Amoebicidal Drugs Lecturer: Danica B

Home , Amebicide, Etofamide

Amoebicidal Drugs Lecturer: Danica B. Quijano, MD Date Lectured: November 20, 2015 DLSHSI – College of Medicine: PHARMACOLOGY

ö Ariba amoeba! Greetings from the amoebas! Yes, ö Improper hygienic practices we’re gonna be talking a lot about the amoeba o Protozoal infections are common among people but only for the Entameoba histolytica , the in underdeveloped tropical & subtropical pathologic agent responsible for the famous countries, where sanitary conditions, hygienic “amoebiasis” we have all heard about. practices, and control of the vectors of ö We will focus our discussion in the transmission are inadequate. However, with pharmacological treatment for infection caused increased world travel, protozoal diseases are by the protozoa Entamoeba histolytica. But first, no longer confined to specific geographical let’s have a glimpse of the offending pathogen. locations. ö Amoebiasis is an infection caused by the E. ö Speaking of diarrhea and travel.. histolytica likewise amoebiasis is sometimes o Good to know: I believe you have heard the incorrectly used to refer to infection with other term Traveler’s diarrhea. Its diagnosis does not amoebae, but strictly speaking it should be imply a specific organism, but Enterotoxigenic E. reserved for E. histolytica infection. coli (ETEC) is the most commonly isolated pathogen. While Backpacker’s diarrhea is also ö Entamoeba is a genus of amoeboid protozoa that known as Giardiasis or Beaver fever because live in the human intestine. giardiasis, caused by the protozoan Giardia o Some species within this genus are harmless, lamblia, frequently infects persons who spend a while others are pathogenic. lot of time camping, backpacking, or hunting, so o One, especially, has the potential to become it has gained the nicknames. dangerous, the Entamoeba histolytica. ö Worth mentioning: ö Clinical features varies from asymptomatic to an o Traveler’s diarrhea (ETEC) infectious diarrhea and the most dreaded life- o Backpacker’s diarrhea (Giardiasis) threatening fulminant colitis. ö Entamoeba histolytica is the only specie that is ö The pathogenic Entamoeba histolytica definitely associated with pathological sequelae in o Amoebiasis – disease caused by E. histolytica humans; § It is estimated that up to 15% of the world's o the other entamoebas are considered population is infected by the pathogen nonpathogenic. Entamoeba histolytica. Every year, over ö The genus Entamoeba contains many species, six 100,000 people die of the disease caused of which, reside in the human intestinal lumen by E. histolytica, amoebiasis, making it the o Entamoeba histolytica, second most common parasitic cause of o Entamoeba dispar, death, after malaria. o Entamoeba moshkovskii, § 2nd most common parasitic cause of death o Entamoeba polecki, after malaria o Entamoeba coli, § Tropical countries with poor sanitation are o Entamoeba hartmanni often hit hardest by outbreaks.

ö The lifecycle of Entamoeba histolytica is pretty typical for a protozoan parasite. Just remember, we have 2 forms of the parasite: the cyst & the trophozoite. Let’s simplify further. ö Infection occurs by ingestion of cysts on fecally contaminated food or hands. o The cyst is resistant to the gastric environment and passes into small intestine where it decysts. o The metacyst divides into four and then eight amoebae which move to the large intestine. o The organisms encyst for mitosis and are passed through with feces. o There are no intermediate or reservoir hosts. ö Cysts and trophozoites are passed in feces. o Cysts are typically found in formed stool, o Trophozoites are typically found in diarrheal stool. ö Infection by Entamoeba histolytica occurs by ingestion of mature cysts in fecally contaminated food, water, or hands. ö Excystation occurs in the small intestine and trophozoites are released, which migrate to the large intestine. ö The trophozoites multiply by binary fission and produce cysts, and both stages are passed in the feces. o Because of the protection conferred by their walls, the cysts can survive days to weeks in the external environment and are responsible for transmission. o Trophozoites passed in the stool are rapidly destroyed once outside the body, and if ingested would not survive exposure to the gastric environment.

