Chemotherapy

CHEMOTHERAPY
Chemotherapy Compiled by Birhanu G. 1

Chemotherapy
 Use of chemical agents (natural/synthetic) to destroy or
inhibit the growth of infective agents &/or cancerous cells
 Antibiotics: s/ces produced by µorganisms to suppress
the growth & replication or kill other µorganisms
 N.B.: now antibiotics are synthesized in the laboratory

Chemotherapy
Antimicrobials Antineoplastics
Antibacterials Antifungals Antivirals Antiparasitics
Antiprotozoals
Antihelminthics
Use of Anti-infective Agents
✍ Prophylactic therapy
✍ Empiric therapy: symptomatic management
✍ Definitive therapy: identification of pathogen & DST
☞ Goal: selective toxicity

Antibacterial Agents: ABX
☞ Can be:
 Narrow spectrum: INH, Cloxacillin, Naldixic acid, Pen-G
 Broad spectrum: CAPH, TTCs, Rifamycins, FQs
 Bactericidal:
 Penicillin, cephalosporins, vancomycin, FQs, aminoglycosides,

metronidazole
✍ MBC: the lowest concentration of ABX reduces the viability of

the initial bacterium inoculum by ≥99.9%
✍ Can be determined from broth dilution MIC

 Bacteriostatic:
 TTCs, macrolides, amphenicols, lincosamides,
 Aminocyclitoles, sulphonamides
✍ Never confuse these terms with potency levels of the drugs or
efficacy: narrow are weak, broad are strong

MOA of ABX

 Drug resistance: unresponsiveness of µ-organism to
antimicrobial agents
 Can be innate/acquired
☞ Origin of Drug Resistance
 Chromosomal mutation & selection: vertical
 Acquisition of chromosomal or extra chromosomal

material/horizontal/
 Conjugation: sexual reproduction
 Transduction: phages
 Transformation: taking genetic material from env’t or dead

bacteria
Mechanisms of Bacterial Resistance

Delaying the emergence of resistance
✍ Antimicrobials should be employed only when actually needed
✍ Narrow agents should be employed whenever possible
✍ Newer antibiotics should be reserved

Systematic Approach for Selection of Antimicrobials
✍ Confirm the presence of infection
☞ Careful history & physical examination
☞ Signs and symptoms
☞ Predisposing factors
✍ Identification of the pathogen
☞ Collection of infected material
☞ Stains, serology, culture and sensitivity
✍ Host & Drug factors

Patient specific considerations
 Age: causative agents, contraindication
 Disruption of host defenses (immunity):
 Compromised → cidal
 Site of infection
 History of recent antimicrobial use
 Antimicrobial allergies
 Renal and/or hepatic function
 Concomitant administration of other medications
 Pregnant & nursing women and compliance

Drug-specific considerations
 Spectrum of activity
 Effects on nontargeted microbial flora
 Appropriate dose
 PK & PD properties
 AE (adverse event) & DI profile
 Cost
Antimicrobial drug combination
 Indication
 Severe infection of unknown etiology
 Mixed infection
 Prevention of resistance
 Decreased toxicity
 Enhanced action: penicillin + aminoglycoside = synergism

Disadvantages of antimicrobial combination
 Increase risk of allergy
 Antagonism of antimicrobial effect: TTC + penicillin
 Increase risk of super infection
 Increased cost

Penicillins
-lactams
Cephalosporins
Carbapenems
Cell wall synthesis Fosfomycin

Monobactams
inhibitors
Cycloserine
Bacitracin: poly peptides
Glycopeptides: Vancomycin
BETA-LACTAM ANTIBIOTICS

Most commonly used β-lactams

 The penicillin nucleus, 6-aminopenicillanic acid (6-APA),
consists of 3 components:
 A thiazolidine ring: five-member
 The β-lactam ring & a side chain
 Cephalosporin nucleus, 7-aminocephalosporanic acid (7-ACA)
contains:
 A six-member dihydrothiazide ring,
 β-lactam ring & a side chain

PENICILLINS
 Bacterial cell wall; cross-linked polymer of polysaccharides
& pentapeptides
 Irreversibly acetylate membrane-binding proteins; PBPs or
transpeptidases/transamidases → inhibit transpeptidation
reactions involved in the cross-linking
 β-lactam ring structurally mimics the D-alanine-D-alanine
portion
Chemotherapy
of the peptidoglycan: suicide substrates of PBPs
Compiled by Birhanu G. 23
 β-lactam ABX are known to bind & inhibit inhibitors of
autolysins → activation of autolysins: destruction of the
existing cell wall
✍ For maximum effectiveness, they require actively proliferating
microorganisms
✍ Little or no effect on bacteria that are not growing & dividing

Peptidoglycan structure
Chemotherapy of bacterial
Compiled by Birhanu G. cell walls 25
NARROW SPECTRUM PENICILLINS
Natural Penicillins: Penicillin G (Benzylpenicillin), Penicillin V
 Active against:
 G+ve cocci & bacilli: except penicillinase producing µbes
 G-ve cocci: N.menigitidis, N.gonorrhea
 Which have slightly larger porins
 G-ve bacilli: have narrow porins, not effective
 Spirochetes: T.pallidum, Borrelia, Leptospira

Therapeutic uses
 Drug of choice for G+ve cocci;
 Pneumonia or meningitis by Streptococcus pneumonia
 Pharyngitis by Streptococcus pyogenes
 Infective endocarditis by Streptococcus viridians
 Infection caused by G+ve bacilli:
 Gangrene by Cl. perfringes
 Tetanus by Cl. tetani
 Anthrax by B. anthracis

Therapeutic uses…
 First choice for meningitis by N. meningitids
 Drug of choice for the treatment of syphilis
 Prophylactic applications;
 Syphilis in sexual partners
 Benzathine pen.G monthly for life in recurrent rheumatic fever
 Bacterial endocarditis

 PKs:
 Pen.-G is available as salts: Na+, K+, Procaine, Benzathine
 Pen.-G: orally ineffective due to the acid
 Procaine & Benzathine salts are intermediate & long acting

respectively
 Both absorbed from muscle slowly & referred to as repository

forms of Pen G
 Distributes well to most tissues; inflammation distribution

into CSF, joints & eye
 Penicillin is eliminated by tubular secretion: 90%
 Excretion
Chemotherapy delayed by probenecid
 Penicillin units
 Its activity originally defined in units
 Crystalline Penicillin G-Na contains 1600 units per mg (1
unit = 0.6 mcg; 1 million units of penicillin = 0.6 g)
 Semisynthetic penicillins prescribed by weight rather than
units

PHENOXYMETHYL PENICILLIN: PENICILLIN-V
 Acid stable: given orally
 Used in streptococcal pharyngitis, prophylaxis of
rheumatic fever; GABHS

VERY NARROW SPECTRUM: -LACTAMASE RESISTANT
 Oxacillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Methicillin, Nafcillin
 Also called anti-staphylococcal penicillins
 They have bulky side chains that protect the -lactam ring
 Can’t get access to G-ve due to bulky size: drawback
 Use: in S.aureus & Staph.epidermdis infections
 Emergence of staphylococcal strains (MRSA): Vancomycin
VRSA: FQs, Linezolid

 Methicillin
 Acid labile; allergic reaction; severe interstitial nephritis
 Only for drug sensitivity testing: nephrotoxicity
 Nafcillin
 Erratic & incomplete absorption from PO, so; IM or IV
 AEs: Neutropenia, Nephritis (less severe)

 Isoxazolyl Penicillins:
 Oxacillin, Cloxacillin, Dicloxacillin, Flucloxacillin
 The only d/ce b/n them is halogen substitution on the
aromatic ring
 These substituents affect PK properties: absorption & plasma
protein binding
 Acid stable; orally & parenterally administered
 Absorption affected by food

 Cloxacillin has better absorption than oxacillin
 Flucloxacillin is less bound to plasma protein →↑free drug
 Have inferior activity to the original pen.: inactive against G-ve
 Flucloxacillin: DOC for penicillin-resistant staphylococcal
infections in the ear
 Co-fluampicil: flucloxacillin + ampicillin
 For streptococcal or staphylococcal infections

BROAD SPECTRUM
 AMINOPENICILLINS
 Ampicillin, Amoxicillin, Bacampicillin, Pivampicillin, Talampicillin
 Antimicrobial spectrum as penicillin G; plus G-ve bacilli:
 They can enter via porins
 Spectrum: HELPS to clear enterococci (G-ve)
 Acid stable: can be administered PO
 Ineffective against -lactamase producing bacteria
 Need to be combined with -lactamase inhibitors
 Can’t cover P.aeruginosa: has tight/few porins

Therapeutic uses
 Ampicillin: can be given PO & parenterally
 Meningitis: L.monocytogenes; with 3rd gen Cephalosporin
 Pneumonia (G-ve) with gentamycin
 Hepatic encephalopathy: reducing NH3 production
 Especially in azotemic patients, since neomycin is not safe
 Bile (biliary tract infection)

 Amoxicillin:
 Pharyngitis, otitis media, tonsillitis, bronchitis, CAP,

sinusitis
 UTI: cystitis, pyelonephritis
 PUD (H. pylori): triple/dual therapy
 Severe dental abscess with spreading cellulitis
 Anthrax: postexposure inhalational prophylaxis
 IE prophylaxis: 2 g PO 30-60’ before dental procedure
 Lyme disease (off-label)
 Chlamydial
Chemotherapy infection inCompiled
pregnant:
by Birhanu G. off-label 41
 Amoxicillin
 Oral absorption is better than ampicillin: food doesn’t
affect
 Incidence of diarrhea is less than ampicillin
 Less active against shigella
 Bacampicillin, Pivampicillin, Talampicillin: prodrugs of
ampicillin

 ANTIPSEUDUOMONAL PENICILLINS
 Carboxypenicillins: Carbenicillin, Ticarcillin
 Carbenicillin
 Active against p.aeruginosa & indole positive proteus
 Neither penicillinase nor acid resistant: very small R-chain
 Carbenicillin Indanyl Sodium: the only PO
 Indanyl ester of carbenicillin: acid stable (PO)
 After absorption, rapidly converted to carbenicillin by

hydrolysis of the ester linkage
 The active moiety excreted rapidly in the urine, where it

achieves
Chemotherapy effective concentrations:
Compiled by BirhanuUTI
G. by Proteus 43
 Ticarcillin
 2-4 times more potent against pseudomonas
 Ureidopenicillins (newer): Piperacillin, Mezlocillin, Azlocillin
 Spectrum: P. aeruginosa, Enterobacteriaceae (non β-lactamase
producing), Bacteroides, E. faecalis
 Piperacillin-tazobactam: has the broadest antibacterial
spectrum of the penicillins: methicillin-susceptible S. aureus,
H. influenzae, B. fragilis, E. coli, Klebsiella

 -lactamase inhibitors:
 Clavulinic Acid, Sulbactam, Tazobactam, Avibactam
 Inhibits bacterial -lactamases
 Most active against -lactamase produced by: S. aureus,
H.influenza, some enterobacteriaceae, Bacteroid spp.
 Chromosomal -lactamases of Serratia spp, Enterobacter spp,
P. aeruginosa are not inhibited

 Amoxicillin-clavulinic acid combo: augmentin®, Enhancin®
 Available in 4:1 combination.
 250-750mg amoxicillin & 62.5-125mg clavulinic acid
 Use:
 Skin infection: streptococci, staphylococci.
 Acute otitis media: H.infleunza, M.catarrhalis
 Sinusitis, Lower RTI
 Diabetic foot infection: staphylococci, aerobic & anaerobic G-ve

 Ampicillin-Sulbactam combo: Unasym®
 Combination is available 1:0.5
 Same spectrum of augmentin: used in mixed infection
 Piperacillin-tozabactam combo: Zosyn®
 Equivalent or superior to 3rd generation cephalosporin
 Ticarcillin-clavulanic acid combo: Timentin®
 750 mg + 50 mg: in 0.8 g Timentin OR 1.5 g + 100 mg: in 1.6

g OR 3 g + 200 mg: in 3.2 g
 For: Klebsiella, E.coli, S aureus, P.aeruginosa, H.influenzae,

Enterobacter, Citrobacter, serratia marcescens, Bacteroides
fragilis,
Chemotherapy Staphylococus epidermidis
Resistance to Penicillins
 Innate/Natural/: all cells w/c have no peptidoglycan
 Fungi: cell wall is made of chitin
 Mycobacteria: cell wall is mycolic acid/thick waxy layer/
 Mycoplasma: have no cell wall
 Pseudomonas: have no porins for Pen-G
 Chlamydia: obligate intracellular µbe: penicillin can’t enter
 Viruses: have no cell wall
 All human cells: have no cell wall; SAFEST ABX

 Acquired:
 -lactamase production: chromosomal or plasmid mediated
 The gene for -lactamase is present in plasmids: can be
transferred to other bacteria w/c were initially non resistant
 Plasmid mediated/conjugation/; the most dangerous: rapid
 A bacterium can transfer plasmids for many bacteria

 Chromosomal mediated: mutation & selection i.e vertical
 Acquisition of chromosomal material/horizontal/
 Transduction: phages
 Transformation: taking genetic material from env’t or dead
bacteria

 Acquired…
 Alteration of porins: dev’t of tight porins
 Due to mutation of the gene  permeability
 Efflux (active) pump: less common
 Alteration of PBPs (trans peptidases): due to mutation of the
gene that codes for trans peptidases: most common

Drug Interactions
 Aminoglycosides: synergism
 Inactive precipitate is formed if mixed in one container
 Probenecid: inhibits the secretion of penicillins
 Bacteriostatic antibiotics: due to antagonism
 Ampicillin and oral contraceptives:
 Decreased enterohepatic circulation

Adverse effects
 The safest drugs: no monitoring
 Hypersensitivity reaction: pencillioc acid & products of
alkaline hydrolysis act as haptens
 Type-I: IgE mediated /immediate hypersensitivity
 IgE-mediated degranulation of mast cells
 Anaphylactic shock is the most dangerous
 Need of skin test for the suspect penicillin

 Type-II: IgG mediated
 Penicillin metabolites alter RBC membrane proteins →
 IgG mediated RBC destruction: penicillin associated hemolytic

anemia
 Type-III:
 Body produces Ab against penicillin
 Ag-Ab complex mediated complement activation
 Ag-Ab interacts & activates complement system → neutrophil

activation →
 Vasculitis: skin rash, glomerulonephritis, pericarditis, pleuritis,

generalized lymphadenopathy,
Chemotherapy polyarthritis
 Maculopapular rash: Ampicillin, direct toxicity especially in
patients with infectious mononucleosis due to EBV
 Diarrhea: due to PO Ampicillin
 Development of Clostridium difficile 
 Bloody diarrhea due to damage of GIT mucosa (Pseudo
membranous colitis)

 Nephritis: naficillin, methicillin (not in clinical use)
 Neurotoxicity: GABAergic inhibition  seizure
 So, not given intrathecally
 Inhibition of platelet function: Piperacillin, Ticarcillin,
Carbencillin
 Neutropenia
 Cation toxicity: since they are given as a salt of Na+ or K+

CEPHALOSPORINS
 Pharmacodynamics:
 Inhibition of bacterial transpeptidases
 Bactericidal

CLASSIFICATION

1st Generation Cephalosporins
 Relatively narrow spectrum (G+ve bacteria)
Selected 1st generation Cephalosporins;

2nd Generation Cephalosporins
 True Cephalosporins: Cefaclor, Cefamandole, Cefonicid,
Cefuroxime, Cefprozil, Cefpodoxime, Loracarbef & Ceforanide
 High activity against: H.infleunza, N.meningitidis,
N.gonorhoeae
 Cephamycins: Cefoxitin, Cefmetazole, Cefotetan
 Active against selected enterobacteriaceae; most active
against
Chemotherapy B.fragilis (G
-ve anaerobes)
3rd Generation Cephalosporins
 Cefotaxime, Ceftriaxone, Ceftazidime, Cefoperazone, Cefixime,
Ceftizoxime
 Less active than 1st generation against G+ve cocci
 More active against Enterobacteriaceae
 Antipseudomonal activity: Cefoperazone & Ceftazidime

 Ceftriaxone: most potent; t1/2 = 8hrs  BID/QD
 High efficacy in bacterial meningitis, multiresistant typhoid

fever, complicated UTI, Abdominal sepsis, Septicaemias
 Ceftazidime: excellent activity against G-ve: p.aeruginosa
 Penetrate CSF & DOC in p.aeruginosa meningitis; given

parenterally
 Cefoperazone: strong against pseudomonas; high ppb
 Do not penetrate into CSF
 Indicated in severe urinary, respiratory, biliary infection and

septicaemia

4th Gen. Cephalosporins: Cefepime, Cefpirome
 Rapidly cross the outer membrane of G-ve
 More resistant to hydrolysis (chromosomal -lactamase:
produced by Enterobacter) & lactamases that inactivate 3rd
generation
 Active against Enterobacteriaceae, P. aeruginosa, H. influenza
& Neisseria spp

5th Generation: Ceftaroline
 Broad spectrum
 Administered IV as a Prodrug, Ceftaroline fosamil
 Active against MRSA
 Use: complicated skin & skin structure infections & CAP
 The unique structure allows Ceftaroline to bind to PBP2a
found with MRSA and PBP2x found with S.pneumoniae

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

 AEs:
 Allergic reactions
 Antibiotic-associated colitis: super infection
 Bleeding: hypoprothrombinemia (methylthioterazole/MTT
containing group, 3rd generation)
 Cefoperazone, Cefotetan, Cefamandole, Cefmetazole
 Local effects: thrombophlebitis from IV injection

Drug interaction
 Probenecid
 Alcohol: Cephalosporins with MTT have disulfiram like rxn
 Drugs that promote bleeding

Other -lactam Antibiotics
 Carbapenems: Ertapenem, Imipenem, Meropenem, Doripenem
 Imipenem, with Cilastatin: Primaxin
 MOA: inhibit bacterial trans peptidases
 -lactamase resistant
 Imipenem (IV)
 Antimicrobial spectrum: G+ve & G-ve: P. aeruginosa &

anaerobes
 Distributed in CSF; metabolized in renal tubule by

dehydropeptidases which can be inhibited by cilastatin
 Therapeutic use
 Serious hospital acquired infection
 Rx of mixed infections: aerobic & anaerobic
 AEs:
 GIT: NVD in rapid IV infusion
 CNS: Seizure
 Hypersensitivity reaction

 MONOBACTAMS: Aztreonam
 Isolated from Chromobacterium violaceum
 MOA:
 Bind to PBP  inhibit cell wall synthesis
 Antimicrobial spectrum: narrow (G-ve aerobic bacteria: H.

