Antimicrobial Therapies 4 (Antiviral Drugs / Antiprotozoal Drugs / Anthelmintic Drugs) Flashcards

Question

Treating Malaria

Answer 1

Primaquine 8 aminoquinoline oral agent that eradicates primary liver forms of Plasmodium and the hypnozoites of recurring malarias [P. vivax; P. ovale]—this is the only agent that prevents relapse of the these strains of the protozoa in the liver The sexual [gametocytic] form of all plasmodia are destroyed in the blood or are prevented from maturing later in the mosquito, interrupting transmission This drug does NOT work on the blood from of malaria, and as a result—cannot be used as monotherapy MOA • Metabolites act as oxidants that disrupt the metabolic processed of the plasmodia mitochondria • Metabolites are responsible for schizonticidal action as well as hemolysis and methemoglobinemia [toxicities seen] Pharmacokinetics • Well absorbed after oral dose • Not concentrated in the tissues • Rapidly oxidized • Which compound causes the schizonticidal activity has not be identified • Minimally excreted in the urine ADEs • Drug induced hemolytic anemia in those with G6PD deficiency • Large doses can cause GI distress • Occasional methemoglobinemia • Should not be used during pregnancy • All species can develop resistance to Primaquine

Answer 2

Aralen is a synthetic 4-aminoquinolone—backbone of malarial therapy—but is now limited due to P. falciparum resistance—which is present in all malaria endemic areas except some parts of Central America Less effective against P. vivax Used to prophylax against malaria in travelers going to Chloroquine sensitive areas Can be used to treat extra intestinal amebiasis MOA • Binds to heme, prevents its polymerization to hemozoin • Increased pH and accumulation of heme causes oxidative damage to the phospholipid membranes, leading to lysis of the parasites and the RBC Pharmacokinetics • Rapidly and completely absorbed after oral dose • Very large volume of distribution, concentrates in RBCs, liver, spleen, kidney, lung, melanin containing tissues and WBCs • It hangs around in the RBCs • Drug also penetrates the CNS and crosses the placenta • Dealkylated by the liver mixed-function oxidase system • Parent drug and metabolites are excreted mainly in the urine ADEs • At low doses—used in prophylaxis—very few • At higher treatment doses—GI upset, itching, headaches, blurred vision • Dilated eye exam should be done routinely with prolonged use—due to toxicity to the retina • Discoloration of nail beds and mucous membranes can occur with chronic use • Use with caution in those with liver dysfunction, severe GI problems or neurologic disease • Patients with psoriasis or porphyria should NOT take this drug—as it can provoke an acute attach • Can prolong QTc interval, so using it in patients on other drugs that prolong the QT interval should be avoided

Answer 3

Malarone—combination agent for Chloroquine resistant strains of P. falciparum—used in the prevention and treatment of malaria for travelers from outside malaria-endemic areas Not routinely used in endemic areas due to the likelihood for emergence of high-level resistance Atovaquone is a hydroxynaphthoquinone with inhibits mitochondrial processes Cycloguanil, the active triazine metabolite of proguanil, inhibits plasmodial dihydrofolate reductase—preventing DNA synthesis Atovaquone can also treat Babesia sp. and Pneumocystis jirovecii Proguanil is metabolized via CYP 450 2C19—known to exhibit a genetic polymorphism causing poor metabolism of the drug in some individuals Take with food or milk to facilitate absorption ADEs—nausea, vomiting, abdominal pain, headache, diarrhea, anorexia and dizziness

Answer 4

Lariam—4-methanolquinolone—structurally like quinine Effective agent to prevent all plasmodia, and for treatment when used in combination with an artemisinin derivative for infections from MDR forms of P. falciparum MOA is unknown; widely distributed to tissues Long ½ life—20 days; because of enterohepatic recirculation and its concentration in various tissues Primarily excreted via the bile into the feces ADEs—at high doses—nausea, vomiting, dizziness, hallucinations and depression Because of the potential for neuropsychiatric reactions, this drug is usually reserved for treating malaria when other agents cannot be used EKG abnormalities and cardiac arrest can occur if Lariam taken with Quinine and Quinidine