ö In many cases, the trophozoites remain confined to the intestinal lumen (: noninvasive infection) of individuals who are asymptomatic carriers, passing cysts in their stool. ö In some patients the trophozoites invade the intestinal mucosa (: intestinal disease), or, through the bloodstream, extraintestinal sites such as the liver, brain, and lungs (: extraintestinal disease), with resultant pathologic manifestations. ö It has been established that the invasive and noninvasive forms represent two separate species, respectively E. histolytica and E. dispar. o These two species are morphologically indistinguishable unless E. histolytica is observed with ingested red blood cells (erythrophagocystosis). ö Transmission can also occur through exposure to fecal matter during sexual contact (in which case not only cysts, but also trophozoites could prove infective) -- o These protozoa are transmitted by the fecal–oral route; high rates of oral–anal sex by MSM are considered the reason for increased rates of carriage. o Because E. histolytica is also transmitted by the fecal–oral route, MSM may also have an increased risk for E. histolytica carriage.

ö Cysts, which are the round, dormant, resistant and infectious stage, are acquired by the fecal-oral route.u o Usually by drinking contaminated water. ö Once in the intestine, excystation occurs, with trophozoites emerging from the cyst.

ö Trophozoites are the motile, feeding stage of Entamoeba histolytica. ö They are amorphous cells containing prominent round vacuoles that move via oozing pseudopod motion through the length of the intestine, until they reach the large intestine. o Once there, they multiply by binary fission and begin to form new cysts.

ö The cyst serves as the protective coat. o These cysts are excreted in the feces, can survive outside the body for several weeks and are capable of infecting new hosts. ö The diagnosis is established by isolating E. histolytica from the feces. ö When exposed to new environments (such as temperature changes, or transit down the intestinal tract, or exposed to a chemical agent), the protozoa can secrete a protective coat and shrink into a round, armored form called the cyst. o It is this cyst form that is infective when ingested by humans. o Following ingestion, it converts back into the motile form, called the trophozoite. ö The cysts can live outside the hosts or be carried asymptomatically in the stool, while trophozoites, passed by people with invasive disease, cannot survive outside the host. ö Only ten percent of those infected with Entamoeba histolytica ever develop amoebiasis and its associated symptoms, most of which are very mild. o Within two to four weeks of exposure, you may experience brief bouts of diarrhea, accompanied by stomach cramping and abdominal pain. o During this time, you can be shedding millions of cysts

ö In rare cases, without treatment, the symptoms can become more severe. ö Entamoeba histolytica is able to survive in the intestinal tract, but can also invade the cells of the intestinal lining. o The trophozoites release proteases, which are enzymes that break down protein, causing deep, painful lesions and ulcers in the intestinal lining. o What results is a more severe form of amoebiasis, called amoebic dysentery. o A patient with amoebic dysentery can experience intense abdominal pain, periodic loose stools with blood and mucus, and fever. o Weight loss and fatigue can also occur.

ö If the amoebic dysentery goes untreated, it can progress to extraintestinal amoebiasis, although this is rare. o The trophozoites can migrate out of the large intestine, travel through the blood and invade other tissues, causing the same lesions found in the gut.

ö The liver receives blood from both systemic and portal circulations. Increased susceptibility to infections would be expected given the increased exposure to a pathogen. o However, Kupffer cells lining the hepatic sinusoids clear bacteria so efficiently that infection rarely occurs. o The predilection for the right hepatic lobe can be attributed to anatomic considerations. § The right hepatic lobe receives blood from both the superior mesenteric and portal veins, § Whereas the left hepatic lobe receives inferior mesenteric and splenic drainage. § Also the right hepatic lobe contains a denser network of biliary canaliculi and, overall, accounts for more hepatic mass. o Untreated, pyogenic liver abscess remains uniformly fatal. Sepsis, Multi-organ failure. Polymicrobial involvement is common. o Gross pathology of amebic abscess of liver. Tube of "chocolate" pus from abscess. ö E. histolytica is the causative agent of amebic dysentery. Dysentery - in Parasitology, you’ve discussed 2 bacterial agents of dysentery namely EIEC and Shigella dysenteriae. o And this one is dysentery, an amebic dysentery. o A patient infected may get the famous flask shaped ulcers in the GIT mucosa and may also have extensions into the liver although that would be a very severe complication from Entamoeba. o One of the things that you could also see in this disease is Pseudoappendicitis (you can also get pseudo appendicitis-like disease in infections caused by Yersinia enterocolitica).

The characteristic “flask-shaped ulcers” of intestinal

amoebiasis (enzymatic degradation) ö The reason why chemotherapy is needed for amebiasis is due to its long term complications. ö I have here some gross pictures. Histopathology of a typical flask-shaped ulcer of intestinal amebiasis due to enzymatic degradation of tissue. o The majority of the organisms are passed out of the body with the feces but, with larger bolus of infection, some amebae attach to and invade the mucosal tissue forming "flask-shaped" lesions (bomb craters).

