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PHARMACOLOGY 6.

01
AMOEBICIDAL DRUGS
Dr. Mar Rustan Enriquez | January 21, 2019
Transcriber group: 13B

TABLE OF CONTENTS ● Definitive Host: Humans


1. Amebiasis ● Habitat: Large intestines
2. Tissue Amoebicides ● Infective stage: Mature cysts (ingestion)
a. Metronidazole ● Diagnostic stage: Trophozoites, Mature and
b. Emetine Hydrochloride immature cysts
c. Chloroquine phosphate ○ Trophozoites – target of amoebicidal
d. Nitazoxanide drugs
3. Luminal Amoebicides ● Once you ingested the cysts of Amoeba, the
a. Iodoquinol cysts will transform into trophozoites in the
b. Diloxanide Furoate large intestine.
c. Paromomycin Sulfate ● The most common amebic infections are
4. Treatment of Specific Forms of Amoebiasis usually asymptomatic.
5. Summary Tables ● Sometimes the trophozoites:
○ can also invade the colonic mucosa
Red text – from lecture recordings which can cause colitis, amebic
Green text – from Katzung dysentery/ bloody diarrhea
INTRODUCTION ○ can travel outside the portal circulation
• Protozoans are unicellular organisms which are which can infect the liver causing
subdivided into 3 Phyla (differences based on their amebic liver abscess
mode of locomotion): ○ can also travel within the lungs and
1. Phylum Sarcomastigaphora brain
a. Subphylum Mastigophora ● Spectrum of disease:
- Mode of locomotion: flagella 1. Asymptomatic intestinal infection
- Examples: Trypanosoma, 2. Mild to moderate amebic colitis
Leishmania 3. Severe amebic colitis
b. Subphylum Sarcodina 4. Extraintestinal infections
- Mode of transportation: a. Hepatic Abscess
pseudopods b. Amoeboma – chronic
- Representative: Amoeba granulation change within the
2. Phylum Ciliophora intestinal tract caused by the
- Ciliated protozoans reaction of the body to the
- Representative: Paramecium parasite
3. Phylum Apicomplexa ● For those people leaving in endemic areas that
- Do not have any recognizable mode of are asymptomatic are not treated actively.
locomotion
- Examples:Plasmodium, CLASSIFICATION OF AMOEBICIDAL DRUGS
Cryptosporidium (in GIT) 1. Luminal Amoebicidals
a. Amides
AMEBIASIS b. Halogenated Hydroquinolines
● Infection caused by a parasite Entamoeba c. Antibiotics
histolytica 2. Tissue Amoebicidals
● Affects 10% of the world’s population and most a. Nitroimidazoles
commonly among individuals living in poverty, b. Emetine
crowded conditions and areas with poor c. Chloroquine
sanitation
● Endemic to third world countries TISSUE AMEBICIDALS
● Drugs that act primarily in the bowel wall, liver
● 3 species of Entamoeba: and the extra intestinal tissues
○ E. dispar
○ E. moshkovskii Nitroimidazoles Metronidazole (most
■ E. dispar and E. moshkovskii commonly used for
cause 90% of human infections
amoebiasis)
(not treated) and are
asymptomatic Tinidazole
○ E. histolytica - 10%, capable of causing
disease; only species that causes Ornidazole
disease (amebiasis)
● Entamoeba is part of protozoans which are Secnidazole
single-celled organism.
● Transmission: Fecal-oral route
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Emetine hydrochloride
need to be absorbed thoroughly
compared to luminal amebecides
Dehydroemetine
A/E ● Disulfiram-like effect
Chloroquine phosphate* (flushing, vomiting,
headache) if px drinks
alcoholic beverages within 3
*also used as an anti-malarial drug
days of therapy
● Neurotoxic effects
(dizziness, vertigo,
METRONIDAZOLE (Flagyl®)
encephalopathy, convulsions,
Class Nitroimidazole ataxia, paresthesia)
● Dysuria, cystitis, & sense of
MOA Reactive reduction (by the pelvic pressure
bacteria / protozoans) of the nitro
group appears to be ***Cephalosporins (beta-
antimicrobial) lactam antibiotics which also
causes Disulfiram-like effect)
Uses ***has antiparasitic and
antibiotic activity ***Disulfiram-like-effect is a
result of an accumulation of
DOC for Extraluminal acetaldehyde due to the inhibition
Amoebiasis (Amebic colitis & of acetaldehyde dehydrogenase
Amebic liver abscess)
***Other adverse effects include
DOC for Giardiasis (Giardia headache, dry mouth, fatigue,
lamblia) metallic bitter taste, and GI
distress
DOC for Trichomoniasis
(Trichomonas vaginalis) ***Advise patient to take the
medicine after meals and to avoid
Act as antibiotic for Anaerobic ANY alcohol-containing products
infections (Bacteroides, (including rubbing alcohol and the
Clostridium difficile, Helicobacter) like)

