CHEMOTHERAPY

OF PROTOZOAL
INFECTIONS
(AMOEBIASIS,
GIARDIASIS)
DRUGS FOR TREATING AMOEBIASIS

• These are drugs useful in infection caused by the

anaerobic protozoa Entamoeba histolytica.
• Other Entamoeba species are generally nonpathogenic.
• Poor environmental sanitation and low socio-economic
status are important factors in the spread of the disease,
which occurs by faecal contamination of food and water
DRUGS FOR TREATING AMOEBIASIS

• Amoebic cysts reaching the intestine transform into

trophozoites which either live on the surface of colonic
mucosa as commensals— form cysts that pass into the
stools (luminal cycle) and serve to propagate the
disease,
• Or invade the mucosa—form amoebic ulcers and cause
acute dysentery or chronic intestinal amoebiasis
 CLASSIFICATION
• Tissue amoebicides
– (a) For both intestinal and extraintestinal amoebiasis:
• Nitroimidazoles: Metronidazole, Tinidazole, Secnidazole, Ornidazole,
Satranidazole
• Alkaloids: Emetine, Dehydroemetine
– (b) For extraintestinal amoebiasis only: Chloroquine
• Luminal amoebicides
– (a) Amide : Diloxanide furoate, Nitazoxanide
– (b) 8-Hydroxyquinolines: Quiniodochlor (Iodochlorohydroxyquin,
Clioquinol), Diiodohydroxyquin (Iodoquinol)
– (c) Antibiotics: Tetracyclines, Paromomycin
 NITROIMIDAZOLES -
METRONIDAZOLE
• Broad spectrum antiprotozoal drug.
• Selectively toxic to anaerobic and microaerophilic
microorganisms such as Giardia lamblia.
• Many anaerobic and microaerophilic bacteria, such as
Bact. fragilis, Fusobacterium, Clostridium perfringens,
Cl. difficile, Helicobacter pylori, Campylobacter,
peptococci, spirochetes and anaerobic Streptococci.
 MECHANISM OF ACTION
• Metronidazole diffuses into the organism, inhibits protein
synthesis by interacting with DNA and causing a loss of
helical DNA structure and strand breakage.
• Therefore, it causes cell death in susceptible organisms.
• Entry into the organism by diffusion across the cell
membranes of anaerobic and aerobic pathogens.
• Reductive activation by intracellular transport proteins.
• Interactions with intracellular targets.
• Breakdown of cytotoxic products
 PHARMACOKINETICS
• Metronidazole is almost completely absorbed from the
small intestines;
• Widely distributed in the body, attaining therapeutic
concentration in vaginal secretion, semen, saliva and
CSF.
• Metabolism occurs in liver primarily by oxidation and
glucuronide conjugation followed by renal excretion.
• Plasma t½ is 8 hrs.
 ADVERSE EFFECTS
• Anorexia, nausea, metallic taste and abdominal cramps.
• headache, glossitis, dryness of mouth and dizziness.
• Urticaria, flushing, heat, itching, rashes.
• Peripheral neuropathy and CNS effects
• Thrombophlebitis of the injected vein
 THERAPEUTIC USES
• Amoebiasis
• Giardiasis
• Trichomonas vaginitis
• Nonspecific bacterial vaginosis
• Anaerobic bacterial infections
• Pseudomembranous enterocolitis
• Acute necrotizing ulcerative gingivitis
• Helicobacter pylori gastritis/peptic ulcer
• Guinea worm infestation
 TINIDAZOLE
• It is an equally efficacious congener of metronidazole
with properties of slow metabolism, high cure rate,
better tolerance with lower side effects.
• Used for Intestinal amoebiasis, Amoebic liver abscess,
Trichomoniasis and giardiasis, Anaerobic infections and
H.pylori infection.
 SECNIDAZOLE
• A congener of metronidazole with the same spectrum of activity and
potency.
• Absorption after oral administration is rapid and complete, but
metabolism is slower resulting in a plasma t½ of 17–29 hours.
• After 48 hr of a single 2 g dose, plasma secnidazole concentration
may still remain within the range of MIC values against sensitive
organisms.
• In intestinal amoebiasis a single 2 g dose has been found to yield
high cure rates.
• Side effect profile is similar to metronidazole and reported incidence
is 2–10%.
 EMETINE
• It is an alkaloid from Cephaelis ipecacuanha. Emetine is a potent and
directly acting amoebicide—kills trophozoites but has no effect on
