Pharm of Protozoans and Helminths Flashcards
what drugs are available for nematode infections?
benzimidazoles
Diethylcarbamazine
Ivermectin
Pyrantel pamoate
Doxycycline
anti-helminth
What are the types of Benzimidazoles?
Albendazole
Mebendazole
Thiabendazole
anti-helminth
MOA of Benzimidazoles
Binds beta-tubulin and inhibits polymerization of parasitic tubulin dimers into microtubules
other effects on the nematodes include - inhibition of mito fumerate reductase, decreased glucose transport causing depleted glycogen stores of larvae, uncoupling of ox-phos -> decreased energy production leads to parasite immobilization and death
Albendazole - PK and Adverse Effects
Benzimidazoles. poor absorption, distributes to CSF and hydatid cysts
hep metabolism w/ active metabolite, fecal excretion, half life 12 h
Adverse Effects - ab discomfort, diarrhea, rash, alopecia, dizziness
In high doses for Echinococcus Rx can cause hepatitis or myelosuppression
Albendazole - Therapeutic Uses
Broad Spectrum -
Intestinal nematodes,
Hydatid disease (echinococcus - cestode),
Neurocysticercosis
Lymphatic filariasis (combination with diethylcarbamezine or ivermectin)
high cure rates – Ascariasis (hookworm), Trichuras trichuria (whipworm), Necator, Ancylostoma, Enterobius vermicularis (pinworm), Trichinella spiralis (undercooked meat)
Mebendazole
Benzimidazoles, anti-helminthic, poor oral absorption, widely distributed with hepatic metabolism
fecal excretion, half life is 3 hours - does the job in the intestines as long as it’s in the intestines
Active against Intestinal nematodes only
Adverse effects are abdominal pain, distention, diarrhea in cases of massive infection»_space; expulsion of GI worms
Thiabendazole
Benzimidazoles, anti-helminthic, rapidly absorbed
extensive hepatic metabolism with renal excretion of glucuronide and sulfate metabolites
short half life
Broad Spectrum - therapy is limited by toxicities
Used for cutaneous larva migrans - eruption of nematodal larvae
used for strongyloidiasis in the past but Ivermectin is now first line
Adverse effects in 50% + pts - diarrhea, headache, tinnitus, hypotension, bradycardia, allergic manifestations, crystallurai and abnormalities in liver function.
Diethylcarbamazine (DEC) - PK and MOA
Anti-helminthic, nematodal
oral with wide distribution, hepatic metabolism and renal excretion.
MOA in adult unknown, action against microfilaraie - inhibition of arachidonic acid metabolism on the surface of microfilariae, this causes the nematode to be immobile and more susceptible to the host immune response
Therapeutic Uses of Diethylcarbamazine (DEC)
Lymphatic filariasis: caused by Wuchereria bancrofti, Brugia malayi/timori
One dose mass treatment with ivermectin/albendazole
Loa loa - microfilariae and adult filariae
Mansonella streptocirca (adult and micro-filariae)
contraindication in onchocerciasis
Adverse Effects of Diethylcarbamazine (DEC)
anti-helminthic,
Anorexia, nausea, headache, vomiting (high dose)
Bancroftian, brugian filiariasis - lymphangitis, swelling and lymphoid abscess
Loiasis - skin wheals, heavy infections with severe side effects (retinal hemorrhages and severe encephalopathy)
Mazzotti reaction when rx Onchocerciasis – from killing of microfilariae – intense itching, papular rash, enlarged tender lymph nodes, tachycardia, arthralgia and headache. Ocular lesions.