Influenza, N. Meningitides & Pseudomonas)
 -lactamase resistant: except AmpC & extended spectrum β-

lactamazes
 No cross sensitivity with other -lactam
 Used as substitute to aminoglycosides in UT, lower RT, skin &

soft tissue infection
FOSFOMYCIN: bactericidal
 Inhibits the first cytoplasmic step in cell wall biosynthesis
 Covalently binds with UDP-N-acetylglucosamine
enolpyruvyl transferase (MurA);
 Involved in the formation of the peptidoglycan precursor
UDP-N-acetylmuramic acid (UDPMurNAc)

 Fosfomycin uses two mechanisms for cellular entry;
 L – alphaglycerophosphate & hexose-6-phosphate transporter
systems
 Fosfomycin reduces adherence of bacteria to urinary epithelial
cells
 It also suppresses PAF receptors in respiratory epithelial cells
→ reducing adhesion of S.pneumoniae & H.influenzae

 Has oral & parenteral forms
 Dose:
 3g Stat PO (FDA) for uncomplicated UTI, OR
 3g Q10 days for UTI prophylaxis
 The oral formulation is a powder (fosfomycin tromethamine) &
 BA is approximately 40%, with a t1/2 of 5-8 h
 Distribution: low in blood but highly concentrated in urine
 AEs: well tolerated; GI distress, vaginitis, headache, dizziness

CYCLOSERINE
 D-4-amino-3-isoxazolidone
 Broad-spectrum, produced by Streptococcus orchidaceous

 MOA:
 Acts within the cytoplasm to prevent the formation of D-
alanine-D-alanine
 It does this by mimicking the structure of D-alanine &
inhibiting;
 L-alanine racemase: racemizing L-alanine to D-alanine
 D-alanine-D-alanine ligase: linking the two D-alanine units
together
 Spectrum: both G-ve & G+ve
 Against MAC, MTB, Enterococci, S. aureus, S. epidermidis,
Nocardia & Chlamydia
 Salmonella, Shigella, E. coli, Klebsiella, Enterobacter, Serratia,
Citrobacter, Proteus mirabilis, L.monocytogenes, Neisseria
gonorrhoeae, Aerococcus urinae, H.pylori

BACITRACIN
 An antibiotic produced by the Tracy-I strain of Bacillus subtilis
 Bacitracins are a group of polypeptide antibiotics; multiple

components have been demonstrated in the commercial pdts
 The major constituent is bacitracin A; its probable structural

formula is:

✍ BACITRACIN:
 Inhibits the recycling of pyrophosphobactoprenol to the inner

leaflet
 Bactoprenol is a lipid synthesized by three d/t species of

lactobacilli. It is a hydrophobic C55 isoprenoid.
 BPP transports NAM & NAG across the cell membrane during
the synthesis of peptidoglycan, by flipping the repeating
monomer units from the cytoplasm to the periplasm
 Bactoprenol remains in the membrane at all times
 Since it is associated with severe nephrotoxicity, not given

systemically
Chemotherapy
rather used Compiled
topically
by Birhanu G. 81
 Clinical Use:
 Alone or in combination with polymyxin or neomycin: Rx of
mixed skin, wound or mucous membrane infections
 AEs:
 Significant nephrotoxicity: systemic administration
 Skin sensitization: on topical use

Glycopeptides
 Vancomycin, Teicoplanin, Telavancin, Oritavancin, Dalbavancin
 VANCOMYCIN
 A tricyclic glycopeptide produced by Streptococcus orientalis
 MOA:
 Binding to peptidoglycan pentapeptide  Transglycosylase
inhibition  inhibition of elongation of peptidoglycan
(glycosylation)  no cross linking

 Spectrum:
 Against G+ve: MRSA, MRSE & Cl.difficile
 PKs: not absorbed orally; given IV except antibiotic induced
colitis
 Resistance: alteration of the D-alanyl-D-alanine target to D-alanyl-
D-lactate or D-alanyl D-serine, to w/c vancomycin can’t bind
 VRSA: FQs, linezolid, streptogramins; quinupristin/dalfopristin

PROTEIN SYNTHESIS INHIBITORS
 Bactericidal: Aminoglycosides
 Bacteriostatic:
 Aminocyclitols
 Tetracyclines & Amphenicols: broad spectrum
 Macrolides: moderate spectrum
 Lincosamides, Streptogramins: Quinupristin, Dalfopristin;

Oxazolidinones: Linezolid, Tedizolid, Sutezolid; narrow
spectrum
 Mupirocin:
Chemotherapy
G -ve & G+ve
PROTEIN SYNTHESIS
Chemotherapy Simplified schematic ofBirhanu

Compiled by mRNA G. translation 88
Protein synthesis inhibitors
 Substances that stop or slow the growth or proliferation of
cells by blocking the generation of new proteins
 Act at the ribosome level (either the ribosome itself or the
translation factor), taking advantages of the major d/ces b/n
prokaryotic & eukaryotic ribosome structures
 Toxins: ricin also function via protein synthesis inhibition
 Ricin acts at the eukaryotic 60S

Mechanism
 Work at d/t stages of prokaryotic mRNA translation into
proteins, like;
 Initiation
 Elongation: aminoacyl tRNA entry, proofreading, peptidyl
transfer & ribosomal translocation &
 Termination

Aminoglycosides
 Streptomycin, Gentamicin, Kanamycin, Amikacin,

Tobramycin, Sisomycin, Neomycin, Paramomycin,…
 General properties:
 Composed of two or more amino sugars connected by a

glycoside linkage
 At physiological pH, they are polycations
 Are water soluble, stable in solution
 Interact chemically with -lactam antibiotics

MOA:
 Transport of aminoglycosides through outer membrane
by passive diffusion via porins; then they are actively
transported across the cell membrane
 Low extracellular pH & anaerobic conditions inhibit
transport by reducing the gradient

MOA…
 The drug binds to 30s rRNA irreversibly 
 Interference with the initiation complex of peptide
formation;
 Misreading of mRNA, w/c causes incorporation of
incorrect amino acids into the peptide & results in a non
functional or toxic protein;
 Breakup
Chemotherapy of polysomes Compiled
into bynon
Birhanufunctional
G. monosomes 93
Effects of aminoglycosides on protein synthesis

 Antimicrobial spectrum
 Aerobic, G-ve: Pseudomonas, Klebsiella, E.coli, others
 PKs:
 Absorption: very poor from intact GIT: IM & IV
 Distribution limited to ECF;
 Bind to renal tissue  nephrotoxicity
 Penetrate to perilymph & endolymph of inner ear  ototoxicity
 Eliminated primarily by kidney

Extended-interval Therapy: Once Daily Dosing
 2-3 equally divided doses (traditional)
 Once daily dosing may be preferred in certain situations, since

they have PAE & conc. dependent killing
 Once daily dose;
 Efficacious as traditional multiple dose method
 Lower but not eliminate: nephrotoxicity & ototoxicity
 Simple, less time consuming & cost effective
 Does not worsen neuromuscular function
 Exceptions: in pts with Enterococcal endocarditis; further

study in pediatrics
Therapeutic uses
 Against G-ve enteric bacteria in bacterimia & sepsis; TB
 In combination with -lactam antibiotics to ↑ coverage
(G+ve) & synergism

Aminoglycosides…

Adverse Effects
 Ototoxicity
 Cochlear toxicity: tinnitus, high frequency hearing loss
 Neomycin, Kanamycin, Amikacin
 Vestibular toxicity: vertigo, ataxia, loss of balance
 Streptomycin & Gentamicine
 Nephrotoxicity: injure cells of proximal renal tubule
 Risk factors: older pts, renal disease, large doses,

frequent dosing interval, concomitant drugs: Vancomycin,
Frusemide, Clindamycin, Piperacillin, Cephalothin, Foscarnet
 Neuromuscular blockade: rarely
 Weakness of respiratory musculature
 Risk is amplified in pts with tubocurarine, succinylcholine
Aminoglycosides prevent internalization of Ca2+ in
presynaptic axon  decrease release of acetylcholine
 Skin rash

Aminocyclitols: Spectinomycin
 Structurally related to aminoglycosides
 It lacks amino sugars & glycosidic bonds
 MOA: binds with 30s sub unit of rRNA
 Active in vitro against many G+ve & G-ve
 Used almost solely as an alternative treatment for drug-

resistant gonorrhea or gonorrhea in penicillin-allergic pts
 The majority of gonococcal isolates are inhibited by 6

mcg/mL of Spectinomycin

 Strains of gonococci may be resistant to spectinomycin, but
there is no cross-resistance with other drugs used in
gonorrhea
 Spectinomycin is rapidly absorbed after IM injection
 A single dose of 40 mg/kg up to a maximum of 2 g is given
 AEs:
 Pain at the injection site &, occasionally, fever & nausea
 Rarely nephrotoxicity & anemia

Tetracyclines
 Oxytetracycline, Tetracycline, Demeclocycline,
Doxycycline, Minocycline
 Antimicrobial spectrum: broad
 G+ve & G-ve aerobic & anaerobic bacteria
 Spirochetes, Mycoplasma, Rickettsia, Chlamydia &

some protozoa
 Glycylcyclines (Tigecycline):
 Related to TTCs in their MOA as well as spectrum

 MOA:
 Enter microorganism by passive & active transport
Act by binding to 30s ribosome reversibly  block the binding
of aminoacyl t-RNA to A site on the mRNA-ribosome
complex/Elongation (tRNA delivery)
TTCs prevent stable binding of the EF-Tu-tRNA-GTP ternary
complex to the ribosome & inhibit accommodation of A-tRNAs
upon EF-Tu-dependent GTP hydrolysis

Pharmacokinetics

Adverse Effects
 GI irritation: oral therapy  burning, cramps & NVD
 Super infection
 Effect on bone & teeth;
 Yellow or brown discoloration of teeth
 Hypoplasia of enamel
 Suppression of long bone growth in infants
Doxycycline bind less with Ca2+  less frequent dental

changes
 Liver toxicity
 Kidney toxicity: in kidney impairment except doxycycline
 Photosensitization: especially demeclocycline induce
sensitivity to sunlight or ultraviolet light, particularly in
fair-skinned persons
 Vestibular reactions: vertigo, nausea & vomiting
 >100mg doses of doxycycline; 200-400mg of Minocycline

Macrolides
 Macro cyclic lactone ring to which deoxysugar is attached
 Erythromycin, Clarithromycin, Azithromycin, Telithromycin

Fidaxomicin
 MOA:
 Binding to 50s rRNA → inhibiting peptidyl transfer,

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

Erythromycin
 PKs:
 Decreased by stomach acid  enteric coating
 Stearate & esters: fairly acid resistant  better absorbed
 Estolate salt best absorbed orally
 Administration: topical, PO, IM, IV
 Excretion: primarily bile & faces

Clarithromycin
 Similar with erythromycin with respect to antibacterial
activity & drug interaction except:
 More active against M. avium complex
 Also against M. leprae, H.pylori, Toxoplasma gondii

Azithromycin
 Semisynthetic derivative of Erythromycin
 Has better oral absorption
 Longer t1/2
 Fewer GI side effects
 Expensive

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

Therapeutic uses

 Fidaxomicin
 Inhibits bacterial protein synthesis by binding to the
sigma subunit of RNA polymerase
 A narrow-spectrum, macrocyclic antibiotic
 Active against G+ve aerobes & anaerobes
 Lacks activity against G-ve bacteria

 Absorption: negligible after PO, but high fecal conc.
 FDA approved for the Rx of C.difficile infection in adults
 As effective as oral vancomycin & may be associated with
lower rates of relapse
 Dosage: 200 mg tablet PO BID for 10 days

 AEs:
 GI effects: ANVD
 Liver toxicity: estolate salts cause acute cholestatic hepatitis
due to hypersensitivity reaction
 Drug interaction
 Erythromycin metabolized to form inactive complexes with
CYP450  ↑level of Terfenadine or Astemizole
 ↑BA of digoxin by interfering with its inactivation in gut flora

Lincosamides: Clindamycin
 MOA: inhibition of protein synthesis via binding to 50s rRNA
 Usually bacteriostatic
 Therapeutic use:
 Infections that involve B.fragilis & penicillin resistant

anaerobic bacteria
 With aminoglycosides/ Cephalosporins to treat penetrating

wounds of the abdomen
 Infections of female genital tract; pelvic abscess
 Aspiration pneumonia (anaerobes above the diaphragm)

 Recommended instead of erythromycin for prophylaxis of
endocarditis
 Clindamycin + Primaquine in TXt of moderate or severe PCP

alternative to Cotrimoxazole
 Clindamycin + Pyrimethamine for AIDS related toxoplasmosis
 AEs:
 Nausea
 Diarrhea
 Skin rashes
 Clindamycin associated colitis

Amphenicoles: Chloramphenicol (CAPH), MOA:
 Binds to specific nucleotides within the 50S ribosome, w/c
inhibits peptidyl transferase activity & peptide bonding
 Inhibit both bacterial & mitochondrial ribosomes (but not
cytoplasmic)
 Suppresses synthesis of important enzymes: cytochromes
a + a3 & b  suppresses mitochondrial respiration 
oxidative
Chemotherapy
stress (mitochondrial toxicity)
 MOA:…
 Inhibition of mitochondrial function is thought to be the
mechanism underlying dose-dependent reversible bone
marrow suppression
 Reactive metabolites of CAPH may be mutagenic  dev’t of
aplastic anemia

 Drug class: broad spectrum antibiotic & bacteriostatic
 Indications:
 Rarely used in US b/c of aplastic anemia
 A “treatment of last choice” for MDR: vancomycin-

resistant Enterococcus
 Used in developing countries: inexpensive & effective
 Broad spectrum: N.meningitidis, C.perfringens,

Bacteroides, H.influenzae (bactericidal effect in this
sensitive organism), Salmonella typhi & Rickettsia

 AEs:
 GI disturbance: NVD
 Bone marrow suppression: dose-dependent & reversible
 Aplastic anemia: idiosyncratic, rare, lethal
 Gray baby syndrome: ed conjugation & excretion
 Vomiting, limb body tone, gray skin color
 Cyanosis: blue lips & skin
 Hypotension, cardiovascular collapse
 Superinfection
 Drug interactions:
 CAPH inhibits some of the hepatic mixed-function
oxidases
 Blocks the metabolism of drugs: warfarin & phenytoin
 Elevating their conc. & potentiating their effects

Summary

NUCLEIC ACID SYNTHESIS INHIBITORS
 Indirect inhibitors: antimetabolites
 Sulfonamides, trimethoprim, pyrimethamine
 Activity & clinical uses:
 Sulfonamides alone limited in use b/c of multiple resistance
 Sulfasalazine is a prodrug used in ulcerative colitis & RA
 Ag sulfadiazine used in burns

 PKs:
 Sulfonamides are hepatically acetylated (conjugation)
 Renally excreted metabolites cause crystalluria (older
drugs)
 High protein binding:
 Drug interaction
 Kernicterus in neonates: avoid in third trimester

Therapeutic uses
UTI: Sulfisoxazole: high solubility, achieve effective

concentration & less expensive
 Bacteria;
 G+ve: Nocardia, Listeria (back up), community acquired

MRSA, Strep.
 G-ve: E.coli, Salmonella, Shigella, H.influenzae
 Fungus: PCP (back-up drugs: pentamidine & atovaquone)
 Protozoa: T.gondii: sulfadiazine + pyrimethamine

Therapeutic uses….
 Trachoma: Sulfacetamide
 Sulphadiazine/Sulfadoxine + Pyrimethamine OR
(FANSIDAR®=Sulfadoxine + Pyrimethamine): to treat
toxoplasmosis
 Ulcerative colitis: sulfasalazine

 AEs:
 Hypersensitivity reactions: Sulphur content
 Mild: rash, fever, photosensitivity
 Severe: SJS; lesion of skin & mucus membrane, fever,

malaise & toxemia
 Hematologic effect
 Hemolytic anemia: G6PDH deficiency
 Agranulocytosis: leucopenia & thrombocytopenia

 Kernicterus: displacing bilirubin from plasma protein 
crosses the BBB; avoid in 3rd trimester & < 2 months age
 Renal damage: they form crystal urea
 Trimethoprim or pyrimethamine:
 Bone marrow suppression: leukopenia

COTRIMOXAZOLE: TMP + SMX
 Trimethoprim & Sulphamethoxazole: to  resistance
 Shows synergism:  Cidal
 Selected because of similarity in pharmacokinetics
 MOA: inhibition of two sequential steps

 Therapeutic Uses
 UTI: caused by E.coli, Klebsiella, Enterobacter, P.mirabilis
 PCP: Txt of choice
 Drug of choice for shigellosis
 Other infections;
 Acute otitis media & chronic bronchitis: H. infleunza,

S.pneumonia
 Urethritis & pharyngitis due to penicillinase producing N.

gonorrhoe
 Alternative to CAPH for typhoid fever

 PKs:
 TMP concentrates in the relatively acidic milieu of prostate &

vaginal fluids  effective
 TMP (1part) & SMX (5part)
 AEs:
 Dermatologic
 GI: NV & stomatitis
 Hematologic: megaloblastic anemia; leukopenia;

thrombocytopenia
 HIV pts with PCP: drug induced fever, rashes, diarrhea

Direct Inhibitors of Nucleic Acid Synthesis
 Quinolones, FQs & Rifamycins
 Naldixic acid, Ciprofloxacin, Levofloxacin, "-floxacins”
 MOA:
 Block DNA replication by inhibit the ligase domains of;
 Topoisomerase II (DNA gyrase): in G-ve bacteria  relaxation

of super coiled DNA  DNA strand breakage &
 Topoisomerase IV: G+ve bacteria  impacts chromosomal

stabilization during cell division, thus interfering with the
separation of newly replicated DNA
Antimicrobial Spectrum
 Norfloxacin is the least active of FQs against G+ve & G-ve
 Ciprofloxacin, Enoxacin, Lemofloxacin, Ofloxacin, Pefloxacin,

Levo-, Moxi-, Gemi- & Gati-floxacin:
 Excellent against G-ve: pseudomonas, enterobacteriaceae,

haemophilus spp., Neisseria spp., Campylobacter
 Moderate to good against G+ve: methicillin susceptible strains

of staph; streptococci & enterococci tend to be less
susceptible
 FQs also have activity against Mycoplasma & Chlamdiae;

Legionella spp. & Mycobacteria
 PKs:
 Absorption: well absorbed, food does not reduce absorption
 Distribution: Vd is high
 Concentration in prostate, kidney, bile, lung, neutrophils/

macrophages exceed serum concentration
 Elimination:
 Most FQs excreted renally: dosage adjustments are needed in

renal dysfunction
 Moxifloxacin is primarily by liver: no need of dose adjustment

in renal failure

 With sucralfate, di or trivalent cations: cation-quinolone
complex
 Inhibit CYP1A2: increase serum methylxanthine
 Can elevate levels of warfarin [PT time monitored]

 Therapeutic uses
 UTI: complicated & uncomplicated, prostatitis
 GIT infection:
 Diarrhea caused by shigella, salmonella, toxigenic E.coli,
campylobacter
 Peritonitis
 STIs: N.gonorrhea, C.trachomatis, H.ducreyi

Therapeutic uses…
 RTIs:
 RTI: H.influenzae, M.catarrhalis & Enteric G-ve
 Atypical pneumonia: M.pneumoniae, C.pneumoniae,
L.pneumoniae
 Exacerbation of chronic bronchitis
 Skin & soft tissue infection
 Others: MTB, for nontubercular mycobacteria, typhoid fever

 AEs:
 GIT: ANV & abdominal discomfort
 CNS: headache, dizziness, insomnia
 Cartilage deterioration in immature animals:
 Not recommended in child 18yrs; & lactating & pregnant
woman

✍ RIFAMYCINS: Rifampin, Rifapentine, Rifabutin, Rifaximin
 Rifaximin:
 A derivative of rifampin in the rifamycin antibiotics
 Inhibits transcription by binding to the β-subunit of DNA-
dependent RNA polymerase
 Active against G+ve & G-ve aerobes & anaerobes
 Absorption: <0.5% after PO, but high fecal conc.