Note Kills Trophozoites (but not Precaution ● May be mutagenic in


cysts) of E. histolytica high doses
● Drug interaction with
A prodrug – reductive activation Lithium (used for
inside protozoans convulsions) – Neurotoxic
● Should be used with
PK ● Rapidly absorbed orally caution in patients with
● Permeate ALL tissues by CNS disease
simple diffusion except ● Dosage adjustments
placenta required for patients
● Peak plasma conc 1-3 hours with severe liver or
● Low plasma binding protein renal disease
● Excreted in the urine;
● t1/2: 7.5 hours
(Metronidazole) = given 3x ***Due to indefinite studies,
a day; 12-14 hours Metronidazole is not used in the
(Tinidazole) first trimester during pregnancy
● Plasma clearance of and in accordance to the study of
Metronidazole is WHO in 2016, it is not
decreased in patients with recommended in early
impaired liver function pregnancy

***Note: Metronidazole can


***since tissue amebecides act CROSS THE PLACENTA.
at the bowel wall and liver, they (Theoretical risk to the fetus)

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A/E Pain, tenderness, sterile
abscesses at the injection site;
diarrhea, nausea, vomiting,
muscle weakness, and discomfort
Cardiac arrythmias, heart
failure, hypotension

CHLOROQUINE
Class -Tissue Amoebicide
-Anti-malarial (DOC)
-DMARD (disease-modifying
antirheumatic drug)

MOA Directly toxic to E. histolytica

Uses -Amoebic liver abscesses ONLY


-DOC for non-falciparum malaria
Chemoprophylaxis (in chloroquine-
Fig.1: Note: Metronidazole is a nitroimidazole drug sensitive areas)
(imidazole ring and nitro group [NO2]). Metronidazole Rheumatoid arthritis
acts as a prodrug (inactive form) so we need to
activate it before it works as an antiparasitic drug.
Prodrug Metronidazole would undergo reductive PK Concentrated in the liver
activation inside the Anaerobes or Protozoans (E.
histolytica, Giardia, and Trichomonas). The reason why S/E GI irritation, skin rash, retinal
it is effective against protozoans because of the damage, auditory impairment
presence of the electrophilic component of the
anaerobes which is the ferredoxin. Ferredoxin is a NITAZOXANIDE
small protein composed of iron, sulfur, and protein
ferredoxin and is used to transform pyruvate into Class Nitrothiazolyl-salicylamide prodrug
acetyl CoA (before it enters the Kreb’s cycle). Tissue amebicide
Ferredoxin acts as an electron donor to Metronidazole
and donates 1 electron to Metronidazole for it to MOA PRODRUG
become Metronidazole (nitro radical) which will target Converted to an active metabolite
the DNA of the amoeba and anaerobes. (TIZOXANIDE) → inhibits
METRONIDAZOLE ACTS AS A PRODRUG FIRST. pyruvate:ferredoxin pathway

EMETINE Uses Infections caused by:


● E. histolytica
Class Alkaloid from Ipecac ● Giardia
Syrup of Ipecac ● T. vaginalis
-Primarily used as an antitussive ● C. parvum
drug (mucolytic) ● H. nana
-Also used as an antidote due to ● T. trichiura
its powerful emetic effect but is ● Ascaris lumbricoides
not used anymore because of its ● Several tapeworms
cardiac effects. ● Fasciola hepatica

Similar Drug Dehydroemetine (synthetic Metronidazole-resistant protozoal


analog)- less toxic strains

Uses For SEVERE invasive intestinal PK - Excellent bioavailability.


and extraintestinal - Hydrolyzed rapidly to Tizoxanide
amoebiasis which undergoes conjugation to
(if metronidazole is Tizoxanide glucuronide.
contraindicated) - Tizoxanide excreted in the urine, bile
• Should me administered and feces.
subcutaneously (preferred) or
intramuscularly A/E MC (Rare)