Answer 5

Alkaloid isolated from the ark of the Cinchona tree Interferes with heme polymerization, causing death of the RBC form of the plasmodial parasite Reserved for severe infections and Chloroquine resistant malaria Usually given with Doxycycline, Tetracycline or Clindamycin TAKEN ORALLY, WELL DISTRIBUTED THROUGHOUT THE BODY ADES—CINCHONISM— NAUSEA, VOMITING, TINNITUS AND VERTIGO ADES ARE REVERSIBLE AND ARE NOT REASONS TO SUSPEND TREATMENT SUSPEND TREATMENT IF HEMOLYSIS OCCURS

Answer 6

Derived from sweet wormwood plant 1st line for MDR P. falciparum malaria Giving with another antimalarial is recommended to prevent resistance One orally available regimen is Artemisinin + Lumefantrine [used successfully in uncomplicated disease]—Brand name Coartem Artesunate + Sulfadoxine-pyrimethamine, Mefloquine, Clindamycin or others—the antimalarial action of Artemisinin derivatives involves the production of free radicals from cleavage of the drug’s endoperoxide bridge by heme iron in the parasite food vacuole Oral, rectal, IM and IV formulas are available Short ½ life prevents use of these drugs for prevention ADEs—nausea, vomiting, diarrhea, rash has occurred High doses can prolong the QTc interval

Answer 7

Daraprim—inhibits plasmodial dihydrofolate reductase needed to synthesize tetrahydrofolate—which is needed to make nucleic acids It is a blood schizonticide and a strong sporonticide Not used alone to treat malaria Fixed dosed combinations with Sulfadoxine Resistance to this combo has developed—so usually given with other agents—Artemisinin derivativesPyrimethamine + Sulfadoxine used to treat Toxoplasma gondii If megaloblastic anemia occurs with this agent during treatment—it can be reversed with Leucovorin

Answer 8

African sleeping sickness [Trypanosomiasis] and American Chagas Disease [Trypanosomiasis] are 2 chronic and eventually fatal disease from Trypanosoma Pentamidine [Pentam or Nebupent] Active against many protozoa—African trypanosomiasis from T. brucei gambiense—it is used to treat early stage disease without CNS involvement Can also treat or prevent Pneumocystis jirovecii and can be used to treat Leishmaniasis MOA • T. brucei concentrates the drug by an energy-dependent high affinity uptake system—resistance occurs if the protozoa cannot concentrate the drug • MOA not fully understood—drug interferes with parasite synthesis of RNA, DNA, phospholipids and proteins Pharmacokinetics • Given IM or IV to treat Trypanosomiasis and pneumonia from P. jirovecii • For prevention of P. jirovecii pneumonia—pentamidine is given via nebulizer • Drug distributes widely and is concentrated in liver, kidney, adrenals, spleen and lungs • It does not enter the CSF— cannot be used for late stage Trypanosomiasis • Drug is not metabolized; excreted very slowly in the urine ADEs • Renal dysfunction, reversible when stopped • Hyperkalemia; low BP, pancreatitis; ventricular arrhythmias; elevated BS Suramin Used in early stage African trypanosomiasis from T. brucei rhodesiense Very reactive and inhibits many enzymes, especially those involved in metabolism—which seems to be action that kills the trypanocite Given IV Germanin binds to plasma proteins and does not penetrate the blood-brain barrier Long ½ life [>40 days], excreted unchanged in the urine ADEs—rare, but nausea, vomiting, shock and loss of consciousness can be seen Other ADEs—acute urticaria, blepharitis, paresthesias, photophobia, hyperesthesia of the hands and feet; renal insufficiency, but is reversible when drug is stopped Test dose should be given, as acute hypersensitivity has been seen Melarsoprol Trivalent arsenic compound Only agent available to treat late stage African trypanosome infections and those with CNS involvement from T. brucei rhodesiense Drug reacts with enzymes in the organism and the host Given by slow IV; can be irritating to surrounding tissues DOC for CNS infections that have occurred rapidly as the trypanocidal concentrations in the CSF are quite adequate Human readily oxidizes the drug to a nontoxic pentavalent arsenic compound Very short ½ life and is rapidly excreted in the urine Its use is limited by CNS toxicities—reactive encephalopathy, which is fatal in 10 percent Hypersensitivity reactions, febrile reactions can follow injection Other ADEs—peripheral neuropathy, HTN, liver toxicity, albuminuria Hemolysis can occur in those with G6PD deficiency