AMOEBICIDAL DRUGS

ö Let us now go to the highlights of the discussion… The pharmacological management of Amebiasis. ö Chemotherapy is the primary means of treating protozoan infections. o Successful chemotherapy depends in a large part on the ability to exploit metabolic differences between the pathogen and the host.

Amoebicidal Generalities • Protozoal diseases are less easily treated than bacterial infections. • Many antiprotozoal cause serious toxic effects on the host (cells with high metabolic activity). ö Because they are unicellular eukaryotes, the protozoal cells have metabolic processes closer to those of the human host than to prokaryotic bacterial pathogens. o Therefore, protozoal diseases are less easily treated than bacterial infections, and many of the antiprotozoal drugs cause serious toxic effects in the host, particularly on cells showing high metabolic activity. o Most antiprotozoal agents are not proven to be safe for pregnant patients.

ö Rememeber in the life cycle of Entamoeba histolytica, they (cyst and/or trophozoite) travel on the lumen of the small & large intestine and most of them are passed on the feces unknowingly, although some can invade the intestinal wall. ö Hence, the drugs are designed and classified to combat these protozoans where they actually reside… ö We’re going to see them primarily in table format…

General Classification

TISSUE AMEBICIDES LUMINAL AMEBICIDES Act primarily in the bowel wall, liver & Act primarily in the bowel lumen extraintestinal tissues ö Nitroimidazoles ö Amides o Metronidazole o Diloxanide Furoate o Tinidazole o Etofamide o Ornidazole o Secnidazole ö Halogenated Hydroxyquinolones o Iodochlorhydroxyquin ö Emetine ö Dehydroemetine ö Antibiotics ö Chloroquine o Paromomycin o Erythromycin o Tetracycline

ö DIP – “DIP into the lumen” as mnemonic for luminal amebicide (Diloxanide, Iodoqionol, Paromomycin). ö Diloxanide is included in CDC’s important drug list. o I don’t find it in current practice might be due in part that the drug is not available in the US and in most country of origin of our available drugs in the Philippines and might be because amebiasis is not a huge hit in the states (only 4% of amebiasis in the US and occurs in some parts of Mexico). o In the new edition of Lippincot: Metronidazole was said to be a mixed amebicide along with Tinidazole hence maybe the reason why some luminal agents did not gain much popularity due in part by the very good action of Metronidazole.

DISEASE FORM DOC ALTERNATIVE DRUG Asymptomatic intestinal Diloxanide Furoate* Iodoquinol, Paromomycin* infection

Mild to moderate Metronidazole Tetracycline or intestinal infection or Tinidazole + LA Erythromycin + LA (Nondysenteric colitis) Severe intestinal infection Metronidazole (PO/IV) Tetracycline or Emetine or (Dysentery) or Tinidazole + LA Dehydroemetine + LA Hepatic abscess, Metronidazole (PO/IV) Emetine or ameboma & other or Tinidazole + LA Dehydroemetine + Chloroquine extraintestinal disease (for liver abscess) + LA *LA: Luminal agent (Diloxanide, Iodoquinol, Paromomycin)

ö We mentioned that the clinical features varies from asymptomatic to a life-threatening fulminant colitis. o The choice of drugs for amebiasis depends on the clinical presentation hence I made a simple table for you to easily understand the treatment goals for certain circumstances. ö This table is the most striking table in my presentation as it directly points out the drug of choice for a specific disease form of amebiasis plus the alternative drugs for each. You will see this in your textbooks & Pharma Didactic Study Guide as well. I did not include the dose, frequency and duration primarily because the dose, frequency and duration of these drugs that we are about to discuss are not asked in your board exams (local & abroad) may be due in part that most antibiotics are not used on a long term basis and not an emergency drug as well. What’s worth mentioning are the ff: mechanism of action, clinical spectrum or indications (drug of choice), contraindications, important PK/PD, prominent adverse effects. Also, get to know in what specific location or targets do they act on the life cycle of the pathogen. ö For severe intestinal infection: If parenteral therapy is required, initially intravenous (IV) Metronidazole until per orem (PO) therapy can be administered.