 Indication: travelers’ diarrhea (E.Coli), hepatic encephalopathy,
irritable bowel syndrome with diarrhea & occasionally as an
adjunct in recurrent/refractory C.difficile colitis in adults
 Doses: 200-550 mg PO BID-TID depending on the indication
 Unlike other rifamycins, rifaximin is not associated with
CYP450-mediated drug interactions due to its limited
absorption
 Refer anti-TB drugs: Rifampin, Rifapentine, Rifabutin

☞ Miscellaneous antimicrobials: Metronidazole, Tinidazole,
Mupirocin, Polymyxins, Daptomycin
 Polymyxins: polymyxin B & polymyxin E (colistin)
 A group of basic peptides active against G-ve bacteria
 Act as cationic detergents;
 They attach to & disrupt bacterial cell membranes
 They also bind & inactivate endotoxin
 G+ve: Proteus sp. & Neisseria sp. are resistant
 Used topically; systemic administration → nephrotoxicity

 Ointments containing polymyxin B, 5000 units/g, in mixtures
with bacitracin or neomycin (or both) are commonly applied to
infected superficial skin lesions
 Emergence of strains of Acinetobacter baumannii,
P.aeruginosa & Enterobacteriaceae that are resistant to all
other agents has renewed interest in polymyxins as parenteral
agents for salvage therapy of infections caused by these
organisms
 Metronidazole,
Chemotherapy Tinidazole: Refer
Compiled anti-protozoal
by Birhanu G. drugs 163
Daptomycin
 A cyclic lipopeptide comprising 13 amino acids with a

water-soluble hydrophilic core & a lipophilic tail
 Fermentation product of Streptomyces roseosporus
Structure of Daptomycin
 MOA: not fully understood
 Binds to the cell membrane via Ca2+-dependent insertion
of its lipid tail → depolarization of the cell membrane with
K+ efflux & rapid cell death
 Spectrum: similar to vancomycin + VRSA & VRE
 In vitro: more rapid bactericidal activity than vancomycin

☞ PKs:
 ROA: IV only, off label: IP
 Distribution:
 Small Vd (highly & reversibly bound to plasma proteins)
 t1/2: 8-9 hrs
 Excretion: renal

 Doses:
 4 mg/kg/dose for Rx of skin & soft tissue infections
 6 mg/kg/dose for Rx of bacteremia & endocarditis
 Once daily in patients with normal renal function & every
other day in pts with CrCl of <30 mL/min
 8-10 mg/kg/dose (safe & well tolerated) for serious
infections

 AEs:
 Myopathy; monitor creatine phosphokinase levels weekly
 Allergic pneumonitis in prolonged therapy (>2 weeks)
 Pulmonary surfactant antagonizes daptomycin: should
not be used to treat pneumonia
 Pregnancy category B

 Mupirocin (pseudomonic acid)
 A natural s/ce produced by Pseudomonas fluorescens
 Mupirocin inhibits staphylococcal isoleucyl tRNA synthetase
 Rapidly inactivated after absorption: undetectable in blood
 Available as an ointment: topical application
 Active against G+ve cocci: methicillin-susceptible-SA & MRSA
 Indicated for topical Rx of minor skin infections: impetigo

 Topical application over large open areas (pressure ulcers
or surgical wounds) → emergence of mupirocin-resistant
strains;
 Not recommended

☞ Urinary Antiseptics: Nitrofurantoin, Methenamine
Mandelate & Methenamine Hippurate
 Nitrofurantoin:
 Activity: bactericidal
 Spectrum: active against G+ve & G-ve bacteria;
 Escherichia.coli, Staphylococcus saprophyticus, Coagulase
negative staphylococci, S.aureus, Streptococcus agalactiae,
 Enterococcus faecalis, Citrobacter, Bacillus subtilis

Pharmacology of Renal System 171
 MOA: Nitrofurantoin is reduced by bacterial flavoproteins
(nitrofuran reductase) to reactive intermediates w/c inactivate
or alter bacterial ribosomal proteins, DNA, respiration,
pyruvate metabolism & other macromolecules
 Commonly used in pregnancy to treat UTIs (category B)
 Poor tissue penetration & low blood levels (rather

concentrated in urine)
 Not recommended for the Rx of pyelonephritis, prostatitis &

intra-abdominal abscess
Pharmacology of Renal System 172

Methenamine Mandelate & Methenamine Hippurate
 Methenamine mandelate is the salt of mandelic acid &
Methenamine & possesses properties of both of these urinary
antiseptics
 Methenamine hippurate is the salt of hippuric acid &

methenamine
 Below pH 5.5, methenamine releases formaldehyde, w/c is

antibacterial
 Oral mandelic acid or hippuric acid: absorbed & excreted

unchanged in the urine
 Bactericidal for some G-ve bacteria when urine pH is <5.5

 Acidifying agents (ascorbic acid, 4-12 g/d) may be given
to lower urinary pH below 5.5
 Sulfonamides shouldn’t be given at the same time b/c
they may form an insoluble compound with the
formaldehyde released by methenamine
 Persons taking methenamine mandelate may exhibit
falsely elevated tests for catecholamine metabolites

Summary of Resistance

Antimycobacterial Agents

Drugs For the Treatment of Mycobacterial infection
 Mycobacterium infection continues to be difficult to treat;
 Slow & rapid growing microbe
 Can also be dormant; resistant to many drugs
 Cell wall: Greek mycos; waxy appearance (lipid rich)
 Efflux pumps: the cell membrane is rich in ABC permeases
 Location in host;
 Needs prolonged treatment
 Drug toxicity & poor patient compliance
 High risk of emergency of resistant bacteria

 The objective of therapy is: to eliminate symptoms & prevent
relapse
 So, must kill actively dividing & resting mycobacteria
 Since the response to chemotherapy is slow: Rx is prolonged
 Combination of drugs: to prevent the emergence of resistance
TB resistance can be:
 Mono drug resistance
 Multi drug resistance (MDR-TB)
 Extensively drug resistance (XDR-TB)
 Total drug resistance – TDR-TB: India, Iran, Italy

ANTIMYCOBACTERIAL DRUGS
☞ Superior efficacy & acceptable toxicity;
 Rifamycins: Rifampin (600mg/d), Rifapentine, Rifabutin
 Pyrazinamide: 25 mg/kg/d
 Isoniazid: 300 mg/day
 Ethambutol: 15-25 mg/kg/d
 Dosage: adult dose in normal renal function

 Aminoglycosides: Streptomycin, Amikacin, Kanamycin
 Bedaquiline
 Bicyclic Nitroimidazoles: Delaminid, Pretomanid
 Capreomycin
 Clofazimine: for leprosy & XDR (empiric therapy)
 Fluoroquinolones: levofloxacin, moxifloxacin

 Ethionamide
 Para-aminosalicylic Acid: PAS
 Cycloserine
 β-lactam antibiotics for the treatment of TB
 Macrolides
 Dapsone: for leprosy
 Oxazolidinones: Linezolid, Tedizolid, Sutezolid

ISONIAZID (INH/Isonicotinic hydrazide)-H
 H enters bacilli by passive diffusion
 H is a prodrug activated by a mycobacterial catalase–
peroxidase (KatG)
 KatG catalyzes the production of an isonicotinoyl radical
from H that subsequently interacts with mycobacterial
NAD & NAPD to produce a dozen adducts: nicotinoyl-NAD
isomer, nicotinoyl-NADP isomer

 Nicotinoyl-NAD isomer, inhibits the activities of enoyl acyl
carrier protein reductase (InhA) & β-ketoacyl-ACP
synthase (KasA) → inhibits synthesis of mycolic acid →
cell death
 Nicotinoyl-NADP isomer, potently inhibits mycobacterial
DHFR, thereby interfering with nucleic acid synthesis

 Other products of KatG activation of H:
 Superoxide, H2O2, alkyl hydroperoxides & the NO radical
 Contribute to the mycobactericidal effects of H
 M.TB especially sensitive to damage from these radicals
b/c the bacilli have a defect in the central regulator of the
oxidative stress response: oxyR

☞ Backup defense against radicals is provided by alkyl
hydroperoxide reductase (encoded by ahpC), w/c
detoxifies organic peroxides
☞ Increased expression of ahpC reduces H effectiveness

Metabolism & activation of Isoniazid

 PKs:
 Absorption: well after PO or IM
 Distributed widely: [CSF] = [plasma]
 Increased in meningeal inflammation
 Metabolism: acetylation (genetically regulated) & hydrolysis
 Fast acetylators (t½ =90’): hepatotoxicity
 Slow acetylators (t½ =3-4 hrs): peripheral neuropathy
 Acetylation status doesn’t affect the outcome
 Excretion: renally as metabolites & parent drug (in slow

acetylators)
 Therapeutic uses:
 The core drug in all TB regimens
 Alone is used to prevent TB: latent TB infection

 AEs:
 Allergic reactions: fever, skin rashes
 Direct toxicities:
 Drug induced hepatitis: the metabolite; acetylhydrazine
 High risk age, rifampin, alcohol
 Peripheral neuropathy:
 Due to relative vit-B6 deficiency: promotes excretion
 Likely to occur in slow acetylators & pts with predisposing

factor: malnutrition, alcoholism, diabetes, AIDS & uremia
✍ Reversed by administration of vitamin B6
Convulsion, optic neuritis,

 Chemotherapy psychosis → reversed by vit-B6 191
Compiled by Birhanu G.
Drug interaction
 H is a potent inhibitor of CYP2C19 & CYP3A & a weak
inhibitor of CYP2D6
 H induces CYP2E1

Resistance
 Resistance follows chromosomal mutations:
 Mutation or deletion of KatG (producing mutants
incapable of prodrug activation)
 Varying mutations of the acyl carrier proteins or
 Overexpression of the target enzyme InhA
 Cross-resistance may occur b/n H & ethionamide

RIFAMYCINS: Rifampin, Rifapentine & Rifabutin
 Rifampicin/Rifampin: R
 MOA: binds to the β subunit of DNA-dependent RNA
polymerase (rpoB) to form a stable drug-enzyme complex 
suppresses chain formation in RNA synthesis  cidal
 PKs:
 Well absorbed, distributed throughout the body
 Excreted mainly through liver into bile

Therapeutic uses
 Mycobacterial infection:
 TB: cidal for intra & extracellular bacteria
 In TB prevention as an alternative to H
 Leprosy
 Atypical mycobacteria
 Prophylaxis in contacts of children with H.influenzae type B
disease (meningitis)
Therapeutic uses…
 In combination with other agents;
 To eradicate staphylococcal carriage
 For Rx of serious staphylococcal infections;
 Osteomyelitis
 Prosthetic valve endocarditis

 AEs:
 Hepatitis
 Hypersensitivity reactions
 Fever, flushing, pruritus
 Thrombocytopenia
 Interstitial nephritis
 Harmless orange color appearing in urine, saliva, tears,

sweat & soft contact lenses
 GI upset

Ethambutol: E
 MOA:
 Inhibits mycobacterial arabinosyl transferase-III, encoded by
the emb AB gene
 Arabinosyl transferases are involved in the polymerization
reaction of arabinoglycan (arabinogalactan biosynthesis), an
essential component of the mycobacterial cell wall
  bacteriostatic
 Therapeutic use: TB
 AEs:
 Retrobulbar neuritis (optic neuritis)
 Loss of visual acuity & red-green color blindness
 GI intolerance
 Hyperuricemia due to deceased uric acid excretion

Pyrazinamide: Z
 Synthetic pyrazine analogue of nicotinamide
 Aka pyrazinoic acid amide, pyrazine carboxylamide &
pyrazinecarboxamide
 Converted to pyrazinoic acid: active form of Z
 Largely bacteriostatic
 But can be cidal on actively replicating mycobacteria

 Pyrazinamide is activated by acidic conditions: 5-6 pH
 Proposed MCZs:
 Z passively diffuses into mycobacterial cells
 M.TB pyrazinamidase deaminates Z to pyrazinoic acid

(POA-)
 POA- passively diffused to the extracellular acidic milieu
 POA- is protonated to the uncharged form; POAH
 POAH (lipid-soluble) reenters the bacillus & accumulates

due to a deficient efflux pump

 Acidification of the intracellular milieu is believed to
inhibit enzyme function & collapse the transmembrane
proton motive force, thereby killing the bacteria
 Inhibitors of energy metabolism or reduced energy
production states lead to enhanced Z effect

 Targets of Z:
 Ribosomal protein S1 in the trans-translation process, so
that toxic proteins due to stress accumulate & kill the
bacteria
 An aspartate decarboxylase involved in making precursors
needed for pantothenate & CoA biosynthesis in persistent
M. tuberculosis

 Therapeutic use: for RX of TB only
 Sterilizing agent in intensive phase of therapy
 Allows total duration of therapy to be shortened to 6 months
 M.bovis & M.leprae are innately resistant to Pyrazinamide
 AEs:
 GI intolerance
 Joint pains (arthralgia)
 Most hepatotoxic agent
 Hyperuricemia: inhibits excretion of urate, which may cause

acute episodes of gout
Mechanisms of resistance of Mycobacteria

ANTI-TB DRUGS
 Available in FDC in Ethiopia:
 ERHZ: 275/150/75/400 mg, RHZ: 150/75/400 mg
 RH: 150/75 mg, EH: 400/150 mg
 Available as loose form:
 Rifampicin 600mg
 Ethambutol 400mg
 Isoniazid 300mg
 Streptomycin sulphate vials 1gm

PHASES OF CHEMOTHERAPY
 There are two phases:
1. Intensive (initial) phase(IP)
 Consists of 4 or more drugs
 Duration: 8 wks for new cases & 12 wks for re-treatment
 The drugs must be swallowed daily under DOT
 Rapid killing of actively growing & semi dormant bacilli
 It renders the patient non infectious ( 2wks)
 Protects against the development of resistance

2. Continuation phase
 Immediately follows the intensive phase
 Consists of 2 or 3 drugs
 Duration is 4 – 6 months
 Except for re-treatment, drugs must be collected every month
 Eliminates bacilli that are still multiplying
 Reduces failures and relapses

1. New Patients
 New patients presumed or known to have drug-susceptible

TB, pulmonary TB: 2HRZE/4HR
 Alternatives:
 2HRZE/4(HR)3: a daily IP followed by thrice weekly

continuation phase, provided that each dose is DOT OR
 2(HRZE)3/4(HR)3: thrice weekly dosing throughout therapy,

provided that every dose is directly observed and the patient
is NOT living with HIV or living in an HIV-prevalent setting
 Settings with high levels of H resistance in new patients:

2HRZE/4HRE
2. Previously Treated Patients
 Specimens for culture & drug susceptibility testing (DST)
should be obtained from all previously treated TB patients at
or before the start of treatment
 DST should be performed for at least for R & H
 Recommendation: 2HRZE(S)/1HRZE/5HRE

Special population
 Co-management of HIV & active TB disease
 It is recommended that TB patients who are living with

HIV should receive at least the same duration of TB
treatment as HIV negative TB patients
 TB Rx should be started first, followed by ART as soon as

possible & within the first 8 wks of starting TB Rx
 The recommended first-line ART regimens for TB patients

are those that contain efavirenz (EFV)

 Pregnancy
 With the exception of streptomycin, the 1st line anti-TB drugs
are safe for use in pregnancy: streptomycin is ototoxic to the
fetus & should not be used during pregnancy
 TB and Leprosy
 R will be common to both regimens and it must be given in
the doses required for TB

 Treatment of patients with renal failure
 Avoid streptomycin & Ethambutol
 Give 2RHZ/4RH
 Treatment of patients known liver disease
 Do not give Z b/c this is the most hepatotoxic anti-TB drug
 Recommended regimens: 2SERH/6EH or 2SEH/10EH

 Treatment of Extrapulmonary TB
 Of the EPTB, lymphatic, pleural & bone or joint disease are
most common, while pericardial, meningeal & disseminated
(miliary) forms are more likely to result in a fatal outcome
 TB meningitis: 9-12 months of treatment
 TB of bones or joints: 9 months of treatment

Bicyclic Nitroimidazoles
 Delaminid, Pretomanid: pro-drugs
 Being used in the treatment of X-DR & MDR-TB
 Are in clinical trials for use in drug-susceptible TB
 Delamanid: dihydro-nitroimidazooxazole derivative
 Activated by the enzyme deazaflavin dependent

nitroreductase (Rv3547)
 Forms a reactive intermediate metabolite that inhibits

mycolic acid production

 Pretomanid
 Activated by the bacteria via a nitroreduction step that
requires, a specific G6PDX, FGD1 & the reduced deazaflavin
cofactor F420 encoded by Rv3547
 Has two mechanisms of action;
 1st, under aerobic conditions it inhibits M.TB mycolic acid &
protein synthesis at the step b/n hydroxymycolate &
ketomycolate
 2nd, in NRPB, it generates reactive nitrogen species such
as NO via its des-nitro metabolite, w/c then augment the
kill of intracellular NRPB by the innate immune system
 In addition, direct poisoning of the respiratory complex in
the NRPB leads to ATP depletion

Bedaquiline
 A cationic amphiphilic drug, which may account for its
high accumulation in tissues
 Acts by targeting subunit c of the ATP synthase of M.TB
→ inhibition of the proton pump activity of the ATP
synthase
 Targets bacillary energy metabolism

Ethionamide
 A congener of thioisonicotinamide
☞ Mycobacterial EthaA, NADPH-specific, FAD-containing
monooxygenase, converts ethionamide to a sulfoxide &
then to 2-ethyl-4-aminopyridine
☞ A closely related & transient intermediate is the active
antibiotic

 Ethionamide inhibits mycobacterial growth by inhibiting
the activity of the inhA gene product, the enoyl-ACP
reductase of fatty acid synthase II
 As INH: inhibition of mycolic acid biosynthesis &
consequent impairment of cell wall synthesis

Para-aminosalicylic Acid: PAS
 A structural analogue of PABA, the substrate of

dihydropteroate synthase (folP1/P2)
 PAS is a competitive inhibitor folP1, but in vitro the

inhibitory activity against folP1 is very poor
 However, mutation of the thymidylate synthase gene

(thyA) results in resistance to PAS, but only 37%
 Unidentified actions of PAS likely play more important

roles in its anti-TB effects

Capreomycin
 A cyclic peptide antibiotic obtained from Streptomyces
capreolus
 Consists of 4 active components: capreomycins IA, IB,
IIA & IIB
 Clinically used agent contains primarily IA & IB
 MOA: protein synthesis inhibition

 Show cross-resistance with kanamycin & neomycin
 Shouldn’t be administered with other drugs that damage
cranial nerve VIII
 Given for MDR-TB
 Recommended daily dose is 1 g (no more than 20 mg/kg)
per day for 60-120 days, followed by 1 g two or three
times a week

Drugs active against atypical Mycobacterium
 M.avium: cause disseminated TB in late stages of AIDS
 Azithromycin or Clarithromycin + Ethambutol: well
tolerated regimen
 Rifabutin & Clarithromycin: prevent M.avium complex
bacterimia in AIDS patients

ANTILEPROTIC DRUGS
 Leprosy (Hansen’s disease) caused by M.leprae
 There are two types of leprosy;
1. Lepromatous Leprosy
 Severe, rapidly progress
 Marked ulceration
 Tissue destruction & nerve damage
 Rx lasts at least 2yrs: Dapsone + R + Clofazimine

2. Tuberculoid Leprosy
 Mild infection
 Slow in progress & loss of sensation
 Rx lasts 6 months: Dapsone + Rifampicin

DAPSONE/SULFONES
 Dapsone: DDS, diamino-diphenylsulfone
 The primary drug: effective, less toxic & inexpensive
 MOA: inhibition of folate synthesis
 PKs: given orally, well absorbed, widely distributed
 Enterohepatic recycling
 Excreted as metabolites renally
 AEs:
 Rashes, GI disturbance
 Show erythema nodusom: inflammatory reaction

CLOFAZIMINE: weakly bactericidal
 Possible MOA include:
 Membrane disruption
 Inhibition of mycobacterial phospholipase A2
 Inhibition of microbial K+ transport
 Generation of hydrogen peroxide
 Interference with the bacterial electron transport chain
 It has also anti-inflammatory effects via inhibition of

macrophages, T cells, neutrophils & complement

 Used together with or as an alternative to Dapsone in sulfone
resistant leprosy or when patients are intolerant to sulfones
 A common dosage is 100 mg/d orally
 AEs:
 Red brown to nearly black discoloration of the skin &
conjunctiva
 GI intolerance (occasionally)

RX of mycobacterial infections other than TB, leprosy & MAC

ANTIFUNGAL AGENTS
Fig. Common pathogenic

Chemotherapy Compiledorganisms
by Birhanu G. of Kingdom Fungi 232
Category of fungal infections
 Fungal infection termed as mycosis
 Systemic infections: affecting deeper tissue & organ
 Meningitis, pneumonia, endocarditis
 Causatives: Aspergillus, Candida albicans, Cryptococcus
neoformans, Blastomyces dermatitidis, Histoplasma
capsulatum, Coccidioises immitis
Chemotherapy Compiled by Birhanu Geta 233

 Superficial infection: caused by dermatophytes & yeasts
 Dermatomycosis: affecting skin, hair, scalp, nail
 Caused by dermatophytes: Trichophyton, Microsporum &
Epidermophyton; causes various types of ring worms & tinea
 Tinea capitis: scalp; Tinea pedis: foot
 Tinea cruris: groin, thigh; Tinea barbae: beard
 Tinea corporis: body

 Yeasts: C.albicans, Pityrosporum orbiculare (Malassezia furfur)
 Superficial candidiasis: mucous membrane of mouth (oral
thrush), esophagus, vagina or skin
 P.orbiculare: (Tinea versicolor) Pityriasis versicolor, dandruff

Difficulties associated with Rx of fungal infections
 Infections increasingly common
 High similarity to animal cells;
 Resistant to antibacterial agents
 Presence of cell wall
 Slow growth rate
 Infections often occur in poorly vascularized tissues

CLASSES OF ANTIFUNGAL DRUGS
 Polyenes: Amphotericin B, Nystatin
 Azoles: Ketoconazole, Fluconazole, Itraconazole, Miconazole,

Clotrimazole, Oxiconazole, Sertaconazole, Sulconazole
 Nucleosides: Flucytosine
 Griseofulvin
 Allylamines: Butenafine, Naftifine, Terbinafine
 Echinocandins: Caspofungin, Micafungin, Anidulafungin
 Other topical agents: Efinaconazole, Econazole, Luliconazole,

Ciclopirox olamine, Tolnaftate

ANTIFUNGAL DRUGS & THEIR TARGETS
Naftifine
Terbinafine
AMPHOTERICIN
 Amphotericin A & B are antifungal antibiotics produced by
Streptomyces nodosus
 Amphotericin A is not in clinical use
 Amphotericin-B:
 An amphoteric polyene macrolide:
 Polyene =containing many double bonds;
 Macrolide = containing a large lactone ring of ≥12 atoms

 MOA:
 Binds to sterols in the fungal cell membrane with its lipophilic
segment → alters the permeability by forming amphotericin B-
associated pores → loss of intracellular K+
 Greater avidity to ergosterol
 Enhances antifungal effect of flucytosine

