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Metronidazole Iodoquinol Paromomycin Chloroquine Emetine /

Dehydroemetine
Mechanism of action: •a halogenated ♦An ♦used in combination ♦alternative drugs for
● reduction of the nitro group to an anion radical 8- aminoglycoside with Metronidazole treatment of
●anion radical is highly reactive and will form adjuncts with proteins and DNA hydroxyquinoline antibiotic and Diloxanide furoate extraintetsinal amebiasis
leading to a loss of function •exact MOA ♦Effective only in the prevention and ♦Mechanism of action:
●Anaerobic bacteria and sensitive protozoans have more reduction potential unknown against intestinal treatment of amebic ♦Inhibit protein synthesis
that activates Nitroimidazoles •amebicidal vs E forms of E. liver abscess by blocking chain
● nitro group of the drug serve as a electron acceptor forming reduced histolytica histolytica ♦eliminates elongation
cytotoxic cpds that binds to proteins and DNA resulting in cell death •effective against ♦Directly trophozoites in liver ♦Dehydroemetine is only
●Anaerobic and protozoal parasites possess ferredoxin-like, low-redox trophozoites and amebicidal abscess available under
potential, electron-transport proteins that participate in metabolic electron cyst forms in the ♦Indirectly – ♦not useful in treating compassionate
removal reactions intestinal lumen reduces population luminal amebiasis investigational new drug
of intestinal flora ♦also effective in the protocol through the
♦negligible treatment of malaria Center for Disease Control
absorption from and Prevention
the GIT
Mode and Spectrum of action:
♦Amebicidal for E. histolytica
♦Bactericidal for Anaerobic bacteria: Bacteroides, Clostridium species
♦also cidal for the protozoans Trichomonas vaginalis and Giardia lamblia
Pharmacokinetics: Pharmacokinetics:
♦oral forms (tablet and suspension) are rapidly and completely absorbed from the GIT ♦ preferrabley given y
♦also available for intravenous injection, intravaginal and topical formulations intramuscular injection
♦ distributes well to all body tissues and fluids ♦concentrated in the liver,
♦Therapeutic levels in vaginal and seminal fluids, saliva, breast milk and CSF
persist for a month after a
♦intracellular concentrations rapidly approximates extracellular levels
♦metabolized by hepatic oxidation of the side chain by CYPs and subsequetly single dose
glucuronylated ♦alowly metabolized and
♦hepatic metabolism accounts for over 50% of the systemic clearance excreted
♦peak plasma concentration is reached in 1-3 hours ♦half-life 5 days
♦ low plasma protein binding (<20%)
♦ half-life of 8 hours
♦ drug and its metabolites are excreted in the urine
Clinical Indications: ♦use is limited by toxicity
1. Anaerobic infection ♦close clinical observation
♦ Intraabdominal infection is necessary when drug is
♦ Brain abscess administered
♦ Peritonsillar abscess
♦not used for more than 5
♦ DOC for Antibiotic associated enterocolitis (pseudomembranous colitis)
2. Amebiasis days
♦ Drug of choice for treatment of all symptomatic forms of amebiasis
♦Both tissue and luminal amebicide
3. Giardiasis
4. Genital infection with Trichomonas vaginalis in both female and male
5. H. pylori infection - in combination with other antimicrobials and proton pump
inhibitors
Adverse Effects: Adverse Adverse effects:
1. GIT effects: 1.pain at site of injection
♦ nausea, vomiting ♦fever and chills, 2.transient nausea
♦epigastric distress, abd cramps rash 3.cardiotoxicity
♦ metallic taste in the mouth ♦diarrhea ♦arrhythmias, congestive
♦ diarrhea ♦thyroid gland heart failure
2. Headache, dizziness, vertigo, insomnia, numbness or paresthesias enlargement 4.neuromuscular weakness
3. Darkening of the urine ♦dose related 5.dizziness
4. Disulfiram-like effect when taken with Alcohol (during and within 3 days of peripheral 6.rashes
therapy) neuropathy
**Disulfiram acts by inhibiting the e.g. optic
enzyme Aldehyde dehydrogenase neuritis
♦produce accumulation of
acetaldehyde
♦When a patient takes alcohol
in the presence of Disulfiram,
acetaldehyde accumulates
producing rxns such as facial
flushing, nausea, vomiting, dizziness and headache
***from Katzung
Amebiasis
- infection with Entamoeba histolyca
- asymptomatic intestinal infection
- mild to moderate colitis
- dysentery: sever intestinal infection
- ameboma
- liver abscess
- other exraintestinal infections

Tx of specific forms of Amebiasis


Asymptomatic Intestinal Infection Amebic Colitis Extraintestinal Infections
- generally not treated in endemic areas, but in - TOC: metronidazole+luminal amebicide (also - TOC: metronidazole+luminal amebicide
nonendemic areas, they are treated with a TOC for dysentery) - 10days of metronidazole cures over 95% of
luinal amebecide (diloxanide furoate, - Tetracyclines, Erythromycin: alternative drugs uncomplicated liver abscesses
iodoquinol, and paromomycin) for moderate colitis but are NOT effective - alternative Tx: aspiration of the abscess +
- each drug eradicates carriage in about 80-90% against extraintestinal disease chloroquine + another course of metronidazole
of Px with a single course of Tx - Dehydroemetine/Emetine: can also be used but - alternative drugs: hydroemetine and emetine
- the said therapy is also required in the Tx of all best avoided coz of toxicity (but both are toxic)
other forms of amebiasis
Metronidazole & Tinidazole Iodoquinol Paromomycin Diloxanide Furoate Emetine /
Sulfate Dehydroemetine
Metronidazole - diiodohydroxyq an dichloroacetamide Emetine
- a nitroimidazole uin aminoglycosid derivative - alkaloid derived
- DOC for extraluminal amebiasis - halogenated e antibiotic from Ipecac
- Kills trophozoites but not cysts of E histolytica hydroxyquinoli that is not Dehydroemetine
- Effectively eradicates intestinal & extraintestinal tissue infections ne significantly - synthetic analog
- effective absorbed in
Tinidazole luminal the GIT
- a related nitroimidazole amebicide
- similar activity, better toxicity profile - commonly
- offers simpler dosing regimens & can be substituted for the indications used w
listed for Metronidazole metronidazole

