Anti-Amoebic
Drugs
Contents
• Antiamoebic Agents – Classification
• Pharmacology of Metronidazole
At the
end of this lecture, the student will be able to:
• Describe
the Pharmacology of Metronidazole
• Explain
the ADR and drug interactions of Metronidazole
Introduction
• Amoebiasis
(Amoebic dysentry) is an infectious disease caused by protozoa, Entamoeba
histolytica, which is produced by the ingestion of cysts of this organism
• The
ingested cysts develop into trophozoites and adhere to the colonial epithelial
cells in the intestine
• These
trophozoites then lyses the host cell and invades the submucosa
• This
produces the amoebic ulcers and cause acute dysentery or chronic intestinal
amoebiasis
• The
parasite may also pass into blood steam and invades the liver causing liver
abscesses
Classification
1. Systemic Amoebicides
a) For both
intestinal and extra intestinal amoebiasis
–
Nitromidazoles: Metronidazole, Tinidazole, Secnidazole, Ornidazole
– Alkaloids:
Emetine, Dehydroemetine
b) For extra intestinal
amoebiasis: Chloroquine
2. Luminal Amoebicides
a) Amides:
Diloxanide furoate
b)
8-Hydroxyquinolines: Diiodohydroxyquin
c) Antibiotics:
Tetracyclines, Paromomycin
Metronidazole
• Metronidazole
is the drug of choice in the treatment of different forms of amoebiasis
• It
kills the trophozites of E. histolytica but has no effects on the cysts
• It
is often used in combination with Diloxanide furoate for the treatment of
amoebiasis
Mechanism of Action
Metronidazole is a pro durg.
It is converted in anaerobic organism by the redox enzyme
pyruvate-ferredoxin oxidoreductase. The notro group of metronidazole is
chemically reduced by ferredoxin or a ferredoxin linked metabolic process and
the products are responsible for disrupting the DNA helical structure, thus
inhibiting nucleic acid synthesis.
Pharmacokinetics
• Disposition
of metronidazole in the body is similar for both oral and intravenous dosage
forms
• Following
oral administration, metronidazole is well absorbed
• Plasma
concentrations of metronidazole are proportional to the administered dose
• Metronidazole
is the major component appearing in the plasma, with lesser quantities of
metabolites also being present
• Less
than 20% of the circulating metronidazole is bound to plasma proteins
• Metronidazole
appears in cerebrospinal fluid, saliva, and breast milk in concentrations
similar to those found in plasma
• Bactericidal
concentrations of metronidazole have also been detected in pus from hepatic
abscesses.
• The
major route of elimination of metronidazole and its metabolites is via the
urine (60% to 80% of the dose)
Anti microbial spectrum
• Metronidazole
has a broad-spectrum cidal activity against protozoa and many anaerobic
bacteria
• It
is drug of choice in treatment of infections caused by E. histolytica, Giardia
lamblia and Trichomonas vaginalis
• It
is also active against Gram-positive bacilli such as Clostridia
Adverse Effects
• The most common unwanted effects are
gastrointestinal disturbances
• It has a metallic, bitter taste in
the mouth
• CNS symptoms such as dizziness,
headache and sensory neuropathies are rarely observed
• If taken with alcohol a disulfiram
like effect occurs
Contraindications
Metronidazole
is contraindicated in:
• Neurological disease
• Blood dyscrasias
• First trimester of pregnancy (though
no teratogenic effect has yet been demonstrated, its mutagenic potential
warrants caution)
• Cautious use in chronic alcoholics.
Interactions
• Disulfiram-like intolerance to
alcohol occurs in some patients taking metronidazole
• Alcohol-metronidazole interaction
occurs only in some individuals, while majority of those taking it can consume
alcohol without any reaction
• There is no convincing evidence of
disulfiram-like action of metronidazole, but manufactures advise caution in
drinking during metronidazole therapy
• Enzyme inducers (phenobarbitone,
rifampin) may reduce its therapeutic effect
• Cimetidine + metronidazole can
reduce metronidazole metabolism: its dose may need to be decreased
• Metronidazole enhances warfarin
action by inhibiting its metabolism
• It can decrease renal elimination of
lithium and precipitate toxicity
Clinical Uses
• It is used in the treatment of
amoebiasis, giardiasis, trichomonas vaginitis and pseudomembranous enterocolitis
• Also used in the treatment of many
anaerobic bacterial infections and in peptic ulcers
Summary
• Amoebiasis
(Amoebic dysentry) is an infectious disease caused by protozoa, Entamoeba
histolytica, which is produced by the ingestion of cysts of this organism
• The
nitro group of metronidazole is chemically reduced by ferrodoxin and the
product of the reaction disrupts nucleic acid synthesis
• ADR
of metronidazole- causes
metallic, bitter taste in the mouth; dizziness, headache and sensory
neuropathies are rarely observed; causes a disulfiram like effect with
alcohol