 PKs:
 ROA: slow, IV infusion; negligible absorption from GIT
 Insoluble in water & must be coformulated with either sodium

deoxycholate (conventional) or a variety of artificial lipids to
form liposomes
 Liposomal preparations: reduced renal & infusion toxicity
 Due to high cost, liposomal preparations are reserved mainly

as salvage therapy for pts who can’t tolerate conventional
amphotericin B

 Amphotericin B is extensively bound to plasma proteins & is
distributed throughout the body
 Inflammation favors penetration into various body fluids, but

little of the drug is found in the CSF, vitreous humor, or
amniotic fluid
 Amphotericin B does cross the placenta
 Dose adjustment: not required in hepatic dysfunction
 When conventional amphotericin B causes renal dysfunction,

the total daily dose is decreased by 50%

 Available formulations:
 Currently four formulations of amphotericin B:
 Conventional Amphotericin B (C-AMB)
 Liposomal Amphotericin B (L-AMB)
 Amphotericin B Colloidal Dispersion (ABCD) &
 Amphotericin B Lipid Complex (ABLC)

 Antifungal activity;
 Systemic fungal infections
 Aspergillus, Candida, Cryptococcus
 Against protozoa: Leishmania braziliensis

 Intrathecal infusion in meningitis caused by coccidioides
 IV used for mucormycosis, extracutaneous sporotrichosis,
aspergillosis, cryptococcosis, trichosporonosis & penicilliosis
morneffei
 Bladder irrigation: in candida cystitis
 Topical: cutaneous candidiasis
 Oral tablet to decrease colonization of intestine by candida

 AEs:
✍ Infusion related toxicity (immediate reactions):
 Nearly universal & consist of fever, chills, muscle spasms,
vomiting, headache & hypotension
 They can be ameliorated by slowing the infusion rate or
decreasing the daily dose
 Premedication with antipyretics, antihistamines, meperidine,
or corticosteroids can be helpful

✍ Cumulative toxicity:
 Renal damage
 Anemia due to reduced erythropoietin production by damaged
renal tubular cells
 Seizures & chemical arachnoiditis after intrathecal therapy
 Abnormalities of liver function tests (occasionally)

FLUCYTOSINE: MOA
 Is taken up by fungal cells via the enzyme cytosine permease
 It is converted intracellularly first to 5-FU & then to 5-FdUMP

& FUTP, which inhibit DNA and RNA synthesis, respectively
(inhibit thymidylate synthetase)
 Human cells; unable to convert
the parent drug to its active
metabolites → selective toxicity

 PKs:
 ROA: IV infusion, PO
 90% excreted renally unchanged
 Combined with amphotericin for severe infections such as
cryptococcal meningitis
 AEs: infrequent; anaemia, neutropenia, alopecia,
thrombocytopenia; reversed when therapy ceases

AZOLES
 According to the number of nitrogen atoms in the five
membered azole ring they can be;
 Triazole: 3-N  Imidazole: 2-N
 Clotrimazole
 Fluconazole
 Miconazole
 Itraconazole  Ketoconazole
 Terconazole  Oxiconazol
 Sulconazole
 Voriconazole  Sertaconazole
 Posaconazole  Econazole
 Tioconazole
 Butoconazole
 MOA: reduction of ergosterol synthesis by inhibition of fungal
cytocrome P450 enzymes
 Greater affinity for fungal than for human CYP450 enzymes
 Imidazoles exhibit a lesser degree of selectivity than the
triazoles, accounting for their higher incidence of drug
interactions & adverse effects

 Systemic fungal infections:
 Cryptococcal meningitis: fluconazole
 Vaginal, oral, esophageal candidiasis: fluconazole
 Severe recalcitrant cutaneous dermatophyte infections

KETOCONAZOLE
 Inhibit CYP450: inhibit metabolism of protease inhibitors,

TCAs, benzodiazepines, warfarin
 Drugs that decrease gastric acidity: ↓ ketoconazole absorption
 AEs:
 Inhibit steroid hormone synthesis: inhibit 11 β-hydroxylase &

17 α-hydroxylase: cortisol; has antiandrogenic effect
 Primarily GI effects, hepatotoxicity

ITRACONAZOLE: PO
 PKs:
 Absorption: reduced in fasting & in reduced gastric acidity
 Itraconazole concentration are decreased by concomitant
therapy with rifampin, phenytoin & carbamazepine, as well as
by drugs that reduce gastric acidity-H2 antagonist & PPIs

 Preferred over ketoconazole for Rx of nonmeningeal
hystoplasmosis
 Cryptococcus may respond better with amphotericin-B or
fluconazole
 AEs: occasionally hepatotoxicity & rash
 Contraindicated during pregnancy

FLUCONAZOLE
 Completely absorbed, not affected by food, gastric acidity
 Diffuses readily into body fluids
 Drug interaction:
 Inhibitor of CYP3A4 & CYP2C9: ↑plasma levels of Phenytoin,
ZDV, Rifabutin, Cyclosporine, Sulfonylureas & Warfarin

 Therapeutic use
 Candidiasis: oropharyngeal, esophageal, vaginal candidiasis,

deep candidiasis
 Cryptococcosis: to prevent relapse cryptococcal meningitis in

AIDS patient whose infection has been controlled by
amphotericin B
 Rx choice for coccidioidal meningitis b/c of much lesser

morbidity than with amphotericin B
 AEs: NVD, headache, skin rash, abdominal pain: antiemetic

drug may be used
 Avoid during pregnancy: skeletal & cardiac deformities

GRISEOFULVIN: fungistatic
 Active against dermatophytes: Microsporum, Trichophyton,

Epidermophyton
 MOA: inhibits microtubule function & disrupts assembly of the

mitotic spindle, which disrupts fungal cell division
 To treat dermatophyte infections of skin & nail
 Treatment should be prolonged
 Given orally: fatty food enhances absorption
 Deposited in keratin precursor cells

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

Allylamines: Naftifine (topical), Terbinafine
 Terbinafine: systemic agent
 MOA: inhibits epoxidation of squalene in fungi
 Increased levels of squalene → toxic to fungi
 Reduces ergosterol, prevents synthesis of fungal cell

membrane
 Used: orally in mucocutaneous fungal infections
 Toxicity: GI-upset, headache, hepatotoxicity
 Interactions: none reported

Echinocandins: Caspofungin, Micafungin, Anidulafungin
 MOA: blocks β-glucan synthase, prevents synthesis of fungal

cell wall → cidal
 Used: in candidiasis, aspergillosis
 IV only, t ½: 11-15 hr
 Toxicity: minor gastrointestinal effects, flushing
 Interactions:
 Caspofungin: ↑tacrolimus (by 16%)
 Micafungin: levels of nifedipine, cyclosporine, sirolimus
 Anidulafungin: free of this interaction

Treatment of Superficial Fungal infections
 Diseases include;
 Dermatophytosis (ring worm)
 Candidiasis
 Tinea versicolor
 Tinea nigra
 Fungal keratitis
 Clotrimazole
 Available as: 1% cream (body, vaginal), lotion & solution,
10mg troches
 Skin apply BID
 Vagina: 100mg/day at bed time for 7 days
» 500mg tab only once
» Troches five times a day for 14 days

 Miconazole
 Therapeutic use: 2% vaginal cream, 100mg suppository at
bed time for 7days (vulvovaginal candidiasis)
 In txt of tinea pedis, tinea cruris & tinea versicolor
 AEs: vaginal application  burning, itching or irritation

 Nystatin
 MOA: binds to fungal sterols
 Therapeutic uses: candidiasis of intestine, mouth, skin, etc.
 AEs: nausea, bitter taste

 Undecylenic Acid (UDA)
 11 carbon, unsaturated compound
 MOA:
 Inhibition of enzymes involved in lipid metabolism → interfere
with the alkalinisation of the cytoplasm which accompanies
germ tube formation → inhibits morphogenesis in candida
 Useful in Rx of various dermatomycosis, especially tinea pedis

 Zinc undecylenate is marketed in combination with other
ingredients
 Zinc provides an astringent action that aids in the suppression
of inflammation
 The formulation is not irritant (Zn)
 Fungi static
 Cure rate is 50% lower than imidazole

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

Agents active against Microsporidia & Pneumocystis
 Albendazole:
 Class: anthelmintic
 MOA: inhibitor of α-tubulin polymerization
 Use: Microsporidia infection
 Fumagillin: used in immunocompromised individuals with

intestinal microsporidiosis due to Enterocytozoon bieneusi
unresponsive to albendazole
 Use: Microsporidia infection
 Not approved in US

 Cotrimoxazole: for PCP
 Pentamidine: for PCP prophylaxis at-risk individuals who
cannot tolerate Cotrimoxazole
 Tavaborole:
 For toenail onychomycosis due to Trichophyton rubrum or T.
mentagrophytes
 Apply daily for 48 weeks

✍ Superficial infectionsSummary
caused by;
☜ Dermatophytic fungi can be treated with;
☞ Topical antifungals: clotrimazole, efinaconazole, econazole,

ketoconazole, luliconazole, miconazole, oxiconazole,
sertaconazole, sulconazole, ciclopirox olamine, naftifine,
terbinafine, butenafine, tolnaftate, haloprogin or
☞ Oral agents: griseofulvin, terbinafine, fluconazole, itraconazole
☜ Candida species treated with topical; clotrimazole, miconazole,

econazole, ketoconazole, oxiconazole, ciclopirox olamine,
nystatin, amphotericin B

ANTIVIRAL AGENTS
 Introduction:
 Viruses are obligate intracellular parasites, rely on host
biosynthetic machinery to reproduce
 They are simple organisms consist of;
 Genetic material (DNA or RNA)
 Lipid envelope derived from the infected host cell

 Viral replication has distinct stages: antiviral drug intervention
 Completely unaffected by antibiotics: no cell wall, ribosome,…
 Do not carry out metabolic processes, use much of the host’s
metabolic machinery
 Few drugs are selective enough to prevent viral replication
without injury to the infected host cells

 Therapy for viral diseases is further complicated by the fact
that the clinical sXs appear late in the course of the disease, at
a time when most of the virus particles have replicated
 At this stage of viral infection, administration of drugs that
block viral replication has limited effectiveness
 However, some antiviral agents are useful as prophylactic
agents

Classification of Viruses
 Based on their genomic content, viruses can be:
 DNA viruses:
 Poxviruses  smallpox
 Herpesviruses  chickenpox, shingles, oral & genital herpes
 Adenoviruses  conjunctivitis, sore throat
 Hepadnaviruses  hepatitis B (HBV)
 Papillomaviruses  warts
 RNA viruses: complete their replication in the cytoplasm,
but influenza are transcribed in the host cell nucleus
 Rubella virus  German measles
 Rhabdoviruses  rabies
 Picornaviruses  poliomyelitis, meningitis, colds, hepatitis-A
 Arenaviruses  meningitis, Lassa fever (by Lassa virus)

RNA viruses…
 Flaviviruses  West Nile meningoencephalitis, yellow fever,
hepatitis C
 Orthomyxoviruses  influenza
 Paramyxoviruses  measles (rubeola), mumps
 Coronaviruses  colds, severe acute respiratory syndrome
(SARS)
 Retroviruses (a special group of RNA viruses): HIV

Drugs for Herpes virus infection
 Herpes virus types: HSV 1 & 2, VZV, EBV, CMV, human herpes
virus-6, human herpes virus-7, Kaposi sarcoma associated
herpes viruses

Acyclovir & Valacyclovir
 Acyclovir is an acyclic guanine nucleoside analog that lacks a

3′-OH on the side chain
 Valacyclovir is the prodrug of acyclovir
 MOA: inhibits viral DNA synthesis  DNA chain termination
 Cellular uptake & initial phosphorylation facilitated by HSV TK
 Affinity of acyclovir for HSV TK is ~200X greater than for the

mammalian enzyme
 Can also be used against VZV, CMV, EBV

 Resistance:
 Impaired production of viral thymidine kinase: most common
 Altered TK substrate specificity (e.g, phosphorylation of

thymidine but not acyclovir) or
 Altered viral DNA polymerase (due to mutation)
 PKs:
 Oral BA of acyclovir is 10-30%
 Widely distributed in body fluids
 t ½: 2.5 hrs
 Excreted in urine as parent drug

 AEs:
 Topical in a PEG base may cause mucosal irritation & transient
burning when applied to genital lesions
 PO: NVD, rash, or headache – frequent
 Renal insufficiency or neurotoxicity: rare & severe
 Thrombocytopenia: sometimes fatal
 Neutropenia in neonates
 Congenital abnormalities: very rare

 With ZDV: somnolence & lethargy
 With nephrotoxic agents (e.g, cyclosporine):  nephrotoxicity
 Probenecid  the acyclovir renal clearance:  t ½
 Acyclovir may  the renal clearance of methotrexate

Ganciclovir
 MOA: similar to that of acyclovir
 1st phosphorylation step is viral-specific;
 Involves TK in HSV & a phosphotransferase (UL97) in CMV
 Triphosphate form inhibits viral DNA polymerase & causes
chain termination

Ganciclovir…
 Resistance mechanisms similar to acyclovir
 Therapeutic use: HSV, VZV, & CMV
 Mostly used in prophylaxis & treatment of CMV infections
 AEs: dose-limiting hematotoxicity (leukopenia,
thrombocytopenia), mucositis, fever, rash & crystalluria
(maintain hydration), seizures

Famciclovir & Penciclovir
 Famciclovir is the diacetyl ester prodrug of 6-deoxy penciclovir

& lacks intrinsic antiviral activity
 Penciclovir is an acyclic guanine nucleoside analog
 Spectrum: against HSV, VZV & HBV
 MOA: inhibition of viral DNA synthesis
 Resistance: due to TK or DNA polymerase mutations
 Cross resistance to TK–deficient, acyclovir-resistant herpes

viruses

 PKs:
 Oral penciclovir has BA <5%
 Famciclovir is well absorbed orally; BA~75% & is converted
rapidly to penciclovir
 Food slows absorption but does not reduce overall BA
 t ½ of penciclovir 2 hrs
 >90% is excreted unchanged in urine

 AEs:
 PO famciclovir is well tolerated: headache, diarrhea & nausea
 Urticaria, rash, hallucinations/confusion (common in elderly)
 Penciclovir is mutagenic, tumorigenic &  spermatogenesis &

fertility in animals
 No teratogenic effects in animals, but no data in humans
 No clinically important drug interactions
 HSV & VZV infections
 Chronic HBV hepatitis but is less effective

Cidofovir
 A cytidine analog with inhibitory activity against human
herpes, papilloma, polyoma, pox, & adenoviruses
 It is a phosphonate that is phosphorylated by cellular but not
virus enzymes

Cidofovir…
 Spectrum: it inhibits;
 Acyclovir-resistant TK - deficient or TK-altered HSV or VZV

strains
 Ganciclovir-resistant CMV strains with UL97 mutations but not

those with DNA polymerase mutations and
 Some foscarnet-resistant CMV strains
 Inhibits CMV with ganciclovir or foscarnet – synergistically

 MOA: inhibits viral DNA synthesis; chain termination
 PK:
 Cidofovir is dianionic at physiological pH & has very low oral

BA
 t ½: 2.6 hrs & CSF levels are low
 Excretion is via urine
 Resistance: mutations in viral DNA polymerase (in CMV)

 AEs:
 Nephrotoxicity; probenecid & saline prehydration reduce the

risk
 Burning, pain, pruritus & ulceration: application site (topical

use)
 Mutagenic, gonadotoxic, embryotoxic, teratogenic &

carcinogenic
 May cause infertility & is classified as pregnancy category C

Trifluridine
 A fluorinated pyrimidine nucleoside analog that is
structurally similar to thymidine
 Once converted to the triphosphate, the agent is believed
to inhibit the incorporation of thymidine triphosphate into
viral DNA & to a lesser extent, lead to the synthesis of
defective DNA that renders the virus unable to replicate
 Active against HSV-1, HSV-2

Chemotherapy
& vaccinia virus
 Use: Rx of HSV keratoconjunctivitis & recurrent epithelial
keratitis
 Restricted to a topical ophthalmic preparation:
 Triphosphate form can also be incorporate into cellular
DNA: too toxic for systemic use
 t ½: short; applied frequently
 AEs: transient irritation of the eye & palpebral (eyelid)
edema
Fomivirsen
 A 21-base phosphorothioate oligionucleotide
 MOA: inhibition of virus binding to cells
 Active against CMV resistant to ganciclovir, foscarnet, &

cidofovir
 t ½: 55 hrs
 Highly distributed to the retina
 Metabolism: locally by exonucleases
 AEs:
 Iritis in up to ¼ of patients: Rx topical corticosteroids
 risk of inflammatory reactions

Foscarnet – tri-sodium phosphonoformate
 An inorganic pyrophosphate analog, inhibitory for all

herpesviruses & HIV
 MOA:
 Inhibits viral nucleic acid synthesis by interacting directly with

herpesvirus DNA polymerase or HIV reverse transcriptase
 Reversibly blocks the pyrophosphate binding site of the viral

polymerase in a non-competitive manner &
 Inhibits cleavage of pyrophosphate from deoxynucleotide

triphosphates
 Resistance:
Chemotherapy
mutationsCompiled
in the viral DNA polymerase
by Birhanu Geta 296
 PKs:
 Poor oral BA
 Use IV infusion
 > 80% excreted unchanged in urine
 t ½: 4-8 hours
 Sequestered in bone

 AEs:
 Nephrotoxicity: adequate hydration & saline loading may

reduce
 Metabolic abnormalities:  Ca2+, PO4-, Mg2+, K+
 Rash, fever, N/V, anemia, leukopenia, abnormal LFT, ECG

changes, infusion-related thrombophlebitis & painful genital
ulcerations
 Mutagenic in animals
 No proven safety in pregnancy or childhood

Docosanol
 A long-chain saturated alcohol
 MOA: inhibits the replication of many lipid-enveloped viruses
 Block fusion b/n the cellular & viral envelope membranes
 FDA-approved as an OTC 10% cream for the Rx of recurrent
orolabial herpes
 Rx should begin with in 12 hrs of prodromal period rather than
popular/later stages
Drugs for influenza virus infection

Amantadine & Rimantadine
 Uniquely configured tricyclic amines
 Inhibit the replication of influenza A viruses
 MOA:
 Inhibit uncoating & viral assembly through altering

hemagglutinin processing by interfering with M2 protein
 Can be used in prophylaxis & Rx of influenza
 Resistance: mutation in the RNA sequence encoding for the

M2 protein transmembrane domain
 All H3N2 strains are resistant

 PKs:
 They are well absorbed after PO
 Both drugs have very large Vd: widely distributed
 Amantadine is excreted largely un-metabolized in the urine
 t½: 12-18 hrs
 Amantadine’s elimination is highly dependent on renal

function
 Dose should be adjusted in renal dysfunction
 Rimantadine is metabolized extensively by phase-II rxn
 60-90% is excreted in the urine as metabolites
 t½ of rimantadine 24-36Compiled
hrs byafter PO
Birhanu Geta 302
 AEs:
 Both have dose related CNS & GI side effects: most common
 Nervousness, light-headedness, difficulty concentrating,

insomnia, delirium, hallucinosis, seizures, coma, & cardiac
arrhythmias
 Antihistamines, psychotropic or anticholinergic drugs,

aggravate neurologic manifestations
 Amantadine is teratogenic in animals
 Both drugs: pregnancy category C

Neuraminidase inhibitors: Oseltamivir, Zanamivir
 MOA: inhibition of neuraminidase  viral aggregation at the
cell surface & reduced virus spread within the respiratory tract
 Resistance: mutations on hemagglutinin &/or neuraminidase
 Most common variants (mutations at positions 292 in N2 &

274 in N1 neuraminidases) have reduced infectivity and
virulence in animal models
 Seasonal influenza A (H1N1) has become virtually 100%

resistant to oseltamivir
 Importantly, novel H1N1 (nH1N1 or swine influenza) remains

susceptible to oseltamivir
 AEs:
 NVD after PO: owing to local irritation, so take with food
 They do not interact with CYPs in vitro
 Have low protein binding
 No clinically significant drug interactions
 Safety in pregnancy is uncertain (category C)
 Treatment & prevention of influenza A & B virus infections

Drugs for Hepatic Viral infections
 Identified hepatitis viruses are A, B, C, D & E, [F, G(orphan)]
 Each has a pathogenesis specifically involving replication in
and destruction of hepatocytes
 Hepatitis A: a common infection due to ingestion of the virus
but not a chronic disease
 HBV & HCV: the most common causes of chronic hepatitis,

cirrhosis & hepatocellular carcinoma
 Currently
Chemotherapy
therapy is available for HBV & HCV infections
Compiled by Birhanu Geta 306
 HCV enters into hepatocyte following interaction with
cellular entry factors
 Then, a viral genome is released from the nucleocapsid &
an HCV polyprotein is translated using the internal
ribosome entry site
 Cleavage of polyprotein by cellular & viral proteases to
yield structural & nonstructural proteins

 The core NS3 & NS5A proteins form the replication complex
on lipid droplets & serve as a scaffold for RNA polymerase to
replicate the viral genome
 Then packaged in envelope glycoproteins before noncytolytic
secretion of mature virions
 DAAs: target the NS3/NS4A protease, NS5B polymerase &
NS5A involved in HCV replication & assembly
 Combination with DAAs: to optimize HCV Rx response rates

NS3/NS4A protease inhibitors: -previr end
 Paritaprevir (requires ritonavir boosting), grazoprevir,
voxilaprevir, glecaprevir, Boceprevir & Telaprevir
 MOA: covalently & reversibly bind to the HCV NS3/4A serine
protease active site & inhibiting viral replication in host cells
 The viral NS3/NS4A serine protease is crucial for processing
the single polyprotein encoded by HCV RNA into individually
active proteins: NS4A, NS4B, NS5A & NS5B

 Without these serine proteins, RNA replication does not occur
& HCV life cycle is disrupted
 Paritaprevir requires ritonavir boosting
 These drugs have a lower barrier to resistance than sofosbuvir
 Metabolized by CYP3A: significant potential for DDIs
 AEs: rash, pruritus, nausea, fatigue, anemia

Boceprevir & Telaprevir
 PO DAAs for Rx of chronic HCV
 High risk of resistance in monotherapy
 Used in combination with interferon- & ribavirin
 Boceprevir is administered with food to improve absorption
 Fatty food enhances absorption of telaprevir
 Metabolized via CYP450 & are strong inhibitors of CYP3A4/5
 AEs: anemia, rash & anorectal discomfort

NS5B polymerase inhibitors: -buvir end
 NS5B: sole RNA polymerase responsible for HCV replication
 Processed with other HCV proteins into an individual
polypeptide by the viral NS3/NS4A serine protease
 Two types of NS5B RNA polymerase inhibitors:
 Nucleoside/nucleotide analogues, compete for active site &
 Nonnucleoside analogues; target allosteric sites
 Sofosbuvir: nucleotide & dasabuvir: nonnucleoside
 AEs: few & well toleratedCompiled by Birhanu G.

