MOD 18: Amebicidals PDF

BASIC PHARMACOLOGY 01/13/2025. MOD 18: AMEBICIDALS Dr. Micah Muriel E. Oliver, MD...

BASIC PHARMACOLOGY 01/13/2025. MOD 18: AMEBICIDALS Dr. Micah Muriel E. Oliver, MD Trans Group/s: 6A OUTLINE B. LIFE CYCLE OF ENTAMOEBA HISTOLYTICA ​ Infection starts when humans ingest mature cysts, enters the body via fecal-oral route I. Amebiasis ○​ Infective stage: Mature cysts ​ Cysts travels down via GI tract, reaches the ileum of A. Species of Entamoeba small intestine then transform into trophozoites B. Life Cycle of Entamoeba Histolytica ○​ Diagnostic stage: Trophozoites C. Clinical Manifestation ○​ Trophozoites are the parasitic form that is capable of invasion II. Anti-Amebic Drugs ○​ In the presence of ineffective amebicidal, this III. Tissue Amebicides trophozoite will survive and has the propensity and A. Metronidazole capability to invade adjacent structures (i.e. liver, B. Emetine lungs, brain) ​ Liver: Amebic liver abscess C. Chloroquine ​ Lungs: Pulmonary Amebiasis IV. Luminal Amebicides ​ Brain: Cerebral Amebiasis (rare) A. Diloxanide Furoate B. Nitazoxanide C. Iodoquinol D. Paromomycin V. Summary OBJECTIVES ​ Identify the prototype drugs for each classification of amebicidals ​ Understand the pharmacokinetics of medication for amoebiasis ​ Select the appropriate amebicidals for given clinical scenarios I. AMEBIASIS ​ A global burden ○​ Affects about 10% of world’s population ○​ It can cause significant morbidity and mortality because of its invasiveness ​ Invasive disease caused by a parasite Entamoeba histolytica ○​ 3rd leading parasitic cause of death in humans, after malaria and schistosomiasis ​ Set up: Mostly seen in individuals living in poverty, Life Cycle of Entamoeba histolytica crowding conditions and areas with poor sanitation C. CLINICAL MANIFESTATION A. SPECIES OF ENTAMOEBA ​ Asymptomatic Amebiasis ○​ Presence of infection but mild or no symptoms ​ Symptomatic Amebiasis – pathological disease 1 E. dispar ○​ Amebic Colitis ○​ Fulminant Amebic Colitis 2 E. moshkovskii ○​ Ameboma E. histolytica ○​ Amebic Liver Abscess 3 ​ Most pathogenic; capable of causing disease as humans are the ONLY known host. Goal of Treatment: Elimination of Entamoeba cyst, trophozoite or both 4 E. polecki 5 E. coli 6 E. hartmanni Pharmacology - Mod 18 Amebicidals 1 of 5 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  II. ANTI-AMEBIC DRUGS A. METRONIDAZOLE ​ Categorized into two: ​ Class: Nitroimidazole ○​ Tissue Amebicides ​ DOC: Extraluminal amebiasis ○​ Luminal Amebicides ​ Related structure but similar activity: ○​ 5-nitroimidazoles ​ Tinidazole ​ Secnidazole ​ ​ 📖 📖 ​ Ornidazole Kills trophozoites but NOT cysts of E. histolytica Effectively eradicates intestinal and extraintestinal tissue infections 1. CLINICAL USE ​ Effectivity among group of bacteria and parasites: ○​ Extraluminal Amebiasis: Amebic Colitis and Amebic Liver Abscess ○​ Giardiasis ○​ Trichomoniasis Outline of Anti-Amebic Drugs ○​ Antibacterial property against: ​ All anaerobic cocci ​ Anaerobic gram-negative bacilli (Bacteroides spp.) ​ Anaerobic spore-forming ​ Gram-positive bacilli (Clostridium) ​ Microaerophilic bacteria (Helicobacter and Campylobacter spp.) ​ Limitation: Metronidazole is ineffective and resistant to non-sporulating gram-positive bacilli, aerobic and facultative anaerobic bacteria 2. MECHANISM OF ACTION ​ Targets the bacterial cellular nucleus → Alteration in the Amebicides and their target in a bacterial cell electron transport and DNA damage ​ “Reactive Reduction/Activation” ○​ Metronidazole is a prodrug requiring reactive SUMMARY ON AMEBICIDES activation of the nitro group by susceptible DRUGS TARGET ○​ 📖 organism. The nitro group of metronidazole is chemically reduced in anaerobic bacteria and sensitive Metronidazole Nucleus Tinidazole ​ Alters electric transport → DNA protozoans which will produce an active reduction Iodoquinol damage Protein synthesis ○​ 📖 product which exerts an antimicrobial action Reactive reduction (by the bacteria/protozoans) of the nitro group appears to be antimicrobial. ​ Important in cellular growth ​ Radical-mediated mechanisms that targets DNA Emetine ​ Without it, there is NO Paromomycin 1 Entry via Diffusion ○​ cellular transmission Diloxanide furoate ○​ enzyme Reductive Activation ○​ cellular function ​ Alteration of Pyruvate-Ferredoxin MOA: raises pH of the bacterial cell Oxidoreductase (PFOR) → key enzyme for Chloroquine ​ Imbalanced pH → ineffective Anaerobic Metabolism metabolism → cellular death ○​ Anaerobic metabolism requires generation of ATP (energy). Without energy inside the cell, Other drugs were not discussed in the video lecture there is ineffective protein transmission, and cellular differentiation and processes would not 2 be possible. III. TISSUE AMEBICIDES ​ Reduction of metronidazole creates a ​ Drugs that act primarily in the bowel wall, liver, and the concentration gradient that drives uptake of more extraintestinal tissues drugs. ○​ As reductive activation happens, there is Nitroimidazoles accumulation of this drug inside the cell → ​ Metronidazole* promotes free radical formation, which is ​ Tinidazole cytotoxic. ​ Secnidazole 3 Destabilization of the DNA helix Intestinal + Extraintestinal ​ Ornidazole Amebiasis ​ Satranidazole 4 Breakdown of Cytotoxic products → cell death Alkaloid ​ Emetine* ​ Dehydroemetine Extraintestinal Chloroquine* * - prototype drug Mode of action of Metronidazole inside the bacterial cell Pharmacology - Mod 18 🏠 Amebicidals 2 of 5 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited. 3. PHARMACOKINETICS B. EMETINE ​ Oral, IV, Intravaginal and Topical ​ Class: Alkaloid ​ From Ipecac Root A Rapid absorption ​ Amebicidal and Emetic Properties ​ Dehydroemetine is a synthetically produced Penetrates well in all body tissues and fluids except antiprotozoal agent that has a similar mode of action to D placenta and with low plasma protein (75% eliminated in the urine ​ Severe invasive and extra intestinal 4. ADVERSE EFFECTS amebiasis Clinical Use ​ Alternative → metronidazole treatment ​ Common: Headache, nausea, dry mouth, metallic taste failure ​ Uncommon: Vomiting, diarrhea, abdominal distress ​ Rare: Dysuria, cystitis, sense of pelvic pressure ​ Used in combination with ​ Neurotoxic effects: Dizziness, vertigo, encephalopathy, paromomycin and diloxanide. convulsions, incoordination, ataxia, numbness, ○​ Acts specifically on protein paresthesia ! synthesis by inhibiting bacterial ○​ Once the neurotoxic effects have been observed in protein synthesis. a patient, this is now the reason for discontinuation MOA ​ Blocks ribosomal protein synthesis by of the therapy inhibiting the movement of ribosomes along the mRNA. 5. DRUG INTERACTION ! ​ Inhibits DNA replication during the ​ “Disulfiram-like effect”: patients will present with early S phase. abdominal distress, vomiting, flushing, or headache after an intake of alcohol during or within 3 days of Adverse Myopathy or Cardiomyopathy metronidazole therapy. Effect ​ Observed in cases of overuse ​ Inducer: Phenobarbital, Prednisone, Rifampin, Ethanol ○​ May accelerate elimination of metronidazole C/I Renal, cardiac, and muscular disease ​ Inhibitor: Cimetidine ○​ Decreases its plasma clearance. MOA - Mechanism of Action; C/I - Contraindication; ​ PK - Pharmacokinetics ​ Lithium toxicity may occur when drug is used or in combination with metronidazole. C. CHLOROQUINE Editor’s Notes: ​ Metronidazole and disulfiram or any disulfiram-like Class Aminoquinoline Derivative drug should not be taken together because confusional and psychotic states may occur [Goodman 14th, p. 1316] ​ Anti-Malarial ​ Extraintestinal Amebiasis * Clinical Use DRUGS THAT MAY PRODUCE A DISULFIRAM-LIKE REACTION ​ Rheumatic Disease [Katzung 16th] ​ Zika Virus Cephalosporins 1 ​ Inhibits growth by concentrating within Cefamandole, cefoperazone, cefotetan, and moxalactam acid vesicles increasing internal pH 2 Chloral hydrate MOA level ​ It also inhibits the organism’s 3 Disulfiram hemoglobin utilization and metabolism 4 Metronidazole ​ Absorption: Bioavailability 52-100% 5 Sulfonylureas (Chlorpropamide) ​ Distribution: 46-47% bound to plasma PK proteins ​ Metabolism: Liver 6. CONTRAINDICATION ​ Excretion: T ½: 20-60 days; Urine ​ Drug sensitivity: Taking metronidazole can exacerbate urticaria, flushing, pruritus ​ Risk of retinopathy ** ​ Steven-Johnsons Syndrome: rare Adverse ​ Muscle weakness Effects ​ Hemolytic anemia in patients with 7. CAUTION G6PD ​ Metronidazole is an effective