Treatment of Specific Forms of Amebiasis Asymptomatic • Luminal Amebicide* Before we go to the nitty-gritty of each drugs, I have here a Intestinal simplified table… I hate memorizing so as much as possible I try Infections • Supportive management to simplify things in such a way that I can totally understand the concept. • Metronidazole + Luminal Amebicide 1. Those infected with Amebiasis without signs & symptoms Amebic Colitis are generally are not treated in endemic areas, but, in • Alternative: Tetracycline & Erythromycin nonendemic areas, they are treated with a LUMINAL amebicide. Therapy is indicated for acutely ill patients and asymptomatic carriers since dormant cyst of E. histolytica Extraintestinal • Metronidazole + Luminal Amebicide may cause future infections in the carrier and be a potential Infections source of infection for others. A tissue amebicidal drug is unnecessary. Standard luminal amebicides are Diloxanide furoate, Iodoquinol, Paromomycin. à Please disregard the 1st paragraph above. This was taken from Goodman basically, what it says here is when you have a patient with a high suspicion for amebiasis, and you collect stool sample and results

revealed that patient has been passing a lot of cyst, you don’t need to treat if the patient is living in an endemic area where E. histolytica is endemic. You only treat if it is a trophozoite that you see in the stool because that entails an acute infection. Its wrong! à As far as the E. histolytica is concerned, it doesn’t care whether the host lives in an endemic or nonendemic area and it wont tell you when it will turn into a trophozoite that invades the intestinal lining. When E. histolytica resides in the gut of the host, you can never tell when it will turn into trophozoite so might as well treat. à AGAIN: If you see E. histolytica trophozoite in the stool, treat with amebicidal agent (depending also on the disease severity & patient factors). If you see E. histolytica cyst only, still it needs treatment. No more endemic or non-endemic.

I put an * here just for you to take note: Therapy with a luminal amebicide is also required in the treatment of ALL other forms of amebiasis, so its is also used in the succeeding cases such as in.. Amebic Colitis

2. METRO + LA is the treatment of choice for amebic colitis & dysentery. Tetracyclines & Erythromycin are alternative drugs for moderate colitis but are not effective against extraintestinal disease. Dehydroemetine or emetine can also be used, but are best avoided because of toxicity.

3. The tx of choice for Extraintestinal infection is METRO + LA . A 10-day course of Metro cures over 90% of uncomplicated liver abscesses. For unusual cases in which initial therapy with Metro has failed, aspiration of the abscess and the addition of Chloroquine to a repeat course of Metro should be considered. Therapeutic needle aspiration/catheter drainage of liver abscess can only considered if: abscess >5cm (therefore at risk for rupture); left lobe liver abscess which carries increased risk of intra- peritoneal/perocardial rupture; failure to gain clinical response to therapy within 1 week. Dehydroemetine & Emetine are toxic alternative drugs.

METRONIDAZOLE

• A nitroimidazole • Tissue amebicide (add DIP) • Active against anaerobic protozoal parasites and anaerobic bacteria. • Effectively eradicates intestinal & extraintestinal infection. • Kills trophozoites but NOT cysts of E. histolytica

ö If there’s one drug that you have to remember, that’s Metro so I purposely put it first along with the tables so that you get the high yield topic before you start snoozing on your seats. ö Remember: The cornerstone of therapy for amebiasis is the nitroimidazole compound metronidazole or its analogs tinidazole and ornidazole. – anything that ends with “azole” (except of course -azoles from other drug classes such as Ketoconazole) ö Metro doesn’t work from the luminal form of the bug (i.e., when the bug is at the intestine) so Diloxanide need to be added for Intestinal Amebiases.. So if you have a case of noninvasive Amebiasis then don’t use Metronidazole. ö Metro and related nitroimidazoles are active in vitro against a wide variety of anaerobic protozoal parasites as well as anaerobic bacteria. ö Some tips in the clinical setting: For all anaerobic infections upwards the diaphragm, use Clindamycin. Below the diaphragm, use Metronidazole. ö The drug has potent amebicidal property for E. histolytica. ö Now the question is how does it exert its effect?

MOA: metronidazole § Metronidazole is a prodrug. The nitro group is chemically reduced in anaerobic bacteria and sensitive protozoans. § Reactive reduction products appear to be responsible for antimicrobial and amebicidal activity.

The drug is preferentially activated by the pathogens. How does it happen? ö Metronidazole is selective for anaerobic bacteria due to their ability to intracellularly reduce the prodrug metronidazole to its active form. o This reduced metronidazole then covalently binds to DNA, disrupt its helical structure, inhibiting bacterial nucleic acid synthesis and resulting in bacterial cell death. ö Let’s be more precise. The nitro group of metronidazole is able to serve as electron acceptor, forming reduced cytotoxic compounds that bind to proteins and DNA to result in cell death. ö So the drug is administered in an inactive form and is activated in the hydrogenosome (membrane bound organelle, named because it releases molecular hydrogen (H ) as a by-product of energy generation under 2 anaerobic (oxygen-deficient) conditions.).