Chemotherapy 312
NS5A replication complex inhibitors: -asvir end
 Ledipasvir, ombitasvir, elbasvir, velpatasvir, pibrentasvir, daclatasvir
 NS5A: essential for HCV RNA replication & assembly
 Provides a platform for replication by forming a membranous
web along with viral protein NS4B
 NS5A inhibitors are coformulated with other DAAs; except
daclatasvir
 They are inhibitors of P-gp & metabolized by CYP450

 Daclatasvir: extensively by CYP3A4;
 Not administered with strong CYP3A4 inducers
 Dose ↓ed when with strong CYP3A4 inhibitors
 Dose ↑ed when with moderate CYP3A4 inducers
 Absorption of ledipasvir is reduced when gastric pH is ↑ed
 Patients receiving PPIs should either stop these agents during

HCV therapy with ledipasvir or
 Take PPI with ledipasvir-containing regimens under fasted

conditions to ensure that gastric pH is at its lowest point

Cyclophilin inhibitors
 Derived from cyclosporine A, but lack calcineurin-binding

properties; don’t exhibit immunosuppressive effects
 Alisporivir the first agent on a phase III trial
 Binds to cyclophilin A, an essential cofactor for HCV replication

& shows additive antiviral effect with pegIFN in pts with
genotype 1 & 4 HCV
 Sometimes referred to as host-targeted agents, but can also

be part of the DAAs b/c interact with the NS5A protein

Interferons
 A family of naturally occurring, inducible glycoproteins
(cytokines) that interfere with the ability of viruses to infect
cells
 Trigger the protective defences of the immune system that
help eradicate pathogens
 Three types of interferons exist: α(15), β & γ
 Synthesized by recombinant DNA technology

 MOA:
 Interfere with RNA & DNA polymerases & activate viral
RNases  degradation of mRNA & tRNA
 Inhibition of transcription:
 Activates Mx protein, blocks mRNA synthesis

 Inhibition of translation:
 Activates methylase, thereby reducing mRNA cap methylation
 Activates 2’5’ oligoadenylate synthetase  2’5’A  inhibits
mRNA splicing and activates RNaseL  cleaves viral RNA
 Activates phosphodiesterase  blocks tRNA function
 Activates protein kinase P1  blocks eIL-2a function 
inhibits initiation of mRNA translation

 Inhibition of post-translational processing
 Inhibits glycosyltransferase, thereby reducing protein

glycosylation
 Inhibition of virus maturation
 Inhibits glycosyltransferase, thereby reducing glycoprotein

maturation
 Inhibition of virus release: causes membrane change 

blocks budding

 PKs:
 Not active in PO, so; administer SC, or IV
 Highly metabolised by liver
 AEs: flu-like symptoms: fever, chills, myalgias & GI
disturbances
 Bone marrow suppression, fatigue & weight loss, neurotoxicity
are common

 Interferon-α: chronic hepatitis B & C, genital warts by HPV,
melanoma, condylomata acuminate, leukemia (hairy cell,
CML), Kaposi sarcoma
 Interferon-: relapsing remitting multiple sclerosis
 Interferon-: chronic granulomatous disease   TNF

Lamivudine: 3TC
 A cytosine analog, an inhibitor of both HBV & HIV RTs
 Must be phosphorylated by host cellular enzymes to the
triphosphate (active) form
 Competitively inhibits HBV RNA-dependent DNA polymerase
 Rate of resistance is high following long-term therapy

 PKs:
 Well absorbed orally & is widely distributed
 Mainly excreted unchanged in urine
 Dose reductions are necessary in renal problem
 AEs: well tolerated, headache & dizziness less common

Adefovir
 A nucleotide analog, phosphorylated by cellular kinases,
which is then incorporated into viral DNA → termination of
chain elongation & prevents replication
 Administered once a day
 Excreted via urine
 Nephrotoxicity in chronic use
 Cautiously use in patients with existing renal dysfunction

Entecavir
 A guanosine nucleoside analog for the Rx of HBV infections
 MOA: phosphorylated intracellularly & competes with the
natural substrate, deoxyguanosine triphosphate, for viral RT
 Effective against 3TC-resistant strains of HBV & dosed QD
 Primarily excreted unchanged in the urine
 Dose adjustment required in renal dysfunction

Telbivudine
 A thymidine analog, used in the treatment of HBV
 MOA: posphorylated intracellularly to the triphosphate,
terminate further elongation of the DNA chain
 Administered orally, once a day
 Eliminated renally as parent drug
 Dose must be adjusted in renal failure
 AEs: fatigue, headache, diarrhea & ↑in liver enzymes &

creatine
Chemotherapy
kinase Compiled by Birhanu Geta 327
Ribavirin
 A synthetic guanosine analog
 Effective against RNA & DNA viruses: used in severe RSV,
chronic HCV infections (standard or pegylated interferon
or with DAAs)

 MOA:
 Inhibits replication of RNA & DNA viruses:
 By inhibiting GTP formation
 Preventing viral mRNA capping &
 Blocking RNA-dependent RNA polymerase

 Combination with other agents:
 Improves viral clearance
 Decreases relapse rates
 Improves rates of sustained virologic response
✍ The addition of ribavirin to DAA-based regimens is based
on HCV genotype/subtype, cirrhosis status, mutational
status & treatment history

 Dose: always weight-based & administered in two daily
divided doses with food (fatty meal ↑es absorption)
 Effective orally & by inhalation (Rx of RSV infection)
 Excretion: via urine (parent drug & metabolites)
 AEs: anemia, elevated bilirubin
 Teratogenic: CI in pregnancy

In a nutshell
 Chronic hepatitis B may be treated with peginterferon-α-2a:

SC injection once weekly
 Oral therapy HBV: lamivudine, adefovir, entecavir & tenofovir
 Preferred Rx for HCV is a combination of DAAs, the selection

of w/c is based on the HCV genotype
 In certain cases, ribavirin is added to a DAA regimen to

enhance virologic response
 With the introduction of new DAAs, pegylated interferon-α is

no longer commonly used in HCV & it is not recommended
due to inferior efficacy & poor tolerability
ANTI-RETROVIRALS
 HIV family: Retroviridae, genus: Lentivirinae (lenti, meaning
slow)
 Enveloped, single-stranded (ssRNA), retrovirus with a DNA

intermediate
 Integrates into host genome & persists with in host-cell DNA
 High potential for genetic diversity
 Can lie dormant within a cell for many years, especially in
resting (memory) CD4+ T4 lymphocytes

 HIV type (distinguished genetically)
 HIV-1: genetically diverse (has d/t subfamilies/clads)
 Most common, worldwide pandemic (current ~ 40 M people)
 HIV-2: isolated in West Africa, closely related to SIV
 Consists of 7 phylogenetic lineages designated as subtypes

(clades) A-G
 Relatively uncommon & less infectious
 Causes AIDS much more slowly than HIV-1 otherwise similar
 HIV-1 & HIV-2: similar sensitivity to most ARV drugs
☞ NNRTIs are HIV-1 specific & have no activity against HIV-2

Classification of HIV-1
 HIV-1: four recognized groups/families/
 M (main/major): cause of current worldwide epidemic
 O (outlier) & N (non-M, non-O): rare HIV-1 groups that arose
separately
 P (pending the identification of further cases)

 HIV-1 M subgroups (clades): genetically diverse
 Nine subtypes of HIV-1 group M are identified;
 A through D, F through H & J & K
 Mixtures of subtypes are referred to as circulating
recombinant forms
 Group M, subtype B, is primarily responsible for the epidemic
in North America & western Europe

Anatomy of HIV

 A small RNA genome of 9300 base pairs
 2 copies of the genome are contained in a nucleocapsid core
 Surrounded by a lipid bilayer, or envelope, derived from the
host cell plasma membrane
 HIV contains 3 species-defining retroviral genes: gag, pol &
env
 gag: encodes group-specific antigens; the inner structural
proteins
 pol: encodes an RNA-dependent DNA polymerase or reverse
transcriptase with RNAase activity, integrase & protease
 Is produced as a C-terminal extension of the Gag protein
 env: encodes the viral envelop: the outer structural proteins
responsible for cell-type specificity (binding & entry)
 HIV tropism is controlled by the envelope protein gp160 (env)

 HIV-1 has additional accessory genes: tat, rev, nef, vif, vpu &
vpr
 Encode regulatory proteins that enhance virion production or
combat host defences
 HIV-2 doesn’t have vpu but instead has the unique gene vpx
 SIV (simian immunodeficiency virus) has vpu: chimpanzees
with active HIV-1 infection are resistant to disease

Life cycle of HIV
 Binding of gp120 to CD4 & co-receptor on the cell surface
 Fusion of the viral envelope with the cell membrane controlled
by gp41 domain of env
 Entry: full-length viral RNA enters the cytoplasm, undergoes
replication to a short-lived RNA-DNA duplex
 The original RNA is degraded by the RNase H activity of RT to
allow creation of a full-length double-stranded DNA

 Since HIV reverse transcriptase is error prone & lacks a
proofreading function, mutation is frequent & occurs at about
three bases of every full-length (9300-base-pair) replication
 Viral DNA moves into cell nucleus & integrated into a host
chromosome by the viral integrase in a random or quasi-
random location
 Following integration, the virus may remain quiescent, not
producing RNA or protein but replicating as the cell divides

 HIV provirus DNA is transcribed back to both viral genomic
RNA & viral mRNA, the latter which is translated to HIV
polyproteins
 The RNA virus & polyproteins are assembled beneath the cell
membrane
 The assembled package becomes enveloped in the host cell

membrane as it buds off to form an HIV virion
 Further assembly & maturation occurs outside the cell by the

protease enzyme, rendering the HIV virion infectious

120

How HIV enters in to the cell?
 gp120 env protein binds to CD4 molecule, found on T-cells
macrophages & microglial cells
 Binding to CD4 is not sufficient for entry
 V3 loop of gp120 env protein binds to co-receptor (CCR5 or
CXCR4)

How HIV enters in to the cell?...
 CCR5 receptor: used by macrophage-tropic HIV variants
 Since it is present on macrophage lineage cells
 Most infected individuals harbor predominantly the CCR5-

tropic virus
 HIV with this tropism is responsible for nearly all naturally

acquired infections
 CXCR4 receptor: used by lymphocyte-tropic HIV variants

 A shift from CCR5 to CXCR4 utilization is associated with
advancing disease &
 The increased affinity of HIV-1 for CXCR4 allows infection of

T-lymphocyte lines
 A phenotypic switch from CCR5 to CXCR4 heralds accelerated

loss of CD4+ helper T cells & ↑ed risk of immunosuppression
 Whether coreceptor switch is a cause or a consequence of

advancing disease is still unknown
 But it is possible to develop clinical AIDS without this switch

Classes of Anti-retroviral drugs
 FDA approved >30 ARV drugs in 7 mechanistic classes
 Seven classes:
 NRTIs, NNRTIs, PIs, INSTIs, a fusion inhibitor, a CCR5
antagonist & a CD4 post-attachment inhibitor
 In addition, 2 drugs, ritonavir (RTV or r) & cobicistat (COBI or
c); used as PK enhancers or boosters to improve the PK
profiles of some ARV drugs (PIs & EVG)

Uses of Anti-retroviral drugs
 For the treatment of HIV disease, PMTCT, PrEP, PEP
 FTC, 3TC & TDF: active against hepatitis B virus (HBV) &
 TDF also has activity against herpesviruses

Reverse Transcriptase Inhibitors (RTIs)
The original inhibitors of reverse transcriptases of HIV are
nucleoside antimetabolites (AZT, the prototype) that are
converted to active forms via phosphorylation reactions
Nuceoside/tide RTIs:
Components of most combination drug regimens
Used together with an INSTI/PI
HAART → ↓viral RNA, reverse CD4 cells & decrease OIs

Other NRTIs
 MOA: identical to that of zidovudine
 Each requires metabolic activation to nucleotide forms that
inhibit RTase
 Used as starter regimen for all RVI patients
 Resistance mechanisms are similar
 Not complete cross-resistance between NRTIs
 Toxicity: less bone-marrow suppressing than AZT

Chemotherapy Intracellular activation
Compiled by Birhanu Getaof NRTIs 354
 ABC: take without regard to meal
 AEs:
 Hypersensitivity rxn: NVD, fever, rash, malaise, shortness of
breath, cough, pharyngitis
 Patients positive for HLA-B*5701 are at highest risk for
hypersensitivity
 Perform HLA screening before initiating

 ddI: adjust the dose in renal impairment
 Take 30’ ac or 2 hr pc; for oral solution, divide daily dose BID
 AEs: peripheral neuropathy, pancreatitis, nausea, lactic

acidosis
 FTC: adjust the dose in renal impairment
 Take without regard to meals
 AEs: minimal toxicity
 Hyperpigmentation, severe acute exacerbation of hepatitis

may occur with HBV-coinfection upon DC

 3TC: adjust the dose in renal impairment
 AEs: minimal toxicity, severe acute exacerbation of hepatitis
may occur with HBV-coinfection upon discontinuation
 d4T: adjust the dose in renal impairment
 AEs: peripheral neuropathy, pancreatitis, lactic acidosis,
lipoatrophy, hyperlipidemia
 Tenofovir:
 A derivative of 5′-AMP, lacks a complete ribose ring
 The only nucleotide
 Available as the disoproxil (TDF) or alafenamide (TAF)

prodrugs w/c substantially improve oral absorption
 Against HIV-1, HIV-2, HBV
✍ TDF: take without regard to meals
 Adjust the dose in renal impairment
 Associated with low lipid levels
 AEs: NVD, headache, asthenia, renal insufficiency, bone

mineral
Chemotherapy density loss (approved for >2years)
✍ Tenofovir alafenamide (TAF):
 Advantages: lower dose & less renal & bone toxicity
 Coformulated with EVG, cobicistat (COBI) & FTC; rilpivirine &

FTC; or FTC
 Do not use in ESRD (CrCl <15 mL/min)
 Safety & efficacy not established: <18 years
 AEs: N, abdominal pain, fatigue, headache, back pain, cough

 ZDV:
 Adjust the dose in renal impairment
 AEs: NV, headache, asthenia, anemia, neutropenia

PK Properties of NRTIs

NNRTIs
 Do not require metabolic activation
 MOA:
 Inhibit reverse transcriptase at a site different from NRTIs
 Additive or synergistic: combination with NRTIs &/or Pls
 Are not myelosuppressant

 DLV: AEs: rash, headache
 EFV: take on empty stomach to decrease AEs
 AEs: rash, CNS (e.g., somnolence, vivid dreams, confusion,
visual hallucinations), hyperlipidemia
 ETV: approved only for ART-experienced pts with drug
resistance
 Take after food
 AEs: rash, nausea

 NVP: take without regard to meals
 AEs: rash, hepatitis
 Rilpivirine: take with meal
 AEs: depressive disorders, insomnia, headache, rash
 Doravirine (DOR): take with or without food
 Coadministration with strong CYP3A inducers may ↓systemic

exposure → loss of therapeutic effect & possible HIV
resistance
 AEs: immune reconstitution syndrome

PK properties of NNRTIs

Protease Inhibitors: PIs
 MOA: aspartate protease (pol gene encoded) is a viral

enzyme that cleaves precursor polypeptides in HIV buds to
form the proteins of the mature virus core
 The enzyme contains a dipeptide structure not seen in

mammalian proteins
 Pls bind to this dipeptide, inhibiting the enzyme
 Resistance occurs via specific point mutations in the pol gene,

such that there is not complete cross-resistance b/n d/t PIs
 Ritonavir: induces CYP 1A2 and inhibits 3A4 & 2D6

 ATV: take with food
 AEs: indirect hyperbilirubinemia, prolonged PR interval,
hyperglycemia, skin rash (20%), hyperlipidemia
 DRV: approved for ART-naïve or -experienced pts without
DRV-resistance mutations
 Take with food
 AEs: rash, nausea, diarrhea, hyperlipidemia, hyperglycemia

 FPV:
 Approved only for ART-naïve or -experienced pts
 Suspension, take without food; boosted with RTV, take with

food
 AEs: rash, NVD, hyperlipidemia, hyperglycemia
 IDV: take 1 h ac or 2 h pc; may take with skim milk or low-fat

meal
 IDV/r: take without regard for meals
 AEs: N, nephrolithiasis, indirect hyperbilirubinemia,

hyperlipidemia, hyperglycemia

 LPV/r:
 Approved for ART-naïve or -experienced pts without LPV-
resistance mutations
 Tablet: take without regard to meals; oral solution: take with
meals
 AEs: NVD, asthenia, hyperlipidemia, hyperglycemia
 NFV: can’t be boosted; take with food
 AEs: D, hyperlipidemia, hyperglycemia

 RTV:
 Boosting dose for other PIs: 100-400 mg/d
 Non boosting dose (ritonavir used as sole protease inhibitor),

600 mg BID (titrate dose over 14 days, beginning with 300 mg
BID on days 1-2, 400 mg BID on days 3-5 & 500 mg BID on
days 6-13)
 Tablet: take with food, capsule or oral solution: food improves

tolerability
 AEs: NVD, asthenia, hyperlipidemia, oral paresthesias,

hyperglycemia

 SQV: unboosted SQV is not recommended
 Take SQV/r with food, or within 2 h pc
 AEs: ND, headache, hyperlipidemia, hyperglycemia, PR & QT

interval prolongation
 TPV: approved only for ART-experienced pts with drug

resistance
 Unboosted TPV is not recommended, take TPV/r without

regard to meals
 AEs: hepatotoxicity, rash, hyperlipidemia, hyperglycemia,

intracranial hemorrhage (rarely)

Integrase Inhibitors: INSTIs
 MOA: bind to HIV integrase while it is in a specific complex
with viral DNA then viral DNA cannot become incorporated
into the human genome and cellular enzymes degrade
unincorporated viral DNA

 RAL: is primarily glucuronidated by UGT1A1 & is not broadly
susceptible to CYP-mediated drug interactions
 For use in ART-naïve or virologically suppressed on an initial
regimen of 400 mg BID
 AEs: ND, headache, CK (creatine kinase) elevations,
myopathy/rhabdomyolysis (rare)

 EVG: is first metabolized by CYP3A then glucuronidated & is
thus susceptible to CYP3A drug interactions
 Higher EVG plasma conce. are achieved when co-administered
with either low-dose RTV or cobicistat
 Adult dose: 85 mg PO QD plus ATV or LPV plus RTV or 150
mg PO QD plus DRV or FPV or TPV plus RTV
 Take with food
 AEs: immune reconstitution syndrome

