formation) thus
interfering with the structure
and function of DNA
Alkylating agents: mechlorethamine,
cyclophosphamide, melphalan, chlorambucil,
busulfan, carmustine, lormustine, dacarbazine
Inhibition of nucleic acid
synthesis by competing with
normal metabolites
Anti-metabolites: methotrexate (dihydrofolate
reductase inhibitor), cytarabine, fluoro-uracil,
capecitabine and gemcitabine (pyrimidine
antagonists) 6-mercaptopurine and 6-thioguanine
(purine antagonists)
Inhibition of mitosis Binding on tubulin thereby inhibiting
polymerization of microtubules: vinca alkaloids
(vincristine, vinblastine and vinorelbine
Disassembly of microtubules: paclitaxel and
docetaxel
Inhibition of topo-isomerase II
resulting in double stranded
DNA breaks
Etoposide
133

Mechanisms of action of anti-cancer drugs …. cont’d
Mechanism of action Drugs acting by this
mechanism
Intercalation with DNA thereby blocking
synthesis of DNA and RNA
Dactinomycin (actinomycin D),
doxorubicin, daunorubicin and
epirubicin
DNA chain scission and fragmentation Bleomycin
Inhibition of topo-isomerase I resulting in DNA
damage
Topotecan and irinotecan
Cross-linking of DNA subunits with resultant
inhibition of DNA synthesis
Platinum compounds (cisplatin,
carboplatin and oxaliplatin)
Chromosomal breaks with inhibition of DNA,
RNA and protein synthesis
Procarbazine
Inhibition of ribonucleotide diphosphate
reductase thereby inhibiting formation of
deoxyribonucleotides
Hydroxyurea
134

Commonly used anti-cancer drugs
Drug Commonly responsive cancers Mechanism of action
Cyclophosphamide
Chlorambucil
Leukemias, Hodgkin’s lymphoma Alkylation of DNA resulting in
DNA strand breakage
Mechlorethamine Lymphomas
Methotrexate Choriocarcinoma, acute leukemias Folate antagonist: inhibits
conversion of DHF to THF –
inhibits protein synthesis
6-Mercaptopurine Choriocarcinoma, acute leukemias Purine antagonist: inhibits protein
synthesis
5-Fluorouracil Carcinoma of the stomach, colon,
rectum, breast and ovaries
Pyrimidine antagonist: inhibits
DNA synthesis
Daunorubicin Acute leukemias Inhibit DNA synthesis
Doxorubicin Leukemias, solid tumours
Actinomycin D
(Dactinomycin)
Wilm’s tumour,
rhabdomyosarcoma,
choriocarcinoma
Inhibits RNA synthesis
135

Commonly used anti-cancer drugs …. cont’d
Drug Commonly responsive cancers Mechanism of action
Vincristine Lymphomas, leukemias, Wilm’s
tumour, brain tumour
Arrest mitosis by inhibiting
polymerization of microtubules
Vinblastine Testicular tumours, Ewing’s sarcoma,
breast cancer, lymphomas, leukemias
Vinorelbine Lung and breast cancer
Paclitaxel
Docetaxel
Breast, ovarian, lung, head and neck,
and bladder cancer
Arrest mitosis
Etoposide Testicular and lung cancers Inhibit topoisomerase and result
in DNA strand breakage
Procarbazine Hodgkin’s lymphoma Damages DNA
L-Aspariginase Acute leukemias Convert aparagine to aspartate
depriving malignant cells of
asparine thereby inhibiting
protein synthesis
Cisplatin Ovarian, testicular, and head and neck
cancers
Inhibits DNA synthesis
136

Choice of drugs in some malignancies
Malignancy Drugs of choice
Acute lymphocytic leukemia Vincristine + prednisolone
Maintenance: mercaptopurine, methotrexate & cyclophosphamide
Acute myeloid leukemia Cytosine arabinoside + daunorubicin
Chronic lymphocytic leukemia Chlorambucil + prednisolone
Chronic myeloid leukemia Busulphan, imatinib, interferons
Hodgkin’s disease Mechlorethamine + vincristine + procarbazine + prednisolone (MOPP)
Vinblastine + doxorubicin + dacarbazine + bleomycin
Burkitt’s lymphoma Etoposide + prednisone + vincristine + cyclophosphamide + doxorubicin +
rituximab
Choriocarcinoma Methotrexate
Carcinoma of the testis Etoposide + bleomycin + cisplatin
Carcinoma of the lung Cisplatin + paclitaxel
Wilm’s tumour Vincristine + actinomycin D after surgery
Osteogenic sarcoma Methotrexate or doxorubicin, vincristine
Multiple myeloma Melphalan + prednisolone
137

Cancer chemotherapy toxicity
Adverse effects are very common with anti-cancer drugs
Therapeutic effects of anti-cancer drugs are usually achieved by killing
actively growing cells, which are most sensitive to cytotoxic drugs
Because normal cells and cancer cells have similar sensitivity to
chemotherapeutic agents, adverse effects are mostly seen in normally
dividing non-neoplastic cells such as bone marrow stem cells, gastric
and intestinal mucosa, and hair follicles
Common adverse effects with most cytotoxic drugs
• Bone marrow suppression: anemia, neutropenia,
thrombocytopenia, immunosuppression
• Skin/mucosa: scaling, mucositis, mucosal haemorrhage, alopecia
• Cardiac: decreased myocardial contractility, arrhythmias
138

