DR.

AMIT M SHAH

ANTIAMOEBIC & OTHER

ANTIPROTOZOAL DRUGS
ANTIAMOEBIC DRUGS
INTRODUCTION
 Protozoal infection of the intestinal tract that
occurs due to ingestion of foods or water
contaminated with Entameba Histolytica cysts
 A worldwide distribution (over 50 million people
are infected)
 Endemic in most parts of India
LIFE CYCLE
CLINICAL PRESENTATIONS
 Asymptomatic Intestinal infection (Carriers,
passing cysts)
 Mild to moderate intestinal disease
(Nondysenteric Colitis)
 Severe Intestinal infection (Dysentery)
 Hepatic abscess, ameboma (localized
granulomatous lesion of colon) and other
extraintestinal disease
 ANTIAMOEBIC DRUGS
 Tissue amoebicides
o For both intestinal and extraintestinal amoebiasis:
• Nitroimidazoles: Metronidazole, Tinidazole
• Alkaloids: Emetine, Dehydroemetine
o For extraintestinal amoebiasis only: Chloroquine
 Luminal amoebicides
o Amide: Diloxanide furoate, Nitazoxanide
o 8-Hydroxyquinolines: Iodochlorohydroxyquin,
Clioquinol, Iodoquinol
o Antibiotics: Tetracyclines
METRONIDAZOLE
 Broad-spectrum cidal activity against protozoa,
including E. histolytica, Giardia, T. vaginalis
 Also active against many anaerobic bacteria, e.g.
o B. fragilis
o Fusobacterium
o Cl. perfringens, Cl. Difficile
o H. pylori
o Campylobacter
o Anaerobic Streptococci
MECHANISM OF ACTION

 Reduced product that binds to DNA, proteins and

cell membrane resulting into parasite death
PHARMACOKINETICS
 Given orally or IV
 Absorption is rapid and complete
 Due to rapid absorption from GIT, not reliably
effective against luminal parasites
 Wide distribution to all tissues and body fluids
(Vaginal secretion, CSF, saliva, milk).
 Metabolized in liver by oxidation and glucuronide
conjugation
 Plasma half life is 8 h
CLINICAL USES
 Amoebiasis:
o 1st line drug for all forms of amoebic infection
o Invasive dysentery and liver abscess: 800 mg TDS
(children 30–50 mg/kg/day) for 7–10 days
o Serious cases of liver abscess 1 g i.v. slowly followed by
0.5 g every 8–12 hr till oral therapy is instituted
o Mild intestinal disease: 400 mg TDS for 5–7 days
o Less effective in eradicating amoebic cysts from the
colon
 Giardiasis: 400 mg TDS X 7 days OR 2 g/day X 3 days
 Trichomonas vaginitis: 400 mg TDS for 7 days
 Anaerobic bacterial infections:
o After colorectal or pelvic surgery, appendicectomy
o Brain abscesses and endocarditis
o Combination with gentamicin or cephalosporins
o IV 15 mg/kg infused over 1 hr ⇒ 7.5 mg/kg every 6 hrs
till oral therapy can be instituted with 400–800 mg TDS
o Prophylactic use in high risk situations (colorectal
surgery)
 Pseudomembranous enterocolitis: due to Cl. Difficile;
Oral metronidazole 800 mg TDS
 Ulcerative gingivitis, trench mouth: 200–400 mg TDS
 Helicobacter pylori gastritis/peptic ulcer:
Metronidazole 400 mg TDS along with
amoxicillin/clarithromycin and a proton pump
inhibitor in triple drug 2 week regimens
ADVERSE EFFECTS
 Frequent and unpleasant, but mostly nonserious.
 MOST COMMON: Anorexia, nausea, metallic taste and
abdominal cramps, looseness of stool
 LESS FREQUENT: Headache, glossitis, dryness of
mouth, dizziness, rashes and transient neutropenia.
 PROLONGED ADMINISTRATION may cause peripheral
neuropathy and Seizures
 Thrombophlebitis of the injected vein
CONTRAINDICATIONS
 Neurological disease
 Blood dyscrasias
 First trimester of pregnancy
 Chronic alcoholism
INTERACTIONS
 Disulfiram-like reaction to alcohol
 Enzyme inducers (phenobarbitone, rifampin)
reduce its therapeutic effect
 Cimetidine reduce metronidazole metabolism
 Enhances warfarin action by inhibiting its
metabolism
 Decrease renal elimination of lithium
TINIDAZOLE
 Similar to metronidazole but,
o Metabolism is slower ⇒ long duration of action (t½
~12 hr) ⇒ single dose or once daily therapy
o Some trials in amoebiasis have reported higher cure
rates
o Better tolerated
CLINICAL USES
 Amoebiasis: 2 g OD for 3 days (children 30–50 mg/
kg/day) OR 0.6 g BD for 5–10 days
 Trichomoniasis and giardiasis: 2 g single dose OR 0.6
g OD for 7 days
 Anaerobic infections:
o Prophylactic: 2 g single dose before colorectal surgery
o Therapeutic: 2 g followed by 0.5 g BD for 5 days

