PHARMACOLOGY: AMEBICIDAL DRUGS

LUMINAL AMEBICIDES: drugs that act in the bowel lumen 1. Iodoquinol (Diiodohydroxyquin) - prototype 2. Paromomycin 3. Erythromycin 4. Tetracycline 5. Diloxanide furoate (Most of them are antibacterials.)

Lecturer: Dra. Maria Luisa D. Dela Cruz

Date of Lecture: November 26, 2013

TISSUE AMEBICIDES: drugs that act primarily in the bowel wall, liver and other extraintestinal tissues 1. Nitroimidazole a. Metronidazole (prototype) b. Ornidazole c. Secnidazole d. Tinidazole 2. Dehydroemetine / Emetine 3. Chloroquine

LUMINAL AMEBICIDES

TISSUE AMEBICIDES

IODOQUINOL
DESCRIPTION a halogenated 8hydroxyquinoline aka Diiodohydroxyquin amebicidal vs E. histolytica effective against trophozoites and cyst forms in the intestinal lumen exact mechanism of action is unknown

PAROMOMYCIN
an aminoglycoside antibiotic
cidal because inhibition of protein synthesis is irreversible

METRONIDAZOLE
Metronidazole, a produg, is activated by the reduction of the nitro group (arrow) leading to the generation of a reactive radical.

EMETINE / DEHYDROEMETINE
Emetine hydrochloride is a plant alkaloid derived from Ipecac (Syrup of Ipecac is an emetic drug; it induces vomiting) Dehydroemetine is a synthetic analogue Dehydroemetine is only available under compassionate investigational new drug protocol through the Center for Disease Control and Prevention acts on trophozoites acts by inhibiting protein synthesis in amoebae by arresting translocation of tRNA-amino acid complex

CHLOROQUINE
Amebicidal activity comparable to Emetine eliminates trophozoites from extraintestinal sites

same antibacterial action as other Aminoglycosides available ONLY for Oral use (capsule and suspension Direct action: causes leakage by its action on cell membrane of parasite Indirect action: reduces population of intestinal flora negligible absorption from the GIT (because aminoglycosides are highly polar) 100% of the drug is recovered in the FECES small amount absorbed is excreted unchanged in the urine (may accumulate with renal insufficiency) aminoglycosides are NEPHROTOXIC nitro group of the drug serve as an electron acceptor forming reduced cytotoxic compounds that bind to proteins and DNA resulting in cell death Mode of Action: CIDAL for anaerobic protozoa and bacteria available in oral, parenteral, intravaginal and topical formulation oral preparations (tablet and suspension) are rapidly and completely absorbed from the GIT (almost 100% oral bioavailability) peak plasma concentration in 0.25-4 hours parenteral preparations for INTRAVENOUS infusion absorption of topical preparations are less complete and more prolonged distributes well to all body tissues and fluids Therapeutic levels in vaginal and seminal fluids, saliva, breast milk, CSF, bones and joints CSF concentration is approximately 45% of serum concentration (makes the drug useful in anaerobic CNS infections) intracellular concentrations rapidly approximates extracellular levels undergoes oxidation and glucuronidation hepatic metabolism accounts for over 50% of the systemic clearance half-life of ~8 hours hydroxy metabolite has t of ~12 hrs low plasma protein binding (<20%) drug and its metabolites are excreted in the urine ~ 10% excreted unchanged
(please see last page for 4-step process of action)

MECHANISM OF ACTION

interacts with surfaces of growing -hematin crystals, inhibits deposition of further heme molecules and thereby indirectly promotes formation of toxic reactive oxygen species

PHARMACOKINETICS

oral preparation (tablet) poor absorption from the GIT 10% of the drug enters the circulation and excreted as glucuronide metabolite in the urine Half-life: 11-14 hrs primarily excreted in the FECES (because most of the drugs do not get absorbed)

erratic oral absorption PARENTERAL FORMULATION preferably given by subcutaneous or intramuscular injection should NEVER be given intravenously concentrated in the: liver lungs spleen kidneys myocardium intestinal wall slowly metabolized and excreted trace amounts could be detected in urine 1- 2 months after last dose should not be used for more than 10 days (usually 3-5 days) half-life 5 days

IODOQUINOL
THERAPEUTIC USES

PAROMOMYCIN
1. Amebiasis asymptomatic cysts passers as adjunct in the treatment of amebic dysentery and amebic liver abscess 2. Adjunct treatment of Hepatic coma (bacterial flora in the intestine synthesize ammonia, the substance causing hepatic encephalopathy) 3. Cutaneous and visceral Leishmaniasis 4. Giardiasis