ö Activation requires the activity of two hydrogenosomal proteins ferredoxin oxidoreductase PFO and ferredoxin Fd. o Fd is the terminal reductant of the drug and by Fd transfering electrons to metronidazole metro is converted into a free radical. o It is believed that the reactivity and dismutation of the free-radical confers the cytoxic effects of the drug; It is the free radical that kills the parasite. ö Metronidazole is catalytically recycled; loss of the active metabolite's electron regenerates the parent compound. ö Increasing levels of O inhibit metronidazole-induced cytotoxicity because O competes with metronidazole for 2 2 electrons generated by energy metabolism. o Thus, O can both decrease reductive activation of metronidazole and increase recycling of the activated drug. 2 o Anaerobic or microaerophilic organisms susceptible to metronidazole derive energy from the oxidative fermentation of ketoacids such as pyruvate. o Pyruvate decarboxylation, catalyzed by pyruvate:ferredoxin oxidoreductase (PFOR), produces electrons that reduce ferredoxin, which, in turn, catalytically donates its electrons to biological electron acceptors or to metronidazole.

ö In the case of metronidazole, reduced ferredoxin appears to be the primary electron donor responsible for its reduction (Figure). o There is a good correlation between the presence of the pyruvate-ferredoxin oxidoreductase (PFOR) and sensitivity to metronidazole. o All three of the protozoa affected by metronidazole (Table) lack mitochondria and have PFOR similar to that found in many anaerobic bacteria. o Aerobic organisms with mitochondria use pyruvate dehydrogenase instead of the PFOR for the production of acetyl-coenzyme A.

Major Protozoal Infection & DOC

Infection DOC Comments Amebiasis Metronidazole Use Diloxanide for Non-invasive intestinal amebiasis Giardiasis Metronidazole Backpacker’s diarrhea from contaminated water/food Trichomoniasis Metronidazole Treat both sexual partners

ö Aside from amebiasis, there are other diseases and organisms that Metro is capable of combating. o For instance, some of them you knew very well. Metronidazole is the DOC for Amebiasis, Giardiasis, and Trichomoniasis o Hence it is popularly known with its brand name or trade name “Flagyl” because it eradicates the flagellated bugs Giardia & Trichomonas. ö For Trichomoniasis, Let’s not forget conservatively that this is a sexually transmitted disease. o Treatment failure owing to Metronidazole reistsant strains of T. vaginalis are increasingly common. o Most cases can be treated successfully by giving a 2nd dose to both patient & partner. o In addition to PO therapy, the use of vaginal suppository may be beneficial for refractory cases. ö Remember: The METRO runs over Entameba, Giardia, Trichomonas, Bacteroides, Clostridum and Gardnerella as well as Helicobacter and Campylobacter. ö Let us also not forget that we also mentioned Metro in passing for Clostridium difficile. o It is the DOC for pseudomembranous colitis caused by anaerobic gram positive bacillus Clostridium. ö Lets cite a case.. o An epidemic diarrhea has broken out in a city hospital. Colonoscopy of one of the affected patients reveals colonic inflammation with exudates & necrosis of the mucosal surface.. o Clue: Assays for toxin A (causes diarrhea) & B (cytotoxic) are positive.. o What microorganism can you think of as an offender in this case? § C. difficile. ö Metro is used increasingly as primary therapy for pseudomembranous colitis due to Clostridium difficile. It is less expensive than PO Vancomycin. METRONIDAZOLE MOA The nitro group of the drug is chemically reduced in anaerobes which will produce an active reduction product that exerts an antimicrobial action Spectrum of • Amebicidal for E. histolytica activity • Bactericidal for Anaerobes (Bacteroides, Clostridium spp) • Also cidal for other protozoans PK - PO, IV form; Peak 1-3 hrs - Low plasma protein binding <20% - T ½ 8 hrs; Excreted in urine • Widely distributed in the body secretions – semen, saliva and CSF • Metabolized by oxidation and glucuronide conjugation and excreted in urine. Adverse effects GIT distress, metallic taste, dizziness, nausea, headache, dry mouth, insomnia, darkening of urine, Disulfiram – like effect (+) alcohol