 H. pylori: 500 mg BD for 2 weeks in triple combination

 SECNIDAZOLE: Rapid & complete oral absorption;
t½ of 17–29 hours

 ORNIDAZOLE: longer t½ (12–14 hr)

 SATRANIDAZOLE: longer t½ (14 hr); better

tolerability
EMETINE
 Alkaloid from Cephaelis ipecacuanha
 Potent and directly acting amoebicide: kills
trophozoites; no effect on cysts (not curative)
 Inhibiting intraribosomal translocation of tRNA-
amino acid complex ⇒ Inhibit protein synthesis
 Rapidly clearance of the trophozoites from stool
(1–3 days) – even faster than metronidazole
 Highly efficacious in amoebic liver abscess also.
 Cannot be given orally because it will be vomited
out
 Administered by s.c. or i.m.: 60 mg OD
 Concentrated in liver, kidney, spleen and lungs ⇒
should not be given more than 10 days
 Very slowly excreted in urine taking 1–2 months
 Cumulative toxicity ⇒ 2nd course should not be
repeated within 6 weeks
ADVERSE EFFECTS: High
 Local: Pain, stiffness and eczematous lesions at the site
of injection
 Nausea and vomiting: Parenteral and oral route
 Abdominal cramps and diarrhoea
 Weakness and stiffness of muscles
 Hypotension, tachycardia, ECG changes and
myocarditis
CONTRAINDICATED: Cardiac or renal dz & pregnancy.
CLINICAL USES: Reserve Drug
 Severe intestinal or extraintestinal amoebiasis
 Patients not responding to or not tolerating
metronidazole
 A luminal amoebicide must always follow to eradicate
the cyst
 Also effective in liver fluke infestation
DEHYDROEMETINE
 Semisynthetic derivative of emetine
 Equally effective
 Less cumulative and less toxic to the heart
 Preferred over emetine
CHLOROQUINE
 Kills trophozoites of E. histolytica
 Completely absorbed from the upper GIT and not
so highly concentrated in the intestinal wall ⇒ Not
effective in invasive dysentery nor in cyst passers
 Highly concentrated in liver ⇒ Used in hepatic
amoebiasis
 Longer duration of treatment
 Relapses are relatively more frequent
 Relative safe to Emetine
 Only when metronidazole is not effective or not
tolerated
 Given concurrently or immediately after a course
of metronidazole to ensure complete eradication of
the trophozoites in liver
 A luminal amoebicide must always be given
 Dose: 600 mg (base) for 2 days ⇒ 300 mg for 2-3
weeks
 DILOXANIDE FUROATE
 Highly effective luminal amoebicide
 Directly kills trophozoites
 Furoate ester is hydrolysed in intestine and the
released diloxanide is largely absorbed
 Diloxanide is a weaker amoebicide than its ester
 Metabolized by glucuronidation and excreted in urine
 No antibacterial action
 Less effective in invasive amoebic dysentery, because
of poor tissue amoebicidal action
 High (80–90%) cure rate with single course
 Drug of choice for mild intestinal/asymptomatic
amoebiasis (500 mg TDS for 5–10 days)
 Given after any tissue amoebicide to eradicate cysts
 Combined with metronidazole/tinidazole
 Some chronic cases require repeat courses for
eradication
 Very well tolerated
 ADR: flatulence, nausea, itching and urticarial
 NITAZOXANIDE
 Congener of the anthelmintic niclosamide
 Active against Giardia, E. histolytica, T. vaginalis,
Cryptosporidium, H. pylori, Ascaris, H. nana
 Prodrug (active form tizoxanide)
 Inhibitor of PFOR enzyme that is an essential pathway
of electron transport energy metabolism
 Active against metronidazole-resistant Giardia
 Indicated in giardiasis, cryptosporidiasis, amoebic
dysentery as luminal amoebicide
 Abdominal pain, vomiting and headache
8-HYDROXYQUINOLINES
 Quiniodochlor (Iodochlorohydroxyquin, Clioquinol),
Diiodohydroxyquin (Iodoquinol)
 Active against Entamoeba, Giardia, Trichomonas, some
fungi (dermatophytes, Candida) and some bacteria
 Mechanism of action - Unknown
 Effective against organisms in GIT only Not intestinal
wall or liver
 Absorption is poor (90%), excreted in feces
 Used as lumen amoebicide for eradication of infection
given along with tissue amoebicide (metronidazole)
 Adverse Effects
o Peripheral neuropathy [Quiniodochlor - Subacute Myelo-
optic Neuropathy (SMON)]
o GIT: Nausea, vomiting, diarrhoea
o Agranulocytosis
o Enlargement of the thyroid gland & interference with
thyroid function tests
o Iodism (furunculosis, inflammation of mucous
membranes)
 TETRACYCLINES
 Older Tetracyclines
 Very weak direct amoebicidal action.
 Mainly act indirectly on bacterial flora
 Used in severe cases of amoebic dysentery not
responding to metronidazole combined with
dehydroemetine
 Clinical Setting Drugs of Choice
Asymptomatic Diloxanide furoate 500 mg orally TDS for 7-10 days
intestinal infection OR
Iodoquinol, 650 mg orally TDS for 21 days