METRONIDAZOLE
1. Anaerobic infection Intra-abdominal infection Brain abscess Peritonsillar abscess primary therapy for infection with Clostridium difficile (pseudomembranous colitis); alternative treatment for C. difficile infection is VANCOMYCIN given orally at a dose of 250-500mg TID for 7-14 days 2. Amebiasis DOC for treatment of all symptomatic forms of amebiasis (amebic colitis, amebic liver abscess) 10-day duration of treatment BOTH TISSUE AND LUMINAL AMEBICIDE (however, its 100% GIT absorption limits its luminal amebicidal action) 3. Giardiasis 4. Genital infection with Trichomonas vaginalis in both female and male (2 g single dose) 5. H. pylori infection in combination with other antimicrobials and proton pump inhibitors 6. Rosacea (a form of acne) topical lotion 7. Acne 1. GIT anorexia, abdominal cramps nausea, vomiting abdominal pain metallic taste in the mouth diarrhea / constipation 2. CNS headache, dizziness , vertigo peripheral neuropathy seizures, ataxia, confusion, irritability 3. Reddish brown urine discoloration Advise the patient that it is harmless 4. Disulfiram-like effect when taken with Alcohol WITHHOLD alcohol during and within 3 days of therapy CAUTION for ethanol-containing medications i.e. cough syrup, elixirs 5. Hypersensitivity reactions skin rashes, urticaria flushing, pruritus Stevens Johnson Syndrome
(see last page for the discussion of Disulfiram)

EMETINE / DEHYDROEMETINE
alternative drugs for treatment of extraintestinal amebiasis use is limited by toxicity; only used if Metronidazole does not work close clinical observation is necessary when drug is administered requires hospitalization to monitor cardiac adverse effects

CHLOROQUINE
combined with Metronidazole and Luminal amebicides in the treatment of amebic liver abscess

ADVERSE EFFECTS

skin rash nausea, vomiting, diarrhea thyroid gland enlargement (because it is halogenated, i.e., contains iodine which may affect thyroid function) dose-related peripheral neuropathy e.g. optic neuritis, optic atrophy blindness

abdominal pain and cramping nausea and vomiting diarrhea skin rashes headache

1. Cardiotoxicity (depression of cardiac conduction and contraction) Arrhythmia Heart failure Hypotension Death 2. Nausea and vomiting central origin 3. Decrease serum potassium May contribute to the development of arrhythmia 4. Pain, sterile abscess at site of injection 5. weakness

FOUR-STEP PROCESS OF METRONIDAZOLE ACTION:

TYPE OF INFECTION
Asymptomatic disease breakdown of cytotoxic intermediate products toxic intermediate particles decay into inactive end products Mild to Moderate Infection (non-dysenteric) Severe Infection (dysenteric) Extraintestinal

TREATMENT OF CHOICE
uminal Amebicide odoquinol/ armomycin etronidazole + etronidazole + LIFE CYCLE OF E. HISTOLYTICA
Cysts and trophozoites are passed in feces. Cysts are typically found in formed stool, whereas trophozoites are typically found in diarrheal stool. Infection by Entamoeba histolytica occurs by ingestion of mature cysts in fecally contaminated food, water, or hands. Excystation occurs in the small intestine and trophozoites are released, which migrate to the large intestine. The trophozoites multiply by binary fission and produce cysts, and both stages are passed in the feces. Because of the protection conferred by their walls, the cysts can survive days to weeks in the external environment and are responsible for transmission. Trophozoites passed in the stool are rapidly destroyed once outside the body, and if ingested would not survive exposure to the gastric environment. In many cases, the trophozoites remain confined to the intestinal lumen of individuals who are asymptomatic carriers, passing cysts in their stool. In some patients the trophozoites invade the intestinal mucosa or, through the bloodstream, extraintestinal sites such as the liver, brain, and lungs, with resultant pathologic manifestations. It has been established that the invasive and noninvasive forms represent two separate species, respectively E. histolytica and E. dispar. These two species are morphologically indistinguishable unless E. histolytica is observed with ingested red blood cells (erythrophagocystosis). Transmission can also occur through exposure to fecal matter during sexual contact (in which case not only cysts, but also trophozoites could prove infective. (CDC)

uminal amebicide uminal amebicide hloroquine uminal amebicide +

Interactions with intracellular targets reductive activation by intracellular transport proteins reduced by the pyruvate:ferredoxin oxidoreductase (PFOR) system in the mitochondria of obligate anaerobes Cytotoxic intermediate particles interact with host cell DNA, resulting in DNA strand breakage and fatal destabilization of the DNA helix

eronidazole (IV) +

entry into the organism diffusion across the cell membranes of anaerobic and aerobic microorganisms

SPECTRUM OF ACTIVITY OF METRONIDAZOLE: ANAEROBIC PROTOZOA Entamoeba histolytica Trichomonas viginalis Balantidium coli Giardia lamblia / G. intestinalis ANAEROBIC BACTERIA [BOTH GRAM (+) AND GRAM (-)] Bacteroides species esp. B. fragilis Clostridial spp. Peptococcus Peptostreptococcus in oral cavity Propionibacterium acnes Fusobacterium, Eubacterium MICROAEROPHILIC BACTERIA H. pylori Campylobacter spp.

DISULFIRAM-LIKE EFFECT OF METRONIDAZOLE:

Disulfiram

Disulfiram acts by inhibiting the enzyme Aldehyde dehydrogenase produce accumulation of acetaldehyde Disulfiram is an aversive therapy to alcoholism DISULFIRAM-LIKE REACTIONS: facial flushing tachycardia nausea and vomiting dizziness headache

VENCEREMOS!

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