Chemotherapy

Anti-infectives
 Topical
 Antiseptics
 Disinfectants
 Systemic
 Antihelmenthics
 Antimicrobials
 Antibacterial
 Antivirals
 Antifungal
 Antiprotozoal
Antimicrobials:
Introduction:
 Antimicrobial: is any substance of natural,
synthetic or semi synthetic origin that has the
ability to kill or inhibits the growth of
microorganisms, but causes little or no host
damage.
  Antibiotics: a chemical that is produced by a
microorganism that inhibits or kills other
microorganisms.
 Selective toxicity
 Means that a chemical produces injury to one kind of
living organism without harming another form of life
even though the two may exist in intimate contact
 Targets of chemotherapy of parasites
 Unique enzymes found only in parasite
 Indispensable enzymes only for parasite
 Common biochemical functions with different
pharmacological effect
 Activity
 Describe the nature of the effect of the antimicrobial
against microorganisms
 Bacteriostatic Vs bacteriocidal
 Spectrum
 Is description of range of activity of an
antimicrobial against microorganisms
 Narrow spectrum Vs broad spectrum
 Drug resistance
 Refers to the unresponsiveness of the microorganisms
to the maximum level of anti – microbial agents.
 Is classified as:
 Natural resistance
 Acquired resistance
 Mutation
 Gene transfer by: - Conjugation,transduction and transformation
 Delaying the emergence of resistance
 Use anti microbial agents only when needed.
 Uses narrow – spectrum antibiotics whenever possible.
 Newer antibiotics should be reserved for situations in
which older drugs are dangerous or no longer effective.
 Antibiotics are used for three general uses
 Empiric therapy: treatment of an infection before
specific culture information
 Definitive therapy: treatment of an infection after the
identification of an organism and its sensitivity to a
particular agent is made
 Prophylactic therapy: using antimicrobials to prevent
infection
 Indications for antimicrobial combinations
 For treatment of mixed bacterial infection.
 For severe infection where the causative agent is
unknown.
 To prevent emergency of resistant strains of organisms.
 To enhance antimicrobial activity.
 Disadvantages of antibiotic combinations
 Increased cost.
 Increased risk of allergic reactions and toxicity
 Increased risk of super infection.
 Possible antagonism of antimicrobial effects.
 Selection of drug resistant bacteria.
 Complications of antibiotic therapy
 Hypersensitivity
 Direct toxicity
 Super infection
Antibacterials

 Antibiotics : classes
 Beta lactams
 TTC (tetracyclines)
 Macrolides
 CAF (chloramphenicol)
 Aminoglycosides
 Peptides (vancomycine)
Beta lactams
 Drugs :

penicillins,cephalosporins,monobactams,carbapen
ems
 Pencillins
 Sir Alexader fleming (1928)
 Hydrolysis…pencillinic acid
 Addition of side chaine …different property
 Narrow spectrum of activity
 MOA:by bindig to PBP (transpeptidase)…dec
peptidoglycan…decrease cell wall synthesis
Classes
 Natural penicillins
 P.G (benzyl penicillin)
 P.V (phenoxymethyl penicillin)
 Semi-synthetic penicillins
 Penicillinase resistant
 Oxacillin,methicillin,cloxacillin,dicloxacillin,nafacilin
 Broad spectrum
 Orally effective
 Ampicillin,amoxacillin
 Orally infective
 Carbenecillin,ticarcillin,mezlocillin and azlocillin
 PG(penicillin G)
 Obtained p. chrysogenium
 Acid labile(not orally)
 Penicillinase sensetive
 Duration can be prologed by : conjugation with procain
 PV (penicillin V)
 Orally effective
 Pencillinase sensetive
 Narrow spectrum
 Penicillinase resistant  BSP
pen  Penicillase sense
 Orally effective  Action prolonged when
 PPB is high given with clavulinic
 NS acid
 ADRs
 Renal damage
 Diarrhea
 Hypersensitivity
 Cephalosporins
 First generations
 Active againest gram+ve
bacteria
 Do not cross BBB
 cephalexin, cephradine and
cefadroxil
 Second generations
 Against gram –ve
 Cefuroxime
 Third generations
 Less active than 1st gen agains
gm +ve cocci
 Have access to CNS
 Ceftriaxone and cefotaxim
 Fourth Generation
 More resistant to betta
lactamase
 cefipime
ADR
 Nephrotoxicity