ö Disulfiram is a drug used in the management of ethanol abuse. o Once it is taken and the patient ingest alcoholic beverage, disulfiram inhibits aldehyde dehydrogenase resulting in accumulation of toxic levels of acetaldehyde. o Acetaldehyde when high is believed to be the cause of the hangover symptoms (nausea, vomiting, flushing, headache, sweating, hypotension, confusion). ö Disulfiram can be toxic even in the presence of small amounts of alcohol (amount in some OTC preparations). ö Metronidazole has this disulfiram-like action that mimics the action of disulfiram in aldehyde dehydrogenase once it is taken concommitantly with ethanol. o Other drugs with Disulfiram-like activity include Griseofulvin, Procarbazine, 1st Generation Sulfonylureas, and some Cephalosporins. ö Metronidazole and Disulfiram actions should not be taken together because confusional and psychotic states may occur.

Rare Adverse Effect - Pancreatitis - Severe CNS toxicity (ataxia, encephalopathy, seizures) - Anaphylaxis - Paresthesia - Oral thrush Drug-drug Interaction • Potentiate Coumarin-type anticoagulants • Phenytoin & Phenobarbital à Elimination • Cimetidine decrease plasma clearance • Lithium toxicity may occur • TEN if taken with Mebendazole Special Precautions - Liver/renal/CNS disease - Pregnant/lactating women - Mutagenic in bacteria - Tumorigenicity in mice

ö These shows the uncommon adverse effects reported and special precautions when taking Metro. o Of course like most per orem drugs, taking this drug with meals lessen the GI irritation. ö The following are worth mentioning: The drug should be withdrawn if numbness or paresthesias occur. Reversal of serious sensory neuropathies may be slow or incomplete. ö Urticaria, flushing and pruritus are indications of drug sensitivity. ö Metro has been reported to potentiate the anticoagulant effect of coumarin-type anticoagulants. ö Phenytoin & Phenobarbital may accelerate elimination of the drug, whereas Cimetidine may decrease plasma clearance. ö The drug may also precipitate CNS signs of Lithium toxicity in patients receiving this agent. ö Metro rarely causes toxic epidermal necrolysis, which may be more common in individuals receiving high doses of metronidazole and concurrent therapy with mebendazole. ö Metro should be used with caution in patients with active CNS disease because of its potential neurotoxicity. ö Metronidazole and its metabolites are mutagenic in bacteria. o Chronic administration of large doses led to tumorigenicity in mice. Data on teratogenicity are inconsistent. o Metronidazole is thus avoided in pregnant or nursing women, although congenital abnormalities have not clearly been associated with use in humans. o There are conflicting data about the teratogenicity of metro in animals. While Metronidazole has been taken during all stages of pregnancy with no apparent adverse effects, its use during the 1st trimester is still not advised.

ö Since we are talking about Cimetidine having an effect with Metronidazole, I wanted to share this to you and you should be able to take note of the following medications that might be useful not only in exams, but in real practice as well. Drug interactions through CYTOCHROME P450 enzymes. Cytochrome P450 a.k.a. mixed function oxidases are of high concentrations in the smooth endoplasmic reticulum of the liver where most drug metabolism occurs. ö Barbiturates: Pentobarbital, Phenobarbital ö When you say cytochrome P450 inducers, since they induce cytochrome P450, they increase the metabolsim & clearance of the drug… o So for instance, a patient is taking warfarin or metronidazole for instance and concomitantly, given with any of these inducers… What will happen? o Clearance of warfarin is increased hence the anticoagulant effect is reduced. o You may need to either increase the dose or the frequency of warfarin, in that case. o In simple explanation, inducers clears the drug faster. o Most common strong inducers are carb, phenytoin, phenobarb & rifampin. Most consist of anticonvulsants. ö Enzyme inhibition. These drugs reduce the activity of cytochrome P450. o Hence if warfarin or metronidazole is taken with any of these inhibitors of cytochrome, what will happen? o The action of warfarin stays longer in the system. o It is not readily cleared. o Hence you increase the anticoagulant effect of warfarin. o Most significant inhibitors are amiodarone, cimetidine, furanocoumarins (+) grapefruit juice, azole antifungals, and the HIV protease inH ritonavir. o As part of inhibition also, metabolism may be decreased by reduction in blood flow to the metabolizing organ. Example: Propranolol reduces hepatic blood flow.

TINIDAZOLE

• Related Nitroimidazole. • Similar activity with Metronidazole. • Better toxicity profile. • Simpler dosing regimens.