Answer 9

Eflornithine Irreversible inhibitor of ornithine decarboxylase; inhibiting this enzyme stops polymerases in the parasite and causes cell division to cease IV form is DOC for late stage African trypanosomiasis from T. brucei gambiense Topical Eflornithine [Vaniqa] is used to treat unwanted facial hair in woman Short ½ life requires IV dose to be given frequently Less toxic than Melarsoprol, but can cause anemia, seizures, and temporary hearing loss

Answer 10

Used to treat T. cruzi [Chagas Disease]—although its use in chronic stage disease has shown variable results Can be used with Eflornithine to treat late stage T. brucei gambiense Undergoes reduction and generates O2 radicals—superoxide and H2O2—that are toxic to the parasite Given orally; extensively metabolized ADEs—common with chronic administration [especially in older patients]—anaphylaxis, dermatitis, GI distress—severe enough to cause weight loss; peripheral neuropathy, dizziness and headache

Answer 11

Nitroimidazole derivative with MOA similar to Nifurtimox—but better tolerated for treating Chagas Disease ADEs—dermatitis, peripheral neuropathy, insomnia, anorexia

Answer 12

Protozoal infection from many species of genus Leishmaniasis 3 manifestations—cutaneous, mucocutaneous and visceral [in this presentation, the parasite is in the liver, spleen and blood, if not treated, it is fatal] Transmitted b the bite of the infected sandflies For the visceral form—treatment options include IV Amphotericin B, pentavalent antimonials—Na+ Stibogluconate or Meglumine antimoniate + Pentamidine and Paromomycin Miltefosine—only oral agent for visceral disease Choice of drug depends on species of parasite, host factors and local resistance patterns Sodium Stibogluconate Pentavalent antimonial is a prodrug which is reduced to active trivalent antimonial compound MOA is not fully understood Minimal absorption; excreted in the urine ADEs—injection site pain, pancreatitis, elevated LFTs, arthralgias, myalgias, GI distress, cardiac arrhythmias Miltefosine 1st oral agent for visceral Leishmaniasis Can also be used for cutaneous and mucocutaneous forms MOA is unknown, but it is thought to interfere with phospholipids and sterols in the parasite membrane ADEs—nausea, vomiting, teratogenic; do not use in pregnant women

Answer 13

One of the most common infections in humans—caused by T. gondii Transmitted to humans from eating inadequately cooked infected meat or accidently ingesting oocysts from cat feces Infected pregnant woman can transmit T. gondii to her fetus Treatment of choice—Sulfadiazine + Pyrimethamine Leucovorin given to prevent folate deficiency If rash occurs, immediately stop Pyrimethamine—because hypersensitivity to this agent can be severe Other treatment options: Pyrimethamine + Clindamycin Trimethoprim/Sulfamethoxazole [Bactrim DS] Trimethoprim/Sulfamethoxazole used to prevent Toxoplasmosis and P. jirovecii in the immunosuppressed

Answer 14

•Binucleate trophozoite [4 flagella] •Four nucleate cyst [drug-resistant] Giardia lamblia commonly diagnosed intestinal parasite Two life cycles Ingestion occurs from fecally contaminated water or food Trophozoites exist in the small intestine Cysts are formed and pass out in feces Many infections are asymptomatic, but those that have symptoms have diarrhea— and it can be very severe, and very serious in those immunosuppressed or frail DOC is Metronidazole orally for 5 days Alternative therapy is a single dose of Tinidazole [Tindamax]—just as effective as Flagyl, but the cost of the 2 gram once time dose is $144-$288 compared to $15 for Metronidazole 5 day course Nitazoxanide, a nitrothiazole derivative, also approve to treat giardiasis This agent also used to treat Cryptosporidiosis from C. parvum For Giardiasis, Nitazoxanide is given orally for 3 days Albendazole can also treat Giardiasis Paromomycin is used for the pregnant patient