 DTG:
 Adult dose: 50 mg PO QD; with UGT1A/CYP3A inducers (EFV,
FPV/r, TPV/r, R) or designated INSTI resistance mutations, 50
mg PO BID
 AEs: ↑cholesterol, TG, CK, liver enzyme & blood glucose
 Not recommended in pregnancy; ↑ed risk of neural tube
defects in infants
CCR5 antagonist
 MVC: blocks CCR5 protein on macrophage surface to prevent
viral entry
 AEs: constipation, dizziness, infection, rash, orthostatic
hypotension

Fusion inhibitor: FI
 T-20: binds gp41 and inhibits fusion of HlV-1 to CD4+ cells
 Approved only for ART-experienced pts with drug resistance
 Adult dose: 90 mg SC BID
 AEs: injection-site rxns: pain, erythema, induration, nodules

Entry inhibitor
 Ibalizumab:
 Approved only for ART-experienced pts with drug resistance
 Adult dose: 1st dose (single LD), 2000 mg IV infused over ≥30’
(begin MD 2 wks after LD); MD, 800 mg IV q2wks infused
over at least 15-30’
 AEs: ND, dizziness, rash (5-8%); immune reconstitution
syndrome (1 case)
ART-regimens
 Should be initiated in all living with HIV, regardless of WHO
clinical stage & at any CD4 cell count
 1st-line ART for adults should consist of;
 Two NRTIs + a NNRTI or INSTI or PI; with a PK enhancer
 A pregnancy test prior to the initiation of ART

 Examples:
 TAF + FTC + BIC
 ABC + 3TC + DTG: only for HLA-B*5701 negative patients
 TAF/TDF + FTC + DTG
 TAF/TDF + FTC + RAL
 TDF + FTC + EVG/c: EVG also has a lower barrier to
resistance than DTG & BIC

Interactions Between NRTIs & PIs
 No significant alterations
 One important interaction involves didanosine and indinavir,

or didanosine and nelfinavir
 The neutralising agents in the oral formulations of didanosine

result in increased gastric pH
 Optimal absorption of indinavir and nelfinavir requires an

acidic pH
 It is recommended that these drugs are given at least one

hour apart from didanosine
Saquinavir – Ritonavir
 The combination reduces the pill burden (from 1200 mg TID
to 400mg/400 mg BID)
 Hence, may also improve adherence and reduce costs of
therapy
 PI “Boosting” using Ritonavir

Interactions Between PIs & NNRTIs
 NNRTIs alter the kinetics of PIs:
 Nevirapine induces hepatic enzymes, reducing the plasma
concentrations of some protease inhibitors
 The dose of indinavir or nelfinavir may be to accommodate
for decreased AUCs when administered with NVP

Interactions: Antiretroviral Agents & Other Drugs
 Hepatic metabolism:
 Macrolide antibiotics, azole antifungals & H-2 blockers are

P450 inhibitors and hence interact with PIs and NNRTIs
 Rifamycin derivatives, alcohol and anticonvulsants are P450

inducers and hence also interact with PIs and NNRTIs
 Simvastatin and lovastatin are potent inducers, and other

agents such as atorvastatin and pravastatin are less likely to
interact and are recommended for use

Oral pre-exposure prophylaxis (PrEP)
 TDF containing regimen should be offered as an additional
prevention choice for people at substantial risk of HIV
infection as part of combination HIV prevention

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

Risk factors for Occupational HIV Transmission
 Type of contact/exposure: percutaneous, muco-cutaneous
non intact skin & bites resulting in blood exposure
 Type and amount of fluid/tissue
 Disease status of source patient:
 Higher viral loads (terminally ill patients or individuals with

Acute HIV infection)
 Host defenses: host immune response may prevent HIV

infection after exposure
 Community HIV status: risk higher in areas with high HIV

sero-prevalence
HIV: non-occupational exposures & PEP
 Survivors of sexual assault
 Children (needle stick, community fights, sexual abuse)
 Unanticipated high risk exposure (sexual or non-sexual e.g.
needle stick injury)
 Sharing of needles in IDUs

Factors that can affect risk of HIV transmission
 Type of sexual contact
 HIV status of the assailant
 Presence/absence of torn or damaged skin
 The number of attackers/assailants
 HIV prevalence in the area

PEP
 A regimen of two ARV drugs is effective, but three drugs are
preferred
 PEP ARV regimens for adults & adolescents:
 TDF + 3TC/FTC + RAL/DTG: for > 13 & CrCl > 60 mL/min
 ZDV + 3TC + RAL/DTG: for > 13 yrs & CrCl < 60 mL/min
 TDF + 3TC/FTC + RAL: for pregnant women, women of
childbearing age
 PEP is taken for a total of 28-days
 Should be given in the shortest time possible (within the first
1-4 hours of exposure)
 Do not consider PEP beyond 72 hours
 Enhanced adherence counselling is necessary
 NVP should not be used in children above the age of 2 years

Summary

ANTIPROTOZOAL AGENTS

Introduction
 Protozoal infections are;
 Common among underdeveloped tropical & subtropical

countries, where;
 Sanitary conditions,
 Hygienic practices &
 Control of the vectors of transmission are inadequate
 However, with increased world travel, protozoal diseases are

no longer confined to specific geographic locations

 Protozoa are unicellular eukaryotes
 Have metabolic processes closer to those of the human host

than to prokaryotic bacterial pathogens
 Less easily treated than bacterial infections,
 Serious toxic effects in the host, particularly on cells showing

high metabolic activity
 Most antiprotozoal agents have not proven to be safe for

pregnant patients

MALARIA
 Caused by protozoa of the genus plasmodium
 Affects  250 million people; killing  900,000 each year
 Five Plasmodium spp. are known to infect humans:
 P. falciparum, P. vivax, P. ovale, P. malariae & P. knowlesi
 P. falciparum & P. vivax: cause most infections worldwide
 P. falciparum: associated with the most severe disease
 Life cycle of malaria parasite: takes place in two hosts
 In human (asexual reproduction) &
 Female anopheles (sexual reproduction)

Biology of Malarial infection
 Sporozoites from the salivary gland of a female anopheline
mosquito are injected under the skin
 They travel through the blood stream to the liver & mature
within hepatocytes to become tissue schizonts, merozoites,
hypnozoites (P. vivax & P.ovale)
☞ Asymptomatic prepatent period, or exoerythrocytic stage of
infection: lasts about 1 wk

 Merozoites (~30,000) released into the blood stream &
produce symptomatic infection as they invade & destroy RBCs
 In the RBCs, merozoites mature to the ring form, w/c becomes
a hemoglobin-metabolizing trophozoite (feeding stage) that
matures into an asexually dividing blood-stage schizont
 Schizont rupture at the end of the growth & division cycle
releases 8-32 merozoites that invade new RBCs

 Merozoites develop into schizonts: majorly & gametocytes
(male & female gametes): a small proportion
 Gametocytes are ingested by the mosquito during an
infectious blood meal; on reaching the midgut of the
mosquito, the gametocytes transform into gametes that
fertilize to become zygotes
 Zygotes mature into ookinetes that invade the mosquito
midgut wall & transform into oocysts

 Numerous rounds of asexual replication occur in the oocyst to
generate sporozoites over 10-14 days
 Fully developed sporozoites rupture from oocysts & invade the
mosquito salivary glands, from w/c they can initiate a new
infection during subsequent mosquito blood meals
 Thus, infection cycles from mosquito to human to mosquito

Classification of Antimalarial Agents
 The various stages of the malarial parasite life cycle in humans

differ in their drug sensitivity
 Chemoprophylaxis:
 No antimalarial drug kills sporozoites, it is not truly possible to

prevent infection
 Drugs can only prevent the dev’t of symptomatic malaria

caused by the asexual erythrocytic forms, either in the
bloodstream or as produced within & released by hepatocytes
prior to erythrocyte invasion

 Treatment of an established infection:
 No single antimalarial is effective against all hepatic &
intraerythrocytic stages of the life cycle that may coexist in the
same patient
 Complete elimination may require >1 drug

Chemotherapy of Malaria
 Three classes of clinically useful antimalarial agents:
 Agents that are against the asexual blood stages:
 Treat, or prevent, clinically symptomatic malaria
 Not reliably effective against primary or latent liver stages
 Artemisinins, chloroquine, mefloquine, quinine, quinidine,
pyrimethamine, sulfadoxine, tetracycline

 Drugs target asexual erythrocytic forms & primary liver stages
of P. falciparum:
 This additional activity shortens to several days the required
period for postexposure chemoprophylaxis
 Atovaquone, proguanil

 Drugs effective against primary & latent liver stages as well as
gametocytes:
 Eradicate the intrahepatic hypnozoites of P. vivax & P. ovale
 Eight-amino quinolones:
 Primaquine (t½: short), Tafenoquine (t½: long)

☞ Aside from their antiparasitic activity, the utility of antimalarials
for chemoprophylaxis or therapy depends on their PK & safety
 Quinine & primaquine: significant toxicity & relatively short t½;
 Generally reserved for the Rx of established infection & not
used for chemoprophylaxis in a healthy traveler
✍ Chloroquine: free from toxicity & has long t½;
 Convenient for chemoprophylaxis (in chloroquine-sensitive
malaria)
 Currently available antimalarial agents target four physiologic
pathways in plasmodia:
 Heme metabolism: chloroquine, quinine, mefloquine,
artemisinin
 Electron transport: primaquine, atovaquone
 Protein translation: doxycycline, tetracycline, clindamycin
 Folate metabolism: sulfadoxine-pyrimethamine, proguanil

ARTEMISININ & ITS SEMISYNTHETIC DERIVATIVES
 Artemisinin or Qinghaosu, a sesquiterpene lactone
endoperoxide
 Isolated in 1972 from Artemisia annua L
 Artemisinin is insoluble & only be used orally
 Analogs synthesized to ↑solubility & improve efficacy
 Derivatives: artemisinin, dihydroartemisinin, artemether,
artesunate
 Potent & fast-acting antimalarials: Rx of severe P. falciparum
 Also effective against the asexual erythrocytic stages of P.vivax
 Standard Rx of malaria employs ACTs to ↑Rx efficacy & reduce
selection pressure for the emergence of drug resistance
 They cause a significant reduction of the parasite burden

 Only 3-4 cycles (6-8 days) of Rx are required to remove all the
parasites from blood
 In addition, artemisinins possess some gametocytocidal
activity results in decrease in malarial parasite transmission

 MOA:
 Not known due to complex chemical interactions
 Activation/free radical production: cleavage of the drug’s
peroxide bridge by reduced heme-iron in the highly acidic
digestive vacuole of the parasite as it digests hemoglobin
 Activated artemisinin might in turn generate free radicals that
alkylate & oxidize macromolecules in the parasite; PfATP6, the
parasite Ca2+ ATPase

 PKs:
 Artemisinin is insoluble & can only be used orally
 Analogs synthesized to ↑solubility & improve efficacy
 Artesunate: water-soluble; PO, IV, IM PR administration
 Artemether: lipid-soluble; PO, IM, PR
 Dihydroartemisinin: water-soluble; PO
 BA: ≤ 30% after PO
 Peak serum levels occur rapidly with artemisinins, in 2-6 h
with IM artemether
 Artesunate & artemether: modest levels of PPB; 43 - 82%
 Extensively metabolized & converted to dihydroartemisinin;
t½: 1-2 h
 BA via PR is highly variable among individual pts
 Repeated dosing, artemisinin & artesunate induce their own
CYP-mediated metabolism, primarily via CYPs 2B6 & 3A4,
which may enhance clearance by as much as 5-fold

 Therapeutic Uses:
 First-line for sever falciparum, MDR malaria in combination
with other agents: rapid & potent activity
 IV artesunate preferred over quinine dihydrochloride or
quinidine gluconate
 Not used alone: limited ability to eradicate infection
completely
 Not used for chemoprophylaxis because of their short t½

 Toxicity & Contraindications:
 ↑ed embryo lethality or malformations in animals
 Dose-related & reversible ↓es in reticulocyte & neutrophil
counts & ↑es in transaminase levels
 Allergic reaction: 1 in 3000 pts
 Although studies of artemisinin
 ACTs shouldn’t be used in the 1st trimester or for the Rx of
children ≤ 5 kg
 ACT partner drugs
 Partner drugs should have substantially better potency & t½
than artemisinin
 ACT regimens well tolerated in adults & children ≥ 5 kg:
 Artemether-lumefantrine
 Artesunate-amodiaquine
 Dihydroartemisinin-piperaquine

✍ Artemether-Lumefantrine: 20 + 120 mg; (1:6) Coartem®
☞ Lumefantrine: structurally similar with arylamino alcohols:

mefloquine & halofantrine
 Coartem®: highly effective for the Rx of uncomplicated malaria
 Artemether is rapidly metabolized into the active metabolite
dihydroartemisinin (DHA)
 Producing an endoperoxide moiety
 Lumefantrine may form a complex with hemin, which inhibits
the formation of beta hematin

 Lumefantrine: has large Vd & t½: 4-5 days
 Administration with a high-fat meal is recommended:
significantly ↑es absorption
 A sweetened dispersible formulation of Coartem® has been
approved for treatment of children

☞ Amodiaquine
 A congener of chloroquine
 Not recommended for for chemoprophylaxis: toxicities (hepatic

& agranulocytosis)
 Rapidly converted by hepatic CYPs into monodesethyl-

amodiaquine
 This metabolite, retains substantial antimalarial activity, has a

t½ of 9-18 days & reaches peak conce. of 500nM, 2 h after PO
 Amodiaquine: t½; 3 h, attaining a peak conce. of 25 nM, 30’

after PO

☞ Piperaquine:
 Potent & well-tolerated bisquinoline, structurally related to
chloroquine
 Has a large Vd & reduced rates of excretion after multiple
doses
 It is rapidly absorbed, with a Tmax of 2 h after a single dose
 Has the longest plasma t½: (5 wks) of all ACT partner drugs;
 Contribute to reducing rates of reinfection following treatment

☞ Pyronaridine:
 Structurally related to amodiaquine
 Well tolerated & potent against: P. falciparum & P. vivax
 Fever resolution in 1-2 days & parasite clearance in 2-3 days
 Under clinical trials as a partner for artemisinin

✍ Atovaquone + proguanil HCl: 250 + 100 mg; Malarone®
☞ Atovaquone: a hydroxynaphthoquinone
 MOA: disrupting mitochondrial electron transport
 Active against tissue & erythrocytic schizonts, allowing
chemoprophylaxis to be discontinued only 1 week after the
end of exposure (compared with 4 weeks for mefloquine or
doxycycline, which lack activity against tissue schizonts)

 PKs:
 ROA: PO only
 BA is low & erratic, but absorption is ↑ed by fatty food
 Heavily protein-bound, has t½ of 2-3 days
 Elimination: unchanged in the feces (mostly)

 Use:
 Mlarone: chemoprophylaxis & Rx of uncomplicated P.

falciparum malaria in adults & children
 For chemoprophylaxis: must be taken daily
 Advantage over mefloquine & doxycycline: requires shorter

periods of treatment before and after the period at risk for
malaria transmission, but it is more expensive
 Atovaquone approved for mild-moderate PCP: 750 mg BID

with food for 21 days, but lower efficacy than Cotrimoxazole
 Effective for unresponsive toxoplasmosis (small pts)

 AEs:
 NVD, abdominal pain, headache, insomnia, rash: at higher
dose required for treatment
 Reversible elevations in liver enzymes have been reported
 Not used in pregnancy: safety is unknown
 Safe for use in children with body weight > 5 kg
 TTC or Rifampin ↓ed  50% plasma conce. of atovaquone

QUININE & QUINIDINE
 Quinine: an alkaloid derived from the bark of cinchona tree
 Consists of a quinoline ring linked by a secondary carbinol to a
quinuclidine ring
 Quinidine: a stereoisomer of quinine, more potent & more
toxic than quinine
 MOA: bind heme & prevent its detoxification

 Pharmacological effects:
 Quinine acts primarily as blood schizonticidal
 Gametocidal for P.Vivax, P.Ovale, P.Malariae
 Not effective in liver stage parasite
 Quinine is the DOC for severe chloroquine resistant & MDR
strains of P.falciparum

 PKs:
 Quinine:
 Rapidly absorbed after PO, Tmax: 1-3 hr
 Bound with plasm proteins & widely distributed
 Metabolized by liver & excreted in the urine
 Quinidine has a shorter t½ than quinine: due to↓ed protein
binding

 For treatment only: as parenteral & oral agent
 Used with a 2nd agent in drug-resistant P.falciparum
 For drug-resistant parasites, the 2nd agent is doxycycline,
tetracycline, pyrimethamine sulfadoxine, or clindamycin
 1st line therapy for Babesiosis (Babesia microti) in combination
with clindamycin

 Quinidine gluconate:
 Indicated for severe or complicated malaria
 Is used in conjunction with doxycycline, tetracycline, or
clindamycin

 AEs:
 Cinchonism: tinnitus, nausea, head ache, dizziness, flushing
 Hyperinsulinema: severe hypoglycemia
 Stimulate uterine contraction
 Black water fever: marked hemolysis & hemoglobinuria due to

hypersensitivity reaction to the drug
 CIs: hypersensitivity reaction to quinine, severe cinchonism
 Absorption blocked by aluminum containing antacids
 Should not be given with Mefloquine: cardiac arrest

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

 Effective against P.vivax, P.ovale, P.malariae & drug-sensitive

P.falciparum
 It can be used for prophylaxis or treatment
 Prophylactic drug of choice for sensitive malaria
 Amebic liver abscess: with metronidazole
 Rheumatoid arthritis
 Discoid lupus erythromatous

 AEs:
 CVS (parenteral dose): vasodilation, hypotension, decrease

myocardial infarction, ECG changes
 Oral route can cause (high dose):
 Visual disturbance, urticarial, head ache, GI upset
 Rare reaction include hemolysis in pts with G6PD deficient
 High daily doses of chloroquine: irreversible ototoxicity &

retinopathy
 Contraindication: psoriasis, porphyria cutanea tarda it may

precipitate acute attacks of these diseases

MEFLOQUINE
 MOA: effective blood schizonticide
 It may act by raising intravesicular pH within the parasite's
acid vesicles
 Mefloquine is structurally similar to quinine
 It is used for the prophylaxis or Rx of drug-resistant malaria

 AEs:
 NVD, abdominal pain, dizziness, dysphoria
 Higher doses cause;
 Neuropsychiatric toxicity: disorientation, seizure,

encephalopathy
 Alter cardiac conduction, arrhythmias & bradycardia
 Contraindications:
 Depression, generalized anxiety disorder, psychosis, or

schizophrenia or other major psychiatric disorders
 Combination with quinine & quinidine  arrhythmia

PRIMAQUINE: synthetic 8-aminoquinoline
 MOA: not completely understood
 Metabolites of primaquine are believed to act as oxidants that
are responsible for the schizonticidal action as well as for the
hemolysis & methemoglobinemia encountered as toxicities
 Active against hepatic stages of all human malarial parasite
 Gametocidal
 Not used to treat the erythrocytic stage of malaria

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

 AEs:
 Infrequently causes: nausea, epigastric pain, abdominal

cramp, head ache
 Hemolysis & methehemoglobinemia especially in persons with

G6PD deficiency
 Contraindication:
 Granulocytopenia, methemoglobinemia
 Pregnancy as the fetus is deficient in G6PD

Tafenoquine
 An 8-aminoquinoline derivative
 The 150-mg tablet is indicated for the radical cure (prevention
of relapse) of P.vivax malaria in pts ≥16 yrs, who are receiving
appropriate antimalarial therapy for acute P.vivax infection
 Administered as a single 300 mg dose co-administered on the
1st or 2nd day of appropriate antimalarial therapy

 Active against all stages of P.vivax life cycle, including
hypnozoites
 Also indicated for adults ≥18 yrs as prophylaxis when traveling
to malarious areas
 For this, 100-mg tablet is administered as a loading dose
(before traveling to endemic area), a maintenance dose while
in malarious area & then a terminal prophylaxis dose in the
week exiting the area

Inhibitors of Folate Synthesis: Pyrimethamine, Proguanil
 MOA: inhibit dihydrofolate reductase of plasmodia
 Therapeutic uses: with sulphonamide
 Not 1st line because it is slow to act
 Suppressive Rx of chloroquine resistant P.falciparum
 Given concurrently with sulfadiazine for Rx of toxoplasmosis
 AEs: erythema multiform, SJS, Toxic epidermal necrosis

PROGUANIL
 Prodrug, metabolized to an active metabolite, cycloguanil
 MOA:
 Inhibits DHFR, inhibition of DNA synthesis, depletion of folate

co-factors
 Slow antimalarial action
 With chloroquine used as alternative to Mefloquine for

prophylaxis
 Not suitable for acute attack
 Considered
Chemotherapy safe during Compiled
pregnancyby Birhanu Geta 453
Antimicrobials
 Doxycycline: prophylaxis or treatment
 For Rx of P falciparum malaria, this drug must be used as part
of combination therapy (eg, typically with quinine or quinidine)
 Tetracycline may specifically impair the progeny of apicoplast
genes, resulting in their abnormal cell division
 Loss of apicoplast function in progeny of treated parasites
leads to slow, but potent, antimalarial effect