 Diarrhea

 hypersensitivity
TTCs
 Demeclocyclin,Methacycline,Doxycycline,Minoc

ycline,Oxytetracycline etc
 Have four ring structure

 Broad spect

 Orally effective

 Cross BBB

 Concentrate in bile

 Form chelates with metallic ions such as

Ca,Mg,Al,Fe
 TTC:mechanism of action
 Bind to 30s ribosomes and prevent access of aminoacyl
tRNA to the acceptor site…inhibit protein synthesis
 Effect is selective to bacteria as active transport not
present in mamal and ribosomal targets are less
sensitive
 ADR
 GI upset
 Photosensitivity
 Teeth staining
 Fanconi syndrome
 Hepato-renal toxicity
 Bone growth retardation
Macrolides
 Erythromycin,clarithromyci
n mitochondrial pro synthesis
 MOA: bind to 50s rib and
inhibit protein synthasis
 ADR
 Superinfection
 Allergic rxns
 Cholestatic hepatitis
CAF
 MOA: bind to 50s rib and
inhibit protein synthesis and
in mammals
 ADR
 Bone marrow depression
 Hypersensitivity rxn
 GI adverse effect
 Gray baby syndrome
Aminoglycosides
 Streptomycine,neomycin,tobramycin,gentamycin,

amikacin etc
 Aminoglycosidic linkage

 Highly polar

 MOA: bind to 30s ribosomal subunit irriversibly

and inhibit protein synthesis

 ADRs:ototoxicity,neprotoxicity and

neuromuscular blockade.
Sulfonamides
 
 The antimetabolite antimicrobial
Mechanism of action
 Sulfonamides are structural analogs and competitive

antagonists of para – aminobenzoic acid (PABA) and

thus prevent normal bacterial utilization of PABA for
the synthesis of folic acid.
 More specifically, sulfonamides are competitive

inhibitors of dihydropteroate synthase

Pharmacokinetics
 Sulfonamides are well absorbed following oral

asministration
 They are widely distributed to tissues, body fluids

(including cerebrospinal fluid and the CNS)

placenta and fetus. They bound to plasma protein
in varying degree.
 Sulfonamides are excreted primarily by the

kidneys, mainly by glomerular filtration. In

significant renal failure, the dosage of
sulfonamide must be reduced.
 Classes:
 For systemic use
 Short acting agent : Sulfisoxazole
 Intermediate acting agent : sulfamethoxazole, Sulfadiazine
 Long acting : Sulfadoxine
 Enteral use : succinyl sulfathiazole
 For topical use : sulfacetamide,silver
sulfadiazine,sulfasalazine
Adverse effects
 Crystalluria, hematuria, renal failure

 Steven – Johnson syndrome, dermatitis

photosensitivity
 Bone marrow depression

 Haemolytic anemia

 Kernicterus
 Combination of a sulfonamide with an inhibitor of
dihydrofolate reductase (trimethoprim or
phyrimethamine) provides synergistic activity
because of sequential inhibition of folate synthesis
 The combination is known as co-trimoxazole
 Is bacteriocidal
Fluoroquinolones
 Synthetic antimicrobials: florinated analogues of
nalidixic acid
 Includees: Nalidixic acid, ciprofloxacin,
norfloxacin, ofloxacin, sparfloxacin,
grepafloxacin, levofloxacin,
 Against –ve and + ve
 Orally effective
 Chelate with divalent cations
 Are bacteriocidal
 Well absorbed orally
Mechanism of action
 The quinolones target bacterial DNA gyrase and