Answer 15

Overview—Yes, it is Treating Worms Nematodes, trematodes and cestodes are 3 major groups of worms Anthelmintic drugs aim for metabolic targets that present in parasite but are absent or different than those of the human Nematodes are long roundworms that cause infections in the intestine, blood and tissues Mebendazole [Emverm] Synthetic benzimidazole; 1st line for whipworms [Trichuris trichiura], pinworms [Enterobius vermicularis], hookworms [Necator americanus; Ancylostoma duodenale] and roundworms [Ascaris lumbricoides] Mebendazole [and all benzimidazoles], act by binding to parasite ß-tubulin and preventing polymerization in the parasite Affected worms are expelled in the feces Do not use in pregnant patient In certain mass prevention/treatment scenarios this drug and Albendazole can be given in 2nd or 3rd trimester

Answer 16

Effective in roundworms, pinworms and hookworms Poorly absorbed after oral dose Acts as a depolarizing, neuromuscular blocking drug The worms are paralyzed and expulsed in the feces ADEs– nausea, vomiting and diarrhea. Thiabendazole Synthetic benzimidazole Potent broad spectrum anthelmintic Use limited to topical treatment of cutaneous larva migrans Has many toxic effects, so not used often

Answer 17

DOC to treat cutaneous Larva migrans, Strongyloidiasis and Onchocerciasis Also used to treat pediculosis [lice] and scabies Targets glutamate gated Cl- channel receptors—causing paralysis and death of the worm Orally dosed—does not readily cross blood-brain barrier Do not use in pregnancy Killing the larvae I n onchocerciasis can cause a Maxxotti reaction—fever, headache, dizziness, somnolence, low BP—severity depends on the parasite load Antihistamines and steroids can reduce the symptoms Diethylcarbamazine DOC for infection with Wuchereria bancrofti, Brugia malayi or Brugia timori Kills the larvae and has action against the worms Rapidly absorbed oral dose with food; excreted in the urine  ADEs—fever, nausea, vomiting, arthralgia, headache

Answer 18

In countries where filariasis is endemic combination of drugs can be used annually as preventative therapy Diethylcarbamazine + Albendazole or Ivermectin + Albendazole Those suspected of having onchocerciasis should not be given Diethylcarbamazine—it can accelerate night blindness and cause a severe Mazzotti reaction Drugs to Treat Trematodes Flukes—leaf shaped flatworms that are characterized by the tissues they infect—liver, lung, blood, etc. Praziquantal [Biltricide] Praziquantel is DOC for all forms of Schistosomiasis, other trematode infections and cestode infections, such as taeniasis Causes contracture and paralysis of parasites by increasing the permeability of cell wall membrane to Ca++ Rapid absorption after oral dose—should be taken with food Extensively metabolized and inactive metabolites are excreted in urine ADEs—dizziness, malaise, headache, GI upset Dexamethasone, Phenytoin, Rifampin, Carbamazepine increase metabolism of this drug; Cimetidine causes increased drug levels Contraindicated for ocular cysticercosis [killing the organism in the eye can call cause irreversible damage]

Answer 19

True tapeworms Worms with a flat segmented body and attach to the host’s intestine Tapeworms lack a mouth and a digestive tract Niclosamide Alternative to Praziquantel to treat taeniasis, diphyllobothriasis and other cestodes Inhibits mitochondrial phosphorylation of ADP in the parasite—killing the cestode, but not the ova Laxative is given before the dose to purge the bowel of all dead segments and to enhance digestion and liberation of the ovaETOH should be avoided for 24 hours This agent is no longer available in US, but used successfully worldwide

Answer 20

Albenza -Inhibits synthesis of glucose uptake in nematodes and is effective against most nematodes -Primary action in treating cestodes, such as cysticercosis and hydatid disease [larvae of Echinococcus granulosis] This agent is effective in treating Microsporidiosis Drug is erratically absorbed after oral dosing High fat meal increases absorption Undergoes extensive 1st pass metabolism Active sulfoxide and its metabolites are excreted in the bile If used 1-3 days for nematodes, ADEs are mild—headache and nausea Treatment long term—90 days—for hydatid disease has the risk of liver toxicity and agranulocytosis or pancytopenia [rare] Medical therapy for neurocysticercosis is associated with inflammation of the CNS from the dying parasites—headache, vomiting, fever and seizures

Antimicrobial Therapies 4 (Antiviral Drugs / Antiprotozoal Drugs / Anthelmintic Drugs) Flashcards

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