Mild to moderate Metronidazole, 400 mg orally TDS for 7-10 days

intestinal infection OR
Tinidazole, 2 g orally daily for 3 days
PLUS
Luminal agent
Severe intestinal Metronidazole 800 mg orally TDS (500 mg IV every
infection, hepatic 8-12 hours) for 7-10 days
abscess, and other OR
extraintestinal Tinidazole, 2 g orally daily for 3 days
disease PLUS
Luminal agent
DRUGS FOR GIARDIASIS
 Metronidazole: 200 mg TDS (15 mg/kg/day) for 7 days
or 2 g daily for 3 days
 Tinidazole: 0.6 g daily for 7 days or 2 g single dose
 Secnidazole: 2 g single dose
 Nitazoxanide: 500 mg (7.5 mg/kg) BD daily for 3 days
 Quiniodochlor: 250 mg TDS for 7 days
 Furazolidone:
o Nitrofuran compound
o Active against gram-negative bacilli (Salmonella and
Shigella), Giardia and Trichomonas
o Inferior to metronidazole or tinidazole
o Dose: 100 mg TDS for 5–7 days
o Also used in bacterial enteritis, food poisoning
diarrhoeas and bacillary dysentery
o ADR: mild & infrequent—nausea, headache, dizziness
 DRUGS FOR
TRICHOMONIASIS
DRUGS USED ORALLY
 Metronidazole: 400 mg TDS for 7 days or 2 g daily for 3
days
 Tinidazole: 0.6 g daily for 7 days or 2 g single dose
 Secnidazole: 2 g single dose
 Nimorazole: 2 g single dose
 Additional intravaginal treatment is required only in
refractory cases
DRUGS USED INTRAVAGINALLY
 Diiodohydroxyquin: 200 mg at bed time for 1–2 weeks
 Quiniodochlor: 200 mg at bed time for 1–3 weeks
 Clotrimazole: 100 mg inserted highup in vagina every
night for 6–12 days
 Hamycin: 4–8 lac U daily for 15 days
 Natamycin: 25 mg at bed time for 10 days
 Povidone-iodine: 400 mg daily at night for 2 weeks
DRUGS FOR LEISHMANIASIS
(KALA-AZAR)
Available Drugs
 Antimonial: Sodium stibogluconate (SSG)
 Diamide: Pentamidine
 Antifungal: Amphotericin B (AMB), Ketoconazole
(KTZ)
 Others: Miltefosine, Paromomycin, Allopurinol
SODIUM STIBOGLUCONATE
 The drug of choice in Leishmaniasis – resistance
 Water soluble pentavalent antimonial compound –
1/3rd antimony by weight
 MOA: Not clear
o -SH dependent enzymes are inhibited – bioenergetics of
the parasite
o Blocks glycolytic and fatty acid oxidation pathways