topoisomerase IV.
Adverse effects
 GI disturbances

 Headache

 Damage to growing cartilage

Anti-tuberculosis
 TB-caused by gram +ve aerobic bacteria-

mycobacterium tuberculosis
 S/S :include fever,night sweating,wt loss,blood

spitting,cough
 Type:TB
 Pulmonary TB
 Extra pulmonary TB
 Classes: anti-TB
 1st line drugs
 INH,rifampicin,ethambutol,pyrazinamide,streptomycin
 2nd line drugs
 Moved from 1st line ;PAS,ethionamide,
 Antibiotics old:capreomycin,cycloserine
 New;amikacin,rifabutin,AZT,clarithromycin,kanamycin
 Flouroquinolones;ofloxacin and ciprofloxacin
 Phases of treatment
 Intial phase:with quadruple therapy
 Objective-to kill vaible bacilli
 Drugs – INH+rifampicin+pyrazinamid+ethambutol
 Duration of Rx 2-3 month(1/3 course of therapy)
 Continued phase: with double therapy
 Obje-to suppress baccilli reproduction
 Drugs – INH + rifampicin
 Duration – 4-6 months
Antimalarial drugs

 Causative agent
 Plasmodium falciparum
 Plasmodium vivax
 Plasmodium ovalea
 Plasmodium malariae
 Vector female anopheles mosquito
Types of malaria chemotherapy
 Primary tissue schizontocidal therapy
 Causal prophylaxis
 Not routinely employed due to need daily adm
 Less effective againt vivax
 Proguanil and pyrimetamine
 Blood schizonticidal therapy
a. Clinical prophylaxis
 Inhibit asexual erythrocytic stage
 Chloquine , mefloquine,porguanil
b. Clinical cure
 Fast acting : chloroquine,quinine,artemisinin
 Slow acting : sulfadoxin/pyrimethamine
 Secondary tissue schizonticidal therapy
 Radical cure
 Para-erythrocytic stage
 Primaquine
 Gametocidal therapy
 Not employed for this purpose
 Primaquin for all
 Chloroquine and quinine for vivax
Specific drugs
 Chloroquine
 MOA: Inhibit conversion of toxic heme to non-toxic
hemozoin. Heme damages plasmodia.
 It is rapidly acting erythrocytic schizontocide against
all species of plasmodium
 No effect on exo-erythrocytic phase
 It is concentrated by intraerythrocytic plasmodia
 Oral absorption is excellent
 Metabolized by liver and excreted in urine
 ADRs:GI symptomes ,blurred vission,
headache,urticarial symptoms retinopathy
 Amodiaquine
 Structurally modified from chloroquine
 Similar kinetic and dynamic profile
 Used to treat chloroquine restistant strains
 Not preferred for prophylaxis due to toxicity
 Primaquine
 Orally effective
 Biotrans in liver and excreted in urine
 Mechanism not known : but oxidative stress
 Destroy hypnozoits and gametes of all species
 Not effective in the erythrocytic stage
 Used for radical cure of relapsing malaria
 Mefloquine
 Orally effective
 Bound to tissues and undergo enterohepatic circulation
 Used to treatment and prophylaxis of drug resistant
falciparum malaria
 Quinine
 Orally effective
 Bound to plasma protein
 Biotransform in liver and excreted in urin
 Used in the case of uncomplicated malaria and cerebral
malaria
 ADR:hypoglycemia ,hypotension ,cardiac arrhythmia and
hypersensetivity.