ö Tinidazole is a prodrug and antiprotozoal agent. ö The MOA of Tinidazole is presumed to be the same as of Metro. ö Tinidazole has a similar adverse effect drug profile although it appears to be somewhat better tolerated than Metronidazole. ö Shorter course of treatment, but more expensive. Alcohol consumption should be avoided.

DILOXANIDE FUROATE

• Dichloroacetamide derivative • Effective luminal amebicide • The unabsorbed diloxanide is the active antiamebic substance. • MOA unknown. • Considered as DOC for asymptomatic luminal infections. Used with Metronidazole. • Does not produce serious adverse effect. • Not recommended for pregnancy.

ö This drug is commonly used as a sole agent for the treatment of asymptomatic amebiasis and is useful in mild intestinal dse when used with other drugs. ö It is converted in the gut in to the diloxanide freebase form, which is the active amebicide. ö Toxic effects are mild and are usually restricted to GI symptoms. ö It is an effective in asymptomatic patients who sheds the cyst but is not active against tissue trophozoites. ö It is taken PO. ö In the gut, it is hydrolyzed in the intetsinal mucosa. o Diloxanide furoate is split into diloxanide and furoic acid; about 90% of the diloxanide is rapidly absorbed and then conjugated to form the glucuronide, which is promptly excreted in the urine. o The unabsorbed diloxanide is the active antiamebic substance. ö The mechanism of action of diloxanide furoate is unknown. ö Diloxanide furoate is considered by many the drug of choice for asymptomatic luminal infections, but it is no longer available in the USA.

ö It is used with a tissue amebicide, usually metronidazole, to treat serious intestinal and extraintestinal infections. ö Diloxanide furoate does not produce serious adverse effects. o Flatulence is common, but nausea and abdominal cramps are infrequent and rashes are rare. ö The drug is not recommended in pregnancy.

IODOQUINOL

• Diiodohydroxyquin • Halogenated hydroxyquinolone • Active against cyst & trophozoites – in the intestinal lumen but not in the wall or extraintestinal tissues • MOA against trophozoites unknown • May increase protein-bound serum iodine à decrease in measured 131I uptake that persists for months. ö Orally active luminal amebicide used as an alternative to diloxanide for mild-severe intestinal infections. ö Adverse GI effects are common but usually mild, esp when taken with meals. ö Systemic absorption after high doses may lead to thyroid enlargement, skin reactions due to iodine toxicity and possibly neurotoxic effects, including peripheral neuropathy and visual dysfunction. ö It is an effective luminal amebicide commonly used with Metro to treat amebic infections. ö Its pharmacokinetics is poorly understood. o 90% retained in the intestine and excreted in feces, the remainder enters the circulation. o T ½ 11-14hrs, excreted as glucoronides. o PK properties poorly understood. ö Contraindicated in patients with Iodine intolerance. o Interfere with thyroid function test (decrease iodine). o Produces GI disturbances and changes in the Iodine level causes toxicity. ö Taken with meals.

PAROMOMYCIN SULFATE

• AminOglycOside • DOC for intestinal colonization with E. histolytica and it is used in combination with Metronidazole to treat amebic colitis & amebic liver abscess. • Advocated as tx of Giardiasis in pregnant. • Also for Trichomoniasis in patients who failed or could not receive Metronidazole. • Causes protozoal cell membrane leakage. • A/E: GI distress ö Broad spectrum antibiotic related to Neomycin & Streptomycin that is as used as an alternative treatment for mild-mod luminal infections or in asymptomatic carriers in place of iodoquinol. ö This drug is an aminoglycoside antibiotic used as a luminal amebicide and may be superior to diloxanide in asymptomatic infection. o Paromomycin may also have some efficacy against cryptosporidiosis in patients with AIDS. ö Systemic absorption in renal insufficiency may lead to headaches, dizziness, rashes, and arthralgia. ö Available as oral preparation, topical & parenteral (PO only in US). o Following PO admin, 100% of the drug is recovered in the feces even with compromised gut integrity. o Not significantly absorbed in the GIT. o Used only as luminal amebicide, has no effect against extraintestinal amebic infections. ö The small amount absorbed is slowly excreted unchanged, mainly by glomerular filtration. o However the drug may accumulate with renal insufficiency and contribute to renal toxicity. ö Recent study, superior to Dilox in clearing asymptomatic infections. ö A/E (abd pain, epigastric pain, n/v, steatorrhea, diarrhea). ö Parenteral is now used to treat visceral leishmaniasis. ö MOA: Causes protozoal cell membrane leakage, also reduces the population of intestinal flora which is a food source of amoeba. o Oxygen-dependent process of transporting in the cell membrane and then irreversibly bind to the 30S ribosomal subunit and inhibit protein synthesis. ö According to Goodman… It can be used in pregnant women esp in 1st Trimester when Metro is contraindicated and as an alternative agent for Metronidazole resistant.

