AMEBIASIS
•Amebiasis (amebic dysentery) is an intestinal tract
infection caused by Entamoeba histolytica
• GI disease can be acute or chronic
• Infection can be symptomatic or latent
•Symptoms can range from mild diarrhea to fulminating dysentery
• E.Histolytica exists in two forms
(1) cysts (can survive outside body)
(2) trophozoites (do not survive outside body)
• Trophozoites are liberated from ingested cysts within the intestinal lumen
• Liberated trophozoites migrate to the large intestine where they multiply and invade the intestinal mucosa.
•Trophozoites can enter bloodstream to result in a systemic invasion
• Life cycle completes by trophozoites returning to the cyst
form in the rectum and being expelled in the feces
ANTIAMEBICS: GAOLS OF THERAPY
1) Eliminate invading trophozoites
&
2) Eradicate intestinal carriage of the organism
ANTIAMEBICS:
• Luminal
Act on parasite in bowel lumen
• Systemic
Active both in intestinal wall and liver
• Mixed
Active against both luminal & systemic disease
MIXED ANTIAMEBICS
METRONIDAZOLE
TINIDAZOLE
METRONIDAZOLE
MOA:
• Once absorbed, metronidazole is non-enzymatically
reduced by reacting with reduced FERREDOXIN
• This reduction causes the production of cytotoxic compounds
• The cytotoxic compounds bind to proteins & DNA, resulting in unstable molecules and cell death
METRONIDAZOLE
PK
AE
MIXED LUMINAL + SYSTEMIC AGENT
PK:
• Oral
• Well distributed (inc. vaginal & seminal fluids, saliva, breast milk & CSF)
• Undergoes hepatic oxidation & glucuronidation (CYP P450’s)
AE:
• GI distress
• ***Disulfiram-like reaction*** (avoid alcohol intake)
• Unpleasant metallic taste
• Oral moniliasis
• Dark coloration of urine
• Leukopenia, dizziness, ataxia.
• Safety in pregnancy NOT established*****
TINIDAZOLE
MIXED LUMINAL + SYSTEMIC AGENT
• 2nd generation nitroimidazole
• Similar to metronidazole but better tolerated and has shorter treatment course
Clinical Applications
• Amebiasis
• Amebic liver abscess
• Giardiasis
• Trichomoniasis
AE:
• Same as metronidazole but reports indicate shorter duration of effects with tinidazole
LUMINAL ANTIAMEBICS
• 1) Diloxanide furoate
• 2) Iodoquinol
• 3) Paromomycin
DILOXANIDE FUROATE
• Used as sole agent for treatment of ASYMPTOMATIC AMEBIASIS
• Converted in gut to active form
Adverse Effects
• Mild (GI distress)
Not currently available in US – however remains
luminal amebicide of choice
IODOQUINOL
LUMINAL AGENT (ANTIAMEBIC)
• Orally active against luminal trophozoite and cyst forms of E.histolytica
• Used as an alternative to diloxanide furoate for mild- severe infections
Adverse Effects
• Rash, diarrhea, dose-related ***peripheral neuropathy**** (exam Q)
• Long term use should be avoided (due to risk of optic neuritis)***
PAROMOMYCIN
LUMINAL ANTIAMEBIC
• Aminoglycoside antibiotic
• Effective only against luminal forms of E.histolytica and tapeworm
•Sometimes used with tetracyclines for mild intestinal
disease
• Alternative agent for cryptosporidiosis in AIDS patient
MOE/AE:
• AmebiCIDAL (causes cell membranes to leak)
• Interferes with bacterial protein synthesis (binds to 30S ribosomal subunits)
• Reduces intestinal flora population
Adverse Effects
• GI distress & diarrhea
• Systemic absorption may lead to headaches, dizziness, rashes and arthralgia
SYSTEMIC ANTIAMEBICS
1) CHLOROQUINE
2) EMETINE
3) DEHYDROEMETINE
-useful for treating liver abscesses or intestinal wall infections
CHLOROQUINE
SYSTEMIC ANTIAMEBIC
• Used in combination with
- metronidazole & ("mixed" luminal and systemic agent)
- diloxanide furoate (luminal agent)
MOA
• Eliminates trophozoites in liver abscesses
EMETINE +
DIHDROEMETINE
SYSTEMIC ANTIAMEBIC
• BACKUP DRUGS for treatment of SEVERE intestinal or hepatic amebiasis
• Used in combination with a luminal agent
MOA
• Inhibit protein synthesis by blocking ribosomal movement along messenger RNA
PK:
• IM or SC
• Concentrate in liver (persists for 1 month)
• Slowly metabolized & eliminated
EMETINE +
DIHDYROEMETINE
AE:
• Pain at site of injection****** on exam!!!
• Transient nausea
• Cardiotoxicity
• Neuromuscular weakness
• Dizziness
• Rash
TREATMENT OF AMEBIASIS
ASYMPTOMATIC, INTESTINAL INFECTION
DOC:
1) DILOXANIDE FUROATE
ALTERNATIVE DRUG(S):
1) IODOQUINOL
2) PAROMOMYCIN
TREATMENT OF AMEBIASIS
MILD-MODERATE INTESTINAL INFECTION
DOC:
1) METRONIDAZOLE AND
2) DILOXANIDE FUROATE
ALTERNATIVE DRUGS:
1) Tinidazole OR
2) Tetracycline OR
3) Erythromycin + diloxanide furoate
TREATMENT OF AMEBIASIS
SEVERE INTESTINAL INFECTION
DOC:
1) METRONIDAZOLE OR TINIDAZOLE
AND
2) DILOXANIDE FUROATE
ALTERNATIVE DRUGS:
1) Tetracycline OR Emetine OR Dihydroemetine
AND
2) DILOXANIDE FUROATE
TREATMENT OF AMEBIASIS
HEPATIC ABSCESS + OTHER EXTRAINTESTINAL DISEASE
DOC:
1) METRONIDAZOLE OR TINIDAZOLE
AND
2) DILOXANIDE FUROATE
Alterative drugs:
1) Emetine OR Dihydroemetine
AND
2) Chloroquine
AND
3) Diloxanide Furoate
HELMINTHS
Nematodes
• Elongated roundworms that possess a complete digestive system.