o Enzyme in leishmania converts SSG to trivalent
compound – causes efflux of glutathione and thiols –
oxidative damage
 Dose: 20-30 mg/kg (max. 850 mg)deep IM or IV daily
in buttock for 20-30 days or more – depends on
response in bone marrow and splenic aspirates
 Adverse Effects: All antimonials are toxic
o Nausea, vomiting, metallic taste, cough and pain
abdomen
o Stiffness and abscess in injected muscles
o Pancreatitis, liver and kidney damage etc.
o Rarely shock and death
PENTAMIDINE
 MOA: Not clear, inhibits Topoisomerase II or interferes
with aerobic glycolysis
 Not metabolized but stored in kidneys and liver –
slowly released
 USES:
o SSG failure cases - AMB is preferred now
o Trypanosomiasis - CNS involvement
o Pneumocystis jiroveci pneumonia in AIDS patients
 Dose: 4 mg/kg IM or slow IV for 1 Hr on alternate days
for 5-15 weeks
 Adverse Effects:
o Histamine release – acute reactions – Sharp fall in BP,
dyspnoea, palpitation, fainting, vomiting and rigor etc.
o Other reactions - rashes, mental confusion, kidney and
liver damage
o Cytolysis of pancreatioc beta cells – initially insulin
release – hypoglycaemia, but later IDDM
MILTEFOSINE
 First oral antileishmania drug approved in 2002
 Interfere with lipid metabolism
 ≥ 95% cure rate with 4 week course
 1st line agent under NVBDCP
 Vomiting and diarrhoea occur in over ½ of the patients
 Reversible derangement of liver and kidney function
 Teratogenic ⇒ C/I in pregnant women
 Dose: 100 mg/day for 4 weeks
Visceral (L Miltefosine 100 mg/day for 4 weeks
donovani, L chagasi, OR
L infantum) Sodium stibogluconate, 20 mg/kg/d IV or IM
or mucosal (L for 28 days
braziliensis) OR
Pentamidine 4 mg/kg deep i.m. or slow i.v.
(over 1 hr) on alternate days for 5–15 weeks
OR
Amphotericin-B 0.5–1.0 mg/kg/day slow i.v.
infusion till 15–20 mg/kg
OR
Paromomycin 10–15 mg/kg/day i.m. × 21 days
Cutaneous Sodium stibogluconate: Infiltrate 2 ml of the
(L major, L tropica, L solution (100 mg antimony/ml) round the sore
mexicana, L OR
braziliensis) Paromomycin ointment
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