Mechanism of Action: unknown MOA unknown MOA


- nitro grp of metronidazole is chemically reduced in anaerobic bacteria
& sensitive protozoans
- reactive reduction products appear to be responsible for antimicrobial
activity
- same for Tinidazole
Pharmacokinetics: - poorly - The small amnt - in the gut, 90% of the - should be used for
♦oral forms (tablet and suspension) are rapidly and completely absorbed from understood absorbed is slowly diloxanide is rapidly the min. period
the GIT (simple diffusion) - 90% of the excreted absorbed and then needed to relieve
♦also available for intravenous injection, intravaginal and topical formulations unchanged mainly conjugated to form
♦ distributes well to all body tissues and fluids drug is by glomerular glucoronide (w/c is severe symptoms
♦Therapeutic levels in vaginal and seminal fluids, saliva, breast milk and CSF retained in the filtration promptly excreted in (3-5 days) and
♦intracellular concentrations rapidly approximates extracellular levels intestine & the urine) should be
♦metabolized by hepatic oxidation of the side chain by CYPs and subsequetly excreted in the unabsorbed diloxanide administered SQ or
glucuronylated feces (the is the active IM (NOT IV)
♦hepatic metabolism accounts for over 50% of the systemic clearance remainder antiamebic substance
♦peak plasma concentration is reached in 1-3 hours (plasma clearance of enters the
metronidazole is decreased in Px w impaired liver problems) circulation)
♦ low plasma protein binding (<20%) - HL: 11-14hrs
♦ half-life of 8 hours (metronidazole); 12-14 hours for Tinidazole (excreted in
♦ drug and its metabolites are excreted in the urine the urine as
glucoronides)
Clinical Indications: effective against Only used as a Effective luminal Effective against tissue
1. Anaerobic infection organisms in the luminal amebicide amebicide but is not trophozoites of E
♦ Intraabdominal infection bowel lumen but and has no effect active against tissue histolytica, but coz of
♦ Brain abscess not against against trophozoites major toxicity concerns
♦ Peritonsillar abscess trophozoites in extraintestinal their use is limited to
♦ DOC for Antibiotic associated enterocolitis (pseudomembranous colitis) the intestinal wall amebic infections **DOC: asymptomatic unusual circumstances in
2. Amebiasis or extraintestinal luminal in fections w/c severe amebiasis
♦ Drug of choice for treatment of all symptomatic forms of amebiasis tissues **appears to have **usually used with requires effective therapy
♦Both tissue and luminal amebicide similar efficacy and metronidazole and metronidazole cannot
3. Giardiasis – DOC: metronidazole; single dose of 2g is effective less toxicity be used
4. Genital infection with Trichomonas vaginalis in both female and compared to other
male agents **dehydroemetine is
5. H. pylori infection - in combination with other antimicrobials and proton **parenteral preferred = better toxicity
pump inhibitors paromomycin is profile
also now used to
treat visceral
leishmanias

Adverse Effects: Adverse - drug may - flatulence is - generally mild AE’s


1. common: effects: accumulate with common w/ use for 3-5 days
- nausea, headache, dry mouth, metallic taste in the mouth - (infrequently) – renal - nausea and abd - increase over time
2. infrequent: diarrhea (stops insufficiency and cramps are include pain,
- vomiting, diarrhea, insomia, weakness, dizziness, thrush, rash, dysuria, dark after several contribute to infrequent tenderness, and
urine, vertigo, paresthesias, neutropenia days), renal toxicity - rashes are rare sterile abscesses
**taking the drug w/ meals lessens GIT irritation anorexia, - occasional abd at the injection site
3. rare: nausea, distress **not recommended in - diarrhea
- pancreatitis, severe CNS toxicity (ataxia, encelopathy, seizures) vomiting, abd - diarrhea pregnancy - nausea
pain, - vomiting
**metronidazole(w/c has a disulfiram-like effect) + alcohol intake = vomiting headache, - muscle weakness
** use w caution for Px w CNS, liver, or renal disease rash, pruritis and discomfort
**Tinidazole has similar AE’s but seems to be better tolerated - some - minor ecg changes
**best avoided in pregnant or nursing Px halogenated - serious toxicities:
**drug interactions: hydroxyquinoli cardiac arrythmias,
- metronidazole potentiates the anticoagulant effect of coumarin-type nes can heart failure, HPN
anticoagulants produce
- phenytoin, Phenobarbital = accelerates elimination of the drug severe **CI: Px w/ renal disease,
- cimitidine = may decrease its plasma clearance; lithium toxicity may neurotoxicity cardiac disease, young
occur w prolonged childres, pregnant Px
used at (unless absolutely
greater than necessary)
recommended
dosage

**should be taken
w meals to limit
GIT toxicity
**use w caution
for Px w/ optic
neuropathy, renal
or thyroid
disease, or
nonamebic
hepatic disease
**CI: Px w/
intolerance to
iodine
(discontinue use
if persistent
diarrhea or signs
of iodine toxicity
are observed:
dermatitis,
urticaria, pruritis,
fever)