• Cause infections of intestine as well as blood & tissue.
Trematodes
• Leaf-shaped flatworms generally characterized by tissues they infect: liver, intestinal, blood flukes
Cestodes
• Flat, segmented body which attach to host’s intestine
• Lack mouth & digestive system throughout life cycle
ANTIHELMINTHIC DRUGS
• In most cases broad spectrum agents cure or control most human worm infections
• Some systemic infections only respond partially to
antihelminthic drugs (cysticercosis, echinococcosis,
filariasis, trichinosis)
Antihelminthic drugs can act either:
• locally (to expel worms from GI tract) or,
• systemically (to eradicate adult helminths or developmental forms)
BENZIMIDAZOLES
ANTIHELMINTHICS
1) ALBENDAZOLE
2) MEBENDAZOLE
3) THIABENDAZOLE
NOTE: ALL are CATEGORY C and CONTRINDICATED IN PREGNANCY!!!!
ALBENDAZOLE
BENZIMIDAZOLE - an ANTIHELMINTHIC DRUG
• Used in the treatment of CESTODE infestations, such as
- cysticercosis (Taenia solium larvae) and
- hydatid disease (Echinococcus granulosis)
MOA
• Inhibits microtubule synthesis & glucose uptake
• ATP production is decreased resulting in worm immobilization and death
PK:
• Oral (erratically absorbed, enhanced by high-fat meal)
• Extensive first-pass metabolism, including rapid sulfoxidation to active metabolite
ALBENDAZOLE
AE
•Short course therapy (1-3 days) = mild & transient (headache, nausea)
• ****HYDATID treatment (3 months) = risk of hepatotoxicity, agranulocytosis or pancytopenia**************
• Treatment is associated with inflammatory responses to dying parasites in CNS******* (headache, vomiting, hyperthermia, convulsions, mental changes)
• Contraindicated in pregnancy & children < 2y (FDA Category C)
MEBENDAZOLE
DOC FOR?
BENZIMIDAZOLE - ANTIHELMINTHIC DRUG
Drug of choice in the treatment of infections by:
• 1) Whipworm (Trichuris trichiura) (in tunnel) pig with spirals on his suit
• 2) Pin worm (Enterobius vermicularis) (in tunnel, "vermin lady" who's first character introduced, going into the hole)
• 3) Hookworms (Necator americanus & Ancylostoma duodenale) (in tunnel, is american dude swinging)
• 4) Roundworm (Ascariasis lumbricoides) (in tunnel, huge lumbering tree man in back)
MEBENDAZOLE
BENZIMIDAZOLE (Antihelminthic drug)
• Inhibits formation of helminth microtubules
• Irreversibly blocks glucose uptake
• Affected parasites are expelled with feces
Pharmacokinetics
• Oral (chewable) – nearly insoluble in aqueous solution, take with high-fat meal
• Undergoes first-pass metabolism to inactive compounds
MEBENDAZOLE
AE
• Abdominal pain, diarrhea, headache, dizziness
• Contraindicated in pregnancy (FDA Category C)
• Use with caution in children < 2
• Use with caution in patients with cirrhosis
THIABENDAZOLE
Effective in treatment of
1) strongyloidiasis caused by Strongyloides stercoralis (threadworm), (strong guy in tunnel kicking wall in on right side)
2) CUTANEOUS LARVA MIGRANS, and
3) early stages of TRICHINOSIS
MOA
• Affects microtubular aggregation
Pharmacokinetics
• Oral
• Nearly insoluble in H20
THIABENDAZOLE
AE
• MOST TOXIC of all the benzimidazoles
• Dizziness, anorexia, nausea, vomiting
• CNS disturbances (dizziness --> seizures)
• Cases of erythema multiforme & Stevens-Johnson reported
• Contraindicated in pregnancy (FDA Category C)
• Should not be used in presence of liver or kidney disease
IVERMECTIN
Drug of choice for the treatment of
1) onchocerciasis (Onchocerca volvulus), (movie scene, back of the room guy covering one eye near the no dumping in river sign)
2) cutaneous larva migrans &
3) strongyloides (in tunnel, guy on right kicking in wall)
MOA
• GABA agonist*******
• Cl- influx increases leading to hyperpolarization of nerve /
muscle cell. Death occurs due to paralysis of parasite*****
Pharmacokinetics
• Oral (does not cross BBB)
IVERMECTIN
AE
• ***Mazotti-like reactions with onchoceriasis (fever, dizziness, somnolence, hypotension)**** --> IS D/T DEATH OF THE PARASITE
• Contraindicated in pregnancy (FDA Category C)
• Contraindicated in meningitis (may cross BBB)******
• Best to avoid concomitant use of ivermectin & other drugs that enhance GABAergic activity (eg, barbiturates, benzodiazepines)