EMETINE & DEHYDROEMETINE

• Alkaloid derivative. • Has major toxicity concerns. • They inhibit protein synthesis by blocking ribosomal movement along mRNA. • Widely distributed to tissues, metabolized by slow renal excretion. • Cardiotoxic! ö Emetine & dehydroemetine inhibits protein synthesis by blocking ribosomal movement along messenger RNA. ö These drugs are used parenterally (SQ or IM) as backup drugs for treatment of severe intestinal or hepatic amebiasis together with a luminal agent in hospitalized patients. à Dehydroemetine intramuscular (IM) is preferred route since it is an irritant when taken orally. Use of this has been largely replaced by Metro because of toxicity. ö The drug may cause severe toxicity, including GI distress, muscle weakness, and cardiovascular dysfunction (arrhythmias & CHF). ö The drugs are restricted to use in severe amebiasis when metronidazole cannot be used.

ö Emetine, an alkaloid derived from ipecac and dehydroemetine, a synthetic analog are effective against tissue trophozoites of E. histolytica o but due to major toxicity concerns, their use is limited to unusual circumstances in which amebiasis requires effective therapy & metro cannot be used. ö Dehydroemetine is preferred because of its somewhat better toxicity profile. ö The drugs should be used for the minimum period needed to relieve severe symptoms (3-5 days) and should be admin SQ (preferred) or IM in a supervised setting; both should not be used IV. ö A/E generally mildwith use for 3-5 days increases over time and include pain, tenderness and sterile abscess at the injection site; diarrhea, n/v, muscle weakness, discomfort, minor ECG changes. ö Serious toxicities: cardiac arrhythmias, heart failure, hypotension. ö Should not be used in pts with cardiac or renal disease in young children, or in pregnancy unless absolutely necessary. ö Because of its severe toxicity, they are used only as back up treatment for severe intestinal or hepatic amebiasis in hospitalized patients. Cardiotoxic!

CHLOROQUINE

• Treatment & prevention of amebic liver abscess in conjunction with Metronidazole and Diloxanide furoate ö What is this antimalarial drug’s clinical use as it relates to amebiasis? o Chloroquine trapping in the plasmodium vacuoles. o Interfere with DNA RNA sythesis. o Blocks heme polymerase which leads to accumulation of toxic hg products. ö Also used in autoimmune disorders.

TETRACYCLINE

• Not a direct amebicide. • Eliminates the normal intestinal flora and therefore the ameba’s main food source. • Used mainly as an adjunct to other amebicides. • Contraindicated in children younger than 8 yo and in pregnant women. • Dairy foods & antacids decrease absorption. • Because they form nonabsorbable chelates with the drug.

NITAZOXANIDE

• Has activity against various protozoans (including Entamoeba) and helminths. • Currently approved in the US for treatment of GI infections caused by G. lamblia and Cryptosporidium parvum. • Appears to have activity against metronidazole-resistant protozoal strains.

Prevention rests on good sanitation, proper disposal of sewage and purification or boiling of drinking water.

This I got from Lippincott… Its nice because it depicts the life cycle of Entamoeba histolytica in harmonious with amebicidal drugs and its site of action. It serves as the summary of all the things we discussed today. Luminal amebicides, in general are not readily absorbed in the GIT, rather as they pass the liver for 1st pass, they go directly to the GIT to act as a luminal amebicide and excreted in the feces unchanged so that they could exert their effect.

References: • Goodman & Gilman’s The Pharmacological Basis of Therapeutics 12th Edition • Katzung & Trevor’s Pharmacology 10th Edition • USMLE Kaplan videos • Board exam review materials • http://www.cdc.gov/dpdx/amebiasis/ • http://www.beatricebiologist.com/p/index.html

END OF TRANSCRIPTION Another direct PowerPoint to Word Conversion that includes Dra. Quijano’s “script”. Lengthy, but worth it J I modified the format a little bit for better understanding. Use at your own risk. Good Luck Batch 2018!