 Artemisinin & Its Derivatives
 The antimalarial activity of artemisinins may result from
the production of free radicals that follows the iron-
catalyzed cleavage of the artemisinin endoperoxide bridge
in the parasite food vacuole or from inhibition of a parasite
calcium ATPase.
 Artemisinin and its analogs are rapidly absorbed, with peak
plasma levels occurring in 1–2 hours and half-lives of 1–3
hours after oral administration.
 The compounds are rapidly metabolized to the active
metabolite dihydroartemisinin.
 Coartem® =lumefanthrine (120mg) + artemether (20mg).
 Other agents:-
 Halofantrine
 Lumefantrine
 Atovaquine
 Pyrimethamine
 Proguanil
 Sulfadoxine
 Doxycycline
 Mefloquine
 Antimalarial agents are usually used in
combination coz
 To reduce toxicity of individual drug
 To avoid recrudescence
 To delay resistance emergence
Treatment of amebiasis, giardiasis and
trichomoniasis
 Metronidazole
 Broad spectrum cidal activity against --- Protozoa –
E.histolytica, T.vaginalis, G.lamblia
 Mechanism : Nitro group is reduced to an intermediate
compounds which causes cytotoxicity by block ETC /
damaging DNA
 Well absorbed from the intestine, widely distributed
 Metronidazole and its metabolites are excreted mainly
in the urine
 ADR:Nausea, headache, dry mouth and metallic
taste are most common,
 Metronidazole has a disulfiram-like effect
 Diloxanide Furoate
 The mechanism of action of diloxanide furoate is
unknown.
 is an effective luminal amebicide but is not active
against tissue trophozoites.
 Diloxanide furoate does not produce serious adverse
effects.
 Flatulence is common, but nausea and abdominal
cramps are infrequent and rashes are rare.
 The drug is not recommended in pregnancy.
 Iodoquinol
 is an effective luminal amebicide that is commonly
used with metronidazole to treat amebic infections.
 excreted in the urine as glucuronides
 It is effective against organisms in the bowel lumen but
not against trophozoites in the intestinal wall or
extraintestinal tissues.
 Iodoquinol should be taken with meals to limit
gastrointestinal toxicity.
 ADRs;-diarrhea—which usually stops after several
days—anorexia, nausea, vomiting, abdominal pain,
headache, rash, and pruritus.
  
 Paromomycin Sulfate
 It is used only as a luminal amebicide and has no effect
against extraintestinal amebic infections.
 The small amount absorbed is slowly excreted
unchanged, mainly by glomerular filtration. However,
the drug may accumulate with renal insufficiency and
contribute to renal toxicity.
 Adverse effects include occasional abdominal distress
and diarrhea.
 Paromomycin should be avoided in patients with
significant renal disease and used with caution in
persons with gastrointestinal ulcerations.
Treatment of Leishmaniasis
 The drug of choice is sodiumantimony gluconate

(sodium stibogluconate).
 Alternative drugs are amphotericin B and

pentamidine.
Antiretroviral therapy
 Steps is HIV replication
 Binding
 Fusion
 Reverse transcription
 Integration
 Transcription
 Protease
 Assembly
 Maturity and release
 Classification
1.reverse transcriptase inhibitors
a. Nucleotide/nucleotide reverse transcriptase
inhibitors(NRTIs/NtRTIs)
 Zidovudine,didanosine,lamivudine,zalcitabine,stavudine,abaca
vir,emtricitabine,tenofovir
b. Non-nucleoside reverse transcriptase inhibitors
 Nevirapine ,efavirenz
2.Protease inhibitors
 Saquinavir,ritonavir,indinavir,nelfinavir,amprenavir ,fos-
amprenavir
4. Fusion inhibitors
 Enfuvirtide
5. Integrase inhibitors
 Raltegravir
 Elvitegravir
Nucleotide/nucleotide reverse transcriptase
inhibitors(NRTIs/NtRTIs)
 Properties
 First agent for the trt of HIV
 Have activity agianst HIV 1 and 2
 Differs in phosphorylation path ways
 Partial cross resistance
 Orally bioavailable
 Little biotransformation and excreted in urine
 Administered 1-2 times a day
 Common adverse effects for NRTIS
 Lactic acidosis
 Bone marrow depression
 Fatty liver
 Peripheral neuropathy/pancratitis
Non-nucleoside reverse transcriptase inhibitors
 Gen properties
 Don’t require intracellular phosphorylation
 Share common mechanism of action
 Have specific activity against HIV 1
 More effective
 Complete cross resistance
 Well absorbed orally
 Bind plasma protien
 Biotransformed by CYP3A4 and excreted by kidney
 Common adverse effects for NNRTIs
 Rash
 Hepatitis
 Depression
Protease inhibitors
 Properties
 Active against HIV 1 and 2
 Partial cross resistance
 Bioavailability increase with food intake except
saquinavir,amprenavir and indinavir
 Bind to plasma protein
 Short half life and frequent adm
 Biotransform by CYP3A4 and excreted in feces
 Common adverse effects for Pis
 Insulin resistance
 Alteration of fat distribution
 Hepatits
 Bleeding
 GI disturbances
 Currently the recommendation for HIV / AIDS
patient is either
 Two Nucleoside reverse transcriptase inhibitors + One
Protease Inhibitors (ZDV+3TC+Lr)
Or
 Two Nucleoside reverse transcriptase inhibitors + Non-
nucleoside RT Inhibitors (ZDV+3TC+NEV).
Anti-helminthics