Common adverse effects with most cytotoxic drugs ….
cont’d
• Renal: acute tubular necrosis, chronic renal insufficiency,
hemorrhagic cystitis,
• Neurologic: hearing loss, peripheral neuropathy
• Reproductive system: sterility (reduced spermatogenesis and
amenorrhoea)
• GIT: nausea/vomiting, diarrhea, mucositis, xerostomia, oral
mucosal infections
• Dental: dental pulp/periapical infections, peridontal infection,
odontogenic pain
• Osteonecrosis
• Teratogenicity
• Carcinogenicity
139

Anti-cancer drugs that cause little or no bone marrow
depression
• Hormones
• Vincristine
• Bleomycin
• L-asparaginase
• Cisplatin
140

Specific adverse effects of some anti-cancer drugs
Drug Specific adverse effects Other prominent adverse effects
Cyclophosphamide Haemorrhagic cystitis,
stomatitis
Myelosuppression, alopecia,
vomiting, amenorrhoea,
teratogenicity, secondary leukemias
Vincristine Neurotoxicity, peripheral
neuritis, mental depression
Muscle weakness, alopecia
Busulfan Pulmonary fibrosis, stomatitis Myelosuppression, alopecia,
vomiting, amenorrhoea,
teratogenicity
Cisplatin Ototoxicity Highly emetogenic, renal dysfunction
Bleomycin Pulmonary fibrosis, oedema of
hands
Stomatitis, alopecia
Daunorubicin
Doxorubicin
Cardiotoxicity (daunorubicin
also causes red coloured urine)
Myelosuppression, alopecia
Mitotane Dermatitis, mental depression Diarrhoea
Aspariginase Pancreatitis, hepatotoxicity Allergic reactions
141

Hormonal therapy
Option for management of cancers from tissues whose
growth is under gonadal hormonal control, especially
breast, prostate, and endometrial cancers
These cancers may regress if the "feeding" hormone is
eliminated or antagonized.
Major organ system toxicity is uncommon from hormonal
treatment, making it the least toxic of systemic anticancer
therapies
Uses of hormonal therapy
• As adjuvant therapy
• To treat disseminated disease
142

Hormonal therapy
Modes of hormonal therapy:
1. Hormone deprivation
– Removal of hormone producing tissue (ablation)
– Inhibition of hormone production
– Blocking of hormone receptors
2. Exogenous hormone treatment
143

Examples of cancers where hormonal therapy is used
• Breast cancer
• Prostate cancer
• Endometrial cancer
• Renal cancer
• Ovarian cancer
144

Hormone therapy for breast cancer
Hormone therapy may be used to prevent the growth, spread, and
recurrence of breast cancer
Estrogen can increase the growth of breast cancer cells in some
women
Hormone therapy may be considered for women whose breast cancers
test positive for estrogen and progesterone receptors
Hormone therapy for breast cancer includes the following:
1. Removal or inhibition of gonadotropin action
2. Estrogen receptor blocking: tamoxifen and fulvestrant (estrogen
receptor antagonists)
3. Inhibition of peripheral estrogen synthesis: aromatase inhibitors
(anastrozole, exemestane, letrozole) which block conversion of
androgen to estrogen
145

Hormonal therapy of breast cancer …. cont’d
Removal or inhibition of gonadotropin action
• GnRH agonists (e.g. goserelin, buserelin, leuprolide):
inhibit gonadotrophin synthesis on continuous
administration
• GnRH antagonists (e.g. danazol): inhibit release of GnRH
and gonadotrophins
• Progestogens (e.g. megestrol acetate): inhibit
gonadotrophin secretion
146

Hormonal therapy of prostate cancer
• Estrogens (diethylstibestrol): inhibit effects of endogenous
androgens
• Androgen receptor antagonists: flutamide, bicalutamide, nilutamide
and cyproterone
• Gonadotrophin-releasing hormone (GnRH) agonists - when given
continuously, they inhibit gonadotrophin synthesis and thus reduce
synthesis of testosterone. GnRH agonists used in the treatment pf
prostate carcinoma are leuprolide , goserelin, triptorelin, histrelin,
and buserelin
• GnRH receptor antagonists – inhibit gonadotrophin synthesis and
thus lower testosterone (usually more rapidly than GnRH agonists).
The GnRH antagonist used in prostate carcinoma is degarelix.
147

Corticosteroids
Corticosteroids are lymphocytotoxic and anti-mitotic
They are useful in malignancies in which lymph tissue is
involved
Prednisolone is used as part of cancer treatment regimens in
the following:
• Acute lymphocytic leukemia
• Chronic lymphocytic leukemia
• Hodgkin’s disease
• Non-Hodgkin’s lymphoma
• Multiple myeloma
148

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