cysts.
• It acts by inhibiting protein synthesis in amoebae by arresting
intraribosomal translocation of tRNAamino acid complex.
• Emetine cannot be given orally because it will be vomited out. It is
administered by s.c. or i.m. injection.
• Emetine is now rarely used for acute amoebic dysentery or for
amoebic liver abscess, only in patients not tolerating metronidazole.
• Dihydroemetine: It is equally effective but less cumulative and less
toxic to the heart. Thus, it is usually preferred over emetine.
 CHLOROQUINE
• The pharmacology of chloroquine is already discussed
in antimalarial drugs.
• It kills trophozoites of E. histolytica and is highly
concentrated in liver.
• Therefore, it is used in hepatic amoebiasis only.
 DILOXANIDE FUROATE
• It is a highly effective luminal amoebicide which directly
kills trophozoites responsible for production of cysts.
• The furoate ester is hydrolysed in intestine and the
released diloxanide is largely absorbed.
• Diloxanide is a weaker amoebicide than its furoate ester.
• It is primarily metabolized in liver and is excreted in urine.
• Diloxanide furoate is very well tolerated; the only side
effects are flatulence, occasional nausea, itching and rarely
urticaria
 GIARDIASIS
• Giardia lamblia is a flagellate protozoon which infects
children and adults by oro-faecal contamination and
mostly lives as a commensal in the intestine.
• If untreated, it may pass on to chronic diarrhoea with
greasy or frothy stools but no blood or mucus.
 DRUGS FOR GIARDIASIS
• Metronidazole 400 mg TDS (children 15 mg/kg/day)
for 5–7 days or 2 g daily for 3 days Or
• Tinidazole 0.6 g daily for 7 days or 2 g single dose Or
• secnidazole 2 g single dose
• Nitazoxanide
• Quiniodochlor
• Paromomycin
• Furazolidone
 TRICHOMONIASIS
• Trichomonas vaginalis is another microaerophilic
flagellate protozoon which causes vulvovaginitis.
• It is a common sexually transmitted disease affecting ~
10% sexually active women.
 DRUGS FOR TRICHOMONIASIS
• Drugs used orally
• Metronidazole or tinidazole or secnidazole
• Drugs used vaginally
• Diiodohydroxyquin 200 mg inserted intravaginally at bed
time for 1–2 weeks;
• Quiniodochlor 200 mg inserted in the vagina every night
for 1–3 weeks;
• Povidone-iodine 400 mg inserted in the vagina daily at
night for 2 weeks;
 ANTHELMINTIC DRUGS
• Anthelmintics are drugs that either kill (vermicide) or expel
(vermifuge) infesting helminths.
• The drugs are
• Mebendazole, Albendazole, Thiabendazole
• Pyrantel pamoate, Piperazine
• Levamisole, Tetramisole
• Diethylcarbamazine citrate (DEC)
• Ivermectin
• Niclosamide
• Praziquantel
 MEBENDAZOLE
• It is a broad-spectrum anthelmintic drug.
• 100% cure rate/reduction in egg count in roundworm,
hook worm (both species), Enterobius and Trichuris
infestations.
• It expels Trichinella spiralis from intestines.
• The site of action of mebendazole appears to be the
microtubular protein ‘β-tubulin’ of the parasite.
• It binds to β-tubulin of susceptible worms with high
affinity and inhibits its polymerization.
 PHARMACOKINETICS AND ADR
• Absorption of mebendazole from intestines is minimal;
75–90% of an oral dose is passed in the faeces.
• The fraction absorbed is excreted mainly as inactive
metabolites in urine/faeces.
• Mebendazole is well tolerated even by patients in poor
health. Allergic reactions, loss of hair and
granulocytopenia
 THERAPEUTIC USE
• Used for infestations due to roundworm, hookworm,
whipworm, pinworm, trichinosis, Hydatid disease,
 ALBENDAZOLE
• It is a congener of mebendazole: retains the broad-
spectrum activity and excellent tolerability.
• Has the advantage of single dose administration in
many infestations.
• One dose treatment has produced cure rates in
ascariasis, hookworm (both species) and enterobiasis
which are comparable to 3 day treatment with
mebendazole.
 PHARMACOKINETICS
• Absorption is significant, and enhanced when the drug is
taken with fatty meal (this may help in treating