Ivermectin
Anti-helminthic, nematodal
Oral, doesnt cross BBB, hepatic meta, fecal excretion, half life 18hr
MOA - induces tonic paralysis of parasite musculature by binding to glutamate-gated Cl- ion channels in invertebrate muscle and nerve cells ↑ permeability of the cell membrane causing hyperpolarization leads to the paralysis and death of the nematode
Ivermectin - Activity and Uses
Activity: anti-helminthic,
- Microfilaria (not adults) of W. bancrofit, B. malayi, L. loa, Mansella ozzardi
- A. lumbricoides, S. stercoralis, cutaneous larva migrans
Drug of choice for -
Onchocerciasis: aborts microfilariae from gravid female, decreases transmission
Strongyloidiasis: as effective as thiabendazole and better tolerated. More effective than albendazole
Contraindicated in meningitix
Adverse Effects of Ivermectin
Generally well tolerated
Mazzotti-like reaction due to killing of microfilariae but usually limited to mild itching and tender, swollen lymph nodes
seldom exacerbates oculra lesions
Loa encephalopathy with high loa microfilariae burden
not known to be safe in pregnancy or breast feeding
interacts with GABA drugs - benzos, barbituates and valproic acid
Doxycycline
Antibacterial that fights Wolbachia species (similar to Rickettsia) within filarial nematodes — Wuchereria and Oncocerca
Doxycycline x6 weeks causes sterility of the adult female
Pyrantel pamoate
anti-helminthic,
Treatment of pinworms caused by Enterobius vermicularis - nematodes - anti-helminthic
Poor oral absorption; Safe and effective
mechanism - Depolarizing NM blocking agent, activation of cholinergic nicotinic R in somatic muscles of nematodes causes a depolarizing blockade and paralysis
no marked effect on neuromuscular function
Praziquantel - Activity
anti-helminthic,
used against cestodes and flukes
- flat, segmented bodies that attach to host intestinal walls with hooks/suckers
Trematodes, parasitic flatworms (flukes)
Intestinal Cestodes - Taenia saginata (beef), Taenia solium (pork), Diphyllobothrium latum (broad fish), Hymenolepis nana (dwarf tapeworm)
Intestinal Trematode - Fasciolopsis buski (giant)
trematode tissue infections - Paragonimus westermani, Schistosoma mansoni (blood fluke), Schistosoma japonicum, and Schistosoma haematobium
Praziquantel - PK and MOA
anti-helminthic,
Oral; good bioavailability; CSF concentrations ~14-20% of plasma
plasma protein binding; extensive hepatic first-pass metabolism with renal excretion, short half life (1 - 4 hours)
MOA - increase cell permeability to Ca2_ whih increase muscular activity and causes spastic paralysis, causes detachment from blood vessel walls.
Damage exposes tegumental antigen - immune system activate
Adverse Effects of Praziquantel
anti-helminthic,
Generally safe - Abdominal pain, nausea, diarrhea, headache, dizziness, drowsiness - transient
Parasite destruction occasionally causes: fever, pruritus, urticaria, rashes, arthralgia, myalgia
In neurocysticercosis: there can be inflammatory reactions - meningismus, seizures, mental changes and CSY pleocytosis, delayed onset and last 2-3 days. Rx - analgesics and anticonvulsants
Safe in pregnancy
interacts with CYP3A4 induces
Triclabendazole
anti-helminthic
Drug of choice for the treatment of chronic fascioliasis in adults and children
Efficacy: • Single dose • Absence of adverse effects • High tolerability • High cure rate
What drugs are used to treat amoebiasis, giardiasis, and other intestinal protozoan infections?
Metronidazole - Tinidazole - Secnidazole:
Paromomycin
Nitazoxanide
Metronidazole - PK and MOA
Oral, 100% bioavailability
-can be given IV, intravaginally, topically
wide distribution including abscessess, hepatic metabolism (oxidation and glucuronidation) with renal excretion.
MOA - radical-mediated killing, electron donated from ferredoxin, the drug is also catalytically recycled
Resistance Mechanisms of Metronidazole
Impaired oxygen scavenging capabilities
An increase in local oxygen causes decreased reduction of metronidozole
leading to decreased PFOR and ferrodoxin levels
Activity and Therapeutic Uses of Metronidazole
Kills E. hystolytica trophozoites - but not cysts
extra-intestinal infections - well absorbed + requires a liminal amebicide for full infectious Rx
Useful against - Amoebiasis Trichomoniasis Giardiasis Bacterial infections - anaerobic bacteria
Tinidazole and Secnidazole
Tinidazole - amoebiasis, giardiasis, trichomoniasis: better tolerated
Secnidazole - bacterial vaginosis
Side Effects of Metronidazole
generally well tolerated
common are headache, nausea, dry mouth, and a metallic taste
occasional - vomiting, diarrhea, and abdominal distress, thrush, dark urine
dizziness, vetigo, rarely - encephalopathy, convulsions
Paresthesias of extremities
Disulfiram-like effect
Avoid in pregnancy in first semester
Paromomycin - PK, MOA, AE’s
Luminal Antiamoebic Agent
PK: oral; poor absorption, 100% fecal excretion
MOA - protein synthesis inhibitor