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• Remember: For your macrolides the most
Abdominal pain
common examples are Erythromycin,
Diarrhea
Clarithromycin and Azithromycin
Vomiting
Headache
IODOQUINOL
*Greenish tint to the urine
Class -Halogenated 8-hydroxyquinoline
Precaution PREGNANCY CATEGORY B (i.e. Animal luminal amoebicide
s reproduction studies have failed to
demonstrate a risk to the fetus and MOA Unknown
there are no adequate and well-
controlled studies in pregnant women) Uses As single agent:
- asymptomatic pxs found to have
E. histolytica
LUMINAL AMOEBICIDES
In combination w/ metronidazole:
● Drugs that act on the parasites present in
- amoebic liver abscess
the bowel lumen
- amoebic colitis
● Drugs which are not well absorbed in the body
because it need to reach the bowel lumen
Effective against organisms in the
where the parasites inhabit
bowel lumen but not against
● Tissue amebicides and luminal amebicides are
trophozoites in the intestinal wall
used simultaneously for 100% treatment
or extraintestinal tissues
● Drug of choice for asymptomatic
amoebiasis
PK Poorly absorbed since 90% of the
drug remains in the intestine, the
rest is excreted via feces
Amides Diloxanide furoate (most t1/2 = 11-14 hours
common amide)
Etofamide A/E -GI upset, abdominal pain, nausea,
vomiting
Clefamide - Iodine toxicity (Dermatitis,
urticaria, pruritus, fever)
-Administration of high doses in
Teclozan children has been associated with
optic atrophy & permanent loss of
Halogenated Iodoquinol a.k.a. vision
Hydroquinolines Diiodohydroxyquin (most
commonly used) CI Iodine intolerance (pxs w/ thyroid
disease as additional iodine in their
Iodochlorhydroxyquin
diet can trigger hyperthyroidism)

Dibromohydroxyquinoline Note Should be taken with meals to limit


GI toxicity
Antibiotics Paromomycin
(Aminoglycosides) Used with caution in patients with
optic neuropathy, renal or thyroid
Erythromycin* (Macrolides)
disease, or nonamebic hepatic disease

Tetracycline*
DILOXANIDE FUROATE
*antibiotics Class -Dichloroacetamide derivative

[Take note of the amebicides in BOLD letters.] MOA Unknown

• Erythromycin - inhibits 50S ribosomal subunit Uses As single agent:


• Tetracycline - inhibits 30S ribosomal subunit - DOC for asymptomatic luminal
• MOA of Erythromycin and Tetracycline: inhibits infection
protein synthesis
• RECALL: BUY at 30 CELLS at 50 In combination w/ metronidazole:

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- For serious intestinal and
extraintestinal amoebic infections

PK Splits into 2 in the gut:


● Diloxanide
- 90% absorbed →
excreted via urine
(Glucoronide)
- 10% unabsorbed →
active anti-amoebic
substance
● Furoic Acid

A/E Flatulence (main adverse effect),


nausea, vomiting, diarrhea, pruritis

CI Pregnancy

PAROMOMYCIN SULFATE Figure 2. Nitazoxanide targets or inhibits Pyruvate


Ferredoxin Oxidoreductase (PFOR) which is the
Class - Aminoglycoside
enzyme that reduces Ferredoxin in its oxidized form.
- Luminal amebicide
PFOR is a complex used in the conversion of pyruvate
to Acetyl CoA. A cofactor component of PFOR that
MOA Binds to 30s ribosomal subunit
Nitazoxanide specifically targets is Thiamine
Pyrophosphate (TPP) which is a derivative of Vitamin
Uses Oral prep:
B1 (thiamine).
- DOC for asymptomatic Intestinal
Amoebiasis
TREATMENT OF SPECIFIC FORMS OF
- Cryptosporidiosis
AMOEBIASIS
- Giardiasis
ASYMPTOMATIC INTESTINAL INFECTIONS
Topical:
- Trichomoniasis Luminal Amebicide* (DOC for this type of amoebiasis)
Supportive Management
Parenteral:
- Visceral leishmaniasis Endemic areas → generally not treated
Nonendemic areas → luminal amebicidal
PK Oral: Tissue amebicidal is unnecessary
- not well absorbed in the GIT
- small amount absorbed is slowly AMOEBIC COLITIS
excreted unchanged, mainly by
glomerular filtration Metronidazole + Luminal Amebicide (treatment of
choice)
A/E Oral: Alternative: Tetracyclines and Erythromycin (but they
- Rare but includes abdominal pain, are not effective against extraintestinal disease)
cramping, nausea, vomiting,
steatorrhea & diarrhea Dehydroemetine or emetine can also be used, but are
avoided because of toxicity
Parenteral:
- NephRotoxicity- Reversible EXTRAINTESTINAL INFECTIONS
- Ototoxicity- irreversible
Metronidazole + Luminal Amebicide (treatment of
Precaution Avoided in patients with renal choice)
s diseases
DOC for Intestinal Amoebiasis: PAROMOMYCIN
SULFATE
Note Alternative to metronidazole in first
DOC for Extraintestinal Amoebiasis:
trimester of pregnancy
METRONIDAZOLE