 Clindamycin is part of combination therapy for drug-resistant
malaria: with quinine or quinidine
 It is a good second agent in pregnant patients

AMOEBICIDES
 Amebiasis: infestation with E.hystolytica
 Usually asymptomatic, when symptoms are present the most
characteristics are: diarrhea & abdominal pain

 Asymptomatic intestinal infection: cyst
 In nonendemic areas they are treated by luminal amebicide:

diloxanide furoate, iodoquinol, paramomycin
 Therapy with a luminal amebicide is also required in the Rx of

all other forms of amebiasis
 Amebic colitis: metronidazole PLUS luminal amebicide is the

Rx of choice for colitis & dysentery
 TTC & erythromycin are alternative for moderate colitis
 Dehydroemetine or emetine can also be used(toxic)
 Extra-intestinal infections: metronidazole + a luminal agent

Classification of Antiamebic agents
 Luminal Amebicides: diloxanide, idoquinol, TTcs, paramomycin
 Tissue Amebicides
 Both intestinal & extraintestinal
 Metronidazole, Tinidazole
 Emetine & Dihydroemetine
 For extraintestinal only: chloroquine

METRONIDAZOLE
 MOA:
 Amebas possess ferredoxin-like, low-redox-potential, electron

transport proteins that participate in metabolic electron
removal reactions
 The nitro group of metronidazole is able to serve as an

electron acceptor, forming reduced cytotoxic compounds that
bind to proteins & DNA → death of the E. histolytica
trophozoites

 PKs:
 Absorption: complete & rapid after PO
 Distribution: well throughout the body
 Found in vaginal & seminal fluids, saliva, breast milk & CSF
 Metabolism: depends on hepatic oxidation of its side chain by

mixed-function oxidase, followed by glucuronidation
 Inducers of CYP450 enhances the rate of metabolism &

inhibitors prolong the plasma half-life
 The drug accumulates in pts with severe hepatic disease
 Excretion: via urine (parent drug & its metabolites)

 Amebiasis: for all symptomatic tissue infections; with luminal

amebicide. Combination provides cure rates of > 90%
 Gardiasis: highly effective, lower dosage than for amebiasis
 Trichomoniasis: highly effective, can be given topically
 Anaerobic (G-ve) bacterial infection: bacteriodes, clostridium

(pseudomembranous colitis), fusobacterium
 H. pylori (PUD): with other ABX
 To facilitate extraction of guinea worm in drancunculiasis

 AEs:
 Common: N, headache, dryness of mouth, metallic taste,
dizziness
 Has a disulfiram like effect: copious vomiting, flushing,
palpitation, head ache
 Used with caution in pts with active disease of CNS
 Not recommended in 1st trimester
 Mutagenic
 Drug interaction:
 With alcohol: disulfiram like effect
 Inhibits inactivation of oral anticoagulant
 Phenobarbitone: enhaced metabolism of metronidazole
 Cimetidine: reduces metabolism of metronidazole

TINIDAZOLE
 2nd generation nitroimidazole
 Similar to Metronidazole
 Differ in: better toxicity profile & higher t½

DILOXANIDE FUROATE
 Useful in the Rx of:
 Asymptomatic passers of cyst.
 In conjugation with metronidazole in the Rx of intestinal &
systemic amebiasis
 90% absorbed & the nonabsorbed is effective
 AEs: flatulence, dryness of mouth, pruritus

EMETINE & DEHYDROEMETINE
 MOA: inhibits protein synthesis by blocking chain elongation
 IM is the preferred route, since it is irritant when taken PO
 Due to its toxicity: replaced by metronidazole
 Use: as alternative agent
 AEs:
 Transient NV, pain at the site of injection
 Cardio toxicity: arrhythmia, CHF
 Neuromuscular weakness
 Dizziness & rash

Nitazoxanide
 A nitrothiazolyl-salicylamide prodrug
 Rapidly absorbed & converted to tizoxanide & tizoxanide
conjugates & subsequently excreted in both urine & feces
 MOA: tizoxanide inhibits the pyruvate-ferredoxin
oxidoreductase pathway
 Approved against Giardiasis & Cryptosporidiosis

 Have activity against metronidazole-resistant protozoal strains
 E.histolytica, H.pylori, A.lumbricoides, several tapeworms,
Fasciola hepatica. The recommended adult dosage is 500 mg
twice daily for 3 days
 AEs: VD, abdominal pain, headache, yellow sclerae (rarely)

Drugs For Pneumocystis Jiroveci Pneumonia (PCP)
 Cotrimoxazole
 Pentamidine
 Trimethoprim + Dapsone
 Primaquine + Clindamycin
 Drugs for Trichomoniasis: Metronidazole, Tinidazole
 Drugs for Toxoplasmosis: Pyrimethamine + Sulfadoxine =

(FANSIDAR®)
 Pyrimethamine + Sulfadiazine

DRUGS FOR LEISHMANIASIS
 Has three different forms:
 Cutaneous leishmaniasis
 Mucocutaneous leishmaniasis
 Visceral leishmaniasis: kalazar

 Drugs include:
 Sodium Stibogluconate (SSG): 1st line agent
 Meglumine antimonite (MA)
 Pentavalent antimony (Sb)
 Allopurinol + SSG
 Miltefosine: visceral
 Amphotericin-B
 Ketoconazole
Drugs for Trypanosomiasis: African Sleeping Sickness
 Caused by:
 Trypanosomia brucei gambiense
 Slow to enter CNS
 Causes sleeping sickness
 Suramine & Pentamidine are used in early stage:

hemolymphatic stage of the disease
 Pentamidine interferes with parasite synthesis of RNA, DNA,

phospholipids & proteins
 Enflornithine: used in early stage or CNS involvement

 Trypanosomia brucei rhodesiense
 Early invasion of the CNS
 Usually fatal if not treated
 Melarsoprol: a trivalent arsenical compound
 MOA: reacts with sulfhydryl groups of various substances:

enzymes in both the organism & host
 Use:
 1st line: in early CNS involvement in East African

trypanosomiasis
 2nd line (after eflornithine): in early CNS involvement in West

African
ChemotherapytrypanosomiasisCompiled by Birhanu Geta 476
Chaga’s Disease: American Trypanosomias
 Caused by Trypanosoma cruzi
 Parasites invade cardiac cells & neurons of myenteric cause
cardiomyopathy & mega colon  death
 Rx options:
 Nifurtimox &
 Benznidazole22

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

ANTHELMINTICS
 Drugs that act either; locally to expel worms from the GIT or
systemically to eradicate adult helminths or dev’tal forms that
invade organs & tissues
 Helminthes: parasitic worms can be classified in to;
 Round worms (nematodes), flat worms (trematodes, cestodes)
480
☞ Nematodes (roundworms)
 Ascaris lumbricoids (common round worms)
 Hook worms (Nectar americanus, Ancylostoma duodenale)
 Whip worm (Trichuris trichiura)
 Thread worm (Strongloides stercolaris)
 Pin worm (Enterobius vermicularis)
 Trichinella spiralis (trichinosis)
 Trichinela spiralis (trichinosis)
 Dranculus medinesis (guinea worm)
 Wuchereria bancrofti (Filareasis )

481
☞ Cestodes (Tapeworms)
 Taenia saginata (Beef tapeworm)
 Taenia solium (Pork tapeworm)
 Diphyllobothrium latum (Fish tapeworm)
 Hymenolopis nana (Dwarf tapeworm)
☞ Trematodes (Flukes)
 Schistosoma haematobium (bilharziasis)
 Schistosoma mansoni
 Shistosoma japonicum
482
Nematode infestation: intestinal
 Ascariasis: giant round worm infestation
 Most prevalent helminthic infestation
 Adult worm inhabit the intestine, heavy infestation 
intestinal blockade
 DOC: Albendazole, Mebendazole, Pyrantel pamoate
 Alternatives: Piperazine citrate 4g stat, Levamisole??

Albendazole
 MOA: produce many biochemical changes
 Inhibits microtubule polymerization  degeneration of

cytoplasmic microtubules
 Decreases ATP production → immobilized → die
 Inhibition of mitochondrial fumarate reductase
 Uncoupling of oxidative phosphorylation
 PKs: erratically absorbed after PO
 Rapid 1st pass metabolism in liver to albendazole sulfoxide
 absorption when taken with fatty meal

 Broad antiparasitic spectrum
 Effective as single dose for the Rx of;
 A.lumricoides: 400mg for children
 Hookworm: Ankylostoma.duodenalis (A.duodenalis) & N.
americanus
 Trichuris trichuria (T.trichuria)

 Also effective against:
 E.vermicularis, T.spiralis
 S.sterocoralis: invermectin is superior
 High dose in Rx of hydatid disease
 Useful for Rx of neurocycticercosis: superior to praziquantel
 Corticosteroids: used to control inflammatory response

 AEs:
 Fewer ADR when used for short term therapy: abdominal pain,
diarrhea, nausea & dizziness, head ache
 With protracted therapy: GI pain, severe head ache, fever,
fatigue, loss of hair, in serum transaminase, leucopenia &
thrombocytopenia

Mebendazole
 MOA: prevents uptake of glucose  immobilization & death
 Therapeutic use: DOC for most intestinal round worms: pin
worm, hookworm, whipworm, Giant worm
 PKs: only 5-10% is absorbed & rapidly metabolized
 AEs:
 Transient abdominal pain & diarrhea: massive infestation
 Embryocytotoxic & teratogenic in rats

Pyrantel Pamoate
 MOA: depolarizing neuromuscular blocker, slowly paralyze the
worm & will be eliminated from GIT
 Alternative to mebendazole for infestation with: hookworm,
pinworm, Giant worms
 DOC: during pregnancy

Piperazine Citrate
 MOA: paralysis of ascaris by blocking Ach
 Alternative to albendazole or mebendazole in the Rx of
ascariasis
 AEs: NVD, dizziness & headache

 Enterobiasis: Pinworm infestation
 Most common helminthic
 Serious infections are rare but may cause intense perineal
itching
 It is readily transmissible; family members should be treated
 DOC: Albendzole, Mebendazole, Pyrantel pamoate

 Ancylostomiasis & Necatoriasis: Hookworm infection
 Common in rural area: barefoot
 Adult worm attach to intestine  chronic blood loss  anemia
 Nausea, vomiting & abdominal pain
 DOC: Albendazole, Mebendazole, Pyrantel pamoate

 Trichuriasis: Whipworm infestation
 DOC: Mebendazole, Albendazole
 Strongloidiasis: Threadworm infestation
 Larva & adult inhabit small intestine
 DOC: Ivermectin, Albendazole, Thiabendazole

Thiabendazole
 MOA: inhibit helminth specific fumarate reductase
 Alternative drug against: Strongloidiasis, Trichinosis
 AEs: incidence is high, most common includes:
 GIT: anorexia, nausea & vomiting
 Neurological: dizziness & drowsines

Nematode infestation: extra intestinal
 Trichinosis: pork roundworm infestation
 Acquired by eating uncooked pork infested with encycted larva

of T.spiralis.
 Adult worm reside in intestine; Lareva migrate to skeletal

muscle & become encysted.
 Symptoms: muscle pain, sore throat
 Potential lethal complications: HF, meningitis & neuritis
 DOC: Mebendazole, Albendazole
 Prednisolone: to inflammation during larva movement

 Wuchereriasis & Bruglasis: lymphatic filarial infestation
 W.bancrofti & B.malayi invade the lymphatic system
 Heavy infestation  lymphatic destruction  Elephantiasis
 DOC: diethylcarbamazine

Diethylcarbamazine
 PKs: readily absorbed & extensively metabolized
 Drug of choice for filarial infestations;
 Destroys microfilariae of W.bancrofti, B.malayi & Loa loa
 Onchocerciasis: but it does not kill the adult worm

 AEs:
 Reactions caused directly by DEC are minor:
 Headache, Dizziness, Nausea, Vomiting
 Occurring 2ndary to the death of the parasite are more serious:
rash, intense itching, encephalitis, fever, tachycardia,
lymphadenitis, leukocytosis, proteinuria
 These can be decreased by pretreatment with glucocorticoids

Onchocerciasis: river blindness
 O.volvulus is found in stream & rivers
 Heavy infestation causes:
 Dermatologic: nodules, pruritic dermatitis
 Opthalmic: occular lesions
 Drug of choice: Ivermectin

Ivermectin
 MOA: disrupts nerve traffic & muscle function in target
parasite
 PKs: administered PO, poor CNS penetration
 Therapeutic uses: onchocerciasis, intestinal strongloidiasis
 Used extensively in veterinary medicine

 AEs:
 Mazotti reaction: fever, urticarial, swollen & tender lymph
nodes, tachycardia, hypotension, edema, athralgias when
used for onchocerciasis
 Due to allergic & inflammatory response to death of
microfilariae
 No data on pregnant women; teratogenic in mice, rats,
rabbits: cleft palate

Cestode infestations
 Taeniasis: beef & pork tape worm
 Treated by: praziquantel, Niclosamide
 Diphyllobothriasis: fish tapeworm infestation
 Worms are killed by: praziquantel, Niclosamide

Niclosamide
 MOA: inhibits mitochondrial oxidative phosphorylation in
tapeworm  cessation of ATP production  death
 Alternative to praziquantel in Rx of Cestode infestation
 AEs:
 Absorption is poor  systemic ADR is minimal
 GIT: ANV
Praziquantel
 MOA: absorbed by helminthes
 At low conce.  spastic paralysis  detachment of worms
 At high concentration  disruption of the tegument of the
worm  rendered vulnerable to lethal effect of host defenses
 Therapeutic uses: against cestodes & trematodes
 AEs: transient headache, abdominal discomfort, drowsiness

Trematode infestation
 Schistosomiasis: blood fluke infestation
 For both acute & chronic phase; DOC: praziquantel
 Faciliasis: liver fluke infestation
 DOC: Praziquantel
 Alternative: Bithionol
 Fasciolopsiasis: intestinal fluke infestation
 DOC: Praziquantel
Summary

Nematodes

ANTINEOPLASTICS
Pharmacology for ADHN Cancer Chemotherapy 510

Introduction
 Cancer is a group of disease characterized by the dev’t of
abnormal cells that divide uncontrollably & have the
ability to infiltrate & destroy normal body tissues
 Carcinogenesis:
 Transformation of a normal cell into a cancerous cell
 A multistage process that is genetically regulated;
 Initiation, promotion, conversion & progression

Causes
 Changes (mutations) to the DNA:
 Allow rapid growth
 Fail to stop uncontrolled cell growth: loss of tumor
suppressor genes
 Make mistakes when repairing DNA errors: mutation in
DNA repair genes

 Four regulatory genes are the main targets of mutation:
 Proto-oncogenes: proto-oncogene → mutation →
oncogene (e.g src, myc, ras)
 Tumor suppressor genes: p53, Rb
 Genes regulating apoptosis
 Genes involved in DNA repair (mutation → fail to repair
DNA mutations)

 Proto-oncogenes:
 In normal cells, code for proteins involved in the stimulus
of cell division
 If altered, may form oncogenes
 Alone, do not cause malignant cancer
 Require other mutations, including one in a tumor
suppressor gene

 Tumor suppressor genes:
 Inhibit cell growth & division; prevent cancer formation
 May prevent expression of oncogenes
 Rb, BRCA1, BRCA2, p53
 The p53 gene is the best-established tumor suppressor
gene identified to date

 p53: codes for a regulatory protein that turns off cell
division when the cell is stressed or damaged
 If mutated, cell division occurs even in the presence of
damaged DNA
 More than half of cancers has a mutated or missing p53
gene

Main Features of Benign & Malignant neoplasms;

The Role of Chemotherapy in the Treatment of Cancer;
☞ Chemotherapy used alone with curative intent
☞ Chemotherapy used as adjuvant therapy with curative
intent
 Chemotherapy is administered after surgery,
 To reduce the incidence of both local & systemic
recurrence & to improve the overall survival of patients

☞ Chemotherapy used as neoadjuvant therapy
 To reduce the size of the primary tumor so that surgical
resection can then be made easier
☞ Chemotherapy used to palliate symptoms in advanced
disease

Effects of various treatments on the cancer cell
burden in a hypothetical patient;

Tumor susceptibility & the growth cycle
 The fraction of tumor cells that are in the replicative cycle
(growth fraction) influences their susceptibility to most
cancer chemotherapeutic agents
 Rapidly dividing cells are more sensitive to chemotherapy
 Slowly dividing cells are less sensitive to chemotherapy
 In general, non dividing cells (those in the G0 phase)
usually survive the toxic effects of many of these agents

Cell Cycle & Cancer

Cell cycle specificity of drugs
 Both normal cells & tumor cells go through growth cycles
 However, the number of cells that are in various stages of the

cycle may differ in normal & neoplastic tissues
 Chemotherapeutic agents that are effective only against

replicating cells are said to be cell cycle specific whereas other
agents are said to be cell cycle nonspecific
 The nonspecific drugs, although having more toxicity in cycling

cells, are also useful against tumors that have a low
percentage of replicating cells

Tumor growth rate
 The growth rate of most solid tumors in vivo is initially
rapid, but growth rate usually ↓es as the tumor size ↑es
 This is due to the unavailability of nutrients & oxygen due
to inadequate vascularization & lack of blood circulation

 Tumor burden can be reduced through surgery, radiation,
or by using cell cycle-nonspecific drugs:
 To promote the remaining cells into active proliferation
 Thus increasing their susceptibility to cell cycle-specific
chemotherapeutic agents

Treatment regimens & scheduling
 Drug dosages are usually calculated on the basis of body

surface area
 Log kill phenomenon:
 Destruction of cancer cells by chemotherapeutic agents

follows first-order kinetics;
 A given dose of drug destroys a constant fraction of cells
 The term “log kill” is used to describe this phenomenon

Pharmacologic sanctuaries:
 Leukemic or other tumor cells find sanctuary in tissues such as
the CNS, where BBB prevent certain chemotherapeutic agents
from entering
 Irradiation of the craniospinal axis or intrathecal administration
of drugs to eliminate the leukemic cells at that site
 Similarly, drugs may be unable to penetrate certain areas of
solid tumors
Treatment protocols:
 Combination drug chemotherapy is more successful than
single-drug treatment in most of the cases
 Cytotoxic agents with qualitatively d/t toxicities & with d/t
molecular sites & MOA, are usually combined at full doses
 Results in higher response rates, due to additive &/or
potentiated cytotoxic effects & non-overlapping toxicities

 Advantages of drug combinations:
 Provide maximal cell killing within the range of tolerated
toxicity
 Effective against a broader range of cell lines in the
heterogeneous tumor population &
 May delay or prevent the dev’t of resistant cell lines

 Many cancer treatment protocols have been developed, and
each one is applicable to a particular neoplastic state
 They are usually identified by an acronym: e.g
 R-CHOP for the Rx of non-Hodgkin lymphoma consists of;
 Rituximab, Cyclophosphamide, Hydroxydaunorubicin
(doxorubicin), Oncovin (vincristine) & Prednisone/prednisolone

 Therapy is scheduled intermittently (14/21 days apart)
 To allow recovery or rescue of the patient’s immune
system, which is also affected by the chemotherapeutic
agents, thus reducing the risk of serious infection

Problems associated with chemotherapy
 Resistance: melanoma: inherently resistant
 Multidrug resistance: P-gp pumps drugs out of cells
 Toxicity: drugs have narrow TI
 Severe vomiting, stomatitis, bone marrow suppression & alopecia
 Myelosuppression: common to many chemotherapeutic agents
 Cystitis: cyclophosphamide; cardiotoxicity: doxorubicin & pulmonary
fibrosis: bleomycin
 Alopecia is transient, but the cardiac, pulmonary & bladder toxicities
can be irreversible
 Treatment-induced tumors:
 Most antineoplastic agents are mutagens,
 Acute non lymphocytic leukemia may arise 10 or more
years after the original cancer is cured
 A problem after therapy with alkylating agents
 Most tumors that develop from cancer chemotherapeutic
agents; respond well to treatment strategies

Classification of Anticancer Drugs

Cell Cycle-Specific (CCS) Agents

Cell Cycle-Nonspecific (CCNS) Agents

Alkylating Agents
 They exert their cytotoxic effects via transfer of their alkyl
groups to various cellular constituents
 Major mechanism: alkylation of DNA → cell death
 The major site of alkylation within DNA is the N7 position of
guanine; however,
 Other bases are also alkylated although to lesser degrees,
including N1 & N3 of adenine, N3 of cytosine & O6 of guanine,
as well as phosphate atoms & proteins associated with DNA