 Benzimidazole: Thiabendazole, Albendazole and

Mebendazole
 Effective against wide spectrum of nematodes
 It acts by binding to β-tubulin and interfering the
assembly of microtubules
 It also decreases the glucose uptake
 Mebendazole
 Poorly and erratically absorbed. Absorption is
increased if the drug is ingested with a fatty meal.
 Plasma levels may be decreased by concomitant use of
carbamazepine or phenytoin and increased by
cimetidine.
 It is excreted mostly in the urine and in the bile.
 Adverse effects
 NVD,abdominal pain,hypersensitivity reactions
(rash, urticaria), agranulocytosis, alopecia, and
elevation of liver enzymes
 Pyrantel pamoate
 Activate nicotinic Ach receptors====spastic paralysis
 It is poorly absorbed from the gastrointestinal tract and
active mainly against luminal organisms.. Over half of
the administered dose is recovered unchanged in the
feces.
 Indication:Ascaris and pinworm,hookworm
infections.
 ADR:headache, fever, dizziness, drowsiness,
insomnia, weakness,NVD, and rash
 Piperazine
 Block nicotinic receptors at NMJ====Flassid paralysis
 It is readily absorbed,most of the drug is excreted
unchanged in the urine
 Highly effective against Ascaris lumbricoides and
Enterobius vermicularis
 Occasional mild adverse effects include: nausea,
vomiting, diarrhea, abdominal pain, dizziness, and
headache.
 Niclosamide
 Acts by inhibition of parasite mitochondrial
phosphorylation of ADP to ATP.
 It appears to be minimally absorbed from the
gastrointestinal tract—neither the drug nor its
metabolites have been recovered from the blood or
urine.
 Praziquantel
 It acts by increasing the permeability of tegument
to calcium – spastic paralysis of the parasite
  Well absorbed orally, with a bioavailability of about
80% after oral administration. Peak serum
concentrations are reached 1–3 hours after a
therapeutic dose.
 Metabolites are excreted in bile and urine
 ADR: headache, dizziness, drowsiness, and lassitude;
others include nausea, vomiting, abdominal pain, loose
stools, pruritus, urticaria, arthralgia, myalgia, and low-
grade fever.
  Other agents : ivermectine,suramin
Antifungal
 MOA of antifungal
 Alteration of membrane permeability
 Polyene antibiotic
 Azole
 Inhibition of fungal mitosis
 Griseofulvin
 Inhibition of nucleic acid synthesis
 Flucytosine
 Polyene antibiotic
 Bind with ergosterol in the fungal cell membrane,This
causes the cell's contents to leak out and the cell dies.
 Animal cells contain cholesterol instead of ergosterol and so
they are much less susceptible.
 Nystatin ,Amphotericin B

 Azole
 Inhibit 14α-demethylase. This enzyme converts lanosterol
to ergosterol
 These drugs also block steroid synthesis in humans.
 Imidazoles:Miconazole,Ketoconazole,Clotrimazole

 Triazoles :Fluconazole ,Itraconazole (newer, and are

less toxic and more effective)

 Amphotericin B
 Bind to ergosterol present in the cell membrane and
forms a micropore thus disrupt the membrane function
and cell death
 It is not absorbed orally
 Half life is ~ 15 days
 Metabolized in liver and excreted in urine and bile
 Relatively safe in pregnancy
 ADR: Fever and chills,nephrotoxicity,
anemia, CNS toxicity
 Flucytosine: Fungi static
 Blockade of fungal DNA synthesis
 Selectivity occurs because mammalian cells do not
accumulate and do not deaminate flucytosine
 Well absorbed orally and penetrates into CSF.
 Ketoconazole:
 First orally effective broad spectrum azole anti-
fungal agent
 Gastric acidity promotes absorption
 Fluconazole
 Oral absorption is very good – not dependent on gastric
acidity