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Notes:
SUMMARY OF DOC
Metronidazole Extraluminal Amoebiasis
Giardiasis
Trichomoniasis
Chloroquine Non-falciparum malaria
Diloxanide Furoate Asymptomatic luminal
infection (as a single
agent)
Paromomycin Sulfate Intestinal Amoebiasis
(oral)

IMPORTANT: Please study Table 52-5 of Katzung,


we attached it on the next page of this trans. ☺

REFERENCES
1. Katzung 13th ed. Chap 52 pp. 898-901
2. PPT
3. Online References

TRANSCRIBED BY:
1. Group 13B
2. Subtranshead: EJA, RPh
3. Proofreader: CG, RRT
4. Transhead: IA, RPh

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PHARMACOLOGY 6.01
AMOEBICIDAL DRUGS
Dr. Mar Rustan Enriquez | January 21, 2019
Transcriber group: 13B

TISSUE AMEBICIDES
METRONIDAZOLE EMETINE CHLOROQUINE
Class Nitroimidazole • Alkaloid from Ipecac → Syrup • Tissue amebicide
of Ipecac • Anti-malarial (DoC)
• DMARD
MOA Reactive reduction (by the Directly toxic to E. histolytica
bacteria / protozoans) of the
nitro group appears to be
antimicrobial)
Uses *has antiparasitic and • Antitussive drug (mucolytic) • Amoebic liver abscesses
antibiotic activity • Antidote → powerful emetic • DoC for non-falciparum
• DOC for Extraluminal • For SEVERE invasive malaria
Amoebiasis (Amebic intestinal and • Chemoprophylaxis (in
colitis & Amebic liver extraintestinal amebiasis chloroquine-sensitive areas)
disease) (if metronidazole is • Rheumatoid arthritis
• DOC for Giardiasis) contraindicated
• DOC for Trichomoniasis
• Act as antibiotic for
Anaerobic infections
(Bacteroides, Clostridium
difficile, Helicobacter)

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PK ● Rapidly absorbed orally Concentrated in the liver
● Permeate ALL tissues
by simple diffusion except
placenta
● Excreted in the urine;
t1/2: 7.5 hours
(Metronidazole) = given 3x
a day

A/E ● Disulfiram-like effect if ● Pain, tenderness, sterile


px drinks alcoholic abscesses at the injection
beverages within 3 days of site; diarrhea, nausea,
therapy vomiting, muscle weakness,
● Neurotoxic effects and discomfort
● Dysuria, cystitis, & ● Cardiac arrythmias, heart
sense of pelvic pressure failure, hypotension

LUMINAL AMOEBICIDES
IODOQUINOL DILOXANIDE PAROMOMYCIN NITAZOXANIDE
FUROATE SULFATE
Class Halogenated 8- Dichloroacetamide Aminoglycoside Nitrothiazolyl-
hydroxyquinoline derivative salicylamide prodrug
luminal amebicide
MoA Unknown Unknown Binds to 30S ribosomal Converted to an active
subunit → inhibits protein metabolite (Tizoxanide)
synthesis that inhibits the
pyruvate:ferredoxin
pathway
Uses • Singly → for • Singly → DoC for • Orally → DoC for • Various infections
asymptomatic px asymptomatic intestinal • Metronidazole-
w/ E. histolytica luminal infxn amoebiasis; resistant protozoal
• In combination w/ • In combination w/ cryptosporidiosis, strains
Metronidazole → Metronidazole → giardiasis
for serious • Topically →
Amoebic liver
intestinal and trichomoniasis
abscess and
extraintestinal • Parenterally →
amoebic colitis
amoebic infxns visceral leishmaniasis
PK Poorly absorbed (90% Splits into 2 in the gut: • Oral → not well • Excellent
of the drug remains in Diloxanide (90% absorbed in GIT; bioavailability
the intestine, the rest absorbed; 10% small amt absorbed • Hydrolyzed rapidly to
excreted in feces) unabsorbed active is slowly excreted Tizoxanide which
substance) and Furoic unchanged undergoes
TAKEN WITH MEALS acid conjugation to
Tizoxanide
glucoronide
A/E • GI disturbances • Flatulence (main • Oral → rare but • Abdominal pain,
• Iodine toxicity a/e), nausea, includes pain, diarrhea, vomiting,
• High doses in vomiting, diarrhea, cramping, nausea, headache
children → Optic pruritus vomiting, steatorrhea
atrophy & • Contraindicated in & diarrhea
permanent loss of pregnancy • Parenteral →
vision Reversible
nephRotoxicity and
Irreversible
ototoxicity
• Avoided in px with
renal diseases

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