 AEs:
 Generally dose-related & occur primarily in rapidly growing
tissues: bone marrow, GIT, reproductive system
 Nausea & vomiting
 Potent vesicants & can damage tissues at the site of
administration as well as produce systemic toxicity
 Carcinogenic: increased risk of secondary malignancies
 Especially acute myelogenous leukemia

Cyclophosphamide & ifosfamide
 Cytotoxic only after generation of their alkylating species, w/c
are produced through hydroxylation by hepatic CYP450
 The hydroxylated intermediates then undergo breakdown to
form the active compds, phosphoramide mustard & acrolein
 Use: have a broad clinical spectrum, used either singly or as
part of a regimen in non-HL, sarcoma & breast cancer

Antineoplastics Compiled by Birhanu Geta 543
 AEs:
 Unique toxicity of both drugs is hemorrhagic cystitis, which
can lead to fibrosis of the bladder
 Neurotoxicity has been reported in pts on high-dose ifosfamide
 Nitrosoureas: Carmustine, lomustine
 B/c of their ability to penetrate CNS, primarily employed in the
Rx of brain tumors

Antimetabolites
 Interfere with the availability of normal purine or pyrimidine
nucleotide precursors, either by;
 Inhibiting their synthesis or competing with them in DNA or
RNA synthesis
 Maximal cytotoxic effects are in S-phase (cell cycle specific)

Methotrexate
 Structurally related to folic acid & acts as an antagonist of the
vitamin by inhibiting mammalian DHFR
 Use: with other agents, against acute lymphocytic leukemia,
Burkitt lymphoma in children, breast cancer, bladder cancer &
head and neck carcinomas
 Low-dose MTX alone: for inflammatory diseases: severe
psoriasis, rheumatoid arthritis, Crohn disease

 AEs:
 N/V/D, stomatitis, rash,
alopecia, myelosuppression,
 High-dose: renal damage
 IT administration: neurologic
toxicities

5-Fluorouracil
 MOA: it self devoid of antineoplastic activity
 It enters the cell via carrier-mediated transport system &

converted to 5-FdUMP, competes with dUMP for thymidylate
synthase, thus inhibiting its action
 Lack of thymidine  DNA synthesis  imbalanced cell

growth & thymidine-less death of rapidly dividing cells
 Leucovorin is administered with 5-FU, b/c the reduced folate

coenzyme is required in the thymidylate synthase inhibition
 A standard regimen for advanced colorectal CA: Irinotecan +

5-FU + Leucovorin
6-Mercaptopurine
 The thiol analog of hypoxanthine
 6-MP & 6-thioguanine were the first purine analog
 Azathioprine, an immunosuppressant, exerts its cytotoxic
effects after conversion to 6-MP

 MOA:
 6-MP must penetrate target cells & converted to the
nucleotide analog, 6-MP-ribose phosphate (aka 6-thioinosinic
acid or TIMP) → inhibition of purine synthesis;
✍ Inhibition of first step of de novo purine ring biosynthesis
(catalyzed by glutamine phosphoribosyl pyrophosphate
amidotransferase)
✍ Blockage of the formation of adenosine monophosphate &
xanthinuric acid from inosinic acid

✍ Incorporation into nucleic acids:
 TIMP is converted to thioguanine monophosphate,
 Which after phosphorylation to di- & triphosphates can be
incorporated into RNA
 The deoxyribonucleotide analogs that are also formed are
incorporated into DNA → nonfunctional RNA & DNA

 Indications:
 Principally in the maintenance of remission in acute
lymphoblastic leukemia
 Crohn disease: 6-MP & its analog, azathioprine

MICROTUBULE INHIBITORS
 The mitotic spindle is:
 Part of a larger cytoskeleton that is essential for the
movements of structures occurring in the cytoplasm of all
eukaryotic cells
 Consists of chromatin plus a system of microtubules
composed of the protein tubulin

 Essential for the equal partitioning of DNA into the 2 daughter
cells that are formed when a eukaryotic cell divides
 Several plant-derived anticancer drugs disrupt this process by
affecting the equilibrium b/n the polymerized & depolymerized
forms of the microtubules  cytotoxicity
 Vinca alkaloids: dis assemble the microtubules

 Vincristine: VX (Oncovin), vinblastine: VBL, vinorelbine: VRB
 Structurally related compounds derived from the periwinkle
plant, Vinca rosea  referred as Vinca alkaloids
 They have different therapeutic indications
 Generally used in combination: e.g R-CHOP
 VX is used for ALL in children, Wilms tumor, Ewing soft tissue
sarcoma & HL & N-HL & other rapidly proliferating neoplasms

 Due to relatively mild myelosuppressive activity, VX is used in
a number of other protocols
 VBL with bleomycin & cisplatin: for RX of metastatic testicular
CA, systemic HL & N-HL
 VRB: for advanced non-small cell lung CA, either as a single
agent or with cisplatin

 Taxane: Paclitaxel & docetaxel
 Paclitaxel the first taxane used in the Rx of cancer
 A semisynthetic & albumin-bound form is also available
 Substitution of a side chain  docetaxel: potent
 Paclitaxel has good activity against advanced ovarian &

metastatic breast cancer
 Favorable results have been obtained in non-small cell lung

cancer when administered with cisplatin
 Docetaxel is commonly used in prostate, breast, GI & non-

small cell lung cancers

 MOA:
 They are active in the G2/M-phase, but unlike the Vinca
alkaloids, they promote polymerization & stabilization of the
polymer rather than disassembly, leading to the accumulation
of microtubules
 The overly stable microtubules formed are non-functional, &
chromosome desegregation doesn’t occur  death of the cell

ANTIBIOTICS
 MOA:
 Interact with DNA/intercalated/  disruption of DNA function
 Inhibit topoisomerases (I & II)
 Produce free radicals: major role in their cytotoxic effect
 E.g: Anthracyclines, bleomycin
 Are cell cycle nonspecific with exception of bleomycin

 Anthracyclines:
 Doxorubicin, Daunorubicin, Idarubicin, Epirubicin & Mitoxantrone
 Doxorubicin: hydroxylated analog of daunorubicin
 Idarubicin: 4-demethoxy analog of daunorubicin
 Despite their structural & MOA similarity, they have d/t applications
 Doxorubicin: most important & widely used
 With other agents for Rx of sarcomas & a variety of carcinomas:

breast & lung CA, ALL & lymphomas
 Daunorubicin & idarubicin: used in the Rx of acute leukemias
 Mitoxantrone: for prostate cancer

 MOA: doxorubicin-derived free radicals can induce membrane
lipid peroxidation, DNA strand scission & direct oxidation of
purine or pyrimidine bases, thiols & amines

 Bleomycin
 A mixture of d/t copper-chelating glycopeptides
 Cause scission of DNA by an oxidative process
 Cell cycle specific & causes cells to accumulate in the G2

phase
 Use: primarily for testicular CA & Hodgkin lymphoma

 MOA:
 A DNA-bleomycin-Fe2+ complex appears to undergo oxidation
to bleomycin-Fe3+
 The liberated electrons react with oxygen to form superoxide
or hydroxyl radicals, which, in turn, attack the phosphodiester
bonds of DNA  strand breakage & chromosomal aberrations

PLATINUM COORDINATION COMPLEXES
 Cisplatin, carboplatin, oxaliplatin
 Cisplatin: the 1st member, severely toxic  dev’t of
carboplatin
 Have same MOA, d/t potency, PK, toxicities
 Cisplatin is synergistic with radiation & chemotherapy

 Cisplatin is used:
 As monotherapy for bladder CA
 With VBL & bleomycin for metastatic testicular CA
 With cyclophosphamide for ovarian CA
 Carboplatin: alternative to cisplatin in pts can’t be vigorously
hydrated or with kidney failure or prone to neuro- or
ototoxicity
 Oxaliplatin related to carboplatin: for Rx of colorectal CA

 MOA: similar to alkylating agents
 In the high-chloride milieu of the plasma, cisplatin persists as

the neutral species, w/c enters the cell and loses its chlorides
in the low-chloride milieu
 Binds to guanine in DNA, forming inter-& intrastrand

crosslinks
  inhibition of both polymerases for DNA & RNA synthesis
 Cytotoxic @ any stage of the cell cycle, but cells at G1 & S-

phases are most vulnerable

TOPOISOMERASE INHIBITORS
 Topoisomerase: reduce supercoiling or relieve torsional strain

in DNA by causing reversible, single-strand breaks
 Camptothecins
 Plant alkaloids originally isolated from the Chinese tree

Camptotheca
 Irinotecan & topotecan: semisynthetic derivatives
 Topotecan is used in metastatic ovarian CA when primary

therapy has failed & in the Rx of small cell lung CA
 Irinotecan + 5-FU + leucovorin: Rx of colorectal CA

 MOA:
 S-phase specific & inhibit topoisomerase I, w/c is essential for
the replication of DNA in human cells
 SN-38 (the active metabolite of irinotecan) is  1000 X as
potent as irinotecan

 Etoposide:
 A semisynthetic derivative of the plant alkaloid,

podophyllotoxin
 Blocks cells in the late S- to G2 phase of the cell cycle
 Major target is topoisomerase II: binding of the drug to the

enzyme-DNA complex  persistence of the transient,
cleavable form of the complex & thus, renders it susceptible
to irreversible double-strand breaks
 Use: lung CA & testicular CA (with bleomycin & cisplatin)

Targeted Therapies: MABs, Tyrosine Kinase Inhibitors
 Monoclonal Antibodies:
 Directed at specific targets & often have fewer ADRs
 Created from B lymphocytes (from immunized mice or
hamsters) fused with “immortal” B-lymphocyte tumor cells
 The resulting hybrid cells can be individually cloned & each
clone will produce antibodies directed against a single antigen
type
 Recombinant technology  creation of humanized antibodies
that overcome the immunologic problems
 E.g: trastuzumab, rituximab, bevacizumab, cetuximab,
alemtuzumab (refractory B-cell CLL), panitumumab
(metastatic colorectal tumors), I131-tositumomab (relapsed
N-HL)

 Trastuzumab
 In patients with metastatic breast CA, overexpression of
transmembrane human epidermal growth factor receptor
protein 2 (HER2) is seen in 25% to 30% of patients
 HER2 overexpression: in gastric & gastroesophageal CAs
 Trastuzumab specifically targets the extracellular domain of
the HER2 growth receptor that has intrinsic tyrosine kinase
activity
 MOA:
 Binds to HER2 sites in breast, gastric, gastroesophageal CA &
inhibits the proliferation of cells that overexpress the HER2
protein, thereby ing the number of cells in the S-phase
 By binding to HER2, it blocks downstream signaling pathways,
induces antibody-dependent cytotoxicity & prevents the
release of HER2
 AEs: CHF; worsened if given with anthracyclines

 Rituximab
 The first mab to be approved for the Rx of cancer
 A genetically engineered, chimeric mab directed against the

CD20 antigen that is found on the surfaces of normal &
malignant B lymphocytes
 CD20 plays a role in the activation process for cell cycle

initiation & differentiation
 CD20 antigen is expressed on nearly all B-cell non-Hodgkin

lymphomas but not in other bone marrow cells
 Use: Rx of lymphomas, CLL, rheumatoid arthritis

 MOA:
 The Fab domain of rituximab binds to the CD20 antigen on
the B lymphocytes & its Fc domain recruits immune effector
functions, inducing complement and antibody dependent, cell-
mediated cytotoxicity of the B cells
 Commonly used in combination: R-CHOP

 Bevacizumab
 An IV antiangiogenesis agent
 With 5-FU for metastatic colorectal cancer
 It attaches to & stops VEGF from stimulating the formation of
new blood vessels (neovascularization)
 Without new blood vessels, tumors do not receive the oxygen
& essential nutrients necessary for growth & proliferation

 Cetuximab & panitumumab
 Cetuximab: a chimeric mab
 IV infusion for metastatic colorectal & head & neck cancers
 Both drugs target EGFR on the surface of cancer cells &
interfer with their growth
 Agents that target EGFR cause a distinct acneiform-type rash
 The appearance of this rash: associated with a positive
response to therapy
Summary of monoclonal antibodies

TYROSINE KINASE INHIBITORS
 Tyrosine kinases: involved in signal transduction, cell division…
 Imatinib, dasatinib, nilotinib
 Imatinib mesylate: for CML, GI stromal tumors
 Acts as a signal transduction inhibitor, used specifically to inhibit
tumor tyrosine kinase activity
 A deregulated BCR-ABL kinase is present in the leukemia cells of
almost every patient with CML

 In the case of GI stromal tumors, an unregulated expression
of tyrosine kinase is associated with a growth factor
 The ability of imatinib to occupy the “kinase pocket” prevents
the phosphorylation of tyrosine on the substrate molecule 
inhibition of subsequent steps that lead to cell proliferation
 Dasatinib & nilotinib are also first-line options for CML
 Available in PO form & associated with fluid retention & QT
prolongation
 Erlotinib:
 Inhibitor of the EGFR tyrosine kinase
 Oral agent for non-small cell lung CA & pancreatic CA
 Absorbed after oral administration
 Metabolism: extensively in liver by the CYP3A4
 AEs: ND, acne-like skin rashes, ocular disorders, interstitial
lung disease (acute dyspnea with cough): rare but fatal

 Sorafenib & sunitinib
 Oral serine/threonine & tyrosine kinase inhibitors
 Used mainly in renal cell carcinoma
 Sorafenib for hepatocellular CA, & sunitinib for GI stromal

tumors & pancreatic neuroendocrine tumors
 They target cell surface kinases that are involved in tumor

signaling, angiogenesis & apoptosis  slow in tumor growth
 AEs: D, fatigue, hand & foot syndrome & HTN

Monoclonal Trastuzumab
Antibodies
Bevacizumab
Cetuximab
Panitumumab
Tipifarnib
Lonafarnib
Lapatinib
Erlotinib
Imatinib
Sorafenib
Small
Molecule mTOR
TKIs/STIs
Hudis CA. NEJM 2007;357(1):41

MISCELLANEOUS AGENTS
 Procarbazine
 MOA: oxidative metabolite methylates DNA & inhibits DNA,
RNA & protein synthesis
 Use: HL & MM
 Distribution: rapidly equilibrates b/n plasma & CSF after PO
 Excretion: renal (metabolites & parent drug)

 AEs:
 BMS (major) & NVD are common
 Neurotoxicity (MAO inhibition): drowsiness, hallucinations,

paresthesias
 Pts should be warned against ingesting foods that contain

high levels of tyramine (aged cheeses, beer, wine):
hypertensive crisis
 With alcohol: disulfiram-like reaction
 Procarbazine is both mutagenic (nonlymphocytic leukemia) &

teratogenic

 Asparaginase & pegaspargase
 Some neoplastic cells require an external source of asparagine
b/c of limited capacity to synthesize sufficient amounts of the
amino acid to support growth & function
 L-Asparaginase & the pegylated formulation pegaspargase
catalyze the deamination of asparagine to aspartic acid &
ammonia, thus depriving the tumor cells of this amino acid,
which is needed for protein synthesis

 The form of the enzyme used chemotherapeutically is derived
from bacteria
 L-Asparaginase: for childhood ALL with VX & prednisone
 ROA: IV or IM, b/c destroyed by gastric enzymes
 AEs: hypersensitivity rxns (b/c foreign protein), a in clotting
factors, liver abnormalities, pancreatitis, seizures, & coma due
to ammonia toxicity

INTERFERONS
 Human INFs are biological response modifiers & classified into
3 types α, β & γ on the basis of their antigenicity
 INF- α: primarily leukocytic, INF-β &-γ are produced by
connective tissue fibroblasts & T lymphocytes, respectively
 Large quantities of pure INFs can be produced by rDNA
techniques
 Two species designated interferon-α-2a & 2b that are
employed in treating neoplastic diseases

 INF-α-2a: for hairy cell leukemia, CML, AIDS-related Kaposi
sarcoma
 INF-α-2b: for hairy cell leukemia, melanoma, AIDS-related

Kaposi sarcoma, follicular lymphoma
 INFs interact with surface receptors on other cells, at which

site they exert their effects
 Bound interferons are neither internalized nor degraded
 As a consequence of the binding of INF, a series of complex

intracellular reactions take place

 These include synthesis of enzymes, suppression of cell
proliferation, activation of macrophages, and increased
cytotoxicity of lymphocytes
 The exact mechanism of cytotoxicity is unknown
 Well absorbed after IM/SC, IV form of interferon-α-2b is also

available
 Undergo glomerular filtration & degraded during reabsorption,

but liver metabolism is minimal
 ADR: flu-like symptoms & GI upset are common, suicidal

ideation & seizures

 Abiraterone acetate
 An oral agent used in the Rx of metastatic castration-resistant

prostate cancer
 Used with prednisone to inhibit the CYP17 enzyme (for

androgen synthesis)  testosterone production
 Coadm.n with prednisone is required to help lessen the effects

of mineralocorticoid excess resulting from CYP17 inhibition
 Hepatotoxicity may occur & pts should be closely monitored

for HTN, hypokalemia, fluid retention
 Joint & muscle discomfort, hot flushes, diarrhea: common

 Enzalutamide
 An oral agent, works at the level of the androgen-signaling
pathway in the Rx of metastatic castrate-resistant prostate CA
in pts that have previously received docetaxel chemotherapy
 MOA: inhibits the binding of androgen to receptors & inhibits
androgen receptor nuclear translocation & interaction with
DNA

Summary: cell-cycle specificity of anticancer drugs
SUMMARY

“CHEMO MAN”

Mechanisms of resistance to anticancer drugs


Chemotherapy

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Chemotherapy

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CHEMOTHERAPY

Chemotherapy Compiled by Birhanu G. 1

 Use of chemical agents (natural/synthetic) to destroy or

inhibit the growth of infective agents &/or cancerous cells

 Antibiotics: s/ces produced by µorganisms to suppress

the growth & replication or kill other µorganisms

 N.B.: now antibiotics are synthesized in the laboratory

Chemotherapy Compiled by Birhanu G. 2

Antibacterials Antifungals Antivirals Antiparasitics

✍ Empiric therapy: symptomatic management

✍ Definitive therapy: identification of pathogen & DST

☞ Goal: selective toxicity

Chemotherapy Compiled by Birhanu G. 6

 Narrow spectrum: INH, Cloxacillin, Naldixic acid, Pen-G

 Broad spectrum: CAPH, TTCs, Rifamycins, FQs

 Penicillin, cephalosporins, vancomycin, FQs, aminoglycosides,

✍ MBC: the lowest concentration of ABX reduces the viability of

✍ Can be determined from broth dilution MIC

Chemotherapy Compiled by Birhanu G. 7

 TTCs, macrolides, amphenicols, lincosamides,

✍ Never confuse these terms with potency levels of the drugs or

efficacy: narrow are weak, broad are strong

Chemotherapy Compiled by Birhanu G. 8

Chemotherapy Compiled by Birhanu G. 10

☞ Origin of Drug Resistance

 Chromosomal mutation & selection: vertical

 Acquisition of chromosomal or extra chromosomal

 Conjugation: sexual reproduction

 Transformation: taking genetic material from env’t or dead

Chemotherapy Compiled by Birhanu G. 12

✍ Antimicrobials should be employed only when actually needed

✍ Narrow agents should be employed whenever possible

✍ Newer antibiotics should be reserved

Chemotherapy Compiled by Birhanu G. 13

✍ Confirm the presence of infection

☞ Careful history & physical examination

☞ Signs and symptoms

✍ Identification of the pathogen

☞ Collection of infected material

☞ Stains, serology, culture and sensitivity

✍ Host & Drug factors

 Age: causative agents, contraindication

 Disruption of host defenses (immunity):

 History of recent antimicrobial use

 Renal and/or hepatic function

 Concomitant administration of other medications

 Pregnant & nursing women and compliance

 Effects on nontargeted microbial flora

 AE (adverse event) & DI profile

 Severe infection of unknown etiology

 Enhanced action: penicillin + aminoglycoside = synergism

Chemotherapy Compiled by Birhanu G. 17

 Increase risk of allergy

 Antagonism of antimicrobial effect: TTC + penicillin

 Increase risk of super infection

Chemotherapy Compiled by Birhanu G. 18

Cell wall synthesis Fosfomycin

Bacitracin: poly peptides

Chemotherapy Compiled by Birhanu G. 20

Chemotherapy Compiled by Birhanu G. 21

 A thiazolidine ring: five-member

 The β-lactam ring & a side chain

 Cephalosporin nucleus, 7-aminocephalosporanic acid (7-ACA)

 A six-member dihydrothiazide ring,