Generally safe but can cause bowel lesions, ototoxicity and nephrotoxicity
Paromomycin - Uses
Use - Acute and chronic intestinal amoebiasis after metronidazole treatment, E. histolytica
Adidtional uses against Dientamoeba fragilis, cryptosporidiosis, giardiasis, cutaneous leishmaniasis and resistant trichomoniasis
Treatment of African trypanosomiasis
Melarsoprol (trivalent arsenical)
Eflornithine (fluorinated ornithine analog)
Suramin (polyanionic compound)
Pentamidine (aromatic diamidine)
East African sleeping sickness
Trypanosoma brucei rhodesiense
Tanzania. Uganda, Malawi, Zambia
Melarsoprol - Meningoencephalitic stage
Suramin - Hemolymphatic stage
West African sleeping sickness
Trypanosoma brucei gambiense
Central and West Africa, Democratic Republic of Congo, Angola, Sudan, Central African Republic, Chad and northern Uganda
Eflornithine - Meningoencephalitic stage
Pentamidine - Hemolymphatic stage
Melarsoprol
East African sleeping sickness - Meningoencephalitic stage
Melarsen oxide reacts with sulfhydryl groups on biomolecules - inactivates
Slow IV infusion, intensely irritating, half like 35 h
Adverse Effects
- reactive encephalopathy (5-10% pts, 50% fatal), cerebral edema, seizures, coma, death
- Myocardial toxicity, renal, hepatic dysfunction, agranulocytosis, hypersensitivity reaction
Suramin
East African sleeping sickness - Hemolymphatic stage
Reversibly complexes with various enzymes essential to parasite energy metabolism
IV (not absorbed), no CNS, 5 doses in 21 days
Adverse effects - Renal toxicity, Hypersensitivity reaction, hypotension, shock, (from the dying parasites)
Eflornithine
West African sleeping sickness - Meningoencephalitic stage
Suicide inhibitor of ornithine decarboxylase, inhibits polyamine synthesis, cell growth and differentiation
IV every 6h x 14d, half life 3h
Adverse Effects - myelosupprion, ototoxicity, diarrhea, nausea, vomiting
Pentamidine
West African sleeping sickness - Hemolymphatic stage
Interference with DNA, RNA, protein synthesis and metabolism
IV and IM, not absorbed, No CNS. Half life 5-8 hours
Adverse Effects - Nephrotoxicity; hypoglycemia; severe hypotension; QT interval prolongation; anemia, neutropenia, thrombocytopenia; GI effects
Treatment of Chagas disease
AMERICAN trypanosomiasis
Nifurtimox
Benznidazole
Nifurtimox
Oral; hepatic CYP metabolism, renal excretion
MOA - reduced by microbe enzyme to nitro anion radicals and superoxide radicals causes membrane injury, enzyme inactivation and DNA damage
Better effiicacy in acute disease
Adverse effects - nausea, vomiting, polyneuropathy, headache, dizziness, vertigo, insomnia
Benznidazole
Oral; hepatic metabolism, excreted in urine/feces, half life 12 h
MOA - activated by trypanosomal nitroreductases making reactive superoxide radicals causing parasitic proteins and DNA
Better effiicacy in acute disease
Adverse Effects - generally well tolerated but pruritic rash and abdominal pain is sometimes experienced
treatment of leishmaniasis
Sodium Stibogluconate / Meglumine Antimoniate
Amphotericin B
Miltefosine
Leishmaniasis
spread by sand fly, obligate intra-macrophage protozoa
visceral, cutaneous or mucocutaneous leishmaniasis
general chemotherapy - first line: Sodium Stibogluconate [Pentosam]* and Meglumine antimoniate
alternatives - Pentamidine, Amphotericin B, Miltefosine*, Paromomycin + gentamicin
Sodium Stibogluconate / Meglumine Antimonate
Used first like for leishmaniasis
Pentavalent antimonial Sb5+ converted into Sb3+ species - kills amastigotes in macrophages, by inhibiting trypanothione reductase
I.V. for treatment of cutaneous and visceral disease
cardiac toxicity; hepatotoxicity; pancreatitis; renal toxicity; muscle aches
Amphotercin B
Leishmaniasis Rx (and probably more)
Complexes with sterol precursors in Leishmania cell and forms pores
I.V. for treatment of visceral leishmaniasis
Adverse Effects - Infusion reactions, nephrotoxicity, anemia and anaphylaxis
Miltefosine
oral; visceral and cutaneous disease; vomiting, diarrhea, ↑ transaminases (reversible); MOA undefined
not starred
Pentamidine:
I.M. for cutaneous leishmaniasis
alternate for visceral disease
hypotension; tachycardia; GI Sx; sterile abscesses; and pancreatic, liver, and kidney abnormalities
treatment of toxoplasmosis
Spiramycin
Pyrimethamine + Atovaquone or Dapsone or Clindamycin
Toxoplasma gondii: cats are natural hosts, Acute, self-limiting illness, immunocompromised people at risk (encephalitis), also congenital toxoplasmosis
Spiramycin
(<18 weeks gestation) acute acquired infection to prevent transmission to the fetus
Treatment of cerebral toxoplasmosis
AIDS patients
Pyramethamine + sulfadiazine + folinic acid (leucovorin)
Clindamycin or atovaquone may be substituted if sulfonamide
Primary prophylaxis: trimethoprim-sulfamethoxazole
Babesiosis:
Tick-borne zoonosis: erythrocyte invasion
protozoan
Clindamycin + Quinine
Atovaquone + Azithromycin (fewer AEs)
Balantidiasis:
− Fecal-oral transmission: intestinal parasite
− Tetracycline