neurocysticercosis and hydatid disease).
• The fraction absorbed is converted by first pass metabolism to
its sulfoxide metabolite which has potent anthelmintic action.
• Albendazole e is widely distributed in the body, enters brain
and is excreted in urine with a t½ of 8.5 hours.
• Thus, albendazole is able to exert antihelmintic activity in
tissues as well.
 THERAPEUTIC USE
• Ascaris, hookworm, Enterobius and Trichuris:.
• Tapeworms and strongyloidosis.
• Trichinosis
• Neurocysticercosis
• Cutaneous larva migrans:
• Hydatid disease:
• Filariasis
• Use in pregnant women is contraindicated.
• It should be given with caution to patients with hepatic or renal
disease.
 PYRANTEL PAMOATE
• Used pin worm infestation in children; use soon extended to roundworm and
hookworm as well.
• Efficacy against Ascaris, Enterobius and Ancylostoma is high and
comparable to that of mebendazole.
• Lower cure rates (about 60%) have been obtained in case of Necator
infestation.
• It is less active against Strongyloides and inactive against Trichuris and other
worms.
• Pyrantel causes activation of nicotinic cholinergic receptors in the worms
resulting in persistent depolarization → slowly developing contracture and
spastic paralysis.
• Worms are then expelled.
 THERAPEUTIC USES
• For Ascaris, Ancylostoma and Enterobius: a single dose
of 10 mg/kg is recommended.
• A 3 day course for Necator and for Strongyloides has
been suggested.
 PIPERAZINE
• Highly active drug against Ascaris and Enterobius; achieves
90–100% cure rates.
• Causes hyperpolarization of Ascaris muscle by a GABA
agonistic action.
• Opening of Cl¯ channels causes relaxation and depresses
responsiveness to contractile action of ACh.
• Flaccid paralysis occurs and worms are expelled alive. They
recover if placed in piperazine free medium.
• A considerable fraction of the oral dose of piperazine is
absorbed.
 PIPERAZINE
• It is partly metabolized in liver and excreted in urine.
• Piperazine is safe, but nausea, vomiting, abdominal
discomfort and urticaria may be felt. Dizziness and
excitement occur at high doses; toxic doses produce
convulsions; death is due to respiratory failure.
• It is contraindicated in renal insufficiency and in
epileptics, but is safe in the pregnant.
 LEVAMISOLE, TETRAMISOLE
• Tetramisole and its levo isomer (levamisole) were
found to be more active and is preferred now.
• Both are active against many nematodes.
• The ganglia in worms are stimulated causing tonic
paralysis and expulsion of live worms.
 DIETHYLCARBAMAZINE CITRATE
(DEC)
• It is the first drug for filariasis caused by the nematodes
Wuchereria bancrofti (90% cases) and Brugia malayi.
• DEC is absorbed after oral ingestion, distributed all over
the body (V = 3–5 L/kg), metabolized in liver and
excreted in urine.
• Excretion is faster in acidic urine. Plasma t½ of usual
clinical doses is 4–12 hours, depending on urinary pH.
• Diethylcarbamazine is microfilaricidal. It has a highly
selective effect on microfilariae (Mf).
 DIETHYLCARBAMAZINE CITRATE
(DEC)
• A dose of 2 mg/kg TDS clears Mf of W. bancrofti and B.
malayi from peripheral blood in 7 days.
• However, Mf present in nodules and transudates (hydrocoele)
are not killed.
• The most important action of DEC appears to be alteration of
organelle membranes of the Mf promoting cell death. It is also
suggested that muscular activity of Mf and adult worms is
affected so that they are dislodged.
• Prolonged treatment may kill adult B. malayi and probably W.
bancrofti worms also.
 IVERMECTIN
• It is an extremely potent semisynthetic derivative of the
antinematodal principle obtained from Streptomyces
avermitilis.
• Ivermectin is the drug of choice for single dose
treatment of onchocerciasis and strongyloidosis and is
comparable to DEC for bancroftian and brugian filaria.
• It is microfilaricidal and highly effective in cutaneous
larva migrans and ascariasis, while efficacy against
Enterobius and Trichuris