amebicidal. However, there Pregnancy Safe is caution when giving this medication in special groups of patients such as: ○​ Patients with active CNS disease may pose potential neurotoxicity ○​ Patients with heart diseases on warfarin therapy can prolong prothrombin time ○​ Pregnancy for its possible teratogenic effects ​ Not advised specially on the 1st trimester ​ Expressed on breast milk Pharmacology - Mod 18 🏠 Amebicidals 3 of 5 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  IV. LUMINAL AMEBICIDES Absorption ​ Drugs that act on the parasites present in the bowel ​ Hydrolyzed rapidly to its active lumen metabolite, Tizoxanide, which undergoes conjugation to Tizoxanide Diloxanide Furoate* Glucuronide Amides Distribution Nitazoxamide PK ​ 99% bound to proteins Quiniodochlor Metabolism 8-Hydroxyquinolines Iodochlorhydroxyquin ​ Liver Note: spelled as “…quinolones” in the lecture Diiodohydroxyquin Excretion Iodoquinol* ​ Half life: 7 hours ​ Urine Tetracycline Antibiotics ​ Diarrhea, vomiting and abdominal pain Paromomycin* Adverse ​ A greenish tint to the urine** * - prototype drug Effects ​ Rare Pregnancy Safe in pregnancy A. DILOXANIDE FUROATE C. IODOQUINOL Class Dichloroacetamide derivative ​ Asymptomatic Intestinal Amebiasis Class Quinoline derivative Clinical ​ In combination after treatment with Use ​ Treatment for Amebiasis Metronidazole ​ Dysentery Inhibits protein synthesis together with Clinical MOA ​ Enteritis paromomycin and emetine Use ​ Infectious diarrhea ​ T. vaginalis Absorption ​ Bioavailability: 90% ​ Acts on the bacterial nucleus ​ Slow absorption in the GI tract ! MOA ​ Alteration in the electron transport and Metabolism DNA damage ​ Hydrolyzed to furoic acid and PK diloxanide, which undergoes extensive ​ 90% of the drug is retained in the glucuronidation PK intestines and excreted in the feces Excretion ​ Half life: 11-14 hours ​ Half life: 2 hours ​ 90% renal as glucuronide metabolite D. PAROMOMYCIN ​ 10% excreted in feces ​ Flatulence ** Class Aminoglycosides Adverse ​ Nausea Effects ​ Against E. histolytica infection, ​ Abdominal cramps Cryptosporidiosis, Giardiasis Pregnancy Contraindicated in pregnancy ​ Topical formulations: Trichomoniasis and Clinical Cutaneous Leishmaniasis Use ​ Parenteral formulations: Visceral B. NITAZOXANIDE Leishmaniasis ​ Amebiasis Class Thiazolides Binding to the 30s ribosomal subunit ​ Used to treat infections by protozoa, MOA ​ Thereby inhibiting the protein synthesis of helminths, anaerobic bacteria, the bacterial cell microaerophilic bacteria, and viruses Clinical ​ Cryptosporidium parvum or Giardia ​ Poor GI absorption PK Use lamblia ​ Excreted in the feces ​ Used to treat infections with G. intestinalis resistant to metronidazole ​ Abdominal cramps and albendazole ​ Nausea and vomiting Adverse ​ Steatorrhea Effects ​ Similar to that of metronidazole ​ Diarrhea ​ Disruption of the energy metabolism in ​ Nephrotoxicity anaerobic microbes by inhibition of the pyruvate: ferredoxin/flavodoxin oxidoreductase (PFOR) cycle MOA ​ Nitazoxanide and its active metabolite, tizoxanide** (desacetyl-nitazoxanide), inhibit the growth of sporozoites and oocytes of C. parvum, as well as the trophozoites of G. intestinalis, E. histolytica, and T. vaginalis in vitro Pharmacology - Mod 18 🏠 Amebicidals 4 of 5 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  V. SUMMARY OF THE TREATMENT FOR AMEBIASIS Disease Form DOC Alternative Drug All luminal amebicide (LA) + Supportive management (IV hydration for frequent loose Asymptomatic bowel movement, pain medication for patients with complaints of abdominal cramps) Mild to Moderate Tetracycline or Metronidazole or (Non-Dysenteric Erythromycin + Tinidazole + LA Colitis) LA Tetracycline or Metronidazole Severe Emetine or (PO/IV) or (Dysentery) Dehydroemetine Tinidazole + LA + LA Emetine or Hepatic Abscess Dehydroemetine Metronidazole Ameboma + Chloroquine (PO/IV) + LA Extraintestinal (For liver abscess) + LA REFERENCES ​ Dr. Oliver’s lecture ​ Basic and Clinical Pharmacology (14th Edition) by Bertram G. Katzung ​ Goodman and Gilman’s The Pharmacological Basis of Therapeutics (13th Edition) by Laurence L. Brunton, et. al. Pharmacology - Mod 18 🏠 Amebicidals 5 of 5 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.